Nucleotide precursors modify the effects of isoproterenol. Studies on heart function and cardiac adenine nucleotide content in intact rats

In closed-chest rats, isoproterenol (ISO, 25 mg/kg), 5 hours after subcutaneous administration, increased heart rate by 53%, left ventricular (LV) dP/dtmax by 80%, and cardiac output by 37%. LV systolic pressure (LVSP, -10%), mean arterial pressure (MAP, -12%), and total peripheral resistance (TPR, -36%) were diminished. In separate experiments, continuous intravenous infusion of adenine (50 mg/kg/hr) for 5 hours reduced heart rate (-11%), LVSP (-16%), MAP (-20%), TPR (-33%), and LV dP/dtmax (-20%). Cardiac output was increased (+20%). Inosine has been shown to have similar effects, except for a decline in cardiac output. Adenine (50 mg/kg/hr) attenuated the ISO-induced increase in heart rate and LV dP/dtmax and aggravated the decline in LVSP, MAP, and TPR. The increase in cardiac output was not changed. Inosine (200 mg/kg/hr) modified the ISO effects to a similar extent. Ribose (200 mg/kg/hr) added to the adenine infusion did not have functional effects. However, it aggravated the modifying influence of inosine on LVSP, LV dP/dtmax, and MAP. ISO reduced the cardiac ATP content (mumol/g) from a control value of 5.02 +/- 0.06 (n = 12) to 3.51 +/- 0.13 (n = 10). Adenine (3.56 +/- 0.21, n = 7) and ribose (3.64 +/- 0.11, n = 9) alone did not affect it, but inosine attenuated it (4.33 +/- 0.08, n = 8). Adenine and inosine in combination with ribose abolished the ISO-induced ATP decline (5.18 +/- 0.23, n = 7, and 4.76 +/- 0.10, n = 8, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma

BackgroundPrimary sclerosing cholangitis confers risk of cholangiocarcinoma. Here, we assessed the primary sclerosing cholangitis-associated variant rs3197999 in the MST1 gene, coding for RON receptor tyrosine kinase ligand macrophage stimulating protein, in a large European cholangiocarcinoma cohort.Materials and methods223 cholangiocarcinoma patients including three primary sclerosing cholangitis individuals and 355 cancer- and primary sclerosing cholangitis-free controls were genotyped for MST1 rs3197999.ResultsThe cancer group departed from Hardy–Weinberg equilibrium (p = 0.022) and exhibited a trend for rs3197999 [A] overrepresentation (31% vs. 26%: p = 0.10). Homozygous rs3197999 [AA] carrier status significantly increased overall (OR = 1.97; p = 0.023) and primary sclerosing cholangitis-unrelated biliary tract cancer risk (OR = 1.84; p = 0.044), relative to homozygous common allele carriers. The association was most pronounced in patients with extrahepatic tumours. This finding was robust to multivariate analysis (p < 0.05), validating the [AA] genotype as an independent cholangiocarcinoma risk factor.ConclusionsThese results suggest that the [AA] genotype of the common MST1 variant rs3197999 enhances genetic risk of sporadic extrahepatic cholangiocarcinoma irrespective of primary sclerosing cholangitis status, presumably by modulating inflammatory responses and/or altered MSP/RON signalling.     

Predicting virologically confirmed influenza using school absences in Allegheny County,Pennsylvania, USA during the 2007‐2015 influenza seasons

BackgroundChildren are important in community‐level influenza transmission. School‐based monitoring may inform influenza surveillance.MethodsWe used reported weekly confirmed influenza in Allegheny County during the 2007 and 2010‐2015 influenza seasons using Pennsylvania''s Allegheny County Health Department all‐age influenza cases from health facilities, and all‐cause and influenza‐like illness (ILI)‐specific absences from nine county school districts. Negative binomial regression predicted influenza cases using all‐cause and illness‐specific absence rates, calendar week, average weekly temperature, and relative humidity, using four cross‐validations.ResultsSchool districts reported 2 184 220 all‐cause absences (2010‐2015). Three one‐season studies reported 19 577 all‐cause and 3012 ILI‐related absences (2007, 2012, 2015). Over seven seasons, 11 946 confirmed influenza cases were reported. Absences improved seasonal model fits and predictions. Multivariate models using elementary school absences outperformed middle and high school models (relative mean absolute error (relMAE) = 0.94, 0.98, 0.99). K‐5 grade‐specific absence models had lowest mean absolute errors (MAE) in cross‐validations. ILI‐specific absences performed marginally better than all‐cause absences in two years, adjusting for other covariates, but markedly worse one year.ConclusionsOur findings suggest seasonal models including K‐5th grade absences predict all‐age‐confirmed influenza and may serve as a useful surveillance tool.     

Peripheral blood stem cell collection in allogeneic donors: impact of venous access

BACKGROUND: Peripheral blood stem cell (PBSC) collection is accepted as a routine procedure in related and unrelated healthy donors worldwide. Venous access can be accomplished by peripheral veins or a central venous catheter (CVC). STUDY DESING AND METHODS: We compared efficacy and tolerability of 40 PBSC collections via CVC with 6267 PBSC collections via peripheral veins in healthy allogeneic donors. Results of the leukapheresis procedures and side effects in the donors were evaluated. RESULTS: The median CD34+ cell counts on Day 5 and the results of the stem cell collection were not significantly different between the two groups of allogeneic donors. Pain or problems at the site of puncture or catheter insertion occurred in 58.6% of the donors with a CVC versus 37.8% of the donors with peripheral venous access (p = 0.03). The incidence and severity of paresthesia during the leukapheresis was not significantly different in both groups of donors (p = 0.09). During follow‐up no major adverse events related to CVC were reported. CONCLUSION: Central femoral lines proved to be safe and tolerable in healthy allogeneic donors but peripheral venous access should be preferred, whenever possible.     

Differential effects of angiotensin II receptor blockade on pressure-induced left ventricular hypertrophy and fibrosis in rats

The effects of the angiotensin II receptor type 1 (AT1) antagonist losartan on pressure overload-induced left ventricular (LV) hypertrophy were studied in female Sprague-Dawley rats. Starting on the day of surgery, losartan (L, 12 mg/kg/day) was administered as continuous intraperitoneal infusion for 2 weeks by using alzet mini-osmotic-pumps (model 2002). This dose of losartan shifted the in vivo dose-response curve of the angiotensin II-induced elevation of left ventricular systolic pressure (LVSP) to the right. Pressure overload was achieved by placing a band around the aortic arch. This caused an aortic stenosis (AS) with an outer diameter of 1.0 mm. The hemodynamic effects were measured in the intact, anesthetized rats (n = 15). The hearts were excised, and the weights of the left (LV) and right ventricle (RV) were determined. Some of these hearts (n = 7) were perfused with collagenase to obtain isolated cardiac myocytes for the measurement of cell volume. Other hearts (n = 8) were examined for morphological changes. In the animals with AS, LVSP was markedly elevated. Furthermore, LV weight and LV myocyte cell volume were increased in this group, while RV weight and RV myocyte cell volume remained stable in all the groups. L had no significant effect on the AS-induced increase in LVSP and cell size parameters, nor on the weight gain of the LV. Histological analysis revealed that the AS-induced enlargement of the mean myocyte diameter was not affected by L. The interstitial collagen fraction was increased in the AS rats and became normalized by L. These data suggest that the renin-angiotensin system might not be involved in the development of pressure-induced cardiac hypertrophy within the time-frame of these experiments, but that it does play a major role in the genesis of the interstitial fibrosis which is a typical feature of this pathophysiological condition.     

Individual and Relationship-Level Correlates of Transactional Sex Among Adolescent Girls and Young Women in Malawi: A Multilevel Analysis

AIDS and Behavior - Transactional sex increases HIV risk among adolescent girls and young women (AGYW). Understanding the individual and dyadic nature of transactional sex may provide evidence for...     

Heart function and molecular biological parameters are comparable in young adult and aged rats after chronic myocardial infarction

OBJECTIVE: To test the hypothesis that IL-1beta and IL-6 play a pivotal role after myocardial infarction (MI) particularly in aged rats. METHODS: Chronic MI was induced in young adult (3.5 months) and aged (18 months) female Sprague-Dawley rats by ligation of the left coronary artery. Sham-operated animals of corresponding age served as controls. Heart function was measured by catheterization 4 weeks after MI. The expression of IL-1beta, IL-6, TGF-beta-isoforms, ANF, and components of the extracellular matrix (pro-collagen I and III, colligin, MMP-2 and TIMP2) was measured by ribonuclease protection assay. RESULTS: Aged control rats differed from young adult rats in that LV-developed pressure (LVDP) was higher (161 vs. 147 mmHg, p<0.05) in response to the elevated total peripheral resistance (0.71 vs. 0.47 mmHg ml min/kg, p<0.05). Contractility was reduced in aged controls as indicated by decreased LV dP/dt (8.106 vs. 10.606 mmHg/s, p<0.05). LV function was severely depressed in both MI groups (reduction in LVDP by about 35% and LV dP/dt by about 30%, increase in LVEDP to 24 mmHg) while RVP and RV dP/dt markedly increased by about 100%. This was not different between both MI groups. ANF expression as a marker of hypertrophy was induced in both MI groups, but less pronounced in the LV of aged rats. Also, the mRNA expression pattern was qualitatively comparable, but showed gradual differences. CONCLUSION: These results indicate that aged rats compensate well for hemodynamic overload induced by MI. Also, the mechanisms of myocardial post-MI remodeling are comparable in young adult and aged rats.