Lung surfactant protein A provides a route of entry for respiratory syncytial virus into host cells

Lung surfactant protein A (SP-A) has a central role in host defense mediated by the interaction of surface carbohydrates of inhaled pathogens with the lectin domains of SP-A. Respiratory syncytial virus (RSV), the most important viral pathogen of neonates and infants, encodes a highly glycosylated attachment protein, G. Binding studies were performed with G-protein from RSV (human, A2 strain) and human SP-A. The effect of SP-A on the interaction between RSV and host cells was determined by two methods: an infectivity study with monolayers of Hep-2C cells and by interleukin-8 (IL-8) release from buffy coat (BC) cells. SP-A binds to RSV G-protein in a concentration-dependent manner that is inhibitable by both ethylenediamine tetraacetic acid (EDTA) and mannan, indicating that binding is through the carbohydrate recognition domain of the SP-A and a carbohydrate moiety of the G-protein. The level of RSV infection of Hep-2C cells increases with increasing concentrations of SP-A. The amount of IL-8 released by BC cells in the presence of RSV is increased with SP-A concentrations of 2.9 microg/mL or greater. Our results show that SP-A enhances the attachment of RSV and subsequent entry into host cells. The effect of SP-A on viral uptake by epithelial cells and macrophage may determine both innate and adaptive immune responses to RSV.     

Urinary tract infection in the neurogenic bladder

There is a high incidence of urinary tract infection (UTI) in patients with neurogenic lower urinary tract function. This results in significant morbidity and health care utilization. Multiple well-established risk factors unique to a neurogenic bladder (NB) exist while others require ongoing investigation. It is important for care providers to have a good understanding of the different structural, physiological, immunological and catheter-related risk factors so that they may be modified when possible. Diagnosis remains complicated. Appropriate specimen collection is of paramount importance and a UTI cannot be diagnosed based on urinalysis or clinical presentation alone. A culture result with a bacterial concentration of ≥10³ CFU/mL in combination with symptoms represents an acceptable definition for UTI diagnosis in NB patients. Cystoscopy, ultrasound and urodynamics should be utilized for the evaluation of recurrent infections in NB patients. An acute, symptomatic UTI should be treated with antibiotics for 5–14 days depending on the severity of the presentation. Antibiotic selection should be based on local and patient-based resistance patterns and the spectrum should be as narrow as possible if there are no concerns regarding urosepsis. Asymptomatic bacteriuria (AB) should not be treated because of rising resistance patterns and lack of clinical efficacy. The most important preventative measures include closed catheter drainage in patients with an indwelling catheter and the use of clean intermittent catheterization (CIC) over other methods of bladder management if possible. The use of hydrophilic or impregnated catheters is not recommended. Intravesical Botox, bacterial interference and sacral neuromodulation show significant promise for the prevention of UTIs in higher risk NB patients and future, multi-center, randomized controlled trials are required.     

High Prevalence of Borrelia miyamotoi among Adult Blacklegged Ticks from White-Tailed Deer

We compared the prevalence of Borrelia miyamotoi infection in questing and deer-associated adult Ixodes scapularis ticks in Wisconsin, USA. Prevalence among deer-associated ticks (4.5% overall, 7.1% in females) was significantly higher than among questing ticks (1.0% overall, 0.6% in females). Deer may be a sylvatic reservoir for this newly recognized zoonotic pathogen.     

Pharmacology and metabolism of renzapride : a novel therapeutic agent for the potential treatment of irritable bowel syndrome

BACKGROUND AND OBJECTIVE: Renzapride (ATL-1251), a novel benzamide, is currently under clinical development for the treatment of irritable bowel syndrome (IBS). Previous in vitro and in vivo experimental studies have characterized renzapride as a full serotonin 5-HT(4) receptor agonist on the gut and a 5-HT(3) receptor antagonist. Clinical studies have confirmed the therapeutic efficacy, tolerability and safety of renzapride in patients with constipation-predominant IBS. This study set out to characterize the pharmacological profile of renzapride and its potential metabolic products at both 5-HT and other monoamine receptors in the gut. METHODS: The affinity of renzapride, its (+) and (-) enantiomers, and its primary metabolite, renzapride N-oxide and its enantiomers, for serotonin receptors was assessed by means of in vitro radioligand binding inhibition studies. After membranes prepared from animal tissue or membranes of cell lines transfected with cloned human receptors had been incubated with radiolabelled ligand with high affinity for a specific receptor, renzapride was added to competitively inhibit this binding. Levels of bound radioligand were measured by filtration and counting of the bound radioactivity. In instances where >50% inhibition of radioligand binding had occurred, the inhibition constant (K(i)) was calculated. Metabolism of renzapride by liver microsomes was assessed by incubating 10 micromol/L renzapride with human liver microsome samples for 60 minutes at 37 degrees C. After the reaction was stopped, the samples were centrifuged and the supernatant analysed for metabolites by high-pressure liquid chromatography (HPLC). The potential inhibitory effects of renzapride on cytochrome P450 (CYP) enzymes were assessed by incubating renzapride at various concentrations over a 1-500 micromol/L concentration range with microsomes genetically engineered to express a single CYP. RESULTS: Renzapride was selective for serotonergic receptors and, in particular, had high affinity for human 5-HT(3) and guinea-pig 5-HT(4) receptors (K(i) 17 and 477 nm, respectively). Inhibitory properties at 5-HT(2B) receptors were also identified for renzapride, as well as some affinity for 5-HT(2A) and 5-HT(2C) receptors. Renzapride N-oxide and its enantiomers demonstrated much lower affinity for all 5-HT receptors compared with renzapride. Renzapride was metabolized by liver microsomes to a limited extent and there was no significant non-microsomal metabolism of renzapride. Renzapride did not inhibit the major CYP drug-metabolizing enzymes CYP2C9, CYP2D6, CYP1A2, CYP2A6, CYP2C19, CYP2E1 or CYP3A4 at concentrations consistent with use in a clinical setting. CONCLUSIONS: These results confirm and extend earlier studies in animal and human receptors that show renzapride is a potent and generally full 5-HT(4) receptor agonist and 5-HT(3) receptor antagonist. The results reported in the present study indicate that the metabolites of renzapride are minor and are unlikely to contribute to its therapeutic profile or lead to interaction of renzapride with other drugs that inhibit the major drug-metabolizing enzymes in the liver at therapeutic doses. These data contribute to the understanding of the pharmacological actions and metabolic fate of renzapride in vivo.     

Clinical trial: renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting

Background  Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required.
Aim  To identify an appropriate dosage of renzapride (a 5-HT₄ receptor full agonist/5-HT₃ receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome.
Methods  In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5–12. Secondary efficacy measures included patients' assessment of their bowel habits, stool consistency and quality of life.
Results  Although there were no statistically significant differences between renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses.
Conclusions  This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.     

Effects of Attribution of Responsibility for Motor Vehicle Accidents on Severity of PTSD Symptoms, Ways of Coping, and Recovery Over Six Months

In light of Delahanty et al.'s (1997) identification of attribution of responsibility for a motor vehicle accident (MVA) as a powerful determinant of initial level of distress from the trauma and of early remission of PTSD, we reexamined data from Blanchard and Hickling's (1997) prospective follow-up of 158 MVA survivors. Despite differences between the two samples (Delahanty sample recruited from hospitals 2–3 weeks post-MVA and predominantly male; our sample recruited from outpatient care 1–4 months post-MVA and predominantly female) we replicated Delahanty's findings: those with PTSD who blame themselves for the MVA are less symptomatic initially and recover more rapidly in the first 6 months than those with PTSD who blame another party for the accident.     

An exploration of Glo‐3A antibody levels in children at increased risk for type 1 diabetes mellitus

Aims: To determine whether Glo‐3A, (formerly referred to as homologue of Glb1 or Glb1) antibodies are associated with islet autoimmunity (IA) in children at increased risk for type 1 diabetes (T1D) and to investigate their relation with environmental correlates of T1D. Methods: We selected a sample from the Diabetes Autoimmunity Study in the Young (DAISY), a prospective study of children at increased risk for T1D. Cases were positive for insulin, glutamic acid decarboxylase (GAD), or insulinoma‐associated antigen‐2 (IA‐2) autoantibodies on two consecutive visits and either diagnosed with diabetes mellitus or still autoantibody positive when selected. Controls were from the same increased risk group, of similar age as the cases but negative for autoantibodies. Sera from 91 IA cases and 82 controls were analyzed in a blinded manner for immunoglobulin G (IgG) antibodies to Glo‐3A by ELISA. Results: Adjusting for family history of T1D and human leukocyte antigen (HLA)‐DR4 positivity, Glo‐3A antibodies were not associated with IA case status (OR: 1.01, 95% CI: 0.99–1.03). Adjusting for age, family history of T1D, and HLA‐DR4 positivity, Glo‐3A antibody levels were inversely associated with breast‐feeding duration (beta = ?0.08, p = 0.001) and directly associated with current intake of foods containing gluten (beta = 0.24, p = 0.007) in IA cases but not in controls. Zonulin, a biomarker of gut permeability, was directly associated with Glo‐3A antibody levels in cases (beta = 0.73, p = 0.003) but not in controls. Conclusion: Differing correlates of Glo‐3A antibodies in IA cases and controls suggest an underlying difference in mucosal immune response.