Tuberoinfundibular peptide of 39 residues produces anxiolytic and antidepressant actions

Tuberoinfundibular peptide of 39 residues (TIP39) potently activates the parathyroid hormone-2 receptor (PTH2-R). A group of neurons in the posterior thalamus and one in the lateral pons synthesize TIP39. TIP39 projections reach most areas of PTH2-R density, including many within the limbic system and hypothalamus. We report that TIP39 induces Fos in the infralimbic cortex, lateral hypothalamus, preoptic area, lateral septum and paraventricular thalamic nucleus, areas believed to be important in anxiety and depression. TIP39 caused anxiolytic-like effects in the elevated plus-maze test and antidepressant-like effects in the forced-swim test. TIP39 did not change activity in the open field test. These findings point to a previously unknown role of the PTH2-R in the regulation of anxiety and depression.     

Small molecule vanilloid TRPV1 receptor antagonists approaching drug status: can they live up to the expectations?

The cloning of the transient receptor potential vanilloid type-1 (TRPV1) receptor initiated the discovery of potent small molecule antagonists, many of which are in preclinical phase or already undergoing clinical trials. While animal experiments imply a therapeutic value for these compounds as novel analgesic-antiphlogistic drugs, new findings with TRPV1 deficient (trpv1 -/-) mice signal troubles for TRPV1 antagonists as clinical research gains impetus. An emerging concept with important implications for drug development is that TRPV1 may be differentially regulated under physiological and pathological conditions. If so, it is conceivable that such TRPV1 ligands can be synthesized that specifically target TRPV1 in diseased (e.g. inflamed or neoplastic) tissues but spare TRPV1 that subserves its physiological functions in healthy organs. This review explores the current status of this field and seeks an answer to the question how these new discoveries could be factored into TRPV1 drug discovery and development.     

A spectrum of mutations in SH2D1A that causes X-linked lymphoproliferative disease and other Epstein-Barr virus-associated illnesses

X-linked lymphoproliferative disease (Duncan's Disease) was first encountered by David T. Purtilo in 1969. The first communication describing the disease was published in 1975. In 1989 the disease locus was mapped to Xq25. Ten years later the gene (SH2D1A, SAP, DSHP), which is absent or mutated in XLP patients was identified. Since that the protein crystal structure of this small, SH2-domain containing protein has been solved, target molecules of the protein have been identified, physiological and pathological protein/protein interactions have been characterized, and the mouse model of the gene mutation has been developed. That said, a complete understanding of the function of the normal SH2D1A protein in immunoregulation and of the altered immune responses in XLP patients is not yet at hand. Therein lies the legacy of Purtilo's discovery for, as with other primary immunodeficiencies, these "experiments of nature" offer a window on the beauty of the immune system. In due course, the manner by which this gene orchestrates an elegant response (akin to a Mozart divertimento) to EBV infection shall be defined.     

The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

Background

Prognostic risk stratification according to acquired or inherited genetic alterations has received increasing attention in acute myeloid leukemia in recent years. A germline Janus kinase 2 haplotype designated as the 46/1 haplotype has been reported to be associated with an inherited predisposition to myeloproliferative neoplasms, and also to acute myeloid leukemia with normal karyotype. The aim of this study was to assess the prognostic impact of the 46/1 haplotype on disease characteristics and treatment outcome in acute myeloid leukemia.

Design and Methods

Janus kinase 2 rs12343867 single nucleotide polymorphism tagging the 46/1 haplotype was genotyped by LightCycler technology applying melting curve analysis with the hybridization probe detection format in 176 patients with acute myeloid leukemia under 60 years diagnosed consecutively and treated with curative intent.

Results

The morphological subtype of acute myeloid leukemia with maturation was less frequent among 46/1 carriers than among non-carriers (5.6% versus 17.2%, P=0.018, cytogenetically normal subgroup: 4.3% versus 20.6%, P=0.031), while the morphological distribution shifted towards the myelomonocytoid form in 46/1 haplotype carriers (28.1% versus 14.9%, P=0.044, cytogenetically normal subgroup: 34.0% versus 11.8%, P=0.035). In cytogenetically normal cases of acute myeloid leukemia, the 46/1 carriers had a considerably lower remission rate (78.7% versus 94.1%, P=0.064) and more deaths in remission or in aplasia caused by infections (46.8% versus 23.5%, P=0.038), resulting in the 46/1 carriers having shorter disease-free survival and overall survival compared to the 46/1 non-carriers. In multivariate analysis, the 46/1 haplotype was an independent adverse prognostic factor for disease-free survival (P=0.024) and overall survival (P=0.024) in patients with a normal karyotype. Janus kinase 2 46/1 haplotype had no impact on prognosis in the subgroup with abnormal karyotype.

Conclusions

Janus kinase 2 46/1 haplotype influences morphological distribution, increasing the predisposition towards an acute myelomonocytoid form. It may be a novel, independent unfavorable risk factor in acute myeloid leukemia with a normal karyotype.     

Gut microbiome and cardiometabolic risk

Reviews in Endocrine and Metabolic Disorders - The last decade has been characterized by an intense research on the composition of the gut microbiome and the links with human health. While previous...     

Should magnesium be given to every migraineur? No

Migraine is one of the most common neurological disorders that affects young people, causing a considerable degree of disability in the active population, with an enormous consequent socio-economic impact. Despite intensive research, the pathomechanism of migraine is not completely understood and its fully effective therapy remains to be achieved. A number of experimental studies have implicated the importance of magnesium ion in the pathophysiology of this condition. Magnesium has been also administered for both prophylactic and acute therapy in migraine, but the question of its efficacy has not been studied adequately. The data available suggest that magnesium has a potential role in the prophylaxis, but the results in acute therapy are far less convincing. With a good side effect profile, magnesium is a relatively safe drug with a possible beneficial effect in the prophylaxis of migraine headache, and it may have its niche in the treatment of migraine patients. However, the current medical evidence that has accumulated and the fact that there are far more effective treatment possibilities clearly indicate that this drug is definitely not to be used by every migraineur.