Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients.

Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR-gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion-dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD.

Proton pump inhibitors and risk of Clostridium difficile infection: a multi-country study using sequence symmetry analysis.

OBJECTIVE: To determine the association between incident proton pump inhibitor (PPI) use and Clostridium difficile infections across multiple countries Method: National data covering the total population in Australia and Korea, the Canadian population over 65 years and a 3 million person random sample data set from Taiwan were assessed, as were data from a worker insurance population and a hospital inpatient/outpatient population in Japan. Sequence symmetry analysis was used to assess the association with oral vancomycin dispensing as the outcome of interest. RESULTS: 54,957 patients were included. Positive associations were observed in Australia; adjusted sequence ratio (ASR) 2.48 (95% CI 1.90, 3.12), Korea ASR 2.15 (95%CI 2.11, 2.19), Canada ASR 1.45 (95% CI 1.16, 1.79), Japan hospital dataset ASR 3.21 (95%CI 2.12, 4.55) and Japan worker insurance dataset ASR 5.40 (95% CI 2.73, 8.75). The pooled result was ASR 2.40 (95%CI 1.88, 3.05) and 3.16 (95%CI 1.95, 5.10) when limited to Japan, Korean and Taiwan. Results did not vary by individual PPI. The temporal analysis showed effects within the first two weeks of PPI initiation. CONCLUSION: Our study confirms the association between PPI initiation and C. difficile infections across countries in the Asia-Pacific region.

Variation in Association Between Thiazolidinediones and Heart Failure Across Ethnic Groups: Retrospective analysis of Large Healthcare Claims Databases in Six Countries.

INTRODUCTION: The prevalence of polymorphisms among the metabolising enzymes and pharmacodynamic receptors relevant for the thiazolidinediones differs by ethnic group, a factor that may modify risk of adverse drug events. OBJECTIVE: The aim of the study was to determine if the risk of oedema or heart failure associated with the thiazolidinediones varies in populations in Australia, Canada, Hong Kong, Japan, Korea and Taiwan. METHODS: Sequence symmetry analyses were undertaken to investigate the risk of peripheral oedema, as measured by incident furosemide dispensing, and risk of hospitalisations for heart failure. Results were pooled, with Australia and Canada representing predominantly Caucasian population and all other countries contributing to Asian population estimates. RESULTS: Pooled estimates of risk for furosemide initiation in the Caucasian populations were significantly increased for pioglitazone [adjusted sequence ratio (ASR) 1.47; 95 % confidence interval (CI) 1.14-1.91] and rosiglitazone (ASR 1.65; 95 % CI 1.58-1.72), while in the Asian populations, the pooled risk estimates were lower (ASR 1.11; 95 % CI 0.93-1.32 and ASR 1.21; 95 % CI 1.01-1.45 for pioglitazone and rosiglitazone, respectively). Results for hospitalisation for heart failure showed a similar trend, with elevated risk in the Australian data (ASR 1.88; 95 % CI 1.01-3.5 and ASR 1.25; 95 % CI 0.76-2.05 for pioglitazone and rosiglitazone, respectively), while no increased risk was found in the pooled results for the Asian populations. CONCLUSION: The risk of both oedema and heart failure with thiazolidinediones was higher in predominantly Caucasian countries than in the Asian countries assessed. Assessment of adverse events by ethnicity may support safer medicine use.

Stress, coping, uplifts, and quality of life in subtypes of depression: a conceptual frame and emerging data.

BACKGROUND: Depressive illness is associated with several functional disturbances, including increased stress perception and reliance on emotion focused coping styles, reduced perception of uplifting events, and impairment of several aspects of quality of life. Inasmuch as different subtypes of depression may be accompanied by differing neuroendocrine profiles, it was of interest to establish whether they could also be distinguished from one another on the basis of functional behavioral indices. METHODS: Major stressors, day-to-day stressors and uplift perception, coping styles, and quality of life were assessed in control participants, as well as in acute or chronically (dysthymia) depressed patients exhibiting either typical or atypical features, and in treatment resistant major depressive patients. RESULTS: Relative to controls, the depressive groups had higher perceptions of day-to-day stressors (hassles), reduced perception of uplifting events, excessive reliance on emotion-focused coping strategies, and diminished quality of life. Among depressed patients the hassles, coping styles and some elements of quality of life were related to symptom severity, as well as treatment-resistance. LIMITATIONS: Data concerning stress, coping and quality of life were collected retrospectively, and the number of subjects in each condition was small. Hence, the relationship of the outcome measures to depression need to be considered cautiously. CONCLUSIONS: Quality of life represents a functional index of the behavioral and cognitive impact of depression. This outcome measure is sensitive to differences as a function of depressive characteristics, and may prove to be a useful assessment tool in evaluating treatment efficacy.