NOD2, CD14 and TLR4 mutations do not influence response to adalimumab in patients with Crohn’s disease: a preliminary report

Introduction: adalimumab is a recombinant fully-human monoclonal immunoglobulin (IgG1) antibody utilized in the treatment of Crohn´s disease. Unfortunately no clinical or genetic markers exist to predict response to anti-tumor necrosis factor-alpha (TNF) therapy. The aim of this study was to evaluate the association between selected genes involved in cytokine regulation and response to adalimumab treatment in Crohn’s disease. Methods: twenty-four patients with Crohn’s disease either naïve (n = 8) or had lost response or were unable to tolerate the chimeric anti-TNF antibody infliximab (n=16) were enrolled in the study. Patients were genotyped for main polymorphisms in NOD2, CD14 and TLR4 genes. Response to adalimumab treatment was defined as a decrease of Crohn’s disease activity index of at least 100 points or a closure of at least 50% of fistulas in case of fistulizing Crohn’s disease. Results: overall, 75% of patients did respond to treatment. However, no statistically significant association was found between any of the genotypes and the response to adalimumab. Conclusions: in our small study group no association between the studied polymorphisms and response to adalimumab was apparent. Systematic studies to search for genetic markers of response to anti-TNF therapy are necessary(AU)

The monoclonal antibody against the major diagnostic antigen of Paracoccidioides brasiliensis mediates immune protection in infected BALB/c mice challenged intratracheally with the fungus.

The protective role of specific antibodies against Paracoccidioides brasiliensis is controversial. In the present study, we analyzed the effects of monoclonal antibodies on the major diagnostic antigen (gp43) using in vitro and in vivo P. brasiliensis infection models. The passive administration of some monoclonal antibodies (MAbs) before and after intratracheal or intravenous infections led to a reduced fungal burden and decreased pulmonary inflammation. The protection mediated by MAb 3E, the most efficient MAb in the reduction of fungal burden, was associated with the enhanced phagocytosis of P. brasiliensis yeast cells by J774.16, MH-S, or primary macrophages. The ingestion of opsonized yeast cells led to an increase in NO production by macrophages. Passive immunization with MAb 3E induced enhanced levels of gamma interferon in the lungs of infected mice. The reactivity of MAb 3E against a panel of gp43-derived peptides suggested that the sequence NHVRIPIGWAV contains the binding epitope. The present work shows that some but not all MAbs against gp43 can reduce the fungal burden and identifies a new peptide candidate for vaccine development.

Abnormalities of prepulse inhibition do not depend on blink reflex excitability: a study in Parkinson's disease and Huntington's disease.

OBJECTIVE: Prepulse inhibition of the blink reflex is a robust phenomenon with an interesting physiology and a large potential for clinical applicability. In the study presented here we investigated whether the blink reflex inhibition by a prepulse (BRIP) is influenced by the blink reflex excitability recovery (BRER). METHODS: The study was undertaken in 20 patients with Parkinson's disease (PD), 20 patients with Huntington's disease (HD) and 20 healthy volunteers. BRER was determined by measuring the size of the response to a test supraorbital nerve stimulus as a percentage of the response to a conditioning stimulus at inter-stimuli intervals of 100-1000 ms. BRIP was determined as the percentage reduction induced in the response to a supraorbital nerve stimulus by either a low intensity auditory click or a weak third finger somatosensory stimulus, applied with a leading interval of 50-110 ms. RESULTS: There was a negative correlation between the percentage BRER and the percentage BRIP (Pearson's correlation coefficient of -0.37). BRER was enhanced in 14 PD patients (70%) and 6 HD patients (30%), while it was depressed in 10 HD patients (50%). BRIP was significantly reduced in 15 PD patients (75%) and 16 HD patients (80%). No significant correlation was found between abnormally enhanced BRER and abnormally reduced BRIP in all patients as a group (chi(2)=2.4;P=0.11). A weak correlation was found in PD patients (P=0.019) and no correlation was observed in HD patients (P=0.8). CONCLUSIONS: Our results indicate that an abnormally reduced BRIP was not always accompanied by an abnormally enhanced BRER in patients with HD. The two tests likely assess specific and distinct brainstem functions, and provide different types of information. While BRIP may be the result of a widespread integrative processing of sensory stimuli, BRER likely reflects the excitability of a chain of brainstem inter-neurons. SIGNIFICANCE: BRER and BRIP provide independent information on the state of functionally separate circuits that converge on trigemino-facial brainstem inter-neurons.

The acoustic startle response is normal in patients with multiple system atrophy.

We investigated the acoustic startle response in eight patients with MSA and compared the results with those from a group of age matched healthy subjects. Onset latency and amplitude of the responses obtained in the orbicularis oculi, masseter and sternocleidomastoid muscles were not different in patients and control subjects. We conclude that, in spite of the pathological derangement described in brainstem reticular nuclei in MSA, the neuronal circuits mediating the auditory startle reflex are functionally preserved.

Effect of omeprazole on Helicobacter pylori urease activity in vivo.

BACKGROUND: Detection of Helicobacter pylori infection in clinical routine is based either on the direct visualization of the bacterium in gastric biopsies by histology or microbiology or on the demonstration of urease activity in gastric biopsies and by the labelled-urea breath test (UBT). Omeprazole has a strong inhibitory effect on H. pylori urease activity in vitro, but its effect in vivo and thus its influence on urease-based diagnostic procedures has not been investigated systematically. AIM: To investigate whether omeprazole is able to inhibit H. pylori urease activity in vivo and, if so, at which doses. PATIENTS: Eighteen patients with H. pylori associated chronic gastritis were studied. METHODS: H pylori diagnosis was based on histology, rapid urease test and culture from antral biopsies. Following a positive H. pylori diagnosis patients received omeprazole 20mg (n = 6), 40mg (n = 6) and 80mg (n = 6) once daily for 5 days and 13C-UBT was performed on day 1, 3 and 5, 30min after each omeprazole administration. The 13C-UBT was performed with 200ml 0.1 N citric acid as test drink and 75mg 13C-urea. Breath samples were collected before and 30 min after 13C-urea administration. RESULTS: A significant inhibition of urease activity was observed only under high dose omeprazole administration (80 mg/day), and the 13C-UBT turned negative in three (50%) of these patients after 5 days therapy. CONCLUSION: Short-term omeprazole administration reduces H. pylori urease activity only at doses as high as 80 mg/day. A direct inhibition of enzyme activity as well as a reduction in the number of viable H. pylori bacteria may be responsible for this omeprazole-mediated reduction in urease activity. Urease-based diagnostic procedures for H. pylori are not suitable for patients under omeprazole therapy depending on the dose and duration of therapy.