Familial Mediterranean fever gene and protection against asthma.

BACKGROUND: Asthma is an inflammatory airway disease caused by interaction between susceptibility genes and diverse environmental factors. In Israel, asthma seems to be familial and more severe in patients of Iraqi Jewish descent. On the other hand, asthma is less frequent in individuals with familial Mediterranean fever, an autoinflammatory disease prevalent in the Iraqi Jewish community and linked to mutations in the familial Mediterranean fever gene, designated MEFV. OBJECTIVES: To explore a possible role for mutated MEFV in the reduced susceptibility to asthma and to determine its expression in Israeli subjects of Iraqi origins. METHODS: Using a case-control approach, we studied the presence of the 3 most common MEFV mutations (M694V, V726A, and E148Q) in DNA samples from 75 patients with asthma and 45 asymptomatic first-degree relatives, all of Iraqi Jewish origin. The severity of asthma was evaluated using a published severity score. RESULTS: Eleven patients with asthma and 14 of their relatives carried 1 or 2 mutations in the MEFV gene, a carrier rate significantly lower in patients with asthma than in their first-degree relatives and in ethnically matched healthy individuals (P < .03 and P < .003, respectively). Carriers of MEFV mutations had less severe disease, compared with noncarriers (P < .002). CONCLUSION: These findings suggest that MEFV mutations may have a protective effect in the pathogenesis of asthma.     

Effects of age and size in the ears of gekkonomorph lizards: middle-ear morphology with evolutionary implications

The function of the ear depends in part on its absolute size and internal proportions. Thus, in both young individuals and small species, the middle ear is expected to be allometrically enlarged despite its smaller absolute size. Here we aim to compare the ontogenetic allometry of relevant middle-ear structures as observed within gecko (gekkonomorph lizards) species, with the evolutionary allometry observed interspecifically. These observations also provide middle-ear data for future evaluation of variation in auditory sensitivity. The material comprised 84 museum specimens of geckos, representing nine species of three gekkonomorph subfamilies. The results of dissections and measurements show that different reports notwithstanding, the middle-ear ossicular chain is indeed structured as described for geckos by Werner and Wever. Some sexual dimorphism is indicated, but this requires further study. During postnatal ontogeny, the allometric growth in the ratio of the columellar footplate area to body length differed between the intraspecific and interspecific levels, hence species differences in the middle ear do not merely result from animal size. The ratio of the tympanic membrane area to the columellar footplate area increased during ontogeny. In this, geckos resemble birds and probably also mammals. Similarly, when the comparison was among adults representing different species, the ratio of the tympanic membrane area to the columellar footplate area increased with body size. In this, however, the geckos differed from birds and mammals, in which this ratio varied taxonomically, irrespective of body size. It would thus seem that middle-ear proportions have evolved among geckos to produce small interspecific differences, but among amniote tetrapods they have evolved according to different principles in the classes reptiles, birds, and mammals.     

Familial Mediterranean fever (FMF)-response to TNF-blockers used for treatment of FMF patients with concurrent inflammatory diseases

ObjectiveFamilial Mediterranean fever (FMF) is the most common interleukin 1 (IL-1)-driven monogenic autoinflammatory disease. Yet published data also suggest that tumor necrosis factor (TNF) may have a role in the pathogenesis of FMF and may serve as a target for treatment. In the present study we evaluate this hypothesis.MethodsTo this goal, we studied the incidental effect on FMF of TNF-directed treatment, administered to colchicine-refractory FMF patients for the management of a concurrent inflammatory disease. The rates of FMF patients and of treatments with complete or nearly complete FMF response were determined, based on the number of FMF attacks during TNF-blocker exposures. The possible effect of various FMF and non-FMF features on the outcome was determined using comparative analysis. Patients were identified and data were retrieved using electronic files from the FMF clinic.ResultsTwenty-six patients were identified, each receiving ≥ 1 of four TNF-blockers for a mean duration of 27.6 ± 16.4 months. The TNF-blockers were found to induce complete or nearly complete FMF response in 10 (38.5%) of the patients, and in 13 of 50 (26%) exposures. No clinical, genetic, demographic, or therapeutic feature could predict which FMF patient would respond favorably to TNF-blocker therapy.ConclusionThis study suggests that TNF-blockers may be beneficial for a small proportion of colchicine-resistant FMF patients.     

Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.     

The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever

OBJECTIVE: The clinical profile in familial Mediterranean fever (FMF), including its major manifestation, amyloidosis, is influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. In this study, we analyzed the contribution of genotypes at the MEFV and SAA1 loci to disease severity and to the development of amyloidosis, and further defined the factors affecting the clinical profile of FMF. METHODS: We investigated a sample of 277 FMF patients (154 men and 123 women), including 62 patients with nephropathic amyloidosis, in whom both FMF alleles had been identified. A detailed chart review, interview, and physical examination were undertaken to determine the patients' demographic characteristics, medical history, clinical manifestations, and treatment. The disease severity score was calculated from the Tel-Hashomer key. Genotypes at the SAA1 locus (isoforms alpha, beta, and gamma) were determined in all patients. The SAA1 13C/T polymorphism of the SAA1 promotor was analyzed in a subset of cases. RESULTS: The male:female ratio (154:123, or 1.3) was higher among patients with amyloidosis (40:22, or 1.8) compared with patients without amyloidosis (114:101, or 1.1). Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio [OR] 4.27, 95% confidence interval [95% CI] 2.01-9.07), the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09), the occurrence of arthritis attacks (OR 2.43, 95% CI 1.17-5.06), and male sex (OR 1.73, 95% CI 0.90-3.33) were significantly and independently associated with renal amyloidosis. Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus. The SAA1 13T allele was rare, being associated mainly with the SAA gamma isoform, and not related to renal amyloidosis. CONCLUSION: Overall, disease severity and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene.     

Dissecting the Roles of Supervised and Unsupervised Learning in Perceptual Discrimination Judgments

Our ability to compare sensory stimuli is a fundamental cognitive function, which is known to be affected by two biases: choice bias, which reflects a preference for a given response, and contraction bias, which reflects a tendency to perceive stimuli as similar to previous ones. To test whether both reflect supervised processes, we designed feedback protocols aimed to modify them and tested them in human participants. Choice bias was readily modifiable. However, contraction bias was not. To compare these results to those predicted from an optimal supervised process, we studied a noise-matched optimal linear discriminator (Perceptron). In this model, both biases were substantially modified, indicating that the “resilience” of contraction bias to feedback does not maximize performance. These results suggest that perceptual discrimination is a hierarchical, two-stage process. In the first, stimulus statistics are learned and integrated with representations in an unsupervised process that is impenetrable to external feedback. In the second, a binary judgment, learned in a supervised way, is applied to the combined percept.SIGNIFICANCE STATEMENT The seemingly effortless process of inferring physical reality from the sensory input is highly influenced by previous knowledge, leading to perceptual biases. Two common ones are contraction bias (the tendency to perceive stimuli as similar to previous ones) and choice bias (the tendency to prefer a specific response). Combining human psychophysical experiments with computational modeling we show that they reflect two different learning processes. Contraction bias reflects unsupervised learning of stimuli statistics, whereas choice bias results from supervised or reinforcement learning. This dissociation reveals a hierarchical, two-stage process. The first, where stimuli statistics are learned and integrated with representations, is unsupervised. The second, where a binary judgment is applied to the combined percept, is learned in a supervised way.