Facile access to [1,2]-oxazine derivatives via annulations of aminoxy-tethered 1,7-enynes.

An efficient approach for the highly diastereoselective construction of functionalized cyclopenta[d][1,2]oxazines via sequential oxyamination and Pauson-Khand reaction of readily accessible propargylic alcohols has been developed. Furthermore, the ring closing metathesis of these N-O linked 1,7-enynes afforded vinylated-[1,2]oxazines in good yields. The reduction of the N-O bond of the obtained cyclopenta[d][1,2]oxazine is accomplished to access cyclopentenone-based amino alcohols.

Oxa-[3+3] annulation of MBH-carbonates of propiolaldehydes with α-nitro/bromo ketones to access 2H-pyrans.

A novel alkyne-assisted annulation reaction of MBH-carbonates of propiolaldehydes with α-nitro/bromo ketones is reported, providing a facile synthesis of substituted 2H-pyrans in good yields. This reaction divulges the inimitable reactivity of the MBH-carbonates of propiolaldehydes as C3-synthons wherein the alkyne functionality promoted the reaction without participating in the oxa-[3+3] annulation. The obtained products, having alkyne and ester functionalities, allowed further annulations to generate diverse pyrano[3,4-c]pyran-1-ones.

Synthesis and biological evaluation of longanlactone analogues as neurotrophic agents.

Longanlactone analogues were synthesized using a route featuring Friedel-Crafts acylation, Sonogashira coupling and 1,3-dipolar cycloaddition reactions. Structure-activity relationships were investigated for neurotrophic activity. Compound 6 was found to have the most potent neurotrophic activity among all the synthesized analogues in Neuro2a cells as evidenced by a battery of in vitro/cell based assays for assessment of neurogenic and potential neurotrophic activity including neurite outgrowth assay and real time PCR for popular markers of augmented neurotrophic activity. Compound 6 might serve as a template for further development of highly effective neurotrophic molecules.

Synthetic Studies toward (±)-Furanocembranoid 1: Construction of the Acyclic Carbon Framework.

Herein, we report the synthesis of the entire acyclic carbon framework toward (±)-furanocembranoid 1 via the longest linear sequence of 12 steps from commercially available linalool and diethyl 2-isopropylmalonate. Key to the success of this synthetic approach is a silver-catalyzed enyne-annulation reaction for the formation of 2,4-disubstituted furan motif of unique furanocembranoid 1, isolated from Croton oblongifolius. Construction of macrocycle has also been explored using the ring-closing metathesis reaction.

A [3 + 2]-annulation approach to tetrasubstituted furans from MBH-carbonates of acetylenic aldehydes via sequential substitution/cycloisomerization.

A novel metal-free approach to construct the tetrasubstituted furans from Morita-Baylis-Hillman (MBH)-carbonates of acetylenic aldehydes has been developed. This strategy involves the cascade nucleophilic substitution/5-exo-dig-cycloisomerization of MBH-carbonates with 1,3-dicarbonyl compounds to give uniquely substituted 2-furan-3-yl acrylates. Additionally, the obtained furan adducts open a new entry to naphthofurans through palladium-catalyzed decarboxylative benzannulation.

Musculoskeletal disorder (MSD) among agricultural workers.

Farming is a large and main industry in Bangladesh. Large numbers of people are directly involved in farming and have very unique exposure compare to other sectors. Musculoskeletal problems among farmer population are not infrequent. This study was carried out among 200 farmers in one selected district. The study revealed that musculoskeletal problems were common among the farmers working in a traditional way. All the respondents were male. The age of all respondents lie between 20-60 years. Among them 22.5% farmers were illiterate, about 45.5% below Class V. About half (42%) of the respondents had reported pain in different parts of the body at least one or more times during working in land. And about two third (65.5%) of the farmers had history of joint pain and stiffness in last 12 month. Most of the farmers who suffered from musculoskeletal symptoms were 41-60 years. Specially who worked more then 20 years (82.6%) and average 6 hours per day (66.7%). The occurrence of musculoskeletal problems in various part of the body included Knee pain - 48.1%, Back pain (back ache) - 22.9%, Waist pain (low back ache) - 13.3%, Neck pain - 18.3% and shoulder pain - 10.7%. Length of work in year and daily average working hours were found significant association with musculoskeletal pain. It was found that musculoskeletal pain were more common among the farmers when they worked in squatting position (52%) and specially during weeding of plants (31%). Among them only 22% also engaged in other business. Most of the farmers complained dull aching pain (40.6%), only 2.3% noticed severe acute pain, but about 86% farmers' temporary stop their work for pain and 80% get relief after discontinue of work. About 75% respondents visited doctors for their pain which was statistically significant (p=0.001). It was found that the rates of musculoskeletal complaints are more among those individuals who worked relatively bad ergonomic condition, such as body position probably play an important role.

Status of blood pressure among individuals consuming saline water.

Climate change is taking its toll in the form of saline water intrusion into the mainland of Bangladesh, which is one of the lowest-altitude countries in the world. The study was carried out with the objective to assess the blood pressure status associated with salinity in saline prone selected areas of Bagherhat and Tangail districts from March 2008 - June 2008 of rural Bangladesh. Two hundred and ninety subjects were selected purposively from both the districts. About 70% of the respondents were males and below forty years of age. More than two thirds of the respondents were illiterate; belong to 4-5 member family, with monthly family income of less than Tk. 4000 per month. Only one third of the respondents were smokers. More than two thirds of the respondents from salinity area had salinity level of 2-3%. Among them majority were drinking saline water for 6-10 years and 26% were drinking for more than ten years. About 20% of the non saline respondents' systolic blood pressure was 110-120 mm of Hg and 26% of saline area had systolic blood pressure >135-140 mm of Hg. Mean systolic BP among salinity area was more than that for non salinity area. About 19% of the non saline respondents' diastolic blood pressure was ≤ 85 mm of Hg. About one third had ≥ 90 mm of Hg, among them 31% were from saline area. Mean diastolic BP among salinity area was more than non salinity area. There was no history of heart disease, and less than 1% was diabetic among them. About two thirds had mean arterial pressure <70 mm of Hg, among them majority were from non saline area. About one third had >70 mm of Hg, among them majority were from saline area. The study concluded that systolic and diastolic blood pressures of saline group were significantly higher than that of the non saline group.

The CCK(2) receptor antagonist, YF476, inhibits Mastomys ECL cell hyperplasia and gastric carcinoid tumor development.

YF476 is a potent and highly selective cholecystokin 2 (CCK(2)) receptor antagonist of the benzodiazepine class. It inhibits gastric neuroendocrine enterochromaffin-like (ECL) cell secretion, proliferation and spontaneous formation of gastric neuroendocrine tumors (carcinoids) in cotton rats. The Mastomys rodent species exhibits a genetic predisposition to gastric ECL neuroendocrine tumor formation which can be accelerated by acid suppression and induction of hypergastrinemia. In this respect, it mimics the human condition of atrophic gastritis, hypergastrinemia and gastric carcinoid development. We investigated whether YF476 could inhibit acid suppression-induced ECL cell hyperplasia and neoplasia in this model. In addition, we examined whether YF476 could reverse established ECL cell hyperplasia and neoplasia. Targeting the CCK(2) receptor during Loxtidine-induced hypergastrinemia resulted in a reduction in ECL cell secretion (plasma and mucosal histamine, and histidine decarboxylase (HDC) transcripts, p<0.05) and proliferation (numbers of HDC-positive cells, connective tissue growth factor (CTGF) and cyclin D1 transcription). This was associated with a decrease in ECL cell hyperplasia and a 60% reduction in gastric ECL cell microcarcinoid (tumors <0.3mm in size) formation. YF476 inhibited ECL cell neoplasia (gastric carcinoid) in animals with hyperplasia, inhibited the formation of ECL cell tumors when co-administered with Loxtidine and reversed the growth and developement of gastric ECL cell carcinoids in long-term acid suppressed Mastomys. Variable importance analysis using a logistic multinomial regression model indicated the effects of YF476 were specific to the ECL cell and alterations in ECL cell function reflected inhibition of transcripts for HDC, Chromogranin A (CgA), CCK(2) and the autocrine growth factor, CTGF. We conclude that specifically targeting the CCK(2) receptor inhibits gastrin-mediated ECL cell secretion and ECL cell proliferation and tumor development in vivo.

Pharmacotherapy of neuroendocrine cancers.

BACKGROUND: Neuroendocrine tumors (NETs) of the diffuse neuroendocrine cell system often present a considerable diagnostic and therapeutic challenge. METHODS: We have reviewed the literature on NET treatment between 1979 and 2008 (PubMed search: carcinoid or neuroendocrine tumor/tumour + treatment or management), and summarized current therapeutic options and recommendations. RESULTS: The majority of tumors are diagnosed at a stage that the only curative treatment, radical surgical intervention, is no longer an option. Biotherapy with somatostatin analogs is currently the most efficient treatment to achieve palliation. The interferon class of agents may have a role in selected individuals but substantial adverse events often limit their use. Conventional chemotherapy has minimal efficacy but may have some utility in undifferentiated or highly proliferating neuroendocrine carcinomas and pancreatic NETs. Hepatic metastases, depending on size, location and number, may be amenable to surgical resection, embolization or radio-frequency ablation. Peptide receptor targeted radiotherapy may lead to reduction in tumor size but in most circumstances has a tumor-stabilizing effect. A variety of antiangiogenesis and growth factor-targeted agents have been evaluated but to date the results have failed to meet expectations. Thus, long-acting somatostatin analogs remain the only effective pharmacotherapeutic option that improves symptomatology and quality of life with minimal adverse effects.

Perinatal glucocorticoid treatment disrupts the hypothalamo-lactotroph axis in adult female, but not male, rats.

This study aimed to test the hypothesis that the tuberoinfundibular dopaminergic neurons of the arcuate nucleus and/or the lactotroph cells of the anterior pituitary gland are key targets for the programming effects of perinatal glucocorticoids (GCs). Dexamethasone was administered noninvasively to fetal or neonatal rats via the mothers' drinking water (1 mug/ml) on embryonic d 16-19 or neonatal d 1-7, and control animals received normal drinking water. At 68 d of age, the numbers of tyrosine hydroxylase-positive (TH+) cells in the arcuate nucleus and morphometric parameters of pituitary lactotrophs were analyzed. In control animals, striking sex differences in TH+ cell numbers, lactotroph cell size, and pituitary prolactin content were observed. Both pre- and neonatal GC treatment regimens were without effect in adult male rats, but in females, the overriding effect was to abolish the sex differences by reducing arcuate TH+ cell numbers (pre- and neonatal treatments) and reducing lactotroph cell size and pituitary prolactin content (prenatal treatment only) without changing lactotroph cell numbers. Changes in circulating prolactin levels represented a net effect of hypothalamic and pituitary alterations that exhibited independent critical windows of susceptibility to perinatal GC treatments. The dopaminergic neurons of the hypothalamic periventricular nucleus and the pituitary somatotroph populations were not significantly affected by either treatment regimen in either sex. These data show that the adult female hypothalamo-lactotroph axis is profoundly affected by perinatal exposure to GCs, which disrupts the tonic inhibitory tuberoinfundibular dopaminergic pathway and changes lactotroph morphology and prolactin levels in the pituitary and circulation. These findings provide new evidence for a long-term disruption in prolactin-dependent homeostasis in females, but not males, after inappropriate GC exposure in perinatal life.

Characterisation of nucleotide sequence variants and disease-specific mutations involving the 3' end of the C1-inhibitor gene in hereditary angio-oedema.

The sixth, seventh and eighth exons of both alleles of the C1-inhibitor gene were nucleotide sequenced in 52 individuals from 20 kindred with type I hereditary angio-oedema (HAE), 5 kindred with type II HAE and 10 control kindred. Four previously unreported nucleotide which had no disease specificity were identified in addition to a sequencing error in the eighth exon. In addition, a T-->C mutation at position 8770 (resulting in a Phe-->Leu substitution at position 291) was identified on the abnormal allele of the affected members of a family with type I HAE due to an exon 6 donor splice site mutation. The significance of this mutation is not known. Disease-specific mutations were identified in 100% of type II HAE kindred and in 20% of type I HAE kindred. The relevance of these findings to the evolving understanding of the molecular genetics of HAE is discussed.

C1-inhibitor gene nucleotide insertion causes type II hereditary angio-oedema.

The polymerase chain reaction and nucleotide sequence analysis have been used to characterise a three nucleotide insertion in the eighth exon of one allele of the C1-inhibitor gene between nucleotides 16749 and 16750 in a kindred with type II hereditary angio-oedema (HAE). The effect of the resulting C1-inhibitor amino acid sequence alteration is discussed. This represents the first report of a nucleotide insertion in the C1-inhibitor gene causing type II HAE.

A point mutation in the C1-inhibitor gene causes type I hereditary angiooedema.

The polymerase chain reaction and nucleotide sequencing have been used to characterise a single base substitution (CAG-->TAG at nucleotide 16842 in the C1-inhibitor gene in the affected members of a single family with type I C1-inhibitor deficiency. This mutation creates the TAG translation termination codon, thereby truncating the C1-inhibitor C-terminus by 17 amino acids. The effects of the mutation are discussed.

Type II hereditary angio-oedema associated with two mutations in one allele of the C1-inhibitor gene around the reactive-site coding region.

The polymerase chain reaction and nucleotide sequence analysis have been used to characterise two point mutations in the eighth exon of one allele of the C1-inhibitor gene in a kindred with type II hereditary angio-oedema (HAE). The mutations comprise a G to A substitution at C1-inhibitor gene nucleotide 16789 and an upstream C to T substitution at nucleotide position 16765. This represents the first report of these two mutations in the same C1-inhibitor allele in type II HAE. The molecular genetic pathogenesis of HAE is discussed in the light of these findings.

A single base deletion from the C1-inhibitor gene causes type I hereditary angio-oedema.

RFLP analysis, the polymerase chain reaction and nucleotide sequencing have been used to characterise a C1-inhibitor gene mutation responsible for type I hereditary angio-oedema (HAE). A single base deletion (C-16698) from the eighth exon of the C1-inhibitor gene alters the reading frame of the exon and generates a premature translation termination codon. This represents the first report of this form of C1-inhibitor gene mutation in type I HAE.

An RNA splice site mutation in the C1-inhibitor gene causes type I hereditary angio-oedema.

Restriction fragment length polymorphism analysis, the polymerase chain reaction and nucleotide sequencing have been used to characterise a single base substitution (G----T) at nucleotide 8863 in the C1-inhibitor gene. This destroys the 5' donor splice site recognition motif of the sixth intron. Family studies suggest that the mutation is responsible for type I hereditary angio-oedema in a studied kindred.