Neuroendocrine synaptic vesicles are formed in vitro by both clathrin-dependent and clathrin-independent pathways

Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome involving a predisposition to cancers of the colon, endometrium and several other extra-colonic sites, accounting for approximately 1-5% of all colorectal cancer cases. It is not easily recognized because of a lack of distinctive clinical markers, making diagnosis and management of this disease problematic. To provide a basis for uniformity in diagnosis of HNPCC, the Amsterdam criteria were proposed and are currently in use. More recently, the discovery of four human mismatch repair genes (hMSH2, hMLH1, hPMS1 and hPMS2) has provided novel insight into the genetic basis of this disease, and raised the possibility of genetic diagnosis for management of HNPCC patients and their family members. This report summarizes the clinicopathologic aspects of HNPCC, reviews the recent genetic findings and surveillance strategies, and suggests a novel designation of certain patients as suspected HNPCC.     

Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine

A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-?(2'S)-[3-(4-hydroxyphenyl)propanamido]-3'-methylbutyl?-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [35S]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor.     

Clinical and health care cost consequences of infective endocarditis in mitral valve prolapse

In 1990-1991, a national survey was conducted to estimate the prevalence of Salmonella species among Canadian commercial turkey flocks. Two hundred and seventy flocks were randomly selected across Canada. The proportion sampled from each province was selected according to each province's share of the national turkey market. Samples, consisting of 12 pooled litter and four pooled dust samples, were used to determine the Salmonella status of the environment of each flock. Additionally, a one kilogram sample of feed was taken from each flock premise. Salmonella was recovered from environmental samples in 234/270 (86.7%) of flocks and from feed samples in 26/266 (9.8%) of flocks. Forty-eight different Salmonella serovars were isolated from flock environmental samples. The most prevalent serovars were S. anatum, S. hadar, S. agona, S. heidelberg and S. saintpaul which were isolated from 53/270 (19.6%), 49/270 (18.1%), 49/270 (18.1%), 42/270 (15.6%) and 34/270 (12.6%) flocks, respectively.     

Systematic relationships of some members of the genera Oesophagostomum and Chabertia (Nematoda: Chabertiidae) based on ribosomal DNA sequence data

The present study characterised seven species of the Chabertiidae (Nematoda: Strongyloidea) belonging to either the subfamily Oesophagostominae (Oesophagostomum radiatum, Oesophagostomum venulosum, Oesophagostomum dentatum, Oesophagostomum quadrispinulatum, Oesophagostomum columbianum, Oesophagostomum bifurcum) or to the subfamily Chabertiinae (Chabertia ovina) by their second internal transcribed spacer rDNA sequence, assessed the extent of intraspecific variation and interspecific differences in the sequence, and inferred the phylogenetic relationship of C. ovina with respect to members of the Oesophagostominae. In both the phenetic and cladistic analyses of the sequence data, Chabertia was nested within Oesophagostomum, suggesting either that the species examined represent members of the same genus, or alternatively, that Oesophagostomum may represent more than one genus.     

Seminar planning guidelines. As I see it

Small local chapter groups can present quality cost effective regional seminars. Key components are dedication of members, teamwork, and a sense of direction. The following guidelines and information can provide a framework for planning and coordinating a seminar.     

A constant-volume gas pump for gas electrodes

A pump suitable for use with gas electrodes, in which recirculation of the gas is necessary, is described. The system to which the cell with the gas electrode and the pump are connected does not change its volume when the pump is in operation. The pump works as follows: an embolus, consisting of a Tefloncoated magnetic stirring bar, placed inside a glass tube having an internal diameter slightly larger than the diameter of the bar, is moved from the outside with a permanent magnet, which in turn is moved horizontally along the tube by means of a mechanical assembly driven by an electric motor. The motion of the embolus is accompanied by the closing and opening of glass valves which allow the gas to circulate in the desired direction. The pump, used in conjunction with a vacuum line, operates from pressures as low as 60 Torr to above atmospheric pressure. The operation of the pump is unaffected by organic gases and most inorganic gases.     

Numerical simulations of failure behavior around a circular opening in a non-persistently jointed rock mass under biaxial compression

Pre-existing discontinuities change the mechanical properties of rock masses,and further influence failure behavior around an underground opening.In present study,the failure behavior in both Inner and Outer zones around a circular opening in a non-persistently jointed rock mass under biaxial compression was investigated through numerical simulations.First,the micro parameters of the PFC^3D model were carefully calibrated using the macro mechanical properties determined in physical experiments implemented on jointed rock models.Then,a parametrical study was undertaken of the effect of stress condition,joint dip angle and joint persistency.Under low initial stress,the confining stress improves the mechanical behavior of the surrounding rock masses;while under high initial stress,the surrounding rock mass failed immediately following excavation.At small dip angles the cracks around the circular opening developed generally outwards in a step-path failure pattern;whereas,at high dip angles the surrounding rock mass failed in an instantaneous intact rock failure pattern.Moreover,the stability of the rock mass around the circular opening deteriorated significantly with increasing joint persistency.     

Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography

BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.