Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study

Summary. Background: Recent studies indicate that arterial cardiovascular diseases and venous thromboembolism (VTE) share common risk factors. A family history of myocardial infarction (MI) is a strong and independent risk factor for future MI. Objectives: The purpose of the present study was to determine the impact of cardiovascular risk factors, including family history of MI, on the incidence of VTE in a prospective, population‐based study. Patients and methods: Traditional cardiovascular risk factors and family history of MI were registered in 21 330 subjects, aged 25–96 years, enrolled in the Tromsø study in 1994–95. First‐lifetime VTE events during follow‐up were registered up to 1 September 2007. Results: There were 327 VTE events (1.40 per 1000 person‐years), 138 (42%) unprovoked, during a mean of 10.9 years of follow‐up. In age‐ and gender‐adjusted analysis, age [hazard ratio (HR) per decade, 1.97; 95% confidence interval (CI), 1.82–2.12], gender (men vs. women; HR, 1.25; 95% CI, 1.01–1.55), body mass index (BMI; HR per 3 kg m^?2, 1.21; 95% CI, 1.13–1.31), and family history of MI (HR, 1.31; 95% CI, 1.04–1.65) were significantly associated with VTE. Family history of MI remained a significant risk factor for total VTE (HR, 1.27; 95% CI, 1.01–1.60) and unprovoked VTE (HR, 1.46; 95% CI, 1.03–2.07) in multivariable analysis. Blood pressure, total cholesterol, HDL‐cholesterol, triglycerides, and smoking were not independently associated with total VTE. Conclusions: Family history of MI is a risk factor for both MI and VTE, and provides further evidence of a link between venous and arterial thrombosis.     

Incidence of acute kidney injury in cancer patients: A Danish population-based cohort study

Background

Cancer patients may be at increased risk of acute kidney injury, but evidence is limited.

Methods

We assembled a cohort of incident cancer patients diagnosed within a population-based hospital setting in Northern Denmark (population:~1.2 million) between 1999 and 2006. Patients were followed up to five years for acute kidney injury, identified using creatinine measurements recorded in a laboratory database covering the study area. Acute kidney injury was defined according to recent consensus criteria as a 50% increase in creatinine level. We computed incidence rate, 1-year, and 5-year risks of acute kidney injury, accounting for competing risk from death. Acute kidney injury incidence was compared between cancers using a Cox regression model adjusted for important confounders.

Results

Among 37,267 incident cancer patients with a creatinine measurement, 9613 (25.8%) developed acute kidney injury during 77,376 person-years. The incidence was 258 (95%CI: 252-264) per 1000 person-years the first year after cancer diagnosis decreasing to 43 (95%CI: 41-44) thereafter. The 1-year risk was 17.5% (95%CI: 17.1-17.9%), and the 5-year risk was 27.0% (95%CI: 26.5-27.5%). We observed the highest 1-year risk in patients with kidney cancer [44.0% (95%CI: 40.5-47.5)], liver cancer [33.0% (95%CI: 28.2-37.8%)], or multiple myeloma [31.8% (95%CI: 27.3-36.3%)]. Similar results were observed after adjustment for confounders. Both overall and for most specific cancer sites, risks were higher among patients with distant metastases at cancer diagnosis.

Conclusion

Acute kidney injury is a common complication in cancer patients, particularly in patients with kidney cancer, liver cancer, or multiple myeloma.     

Prenatal maternal alcohol consumption and hospitalization with asthma in childhood: a population-based follow-up study

BACKGROUND: Asthma may have a prenatal origin. We examined whether maternal alcohol consumption during pregnancy increases the risk of hospitalization with asthma in children. METHODS: We conducted a follow-up study on 10,440 singletons born at approximately 36 weeks of gestation or later to mothers attending midwife centers between April 1984 and April 1987 in Denmark. The mothers completed a questionnaire regarding lifestyle and socioeconomic factors, including alcohol consumption. The children were followed up through the Danish Hospital Discharge Registry. We determined the first hospitalization with a discharge diagnosis of asthma as recorded in the Danish Hospital Discharge Registry. RESULTS: Most pregnant women (81.5%) drank at least some alcohol during pregnancy, but only a few (2.1%) consumed 120 g or more per week. In total, 307 children were hospitalized at least once with a discharge diagnosis of asthma during follow-up (the cumulative incidence risk was 3.5% from birth to 12 years of age or the end of follow-up). After adjusting for maternal socioeconomic factors, dietary components, and other lifestyle factors, children whose mothers drank alcohol during pregnancy did not have an increased risk of hospitalization with asthma compared with the children of mothers who reported no alcohol consumption during pregnancy (adjusted incidence rate ratio, 0.95; 95% confidence interval, 0.70-1.29). Further analyses showed no association with the dose and type of alcohol or with binge drinking. CONCLUSIONS: The study provides no support for a causal link between maternal alcohol intake during pregnancy and asthma in childhood.     

Autoregulation of endogenous glucose production during hyperglucagonemia

Increased endogenous glucose production (EGP) contributes to fasting hyperglycemia in type II diabetes. In nondiabetic subjects, increased gluconeogenesis from lactate does not increase EGP. Type 2 diabetes is associated with hyperglucagonemia. The present study was undertaken to examine whether physiologic elevation of plasma glucagon overrides autoregulation of EGP. Eight healthy volunteers were studied on 2 occasions, once during a 3-hour infusion of 30 micromol/kg/min Na-lactate and once during a control infusion of Na-bicarbonate. Plasma glucagon, insulin, and growth hormone were clamped at identical levels in both experiments. Rates of appearance of glucose, lactate, and gluconeogenesis from lactate were measured by tracer techniques. Glucagon infusion rate was elevated when the lactate or bicarbonate infusions were started to induce physiologic hyperglucagonemia. Plasma glucagon increased from baseline levels (234 +/- 21 ng/L and 211 +/- 23 ng/L) to 313 +/- 47 ng/L (bicarbonate experiments) and 329 +/- 43 ng/L (lactate experiments, means +/- SE, P >.3). Lactate infusion increased plasma lactate concentrations from 1.1 +/- 0.9 to 4.6 +/- 0.5 mmol/L (P =.0003). Lactate conversion to glucose increased from 1.5+/-0.3 to 2.8+/-0.8 micromol/kg/min (P =.03) and from 1.7 +/- 0.3 to 8.1 +/- 0.8 micromol/kg/min (P =.0003) in the bicarbonate and lactate experiments, respectively. The increments in lactate conversion to glucose differed significantly (P =.0008). Nevertheless, plasma glucose and EGP were not different in the bicarbonate and lactate experiments: 5.4 +/- 0.5 versus 6.6 +/- 0.7 mmol/L (P =.21), and 10.5 +/- 0.6 versus 11.6 +/- 0.6 micromol/kg/min (P =.19). We conclude that in normal volunteers, neither hyperglucagonemia nor the combination of hyperglucagonemia and increased substrate availability alters the autoregulation of EGP.     

Wound healing activity of aqueous extract of Crotalaria verrucosa in Wistar albino rats

ObjectiveTo evaluate the wound healing effect of aqueous extract of Crotalaria verrucosa (C. verrucosa) in rats.MethodsThree wound models including incision, excision and dead space wounds were used in this study. The parameters studied were breaking strength in incision models, granulation tissue dry weight, breaking strength and hydroxyproline content in dead space wounds, percentage of wound contraction and period of epithelialization in excision wound model.ResultsTwo doses of the extract with and without dexamethasone showed significant increases in mean hydroxyproline, total protein content and dry weight of granulation tissue but it was higher with dose 800 mg/kg comparing with the control. The dexamethasone treated group showed a significant (P<0.001) reduction in the wound breaking strength when compared to control group in incision type of wound model. Coadministration of C. verrucosa with dexamethasone significantly (P<0.001) increased the breaking strength compared to the dexamethasone treated only group. In excision wound model, the percentage of the wound contraction was significantly (P<0.01) increased by two doses of test extract on all the days except the lower dose which exhibited only on 12 th, 16 th days of drug treatment and it also reversed the dexamethasone suppressed wound contraction. It significantly (P <0.001) reduced the time required for epithelialization and reversed the epithelialization delaying effect of dexamethasone (P<0.001).ConclusionsC. verrucosa was found to possess significant wound healing property. This was evident by decrease in the period of epithelialization, increase in the rate of wound contraction, skin breaking strength, and granulation tissue dry weight content. Hence C. verrucosa could be a good wound healing agent.     

Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages

The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC- IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth- inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14- cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14- mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.     

Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin

A new pharmacologic agent, anti-CD3F(ab')2-ricin toxin A chain (RTA), was synthesized for the purpose of targeting T cells and as a means of treating established graft-versus-host disease (GVHD). The Fc region of anti-CD3 monoclonal antibody (MoAb) was removed to prevent its ability to activate T cells. The resulting F(ab')2 fragments were conjugated to deglycosylated RTA (dgRTA), a catalytic and potent phytotoxin. The resulting immunotoxin (IT) was potent (greater than 95% inhibition) and selective in inhibiting T-cell mitogenesis in vitro. In vivo, the IT depleted 80% of T cells in mice receiving bone marrow (BM) transplants. Transplantation in an aggressive acute GVHD model using C57BL/6 donor cells and H-2 disparate B10.BR recipients resulted in an infiltration of CD3-expressing cells and a median survival time (MST) of 20 to 30 days. A 5-day course of anti-CD3F(ab')2-RTA (30 micrograms/d intraperitoneally) beginning 7 days after GVHD induction was beneficial in treating established GVHD in these mice, as evidenced by significantly prolonged survival (MST, greater than 80 days), superior mean weight values, and improved clinical appearance. Neither intact anti-CD3, unconjugated anti-CD3 F(ab')2 fragments, nor a mixture of anti-CD4 and anti-CD8 MoAbs (which are highly effective in prophylactic models) were as effective. F(ab')2 fragments made from anti-Lyt-1 (the murine homologue of human anti-CD5) linked to RTA were also not effective, despite the fact that both anti-CD3F(ab')2-RTA and anti-Lyt- 1F(ab')2-RTA had similar half-lives of about 9 hours. The IT also increased MST in two aggressive models of GVHD across non-H-2 minor histocompatibility barriers, indicating that the usefulness of anti- CD3F(ab')2-dgRTA is not limited to a single-strain combination. This agent should be further investigated as an alternative to current strategies for treating steroid refractory GVHD.     

Antibiotic-treated versus germ-free rodents for microbiota transplantation studies

We recently investigated the applicability of antibiotic-treated recipient mice for transfer of different gut microbiota profiles. With this addendum we elaborate on perspectives and limitations of using antibiotics as an alternative to germ-free (GF) technology in microbial transplantation studies, and we speculate on the housing effect. It is possible to transfer host phenotypes via fecal transplantation to antibiotic-treated animals, but problems with reproducibility, baseline values, and antibiotic resistance genes should be considered. GF animals maintained in isolators still seem to be the best controlled models for long-term microbial transplantation, but antibiotic-treated recipients are also commonly utilized. We identify a need for systematic experiments investigating the stability of microbial transplantations by addressing 1) the recipient status as either GF, antibiotic-treated or specific pathogen free and 2) different levels of protected housing systems. In addition, the developmental effect of microbes on host physiological functions should be evaluated in the different scenarios.