Over 100 families with 38 different mutations in the tau gene have been identified worldwide. The phenotype of FTDP-17 varies not only between families carrying different mutations but also between and within families carrying the same mutations. The pathogenetic mechanisms underlying the disorder are thought to be related to the altered proportion of tau isoforms or to the ability of tau to bind microtubules and to promote microtubule assembly. Definitive diagnosis of FTDP-17 requires a combination of characteristic clinical and pathological features and molecular genetic analysis. Genetic counseling should be offered to affected and at-risk individuals; for most subtypes, penetrance is incomplete. Currently, treatment for FTDP-17 is only symptomatic and supportive. The prognosis and rate of the disease's progression vary considerably among individual patients and genetic kindreds, ranging from life expectancies of several months to several years, and, in exceptional cases, as long as two decades.Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder, which has three cardinal features: behavioral and personality changes, cognitive impairment, and motor symptoms. FTDP-17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996. The prevalence and incidence remain unknown but FTDP-17 is an extremely rare condition. It is caused by mutations in the  Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).wld locus on chromosome 17 had been identified within 13 families. This syndrome is a familial disorder with autosomal dominant inheritance. The three major clinical features include behavioral disturbances, cognitive impairment, and parkinsonism. There are no strict diagnostic criteria for FTDP-17. Nevertheless, FTDP-17 should be considered in the differential diagnosis in the presence of one or more of the following -D-glucose (FDG) usually shows reduced frontal-parietal-temporal uptake patterns similar to those seen in sporadic frontotemporal dementia (FTD). PET with [18F]-fluoro-L-dopa (6FD) and [11C]-raclopride tracers reveals uptake abnormalities distinct from those seen in PD, in which the putamen is affected more than the caudate nucleus .-22.17-22 nucleus .The routine serum, urine, cerebrospinal fluid and other body fluid studies are usually negative. Electroencephalography (EEG) findings are normal early in the disease process and progress to diffuse slowing as the disease advances, although slowing can sometimes be seen earlier in the course of the FTDP-17 illness . In sportau gene are essential steps towards distinguishing FTDP-17 from other neurodegenerative diseases associated with tau deposition. The pathologic analysis should include immunohistochemical studies using multiple anti-tau antibodies.Clinically, FTDP-17 may mimic several neurodegenerative diseases. The differential diagnosis of FTDP-17 includes disorders with initial signs such as behavioral and personality abnormalities, parkinsonism, lower motor neuron dysfunction or cognitive impairments. In the absence of a positive family history or molecular genetic data, FTDP-17 is most frequently confused with Pick's disease, sporadic progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Other familial frontotemporal dementias, parkinson-plus syndromes, dementia with Lewy bodies (DLB), Parkinson's disease (PD), multiple system atrophy (MSA) should be excluded. A neuropathologic examination coupled with molecular genetic analysis of the Affected individuals should be counseled regarding the estimated probability of passing the genetic bases for their illness on to their offspring. As FTDP-17 is an autosomal dominantly inherited condition, each offspring of an affected individual will carry a 50% risk of inheriting the abnormal gene. Some of these mutations can be detected through genetic testing. The individual who inherits a mutation will not necessarily develop the same clinical syndrome as the parent, because penetrance may be incomplete, neurologic manifestations vary greatly even within families, or the individual might die from unrelated causes. In the case of the pallido-ponto-nigral degeneration (PPND) subtype of FTDP-17, however, penetrance is complete and virtually all individuals who inherit the mutation will become symptomatic during middle age.At-risk individuals may sometimes choose to adopt rather than bear their own children. When faced with the option of genetic testing, some people prefer the greater certainty that a genetic diagnosis may afford when planning life decisions, while others find not knowing to be a lesser emotional burden as well as a lesser risk of being denied healthcare should their insurance carrier learn the test result. In either case the patient's choice should be respected.Inquiring into the family history can also identify relatives who may be at risk of having inherited the genetic basis for FTDP-17 and who thus may be presymptomatic.Clinical genetic testing of affected and presymptomatic individuals is commercially available for some mutations. However, there tends to be little interest among at-risk family members to undergo clinical genetic testing .Once a genetic basis for a subtype of FTDP-17 is discovered and testing for that gene becomes commercially available, it becomes possible, in principle, to identify that gene antenatally by sampling amniotic fluid or by preimplantation genetic diagnosis. Genetic counseling should accompany antenatal genetic diagnosis.Currently, a curative treatment for FTDP-17 does not exist, and most patients respond poorly, if at all, to levodopa. Palliative and symptomatic interventions are the mainstay of treatment. Physical therapy can be helpful to preserve some measure of mobility and independence in activities of daily living and to reduce the risk of falling. Stool softening agents are recommended for constipation. Speech therapy, swallowing assessment, and switching to a softer diet may be helpful for dysphagia. Anticholinergics may be helpful for sialorrhea or urinary frequency but carry the risk of aggravating mental confusion. Clozapine or quetiapine may be helpful for psychosis not explained by systemic infection or responsive to medication withdrawal. Antidepressant medications may be indicated for concurrent depression. Bed-bound patients will require frequent repositioning or air flow mattresses. Patients should be encouraged to discuss their treatment preferences with their families and their physicians and to indicate their choices by advance directives.The prognosis varies considerably. Most patients with FTDP-17 will experience several months to one or two years of moderate impairment followed by an unremitting downward course of physical and cognitive decline. The rate of progression varies greatly among individual patients and genetic kindreds, ranging from life expectancies of several months to several years, and, in exceptional cases, as long as two decades. In addition to the clinical features described above, in the late stages of illness these patients often develop secondary medical problems associated with immobility including falling injuries and respiratory and urinary tract infections.It is hoped that further research will identify the genetic modifiers and environmental factors that influence the variable penetrance and clinical expression of FTDP-17. The development of transgenic mice may provide an opportunity to test novel therapeutic agents in the near future.


Function prediction by transfer of annotation from the top database hit in a homology search has been shown to be prone to systematic error. Phylogenomic analysis reduces these errors by inferring protein function within the evolutionary context of the entire family. However, accuracy of function prediction for multi-domain proteins depends on all members having the same overall domain structure. By contrast, most common homolog detection methods are optimized for retrieving local homologs, and do not address this requirement.We present FlowerPower, a novel clustering algorithm designed for the identification of global homologs as a precursor to structural phylogenomic analysis. Similar to methods such as PSIBLAST, FlowerPower employs an iterative approach to clustering sequences. However, rather than using a single HMM or profile to expand the cluster, FlowerPower identifies subfamilies using the SCI-PHY algorithm and then selects and aligns new homologs using subfamily hidden Markov models. FlowerPower is shown to outperform BLAST, PSI-BLAST and the UCSC SAM-Target 2K methods at discrimination between proteins in the same domain architecture class and those having different overall domain structures.Structural phylogenomic analysis enables biologists to avoid the systematic errors associated with annotation transfer; clustering sequences based on sharing the same domain architecture is a critical first step in this process. FlowerPower is shown to consistently identify homologous sequences having the same domain architecture as the query..FlowerPower is available as a webserver at  Biological processes such as speciation, gene duplication, and domain shuffling produce families of related genes whose gene products can have vastly different molecular functions. Inference of protein function in these cases has been shown to be prone to systematic error -3. PhyloProtein domains are independently folding structural units that often confer specific functions. Roughly 65% of eukaryotic proteins and 40% of prokaryotic proteins are composed of multiple domains [GenBank:FN: False Negative, FP: False Positive, HMM: Hidden Markov model, SCOP: Structural Classification of Proteins, T2K: SAM Target2K, TN: True Negative, TP: True PositiveKS conceived the work. NK and DB developed the required software, created the dataset and evaluated the methods. KS, NK and DB wrote the paper and created the figures.


Cyanobacteria are common inhabitants of freshwater lakes and reservoirs throughout the world. Under favourable conditions, certain cyanobacteria can dominate the phytoplankton within a waterbody and form nuisance blooms. Case reports and anecdotal references dating from 1949 describe a range of illnesses associated with recreational exposure to cyanobacteria: hay fever-like symptoms, pruritic skin rashes and gastro-intestinal symptoms are most frequently reported. Some papers give convincing descriptions of allergic reactions while others describe more serious acute illnesses, with symptoms such as severe headache, pneumonia, fever, myalgia, vertigo and blistering in the mouth. A coroner in the United States found that a teenage boy died as a result of accidentally ingesting a neurotoxic cyanotoxin from a golf course pond. This death is the first recorded human fatality attributed to recreational exposure to cyanobacteria, although uncertainties surround the forensic identification of the suspected cyanotoxin in this case.We systematically reviewed the literature on recreational exposure to freshwater cyanobacteria. Epidemiological data are limited, with six studies conducted since 1990. Statistically significant increases in symptoms were reported in individuals exposed to cyanobacteria compared to unexposed counterparts in two Australian cohort studies, though minor morbidity appeared to be the main finding. The four other small studies  did not report any significant association. However, the potential for serious injury or death remains, as freshwater cyanobacteria under bloom conditions are capable of producing potent toxins that cause specific and severe dysfunction to hepatic or central nervous systems. The exposure route for these toxins is oral, from ingestion of recreational water, and possibly by inhalation.A range of freshwater microbial agents may cause acute conditions that present with features that resemble illnesses attributed to contact with cyanobacteria and, conversely, acute illness resulting from exposure to cyanobacteria or cyanotoxins in recreational waters could be misdiagnosed. Accurately assessing exposure to cyanobacteria in recreational waters is difficult and unreliable at present, as specific biomarkers are unavailable. However, diagnosis of cyanobacteria-related illness should be considered for individuals presenting with acute illness following freshwater contact if a description is given of a waterbody visibly affected by planktonic mass development. Cyanobacteria are a diverse group of prokaryotes that occupy a broad range of ecological niches by virtue of their age, having first appeared some 2.5 billion years ago, and specialisation. All cyanobacteria are photoautotrophic organisms, yet many can grow heterotrophically, using light for energy and organic compounds as a carbon source . The cyaNodularia spumigena [Cyanobacteria have come to the attention of public health workers because many freshwater and brackish species can produce a range of potent toxins. This observation was first reported over 120 years ago, when sheep, horses, dogs and pigs were seen to die within hours of drinking from a lake affected by a bloom of the brackish-water cyanobacterium pumigena . Since tpumigena -10. Somepumigena , and larpumigena -10,13-26pumigena . Cyanobapumigena  and Forcpumigena .β-N-methylamino-L-alanine (BMAA), a neurotoxic non-protein amino acid associated with an atypical motor neurone disease/Parkinsonism/Alzheimer's-like dementia complex, is produced by a wide variety of cyanobacteria [A recent report has shown that bacteria . BMAA isbacteria . The pubbacteria .Cyanobacterial poisoning of humans has occurred through known and suspected exposure to cyanotoxin-contaminated drinking water supplies  and reviAll references that could be found in the medical and scientific literature, including conference proceedings, which describe specific incidents involving human illness and exposure to freshwater cyanobacteria in recreational or in-field occupational settings are summarised in • Reports of cyanobacteria-associated illness from recreational exposures to marine or estuarine waters.• Publications written in languages other than English – with the exception of three papers which we were opportunistically able to have translated -42.• Newspaper reports – with three exceptions: two reports describe the first human fatality to be attributed to recreational contact with cyanobacteria ,44. At tAnecdotal and case reports presented in this review were identified by the following search strategy:1. PubMed and Web of Science electronic databases were searched with the MeSH and textword string "(cyanobacter* AND disease outbreaks) OR  OR (cyanobacter* AND recreation*) OR (cyanobacter* AND epidemiology)".2. Titles and abstracts  were perused to determine suitability for inclusion.3. Bibliographies of identified primary papers and related review articles were reviewed to search for references not identified by electronic sources.4. Publications and other sources identified and forwarded by experts working in this field were included.The most recent update of the aforementioned electronic searches, conducted in June 2005, gave 257 citations, of which 244 were English-language publications and 13 were non-English-language papers. Of these 13 reports, three (two reviews and one primary article) were identified from abstracts and/or article titles as worth perusing for the presence of information about health-related events associated with recreational exposure to cyanobacteria ,49,50. OCase reports and anecdotal references presented in The principal public health concerns regarding recreational exposures relate to the potential, presumably a now-realised potential if the aforementioned fatality is indeed attributable to cyanotoxin poisoning, for exposure to hazardous levels of cyanotoxins in untreated waters. Routes of exposure are through direct contact with skin and mucous membranes, via inhalation, and by ingestion, either accidental or deliberate.Some reports listed in The observation that repeated water contact in a particular lake preceded a skin eruption on a six year-old girl, while other bathers appeared unaffected, helped support a diagnosis of hypersensitivity in that case . One of Those reports that have indicated symptom onset time suggest that responses can be rapid, with some urticarial and hay fever-like symptoms commencing while subjects are still in the water ,68. WhilMicrocystis sp. and Anabaena circinalis. After some three hours he developed cramping abdominal pain and nausea, which progressed to painful diarrhoea followed by a fever of 38.9°C, severe headache, lassitude, myalgia and arthralgia. Such illnesses are worrying, considering the two boys that were sickened – one of whom subsequently died – after possible exposure to cyanobacteria in a golf course pond suffered acute and severe gastro-intestinal illnesses [Some serious though apparently self-limiting gastro-intestinal illnesses have been reported after contact with cyanobacteria in recreational waters, presumably through ingestion of affected water. Dillenberg & Dehnel  describellnesses .Microcystis spp" [Oscillatoria..." [Occupational exposures were included in this review, although some caution should be exercised when comparing occupational and recreational exposures. Waters that are obviously discoloured or visibly affected by cyanobacteria scums may be of interest to aquatic field workers who are keen and/or obliged to collect samples. The two incidents involving British soldiers and sea cadets conducting canoe capsizing activities, presumably under orders from their supervising officers, occurred in waters that were reportedly subject to a "heavy bloom of tis spp"  and a "soria..." . Waters oria..." .The other reports that are of particular interest are those grouped under "cold & flu-like symptoms". Several publications describe individuals presenting with a flu-like illness, with signs and symptoms including fever, headache, lassitude, arthralgia, myalgia, sore throat, cough, diarrhoea and vomiting. A proposed explanation for this constellation of symptoms is that of a coordinated, cytokine-mediated innate immune response. Fever and malaise are events that are directed by endogenous mediators; for further discussion see . This spSix epidemiological studies of recreational exposure to cyanobacteria were identified with the search strategy discussed previously: three analytical cross-sectional studies from the U.K. using similar survey instruments -88, a smThe three cross-sectional studies were conducted by Philipp and co-workers -88. QuesThe theoretical advantages of this study type are that it is reasonably cost-effective, and in this context – recreational exposure to cyanobacteria – it can be conducted opportunistically to take advantage of any sudden-onset cyanobacteria blooms. Disadvantages relate to the difficulty in establishing that exposure occurred before the outcome ,93. The Anabaena circinalis-dominant bloom along South Australia's Murray River in the summer of 1991–1992 [A case-control study of illness rates was conducted after an extensive 991–1992 . Patient991–1992 .The advantages of a case-control design for investigating recreational exposure to cyanobacteria are that studies can be conducted opportunistically in response to the development of cyanobacteria blooms, and they are very useful for investigating infrequent outcomes. The study of El Saadi et al  has anotRecall bias may not be so much of a problem for investigating acute illnesses following recreational exposure to cyanobacteria, where a fairly short time lag between exposure and symptom onset can be anticipated, especially if recreational exposure is determined by a yes/no response. The main problem with a case-control study in this context will be in actually identifying cases. A case-control design would not be suitable for investigating outcomes from exposure to a cyanobacteria bloom in a lake adjacent to a city, as most recreational users who do develop symptoms would presumably seek medical attention after they return home, i.e. from one of a large number of medical practitioners. El Saadi et al  alluded nd day follow-up, but the authors concluded there was a significant increase in symptoms at 7 days, after excluding subjects with symptoms or previous recent recreational water exposure. The cohort size from which these significant results were drawn was rather small, with 93 exposed subjects, and 43 unexposed controls. Pilotto et al [The studies by Pilotto et al  and Stewto et al  interpreto et al ,94,95.Stewart et al  also conbefore any outcomes occurred).The studies of Pilotto et al  and StewWhether a cohort study is conducted prospectively or retrospectively, the basic study design is identical – exposed and unexposed groups are compared with respect to disease outcome . GeneralFurther discussion of some common epidemiological study designs that may be useful for investigating the topic of recreational exposure to aquatic cyanobacteria, with particular emphasis on the relative advantages and disadvantages of experimental epidemiology  is presented by Stewart .Other explanations for disease need to be considered by both clinicians and epidemiologists in their respective endeavours. Epidemiological studies usually aim to identify and adjust for confounding variables such as smoking and age of study participants. The following sections will discuss some freshwater-related risk factors, mostly microbial, that may confound epidemiological studies and complicate clinical diagnoses of cyanobacteria-related illness linked to recreational exposures. The final section of this review will discuss the possibility of misdiagnosis from the opposite direction: a water-borne disease outbreak in Finland that was subject to epidemiological scrutiny, but cyanobacterial exotoxin contamination of reticulated supplies was apparently not considered at the time.Avian cercariae: avian cercariae are schistosome larvae for which humans are an accidental host. Pruritus and macules are the initial signs and symptoms; sometimes a diffuse erythema and urticaria can develop and last for several hours [• al hours -99. Feveal hours ,100. TheGram-negative bacteria: Aeromonas hydrophila and Chromobacterium violaceum are abundant in freshwater habitats. Both usually cause infection through a pre-existing skin wound, though the clinical presentations in each case do not match of any of the reports listed in A. hydrophila causes cellulitis and a purulent discharge; aspiration of water can cause pneumonia and septicaemia. C. violaceum infections present with various cutaneous signs that are secondary to systemic disease, including sepsis [Vibrio vulnificus has reportedly caused soft tissue infection after contact in brackish inland waters, though most cases are associated with estuarine contact [Pseudomonas aeruginosa is widely-distributed in natural and artificial aquatic environments. Cutaneous infection presents as an erythematous or urticarial rash some 18–24 hours after water contact and progresses to a follicular dermatitis. Fever and pruritus are uncommon. Most reports of pseudomonal dermatitis are related to spa pool or hot-tub exposures [P. aeruginosa in recreational waters is a common cause of otitis externa, presenting as a purulent discharge [P. aeruginosa infection from cyanobacteria-related dermatoses.• g sepsis . Vibrio  contact . Pseudomxposures ,103. P. ischarge . DiagnosNon-allergic urticaria: physical stimuli such as heat, cold and exercise can induce itching and hives in susceptible individuals [• ividuals ,104.Shigellosis: Shigella outbreaks are the most commonly reported cause of disease associated with untreated inland recreational water in the USA, with 16 events affecting almost 1,300 people between 1985 and 1994 [S. sonnei infections being mild and self-limiting, and S. dysenteriae type 1 associated with severe diarrhoea which may progress to a life-threatening illness [• and 1994 . The inc illness .Escherichia coli: E. coli are markers of faecal pollution in recreational waters. Disease outbreaks traced to enterohaemorrhagic E. coli 0157 have been reported from recreational water exposures [• xposures ,105.Norwalk-like viruses: Various transmission routes, including recreational water outbreaks have been documented [• cumented .Naegleria fowleri: N. fowleri is a free-living thermotolerant amoeba found in warm or thermally polluted waters. It is the causative organism of primary amoebic meningoencephalitis, a fulminating, typically fatal illness. The entry route is via the nasal mucosa; fit, immunocompetent children and young adults with a recent history of freshwater recreational activity are those most commonly affected. The causative organism and diagnosis are usually confirmed at autopsy. Several reviews are available, e.g. [• le, e.g. -113.Viruses: Pharyngo-conjunctival fever outbreaks associated with non-enteric adenoviruses in recreational waters have been reported [• reported .Legionella: Legionella infections have been associated with recreational water contact [•  contact .The examples given above highlight some of the differential diagnoses that need to be worked through when considering possible cases of cyanobacteria-related illness from recreational exposures. Competent history-taking and diagnostic microbiology support will correctly diagnose many such cases. Competent history-taking and clinical diagnostic support also operated in several of the case reports listed in Aspergillus fumigatus and unspecified blue-green algae. Investigations centred on identifying antibodies to mesophilic actinomycetes, which the authors [Misdiagnosis of cyanobacteria-related disease may occur in both directions. In 1978, nearly half the population of an industrial town in Finland were affected by a flu-like illness, with symptoms of fever, fatigue, cough, dyspnoea and myalgia. Symptoms occurred some 3–6 hours after taking a bath, shower or sauna and persisted for 8–16 hours. The outbreak lasted for some four months. This epidemic was investigated on several fronts, and provocation testing demonstrated an obvious link to the reticulated water supply. Tap water was cultured in a range of organic media for fungal and bacterial pathogens. No definitive pathogen was identified to explain the epidemic, yet in three published reports the authors describe how the shallow lake that was the town water source had taken on a distinct opaque blue-green appearance, had a musty smell, and the sand filtration system was covered by a mat of cyanobacteria. This change occurred in the same month  that the epidemic began. Analysis of crude lake water in the third month after the onset of the epidemic showed high coliform counts,  authors  note wer authors -118. The authors  came clo authors . A simil authors , though A similar outbreak occurred more recently in Homa Bay, Kenya, in 1998. Apparently associated with a mass development of cyanobacteria in Lake Victoria, an epidemic of fever, malaise, dizziness and upper respiratory symptoms was related to hot water bathing. Symptoms lasted 12–24 hours, and returned when a shower or bath was taken again. This outbreak was reported in a conference abstract; the authors suggested cyanobacterial endotoxins were responsible, though it is not stated whether any investigation of cyanobacterial exotoxins was conducted .The true incidence of acute cyanobacteria-associated illness from recreational exposure is unknown, as many outcomes are likely to be mild and self-limiting, so medical attention is not sought. With a long-standing knowledge gap amongst primary healthcare providers, non-specific signs and symptoms caused by cyanobacterial products are likely to be under-diagnosed . Codd 1 stated:"Evidence linking human illnesses with cyanobacterial cells and toxins is open to criticism because of shortfalls in early detailed case definitions, because diagnoses were made by exclusion, and because identification and quantification of cyanobacterial toxins in health incidents have, until recently, been lacking."The collation of anecdotal and case reports of illness associated with recreational exposure to cyanobacteria in A recent initiative of UNESCO's International Hydrology Programme has been to establish CyanoNet, which is a "Global network for the hazard management of cyanobacterial blooms and toxins in water resources". The CyanoNet website will carry information on various associated topics, including "Reported incidents of adverse health effects including case studies" and "Surveys and epidemiological studies investigating associations between cyanobacterial populations, cyanotoxins and health" .The most important advances in understanding the health impacts of cyanobacteria have come from the discipline of toxicology. The major toxins have been extensively studied and characterised, and while there is still much to be discovered in the field of cyanobacterial toxicology, significant advances in the future will be made at the interface of toxicology and epidemiology. Molecular epidemiology techniques using yet-to-be discovered biomarkers of exposure, susceptibility and outcome will refine knowledge of the risks associated with various acute and chronic exposures to cyanotoxins. The collaborative skills that epidemiologists and toxicologists can bring to this endeavour were viewed with a mildly jaundiced eye by Paddle , whose c"The total evidence about the risk to humans...will consist of the toxicologist's precise, experimental data about the wrong species at the wrong exposure, and the epidemiologist's imprecise, observational data about the right species at the right exposure."In conclusion, anecdotal and case reports of variable reliability have suggested a range of symptoms are associated with exposure to cyanobacteria in recreational or occupational settings. Some reports of cutaneous reactions are strongly suggestive of allergic reactions, and symptoms such as rhinitis, conjunctivitis, asthma and urticaria also hint at immediate hypersensitivity responses. Flu-like illnesses involving a constellation of symptoms including fever, malaise, myalgia, arthralgia, severe headache, cough and sore throat are, in our opinion, explained by a cascade action of pro-inflammatory cytokines. If correct, this implies that some cyanobacterial products possess ligands that induce innate immune responses, and such responses may need to be considered in terms of their potential to direct pathological changes in the liver and other organ systems.The epidemiology of recreational exposure to cyanobacteria is incomplete at present. All common epidemiological approaches have their own inherent advantages and disadvantages; identification of biomarkers for exposure, susceptibility and outcome in the future should lead to a significantly improved perception of the risks of bathing in cyanobacteria-affected waters.β-N-methylamino-L-alanineBMAA G-I gastro-intestinalGP General Practitioner (aka Family Physician)IFN interferonIgE immunoglobulin-EIL interleukini.p. intra-peritoneal50 lethal dose for 50% of test animalsLDLPS lipopolysaccharide(s)TNF-α tumour necrosis factor-alphaUNESCO United Nations Educational, Scientific and Cultural OrganizationThe author(s) declare that they have no competing interests.IS conducted the review; PMW, PJS and GRS supervised the work and contributed to redrafting the paper. All authors read and endorsed the final manuscript.Anecdotal and case reports of human morbidity and mortality attributed to recreational or occupational field exposure to freshwater cyanobacteria.Click here for file


Infections as well as environmental exposures are proposed determinants of childhood acute lymphoblastic leukemia (ALL), particularly common precursor B-cell ALL (cALL). Lines of investigation test hypotheses that cALL is a rarer result of common infection, that it results from uncommon infection, or that it ensues from abnormal immune development; perhaps it requires a preceding prenatal or early childhood insult. Ideally, studies should document that particular infections precede leukemia and induce malignant transformation. However, limited detection studies have not directly linked specific human or nonhuman infectious agents with ALL or cALL. Primarily based on surrogate markers of infectious exposure, indirect evidence from ecologic and epidemiologic studies varies widely, but some suggest that infancy or early childhood infectious exposures might protect against childhood ALL or cALL. Several others suggest that maternal infection during pregnancy might increase risk or that certain breast-feeding practices decrease risk. To date, evidence cannot confirm or refute whether at least one infection induces or is a major co-factor for developing ALL or cALL, or perhaps actually protects against disease. Differences in methodology and populations studied may explain some inconsistencies. Other challenges to proof include the likely time lag between infection and diagnosis, the ubiquity of many infections, the influence of age at infection, and the limitations in laboratory assays; small numbers of cases, inaccurate background leukemia rates, and difficulty tracking mobile populations further affect cluster investigations. Nevertheless, existing evidence partially supports plausibility and warrants further investigation into potential infectious determinants of ALL and cALL, particularly in the context of multifactorial or complex systems. Researchers and physicians have long proposed that infection(s) might cause diverse childhood leukemias. Several lines of scientific evidence support the plausibility of these hypotheses but definitive proof remains elusive. In this overview we highlight the general rationale behind proposals that one or more infections determine or are important co-factors in the development of childhood acute lymphoblastic leukemia (ALL). We briefly outline existing direct and indirect evidence for and against these hypotheses and the challenges to proving infectious causality, even in leukemia clusters. Against a background of assertions that non-microbial environmental exposures and other factors cause ALL, this synopsis draws attention to the very plausible possibility that infection(s), perhaps in the context of multifactorial or complex systems, do contribute to childhood ALL. We underscore the importance of continuing to investigate whether potentially preventable or treatable infections influence the development of childhood ALL, particularly common precursor B-cell ALL (cALL) but also emphasizes the ongoing need for optimal study design and detection tools in this effort.Leukemias and lymphomas represent malignant, clonal expansions of white blood cell populations. Simplistically, white blood cells act as the body’s primary defense against infections, where normal, regulated expansions of lymphocytes, monocytes, and neutrophils neutralize and eliminate pathogens. Therefore, aberrant responses to infection(s) could lead to leukemia through the abnormal proliferation of immune cells or a failure to curb the malignant expansion of an abnormal immune cell. Direct infection of lymphocytes might induce unchecked proliferation of a normal or a susceptible (preleukemic) lymphocyte to produce ALL; either persistent infection or malignant transformation triggered by past infection (one cleared from the body some time before ALL is diagnosed) is a conceivable route from direct lymphocyte infection to ALL. Alternatively, infection might indirectly induce ALL by stimulating an overly robust or poorly regulated immune response that would otherwise be protective. Last, other plausible hypotheses suggest that certain patterns of microbial exposure might actually protect against an abnormal lymphocyte proliferation that develops into ALL.Most childhood leukemias are diagnosed under the age of 8 years, with reports of peak incidences ranging from 2–3 years to 2–5 years ; cALL acIn this vein, cALL could represent a relatively rare response to one or more common childhood infections. Only some of many infected children would be at risk for the abnormal immunologic response, acute lymphoblastic leukemia. Age at infection , preceding or concurrent environmental exposures, and even the child’s cumulative number and types of infections might play critical roles in determining which children ultimately develop cALL. For example, infections early in life might increase or decrease leukemia risk, respectively, by either triggering malignant proliferation or ensuring normal immune development so that later infectious exposures do not produce aberrant lymphoproliferative or immune-mediated syndromes , 2000.Alternatively, uncommon or rare agents might induce cALL in many of the small numbers of infected children—existing studies simply may not have detected these microbes or not yet associated them with disease. Current scientific evidence cannot confirm or refute either scenario. For both, it remains unclear whether infection would need to occur after birth, before birth, or if infection during either time period could elicit acute leukemia.in vitro studies demonstrate that some viruses can incorporate into the human genome, persist in an episomal state, or alter crucial intracellular functions. In vitro, Epstein-Barr virus (EBV) transforms B-lymphocytes, creating immortalized cell lines. Intuitively, then, EBV might be capable of inducing B-lymphocyte malignancies such as cALL. However, although a number of studies have associated EBV infection or infectious mononucleosis with solid lymphoproliferative tumors, none have yet linked the virus with leukemia. Irrefutable evidence does confirm that the nonhuman retroviruses avian leukosis virus (ALV), bovine leukemia virus (BLV), feline leukemia virus (FeLV), and murine leukemia virus (MuLV) induce lymphoproliferative disease in birds, cattle, cats, and mice, respectively; all are usually associated with T-cell leukemias. Nevertheless, investigators have never detected FeLV, ALV, BLV, or natural MuLV infection in humans  in the malignant cells of adult T-cell leukemia/lymphoma (ATLL) but, preceding the development of ATLL, detect the virus in lymphocytes as well as serum antibodies to HTLV-1 . Epidemiphocytes . Yet, ATphocytes , and theLaboratory and epidemiologic evidence also link EBV infection to subsets of Hodgkin disease/Hodgkin lymphoma (HD), a solid tumor malignancy of lymphocytes . GeneralBurkitt lymphoma, however, was the prelude to all confirmed and proposed infectious etiologies of cancers, including childhood leukemias. Epidemiologic data and detection of the virus in tumors consistently implicated EBV as the viral etiology of Burkitt lymphoma in specific regions of sub-Saharan Africa. Although some researchers have recently challenged whether EBV actually induces tumori-genesis, the long-standing association is clear .in utero infections during pregnancy influence a child’s risk for developing cALL. In 1988, Greaves proposed that reduced exposure to infectious agents during infancy and early childhood might lead to childhood leukemia; essentially, delayed infectious exposure  would increase a child’s risk of developing cALL  might produce damaged or preleukemic cells  blood spots ; one alsLMO2 locus, a point insertion rate higher than would be expected with random viral integration. Extensive investigation of these cases, however, detected no replication-competent retrovirus in any cells tested. The investigators concluded that the insertion likely deregulated normal hematopoiesis. It is important that although immune deficiency itself has not been noted as a risk factor for ALL or cALL, medical experiences not infrequently find that immunodeficient or immunocompromised states, including SCID, may predispose individuals to develop lymphoproliferative solid tumors ; factors protecting from infection ; population density or changes in population density; and differences in SES.Primarily using surrogate markers for the likelihood of childhood infection  but occasionally analyzing documented clinical syndromes , a number of population-based and smaller epidemiologic studies have now associated delayed or reduced childhood infections with increased risk of childhood leukemia, ALL or cALL . Yet theMultiple, but not all, ecologic studies have correlated indicators of population mixing and increased population density with increased rates of childhood leukemia . Of noteHaemophilus influenzae type b, particularly during infancy, might reduce the risk of developing childhood ALL (Other indirect evidence variably suggests that infection(s) might influence the development of childhood ALL. For example, a few investigators have separately examined the effects of vaccination in the U.S. and Finland. The results suggested that immunization against hood ALL , 2000. Ehood ALL .Overall, widely varying and inconclusive indirect evidence still suggests that infectious exposures do alter a child’s risk for developing ALL. In particular, a level of exposures during infancy and early childhood might protect against childhood ALL. Yet contrasting evidence also suggests that certain types of infections, or infection at certain ages or stages of development, might increase the risk of developing childhood ALL, particularly cALL.Studies seeking to prove that one or more infectious agents contribute to the development of childhood ALL or cALL face numerous challenges. Ideally, results should document that a particular infection (or infectious syndrome) precedes the development of leukemia and directly causes (as a primary or secondary factor) the malignant transformation . HoweverChildhood leukemia clusters pose additional investigational challenges. If the available background cancer rates are inaccurate, it is impossible to reliably identify an excess of leukemia cases or increased leukemia rates. Clusters are usually small, limiting the power of statistical analyses. Investigations are usually retrospective because the cluster is identified only after someone suspects that an excess number of cases have accumulated over a defined period of time. At that point, most cluster cases have already undergone treatment and many are in remission. Ideally they have no remaining leukemic cells, the cells most likely to harbor a persistent etiologic infectious agent. Indirect markers of past or present infection obtained during the cluster investigation can rarely confirm that infection preceded the diagnosis of leukemia, and retrospective histories inherently have recall bias. Long characteristic of the United States but perhaps increasingly so in other global regions, a highly mobile population with few means to track health care and exposure histories, along with a paucity of large, population-based longitudinal data sets and specimen collections, make testing the population mixing hypothesis difficult, particularly in cluster investigations.Collectively, the existing scientific data continue to suggest that infection plays a critical role in the development of childhood ALL and cALL, perhaps in conjunction with other risk factors. However, no specific microbes—viruses, retroviruses, or bacteria—are definitively associated with disease. Nevertheless, enough direct and indirect evidence correlates ALL or cALL with surrogates of infection or even protection from infection to warrant continued investigations.The key to future investigations may be in complex systems of multifactorial disease , where i


Contrast enhancement within primary stimulus representations is a common feature of sensory systems that regulates the discrimination of similar stimuli. Whereas most sensory stimulus features can be mapped onto one or two dimensions of quality or location , the analogous similarities among odor stimuli are distributed high-dimensionally, necessarily yielding a chemotopically fragmented map upon the surface of the olfactory bulb. While olfactory contrast enhancement has been attributed to decremental lateral inhibitory processes among olfactory bulb projection neurons modeled after those in the retina, the two-dimensional topology of this mechanism is intrinsically incapable of mediating effective contrast enhancement on such fragmented maps. Consequently, current theories are unable to explain the existence of olfactory contrast enhancement.We describe a novel neural circuit mechanism, non-topographical contrast enhancement (NTCE), which enables contrast enhancement among high-dimensional odor representations exhibiting unpredictable patterns of similarity. The NTCE algorithm relies solely on local intraglomerular computations and broad feedback inhibition, and is consistent with known properties of the olfactory bulb input layer. Unlike mechanisms based upon lateral projections, NTCE does not require a built-in foreknowledge of the similarities in molecular receptive ranges expressed by different olfactory bulb glomeruli, and is independent of the physical location of glomeruli within the olfactory bulb.Non-topographical contrast enhancement demonstrates how intrinsically high-dimensional sensory data can be represented and processed within a physically two-dimensional neural cortex while retaining the capacity to represent stimulus similarity. In a biophysically constrained computational model of the olfactory bulb, NTCE successfully mediates contrast enhancement among odorant representations in the natural, high-dimensional similarity space defined by the olfactory receptor complement and underlies the concentration-independence of odor quality representations. Each OSN expresses only one or a few species of olfactory receptor, which define the molecular receptive range , or chemet al. .Due to the convergence of OSNs expressing the same olfactory receptor proteins, the pattern of activated glomeruli on the surface of the olfactory bulb reflects the pattern of activated olfactory receptors, identifying the constellation of chemical qualities that together constitute the presented odor. Many studies have attempted to elucidate the organization of this chemosensory map on the surface of the olfactory bulb. However, while great efforts have been made to infer meaningful patterns in these data, essentially all such studies have revealed fragmented, patchy maps without a clear, predictive ordering of the characteristics of chemical stimuli. This result stands in sharp contrast to analogous sensory maps in, for example, somatosensory, visual, and auditory cortices, in which neurons with overlapping receptive fields are located in predictable locations adjacent to one another . FragmenContrast enhancement is a common property of sensory systems that serves to narrow, or sharpen, sensory representations by specifically inhibiting neurons on the periphery of the representation – e.g., the edges of a retinal image – in order to enhance its figure-background contrast. In many sensory systems, contrast enhancement is mediated by lateral inhibitory projections. Crucially, the effectiveness of lateral inhibition in this context depends upon the topographical mapping of stimulus similarities within the relevant brain region, such that the physical proximity of neurons reliably reflects the similarity of the information that they mediate. In the retina, for example, the spatial contrast of visual images is enhanced by lateral inhibitory projections within the two dimensions of the retinal field . OverlapWhile odor quality representations within the olfactory bulb are clearly sharpened by contrast enhancement , the fraWe here propose and demonstrate a novel neural mechanism, non-topographical contrast enhancement (NTCE), which permits the regulation of olfactory tuning curves in an arbitrarily high-dimensional sensory space, using established olfactory bulb circuitry, without reliance on specific connections among glomeruli. This lack of dependence on the anatomical proximity of glomeruli enables the bulb to remain optimized with respect to the statistics of changing odor environments, and additionally renders the system robust to the generation of novel glomeruli over the course of development, evolution, or experimental manipulation -18. The All auditory stimuli can be mapped as spectra along a single axis of frequency. Retinotopic images of visual stimuli can be unambiguously represented as two-dimensional patterns of ganglion cell activation. However, substantially higher-dimensional spaces are required to map the analogous sensory space in which odor stimuli are distributed ,19-21. Hthumb and neck are represented in adjacent cortical regions, as are toes and genitalia, along with many more subtle examples, while representations of the arms and hands are interposed between those of the face and the rest of the head. The existence of such discontinuities in the neural representation is inevitable, as illustrated in Figure As the olfactory sensory neuron complement converges onto the glomerular layer of the olfactory bulb, these high-dimensional representations of odorant similarity are projected onto the two physical dimensions of the olfactory bulb input layer, a process facilitated by the glomerular architecture of that layer. Mathematically, whenever high-dimensional representational patterns are projected onto lower-dimensional spaces, they form discrete maps, that is, patchy maps with embedded discontinuities Figure . Neural in vivo imaging studies), longer chain lengths have been associated with centroids of activation positioned more rostrally and laterally [ad hoc modules or clusters within the olfactory bulb that exhibit greater densities of glomeruli sensitive to particular odorant moieties than would be expected by chance [Substantial efforts have been made by several laboratories to elucidate an underlying order to the distribution of glomeruli across the surface of the olfactory bulb. While the multiple glomeruli activated by a given odorant stimulus are typically scattered, imaging studies of odorant-specific glomerular activation patterns have observed a broad tendency for the centroids of these activated groups to migrate to progressively more ventral regions as the odorant molecules become larger – e.g., straight-chain aldehydes of increasing aliphatic chain lengths – and more hydrophobic -35. Thisaterally ,37-39, ty chance -44. Howey chance . In eachsee below) such that mitral cells connected to moderately activated glomeruli – i.e., the "edges" of the high-dimensional odor representation – are specifically inhibited out of the active ensemble. When all glomeruli are combined, their collective output activity reflects the input pattern of glomerular activation filtered through a Mexican hat function with a maximum dimensionality equal to the number of glomeruli and a topology of similarity inherited from the odor environment. In other words, NTCE generates a pattern of inhibition equivalent to that which would be generated by a competitive lateral inhibitory network in which the strength of inhibition between any two glomeruli was proportional to the similarity in their molecular receptive ranges. This mechanism is illustrated below in an abstract model and in a uniglomerular compartmental model.Contrast enhancement can be functionally defined as a process of competition between neurons proportional to the similarity of the information that they mediate; this definition is, of course, agnostic to mechanism. The olfactory bulb input layer provides precisely the architecture necessary to implement a form of non-topographical contrast enhancement that is not limited by its anatomically two-dimensional architecture. The NTCE algorithm described here depends upon two interacting computational mechanisms derived from established bulbar circuitry. The first mechanism operates independently within each glomerulus at the synaptic triad between OSN axons, periglomerular cell spines, and mitral cell apical dendrites -48. DireThe second mechanism of NTCE is a global negative feedback loop utilizing the lateral excitatory network of external tufted and short-axon cells , the generator of the familiar Mexican hat function  and a signature function of contrast enhancement. As shown in a simple illustrative model (see Methods), this half-hat function can be generated independently within each glomerulus by driving parallel sigmoidal excitatory and inhibitory processes with the same sensory input, given that the inhibitory process both is more sensitive to that input than the parallel excitatory process and saturates at a lower activity level. Both of these conditions are favored by the much smaller volume and higher input resistance of periglomerular cell spines compared with mitral cell dendrites. Under these conditions, each glomerulus inhibits its own mitral cell-mediated output in scaled proportion to its sensory input, such that its net mitral output level exhibits a half-hat function along the axis of ligand-receptor affinity . Hence, mitral cells innervating glomeruli that are the most strongly tuned to a given odorant feature will be activated, while mitral cells innervating moderately well-tuned glomeruli will be inhibited. Because of this natural attunement to relative degrees of glomerular activation irrespective of their location or interconnectivity, NTCE naturally inherits the intrinsic topology of the external chemosensory environment . This is a critical property for a system likely to encounter environments in which the distribution of relevant odorants is unpredictable.Irrespective of modality or dimensionality, successful contrast enhancement implies that the single or few most strongly activated units will yield robust output in response to a given stimulus, while output activity in more modestly activated units will be specifically inhibited and minimally-activated units will remain inactive. That is, output activity as a function of input activity yields a half-hat function , demonstrating a successful, classical contrast enhancement generator element within a single glomerulus. In contrast, mitral cells exhibited monotonically increasing activation in response to presentation of higher-affinity odorants when PG-mediated inhibition was absent  preceding mitral cell spike initiation even in the most rapidly-responding mitral cells [In our analysis, the established biophysical characteristics of glomerular neurons and synapses materially contribute to the effectiveness of NTCE. The synaptic triad between OSNs, periglomerular cell spines, and mitral cells -48 is opal cells ,63,64. Wal cells ,65; see al cells ). Furtheal cells , while nal cells ,68.relative odor ligand-receptor affinities and efficacies and hence preserve the representation of odor quality across a reasonable concentration range. We constructed a multiglomerular version of this model in order to directly illustrate non-topographical contrast enhancement among multiple glomeruli differentially activated by the same odorant, and to assess the ability of the olfactory bulb ET/SA network to normalize bulbar responses to different odor concentrations via global feedback inhibition (see Methods). In the present model, ET/SA network activity was simulated by projecting slow synaptic inhibition from each of the other glomeruli onto mitral cell primary dendrites , effectively translating the NTCE half-hat function of each glomerulus on its abscissa in proportion to average bulbar input intensity such that only a small and consistent population of the most strongly activated mitral cells overcame this activity-dependent inhibition. Ten glomeruli were interconnected via the ET/SA network such that all mitral cells received identically-weighted inhibitory inputs from each of the other nine glomeruli. The ten glomeruli were assigned different affinities for each test odorant such that each odorant representation constituted a unique ten-dimensional vector. Addition of intraglomerular inhibition mediated by periglomerular cells and global normalizing inhibition mediated by the ET/SA network strongly disambiguated the mitral cell response profiles evoked by two similar odorants . As NTCE is independent of specific lateral projections, the model did not have to be adjusted to perform contrast enhancement along the particular axes of variation used to model the homologous series of odorants. NTCE was able to replicate the contrast enhancement function within model mitral cells based on periglomerular inhibition alone . Increasing odorant concentrations increased glomerular activation levels and recruited additional glomeruli, as in the vertebrate OB, while PNs tended to become more inhibited as odorant concentrations increased, particularly within reasonable concentration ranges . Furtherin vivo recordings coupled with calcium imaging data have suggested that action potential amplitudes and evoked calcium transients in mitral cell lateral dendrites do not decline in amplitude with increasing distance from the soma, but instead are propagated nondecrementally, suggesting an axon-like mechanism [Even within the vertebrate olfactory bulb, the hypothesis of proximity-based representations of odor similarity, while popular, is contraindicated in the literature. Mitral cells innervating neighboring glomeruli exhibit unrelated odorant response profiles , in contechanism . Both ofechanism , these iechanism ,62,95. Techanism -99, and echanism ,100-103.echanism ,104.B-ergic and D2 dopaminergic presynaptic inhibition onto the axon terminals of convergent OSNs [In the interests of simplicity, some known glomerular circuit elements were omitted from the present model. First, periglomerular cells deliver GABAent OSNs -109. Thient OSNs -113 woulent OSNs . This puent OSNs ,83. The ent OSNs .The compartmentalized architecture of olfactory glomeruli may reflect a specific adaptation for the representation and processing of high-dimensional computational spaces within the physical constraints of two-dimensional cortical layers. If true, this would explain the observation that a functionally similar glomerular architecture has evolved independently several times in diverse phyla , and indet al. [A receptors. NTCE innately distributes inhibition among mitral cells according to the similarities in their molecular receptive ranges, an intractable problem for mechanisms based on lateral inhibitory projections embedded in discontinuous feature maps. Unlike mechanisms based on decremental lateral inhibitory projections, NTCE is independent of the physical proximity of similarly-tuned glomeruli, an important advantage given the broadly distributed representations of odor stimuli observed in the olfactory bulb. It offers a mechanism for the normalization of odorant representations with respect to concentration, reflecting the observation that mitral cell spike counts do not monotonically increase in proportion to primary sensory neuron spike counts as odorant concentrations are increased. Rather, it predicts complex effects on mitral cell activity patterns, including fast initial inhibition in response to odors and a variety of responses to odor concentration series owing in part to the unpredictable pattern of associations of multiple odor ligands with different odorant receptors. Finally, NTCE depends only on known properties of the olfactory bulb input layer, including its cellular morphologies and connectivity, passive membrane properties, active electrophysiological and pharmacological responses, and specialized glomerular architecture, to enable robust contrast enhancement in an objective, externally-defined, and high-dimensional similarity space.The NTCE algorithm presented here is the basis of a novel theory of bulbar function, integrating diverse data sets gathered by several laboratories. Fundamentally, it is a winner-take-most algorithm utilizing local feed-forward inhibition and global feedback inhibition to generate the competitive interactions among glomeruli typically associated with lateral inhibitory projections. Most importantly, it solves the problem of how to represent and process intrinsically high-dimensional sensory data within a physically two-dimensional neural cortex, while offering an explanation of the patchy, discontinuous odor quality maps observed in the olfactory bulb. As a model of contrast enhancement, it replicates the results of Yokoi et al.  illustrarelative odor ligand-receptor affinities and efficacies and hence preserve the representation of odor quality across a reasonable concentration range.NTCE depends upon two interacting computational mechanisms, each of which is consistent with available anatomical and physiological data. The first of these mechanisms, based on the rapid shunt inhibition of activated mitral cells by coactivated periglomerular spines, narrows the population of activated mitral cells with respect to the population of activated glomeruli such that only the most strongly activated subset of activated glomeruli generates action potentials in its associated mitral cells. Crucially, this contrast enhancement mechanism is independent of interglomerular projections, depending only upon relative degrees of glomerular activation and hence naturally inheriting the topology of odor similarity that is generated by the olfactory receptor complement. The second mechanism, essentially a global negative feedback loop, mitigates the effects of absolute odor concentration, thus enabling mitral cell activity patterns to reflect in) and periglomerular cells (PG) within a given glomerulus independently receive identical levels of direct sensory input , although they respond to this input differently based on their passive membrane properties (see Results and Discussion). As neuronal activation levels in this illustration (ordinate) depend upon ligand-receptor binding between the odorant and the olfactory receptor species projecting to the glomerulus in question, the direct activations of both Mi and PG cells vary sigmoidally as a function of odor ligand-receptor affinity:The model depicted in Figure K is a scaling constant determining relative excitability (due to input resistance), Y1/2 is the odor ligand-receptor affinity at which half-maximal output activity would be evoked in the mitral or PG cell via direct sensory input, A denotes the odor ligand-receptor affinity variable (abscissa), and m is the cooperativity  – i.e., the generation of spiking activity – depends on both direct mitral cell activation by sensory input (Miin) and on the secondary inhibitory influence of periglomerular cell activity (PG), resulting in a net activation function for mitral cell output that depends on the difference between these two sigmoids:where ivalent; ) of eache denotes the parameters of mitral cell direct excitation (Miin) and subscript i denotes the inhibitory effect of periglomerular cell activity (PG). In the example shown in Figure Ke = 1, Ki = 0.6, Y(e) 1/2= 10-5 M, Y(i) 1/2= 10-4 M, and both m terms are unity.in which subscript inset). Traditional Mexican hat functions in one dimension are typically modeled as a difference of Gaussians, or as the difference between two differences of sigmoids. Differences between sigmoids of equal maxima  and cooperativities  yield bell-like curves; the difference between two bell-like curves (whether gaussians or differences of sigmoids) generates a Mexican hat function given that the excitatory difference is of greater maximum magnitude and the inhibitory difference is of greater breadth. The corresponding function in NTCE is one half of a Mexican hat, modeled as a difference between sigmoids in which Ke > Ki and Y1/2(e) < Y1/2(i) and referred to as a half-hat function . Mexican hat functions of arbitrary dimensionality can be generated by rotating this half-hat function around the coordinate of its maximum activation level in a given context. When Ke > Ki and Y1/2(e) < Y1/2(i) – both conditions which are favored by the smaller volume and higher input resistance of periglomerular cell spines compared with mitral cell dendrites [out (equation 2) exhibits contrast enhancement along the axis of odor ligand-receptor affinity A (see Results and Discussion).Contrast enhancement is typically described with an on-center/inhibitory surround, or Mexican hat, function ; Figure endrites  – the ouin vivo  or the spike density functions of large neuronal populations , and approached steady-state exponentially.The compartmental model depicted in Figures Na, IK) with heterogeneous expression levels and optimized for its spike initiation properties. Model morphology and kinetic parameters were as in reference [Na at relatively low levels. The axon hillock in turn was connected to an initial segment and an axon with five node/internode pairs; the initial segment and nodes contained high levels of INa, facilitating spike initiation. For the present simulations, glutamatergic excitatory and GABAA-ergic inhibitory synaptic inputs were inserted at the distal ends of apical dendrites.The mitral cell model was modified from that of Chen and colleagues ,53, whicThe periglomerular soma was connected to two narrow dendrites  from which protruded spine shafts and bodies (1 um diam). All periglomerular synaptic inputs and outputs were localized on spine bodies. While the axon contained only Hodgkin-Huxley currents, the dendrites and spines additionally contained a complement of currents capable of replicating low-threshold calcium bursts as observed in periglomerular cell recordings ; see alsThe OSN arbor was a passive, single-compartment model, serving as a source for graded glutamatergic excitation of mitral and periglomerular neurons; this graded excitation represented the spike density function of a large and highly convergent population of similarly tuned spiking neurons.A-ergic synapses . All synaptic time constants were set to 1 ms to reflect multiple, imprecisely timed inputs. The uniglomerular network was stimulated with four different levels of olfactory sensory neuronal input ; for each level of sensory input, the evoked activity was measured in (a) mitral cell somata in the absence of a PG-to-Mi inhibitory synapse, (b) mitral cells in the presence of a PG-to-Mi inhibitory synapse, and (c) periglomerular cells (Figure The uniglomerular compartmental model included only mitral and periglomerular cells and OSN axonal arbors, and is directly comparable to the illustrative model described above and in Figure Glomerular activation levels contribute to odor representations in that they reflect the pattern of relative affinities that the olfactory receptor complement has for odor ligands. However, ligands of lower affinity presented at higher concentrations can evoke levels of glomerular activation indiscriminable from those evoked by high-affinity ligands at lower concentrations . This enet al. [et al. [A receptors with bicuculline could transform an mitral cell inhibitory odor response into a neutral or excitatory response. Using the ten-glomerulus model, we applied an odorant stimulus with moderate affinity for our glomerulus of interest, evoking an inhibitory response. We then blocked periglomerular synapses onto mitral cells and applied this stimulus again in order to replicate Figure et al. [In order to replicate Figure et al. , the can [et al.  also ille et al. .ThAC conceived and designed the study, coded and analyzed models in Matlab and NEURON, and drafted the manuscript. PS coded and analyzed models in NEURON.


Three randomized controlled trials (RCTs) of male circumcision (MC) have been halted when interim analyses showed significant reductions in HIV infection among men who received this intervention –3. ModelCircumcised men in the ANRS 1265 trial reported 18% more sexual contacts at follow-up than did uncircumcised men, but no other sexual behavior differences were obtained , but notThere is no evidence that circumcision increases or decreases the risk of HIV transmission by HIV-infected men. However, risk compensation by HIV-infected circumcised men will substantially increase the risk of transmission to their sex partners. This suggests that, in the short term at least, circumcision would reduce the incidence of HIV among men, but increase the incidence among women, translating to increased prevalence among women, which in turn translates to greater risk to men. Epidemiological models of MC should take this dynamic into account.Countless studies have shown that ulcerative and non-ulcerative STIs account for at least some of the rapid increases in HIV transmission in southern Africa . Non-HIV


Cell therapy has emerged as an important component of life-saving procedures in treating burns. Over past decades, advances in stem cells and regenerative medicine have offered exciting opportunities of developing cell-based alternatives and demonstrated the potential and feasibility of various stem cells for burn wound healing. However, there are still scientific and technical issues that should be resolved to facilitate the full potential of the cellular devices. More evidence from large, randomly controlled trials is also needed to understand the clinical impact of cell therapy in burns. This article aims to provide an up-to-date review of the research development and clinical applications of cell therapies in burn wound healing and skin regeneration. Burns remain one of the most traumatic injuries causing significant health, social and economic consequences . GloballSevere burn wound is characterised by the destruction of skin structures, functions and more importantly the loss of the progenitor cell populations that are essential for regenerating and restoring the structures and functions . Until nTo overcome the autograft shortage, a variety of alternatives for autologous skin grafts including allogeneic skin, xenografts and synthetic skin substitutes have been widely adopted in burn wound care , 4. WhilCell therapy which also called cellular therapy or cytotherapy involves delivering an autologous or allogenic cellular component into a patient to repair or regenerate the damaged tissue due to injuries or diseases, to rectify the diseased conditions associated with the damages or deficiency of the unique cell population and to restore the physiological functions.Skin as the multi-functional and protective barrier in human contains essential stem cell population and various cellular types that are critical for renewing and maintaining its structural integrity and functions. Research on skin cell transplantation for wound healing was first reported by Billingham and Reynolds in 1952 . For theWound healing and restoration of skin structures and functions depend on many factors including the availability of essential progenitor cells, dermal extracellular matrix (ECM), and bio-factors and cytokines for angiogenesis and regulation of cell-matrix and cell-cell interactions. The following cell types have demonstrated potentials as therapeutic devices in skin wound healing and tissue regeneration. Many autologous and allogeneic cell products were developed using cells of skin and non-skin origins for therapeutic application in burn wound management.The epidermis is mainly comprised of keratinocytes which are renewed and sustained by keratinocyte stem cell (KSC) populations anchored at the membrane in the epidermal-dermal junction, the hair follicle bulge and the sebaceous gland , 10.  KSBased on molecular biomarkers, regenerative capability and the status of cellular differentiation, keratinocytes in human skin could be classified as KSCs, transient-amplifying keratinocytes and differentiated keratinocytes . The KSCThe keratinocytes can be easily isolated and expanded in numbers under in vitro cell culture conditions. Keratinocytes produce various bio-factors and cytokines including interleukin (IL)-1, IL-6, IL-7, IL-8, IL-10, IL-12, IL-15, IL-18, and IL-20 and tumour necrosis factor alpha (TNF-α) , which aA population of circulating keratinocyte progenitor cells (KPCs) was identified with p63 in peripheral blood, which differentiated into keratinocytes with expression of the cytokeratins, involucrin and filaggrin .Dermal fibroblast cells play an important role in normal skin and skin wound healing post-burn. They produce the key ECM proteins in the dermis including laminins, fibronectins, collagens, elastic fibres, non-collagen molecules and bio-factors to regulate cell function, migration and the cell-matrix and cell-cell interactions in normal skin homeostasis and wound healing –21. DermSkin-derived precursor (SKP) cells have also been isolated from dermal papillae and can be differentiated into adipocytes, smooth myocytes and neurons in vitro , 26. FibMesenchymal stem cells (MSCs), a unique population of multipotent cells with self-renewal and regenerative capacity can be derived from autologous or allogenic tissues including bone marrow, adipose tissue, nerve tissue and umbilical cord and cord blood, and dermis. MSCs express surface CD markers including CD44+, CD73+, CD90+ and CD105+ and are distinguished from haematopoietic cells by a lack of CD34, CD14, CD45, CD11b/CD79 and CD19/HLA-DR –32.MSCs produce and release bio-factors –37 such Studies demonstrated that both autologous and allogenic MSCs, administered both systemically or and locally, exhibit therapeutic potentials promoting cutaneous wound healing and tissue regeneration via the paracrine bio-factors and cytokines and the multi-potency in tissue regeneration , 38–40. Human embryonic stem cells (hESCs), derived from human embryos are well known for their pluripotent capacities in tissue regeneration. Research demonstrated that hESCs could be induced to efficiently differentiate into functional basal keratinocytes that regenerate a pluristratified epidermis –51. ImmoAlthough hESCs could be developed to provide temporary skin substitutes for burn patients awaiting autologous grafts, the potential applications are however complicated due to the ethical issues in relation to using human embryos.The Nobel Prize winning discovery of induced pluripotent stem cells (iPSCs) by Yamananka and his team brought an alternative source of stem cells with pluripotent potentials for therapeutic applications , 28. WhiThe key technique that Rheinwald and Green established in the 1970s for serial culture of keratinocytes opened the era of research and therapeutic uses of cultured autologous keratinocytes in burn wound healing. Under laboratory conditions, KSCs could be isolated from a small skin biopsy and cultivated in the presence of growth-arrested 3T3 mouse fibroblasts as feeder cells to form epidermal sheets that could be transplanted back to the same patient for treatment. The innovative technology quickly gained global attention and emerged as a popular way to generate alternative autografts to facilitate permanent wound closure when treating severe burns. Since 1981, both cultured living keratinocytes and epithelial autograft sheets (CEAs), either produced in house or by commercial companies, have been used as clinical devices in treating large burns –67.Cultured keratinocytes were used for treating burns in various ways. Commonly, the cells from a skin biopsy are cultivated, screened and passaged in a cell culture system to expand the numbers of KPCs. In the presence of feeder fibroblast cells, the keratinocytes could proliferate and differentiate to form an epidermis-like tissue in cell culture. The process of CEA cultivation usually requires about 3 weeks depending on many factors including patient age, health condition and severity of burn injuries. The colony-forming efficiency of keratinocytes from freshly trypsinised skin was reported very low, between 0.15% and 3.8% in the primary cell culture –70 but wCultured human sole-derived keratinocyte grafts re-express site-specific differentiation after transplantation . The forVery often, CEAs were used in combination with widely meshed skin grafts for wound closure. CEAs could be transplanted directly to the wound area , 73 withIn addition, the procedure can be initiated with a small skin biopsy causing minimum donor site morbidity. This would be particularly important for patients with extensive burns as a life-saving device. CEAs deliver living autologous epidermal stem cells for permanent wound closure without eliciting immunological rejection. CEAs could also function as biological wound dressings delivering the much needed biological factors and niche environment for wound healing.In 1952, Billingham and Reynolds examined the potentials of transplanting sheets of pure epidermal epithelium and non-cultured epidermal cell suspensions for wound healing in guinea pigs , 89.Autologous keratinocytes isolated from any available donor site area including sole and scalp  could beTo ensure the effectiveness of living keratinocytes for burn wound healing, the cells were delivered in many ways. Co-spray of cultured keratinocytes and autologous fibrin sealant helped retaining the cells in wound and appeared an effective means of keratinocyte delivery for wound healing , 97. GraSub-confluent autologous keratinocytes were also grown on polymer materials and successfully transferred to achieve would closure –105. TheA quick procedure using non-cultured autologous epidermal cells for wound healing was also reported , 109. ItThe use of non-cultured epidermal suspension is a fast procedure that involves minimal tissue manipulation and can be completed within a couple of hours in surgical settings. The non-cultured epidermal cells can be used alone or in combination with meshed grafts for wound healing. It was reported to promote wound epithelialisation and reduce the required surgical intervention and total length of stay in treating burns and donor site wounds , 111. HoDue to the existence of melanocytes in epidermal harvests, the non-cultured epidermal cell suspension helped in correcting the skin hypopigmentation post burns or repigmenting vitiligo –115.Severe burns usually involve detrimental damages to the dermal matrix niche that is essential for structural support, cell attachment, migration, proliferation and differentiation. While CEAs, cultured keratinocytes or epidermal cell suspensions facilitate wound healing and epithelialisation, they showed limitations in treating deep burn wounds that lack dermal foundation. Artificial dermal regenerative templates such as Integra and MatriDerm  are commMSCs including BM-MSCs and ADSCs have demonstrated great potentials in acute and chronic wound healing and skin repair –125. TheThe subcutaneous adipose tissue from debrided skin in burn surgery can be a rich source of ADSCs for many applications such as being grafted as cutaneous wound therapy or for tissue engineering . AutologBM-MSCs were reported to enhance wound healing quality and facilitate skin regeneration after full-thickness injury, with the grafted cells transdifferentiating into cell types including vascular endothelial cells, sebaceous duct cells and epidermal cells .Allogenic human umbilical cord mesenchymal stem cells (hUCMSCs) and BM-MSCs are being trialled clinically for treating acute or second-degree burns , 131 butPatient-specific and gene-corrected iPSCs, expressing collagen 7, were developed with the inherent capacity to treat recessive dystrophic epidermolysis bullosa, a severe and often lethal condition caused by mutations in the COL7A1 gene-encoding type VII collagen . Very reThe evidence from laboratory, animal and clinical studies demonstrate that cell-based therapy is becoming an important alternative or conjunctive treatment for burn wound management. It is important to point out that cell therapy devices and associated procedures are now highly regulated by global authorities to ensure their bio-safety and efficacy. While animal sourced reagents could cause concerns, unresolved issues also exist in the potential applications using MSCs and iPSCs. It is also important to understand that MSCs from different sources could have different immunomodulation capabilities and varied capacities to proliferate and differentiate to various cells. If allogeneic MSCs are used, their immunogenicity could have impact on their in vivo durability. More studies are needed to define those issues as they could potentially affect the therapeutic outcomes . Also, MUntil now, cultured keratinocytes and non-cultured epidermal isolates are the most used devices for treating burns. Cultured epidermis and skin substitutes are only structurally similar but will never be identical to natural skin as evidenced by the differences in their gene expression profiles . They arMore research and development should be carried out to address the following technical problems and factors that could affect the outcomes of cell therapy. For example, the time needed for generating autologous CEAs or scaffold-guided living skin substitutes is often too long for managing acute burns. Technical improvement is needed to ensure the timely supply of cultured cellular products for burn wound healing when early debridement was carried out in treating burns. The use of cultured cell suspension as well as non-cultured cells significantly reduced the preparation time for cellular products but came across other issues following their delivery. The cloning efficiency is more of a concern with non-cultured epidermal cells as the freshly isolated cells showed very low efficiency in cloning or replicating themselves , 68, 70.Cell therapy has emerged as an important component of life-saving and wound healing procedures in treating burns. Although progresses have been made to demonstrate the potential and feasibility of various stem cells for burn wound healing, there are still scientific and technical issues that should be resolved to facilitate the full potential of the cellular devices. More evidence is needed from research and large, randomly controlled trials to define the clinical efficacy and safety of cell therapy in burns.