New product, old problem(s): multistate outbreak of Salmonella Paratyphi B variant L(+) tartrate(+) infections linked to raw sprouted nut butters, October 2015.

A cluster of Salmonella Paratyphi B variant L(+) tartrate(+) infections with indistinguishable pulsed-field gel electrophoresis patterns was detected in October 2015. Interviews initially identified nut butters, kale, kombucha, chia seeds and nutrition bars as common exposures. Epidemiologic, environmental and traceback investigations were conducted. Thirteen ill people infected with the outbreak strain were identified in 10 states with illness onset during 18 July-22 November 2015. Eight of 10 (80%) ill people reported eating Brand A raw sprouted nut butters. Brand A conducted a voluntary recall. Raw sprouted nut butters are a novel outbreak vehicle, though contaminated raw nuts, nut butters and sprouted seeds have all caused outbreaks previously. Firms producing raw sprouted products, including nut butters, should consider a kill step to reduce the risk of contamination. People at greater risk for foodborne illness may wish to consider avoiding raw products containing raw sprouted ingredients.

Notes from the Field: Clostridium perfringens Gastroenteritis Outbreak Associated with a Catered Lunch - North Carolina, November 2015.

During November 2015, the North Carolina Division of Public Health was notified by the Pitt County Health Department (PCHD) that approximately 40 persons who attended a catered company Thanksgiving lunch the previous day were ill with diarrhea and abdominal pain. The North Carolina Division of Public Health and PCHD worked together to investigate the source of illness and implement control measures. Within hours of notification, investigators developed and distributed an online survey to all lunch attendees regarding symptoms and foods consumed and initiated a cohort study. A case of illness was defined as abdominal pain or diarrhea in a lunch attendee with illness onset <24 hours after the event. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated for all menu items. Among 80 attendees, 58 (73%) completed the survey, including 44 respondents (76%) who reported illnesses meeting the case definition; among these, 41 (93%) reported diarrhea, and 40 (91%) reported abdominal pain. There were no hospitalizations. Symptom onset began a median of 13 hours after lunch (range = 1-22 hours). Risk for illness among persons who ate turkey or stuffing (38 of 44; 86%), which were plated and served together, was significantly higher than risk for illness among those who did not eat turkey or stuffing (six of 14; 43%) (RR = 2.02; 95% CI = 1.09-3.73).

Expression of leptin and iNOS in oral melanomas in dogs.

BACKGROUND: Oral melanoma (OM) in dogs is an aggressive malignancy, with clinical behavior resembling cutaneous melanomas in humans. Melanoma in humans is promoted by an inflammatory environment that is contributed to by leptin and inducible nitric oxide synthase (iNOS). OBJECTIVE: To determine if the patterns of leptin and iNOS expression are similar in OM in dogs and cutaneous melanomas in humans. ANIMALS: Twenty client-owned dogs. METHODS: Retrospective case study. Immunostaining of the OM tumors from each dog was scored for percentage and intensity of leptin and iNOS expression. Mitotic index was used as an indicator of tumor aggression. RESULTS: Leptin was detected in ≥75% of the tumor cells in specimens from 11 dogs. One tumor expressed leptin in ≤25% of the cells. The intensity of leptin expression was variable with 6, 9, and 5 cases exhibiting low-, moderate-, and high-intensity staining, respectively. OM with the lowest percentage of iNOS positive cells displayed the highest mitotic indices (P = .006, ANOVA). CONCLUSIONS AND CLINICAL IMPORTANCE: The expression of leptin is a common finding in melanomas in dogs. These data suggest that the possibility of future clinical applications, such as measuring the concentrations of plasma leptin as a screening tool or leptin as a target for therapy. The relevance of iNOS is not as clear in dogs with OM, for which other directed therapeutics might be more appropriate.

Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly.

The ciliopathies are an expanding group of disorders caused by mutations in genes implicated in the biogenesis and function of primary cilia. Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by progressive retinal degeneration, obesity, polydactyly, cognitive impairment, kidney anomalies and hypogonadism. Mutations in SDCCAG8(NPHP10) were described recently in patients with nephronophthisis and retinal degeneration (Senior-Loken syndrome; SLS). Given the phenotypic and genetic overlap between known ciliopathy genes, we hypothesized that mutations in SDCCAG8 might also contribute alleles to more severe, multisystemic ciliopathies. We performed genetic and phenotypic analyses of 2 independent BBS cohorts. Subsequent to mutation screening, we made a detailed phenotypic analysis of 5 families mutated for SDCCAG8 (3 homozygous and 2 compound heterozygous mutations) and conducted statistical analyses across both cohorts to examine possible phenotype-genotype correlations with mutations at this locus. All patients with mutations in SDCCAG8 fulfilled the diagnostic criteria for BBS (retinal degeneration, obesity, cognitive defects, renal failure, hypogonadism). Interestingly, none of the patients with primary SDCCAG8 mutations had polydactyly, a frequent but not obligatory BBS feature. In contrast, the same patients displayed early-onset renal failure, obesity, as well as recurrent pulmonary and ENT infections. Comparison of the phenotypes of these families with our entire BBS cohort indicated that renal impairment and absent polydactyly correlated significantly with causal SDCCAG8 mutations. Thus, SDCCAG8 mutations are sufficient to cause BBS in 1-2% of our combined cohorts, and define this gene as the sixteenth BBS locus (BBS16). The absence of polydactyly and the concomitant, apparently fully penetrant association with early kidney failure represents the first significant genotype-phenotype correlation in BBS that potentially represents an indicator for phenotype-driven priority screening and informs specific patient management.

Hippocampal dysgenesis and variable neuropsychiatric phenotypes in patients with Bardet-Biedl syndrome underline complex CNS impact of primary cilia.

The Bardet-Biedl syndrome (BBS) is a rare ciliopathy clinically defined by the association of retinitis pigmentosa, polydactyly, obesity, kidney disease and cognitive impairment. The cognitive functioning, behavioral phenotype, prevalence of psychiatric diseases and memory performances of a cohort of 34 patients with BBS were evaluated and a systemic brain magnetic resonance imaging (MRI) was performed. The patients' cognitive functioning was of marked variable efficiency ranging from normal to disabling performances. Neuropsychological disorders such as slow thought process, attention difficulties and obsessive-compulsive traits were observed. Our main finding was hippocampal dysgenesis, diagnosed by MRI, found in 42.31% of the patients in this cohort. Moreover, we show that BBS proteins are expressed in the human hippocampus and in the human brain in the normal subject. Recent literature in the murine model shows that hippocampal neurogenesis, in particular in the adult mouse, requires an intact primary cilia. These results encourage us to further investigate the possible role of BBS proteins in the hippocampus and related central nervous system structures.

The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.

Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features.

Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis.

Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.

Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Confirmation of TFAP2A gene involvement in branchio-oculo-facial syndrome (BOFS) and report of temporal bone anomalies.

Branchio-oculo-facial syndrome (BOFS) is an autosomal-dominant condition characterized by three main features, respectively: branchial defects, ocular anomalies, and craniofacial defects including cleft lip and/or palate (CL/P). We report on one family with three affected, and two sporadic cases that have been found to carry missense mutations in the newly reported BOFS gene: TFAP2A. This report confirms the involvement of this transcription factor in this developmental syndrome with clinical variability. Moreover, we present CT scan temporal bone anomalies in the familial cases, related to branchial arch defects, highlighting the importance of radiological investigations for differential diagnosis.

[Cholinergic hypothesis in psychosis following traumatic brain injury and cholinergic hypothesis in schizophrenia: a link?]. / Théorie cholinergique dans les psychoses après un traumatisme crânien et dans la schizophrénie: un lien?

INTRODUCTION: While traumatic brain injury is a major public health issue, schizophrenia-like psychosis following traumatic brain injury is relatively rare and poorly studied. Yet the risk of developing schizophrenia-like psychosis after traumatic brain injury is 3 times more important than in the general population. LITERATURE FINDINGS: Risk factors associated with onset of psychosis after traumatic brain injury include: left hemispheric lesions, closed head injury and coma of duration superior to 24 hours. Most patients develop symptoms of psychosis after a moderate to severe traumatic brain injury and often have lesions of the frontal and temporal lobes. CHOLINERGIC HYPOTHESIS: ARGUMENTS: Neuropathologic, electrophysiological and pharmacologic evidence show that cognitive impairment including attention, memory and executive functioning impairment may be related with cholinergic dysfunction in patients with traumatic brain injury. The cholinergic hypothesis is also incriminated in the genesis of schizophrenia. The same biochemical disorders found in schizophrenia which imply many neurotransmitters are often present immediately after traumatic brain injury. However in chronic cognitive disorders secondary to traumatic brain injury, the cholinergic system alone seems to be specifically implied. This is due to the fragility of the cholinergic fibres and a chronic yet reversible reduction of the cholinergic reserves after traumatic brain injury. Cholinergic function can be studied by the P50 evoked response to paired auditory stimuli.While this is disturbed in patients presenting with cognitive impairment after traumatic brain injury its normalisation can be obtained after administration of an acetylcholine esterase inhibitor. In schizophrenic patients there is also an abnormal P50 evoked response due in part to a low number of alpha 7 nicotinic receptors which are implicated in sensory filtering in the frontal lobe. Moreover in schizophrenia, post-mortem studies show a negative correlation between the activity of acetylcholine transferase in the parietal cortex and the severity of the cognitive deficits, as well as a lesser density of the muscarinic M1 and M4 receptors in the frontal lobe. The lower concentration of M1 receptors in the frontal cortex is correlated with the severity of the positive symptoms. THERAPEUTICAL PERSPECTIVES: Antipsychotics have emerged as the first line treatment of psychotic disorders. In research, their ability for enhancing cognitive function could result in the increase of acetylcholine in the medial prefrontal cortex. Acetylcholinesterase inhibitors have been widely used for treatment of cognitive impairment in Alzheimer's disease. Galantamine could be interesting in schizophrenia and psychosis following traumatic brain injury because it has a dual mechanism of action: selective competitive inhibition of acetylcholinesterase and allosteric potentialisation of nicotinic receptor response. Therefore Galantamine remains active in nicotine addicted schizophrenic patients who may smoke as an auto treatment. Galantamine has shown efficacy in adjunction to Risperidone in one patient presenting with psychosis following traumatic brain injury and in 3 case reports of schizophrenic patients. CONCLUSION: Further systematic studies are needed to confirm this hypothesis.