Comparative effects of vasopressin, norepinephrine, and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock

Norepinephrine (NE), a standard of care, AVP, an alternative candidate, and L-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased ( approximately 35%) but aortic blood flow increased during endotoxin infusion (P < 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio (P < 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance ( approximately 3- to 4-fold), whereas AVP or LC attenuated this drop (P < 0.05 vs. control). In contrast, NE did not improve endotoxin-induced renal dysfunction. Endotoxin induced gut and lung hyperpermeability (P < 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE ( approximately 2-fold increase) but not AVP infusion (P < 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P ( approximately 2- and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function.     

Photosynthate production in laboratory cultures (UV conditioned and unconditioned) of Cryptomonas erosa under simulated doses of UV radiation

We used a device called a Phototron to measure the effects of UV radiation on the cosmopolitan algae, Cryptomonas erosa, grown in continuous cultures. In the Phototron, we investigated changes in photosynthetic parameters (Pmax – specific production rate at optimal light intensity; – initial slope of the linear portion of the Photosynthesis-Irradiance curve; and – the convexity or rate of bending) and carbon allocation as a function of irradiance at three different environmentally-realistic doses of UV radiation in unconditioned (no prior UV exposure) and conditioned algae (15 d previous UV exposure). For unconditioned control algae, Pmax-Total was lower, although not significantly, than the two highest UV treatments. For conditioned control algae, Pmax-Total was higher, although not significantly, than all UV treatments. Our data suggest that short term (4 h) exposure to low levels of UV (8.09 W m–2 unweighted) does not affect Pmax-Total in C. erosa, but does change the proportion of carbon allocated to lipids and proteins. Also, comparisons of lipids, polysaccharides and proteins as a percent of total carbon uptake between unconditioned and conditioned algae indicate that exposure history to UV radiation can have a negative impact on carbon allocation to lipids and proteins, in a wetland alga species that is crucial to the efficient transfer of energy through freshwater food webs.     

The physical mechanisms of the perception of dampness in fabrics

1. 1. The detection of dampness in hygroscopic materials has been investigated both by subjective tests and by the application of a model of the physical mechanisms involved.

2. 2. Subjects were asked to rate the degree of dampness of a range of materials of different moisture contents after a short period of contact with the inner forearm.

3. 3. Skin and fabric inner surface temperatures were recorded

4. 4. It was found that highly hygroscopic wool fabrics were perceived as being dryer and maintained a higher temperature at the skin surface than polyester, a less hygroscopic fabric, during fabric-skin contact.

5. 5. A physical model of the sorption/desorption process in hygroscopic materials has been developed from knowledge of fibre sorption kinetics and has been used to study the physical processes which take place at the skin-fabric interface during transient contact.

6. 6. These predictions agree well with the subjective responses and the measured temperatures.

MUCILAGE PROCESSING AND SECRETION IN THE GREEN ALGA CLOSTERIUM. I. CYTOLOGY AND BIOCHEMISTRY1

Placoderm desmids (Conjugates, Chlorophyta) such as Closterium exhibit a gliding locomotory behavior. This results from the forceful extrusion of an acidic polysaccharide from one pole of the cell causing the cell to glide in the opposite direction. A biochemical and cytological analysis of gliding behavior was performed. The mucilage is a high molecular weight polysaccharide rich in glucuronic acid and fucose. Under normal growth conditions, 3 μg of mucilage is produced per cell in 30 days. Mucilage production increased 3–4 fold in cells challenged with low phosphate or nitrate conditions. A polyclonal antibody was raised against the mucilage and used in immunofluorescence studies. These results show that upon contact with another object Closterium aligns itself parallel to that object by a “jack-knife” motion. Subsequently, large amounts of mucilage are released to form elongate tubes enmeshing the cell with that object. In post-cytokinetic phases of the cell cycle, mucilage is extruded only through the pole of the developing semi-cell. Chlorotetracyclene-labeling of mucilage-secreting cells shows a correlation between calcium-rich loci on the cell surface and sites of mucilage release.     

Hereditary Nonpolyposis Colon Cancer: Analysis of Linkage to 2p15-16 Places the COCA1 Locus Telomeric to D2S123 and Reveals Genetic Heterogeneity in Seven Canadian Families

Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominant trait responsible for approximately 6% of colorectal cancers. Linkage of the HNPCC trait to the D2S123 locus on 2p15-16 has previously been reported in two families. This HNPCC locus is now designated “COCA1.” We have tested seven Canadian HNPCC families, who have a variety of clinical presentations, for linkage to a panel of microsatellite polymorphisms in the vicinity of D2S123. One family was clearly linked to the COCA1 locus (LOD = 4.21), and a second family is likely to be linked (LOD = 0.92). In three families linkage was excluded. In the remaining two families the data were inconclusive. In the linked family, individuals with cancer of the endometrium or ureter share a common haplotype with 12 family members with colorectal cancer. This supports the suspected association between these extracolonic neoplasms and the HNPCC syndrome. In addition, five of the six individuals with adenomatous polyps (but no colorectal cancer) have the same haplotype as the affected individuals, while the sixth carries a recombination. One individual with colorectal cancer carries a recombination that places the COCA1 locus telomeric to D2S123. This study localizes the COCA1 gene to an 8-cM region that is consistent with the location of the hMSH2 gene. We also confirm that families presently classified as HNPCC are genetically heterogeneous.     

Participation of alkaline phosphatase in the active transport of phosphates in brush border membrane vesicles

This paper reports the separation and preliminary characterization of the products formed by the reaction of the antitumor compound cis-Pt(NH₃)₂Cl₂ with DNA. Electrophoresis of the acid hydrolysed platinum-DNA complex gave a profile of platinum concentration which contained 5 peaks whose relative intensities varied with the amount of cis-Pt(NH₃)₂Cl₂ fixed on the DNA. Similar analysis of the products formed between DNA and trans-Pt(NH₃)₂Cl₂ or [Pt(dien)Cl]Cl, which are not active antitumor agents, indicated that these compounds bound to DNA in a different manner than cis-Pt(NH₃)₂Cl₂. DNA isolated from Escherichia coli which had been treated with cis-Pt(NH₃)₂Cl₂ or [Pt(dien)Cl]Cl did not give the same electrophoresis profiles as the corresponding platinum-DNA complexes formed in vitro.     

Novel nevirapine-like inhibitors with improved activity against NNRTI-resistant HIV: 8-heteroarylthiomethyldipyridodiazepinone derivatives

A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes.     

Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families

The Quebec population contains about six-million French Canadians, descended from the French settlers who colonized Nouvelle-France between 1608 and 1765. Although the relative genetic contribution of each of these founders is highly variable, altogether they account for the major part of the contemporary French-Canadian gene pool. This study was designed to analyze the role of this founder effect in the introduction and diffusion of the BRCA1 recurrent R1443X mutant allele. A highly conserved haplotype, observed in 18 French-Canadian families and generated using 17 microsatellite markers surrounding the BRCA1 locus, supports the fact that the R1443X mutation is a founder mutation in the Quebec population. We also performed haplotyping analysis of R1443X carriers on 19 other families from seven different nationalities; although the same alleles are shared for three markers surrounding the BRCA1 gene, distinct haplotypes were obtained in four families, suggesting multiple origins for the R1443X mutation. Ascending genealogies of the 18 French Canadian families and of controls were reconstructed on an average depth of 10 generations. We identified the founder couple with the highest probability of having introduced the mutation in the population. Based on the descending genealogy of this couple, we detected the presence of geographical concentration in the diffusion pattern of the mutation. This study demonstrates how molecular genetics and demogenetic analyses can complement each other to provide findings that could have an impact on public health. Moreover, this approach is certainly not unique to breast cancer genetics and could be used to understand other complex traits.Other members of the BCLC Haplotype Group involved in this study are listed in Appendix 1Other members of INHERIT BRCAs involved in this study are listed in Appendix 2H. Vézina and F. Durocher contributed equally to this work and should be regarded as joint first author