Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study

OBJECTIVE: The renin-angiotensin system has a pathophysiological role in cardiovascular disease through a variety of processes. Polymorphisms in involved genes have been described and implicated in stroke. The aim of this study was to investigate two polymorphisms in two genes in the renin-angiotensin system and the risk of stroke. DESIGN: A nested case-control study using baseline data obtained from population-based surveys in northern Sweden was performed. There were 275 individuals without major concomitant disease who suffered a first ever stroke during follow-up and 549 controls matched for age, sex and domicile. METHODS: Blood samples obtained at baseline were analyzed for potential risk factors including the A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene and the functional insertion/deletion polymorphism of the angiotensin-converting enzyme gene. RESULTS: Individuals with the AA genotype of the AT1R gene were at increased risk of ischemic stroke (odds ratio = 1.60; P = 0.005) compared with those with the AC and CC genotypes. The D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with a higher risk of stroke (odds ratio = 1.58; P = 0.014). CONCLUSION: In this prospective study, there was an association between A1166C polymorphism in the angiotensin II receptor gene and ischemic stroke. We also replicated previous observations that the D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with increased risk of stroke. The observed elevated stroke risks conferred by these two polymorphisms are independent of each other and common risk factors such as blood pressure, diabetes, smoking and high cholesterol levels.     

Infection of donor lymphocytes with human T lymphotrophic virus type 1 (HTLV-I) following allogeneic bone marrow transplantation for HTLV-I positive adult T-cell leukaemia

Summary. Human T lymphotrophic virus type 1 (HTLV-I) associated leukaemia has a poor prognosis even with chemotherapy. We describe a patient with adult T-cell leukaemia treated with allogeneic bone marrow transplantation from an HTLV-I negative identical sibling donor. During follow-up after bone marrow transplantation, HTLV-I could be repeatedly isolated inspite of anti-viral prophylaxis. The patient died of an acute encephalitis and HTLV-I could be detected in autopsy material from the brain. By a PCR-based technique using short tandem repeats (STRs) it was shown that the patient's haemopoiesis was of donor origin. This shows the infection of donor cells in vivo by an aetiological agent which has been implicated in the leukaemogenic process for adult T-cell leukaemia.     

Longitudinal Study of Extended-Spectrum-β-Lactamase- and AmpC-Producing Enterobacteriaceae in Household Dogs

A longitudinal study was performed to (i) investigate the continuity of shedding of extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae in dogs without clinical signs, (ii) identify dominant plasmid-mediated ESBL genes, and (iii) quantify ESBL-producing Enterobacteriaceae in feces. Fecal samples from 38 dogs were collected monthly for 6 months. Additional samples were collected from 7 included dogs on a weekly basis for 6 weeks. Numbers of CFU per gram of feces for non-wild-type Enterobacteriaceae were determined by using MacConkey agar supplemented with 1 mg/liter cefotaxime (MCC), and those for total Enterobacteriaceae were determined by using MacConkey agar. Cefotaxime-resistant isolates were screened by PCR and sequence analysis for the presence of bla_CTX-M, bla_CMY, bla_SHV, bla_OXA, and bla_TEM gene families. Bacterial species were identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) analysis. PCR-negative isolates were tested by a double-disk synergy test for enhanced AmpC expression. A total of 259 samples were screened, and 126 samples were culture positive on MCC, resulting in 352 isolates, 327 of which were Escherichia coli. Nine dogs were continuously positive during this study, and 6 dogs were continuously negative. Monthly or weekly shifts in fecal shedding were observed for 23 dogs. Genotyping showed a large variety of ESBL genes and gene combinations at single and multiple consecutive sampling moments. The ESBL genes bla_CTX-M-1, bla_CTX-M-14, bla_CTX-M-15, bla_SHV-12, and bla_CMY-2 were most frequently found. The mean number of CFU of non-wild-type Enterobacteriaceae was 6.11 × 10⁸ CFU/g feces. This study showed an abundance of ESBL-producing Enterobacteriaceae in dogs in the Netherlands, mostly in high concentrations. Fecal shedding was shown to be highly dynamic over time, which is important to consider when studying ESBL epidemiology.     

A CGG‐Repeat Expansion Mutation in ZNF713 Causes FRA7A: Association with Autistic Spectrum Disorder in Two Families

We report de novo occurrence of the 7p11.2 folate‐sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG‐repeat expansion mutation (～450 repeats) in a 5′ intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband‐derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG‐repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed.     

Active online assessment of patients using new oral anticoagulants: bleeding risk, compliance, and coagulation analysis

Clinicians prescribing new oral anticoagulants (OACs; dabigatran, rivaroxaban, and apixaban) should be aware of the exclusion criteria related to bleeding risks defined in published clinical studies. At least a quarter of patients currently using warfarin have an exclusion criterion that may prevent easy transition to the new OACs. In the summary of product characteristics for dabigatran, as an example, the target populations appear generalized. Due to fixed dosing and predictable pharmacology, routine laboratory monitoring of new OACs is deemed unnecessary. Under special circumstances, however, understanding the extent of thrombin or factor (F) Xa inhibition may aid in evaluating compliance and handling emergency interventions, bleeding complications, or overdoses. Although commonly available global coagulation-time assessments (prothrombin time and activated partial thromboplastin time) are insensitive, they may assist clinical management by indicating a severe accumulation of OACs; moreover, a normal thrombin time (TT) excludes a thrombin-inhibitor effect. In particular circumstances, specific assays (diluted TT, Ecarin clotting time, anti-FIIa or anti-FXa activity) may quantify the anticoagulant effect, but therapeutic ranges for dose adjustment are not yet established. Laboratory results are also influenced by clinical situation: e.g. bleed (consumption of coagulation factors) versus postoperative state (activation of coagulation). Without specific antidotes and evidence-based treatment strategies, new OACs are clinically worrisome in patients with impaired renal or liver function. Postmarketing surveillance and recording of bleeding complications (ICD-10 D68.32) are therefore of major importance.     

C-reactive protein in relation to early atherosclerosis and periodontitis

Periodontitis may affect atherosclerosis via the chronic inflammation. We investigated high-sensitivity C-reactive protein (hsCRP) in relation to early vascular atherosclerotic changes in non-symptomatic subjects with and without long-term periodontitis. Carotid ultrasonography with calculation of common carotid artery intima-media area (cIMA) was performed, and hsCRP and atherosclerosis risk factors were analysed in randomly chosen 93 patients with periodontitis and 41 controls. The relationship between hsCRP, cIMA and atherosclerosis risk factors was evaluated with multiple logistic regression analysis. Women displayed lower hsCRP (p < 0.05) and higher serum HDL (p < 0.001) than men. In all patients with periodontitis, cIMA values were higher than in controls. Periodontitis appeared to be a major predictor for increased cIMA (odds ratio, 3.82; 95% confidence interval, 1.19–12.26). Neither of these factors was significantly associated with hsCRP which thus appeared not sensitive enough to be a marker for periodontitis or atherosclerosis. Hence, irrespective of low hsCRP levels, periodontitis appeared to increase the risk for atherosclerosis.     

Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times

The prognostic value of grading follicular lymphoma has been debated since the 1980s. There is consensus that World Health Organization (WHO) grades 1 and 2 are indolent, but not whether grades 3A or 3B are aggressive. We retrospectively reviewed the follicular lymphoma diagnoses according to the 2008 WHO classification in all diagnostic specimens from a population-based cohort of 505 patients with a median follow-up time of 10·0years (range, 4·6-16·0). After excluding 43 patients with concomitant diffuse large B-cell lymphoma, 345 remained with grade 1-2, 94 with grade 3A, and 23 with grade 3B follicular lymphoma. Grades 1-2 and 3A seemed equally indolent, with indistinguishable clinical courses, even in patients receiving anthracyclines. Compared with grades 1-3A and independently of clinical factors, grade 3B correlated with higher mortality (P=0·008), but outcome was improved after upfront anthracycline-containing therapy (P=0·015). In contrast to grade 1-3A patients, grade 3B patients experienced no relapses or deaths beyond 5years of follow-up. Furthermore, patients with grade 3B were predominantly male and seldom presented with bone-marrow involvement. We conclude that follicular lymphoma grade 1-3A is indolent and incurable with conventional therapy. Grade 3B appears to be an aggressive but curable disease.     

The immediate effects of deep breathing exercises on atelectasis and oxygenation after cardiac surgery

Objective—To investigate the effects of deep breathing performed on the second postoperative day after coronary artery bypass graft surgery.

Design—The immediate effects of 30 deep breaths performed without a mechanical device (n?=?21), with a blow bottle device (n?=?20) and with an inspiratory resistance‐positive expiratory pressure mask (n?=?20) were studied. Spiral computed tomography and arterial blood gas analyses were performed immediately before and after the intervention.

Results—Deep breathing caused a significant decrease in atelectatic area from 12.3?±?7.3% to 10.2?±?6.7% (p?<?0.0001) of total lung area 1?cm above the diaphragm and from 3.9?±?3.5% to 3.3?±?3.1% (p?<?0.05) 5?cm above the diaphragm. No difference between the breathing techniques was found. The aerated lung area increased by 5% (p?<?0.001). The PaO ₂ increased by 0.2?kPa (p?<?0.05), while PaCO ₂ was unchanged in the three groups.

Conclusion—A significant decrease of atelectatic area, increase in aerated lung area and a small increase in PaO ₂ were found after performance of 30 deep breaths. No difference between the three breathing techniques was found.