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Metabolic and Genetic Screening of Electromagnetic Hypersensitive Subjects as a Feasible Tool for Diagnostics and Intervention

Posted on March 13, 2020 at 8:25 AM Comments comments (0)

 


Chiara De Luca, Jeffrey Chung Sheun Thai, [...], and Liudmila Korkina

 

Additional article information

 

Abstract

Growing numbers of “electromagnetic hypersensitive” (EHS) people worldwide self-report severely disabling, multiorgan, non-specific symptoms when exposed to low-dose electromagnetic radiations, often associated with symptoms of multiple chemical sensitivity (MCS) and/or other environmental “sensitivity-related illnesses” (SRI). This cluster of chronic inflammatory disorders still lacks validated pathogenetic mechanism, diagnostic biomarkers, and management guidelines. We hypothesized that SRI, not being merely psychogenic, may share organic determinants of impaired detoxification of common physic-chemical stressors. Based on our previous MCS studies, we tested a panel of 12 metabolic blood redox-related parameters and of selected drug-metabolizing-enzyme gene polymorphisms, on 153 EHS, 147 MCS, and 132 control Italians, confirming MCS altered (P < 0.05–0.0001) glutathione-(GSH), GSH-peroxidase/S-transferase, and catalase erythrocyte activities. We first described comparable—though milder—metabolic pro-oxidant/proinflammatory alterations in EHS with distinctively increased plasma coenzyme-Q10 oxidation ratio. Severe depletion of erythrocyte membrane polyunsaturated fatty acids with increased ω6/ω3 ratio was confirmed in MCS, but not in EHS. We also identified significantly (P = 0.003) altered distribution-versus-control of the CYP2C19∗1/∗2 SNP variants in EHS, and a 9.7-fold increased risk (OR: 95% C.I. = 1.3–74.5) of developing EHS for the haplotype (null)GSTT1 + (null)GSTM1 variants. Altogether, results on MCS and EHS strengthen our proposal to adopt this blood metabolic/genetic biomarkers' panel as suitable diagnostic tool for SRI.

 

1. Introduction

The term electromagnetic hypersensitivity or electrosensitivity (EHS) referred to a clinical condition characterized by a complex array of symptoms typically occurring following exposure to electromagnetic fields (EMFs) even below recommended reference levels and is followed by remission through the complete isolation [1, 2]. The most frequently claimed trigger factors include video display units, radio, televisions, electrical installations, extremely low-frequency ranges of electromagnetic fields or radio-frequencies—including the so-called dirty electricity due to poor isolation of electric wires and telephonic lines, wireless devices, and wi-fi—fluorescent lamps and low-energy lights, appliances with motors, photocopiers, microwave transmitters, and high tension power lines (reviewed in [3, 4]). EHS is characterized by a broad range of nonspecific multiple-organ symptoms implying both acute and chronic inflammatory processes, involving mainly skin and nervous, respiratory, cardiovascular, musculoskeletal, and gastrointestinal systems, in most cases self-reported in absence of organic pathological signs except skin manifestations (reviewed in [2, 5]).

 

Many efforts have been made to determine if a causal relationship between exposure to EMFs and claimed health symptoms does exist and to identify biologically plausible mechanisms underlying this syndrome (for review, see [2, 6, 7]). Despite the growing wealth of evidences gathered both in vitro and in vivo on animal models, data from human case-control and double-blind trials attempting to correlate EMFs exposure and claimed symptoms, resulted so far controversial [8–10]. Nowadays, wide gaps still exist in understanding EHS, which most often remains neglected by the medical community or confined within the frame of mere psychogenic etiology [11, 12]. In the persistent lack of a proven pathogenetic mechanism for electromagnetic hypersensitivity and of clinical consensus on the few proposed diagnostic and therapeutic approaches hypothesized, no guideline for safe and efficient validated treatments has been made available until now to the patients worldwide [13, 14].

 

Nevertheless, the number of subjects self-reporting EHS is progressively increasing, especially in European countries [15–17], with symptoms that are often strongly disabling both professionally and socially, motivating patients to leave home and job to find rescue in “electromagnetic pollution-free” environmental settings. Because of the huge socioeconomic impact anticipated for EHS syndrome worldwide, the World Health Organization has devoted considerable attention to EHS, acknowledging this condition and recommending that people self-reporting sensitivities receive a comprehensive health evaluation [18].

 

Clinical similarities and frequent comorbidity between EHS and the other medically unexplained multisystem conditions of environmental origin, like multiple chemical sensitivity (MCS), fibromyalgia (FM), chronic fatigue syndrome (CFS), sick building syndrome, Persian Gulf War veteran syndrome, and amalgam disease, to which EHS is often associated [19, 20], have induced many authors to hypothesize that these so-called idiopathic environmental intolerances (IEI), more extensively also defined as sensitivity-related illnesses (SRI) [21], may share common genetic and/or metabolic molecular determinants connected with an impaired capability to detoxify xenobiotics (for review, see [19, 22]). Our group has evidenced for the first time a set of altered metabolic blood parameters—comprising selected redox-active and detoxifying enzymes, low-molecular weight antioxidants and oxidation markers, membrane polyunsaturated fatty acid, and proinflammatory cytokine patterns—specifically and selectively compatible with the MCS condition [23]. Recently, we contributed to the still open issue of possible genetic polymorphic patterns associated with MCS proneness, proposing a pattern of genotypic alterations of the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and CYP2D6, as candidate risk factors for this specific condition, also being potentially able to discriminate different environmental-borne hypersensitivities (MCS, FM, and CFS), depending on specific combinations of their mutated alleles [24].

 

In this study, the working hypothesis was that EHS, as previously proposed for MCS and other environmental SRI [19, 22], may as well be based on aberrant responses to physic or chemical xenobiotic stressors through airborne or other routes of exposure, due to inherited or/and acquired dysfunction of the chemical defensive system, that is the interrelated network of phase I and II xenobiotic-metabolizing and antioxidant enzymes [19]. Based on the results of our past clinical studies on MCS, FM, and CFS, we sought to assess if similar profiles of metabolic or genetic dysfunctions could be found in those subjects self-reporting EHS phenotype. To this purpose, we measured possible alterations of a previously identified panel of twelve blood redox and lipid parameters and frequencies of selected genetic mutated variants of a set of drug-metabolizing enzymes and transcription factors with first-line roles in the detoxification of physical and chemical xenobiotics, in a group of 153 patients self-reporting EHS symptoms, co-morbid in most cases with different degrees of MCS symptoms. Results were compared to those obtained on 147 MCS patients without EHS symptoms and on a healthy control group of 132 age- and sex-matched subjects, all groups enrolled within the Italian population. ....... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000647/#!po=74.0385

Treatment Research And NeuroSCience Evaluation of NeuroDevelopmental Disorders.

Posted on March 13, 2020 at 8:10 AM Comments comments (0)

Treatment Research And NeuroSCience Evaluation of NeuroDevelopmental Disorders

December 12, 2015

Montgomery County Schools

Carver Educational Services Center

850 Hungerford Drive

Rockville, MD 20850

cc Montgomery County City Council

Dear Montgomery County School District,

I am a pediatric neurologist and neuroscientist on the faculty of Harvard Medical School and on

staff at the Massachusetts General Hospital. I am Board Certified in Neurology with Special

Competency in Child Neurology, and Subspecialty Certification in Neurodevelopmental Disorders.

I have an extensive history of research and clinical practice in neurodevelopmental disorders,

particularly autism spectrum disorders. I have published papers in brain imaging research, in

physiological abnormalities in autism spectrum disorders, and in environmental influences on

neurodevelopmental disorders such as autism and on brain development and function.

A few years ago I accepted an invitation to review literature pertinent to a potential link between

Autism Spectrum Disorders and Electromagnetic Frequencies (EMF) and Radiofrequency

Radiation(RFR). I set out to write a paper of modest length, but found much more literature than I

had anticipated to review. I ended up producing a 60 page single spaced paper with over 550

citations. It is available at http://www.bioinitiative.org/report/wp-

content/uploads/pdfs/sec20_2012_Findings_in_Autism.pdf and it was published in a revised and

somewhat shortened form in two parts in the peer reviewed indexed journal Pathophysiology

(2013)with the title: Áutism and EMF? Plausibility of a pathophysiological link.” Please also see the

appendix to this letter which contains a summary of this material and includes substantial scientific

citations.

HARVARD MEDICAL SCHOOL

Martha R. Herbert, Ph.D., M.D.

Assistant Professor, Neurology

Director, TRANSCEND Research Program

www.transcendresearch.org

transcend@partners.org

MASSACHUSETTS

GENERAL HOSPITAL

Martinos Center for Biomedical Imaging

149 13th Street, Room 10.043

Charlestown (Boston), Massachusetts

02129

martha.herbert@mgh.harvard.edu

https://connects.catalyst.harvard.edu/prof

iles/display/Person/47629


 

Treatment Research And NeuroSCience Evaluation of NeuroDevelopmental Disorders

More recently I published an article entitled “Connections in Our Environment: Sizing up

Electromagnetic Fields,” in Autism Notebook Spring 2015 edition in which I summarized and

personalized the information in the . In this article I describe how here is a whole series of

problems at the cellular, sub-cellular and metabolic levels and immune levels that have been

identified in autism. And interestingly, for every single one of those problems, there’s literature

about how EMFs can create those kinds of problems.

The argument I made in these articles is not that EMF is proven to cause autism, but rather, that

EMF can certainly contribute to degrading the physiological integrity of the system at the cellular

and molecular level” – and this in turn appears to contribute to the pathogenesis/causation not only

of autism but of many highly common chronic illnesses, including cancer, obesity, diabetes and

heart disease.. Please see this article on page 24-25 at the link

http://virtualpublications.soloprinting.com/publication/?i=252361

In fact, there are thousands of papers that have accumulated over decades –and are now

accumulating at an accelerating pace, as our ability to measure impacts become more sensitive –

that document adverse health and neurological impacts of EMF/RFR. Children are more vulnerable

than adults, and children with chronic illnesses and/or neurodevelopmental disabilities are even

more vulnerable. Elderly or chronically ill adults are more vulnerable than healthy adults.

Current technologies were designed and promulgated without taking account of biological impacts

other than thermal impacts. We now know that there are a large array of impacts that have nothing

to do with the heating of tissue. The claim from wifi proponents that the only concern is thermal

impacts is now definitively outdated scientifically.

Radiofrequency electromagnetic radiation from wifi and cell towers can exert a disorganizing effect

on the ability to learn and remember, and can also be destabilizing to immune and metabolic

function. This will make it harder for some children to learn, particularly those who are already

having learning or medical problems in the first place. And since half of the children in this country

have some kind of chronic illness, this means that a lot of people are more vulnerable than you

might expect to these issues.

Powerful industrial entities have a vested interest in leading the public to believe that EMF/RFR,

which we cannot see, taste or touch, is harmless, but this is not true. Please do the right and

precautionary thing for our children.

I urge you to opt for wired technologies in Montgomery County classrooms, particularly for those

subpopulations that are most sensitive. It will be easier for you to make a healthier decision now

than to undo misguided decisions later.

Thank you.

Martha Herbert, PhD, MD


 

Treatment Research And NeuroSCience Evaluation of NeuroDevelopmental Disorders

Selected pertinent publications

Connections in our Environment: Sizing up Electromagnetic Fields by M.R. Herbert (published in

Autism Notebook Spring 2015, pp.. 24-25) reviews in two pages key points of the more technical

Herbert & Sage Autism-EMF paper

Herbert, M.R. and Sage, C. “Autism and EMF? Plausibility of a Pathophysiological Link”. Part 1:

Pathophysiology , 2013, Jun;20(3):191-209, epub Oct 4, PMID 24095003. Pubmed abstract for Part

1. Part II: Pathophysiology, 2013 Jun;20(3):211-34. Epub 2013 Oct 8, PMID 24113318. Pubmed

abstract for Part II.

APPENDIX: MORE DETAILED SUMMARY OF THE PATHOPHYSIOLOGY

I became interested in the health and brain effects of electromagnetic frequency (EMF) and

radiofrequency radiation (RFR) exposures in relation to my brain research because I was

interested in how such exposures might alter brain function. In order to familiarize myself in

more detail existing literature on the pathophysiological impacts of EMF/RFR, I coauthored a

40,000 word chapter in the 2012 update of the Bioinitiative, 1 and published an updated

30,000 word version of that paper (“Autism and EMF? Plausibility of a Pathophysiological Link”) in 2013 in two parts in the peer reviewed journal Pathophysiology. 2, 3 My intention

was to assess the plausibility of an association between increasing incidence of autism

spectrum disorder and increasing EMF/RFR exposures. Rather than directly address the

epidemiological issues, I looked at the parallels between the pathophysiological features

documented in autism and the pathophysiological impacts of EMF/RFR documented in the

peer-reviewed published scientific literature.

I will include here a brief summary of the paper (prepared for a lay audience) of the features

of EMF/RFR that I reviewed (with citations at the end of this letter):

x EMF/RFR stresses cells. It lead to cellular stress, such as production of heat shock

proteins, even when The EMF/RFR isn’t intense enough to cause measurable heat

increase. 4-6 x EMF/RFR damages cell membranes, and make them leaky, which makes it hard for

them to maintain important chemical and electrical differences between what is

inside and outside the membrane. This degrades metabolism in many ways – makes

it inefficient. 7-15

x EMF/RFR damages mitochondria. Mitochondria are the energy factories of our cells.

Mitochondria conduct their chemical reactions on their membranes. When those

membranes get damaged, the mitochondria struggle to do their work and don’t do it

so well. Mitochondria can also be damaged through direct hits to steps in their

chemical assembly line. When mitochondria get inefficient, so do we. This can hit our

brains especially hard, since electrical communication and synapses in the brain

demands huge amounts of energy.

x EMF/RFR creates “oxidative stress.” Oxidative stress is something that occurs when

the system can’t keep up with the stress caused by utilizing oxygen, because the

price we pay for using oxygen is that it generates free radicals. These are generated

in the normal course of events, and they are “quenched” by antioxidants like we get

Treatment Research And NeuroSCience Evaluation of NeuroDevelopmental Disorders

in fresh fruits and vegetables; but when the antioxidants can’t keep up or the

damage is too great, the free radicals start damaging things.

x EMF/RFR is genotoxic and damages proteins, with a major mechanism being

EMF/RFR-created free radicals which damage cell membranes, DNA, proteins,

anything they touch. When free radicals damage DNA they can cause mutations.

This is one of the main ways that EMF/RFR is genotoxic – toxic to the genes. When

they damage proteins they can cause them to fold up in peculiar ways. We are

learning that diseases like Alzheimer’s are related to the accumulation of mis-folded

proteins, and the failure of the brain to clear out this biological trash from its tissues

and fluids.

x EMF/RFR depletes glutathione, which is the body’s premier antioxidant and

detoxification substance. So on the one hand EMF/RFR creates damage that

increases the need for antioxidants, and on the other hand they deplete those very

antioxidants.1, 16

x EMF/RFR damages vital barriers in the body, particularly the blood-brain barrier,

which protects the brain from things in the blood that might hurt the brain. When

the blood-brain barrier gets leaky, cells inside the brain suffer, be damaged, and get

killed. 1, 16, 17

x EMF/RFR can alter the function of calcium channels, which are openings in the cell

membranes that play a huge number of vital roles in brain and body. 18-27

x EMF/RFR degrades the rich, complex integration of brainwaves, and increase the

“entropy” or disorganization of signals in the brain – this means that they can

become less synchronized or coordinated; such reduced brain coordination has been

measured in autism. 28-40

x EMF/RFR can interfere with sleep and the brain’s production of melatonin. 41-43

x EMF/RFR can contribute to immune problems. 44-50

x EMF/RFR contribute to increasing stress at the chemical, immune and electrical

levels, which we experience psychologically. 51-57 17, 58-62 63-68

Please note that:

1. There are a lot of other things that can create similar damaging effects, such as

thousands of “xenobiotic” substances that we call toxicants. Significantly, toxic

chemicals (including those that contain naturally occurring toxic elements such as

lead and mercury) cause damage through many of the same mechanisms outlined

above.

2. In many of the experimental studies with EMF/RFR, damage could be diminished by

improving nutrient status, particularly by adding antioxidants and melatonin. 69-72

I understand that the concept of electromagnetic hypersensitivity is not always well

understood in the medical and scientific communities. Indeed, the inter-individual variability

is perplexing to those who would expect a more consistent set of features.

But given the range of challenges I have listed that EMF/RFR poses to core processes in

biological systems, and given the inter-individually variable vulnerability across these

symptoms, it is really not surprising that there would be subgroups with different

combinations of symptom clusters.

It also appears to be the case that the onset and duration of symptoms or even brain

response to EMR/RFR can be variable. This again is to be expected given the mediation of

these symptoms through a variety of the above-listed pathophysiological processes, many

of which differ in scale (ranging from molecular to cellular to tissue and organ) and time

course of impact. The different parts of the body also absorb this energy differently, both

Treatment Research And NeuroSCience Evaluation of NeuroDevelopmental Disorders

because of their biophysical properties and as a function of their state of health or

compromise thereof.

Here is a list of subgroups of symptom clusters identified by a group of German physicians, t

exemplifies these variability issues:

Group 1 no symptoms

Group 2 sleep disturbance, tiredness, depressive mood

Group 3 headaches, restlessness, dazed state, irritability, disturbance of concentration,

forgetfulness, learning difficulties, difficulty finding words

Group 4 frequent infections, sinusitis, lymph node swellings, joint and limb pains, nerve

and soft tissue pains, numbness or tingling, allergies

Group 5 tinnitus, hearing loss, sudden hearing loss, giddiness, impaired balance, visual

disturbances, eye inflammation, dry eyes

Group 6 tachycardia, episodic hypertension, collapse

Group 7 other symptoms: hormonal disturbances, thyroid disease, night sweats, frequent

urge to urinate, weight increase, nausea, loss of appetite, nose bleeds, skin

complaints, tumors, diabetes

CITATIONS

1. Herbert MR, Sage C. Findings in autism spectrum disorders consistent with electromagnetic

frequencies (emf) and radiofrequency radiation (rfr). BioInitiative Update. 2012

2. Herbert MR, Sage C. Autism and emf? Plausibility of a pathophysiological link - part i. Pathophysiology.

2013;20:191-209

3. Herbert MR, Sage C. Autism and emf? Plausibility of a pathophysiological link - part ii. Pathophysiology.

2013;20:211-234

4. Blank M. Electromagnetic fields. Pathophysiology. 2009;16 (2-3)

5. Blank M. Evidence for stress response (stress proteins) (section 7). The BioInitiative Report 2012: A

Rationale for a Biologically-based Public Exposure Standard for Electromagnetic Fields (ELF and RF).

2012:http://www.bioinitiative.org/table-of-contents/

6. Evers M, Cunningham-Rundles C, Hollander E. Heat shock protein 90 antibodies in autism. Mol

Psychiatry. 2002;7 Suppl 2:S26-28

7. Desai NR, Kesari KK, Agarwal A. Pathophysiology of cell phone radiation: Oxidative stress and

carcinogenesis with focus on male reproductive system. Reprod Biol Endocrinol. 2009;7:114

8. Phelan AM, Lange DG, Kues HA, Lutty GA. Modification of membrane fluidity in melanin-containing

cells by low-level microwave radiation. Bioelectromagnetics. 1992;13:131-146

9. Beneduci A, Filippelli L, Cosentino K, Calabrese ML, Massa R, Chidichimo G. Microwave induced shift of

the main phase transition in phosphatidylcholine membranes. Bioelectrochemistry. 2012;84:18-24

10. El-Ansary A, Al-Ayadhi L. Lipid mediators in plasma of autism spectrum disorders. Lipids Health Dis.

2012;11:160

11. El-Ansary AK, Bacha AG, Al-Ayahdi LY. Plasma fatty acids as diagnostic markers in autistic patients from

saudi arabia. Lipids Health Dis. 2011;10:62

12. Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: Increased lipid peroxidation

and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci.

2004;75:2539-2549

13. Pecorelli A, Leoncini S, De Felice C, Signorini C, Cerrone C, Valacchi G, et al. Non-protein-bound iron and

4-hydroxynonenal protein adducts in classic autism. Brain Dev. 2012:epub.

14. Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid

peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005;73:379-384

15. Yao Y, Walsh WJ, McGinnis WR, Pratico D. Altered vascular phenotype in autism: Correlation with

oxidative stress. Arch Neurol. 2006;63:1161-1164

16. Herbert MR, Sage C. Autism and emf? Plausibility of a pathophysiological link, parts i and ii.

Pathophysiology. In press ......... https://phpa.health.maryland.gov/OEHFP/EH/Shared%20Documents/CEHPAC/Doctor%20Letters%20on%20Wi-Fi%20In%20School%20%20Full%20Compilation%20.pdf


Ion-molecule reactions: Significance of Exhaled Breath Test in Clinical Diagnosis

Posted on February 27, 2020 at 8:15 AM Comments comments (0)

Analysis of volatile organic compounds (VOCs) emanating from human exhaled breath can provide deep insight into the status of various biochemical processes in the human body. VOCs can serve as potential biomarkers of physiological and pathophysiological conditions related to several diseases. Breath VOC analysis, a noninvasive and quick biomonitoring approach, also has potential for the early detection and progress monitoring of several diseases. This paper gives an overview of the major VOCs present in human exhaled breath, possible biochemical pathways of breath VOC generation, diagnostic importance of their analysis, and analytical techniques used in the breath test. Breath analysis relating to diabetes mellitus and its characteristic breath biomarkers is focused on. Finally, some challenges and limitations of the breath test are discussed.

 

Keywords: Breath analysis, Volatile organic compound, Disease diagnosis, Noninvasive method, Breath biomarkers, Diabetes mellitus

Introduction

Bioinformation obtained from volatile organic compounds (VOCs) in the exhaled breath of humans can aid the early diagnosis of several diseases and can be used to decide relevant medical therapies. The analysis of exhaled breath and associated VOCs has gained a considerable scientific, clinical, and research attention due to its potential in enabling the noninvasive observation of the biochemical processes of the human body [1–3]. The first initiatives of breath analysis for determining the physiological state of humans originated during the time of Hippocrates (460-370 BC), when the ancient Greek physicians realized that some diseases could be diagnosed from the characteristic odor of patients’ breath and knew that the human breath might provide sound information on health conditions [1–6]. In the period 1782–1783, Lavoisier for the first time analyzed the breath CO2 of Guinea pigs and showed that the gas is a product of combustion in the body [1, 5]. Practically, it is not difficult for a skilled technician to recognize the characteristic ‘fruity smell’ of acetone, ‘musty and fishy smell’, ‘urine-like smell’, and ‘putrid smell’ in the breath of patients with diabetes, advanced liver disease, kidney failure, and lung abscess, respectively [1]. The analysis of VOCs present in exhaled breath can thus provide valuable information about the subjects’ physiological and pathophysiological conditions. Such compounds can be useful indicators and potential biomarkers of various diseases and metabolic activities, facilitating disease diagnosis. It 

should be noted that biological monitoring is generally based on the analysis of blood. However, this involves an invasive and time-consuming technique, which is often unacceptable concerning patient care system. This invasive technique also needs skilled medical staff. Breath analysis is thus a very attractive alternative as it is a noninvasive and quick method that allows repeated sampling. .... 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083779/

Molecular and Microscopic Analysis of Bacteria and Viruses in Exhaled Breath Collected Using a Simple Impaction and Condensing Method

Posted on February 27, 2020 at 7:35 AM Comments comments (0)

Exhaled breath condensate (EBC) is increasingly being used as a non-invasive method for disease diagnosis and environmental exposure assessment. By using hydrophobic surface, ice, and droplet scavenging, a simple impaction and condensing based collection method is reported here. Human subjects were recruited to exhale toward the device for 1, 2, 3, and 4 min. The exhaled breath quickly formed into tiny droplets on the hydrophobic surface, which were subsequently scavenged into a 10 µL rolling deionized water droplet. The collected EBC was further analyzed using culturing, DNA stain, Scanning Electron Microscope (SEM), polymerase chain reaction (PCR) and colorimetry (VITEK 2) for bacteria and viruses.

 

Experimental data revealed that bacteria and viruses in EBC can be rapidly collected using the method developed here, with an observed efficiency of 100 µL EBC within 1 min. Culturing, DNA stain, SEM, and qPCR methods all detected high bacterial concentrations up to 7000 CFU/m3 in exhaled breath, including both viable and dead cells of various types. Sphingomonas paucimobilis and Kocuria variants were found dominant in EBC samples using VITEK 2 system. SEM images revealed that most bacteria in exhaled breath are detected in the size range of 0.5–1.0 µm, which is able to enable them to remain airborne for a longer time, thus presenting a risk for airborne transmission of potential diseases. Using qPCR, influenza A H3N2 viruses were also detected in one EBC sample. Different from other devices restricted solely to condensation, the developed method can be easily achieved both by impaction and condensation in a laboratory and could impact current practice of EBC collection. Nonetheless, the reported work is a proof-of-concept demonstration, and its performance in non-invasive disease diagnosis such as bacterimia and virus infections needs to be further validated including effects of its influencing matrix.

 

Introduction

Bioaerosols are present virtually anywhere in the environment, and their exposure is shown to cause numerous adverse health effects [1]–[2]. In addition, there is also a possible release of bio-warfare agents in a man-made bio-terror event. A number of studies demonstrated that the respiratory tract can be colonized with disease organisms [3]–[5]. Through talking, coughing, sneezing or singing, the potential virulent organisms can be exhaled and spread into the ambient environment [6], which accordingly causes air contamination. For example, SARS in 2003 and H1N1 in 2009 outbreaks were shown to be attributed to the airborne route of disease transmission [7]–[10].

 

Among many other diseases, respiratory infection accounts for 23.3–42.1% of the total hospital infections [11], and is listed as the third leading killer [12]. However, present diagnosis procedures using nasal swabs, bronchoalveolar lavages, nasopharyngeal aspirates or sputum samples, appear to cause unpleasant experiences in addition to long detection time. During flu outbreaks, body temperature or isolation procedures are often used to control and prevent further spread, however such methods are lacking scientific evidence and not always effective with those patients infected but in latent period. On another front, exhaled breath condensate (EBC) as a simple and noninvasive method is increasingly being utilized in early disease screening and infectious aerosols measurements, e.g., lung cancer [13], [14], asthma [15], [16], and other respiratory problems [17], [18]. In previous studies, human influenza A viruses were detected in exhaled breath using EBC [19], [20] as well as filter [21], mask [22], [23] and a liquid sampler [24]. In another study, foot-and-mouth disease viruses were also found in the exhaled air from experimentally infected cattle [25]. In addition, high levels of bacterial concentrations in EBC were also observed in other studies [26]–[29]. It was recently shown that exhaled breath could be also analyzed for fungal infection by relevant biomarker, e.g., 2-Pentyl furan (2PF) for aspergillosis [30]. Overall, EBC has demonstrated great potential and advantages in early disease screening and diagnosis [31], opening a new arena for studying airway inflammation and chemistry [32]. Recently, Vereb et al (2011) suggested that exhaled breath can be also used for assessing a variety of environmental exposures. ..... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405091/

Cancers Are Newly Evolved Parasitic Species, Biologist Argues. Cancer patients may feel like they have alien creatures or parasites growing inside their bodies, robbing them of health and vigor. According to one cell biologist, that's exactly right.

Posted on February 27, 2020 at 7:15 AM Comments comments (0)

Cancer patients may feel like they have alien creatures or parasites growing inside their bodies, robbing them of health and vigor. According to one cell biologist, that's exactly right. The formation of cancers is really the evolution of a new parasitic species.

 

Just as parasites do, cancer depends on its host for sustenance, which is why treatments that choke off tumors can be so effective. Thanks to this parasite-host relationship, cancer can grow however it wants, wherever it wants. Cancerous cells do not depend on other cells for survival, and they develop chromosome patterns that are distinct from their human hosts, according to Peter Duesberg, a molecular and cell biology professor at the University of California-Berkeley. As such, they're novel species.

 

He argues that the prevailing theories of carcinogenesis, or cancer formation, are wrong. Rather than springing from a few genetic mutations that spur cells to grow at an uncontrolled pace, cancerous tumors grow from a disruption of entire chromosomes, he says. Chromosomes contain many genes, so mis-copies, breaks and omissions lead to tens of thousands of genetic changes. The result is a cell with completely new traits: A new phenotype.

 

Cancer as evolution in action, which represents a fundamental re-thinking of the disease, has been proposed before — evolutionary biologist Julian S. Huxley first described autonomously growing tumors as a new species back in 1956, according to a Cal news release. But the prevailing view has long been that cancer is the result of genetic mutations.

 

Oncologists and pharmaceutical researchers are studying ways to find and block those mutations, aiming to turn off the switch that sparks carcinogenesis. But gene therapy has largely failed to deliver many meaningful results.

 

Duesberg argues, controversially, that it's misguided. Chromosomal mutation, called aneuploidy, is the cause instead, and it destabilizes chromosomal patterns. Some of the disrupted chromosomes are able to divide, seeding cancer. The result is a new chromosomal pattern that is distinct from our own. The Cal news office explains this in much greater detail.

 

Duesberg said he hopes this theory will spark new types of cancer diagnosis and treatment. Chromosomal tests could potentially pick out aneuploidy very early, before the damaged chromosomes have had a chance to divide, for instance. And new treatments could target the chromosomal disruptions, rather than knocking out or switching off genes. ...... https://www.popsci.com/science/article/2011-07/cancers-are-newly-evolved-parasitic-species-biologist-argues/

Is a breath test key to detecting cancer? - BBC News

Posted on February 27, 2020 at 7:10 AM Comments comments (0)



A clinical trial has been launched to see if a breath test could detect the presence of cancer. ..... https://www.startpage.com/sp/search

Eye Movement Studies To Help Diagnose Mental Illness

Posted on February 27, 2020 at 7:10 AM Comments comments (0)

Irregularities in how the eyes track a moving object reflect defects in the neural circuitry of the brain and appear to correspond with particular types of mental disorders. Schizophrenic patients, for example, have difficulty keeping their eyes focused on slow-moving objects. With new technology, these abnormalities can be measured precisely and compared with normal patterns.

 

"Psychiatric illnesses are not well understood neurologically," said John Sweeney, director of the Center for Cognitive Medicine in UIC's department of psychiatry. "Eye movement tests offer a way to investigate abnormalities in the brain that are causing these disturbances."

 

The goal, Sweeney said, is to develop eye movement tests as a simple, noninvasive tool for diagnosing brain disorders, including schizophrenia, depression and developmental illnesses such as autism. "At present, however, the field is still in its infancy," he said.

 

Under a $1.2 million grant from the National Institute of Mental Health, Sweeney and his colleagues are testing eye movement patterns in patients diagnosed with psychotic disorders, including schizophrenia, bipolar disorder and depression, in order to begin to validate eye movement abnormalities as markers for different brain diseases. ........ https://www.sciencedaily.com/releases/2003/06/030618080220.htm

Eye Test Identifies People with Schizophrenia - Psych Central

Posted on February 27, 2020 at 7:05 AM Comments comments (0)


Impaired eye movements have long been associated with schizophrenia. In a new study, researchers have discovered they can distinguish ...



Http://psychcentral.com/news/2012/10/31/eye-test-identifies-people-with-schizophrenia/46930.html

Diagnostics Methods in Ocular Infections From Microorganism Culture to Molecular Methods

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Conventional methods of microbiological diagnosis: Culture, isolation and phenotypic identification

Despite advances in the medical field, 4 of the 10 leading causes of death worldwide are due to infectious diseases [1]. At the eye, infections are one of the most common diseases, and bacterias are the first causative agent, followed by fungus and virus. Between these bacterias, Staphylococcus genus, Streptococcus genus, Corinebacterium sp, Chlamydia sp, Pseudomonas aeruginosa, Escherichia coli, Enterococcus sp, Serratia spare frequent in keratitis, conjunctivitis, endophthalmitis and cornea ulcer [2]; Fusarium sp, Aspergillus sp and Candida sp, are the commonly fungus found in keratitis infections [3]; Adenovirus, HSV-1 (Herpes Simplex Virus-1), HSV-2 (Herpes Simplex Virus-2), VZV (Varicella Zoster Virus), HPV (Human Papilloma Virus) are important in conjunctivitis and keratitis [4].

 

In order to reduce complications from ocular infectious diseases is very important to provide appropriate early treatment. To make this possible, is essential microbiological identification of the causative agent of infection in the shortest time possible. However, the microbiological diagnosis by conventional methods considered as gold standards, based on the culture followed by phenotypic identification of the microorganism once isolated, taken between 48 and 72 hours, depending on the requirements of the microorganism, and in the case of fungal infections, identifying and obtaining the antifungal susceptibility profile, come to take over a week. Identification time may be reduced by using automated equipment whose bases are the same as those used for manual identification, through biochemical profile of microorganisms. These tests are based on the ability to ferment, oxidize, degrade or hydrolyze different substrates or to grow on different carbon sources producing changes in pH that may be monitored using compounds that turn color depending on the pH. Automated systems work with cards containing dehydrated culture media with suitable substrates. Culture time elapses while the cards are automatically read and data are collected by a system confronts the data collected with a database through the microorganism is identified. Among the available automated identification systems are the VITEK 2 (bioMérieux, France) and BD Phoenix (USA), these Systems reduce time of identification to 6-12 h.

 

Although the main disadvantage is the time it takes the identification, cultivation allows the discovery of new or atypical strains, conservation of strains for further characterization and the ability to determine the antimicrobial susceptibility directly [5].

 

Given the urgency with which requires identification of microorganisms other strategies have been designed which further reduce the periods of time. These include the identification by endpoint PCR, real time PCR, microarrays and mass spectrometry directed to the detection of proteins or nucleic acids.

 

1.1.1. Endpoint PCR and real time PCR

Although the identification of microorganisms through culture is the gold standard this methodology presents some complications that are resolved using molecular biology techniques such as endpoint PCR and real time PCR, significantly reducing the outcome of days to a couple of hours. The identification of microorganisms using traditional microbiology is limited by slow growing organisms or poorly viable, besides giving false negative results due to treatment of patients with pre antimicrobial sampling [5]. Identification by culturing are required pure colonies, because in mixtures of microorganisms is impossible to identify the components of the mixture. All these constraints are solved by PCR. Using real time PCR is possible the detection of several microorganisms in the same assay [6]. This requires assembling multiple reactions in which the detection of microorganisms is carried out at the end of the amplification when by increasing the temperature gradually build dissociation curve (melt curve). Thus, if we know the temperature to which the DNA strands of amplicons are separated from each microorganism, then microorganisms present in the specimen can be identified. ..... https://www.intechopen.com/books/common-eye-infections/diagnostics-methods-in-ocular-infections-from-microorganism-culture-to-molecular-methods

Eye Infections - Johns Hopkins Medicine: Physicians diagnose and treat viral, bacterial, fungal and parasitic infections of the eye

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Eye Infections

Physicians treat viral, bacterial, fungal and parasitic infections of the eye and potentially serious complications of allergies and infections, especially conjunctivitis, or pinkeye. Conjunctivitis can be caused by an allergic reaction and turn into a chronic problem. Uveitis is an inflammation of the uvea - which is composed of the iris (colored portion of the eye that surrounds the pupil), the ciliary body (muscle behind the iris that helps change the shape of the lens to focus light on the retina), and the choroid layer (lining of the eye that contains blood vessels). Uveitis causes eye pain, sensitivity to light, blurred vision and spots in the field of vision. Untreated, the condition can cause permanent vision loss or complications such as glaucoma, cataracts and retinal detachment.

 

Another potentially blinding eye infection, AIDS-related cytomegalovirus retinitis (CMV retinitis), is caused by an impaired immune system that makes the eye vulnerable to a variety of eye infections. CMV retinitis is a viral infection of the light-sensitive part of the eye. Before treatment was developed, CMV invariably caused blindness by destroying the retina.

 

Diagnosis:

A skilled physician is critical to diagnosing uveitis. Although the cause of this condition is often unknown, in some cases, uveitis may result from an autoimmune reaction (where the immune system attacks the body) or from infections by microorganisms. Wilmer ophthalmologists also have extensive experience in diagnosing CMV retinitis and monitoring response to therapy.

 

Treatment:

Pinkeye, an inflammation of mucous membrane lining the inner surface of the eyelids and the whites of the eyes, is treated with antibiotics, steroids or, occasionally special contact lenses or surgery. Uveitis is treated with anti-inflammatory eye drops or systemic immuno-suppressant drugs.

 

Wilmer researchers are among the leaders in the treatment of AIDS-related eye infections, especially those due to CMV. They use numerous medications for this condition and led a national study demonstrating that a combination of two antiviral drugs, ganciclovir and foscarnet, is a more effective way to treat repeat episodes of the potentially blinding infection than with either drug alone. 


https://www.hopkinsmedicine.org/wilmer/conditions/infections.html

A 31-year-old man with bilateral blurry vision and floaters

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A 31-year-old man with bilateral blurry vision and floaters

Azin Abazari, MD, Kevin Kaplowitz, MD, and Patrick Sibony, MD

 


 

Summary

We report a case of bilateral multifocal retinochoroiditis and bilateral optic disc edema in a patient with cat-scratch disease from Bartonella henselae. The patient initially had negative serologic testing. Repeat testing showed a markedly increased IgG and IgM convalescent titer and the development of a branch retinal artery and vein occlusion. In patients for whom there is a high clinical suspicion of cat-scratch disease, a convalescent titer should be obtained 2–3 weeks following a negative initial result.

 

History

A 31-year-old male presented to Stony Brook University with bilateral blurry vision and floaters. The vision loss was of sudden onset, but the patient denied ocular pain. He had a history of flulike illness with malaise, fever, myalgia, and upper respiratory symptoms 1 week earlier.

 

Examination

On examination, best-corrected visual acuity was 20/20 in each eye. Slit-lamp examination was remarkable for 1+ anterior chamber cell in both eyes, 3+ anterior vitreous cell in the right eye and +1 in the left eye. Dilated fundus examination disclosed bilateral disc edema, more prominent on the right more than the left, and multifocal deep retinal and choroidal yellowish infiltrates 100–300 μm in diameter (Figure 1).

 


Fundus photographs of a 31-year-old man initially presenting with bilateral disc edema, in evidence more on the right (A) than the left (B), and multifocal deep retinal and choroidal yellowish infiltrates 100–300 μm in diameter. Representative ...

Ancillary Testing

Laboratory workup for bilateral uveitis and multifocal retinochoroiditis included negative serology for Lyme IgM and IgG; Bartonella IgM and IgG; Epstein-Barr virus; hepatitis A, B, and C; toxoplasma; syphilis; HIV; anti-nuclear antibody; anti-neutrophil cytoplasmic antibody; anti–double stranded DNA; and complement levels. He had a slightly elevated angiotensin converting enzyme (ACE) titer (74 U/L; normal range, 12–68 U/L). Because of his borderline ACE and to rule out sarcoidosis, he underwent chest computed tomography, which did not show any evidence of hilar adenopathy or interstitial lung disease.

 

Treatment

The patient was started on 60 mg oral prednisone daily, which was tapered over 1 month. At 1 month after the initial presentation, his visual acuity was 20/20 in each eye. He had mild vitreous cells and mild disc edema bilaterally. In addition, he had developed stellate macular exudates (macular star) in the right eye, retinal vasculitis, and a branch retinal artery and vein occlusion in the left eye (Figure 2). A repeat Bartonella titer was positive at IgG > 1/2560 (negative, <1/320) and IgM 1/200 (negative, <1/100). On further questioning, the patient mentioned he had recently been exposed to a cat. He was started on doxycycline and rifampin. Two months later, his visual acuity remained 20/20, and the disc edema had resolved. The vitritis and macular exudates had cleared completely, but he had developed nasal chorioretinal scars (Figure 3). On his most recent examination, 1 year after initial presentation, his visual acuity was 20/20 in each eye.

 


Fundus photographs 1 month after presentation shows stellate macular exudates (macular star) in the right eye (A) as well as a branch retinal artery and vein occlusion in the left eye (B). Representative fluorescein angiography of the right eye (at 1 ...


Fundus photograph showing the areas of retinitis becoming chorioretinal scars.

Differential Diagnosis

For unilateral granulomatous conjunctivitis (Parinaud syndrome), the main differential diagnosis includes tuberculosis, syphilis, tularemia, and chlamydia.1,2

 

For neuroretinitis the main differential includes Lyme disease, malignant hypertension, syphilis, and idiopathic stellate neuroretinitis.

 

For the isolated retinal or choroidal infiltrates, the differential includes the white dot syndromes, particularly multiple evanescent white dot syndrome3 and toxoplasmosis, which, unlike Bartonella infections, classically have infiltrate adjacent to chorioretinal scarring and are not multifocal.4

 

Our patient’s differential diagnosis included white dot syndromes such as multifocal choroiditis, sarcoidosis, syphilis, lyme, and infectious and idiopathic neuroretinitis.

 

Diagnosis and Discussion

Cat-scratch disease is usually a self-limited infection, most commonly caused by an intracellular Gram-negative rod, Bartonella henselae. The estimated incidence of the disease in the US is 9.3/100,000.(5) Although Bartonella infection was historically reported in children,1 45% of patients in the database were >18 years of age.5 The bacteria is transmitted from a young cat through a bite, scratch, or previous break in the skin,1 although fleas can transmit the disease directly.6 A nonpruritic papule, usually <1 cm, develops at the inoculation site 3–5 days after exposure, accompanied by flulike illness.1 Regional lymphadenopathy occurred in 100% of 1,200 cases within 1–2 weeks.1 It is at this point that bacteremia can rarely lead to systemic complications, which have been reported to occur in every organ system,7 including encephalitis in 0.2%.1

 

After regional lymphadenopathy, ocular Bartonella infection is the most common manifestation of the disease. Both the presenting and final visual acuity can vary greatly, from 20/20 to counting fingers.8 The most common ocular presentation is unilateral Parinaud oculoglandular syndrome, consisting of preauricular lymphadenopathy and follicular conjunctivitis, which was reported in 48 of 1200 patients (4%).1 The second most common ocular finding is chorioretinal infiltrates, reported in 16 of 37 (43%) and 29 of 35 cases (83%) of ocular Bartonella infection.10,8 Neuroretinitis (optic disc edema accompanied by a stellate pattern of exudative maculopathy) sometimes with peripapillary or equatorial dot-blot hemorrhages, is a classic finding.8 Although neuroretinitis only occurs in 1%–2% of cases of systemic Bartonella infection,2,9 a frequently cited study reported neuroretinitis caused by Bartonella in 9 of 14 cases (64%).11

 

Solley et al8 reported unilateral optic disc edema in 16 of 35 (46%) of ocular Bartonella cases. Chi et al12 reported bilateral disc edema in only 9 of 53 patients (17%). In their unilateral cases, an afferent pupillary defect was common, occurring in 40 of 44 cases (91%).12 Optic disc edema progressed to neuroretinitis in 28 of 62 cases (45%).12 Neuoretinitis is thought to be segmental inflammation of superficial optic nerve head arterioles leading to exudative disc edema, which spreads into the outer plexiform layer. Purvin et al13 reported unilateral neuroretinitis in 65 of 69 cases (94%). The exudates appear 1–3 weeks after the disc edema and take 2–3 months to resolve.14

 

Omerod noted up to 27 central retinal or choroidal white dots (bilateral in an estimated 75% of cases), usually clearing completely but sometimes leaving pigmented scars: retinal disease was associated with vitritis in 50% and nongranulomatous anterior uveitis in <15% of their cases.15 Retinal biopsy can confirm that the lesions contain Bartonella colonies.16 In a relatively large study (n = 35), Solley et al8 reviewed photographs to determine the depth of infiltrates: 30% occurred in the superficial retina; 49%, in deep retina; 14% were full-thickness; and 7% were in the choroid.

 

Branch retinal artery occlusion has been reported as frequently as in 11% of 35 cases of ocular Bartonella.8 There is a case report of a branch retinal venous occlusion8 and combined central retinal artery and vein occlusion.17 Less common ocular complications include optic nerve head vasoproliferative, granulomatous angiomas that are composed of superficial abnormal vascular networks in 5% of cases.10,18 Peripapillary serous retinal detachments, thought to be caused by spreading of fluid from the disc edema, occurred in 20% of 35 cases.8 The subretinal fluid usually resolves after 2 months.19 Cases of macular holes and a choroidal detachment have also been reported.20,21

 

Bartonella henselae is difficult to culture. It can be identified with the Warthin-Starry stain, but it is uncommon and usually unnecessary to culture a lymph node.1,20 Serum indirect fluorescent antibody (IFA) with a titer ≤1:64 is 88% sensitive and 94% specific,20 except in immunocompromised patients, where the sensitivity is <70%.2 Seroconversion requires 2–3 weeks, and a fourfold rise in titers strongly suggests the diagnosis,21 although this only occurs in 66% of cases.22 Although enzyme-linked immunosorbent assay (ELISA) is available to distinguish between IgG and IgM and was initially reported to be 95% sensitive and 100% specific,21 others report that ELISA is not accurate because of high false negatives.2,3 The combination of a papule, regional adenopathy, and a positive IFA is 95% sensitive.22 Tissue polymerase chain reaction can be used as a confirmatory test, because it was reported to be 100% specific and 76% sensitive.23

 

Ancillary testing beyond antibody testing may offer evidence in support of positive diagnosis. Optical coherence tomography can be used to demonstrate optic disc edema and peripapillary subretinal fluid.19 The chorioretinal infiltrates are hypofluorescent early and hyperfluorescent late on fluorescein angiography but hypofluorescent throughout indocyanine green angiography.18

 

Recommended antibiotics include ciprofloxacin (azithromycin in children),9 sulfamethoxazole with trimethoprim, and rifampin.24 A randomized control trial to determine the efficacy of any treatment for ocular Bartonella has not yet been reported. Although investigators have reported using antibiotics for 2–4 weeks with or without steroids,2 neither appear to improve the visual outcome.12 One study showed that the final median visual acuity in both treated and nontreated groups was 20/20.8 The only cases consistently reported to require treatment are immunocompromised patients, who are at higher risk for symptomatic bacteremia. Immunocompromised patients should be treated for at least 1–4 months.7,25,26

 

Final visual acuity depends on the extent of posterior segment involvement. Chi et al12 reported that of 53 cases with disc edema and a mean presenting visual acuity of 20/160, 36 (68%) had a final visual acuity of 20/40 or better, and 3 (6%) had final visual acuity of 20/200 or worse. While the progression from disc edema to neuroretinitis12 or a serous retinal detachment14 does not appear to affect final visual acuity, the presence of a vascular occlusion involving the disc or macula limits the visual outcome.14 Purvin et al13 reported that disc edema and macular edema led to a central visual field deficit in 88% of tested cases, but these deficits may not persist after disease resolution.(27) Reed et al27 reported a case series where all 7patients finished with final visual acuity of 20/20 to 20/30: subtle residual deficits were detected 2 years later in all 3 of those patients who were tested, including decreased contrast sensitivity, a 30% reduction in the visual evoked potential amplitude, and decreased color vision.

 

The present case demonstrates the different stages of ocular manifestation of a patient with Bartonella. Unlike previously reported cases, where artery occlusion was noted simultaneous to the retinal infiltrates,4,15,26 our case showed an unusually progressive course. In addition, initial Bartonella serology for both IgG and IgM were negative, but repeat convalescent titers were positive for both. In patients for whom there is a high clinical suspicion of cat-scratch disease, a convalescent titer should be obtained 2–3 weeks following a negative initial result. ....... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902642/

Candida endophthalmitis: A critical diagnosis in the critically ill. Evidence of severe ulcerative colitis with cytomegalovirus infection. ... disseminated Candida infection include the recent onset of floaters and reduced vision

Posted on February 27, 2020 at 12:25 AM Comments comments (0)

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704539/

Recent Updates on Treatment of Ocular Microbial Infections by Stem Cell Therapy: A Review

Posted on February 27, 2020 at 12:10 AM Comments comments (0)

Recent Updates on Treatment of Ocular Microbial Infections by Stem Cell Therapy: A Review

Seoh Wei Teh, Pooi Ling Mok, [...], and Suresh Kumar Subbiah

 


 

Abstract

Ocular microbial infection has emerged as a major public health crisis during the past two decades. A variety of causative agents can cause ocular microbial infections; which are characterized by persistent and destructive inflammation of the ocular tissue; progressive visual disturbance; and may result in loss of visual function in patients if early and effective treatments are not received. The conventional therapeutic approaches to treat vision impairment and blindness resulting from microbial infections involve antimicrobial therapy to eliminate the offending pathogens or in severe cases; by surgical methods and retinal prosthesis replacing of the infected area. In cases where there is concurrent inflammation, once infection is controlled, anti-inflammatory agents are indicated to reduce ocular damage from inflammation which ensues. Despite advances in medical research; progress in the control of ocular microbial infections remains slow. The varying level of ocular tissue recovery in individuals and the incomplete visual functional restoration indicate the chief limitations of current strategies. The development of a more extensive therapy is needed to help in healing to regain vision in patients. Stem cells are multipotent stromal cells that can give rise to a vast variety of cell types following proper differentiation protocol. Stem cell therapy shows promise in reducing inflammation and repairing tissue damage on the eye caused by microbial infections by its ability to modulate immune response and promote tissue regeneration. This article reviews a selected list of common infectious agents affecting the eye; which include fungi; viruses; parasites and bacteria with the aim of discussing the current antimicrobial treatments and the associated therapeutic challenges. We also provide recent updates of the advances in stem cells studies on sepsis therapy as a suggestion of optimum treatment regime for ocular microbial infections.

 

Keywords: ocular microbial infections, endophthalmitis, stem cells, inflammation, tissue regeneration

1. Introduction

Ocular microbial infections can cause endophthalmitis (an inflammation of the interior of the eye), an inflammatory reaction that will lead to visual disturbance and potentially produce blinding outcome [1]. Inner eye inflammation can damage the ocular layers which are important for visual processing, such as cornea and retina, which is irremediable by common antimicrobial treatment [2]. Thus, a potent management regime is urgently required, which could be discovered in stem cells treatment.

 

The eye is one of the major sensory organs in the human body responsible for visual functions, which has a spherical structure. The cornea is the outmost transparent layer of the eyes that refract light onto the retina [3,4]. The retina is the inner coat of the ocular tunics, comprised of 10 different layers of highly organized and complex neurons interconnected by synapses, with the innermost layer of light-sensitive rods and cones photoreceptor cells. Rods support the perception of black-and-white image while cones are responsible for color vision. Neural signals produced are then processed by other retinal neurons in the visual pathway [3,4]. Ocular microbial infections can lead to opacification and intraocular tissue damages which in turn affect retinal encoding and light processing and eventually produces irreversible vision loss [1,5]. Considering the structure and the elements of the retina, conditions spread to the retina, particularly disintegrating the architecture of the retina represent the most tragic clinical manifestations among the intraocular infections [1]. Although the rate of mortality caused by microbial infections in the eyes is relative low, the resulted visual loss intensely affects the quality of life (QOL) of the patients [5]. Hence, effective therapeutic strategies should be sought in alternative remedies such as stem cells.

 

Introduction of infectious pathogens to the eyes either exogenously (post-traumatic or post-operative), or endogenously (hematogenous microbial dissemination from a distant infected body part) causes chronic inflammation of the eyes [6,7]. The severe and lasting inflammatory response in the eyes is a potentially devastating condition as it may result in edema, opacity and eventually ocular tissue damages [1,5]. Consequently, the inflammation caused by microbial infections intensely aggravate the quality of eye vision of an affected individual. The inflammatory response could lead to rapid loss of visual acuity within several days [8,9] and could even result in retinal detachment within 12 h [10], depending on the severity of the infection. Therefore, prompt and effective treatment should be given to the patient after an infection.

 

The infectious microorganisms cause intensive tissue inflammation, structural disturbance and ocular tissue remodeling by the stimulation of tissue fibrosis [11]. Upon invasion into the host eyes, secretion of fungal endotoxins and proteinases can trigger the release of interleukin (IL)-1α, IL-1β and IL-17 in the eye [12,13], resulting in intense inflammation (Figure 1). Whereas, viral capsid proteins can attach and penetrate host cells to integrate viral DNA into the host nucleus, after which the host cells will undergo lysis to release the produced progeny [14]. In addition, certain parasites also induce expression of IL-12 and tumor necrosis factor-α (TNF-α) during infection, causing tissue necrosis [15]. On the other hand, bacteria can excrete toxins and antigenic proteins capable of stimulating inflammatory reactions and suffice to induce damage in the ocular tissue [16].

 


Molecular pathogenesis of ocular microbial infections. The infectious microorganisms can cause inflammation, retinal detachment and tissue fibrosis in affected eyes. Fungus attacks host cells by the formation of germ tube to penetrate and release endotoxins ...

When human eyes are infected by microorganisms, the injured tissue undergo healing by the release of cytokines, chemokines and growth factors [17]. Infectious microorganisms and infected cells are removed by neutrophils and monocytes via macrophage differentiation [18]. Macrophage differentiation activates fibrogenesis and angiogenesis, induces re-epithelialization and the secretion of connective tissue proteins such as vimentin and collagens I and III [19]. Fibrotic response and tissue scarring due to excessive extracellular matrix deposition results in opacity in the patient eyes [11]. Hence, extrinsic medication is required to promptly overcome the infections, halt progression of tissue damage by microbes and reduce scarring.

 

Infectious pathogens could be killed by antimicrobials in which local therapy can be administered via ocular injections, oral or intravenous medications. Treatment for endogenous intraocular infections, meanwhile, can be provided at the primary site of infection [7,20,21]. Despite successful elimination of most microbes, damages to the ocular layers can never be reverted [22,23]. In adult mammals, the neuroretina and retinal pigment epithelium (RPE) do not support neurogenesis as observed in the lower vertebrates [24]. Microbial infections affecting the retina can cause permanent visual impairment when the photoreceptor cells do not spontaneously regenerate after experiencing the unalterable damage [24]. Furthermore, in some serious cases of microbial infections such as Histoplasmosis, laser treatment is required. Even with the repeated laser therapy, the procedure is inadequate to heal the ocular tissue damage [2]. In other cases, retinal prosthesis is needed to replace the infected area following the removal of the damaged region surgically [25]. However, this invasive strategy has the possible drawback of imposing heat damage to the retinal tissue due to close proximity of the implant to retina layers within the compact ocular space [25].

 

Owing to the limitations possessed by the conventional antimicrobial and surgical approaches, the battle against ocular infections due to contaminating microorganisms is ought to be participated by stem cell therapy, helpful in the successful management of microbial diseases in many recent studies [26,27,28,29]. The idea of potent therapeutic arsenal by stem cells is also supported by their self-renewal and regenerative potential [30,31,32]. Thus, the concept to suppress inflammation and replace the infection damaged photoreceptor cells and RPE by stem cells transplantation represents a highly appealing therapeutic intervention. This review emphasizes the urgent need of an alternative strategy in stem cells treatment to supplement the conventional antimicrobial management, in treating ocular microbial infections.

 

2. Challenges of Conventional Antimicrobial Treatments for Ocular Microbial Infections

Ocular microbial infections are caused by a variety of pathogenic microorganisms such as fungi [6,7,33], viruses [20,34,35], parasites [36,37,38] and bacteria [39,40,41]. These microbes reach the inner eyes following intraocular surgery [41,42,43,44,45,46,47,48], trauma [49,50], or access by the metastatic spread from other affected anatomical regions [39,51,52,53,54,55,56] and give rise to different effects in patients according to the virulence of microorganisms and the patient immune status [22,23,57,58,59,60]. The primary symptoms of these infections damaging the inner eyes is blurred vision and rapidly deteriorating visual acuity within a few days of infections [8,9]. During the onset of the infections, immune cells and other immunologically active substances infiltrate into the intraocular layers [61] and result in inflammatory reactions. Inflammation-mediated ocular opacification hinders the clear image formation on the retina for a meaningful visual perception [61]. Moreover, retinal tissue damage involving the photoreceptor cells and RPE induced by inflammatory response impedes the basic light-processing photochemical pathway of vision [61]. The outcomes of these complications are the irreversible loss of vision in the affected individuals.

 

Intraocular infections caused by microorganisms are usually treated by antimicrobials, which produce variable yet poor results in patients due to several challenges encountered during the course of treatment [21,62]. The challenges of conventional antimicrobial therapy lie on the fact that even with aggressive therapy, damaged tissue could not be recovered and frequently results in vision impairment [2,22,23,63,64]. Depending on the severity of the infections, antimicrobials treatment could take a long period of time to effectively eradicate the pathogenic agents in the eyes [7,21,62,65,66,67]. For some infections, visual disturbance will recur despite laser procedures or surgery treatment [2,64]. There are many hypothetical questions about ocular infections in the scientific community, one of the major questions has to be “is conventional antimicrobials therapy enough for the treatment of ocular tissue damage?” The outcomes of treatment vary due to the age of the patient, species of pathogens, duration between injury and treatment and the extent of the ocular tissue damage [68]. Delay in delivery of efficient therapeutic management could lead to poor and potentially blinding outcome [6,43,54,69,70,71].

 

The offending pathogens affecting the eyes are conventionally combated with antimicrobial agents, which demonstrated low efficiency due to problems in drug administration and diffusion to infected site [72,73,74]. At the onset of microbial infections in the eyes where the causative microbes have not been identified, the antimicrobial drug administered is decided empirically. However, difficulty in correlating infection clinical manifestations and culture results provides minimal assistance on antimicrobial decision [75]. In most of the cases, visual impairment remains as the common outcome even when broad-spectrum antimicrobials were used [45,76]. Furthermore, severe inflammatory reaction occurs in the inner eyes leads to edema and exacerbates the ocular condition [5]. Therefore, anti-inflammatory drugs are often administered concurrently with a high dose of antimicrobials to suppress the intraocular inflammation while killing the offending agents. Nevertheless, clinical evidences have proven that these drugs do not pose any consequences on the inflammation-derived enzymes and toxins that adversely influence the retinal architecture and function [16,77]. Destructed retinal structure and neuroretinal function inevitably lead to the result of blindness.

 

Despite enormous effort in the science and medicine to heal ocular microbial infections, the severity of ocular diseases continues to pose various risks and complications to the infected individuals. This is due to the delicate ocular cells such as photoreceptor cells and RPE, which possess extreme sensitivity towards the insulting microorganisms, the inflammatory response elicited there upon and the high doses of antimicrobials administered onsite [45,78,79,80]. The traditional treatments of endophthalmitis includes intravitreal administration of antimicrobial agents [45,81,82,83] and simultaneous systemic drug injection [6,44]. However, the isolation of the retina by an avascular vitreous and anterior chamber hamper the effective penetration of the potentially effective antimicrobials to the infected site [72,73,74] following drug injection systemically. Such unique feature as blood-ocular fluid barrier represents a major obstruction for the antimicrobial agents to be delivered by the systemic circulation to the blood-rich retinal layers. The inflammation in the inner eye enhances blood-ocular fluid barrier permeability, thereby promoting the antimicrobial diffusion into the vitreous cavity [74]. However, the intravitreal levels of antimicrobial following direct injection of drugs into the systemic circulation are highly variable and often failed to achieve the minimal inhibitory concentration for various infectious microbes [46]. The physiological challenges of and complications resulted from antimicrobial drugs administrated locally and intravenously exert significant effects on the extension of treatment duration. This, in turn, gives rise to adverse drug reactions, including drug toxicity and drug susceptibility. The most blatant examples of drug toxicity are demonstrated by amphotericin B usage in Cryptococcus neoformans infections [84,85] and the utilization of foscarnet and cidofovir against cytomegalovirus (CMV) [57,86]. All the challenges possess by the anatomical structure of the human eye and drug delivery serve as immense hurdles on the traditional antimicrobials therapy to heal endophthalmitis. The invention of a new modality to fight against ocular microbial infection in stem cell therapy is, thus, in pressing need.

 

2.1. Ocular Fungal Infections and the Challenges of Conventional Antifungal Treatment

Human eyes are vulnerable to microbial attack and fungus represents one of the most frequent causative agents among the microorganisms infecting the delicate ocular tissues [33]. Fungal infections in the eyes are commonly treated with antifungal, however, the effective treatments are not successfully delivered due to various challenges. The common pathogenic fungus causing severe infections are Candida sp. [7], Aspergillus sp. [33], Cryptococcus sp. [84] and Histoplasma sp. [2] (Table 1). Among all, the most widely seen fungus species causing endophthalmitis is Candida sp. such as Candida albicans, which appear as dermal commensal microbes in healthy individuals and opportunistic pathogens in immune-deficient patients [60]. Fungal infections in the eyes may be caused by hematogenous spread from a distant body area harboring infection caused by Candida sp. or Aspergillus sp. and produce ocular manifestations such as white infiltrates in the inner ocular cavity and hemorrhages [6,7,33]

The causative agents of ocular microbial infections, antimicrobial treatments, route and duration of administration.

Upon Candida sp. adhesion to host epithelial cell walls, germ tubes are formed, candidalysin, endotoxins and proteinases are secreted [12,13,100]. During infection, up-regulation of IL-1α, IL-1β, IL-17 and TNF can cause ocular tissue destruction [12,13]. Ocular candidiasis can be overcome by antifungal caspofungin, micafungin or anidulafungin [7]. On the other hand, antifungal voriconazole or posaconazole is used against Aspergillus sp. [7,33,87,88], administered either intravenously or orally. These antifungal treatments require prescription over a long period of time that spans across few months [7], therefore, a more effective intervention should be sought in stem cells for more rapidly healing mechanisms in the affected patients.

 

Cryptococcus neoformans infecting the eyes can be eliminated by intravenous amphotericin B. However, it demonstrates poor diffusion into the vitreous cavity, toxic to human and can cause complications such as renal failure and anaphylaxis in patients receiving high dosage or exposed to long-term therapy [101,102,103]. On the other hand, the use of flucytosine as alternative treatment for Cryptococcal infections has been reported to be associated with rapid development of antifungal resistance [84,85]. Even with the drawbacks of these antifungal therapy, many clinicians are still using them to treat infections. Stem cell therapy should be looked into for its effectiveness in the elimination of pathogens.

 

Histoplasma capsulatum infections, commonly occurring in patients with compromised immune system, represent the most critical ocular fungal infection. Patients commonly show symptoms of chronic inflammation, hemorrhage and rapid visual impairment [2]. An acquired immune deficiency syndrome (AIDS) patient was reported to have developed retinitis from the disseminated pulmonary Histoplasma capsulatum and CMV infection and demonstrated characteristic of creamy white infiltrates with histoplasma yeast cells, lymphocytes and histiocytes in retinal layers. The patient died within a month from the opportunistic infection [64]. In cases of ocular histoplasmosis, the adopted management is usually repetitive laser cauterization of the affected area to slow the macula destruction process [2]. Despite the laser procedures, the repair of the induced damage is still unfeasible. The severity of ocular fungal infections and the limitations of traditional therapeutic intervention call for the discovery of a more potent treatment approach in stem cell therapy for the substantial recovery of ocular tissue damaged by insulting microorganisms.

 

2.2. Ocular Viral Infections and the Challenges of Conventional Antiviral Treatment

CMV retinitis caused by CMV is usually seen in hosts with compromised immune systems [62]. Frequent ocular manifestations include diffusion of white granular lesion over 8 months, vessel sheating and hemorrhages. A case report stated that within an average of 10 weeks, retinal scar was produced in two patients with a reduction in visual acuity in 50% of the eyes [9]. CMV retinitis progressively results in full-thickness retinal necrosis followed by retinal vascular endothelial cells loss and ultimately retinal detachment in the late stage [9,59,104]. CMV first targets on retinal vascular endothelial cells and spread through retinal vasculature to the RPE in the development of retinal vasculopathy and CMV retinitis [104]. Initially, FasL-mediated apoptosis of RPE could protects host against immune invasion stimulated by CMV. However, this mechanism fails to completely clear CMV in RPE and elicit further immune responses which leads to retinitis [105]. High secretion of TNF-α and interferon-γ (IFN-γ) in immunocompromised patients could aggravate the condition by increasing the sensitivity of RPE to FasL pathway, causing retinal necrosis [14].

 

Ganciclovir [21], foscarnet [57], cidofovir [62] and fomivirsen [89] serve as the common management options to combat CMV endophthalmitis. Intravenous or intravitreous administration of ganciclovir takes more than 3 weeks to completely eliminate the pathogenic agents [21]. Whereas, intravenous delivery of foscarnet causes nephrotoxicity and electrolyte disturbance [57]. The side effects of nephrotoxicity and the outcome of sight-threatening uveitis and hypotony are also observed with cidofovir treatment [62]. Furthermore, drug resistance can develop specifically in patients with impaired immune function. When AIDS patient is infected with CMV endophthalmitis, highly active antiretroviral therapy (HAART) should be initiated immediately. Nevertheless, HAART is highly associated to the development of immune recovery uveitis [22,23,63] and eventually results in blindness. Currently, patients infected with virus are still treated with these antiviral drugs although there are reports of complications. Stem cell therapy should be sought as a more effective therapeutic regime for ocular infections.

 

A 41-year old man from Sabah, Malaysia, with history of disseminated Cryptococcal meningitis and Klebsiella septicaemia, was infected with CMV retinitis and treated in Universiti Kebangsaan Malaysia Medical Center (UKMMC). The patient presented floaters in his right eye for 1 month, with vision of 6/18 and pin hole of 6/9 N6 for right eye. Whereas, his left eye had vision of 6/24 and pinhole 6/18 N6. Examination of the HIV positive patient’s eyes revealed fine white keratic precipitate and anterior chamber cells bilaterally. On fundus examination, there was vitritis grade 1, retinitis, vasculitis, retinal hemorrhages and optic disc swelling (Figure 2A). Intravitreal tap also showed positive result for CMV analysis. The patient was treated with intravitreal ganciclovir (0.1 mL/20 mg) and oral valganciclovir (900 mg BD) for 6 weeks. Simultaneously, HAART was administered to increase cluster of differentiation (CD)4 and CD8 counts. On day 18 of the treatment, the right eye of the patient developed superotemporal retinal detachment from atrophic hole and underwent scleral buckle procedure for repairing. However, the right eye retina developed redetachment and the patient was then subjected to laser photocoagulation and gas tamponade. Upon completion of 6 weeks oral valganciclovir treatment, the retina demonstrated scarring (Figure 2B), with vision 6/12 pinhole 6/9 for right eye and vision 6/9 pinhole 6/9 for left eye. This case study has proven that the traditional antiviral therapy is not very effective and failed to completely repair damages even after a long duration of treatment. Therefore, stem cell therapy may be adopted in treating ocular infections to complement the current therapeutic management.

 


Fundus of patient with CMV retinitis. (A) Before antimicrobial treatment, the patient had vitritis grade 1, retinitis in the temporal periphery, vasculitis, retinal hemorrhages and optic disc swelling. (B) After antimicrobial treatment, the fundus shows ...

In addition to CMV infection, herpetic and varicella viral infections are likewise dreadful and can result from systemic infection regardless of the immune status of the host. Herpes simplex virus (HSV), herpes zoster virus (HZV) and varicella zoster virus (VZV) can lead to acute retinal necrosis (ARN) in immune-competent individuals and progressive outer retinal necrosis (PORN) in patients with compromised cell-mediated immunity [20,34,35,55,62,106,107]. The rapidly progressive retinitis was featured by retina tissue sparing, retinal vasculature, hemorrhage, massive necrosis and the complication of rhegmatogenous retinal detachment [107].

 

Patients are commonly given oral valaciclovir [62,90], famciclovir [62,91], or intravenous acyclovir therapy [62,107], which requires 7 to 12 weeks of treatment period [67]. These strategies have been shown to produce poor outcomes [107,108,109], mainly due to drug resistance [110]. Alternatively, intravitreal foscarnet [20] is employed to combat the infections. Laser treatment and surgery may also be required to repair rhegmatogenous retinal detachments. Prophylactic argon laser could be used to minimize the risk of retinal detachment but its use is controversial [8,111,112,113,114]. Meanwhile, cryosurgery procedure will simultaneously destroy the functioning retina [115]. The prolonged period of antiviral therapy and ineffective operative strategy validate the need of stem cells intervention as a useful regime in treating microbial infections.

 

2.3. Ocular Parasitic Infections and the Challenges of Conventional Antiparasitic Treatment

Microbial infections in the inner eyes could be caused by various parasites, which produce very serious ocular manifestations within a short period of time. The most common species of parasite causing endophthalmitis are Toxocara canis [37,38], Toxocara cati [92,116] and Toxoplasma gondii [62,117]. Toxocariasis caused by Toxocara canis (roundworm from dogs) and Toxocara cati (roundworm from cats) can cause uveitis, tissue scarring and loss of vision within 2 days [116]. Prompt and useful treatment is required to prevent the rapid visual impairment induced by the parasite. The infections are counter-attacked by albendazole or thiabendazole with corticosteroid anti-inflammatory agents applied topically or periocularly [37,38,92]. Direct laser photocoagulation is adopted in the cases in which mobile larvae are seen [36].

 

Whereas, Toxoplasma gondii induced ocular toxoplasmosis is mainly observed in immune-compromised hosts, causing hemorrhage, scarring and tissue destruction in retinitis [62]. Toxoplasmosis can also be acquired during pregnancy, leading to congenital infection in the newborn. Macula involvement is widely seen, where the developing fetus will experience devastated central vision [117]. At the early stage of parasitic infection, apoptosis mechanisms and Fas/FasL pathways serve as host protective mechanism. However, the overexpression of Fas and FasL in response to Toxoplasma gondii infections could result in excessive ocular tissue damage [118,119]. Moreover, host monocytes phagocytosis of toxoplasma tachyzoites stimulated the production of IL-12 and TNF-α [15]. The infectious diseases are commonly treated with the combination of sulfadiazine with pyrimethamine, sulfamethoxazole with trimethoprim or azithromycin with pyrimethamine [93,94,95]. However, clinical trials have provided inadequate evidences where the medications can improve the outcome of the infections [77]. Over 80% of patients experience relapses for more than 5 years [117]. Moreover, the killing of parasites could trigger an intensified inflammatory response in the eyes, thus render the treatment strategies debatable. The clinical data has proven that antimicrobials are insufficient in overcoming infections due to parasites. To reduce inflammation and prevent ocular tissue damage while eliminating the parasites in the inner ocular layers, stem cell therapy should be considered as an ideal treatment for parasitic endophthalmitis.

 

2.4. Ocular Bacterial Infections and the Challenges of Conventional Antibiotics Treatment

Bacteria such as Enterococci [120], Staphylococci [44,47,96] and Bacilli [68,121] are common cause of infectious diseases in the eyes. Among all, Staphylococcus aureus, Bacillus cereus and gram-negative bacteria, such as Escherichia coli, Neisseria meningitides and Klebsiella species are responsible for endogenous retinal infections spread from other anatomical area [6,39,40,51,56]. For instance, drug abusers may contract Bacillus infection from contaminated drug taken intravenously or from injection paraphernalia [52]. The alpha-toxin of Staphylococcus aureus [16], cytolysin of Enterococcus faecalis [122] and pneumolysin of Streptococcus pneumoniae [123] secreted during infection can induce intensive injury to ocular tissue. The production of virulence factors such as proteases [124], lipases [125], enterotoxins [126] and hemolysins [127] by Bacillus cereus cause endophthalmitis, retinal layer folding and detachment within 12 h [10], with complete central visual loss, or entire eye loss often occur within 2 days [16]. The antibacterial widely used to combat the infections are amikacin [45], ceftazidime [96] and vancomycin [45,96] via intravitreal treatment. However, the aminoglycosides such as amikacin commonly used to combat sepsis serves as poor choice of antibacterial agent due to dose-dependent toxicity which may lead to destructive retinal microvasculitis [128]. In addition, the emergence of antimicrobial-resistant species, such as vancomycin-resistant Enterococcus faecalis and Staphylococcus aureus can transform the management of bacterial infections [48,53]. In addition, the broad-spectrum fluoroquinolones should not be utilized in intraocular therapy due to its potential toxicity [48,53]. Instead of subjecting the patients to the disadvantages posed by these prescribed antibiotics, stem cell therapy should be adopted to heal the infections more rapidly, thereby reducing the probability of gaining antimicrobial toxicity.

 

Retinal infections may also be associated with syphilis caused by Treponema pallidum, which could infect individuals regardless of their immune status. Infected patients show manifestations such as retinitis, chorioretinitis and retinal vasculitis [97]. The flagellar filament outer layer protein (FlaA2) of Treponema pallidum, triggers the inflammatory reaction in monocytes by stimulating the signaling pathways involving toll-like receptor 2 (TLR2), myeloid differentiation primary response 88 (MyD88), extracellular-signal-regulated kinase (ERK), p38 and nuclear factor (NF)-κB, resulting in the release of pro-inflammatory cytokines IL-6 and activation of TNF [129,130]. Common antifungal used to treat infections due to Treponema pallidum include penicillin, ceftriaxone and doxycycline, which required up to 3 weeks of administration [58,64,97,98]. Stem cell intervention should be involved to shorten the treatment period, thereby reducing the period of time on which the bacteria exert its pathogenic effect and induce damage on host cells.

 

Other than that, Mycobacterium tuberculosis could also infect humans irrespective of immune status and give rise to retinal vasculitis. Conventional therapy starts with 2 months of rifampin, isoniazid and pyrazinamide intervention with or without ethambutol and followed by rifampin and isoniazid therapy. The completion of the regime will take up to 9 months [65]. On the other hand, multidrug-resistant tuberculosis associated infections are treated by streptomycin, capreomycin and quinolones [99]. Nevertheless, a study by Garhyan et al. showed that the Mycobacterium tuberculosis can reside in dormancy in bone marrow-mesenchymal stem cells (BM-MSCs) and persist in the intracellular milieu even after 3 months of extensive pyrazinamide and isoniazid treatment [131]. Mycobacterium tuberculosis can emerge and cause relapse in the patient after the discontinuation of antibiotic treatment, thus, rendering the therapy inadequate [131]. Therefore, a powerful regime is urgently required to supplement conventional antimicrobial therapy, which could be sought in stem cells.

 

In another case reported in UKMMC, the patient complained of right eye blurring of vision without previous significant history of injury or trauma to the eyes. Clinical suspicion was of a bacterial infection. However, multiple samples from the vitreous was taken and revealed pus with no evidence of bacterial or fungal growth. Clinical examination revealed right eye circumcorneal injection, descement folds over the cornea and hypopyon in the anterior chamber (Figure 3A). Moreover, the fundus was obscured by a yellowish pus like material. Microbial insult to the delicate ocular tissue without the isolation of causative microorganisms is not surprising. In fact, it has been reported that patients infected with leptospirosis demonstrate ocular manifestation of uveitis which can manifest in either septic or aseptic form. ....... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855780/

Acoustic Sonification of Arm Movements in Stroke Rehabilitation - A Novel Approach in Neurologic Music Therapy

Posted on February 26, 2020 at 8:15 AM Comments comments (0)

Abstract

Gross motor impairments are common after stroke, but efficient and motivating therapies for these impairments are scarce. We present an innovative musical sonification therapy, especially designed to retrain patients’ gross motor functions. Sonification should motivate patients and provide additional sensory input informing about relative limb position. Twenty-five stroke patients were included in a clinical pre–post study and took part in the sonification training. The patients’ upper extremity functions, their psychological states, and their arm movement smoothness were assessed pre and post training. Patients were randomly assigned to either of two groups. Both groups received an average of 10 days (M = 9.88; SD = 2.03; 30 min/day) of musical sonification therapy [music group (MG)] or a sham sonification movement training [control group (CG)], respectively. The only difference between the two protocols was that in the CG no sound was played back during training. In the beginning, patients explored the acoustic effects of their arm movements in space. At the end of the training, the patients played simple melodies by coordinated arm movements. The 15 patients in the MG showed significantly reduced joint pain (F = 19.96, p < 0.001) in the Fugl–Meyer assessment after training. They also reported a trend to have improved hand function in the stroke impact scale as compared to the CG. Movement smoothness at day 1, day 5, and the last day of the intervention was compared in MG patients and found to be significantly better after the therapy. Taken together, musical sonification may be a promising therapy for motor impairments after stroke, but further research is required since estimated effect sizes point to moderate treatment outcomes.

 

Keywords: sonification, stroke, neurorehabilitation, neuroplasticity, music-supported therapy

Introduction

Stroke is a major cause of mortality and morbidity in both the developed and developing world (1). In Germany, stroke is one of the most common disorders with an estimated 200,000 first events and 66,000 recurrent events in 2008 (2). The World Health Organization stresses the need to collect high quality longitudinal data on rehabilitation and to improve the comparability between studies (3).

 

The rehabilitation of stroke patients remains a challenge, although there are currently several new training programs under development that aim at improved efficiency and sustainability of stroke rehabilitation (4). Some of the traditional rehabilitation programs lack general acceptance by patients, due to the required endurance and high demands on the patients’ cooperation, which sometimes is perceived as a frustrating experience (5). Yet, even the well-established standard physiotherapies do not unambiguously provide evidence of efficacy when it comes to improvement of skilled motor behavior . Therefore, there is an urgent need for innovative, motivating, and goal-directed training protocols in stroke rehabilitation.

 

In this article, we present an innovative approach to rehabilitation by retraining the gross motor functions of the affected upper limbs using musical sonification. In an earlier clinical feasibility study (9), we showed how a musical sonification therapy could be applied. The data presented herein were obtained with this method from a larger number of patients. Sonification stands for the usage of non-speech sound representing otherwise not audible information. 


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928599/

The antibacterial effect of sonication and its potential medical application

Posted on February 26, 2020 at 8:10 AM Comments comments (0)

This study demonstrates that a clinically available ultrasonic probe has an antibacterial effect against a wide spectrum of gram-positive, gram-negative, aerobic and anaerobic bacterial species. This may partially explain the dramatic healing of long-standing recalcitrant diabetic ulcers debrided with this device and may have a place in treating pathologies with bacterial mechanisms. ...... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572995/

Blue water is the only known example of a natural color caused by vibrational transitions. In most other cases, color is caused by the interaction of photons of light with electrons

Posted on February 26, 2020 at 8:05 AM Comments comments (0)

Colors From Vibration


The inviting blue of a mountain lake or a sea is unique in nature, in that it is caused by vibrational transitions involving hydrogen bonding.

 

Why is water blue?

Water’s intrinsically blue color is easy to see when the water is sufficiently deep, such as in the Caribbean and Mediterranean Seas, and in Colorado mountain lakes. Pure water and ice have a pale blue color, which is most noticeable at tropical white-sand beaches or in ice caves in glaciers. (Green colors are usually derived from algae.) The blueness of the water is neither due to light scattering (which gives the sky its blue color) nor dissolved impurities (such as copper). Because the absorption that gives water its color is in the red end of the visible spectrum, one sees blue, the complementary color of orange, when observing light that has passed through several meters of water. Snow and ice has the same intense blue color, scattered back from deep holes in fresh snow.

 

Blue water is the only known example of a natural color caused by vibrational transitions. In most other cases, color is caused by the interaction of photons of light with electrons. Some of these mechanisms are resonant interactions, such as absorption, emission, and selective reflection. Others are non-resonant, including Rayleigh scattering, interference, diffraction, and refraction. Unlike with water, these mechanisms rely primarily on the interaction of photons with electrons. ...... http://www.webexhibits.org/causesofcolor/5B.html


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