Regulation of capillary perfusion by small arterioles is spatially organized

To explore a mechanism for spatial recruitment of capillaries, this study determined whether the arterioles controlling capillary perfusion, which typically arise as sequential branches along a transverse arteriole, could respond differently from each other in situ in a spatially ordered way. Diameter changes were measured for these arterioles at a known location in the intact microvasculature in the cremaster muscle of anesthetized Golden hamsters (N = 67); each arteriole controls separate capillary groups. These arterioles all had the same concentration dependence to locally (by micropipette) applied norepinephrine (NE, 10(-9) to 10(-3) mol/L), and 10(-9) mol/L NE did not induce diameter changes when applied locally to individual vessels. However, 10(-9) mol/L NE added to the tissue superfusate, or 5% added superfusate oxygen (also locally subthreshold), each induced significant diameter changes (both constrictions and dilations), in different branches, that were presumably due to summation of individually subthreshold events that changed the prevailing conditions at the point of observation. These significant diameter changes were related to the maximal diameter or to initial tone of the branches, but these changes occurred in different ways for NE versus oxygen. With NE, the branch arterioles that constricted (versus dilated) were significantly larger (maximal diameter, 22.3 +/- 2.6 versus 15.9 +/- 2.1 microns) and had higher tone (fractional constriction, 0.53 +/- 0.05 versus 0.63 +/- 0.05); with oxygen, those that constricted were the same size as those that dilated (maximal diameter, 28.6 +/- 1.1 versus 30.5 +/- 2.7 microns), but constrictors had lower tone (fractional constriction, 0.49 +/- 0.04 versus 0.39 +/- 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of recombinant human mitochondrial aldehyde dehydrogenase by two intermediate metabolites of disulfiram

Disulfiram is used in aversion therapy for alcoholism. S-Methyl-N,N-diethylthiocarbamate (MeDTC) sulfoxide, a potent inhibitor of the target enzyme mitochondrial aldehyde dehydrogenase (ALDH2), is thought to be the principal active metabolite of disulfiram in vivo. We examined the effects on recombinant human ALDH2 of two intermediate metabolites of disulfiram, S-methyl-N,N-diethyldithiocarbamate (MeDDC) sulfoxide and MeDDC sulfine. MeDDC sulfoxide was a potent inhibitor of ALDH2 with an IC50 of 2.2 +/- 0.5 microM (mean +/- SD, N = 4) after preincubation with enzyme for 30 min. MeDDC sulfine was a relatively weak inhibitor of ALDH2 under the same conditions with an IC50 value of 62 +/- 14 microM. The inhibition of ALDH2 by both compounds was irreversible and did not require the cofactor NAD. The latter finding demonstrates that inactivation of ALDH2 is independent of the dehydrogenase activity of the enzyme. GSH blocked almost completely the inhibition by 20 microM of MeDDC sulfoxide and greatly diminished the inhibition by 200 microM of MeDDC sulfine. Inactivation by MeDDC sulfoxide was time dependent. MeDTC sulfoxide was a more potent inhibitor of recombinant human ALDH2 (IC50 = 1.4 +/- 0.3 microM after preincubation for 15 min) than either of the intermediate metabolites, and its inhibition was unaffected by GSH. Our results suggest that these newer intermediate metabolites of disulfiram, especially the more potent MeDTC sulfoxide, have the potential to inhibit the target enzyme ALDH2 in patients receiving disulfiram. However, until the significance of the interactions of the inhibitors with GSH is more fully understood, the contribution of MeDDC sulfine and MeDDC sulfoxide to the pharmacological effects of disulfiram in vivo is uncertain.     

Activation of phospholipase C and guanylyl cyclase by endothelins in human trabecular meshwork cells

PURPOSE: To characterize effects of endothelins on activities of phospholipase C (PLC) and nucleotide cyclases in human trabecular meshwork (TM) cells. METHODS: Cultured simian virus 40-transformed human TM (HTM-3) or non-transformed (HTM-16) cells were used. Changes in the PLC activity were determined by assaying the production of [3H] inositol phosphates. Accumulation of cyclic GMP or cyclic AMP in cell lysate was measured by radioimmunoassay. RESULTS: Endothelin-1 (ET-1; 1 microM) stimulated PLC in HTM-16 cells, but Sarafotoxin S6c (SRTX), an ET(B) receptor subtype-selective agonist (1 microM), did not. Similar results were obtained in HTM-3 cells: ET-1, but not ET-3 or SRTX, activated PLC in a dose-dependent manner, with a calculated EC50 of 646 pM. The peptide also stimulated the accumulation of cGMP in a concentration-dependent manner with an EC50 of 37.2 pM. ET-3 or SRTX was not effective except at much higher concentrations. Both the PLC and guanylyl cyclase stimulation induced by ET-1 (10 nM) were completely inhibited by pretreating the cells with BQ-123 (<10 microM), an ET(A) receptor selective antagonist, but not by BQ-788 (10 microM), an ET(B) receptor subtype-specific antagonist. Neither ET-1 nor ET-3 stimulated adenylyl cyclase activity in HTM-3 cells at concentration as high as 1 microM. CONCLUSION: ET-1 activates PLC and guanylyl cyclase in TM cells. Potency profiles of ET receptor agonists and antagonists suggest that the ET(A) receptor subtype is involved in both actions of ET-1. The effects of the ET peptides in TM cells are interesting and could be part of the mechanism of their IOP-lowering effect.     

Disseminated candidiasis (moniliasis) in a dog. A case report

A case of systemic candidiasis (Candida albicans) in a 1 1/2 year old dog is reported. Clinically, the first manifestation was enlargement of a superficial inguinal lymph node. Later several peripheral lymph nodes were affected and a fistulous opening appeared, communicating with an inflammatory process in the right humerus. Necropsy revealed gross lesions in the kidneys, pancreas and multiple lymph nodes. In addition, microscopic lesions were observed in the myocardium and the bone marrow of the right humerus. The lesions, which contained large fungal colonies, were mainly granulomatous with numerous multinuclear giant and epitheloid cells, but necrosis and suppuration were also evident. The site of invasion is not known. However, a previous perianal and abdominal dermatitis, which was treated locally with antibiotics and corticoids, could possibly have been a mycotic infection.     

Do workshops make a difference in improving the capability of physicians?

Continuing medical education (CME) activities have been shown to improve the capability and capacity of physicians for appropriate management of their patients. However, doubts have been raised about the role of workshops and seminars. This study is an attempt to find out whether workshops can improve the knowledge (capability) of practicing physician. Participants of 10 randomly selected workshops conducted in whole of Sindh were included for this study. A pre-test followed by post-test methodology used for 214 participants demonstrated that physicians' knowledge increased for some of the basic facts after attending the workshop. However, when their knowledge was assessed with some problem-solving approach, no significant (P < 0.05) change could be noted. It is recommended that workshops should be designed and conducted more carefully. Besides, some innovative approaches for CME should be compared with 'workshops' approach to determine their effectiveness.     

Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer

BACKGROUND: Radiotherapy after mastectomy to treat early breast cancer has been known since the 1940s to reduce rates of local relapse. However, the routine use of postoperative radiotherapy began to decline in the 1980s because it failed to improve overall survival. We prospectively tested the efficacy of combining radiotherapy with chemotherapy. METHODS: From 1978 through 1986, 318 premenopausal women with node-positive breast cancer were randomly assigned, after modified radical mastectomy, to receive chemotherapy plus radiotherapy or chemotherapy alone. Radiotherapy was given to the chest wall and locoregional lymph nodes between the fourth and fifth cycles of cyclophosphamide, methotrexate, and fluorouracil. RESULTS: After 15 years of follow-up, the women assigned to chemotherapy plus radiotherapy had a 33 percent reduction in the rate of recurrence (relative risk, 0.67; 95 percent confidence interval, 0.50 to 0.90) and a 29 percent reduction in mortality from breast cancer (relative risk, 0.71; 95 percent confidence interval, 0.51 to 0.99), as compared with the women treated with chemotherapy alone. CONCLUSIONS: Radiotherapy combined with chemotherapy after modified radical mastectomy decreases rates of locoregional and systemic relapse and reduces mortality from breast cancer.     

Co-existence of leukoderma with features of Dowling-Degos disease: reticulate acropigmentation of Kitamura spectrum in five unrelated patients

Flavobacterium rigense strain PR2, a broad-spectrum mercury-resistant bacterium abundantly present in soil exhibited multiple metal resistance properties. Mercury resistance was due to the sequential action of two mercury-detoxicating enzymes, organomercurial lyase and mercuric reductase. The levels of these enzyme activities were determined using different mercury compounds as inducers and substrates. Mercuric reductase was partially purified from the bacterium and the physicochemical properties of the enzyme were studied. The effect of several enzyme inhibitors and heavy metal ions on the enzyme activity was also studied.     

Outcome and predictive factors in children with chronic idiopathic musculoskeletal pain

The 18S rDNA sequences of the six most common European Lymnaeidae species (Mollusca:Gastropoda:Basommatophora) have been obtained by direct PCR cycle sequencing and silver staining methods. The sequence alignment and secondary structures of the 18S rRNA gene of Lymnaea stagnalis, L. auricularia, L. peregra, L. palustris, L. glabra, and L. truncatula are analyzed. This gene proves to be a good marker for both specific determination and supraspecific lymnaeid phylogeny. The malacological importance is evident, considering the specific determination problems of individual snails and the present systematic chaos in Lymnaeidae due to their pronounced morphoanatomic uniformity, which makes a classification by traditional methods impossible. The majority (17) of the total of 43 nucleotide-substituted positions appears to be confined to a small region included in helix E10-1 of the variable region V2, enabling species group distinction: (1) the first sequence is common to L. auricularia and L. peregra; (2) the second sequence is unique to L. truncatula; and (3) the third sequence is identical for L. glabra, L. palustris, and L. stagnalis. The other 26 nucleotide-substituted positions are dispersed over the entire gene, although four grouped nucleotide positions in helix 6 of V1 are of interest in distinguishing L. glabra from both L. palustris and L. stagnalis. The phylogenetic trees obtained by comparison with four other molluscan species (a polyplacophoran, two bivalves, and a stylommatophoran gastropod) show the presence of four well-defined subgenera among the genus Lymnaea sensu lato: (1) Lymnaea (Radix), (2) Lymnaea (Galba), (3) Lymnaea (Leptolimnaea), and (4) Lymnaea (Lymnaea). Two branches, L. auricularia-L. peregra-L. truncatula and L. glabra-L. palustris-L. stagnalis, are worth mentioning from the parasitological point of view, since the two digenean species of large medical and veterinary impact transmitted by lymnaeids, Fasciola hepatica and F. gigantica, appear to be linked to the first branch.