Comparative effectiveness of cardioprotective drugs in elderly individuals with type 2 diabetes.

AIMS: Although many elderly individuals suffer from type 2 diabetes, the effectiveness of cardioprotective drugs in primary prevention of cardiovascular events in clinical practice in this population has rarely been evaluated. We aimed to assess the effectiveness of, (i) angiotensin converting enzyme inhibitors or angiotensin receptor blockers, (ii) statins, (iii) antiplatelet drugs and (iv) the combination of these three drugs, in the prevention of myocardial infarction (MI) and stroke in elderly individuals with type 2 diabetes. METHODS: Using Quebec administrative databases, we conducted nested case-control analyses among a cohort of 17,384 individuals without a history of cardiovascular disease. Individuals were aged ≥ 66 years, newly treated with oral antidiabetes drugs and had not used any of the three above classes of cardioprotective drugs in the year before cohort entry. For each case (MI/stroke during follow-up), five controls were matched for age, year of cohort entry and sex. Use of each drug and of their combination was defined as current, past or no use. We calculated adjusted odds ratios (AOR) of MI/stroke. RESULTS: We observed no reduction in the MI/stroke risk for users of ACEI/ARB nor for users of the three drugs combination. Longer exposure to statins was associated with a lower risk (AOR for every 30 days of therapy: 0.97; 95% CI: 0.96-0.99). By contrast, current use of antiplatelet drugs was associated with an increased risk of MI/stroke (1.40; 1.12-1.75). CONCLUSION: The benefit of cardioprotective drugs in primary prevention was not clear in this cohort of elderly individuals with type 2 diabetes. A short duration of exposure to these drugs might explain the lack of benefit.

Underuse of cardioprotective treatment by the elderly with type 2 diabetes.

AIMS: To assess whether elderly patients with type 2 diabetes use a comprehensive cardioprotective regimen (CCR) of antihypertensive, lipid-lowering and antiplatelet drugs in the year following oral antidiabetic drug initiation and, if so, to identify the determinants of such use. METHODS: Using the Quebec Diabetes Surveillance System administrative database, we carried out an inception cohort study of individuals aged 66 years and over who began oral antidiabetic therapy between 1998 and 2002. Those individuals with at least one claim in the year after starting antidiabetic treatment for an antihypertensive, a lipid-lowering and an antiplatelet drugs were deemed to be using a CCR. A multivariate logistic regression model was built to identify the characteristics associated with CCR use. RESULTS: Of the 48,505 individuals included in the study, 9912 (20.4%) used a CCR during the year following the first antidiabetic claim. Those more likely to use a CCR were men (odds ratio [OR]: 1.2; 99% confidence intervals [CI]: 1.1-1.3), those who had used an antihypertensive (1.6; 1.4-1.7), lipid-lowering (7.4; 6.8-8.0) or antiplatelet (7.3; 6.7-7.9) drug in the year before the first antidiabetic claim and those with a preexisting diagnosis of cardiovascular disease (1.9; 1.8-2.1). The odds of using a CCR increased every year. CONCLUSIONS: CCR use by the elderly with type 2 diabetes in the year following antidiabetic initiation is low, and prior use of individual cardioprotective drugs is a strong predictor of its use. These findings suggest that the treatment of important modifiable risk factors for cardiovascular disease is suboptimal.

Adherence to the evidence-based heart failure drug treatment: Are there sex-specific differences among new users?

BACKGROUND: The evidence-based heart failure (HF) drug treatment is made of a ß-blocker and an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, or hydralazine + isosorbide dinitrate. Little is known about sex-based difference in adherence to the evidence-based HF drug treatment. OBJECTIVES: To assess among new users of the evidence-based HF drug treatment, the association between sex and 1) persistence with the treatment 1 year after its initiation, 2) implementation of the treatment among those who persisted, and 3) overall adherence to treatment in the year following its initiation. METHODS: A cohort study was conducted among new users of this treatment using Quebec medico-administrative data. Patients still on the evidence-based HF drug treatment one year after initiation were considered persistent. Among persistent users, those with ≥88% of days covered by the treatment were deemed to have adequately implemented it. Persistent patients who have adequately implemented the treatment were considered adherent. To measure the association between, on one hand sex, and on the other persistence, implementation and adherence, adjusted proportion ratios (APR) with their 95% confidence intervals (CI) were calculated. RESULTS: Among 13,453 women, 72.1% were persistent, 72.2% adequately implemented the treatment, and 52.8% were adherent. Among the 14,614 men, these proportions were 73.6%, 67.9% and 50.1%, respectively. Men were less likely than women to be adherent to their treatment (APR: 0.96, 95% CI: 0.94-0.99). CONCLUSION: Among individuals initiating an evidence-based multi-drug treatment for HF, men are less likely than women to be adherent to this treatment.

The impact of incident depression on medication adherence in patients with type 2 diabetes.

BACKGROUND: Depression has been correlated with suboptimal adherence to antidiabetic drugs (ADs). Most studies on this topic were cross-sectional; thus, the directionality of this relationship could not be established. The objective of this study was to measure the association between incident depression and AD nonadherence among newly treated patients with diabetes. METHODS: We performed a population-based cohort study among new AD users using the Quebec public health insurance data. To avoid immortal time bias, we carried out depression diagnosis-time distribution matching by assigning a date of depression diagnosis to individuals without depression. Nonadherence (i.e.,<90% of days covered by≥1 AD) during the year following depression diagnosis (real or assigned date) was the outcome. Multivariate logistic regression analyses that adjusted for baseline adherence and other confounders were used to estimate the adjusted effect of depression on AD nonadherence. RESULTS: Between 2000 and 2006, we identified 3,106 new AD users with a subsequent diagnosis of depression and 70,633 without depression, of which 52% and 49% became non-adherent to AD treatment, respectively. Among patients with depression, 52.0% were considered AD non-adherent in the year after depression diagnosis compared with 49.0% of matched patients without depression. Depression was associated with AD nonadherence after accounting for baseline adherence and other confounders with an adjusted odds ratio of 1.24 (95% confidence interval: 1.13-1.37). CONCLUSIONS: The results suggest that depression is an independent risk factor for AD nonadherence. Patients with type 2 diabetes and depression might benefit from adherence-enhancing interventions.

Toll-like receptors, cytokines and the immunotherapeutics of asthma.

Asthma is a complex disease caused by a poorly characterized set of genetic and environmental factors whose pathology is a result of immune dysregulation. Toll-like receptors are pathogen associated molecular pattern receptors expressed by many airway and pulmonary tissues as well as cells of the innate and adaptive immune system. Ligation of toll-like receptors can lead to a change in the expression levels of multiple inflammatory and anti-inflammatory mediators which are involved in the pathogenesis of asthma. These ligands and their receptors are therefore prime candidates in the search for immunotherapeutic treatments of asthma. The use of murine models of allergic asthma as tools for the genetic dissection of this disease should allow the molecular mechanisms underlying asthma to be identified and possibly used as further immunotherapeutic targets.

Deletion cartography around the D13S25 locus in B cell chronic lymphocytic leukemia and accurate mapping of the involved tumor suppressor gene.

The presence of an unidentified tumor suppressor gene on the long arm of chromosome 13 which could be involved in the development of B cell chronic lymphocytic leukemia has been suspected because of frequent deletions of the locus D13S25 which lies 1.6 cM telomeric to the retinoblastoma gene. In order to accurately map this gene, cells from 25 B cell chronic lymphocytic leukemia tumors have been analyzed for allelic loss using a panel of microsatellite markers located in this region. These markers, which stretch from the retinoblastoma gene to the Wilson disease gene, have been ordered for their rank from centromere to telomere. In addition to the data obtained from deletion pattern of these markers, results from preliminary pulse-field electrophoresis studies enable us to redefine the minimal deleted area from more than 1 cM to 280 kilobase around D13S25.

Underexposure of Seniors to Heart Failure Drug Therapy.

BACKGROUND: Little is known about exposure to heart failure (HF) treatment among seniors with ischemic heart disease. OBJECTIVES: In a population of seniors, we: 1) estimated the association between age and exposure to HF drug therapy at 6, 12, 36 and 60 month intervals after HF diagnosis, and 2) determined the influence of the passage of time on exposure to drug therapy. METHODS: Using the Quebec provincial administrative databases, we conducted a population-based inception cohort study that included all individuals aged ≥ 65 with a first HF diagnosis between 2000 and 2009 and an ischemic heart disease diagnosis in the year before HF diagnosis. We assessed exposure to HF drug therapy and to drug therapy at target doses at 6, 12, 36 and 60 month intervals after HF diagnosis. Adjusted prevalence ratios (aPR) between age at diagnosis and exposure to drug therapy and the influence of time (6-month periods) were assessed using multivariate modified Poisson regressions. RESULTS: Among the 86,428 seniors, those who were older were less likely to be exposed to both HF drug therapy and drug therapy at target doses at each time point, than were the younger ones (aged 65-69). The aPRs for exposure to drug therapy for the 90+ age group were 0.64, 0.64, 0.56 and 0.53 at the 6, 12, 36 and 60 month intervals, respectively. After HF diagnosis, exposure increased by a maximum of 8% per 6-month period. CONCLUSION: Increasing age is associated with a decrease in exposure to drug therapy, with only slight improvement in exposure after HF diagnosis.

Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.

BACKGROUND: The SCN5A gene encoding the human cardiac sodium channel alpha subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease). METHODS AND RESULTS: In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na(+) current but normal protein trafficking. CONCLUSIONS: We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation.

Spatial and temporal distribution of the neutral polymorphisms in the last ZFX intron: analysis of the haplotype structure and genealogy.

With 10 segregating sites (simple nucleotide polymorphisms) in the last intron (1089 bp) of the ZFX gene we have observed 11 haplotypes in 336 chromosomes representing a worldwide array of 15 human populations. Two haplotypes representing 77% of all chromosomes were distributed almost evenly among four continents. Five of the remaining haplotypes were detected in Africa and 4 others were restricted to Eurasia and the Americas. Using the information about the ancestral state of the segregating positions (inferred from human-great ape comparisons), we applied coalescent analysis to estimate the age of the polymorphisms and the resulting haplotypes. The oldest haplotype, with the ancestral alleles at all the sites, was observed at low frequency only in two groups of African origin. Its estimated age of 740 to 1100 kyr corresponded to the time to the most recent common ancestor. The two most frequent worldwide distributed haplotypes were estimated at 550 to 840 and 260 to 400 kyr, respectively, while the age of the continentally restricted polymorphisms was 120 to 180 kyr and smaller. Comparison of spatial and temporal distribution of the ZFX haplotypes suggests that modern humans diverged from the common ancestral stock in the Middle Paleolithic era. Subsequent range expansion prevented substantial gene flow among continents, separating African groups from populations that colonized Eurasia and the New World.

Exclusion of Leu1 and Leu2 genes as tumor suppressor genes in 13q14.3-deleted B-CLL.

The chromosomal region 13q14.3 is frequently deleted in B cell chronic lymphocytic leukemia (B-CLL) and it is supposed that a tumor suppressor gene, involved in this leukemogenesis, is located in this area. The first exons of two genes, Leu1 and Leu2, mapped in a minimally deleted 13q14.3 region, are systematically lost in B-CLL sharing a 13q14.3 deletion. These two genes have been proposed as strong tumor suppressor gene candidates. However, in a study on 15 13q14.3 deleted B-CLL, we found three patients in which this critical region was not involved. Because of these results and that no mutations were detected on the two genes in a previous study, we think that Leu1 and Leu2 can be excluded as tumor suppressor genes.

13q14 deletions are not primary events in B-cell chronic lymphocytic leukemia: a study of 100 patients using fluorescence in situ hybridization.

Fluorescence in situ hybridization with a chromosome 12-specific alpha-centromeric probe and a 13q14 yeast artificial chromosome probe was performed on interphase cells from 100 patients with B-cell chronic lymphocytic leukemia. Thirty-one patients exhibited a 13q14 deletion. No correlation was found between 13q14 deletions and clinical stage, sex, or morphology. Sixteen patients had trisomy 12, including 6 (of 12) with an atypical morphology. Trisomy 12 and 13q14 abnormalities were detected concomitantly in three patients only. The analysis of patients with deletions clearly showed that in five cases a significant number of cells retained two signals with the yeast artificial chromosome probe, indicating a genetic heterogeneity among the leukemic population. Our data confirm that the 13q14 deletion is a frequent event, indicate that the concomitant occurrence of 13q14 deletion and trisomy 12 is rare but possible, and show that both abnormalities are secondary events in B-cell chronic lymphocytic leukemia.

[Acrodermatitis enteropathica in full-term breast-fed infant]. / Acrodermatite entéropathique chez un nourrisson né à terme nourri exclusivement au sein.

BACKGROUND: Acrodermatitis enteropathica is a rare autosomal recessive disorder, caused by impaired absorption of zinc from the gastrointestinal tract. Symptoms of acrodermatitis enteropathica occur within the first few months after birth and tend to appear shortly after discontinuation of breast-feeding. We report a breast-fed infant with acrodermatitis enteropathica. CASE REPORT: A full term, 4-month-old girl, consulted in dermatologic department for persistent and refractory anogenital lesions since the age of 1 month, with progressive erythematous, vesiculous and squamous lesions, sometimes erosive in a peri orificial and acral pattern. She was calm and healthy baby. She was breast feeding. The diagnosis of acrodermatitis enteropathica was confirmed by decreased plasma zinc level (14 microg/100 ml). Breast milk zinc levels was low (46 microg/100 ml), as plasma zinc level of the mother (94 microg/100 ml). A genetic study showed that she was homozygous for the mutation, whereas her brother and parents were heterozygous. She was given zinc sulphate, and her condition has improved significantly. DISCUSSION: Acrodermatitis enteropathica is characterized by a characteristic clinical feature and the diagnosis is confirmed by decreased plasma zinc level. Acrodermatitis enteropathica in exclusively breast fed infant is rare, it was essentially reported in premature babies. Our case report is particular because it's concerning a full-term breast-fed infant, with zinc deficiency in breast milk and mother's decreased plasma zinc level.

High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis.

Using allele-specific amplification method (ARMS), a highly sensitive one-stage allele-specific PCR, we have evaluated the incidence of NRAS and KRAS2 activating mutations (codons 12, 13, and 61) in 62 patients with either monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM), primary plasma-cell leukemia (P-PCL), and also in human myeloma cell lines (HMCL). NRAS and/or KRAS2 mutations were found in 54.5% of MM at diagnosis (but in 81% at the time of relapse), in 50% of P-PCL, and in 50% of 16 HMCL. In contrast, the occurrence of such mutations was very low in MGUS and indolent MM (12.50%). Of note, KRAS2 mutations were always more frequent than NRAS. The validity of the technique was assessed by direct sequencing of cell lines and of some patients. Multiple mutations found in two patients were confirmed by subcloning exon PCR amplification products, testing clones with our method, and sequencing them. Thus, these early mutations could play a major role in the oncogenesis of MM and P-PCL.

Interleukin 2-like material in human epidermis: a ligand for the human interleukin 2-receptor 55 kD alpha chain.

The antirecombinant interleukin 2 (rec-IL-2) monoclonal antibody (moAb) 15.2 cross-reacts with a skin antigen located at the cell surface of human keratinocytes within the granular layer. This study extends the analysis of this IL-2-like material to its reactivity with eight antibodies raised against natural IL-2, rec-IL-2 or IL-2 peptides. Four among them were found to react with the granular epidermal layer as well as with a simian virus 40 (SV40) transformed human keratinocyte cell line. Each of these four antibodies gave similar labeling patterns, although with different intensities, and competitively inhibited each other. Analysis at the messenger RNA level in epidermal cells and SVK 14 also indicated that this material is very likely different from IL-2. From the knowledge, for some of these antibodies, of the amino-acid regions they recognize on the IL-2 molecule, it is inferred that the skin antigen shares with IL-2 at least two overlapping epitopes located in the 33-54 amino-acid region of IL-2, a region that has been shown to be involved in the binding of IL-2 to the IL-2-receptor (IL-2-R) 55 kD chain. Indeed, a purified recombinant soluble species of this IL-2-R is shown in this study to bind specifically to the IL-2-like skin material. As far as IL-2-R bearing cells are found in normal epidermis (Langerhans cells) and as important infiltrates of IL-2-R positive T lymphocytes are often encountered in cutaneous diseases, a potential role for this IL-2-like material in skin immunophysiopathology is suggested.

Mitochondrial DNA analysis on remains of a putative son of Louis XVI, King of France and Marie-Antoinette.

Carl Wilhelm Naundorff was buried in 1845 in Delft as Louis Charles, Duc de Normandie, 'Louis XVII'. However, the son of Louis XVI and Marie-Antoinette-Louis XVII--officially died in the Temple of Paris in 1795. In order to resolve the identity of Naundorff, mitochondrial DNA (mtDNA) D-loop sequences of his remains were compared with the sequences obtained from the hairs of two sisters of Marie-Antoinette, Marie-Antoinette herself, and with the sequences obtained from DNA samples of two living maternal relatives. The mtDNA sequence of a bone sample from Naundorff showed two nucleotide differences from the sequences of the three sisters and four differences from the sequences of living maternal relatives. Based on this evidence it becomes very unlikely that Naundroff is the son of Marie-Antoinette.

Characterization of T-cell-receptor gamma (TRG) gene rearrangements in alloreactive T-cell clones.

Rearrangements of the T-cell Rearranging Gene (TRG) or T-cell-receptor gamma-chain genes were analyzed in 24 in vivo-sensitized alloreactive T-cell clones. This analysis represents the first complete assignment of TRG gene rearrangements to given variable and joining gene segments in nonleukemic T cells and provides some evidence for the hypothesis of sequential gamma genes rearrangements during T-lymphocyte differentiation. TRG gene rearrangements in our T-cell panel involved the known "active" V gamma genes, with a preferential use of V2 and V4 genes. In most clones, rearrangements occurred on both chromosomes and involved the J2 segment, but only 2 and 4 out of the 49 described rearrangements involved the additional J gamma segments JP1 and JP2, respectively. Two peculiar rearrangements were found. The first one was probably due to the creation of a new restriction enzyme site in the N-region at the V-J junction; the second can be explained by an aberrant rearrangement of a V gene to a sequence located between exons 2 and 3 of the TRGC1 gene.

Tolerability of antihypertensive drugs in a community-based setting.

BACKGROUND: Outside the experimental environment of clinical trials, the tolerability of angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and the angiotensin II antagonist losartan has not been compared. OBJECTIVES: The purpose of this study was to estimate, in current clinical practice, the 3-month cumulative incidence of side effects among first-time users of losartan, ACEIs, and CCBs for hypertension. METHODS: We conducted a prospective cohort study through a network of 173 pharmacies across Canada to identify patients with hypertension who were newly prescribed monotherapy with losartan, an ACEI, or a CCB. Individuals were interviewed by telephone 3 times over a 3-month period to determine perceived side effects of the antihypertensive medication prescribed. Data were analyzed using a multivariate logistic regression model. RESULTS: Among the 663 eligible individuals, the 3-month cumulative incidence of perceived side effects was 52.5% (42/80), 60.2% (222/369), and 69.6% (149/214) for those treated with losartan, an ACEI, and a CCB, respectively. After adjustment for sex, age, level of education, number of symptoms perceived the week before entering the study, prior use of antihypertensive drugs, current use of any other drug, drug insurance coverage, and duration of hypertension, the odds of reporting a side effect were significantly higher among patients treated with an ACEI (odds ratio [OR] = 1.78: 95% CI, 1.02-3.12) or a CCB (OR = 2.65; 95% CI, 1.47-4.78) compared with patients treated with losartan. CONCLUSIONS: In a community-based setting, we observed that losartan is better tolerated than ACEIs and CCBs. Given that the occurrence of side effects may contribute to lower adherence to drug treatment, the low incidence of side effects associated with losartan makes it an attractive antihypertensive drug choice.