Sustained activity in the medial wall during working memory delays

We have taken advantage of the temporal resolution afforded by functional magnetic resonance imaging (fMRI) to investigate the role played by medial wall areas in humans during working memory tasks. We demarcated the medial motor areas activated during simple manual movement, namely the supplementary motor area (SMA) and the cingulate motor area (CMA), and those activated during visually guided saccadic eye movements, namely the supplementary eye field (SEF). We determined the location of sustained activity over working memory delays in the medial wall in relation to these functional landmarks during both spatial and face working memory tasks. We identified two distinct areas, namely the pre-SMA and the caudal part of the anterior cingulate cortex (caudal-AC), that showed similar sustained activity during both spatial and face working memory delays. These areas were distinct from and anterior to the SMA, CMA, and SEF. Both the pre-SMA and caudal-AC activation were identified by a contrast between sustained activity during working memory delays as compared with sustained activity during control delays in which subjects were waiting for a cue to make a simple manual motor response. Thus, the present findings suggest that sustained activity during working memory delays in both the pre-SMA and caudal-AC does not reflect simple motor preparation but rather a state of preparedness for selecting a motor response based on the information held on-line.     

Substance P regulates somatostatin expression in inflammation

Substance P (SP) and somatostatin (SOM) are made at mucosal surfaces and sites of inflammation. There is a SP/SOM immunoregulatory circuit that modulates the IFN-gamma response in murine schistosomiasis. SP enhances, while SOM decreases, IFN-gamma secretion. Various inflammatory mediators induce macrophages to make SOM, but no known factor limits this expression. It was discovered that SP regulates SOM synthesis. Splenocytes from normal, uninfected mice cultured with LPS, IFN-gamma, or IL-10 for 4 h strongly expressed SOM mRNA, but failed to do so in the presence of SP. The inhibition with 10(-9) M SP was > 85% shown by quantitative PCR. Also, splenocyte SOM content decreased from 1048 +/- 275 to < 10 pg/4 x 10(8) cells following SP exposure. Immunohistochemistry identified SOM solely within splenic macrophages following cytokine stimulation. Mice infected with Schistosoma mansoni form granulomas in the liver and intestines resulting from deposition of parasite eggs in these organs. The granulomas contain macrophages that make SOM constitutively. SP at 10(-8) M decreased SOM mRNA expression > 90% in dispersed granuloma cells cultured for 4 h or longer. Specific SP receptor antagonists blocked SP suppression of SOM expression in splenocytes and dispersed granuloma cells, showing that an authentic SP receptor mediated the regulation. Additional studies revealed that IL-4 antagonized the SP effect in the spleen. It is concluded that in granulomas and splenocytes from mice with schistosomiasis and in splenocytes from uninfected animals that 1) SP inhibits macrophage SOM induction and ongoing expression at the mRNA and protein levels acting through the SP receptor, and 2) IL-4 can antagonizes this SP effect.     

Myofibroblastoma of the breast revisited: an etiologic association with androgens?

In order to test the hypothesis that normal gravity is an important influence on human serum [Erythropoietin] ([Epo]), the hematologic response to 16 d of 6 degrees head-down tilt (HDT, n = 6 men) was compared with 16 d of normal gravity exposure (CON, n = 7 men). Prior to bed rest, CON and HDT subjects, respectively, were similar in the following characteristics (mean +/- SD): age = 40 +/- 3, 39 +/- 6 yr; height = 181 +/- 5, 182 +/- 6 cm; weight = 88.5 +/- 11.3, 81.7 +/- 12.0 kg; maximal oxygen consumption in supine 6 degrees head-down tilt position (VO2max) = 2.63 +/- 0.38, 2.67 +/- 0.52 L.min-1; hematocrit = (Hct) 41.6 +/- 2.4, 43.0 +/- 3.4%; hemoglobin ([Hb]) = 15.1 +/- 1.0, 14.5 +/- 1.0 g.100 ml-1; plasma volume (PV) = 3829 +/- 857, 3768 +/- 512 ml; and [Epo] = 11.6 +/- 2.9, 10.0 +/- 6.2 mU.ml-1. Calculated red cell volume (RCV) was greater in HDT than CON (2845 +/- 410 vs. 2139 +/- 253 ml, p < 0.05) at baseline. Decreases in PV (-15%, 580 ml, p < 0.05) and an insignificant decrease in RCV (-12%, 354 ml, p = 0.07) were observed in the HDT group, with a concurrent 6% increase in [Hb] (p < 0.05). PV, RCV and [Hb] remained unchanged in the CON group. [Epo] remained unchanged during HDT (12.2 +/- 3.2; 10.8 +/- 3.8; 11.2 +/- 3.1; 11.2 +/- 2.6 mU.ml-1 for HDT days 1, 2, 8 and 16, respectively). There was no difference between CON and HDT groups in [Epo] before or during HDT. It was concluded that the insignificant change (-12%) in RCV observed during HDT was insufficient to stimulate an increase in [Epo], probably because the content of oxygen in arterial blood remained unaffected. The observation that [Epo] remained unchanged despite this loss of RCV during HDT also suggests a possible decrease in the responsiveness of the erythropoietic system to [Epo].     

In vitro repression of Brca1-associated RING domain gene, Bard1, induces phenotypic changes in mammary epithelial cells

BRCA1-associated RING domain (BARD1) was identified as a protein interacting with the breast cancer gene product BRCA1. The identification of tumorigenic missense mutations within BRCA1 that impair the formation of BARD1-BRCA1 complexes, and of BARD1 mutations in breast carcinomas, sustain the view that BARD1 is involved in BRCA1-mediated tumor suppression. We have cloned the murine Bard1 gene and determined that its expression in different tissues correlates with the expression profile of Brca1. To investigate the function of Bard1, we have reduced Bard1 gene expression in TAC-2 cells, a murine mammary epithelial cell line that retains morphogenetic properties characteristic of normal breast epithelium. Partial repression of Bard1, achieved by the transfection of TAC-2 cells with plasmids constitutively expressing ribozymes or antisense RNAs, resulted in marked phenotypic changes, consisting of altered cell shape, increased cell size, high frequency of multinucleated cells, and aberrant cell cycle progression. Furthermore, Bard1-repressed cell clones overcame contact inhibition of cell proliferation when grown in monolayer cultures and lost the capacity to form luminal structures in three-dimensional collagen gels. These results demonstrate that Bard1 repression induces complex changes in mammary epithelial cell properties which are suggestive of a premalignant phenotype.     

Evaluation of once-weekly therapy for tuberculosis using isoniazid plus rifamycins in the mouse aerosol infection model

Once-weekly therapy with combinations of isoniazid plus a rifamycin was tested in the mouse low-dose aerosol infection model against two strains of Mycobacterium tuberculosis. Combinations of isoniazid and rifalizil and isoniazid and rifapentine were both highly effective. These animal model data thus support the evaluation of these regimens under clinical conditions.     

Accuracy of technicians versus pharmacists in checking syringes prepared for a dialysis program

The accuracy of pharmacy technicians versus pharmacists in checking drug doses prepared in syringes for a dialysis program was studied. Three pharmacy technicians from the pharmacy of a regional kidney disease program in Minnesota participated in the study after completing a training program and after common preparation errors had been identified by pharmacists. From November 1995 to April 1996, the technicians used labels printed from a database of pharmacist-verified orders to prepare and label i.v. syringes. Four medications were used-epoetin alfa, calcitriol, heparin prepared from beef lung, and heparin prepared from porcine intestinal mucosa. Each syringe was checked by one of nine pharmacists for accuracy of dose and medication, and all errors were recorded. The technicians checked syringes prepared by other technicians and also recorded errors. Accuracy rates (percentages of syringes correctly evaluated) for pharmacists and technicians were compared. A total of 10,608 syringes were checked. Accuracy rates for pharmacists and pharmacy technicians were 99.86% and 99.83%, respectively. Accuracy rates in checking syringes did not differ significantly between pharmacists and technicians in this study setting.     

Conservative surgical management of tubal pregnancy

In an attempt to maintain optimal fertility in the patient treated for midtubal pregnancy, an investigation of conservative surgical procedure was made. The technic developed utilizes tubal excision, reanastomosis, and a single hydrotubation with Dextran. Tubal patency was maintained without the use of stents that may damage the fimbria. The procedure is compared to other conservative technics and its advantages discused. Thus far 2 patients have undergone this excision and reanastomosis, and both patients successfully established intrauterine gestations within 2 months of returning to normal active coital frequency. Both were in the midtrimester of pregnancy at the time of this report.     

Change in fluconazole susceptibility patterns and genetic relationship among oral Candida albicans isolates

OBJECTIVE: To assess the genetic homogeneity or heterogeneity within each set of Candida albicans isolates colonizing/infecting the oral cavities of HIV-infected patients undergoing azole therapy when changes in susceptibility to fluconazole were detected. DESIGN: Fourteen HIV-positive patients suffering recurrent episodes of oral candidosis were prospectively followed from the first episode to the isolation of strains with decreased susceptibility to fluconazole. The strains of C. albicans isolated either from episodes or controls throughout the prospective study were analysed. METHODS: Electrophoretic karyotyping and hybridization with the repeated sequence probe 27A were used to delineate sequential isolates. In vitro susceptibility tests to fluconazole and ketoconazole were also performed. The results obtained by DNA fingerprinting with the probe combined with computer-assisted analysis were used to assess the genetic relationships amongst the strains. In addition, comparison with the genetic relatedness of a group of geographically unrelated strains was made. RESULTS: Isogenic populations of sequential isolates were observed only in two patients; 12 patients harboured heterogenic populations over time, although in 11 patients there was a predominant strain that was isolated more than once, and only one of these patients carried strains with a similarity index less than 80%. With the exception of two patients, each patient carried a major strain that became less susceptible to fluconazole. The similarity index for the unrelated strains was 59%. CONCLUSIONS: HIV-infected patients may carry a mixed population of strains, but the strains tend to be related to each other. The strains were maintained throughout the course of infection and at least one developed secondary resistance to fluconazole.