Collaborative investigation of an outbreak of Salmonella enterica serotype Newport in England and Wales in 2001 associated with ready-to-eat salad vegetables

In June 2001, as part of a microbiological study of bagged, ready-to-eat salad products, Salmonella enterica serotype Newport was isolated from a sample of pre-packed green salad distributed by a major supermarket retailer. The strain was characterised by phage typing, plasmid profile typing and pulsed-field gel electrophoresis. Other isolates of S. Newport from cases of human infection in England and Wales in the first six months of 2001 were similarly characterised. Of 60 strains from cases of human infection, 19 were found to be indistinguishable from that isolated from the salad product. This study highlights the benefits of an integrated approach to outbreak investigations, involving the various elements of the PHLS and the Food Standards Agency, and acknowledges the full co-operation of the retailer in ensuring the rapid withdrawal of the contaminated product.     

Structure-activity relationship for enhancement of paracellular permeability across Caco-2 cell monolayers by 3-alkylamido-2-alkoxypropylphosphocholines

Paracellular permeability enhancers have been used to improve the oral bioavailability of hydrophilic drugs; however, the mechanism of action of many enhancers is poorly understood. In this study, highly potent enhancers of paracellular permeability were identified in the 3-alkylamido-2-alkoxypropylphosphocholine series, and a structure-activity relationship was developed for enhancement of paracellular permeability across Caco-2 cell monolayers. Compounds with short (<5 carbons) hydrocarbon chains at both C-2 and C-3 were generally inactive. The potency exhibited a parabolic relationship with respect to the chain length at either C-2 or C-3. Linear molecules (i.e., compounds with a short hydrocarbon chain at C-2 or C-3 and a long hydrocarbon chain on C-3 or C-2, respectively) were more potent than the corresponding branched molecules with the same carbon load. The efficacy of 3-alkylamido-2-alkoxypropylphosphocholines as enhancers of paracellular permeability was not dependent on their existence in micellar form or their ability to alter the fluidity of cell membrane. Previously, a correlation between the potency of alkylphosphocholines as enhancers of paracellular permeability and the inhibitors of phospholipase C (PLC) was established in Madine Darby canine kidney (MDCK) cell monolayers. The potencies of selected 3-alkylamido-2-alkoxypropylphosphocholines as inhibitors of PLC and enhancers of paracellular permeability fit well into this correlation. Therefore, phosphocholines are likely to increase paracellular permeability by modulating the signal transduction pathway initiated by a PLC-catalyzed reaction rather than by physically altering the cell membrane.     

Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors

The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.     

Brain stem encephalitis caused by primary herpes simplex 2 infection in a young woman

A 27 year old woman developed a vesicular genital rash and cerebellar dysfunction with progressive neurological deterioration suggesting brain stem encephalitis. Respiratory support was required. Magnetic resonance imaging (MRI) of the brain on day 7 showed signal hyperintensity in the central medulla and ventral pons, typical of acute inflammation. The course was severe and relapse occurred. MRI on day 33 showed a haemorrhagic area in the medulla. Treatment with aciclovir/valaciclovir eventually led to gradual recovery. Herpes simplex virus 2 (HSV-2) DNA was detected in CSF on days 11 and 14. HSV-2 was also detected in vesicle fluid from the genital rash. Serum was initially negative for HSV-1 and HSV-2 antibodies, but convalescent samples showed seroconversion to HSV-2, indicating primary infection. Intrathecal synthesis of oligoclonal IgG bands specific for HSV was identified in the CSF. It is important to differentiate HSV-2 from HSV-1, and primary from initial or reactivated infection, so that prolonged aciclovir treatment followed by prophylaxis is instituted to prevent the high likelihood of symptomatic relapse in primary HSV-2 infection.     

Inappropriate association of semantics and context to novel stimuli can give rise to the false recognition of unfamiliar people

This paper reports further experiments with a patient (MR) who has a tendency to claim that unfamous people are familiar together with good ability at identifying truly famous people. The first experiment examines the role that the typicality of stimuli plays in his false recognition. Although, typicality may have some influence over false recognition (as it does for normal controls) there is little evidence to suggest that MR is over-reliant on such information. It is unlikely that perceptual fluency can entirely explain his deficit. This is bolstered by a further study using morphed images of famous and unfamous faces, suggesting that false recognition is associated with inappropriate retrieval of semantic-biographical information. It is argued that MR's judgement of 'fame' is subjectively appropriate, given the information that he retrieves. This information is thought to derive from currently activated, or recently activated, contextual information which becomes inappropriately bound to the novel stimulus, giving rise to a false sense of familiarity. These findings underscore the importance of viewing memory as an attributional process, whereby current mental constructions/processes are attributed to some event(s) in the past.     

Anti-complement strategies in experimental sepsis

Using the cecal ligation/puncture (CLP) model of sepsis in rodents, evidence was obtained for excessive activation of the complement system, which leads to nearly total loss of innate immune protective functions of blood neutrophils. These defects are associated with profound defects in chemotaxis, respiratory burst (H2O2 production) and phagocytosis. The molecular mechanisms of these defects are linked to the complement activation product C5a. In CLP rats and mice, the C5a receptor (C5aR) is widely up-regulated in organs, in part owing to the production of interleukin-6 (IL-6). The up-regulation of C5aR in the thymus is linked to C5a-dependent induction of apoptosis in thymocytes, as revealed by caspase activation, increased binding of C5a and DNA laddering. Such events in thymocytes are prevented if rats first are treated with anti-C5a or with anti-C5aR at the time of CLP. Treatment of CLP rats and mice with anti-C5a, anti-IL-6 or anti-C5aR dramatically improves survival rates after CLP, indicating a linkage between C5a and C5aR in the harmful outcomes of sepsis in rodents. Studies are underway in humans with sepsis to determine whether similar mechanisms are in play.     

Evidence for metabolic and endocrine abnormalities in subjects recovered from anorexia nervosa

Subjects with anorexia nervosa (AN) at low weight display metabolic, endocrine, and behavioral abnormalities. Whether these various differences are a consequence of the condition and persist after recovery is unclear. We tested the hypothesis that abnormalities in the insulin and leptin axes and in the desire to eat persisted in subjects who had recovered from AN in terms of body mass index (BMI) and menstrual function. Endocrine, metabolic, and psychological parameters were assessed by sampling under fasting conditions and serially in response to a standard meal. Subjects included 18 females recovered from AN and 18 female controls and measures included plasma insulin, leptin, glucose and beta-hydroxybutyrate (beta-HBA) concentrations together with desire to eat. Fasting glucose concentrations were normal in both groups, but fasting insulin concentrations were significantly lower and the fasting glucose/insulin ratio significantly higher in the recovered subjects. The glucose concentration was significantly higher at the end of the meal period in the recovered group. The peak increase of insulin during the meal was significantly less in the recovered group and in response to the meal, glucose/insulin ratios were significantly higher for the first 45 minutes indicating a delayed insulin response. Fasting beta-HBA concentrations were not significantly different between groups, but postmeal decreases were significant and larger in the recovered AN group. Fasting and meal-related leptin concentrations were not significantly different between the groups and in both groups were correlated with BMI. In controls, but not in recovered subjects, the reported desire to eat was correlated with plasma glucose and leptin concentrations. The insulin, glucose and beta-HBA data indicated the presence of insulin hypersensitivity in the recovered subjects. As the insulin response to the meal was blunted and apparently delayed, there may be a persistent alteration in pancreatic function as a long-term pathological consequence of the anorexia. Alternatively, these data indicate a possible trait marker for AN.     

Amyloid tumor: a clinical and cytomorphologic study

We describe the cytologic findings and clinical presentation of three unusual cases of amyloid tumor. Two of our patients had low-grade lymphoid malignancies and the third insulin-dependent diabetes mellitus. In no cases was amyloid suspected as the cause of mass lesion. Two of our cases presented with superficial soft tissue mass and the third with right breast masses and bilateral axillary lymph node enlargement. Air-dried slides from all aspirated cases were stained with Diff-Quik for specimen adequacy evaluation. The remaining fixed slides were stained with Papanicolaou stain. Amyloid appeared as dark-blue to purple clumps of acellular material on Diff-Quik stain, accompanied with chronic inflammatory cell infiltrates and multinucleated giant cells, simulating granulomatous inflammation. Papanicolaou stain demonstrated cyanophilic to orangophilic acellular material. Amyloid was suspected and subsequently confirmed by Congo red stain.