Central sleep apnea after acute coronary syndrome and association with ticagrelor use.

STUDY OBJECTIVES: By modifying the apneic threshold, the antiplatelet agent ticagrelor could promote central sleep apnea hypopnea syndrome (CSAHS). We aimed to assess the association between CSAHS and ticagrelor administration. METHODS: Patients were prospectively included within 1 year after acute coronary syndrome (ACS), if they had no heart failure (and left ventricular ejection fraction ≥ 45%) and no history of sleep apnea. After an overnight sleep study, patients were classified as "normal" with apnea hypopnea index (AHI) < 15, "CSAHS patients" with AHI ≥ 15 mostly with central sleep apneas, and "obstructive sleep apnea hypopnea syndrome (OSAHS) patients" with AHI ≥ 15 mostly with obstructive sleep apneas. RESULTS: We included 121 consecutive patients (mean age 56.8 ± 10.8, 88% men, mean body mass index 28.3 ± 4.4 kg/m2, left ventricular ejection fraction 56 ± 5%, at a mean of 67 ± 60 days (median 40 days, interquartile range: 30-80 days) after ACS. In total, 49 (45.3%) patients had AHI ≥ 15 (27 [22.3%] CSAHS %, 22 [18.2%] OSAHS). For 80 patients receiving ticagrelor, 24 (30%) had CSAHS with AHI ≥ 15, and for 41 patients not taking ticagrelor, only 3 (7.3%) had CSAHS with AHI ≥ 15 (chi-square = 8, p = 0.004). On multivariable analysis only age and ticagrelor administration were associated with the occurrence of CSAHS, (p = 0.0007 and p = 0.0006). CONCLUSION: CSA prevalence after ACS is high and seems promoted by ticagrelor administration. Results from monocentric study suggest a preliminary signal of safety. CLINICAL TRIALS. GOV ID: NCT03540459.

Cost-effectiveness of family history-based colorectal cancer screening in Australia.

BACKGROUND: With 14.234 diagnoses and over 4047 deaths reported in 2007, colorectal cancer (CRC) is the second most common cancer and second most common cause of cancer-related mortality in Australia. The direct treatment cost has recently been estimated to be around AU$1.2 billion for the year 2011, which corresponds to a four-fold increase, compared the cost reported in 2001. Excluding CRCs due to known rare genetic disorders, 20% to 25% of all CRCs occur in a familial aggregation setting due to genetic variants or shared environmental risk factors that are yet to be characterised. A targeted screening strategy addressed to this segment of the population is a potentially valuable tool for reducing the overall burden of CRC. METHODS: We developed a Markov model to assess the cost-effectiveness of three screening strategies offered to people at increased risk due to a strong family history of CRC. The model simulated the evolution of a cohort of 10,000 individuals from age 50 to 90 years. We compared screening with biennial iFOBT, five-yearly colonoscopy and ten-yearly colonoscopy versus the current strategy of the Australian National Bowel Cancer Screening Programme (i.e. base case). RESULTS: Under the NBCSP scenario, 6,491 persons developed CRC with an average screening lifetime cost of AU$3,441 per person. In comparison, screening with biennial iFOBT, colonoscopy every ten years, and colonoscopy every five years reduced CRC incidence by 27%, 35% and 60%, and mortality by 15%, 26% and 46% respectively. All three screening strategies had a cost under AU$50,000 per life year gained, which is regarded as the upper limit of acceptable cost-effectiveness in the Australian health system. At AU$12,405 per life year gained and an average lifetime expectancy of 16.084 years, five-yearly colonoscopy screening was the most cost-effective strategy. CONCLUSION: The model demonstrates that intensive CRC screening strategies targeting people at increased risk would be cost-effective in the Australian context. Our findings provide evidence that substantial health benefits can be generated from risk-based CRC screening at a relatively modest incremental cost.

The one-dimensional organic-inorganic hybrid: catena-poly[bis-[1-(3-ammonio-prop-yl)-1H-imidazolium] [[iodidoplumbate(II)]-tri-µ-iodido-plumbate(II)-tri-µ-iodido-[iodidoplumbate(II)]-di-µ-iodido]].

The organic-inorganic hybrid, {(C(6)H(13)N(3))(2)[Pb(3)I(10)]}(n), was obtained by the reaction of 1-(3-ammonio-prop-yl)imidazolium triiodide and PbI(2) at room temperature. The structure contains one-dimensional {[Pb(3)I(10)](4-)}(n) polymeric anions spreading parallel to [001], resulting from face-face-edge association of PbI(6) distorted octa-hedra. One of the Pb(II) cations is imposed at an inversion centre, whereas the second occupies a general position. N-H⋯I hydrogen bonds connect the organic cations and inorganic anions.

Accuracy of a portable international normalized ratio monitor for patients receiving a low molecular weight heparin as a bridge pending full oral anticoagulant efficacy.

BACKGROUND: Point of care (POC) devices measuring the international normalized ratio (INR) are accurate for patients with stable disease, but their efficiency has not been prospectively assessed during the "bridging period" when patients are receiving a low molecular weight heparin (LMWH) on top of a vitamin K antagonist (VKA) until the target INR is reached. METHODS: 188 dual INR measurement using the POC (INR(POC)) and the laboratory (INR(lab)) at the same time were consecutively determined : 69 in patients receiving LMWH+VKA (bridging group) and 119 in patients receiving only a VKA (control group). INRpoc was compared to INR(lab). RESULTS: Test strip failure rate was higher in the bridging group than in the control group (29% vs 4%; p<0,001). In successful tests, POC accuracy was not modified by LMWH administration: the correlation coefficients between POC and lab INR values for the bridging group and the control group were 0,81 and 0,87 respectively, and the relative measure of divergence (RMD=INR(lab) - INR(poc)/INR(lab)) was lower in the bridging group than in the control group (4+/-7% vs 10+/-14%; p=0,02). Finally, clinically relevant agreement between POC and laboratory was of 90% in the bridging group and 92.1% in the control group (p=0.6). CONCLUSION: With the POC used (INRatio), in patients receiving LMWH when the POC gives a result, it is as accurate as in patients not receiving a LMWH.

Sickle Cell Disease in the Post Genomic Era: A Monogenic Disease with a Polygenic Phenotype.

More than half a century after the discovery of the molecular basis of Sickle Cell Disease (SCD), the causes of the phenotypic heterogeneity of the disease remain unclear. This heterogeneity manifests with different clinical outcomes such as stroke, vaso-occlusive episodes, acute chest syndrome, avascular necrosis, leg ulcers, priapism and retinopathy. These outcomes cannot be explained by the single mutation in the beta-globin gene alone but may be attributed to genetic modifiers and environmental effects. Recent advances in the post human genome sequence era have opened the door for the identification of novel genetic modifiers in SCD. Studies are showing that phenotypes of SCD seem to be modulated by polymorphisms in genes that are involved in inflammation, cell-cell interaction and modulators of oxidant injury and nitric oxide biology. The discovery of genes implicated in different phenotypes will help understanding of the physiopathology of the disease and aid in establishing targeted cures. However, caution is needed in asserting that genetic modifiers are the cause of all SCD phenotypes, because there are other factors such as genetic background of the population, environmental components, socio-economics and psychology that can play significant roles in the clinical heterogeneity.

The one-dimensional organic inorganic hybrid compound poly[(diethyl-ene-triamine)tetra-µ-iodido-dilead(II)].

A new organic-inorganic hybrid, [Pb(2)I(4)(C(4)H(13)N(3))](n), was obtained by the reaction of C(4)N(3)H(10) and PbI(2) at room temperature. The structure is a three-dimensional polymer resulting from the association of PbI(6) octa-hedra and a mixed lead organic-inorganic PbI(4)(C(4)N(3)H(13)) coordination polyhedron. Both Pb atoms, two I atoms and one N atom lie on a mirror plane. N-H⋯I hydrogen bonds further connect the organic unit and some I atoms.

[BNP and echocardiography can predict the occurrence of acute cardiac decompensation during titration of bisoprolol in chronic systolic heart failure]. / Le BNP et l'échocardiographie prédisent la survenue de décompensation cardiaque aigue au cours de la titration du bisoprolol dans l'insuffisance cardiaque chronique systolique.

OBJECTIVES: Based on the fact that NYHA class, plasma BNP level, and echocardiographic indices of left ventricular filling pressures are prognostic factors in chronic systolic heart failure, we evaluated their predictive value for acute decompensation following initiation and titration of bisoprolol in this illness. METHODS AND RESULTS: Bisoprolol was initiated and/or increased according to the ESC/ACC/AHA recommendations in 50 patients with stable chronic systolic heart failure (age: 60+/-2 years, males: 88%) in NYHA class? 2 with a left ventricular ejection fraction (LVEF)<40% and a plasma creatinine<250 micromol/l. The clinical parameters, plasma BNP levels and echocardiographic indices were measured blind on the same day, on admission and then once a week for three weeks. On admission, the NYHA was 2.9+/-0.1, mean plasma creatinine 99+/-3 micromol/l, plasma BNP 503+/-57 pg/ml, LVEF 29+/-1%, E/A ratio 1.9+/-0.2, E/Ea ratio 8.8+/-0.3, E wave deceleration time 155+/-9 ms, systolic pulmonary artery pressure 40+/-2 mmHg and the diameter of the inferior vena cava was 16+/-1 mm. Over the course of follow up, an episode of acute decompensation occurred in 16% of the patients (8/50). Using univariate analysis, age and initial (admission) values for NYHA class, blood pressure, plasma BNP level, E/A ratio, E wave deceleration time, E/Ea ratio and the systolic pulmonary arterial pressure allowed prediction of the occurrence of acute decompensation following initiation and titration of bisoprolol. The use of the initial value of NYHA class alone allowed prediction of the occurrence of acute decompensation in just 56% of the patients, and the absence of an occurrence of acute decompensation in 93% of them. Normal results for the echocardiographic indices (systolic pulmonary arterial pressure<40 mmHg or E/A ratio<1.4 or E wave deceleration time>145 ms) as recorded on admission were associated with the absence of an occurrence of acute decompensation is 100% of cases. The combined use of NYHA class>3 and either a BNP>398 pg/ml or echocardiographic indices in favour of an elevation in left ventricular filling pressures (systolic pulmonary arterial pressure>40 mmHg, E/A ratio>1.4 or E wave deceleration time<145 ms) allowed prediction of the occurrence of acute heart failure in 100% of cases CONCLUSION: The combined use of NYHA class, BNP level and echocardiographic indices for measuring left ventricular filling pressures is more pertinent than the isolated use of clinical parameters for predicting tolerance to bisoprolol in chronic heart failure with a LVEF<40%.

[Exercise training in cardiac patients: usefulness of the cardiopulmonary exercise test]. / Réadaptation des patients porteurs d'une cardiopathie: intérêt de la mesure des echanges gazeux a l'effort (VO2).

Exercise training is currently including in the treatment of coronary arterial disease patients, in patients with left ventricular dysfunction as well as in patients who underwent cardiac transplantation or cardiac surgery. However methods of prescribing exercise-training programs are difficult to determine and must be adapted for each patient Exercise test with gas analysis through the determination of anaerobic threshold may help to understand the physiopathological mechanism related to exercise limitation in these patients. Exercise test may help to precise exercise intensity during cardiac rehabilitation and may assess the benefits on exercise tolerance.

[Heart failure and cachexia]. / Insuffisance cardiaque et cachexie.

Cachexia is related to a malnutrition state related to hypercatabolism. Initially described in cancer, it is also related to several chronic diseases including heart failure. Defined by an unintentional weight loss exceeding 7.5% of body mass during more than 6 months, it is presented by the association of nutritional deficiencies, digestive and/or urinary losses as well as metabolic abnormalities causing fat and lean mass loss and is associated to a poor prognosis. The pathophysiology of cachexia and heart failure presented some similarities associating especially neuro-hormonal activation, a cortisol/DHEA ratio imbalance, as well as pro-inflammatory cytokines activation. Currently the treatment of cachexia is mainly preventive, based on ACE-inhibitors and beta-blockers therapy and physical reconditioning. The benefits of hormonal and nutritional substitutes remains to be evidenced.

Allelic heterogeneity of GNE gene mutation in two Tunisian families with autosomal recessive inclusion body myopathy.

Autosomal recessive hereditary inclusion body myopathy (AR-HIBM), with sparing of the quadriceps, is characterized by adult-onset, with weakness and atrophy of distal lower limb muscles, and typical histopathological findings in muscle biopsy. AR hIBM is associated with mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene on chromosome 9p12-13 . We report two unrelated Tunisian families with clinical and pathological features of AR HIBM. One distinct homozygous GNE missense mutation, M712T, previously reported in Middle Eastern Jewish patients, and a newly identified one, L379H, were found in one patient from each family. We conclude that AR HIBM in Tunisia shows an allelic genetic heterogeneity.

Phenotype and sarcoglycan expression in Tunisian LGMD 2C patients sharing the same del521-T mutation.

Limb-girdle muscular dystrophy type 2C is an autosomal recessive muscular disorder caused by mutations in the gene encoding the gamma-sarcoglycan subunit. This gamma-sarcoglycanopathy is prevalent in Tunisia where only one homozygous mutation a 521-T deletion has been identified. The aim of this study was to carry out a comparative clinical and immunocytochemical analysis of Tunisian patients sharing the same gamma-sarcoglycan gene mutation. One hundred and thirty-two patients were classified as severe, moderate or mild according to a calculated severity score. Heterogeneous phenotypes between siblings were encountered in 75% of the families. The severity of the disease was not found to be related to the age of onset. Immunohistochemical studies of muscle biopsy showed a total absence of gamma-sarcoglycan, a normal or slightly reduced alpha and delta-sarcoglycans whereas the expression of beta-sarcoglycan was variable. The residual sarcoglycan expression was not related to the clinical phenotype. In conclusion, the phenotypic variability in sarcoglycanopathies in Tunisia seems to involve a modifying gene controlling the course of the disease.

[Treatment of left intraventricular thrombosis with low molecular weight heparin]. / Traitement des thrombus intraventriculaires gauches par héparine de bas poids moléculaire.

UNLABELLED: Following the discovery of a left intra ventricular thrombus (LIVT), the classical approach consists of treatment with non-fractionated heparin (NFH) followed by oral anticoagulants. The use of NFH for this indication has only been evaluated in one open, non randomised study of 23 patients with no control group. Low molecular weight heparins (LMWH) have not been the object of any study although they are routinely used by certain teams. The objective of this study was to evaluate the feasibility of the use of LMWH in the treatment of left intra ventricular thrombus. This was an open, non randomised prospective study. All patients having a newly diagnosed LIVT between September 2000 and September 2002 were treated with enoxaparine (100 IU/kg twice daily) for an average duration of 13 days; replacement with fluindione was started on the fifth day. The progression of the LIVT was followed using twice weekly transthoracic echocardiography for 3 weeks. RESULTS: 19 LIVT were discovered in 2 years (13 complicating an anterior infarct and 6 with a dilated cardiomyopathy). The average area was between 2.64 +/- 0.41 cm2 and 0.43 +/- 0.21 cm2 (p < 0.0001). Thirteen out of 19 thrombi disappeared with treatment (68.5%). There was no thrombocytopenia or haemorrhage. One transient ischaemic attack was noted. CONCLUSION: This preliminary work shows that LMWH are well tolerated and effective to make a thrombus disappear or to reduce its size.

Fukutin-related protein gene mutated in the original kindred limb-girdle MD 2I.

The authors mapped an autosomal recessive form of limb-girdle MD on chromosome 19q13.3 (LGMD2I), further narrowed down the candidate region to 1.1 Mb, and identified one new homozygous mutation in the fukutin-related protein (FKRP) gene on patients of the original Tunisian family. Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and laminin-alpha2 supporting the hypothesis that FKRP has a role in the interaction between the extracellular matrix components.

Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy.

BACKGROUND: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal-recessive disorder with preferential involvement of the tibialis anterior muscle that starts in young adulthood and spares quadriceps muscles. The disease locus has been mapped to chromosome 9p1-q1, the same region as the hereditary inclusion body myopathy (HIBM) locus. HIBM was originally described as rimmed vacuole myopathy sparing the quadriceps; therefore, the two diseases have been suspected to be allelic. Recently, HIBM was shown to be associated with the mutations in the gene encoding the bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). OBJECTIVE: To determine whether DMRV and HIBM are allelic. METHODS: The GNE gene was sequenced in 34 patients with DMRV. The epimerase activity in lymphocytes from eight DMRV patients was also measured. RESULTS: The authors identified 27 unrelated DMRV patients with homozygous or compound-heterozygous mutations in the GNE gene. DMRV patients had markedly decreased epimerase activity. CONCLUSIONS: DMRV is allelic to HIBM. Various mutations are associated with DMRV in Japan. The loss-of-function mutations in the GNE gene appear to cause DMRV/HIBM.

4-ammonio-2,2,6,6-tétraméthylpipéridinium chromate dihydrate.

The title compound, 4-ammonio-2,2,6,6-tetramethylpiperidinium chromate dihydrate, (C9H22N2)[CrO4]*2H2O, crystallizes in the monoclinic system with one organic cation and one chromate anion in the asymmetric unit, together with three independent sites for water molecules, two of which have their O atoms located on twofold axes. The structure is composed of layers built up from CrO4(2-) tetrahedra and water molecules alternating with C9H22N2(2+) cations and additional water molecules. Two types of hydrogen bonds, O-H...O and N-H...O, ensure the cohesion and stability of the structure.

Enhanced flow-dependent vasodilatation after bed rest, a possible mechanism for orthostatic intolerance in humans.

We investigated the alteration in flow-dependent-dilatation in the orthostatic intolerance occurring after bed-rest deconditioning. Eight men [aged mean (SEM) 32 (2) years] underwent two consecutive periods of 7 days of head-down-tilt (HDT, -6 degrees) during bed rest. A control age and sex matched group [n = 8, 30 (2) years], maintained its usual physical activity. Blood flow velocity (BFV) and diameter (Doppler and echotracking systems) were measured in the brachial artery, under basal conditions and during the post ischaemic hyperaemia following occlusion. The increase in BFV post-ischaemia did not change before, during and after HDT but the relative increase in the diameter was greater on the 7th day of the HDT period than before HDT [+8.8(1.6)% compared to +3.7(1.0)%, P < 0.001]. After HDT, 11 of 16 standing tests (comprising eight subjects in the two HDT periods) had to be stopped because of orthostatic intolerance. The flow-dependent-dilatation measured at the end of HDT was negatively correlated with the post-bed-rest duration of orthostatic tolerance (r = 0.78, P < 0.01). After the sublingual administration of glyceryl trinitrate, there was no change in the increase in diameter. No significant changes were observed in the control group. Bed-rest deconditioning enhances the flow-dependent vasodilatation of large arteries and might contribute to the orthostatic intolerance observed following bed-rest.

A new locus for autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3.

Autosomal recessive limb-girdle muscular dystrophies represent a genetically heterogeneous group of diseases characterized by a progressive involvement of skeletal muscles. They show a wide spectrum of clinical courses, varying from very mild to severe. Eight loci responsible for autosomal recessive limb-girdle muscular dystrophies have been mapped and six defective genes identified. In this study, we report the clinical data, muscle biopsy findings and results of genetic linkage analysis in a large consanguineous Tunisian family with 13 individuals suffering from autosomal recessive limb-girdle muscular dystrophy. Clinical features include variable age of onset, proximal limb muscle weakness and wasting predominantly affecting the pelvic girdle, and variable course between siblings. CK rate was usually high in younger patients. Muscle biopsy showed dystrophic changes with normal expression of dystrophin and various proteins of the dystrophin-associated protein complex (sarcoglycan sub-units, dystroglycan, and sarcospan). Genetic linkage analysis excluded the known limb-girdle muscular dystrophies loci as well as ten additional candidate genes. A maximum LOD score of 4.36 at θ=0.00 was obtained with marker D19S606, mapping this new form of autosomal recessive limb-girdle muscular dystrophy to chromosome 19q13.3.

Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure.

BACKGROUND: We hypothesized that, in compensated heart failure (HF), hemodynamic perturbations and their consequences exist in pulmonary artery (PA) despite the absence of any perturbation in thoracic aorta (TA). METHODS AND RESULTS: The left coronary artery was ligated in 20 male Wistar rats with compensated HF. Four months after ligation, these rats were compared with 20 sham-operated control rats. Blood pressure, velocity, viscosity, luminal diameter, and wall tensile and shear stresses were determined in PA and TA. Arterial rings were mounted in a myograph for ex vivo study. Endothelial nitric oxide synthase (eNOS) mRNA expression was determined in lung and aorta. Sections of PA and TA were used for histomorphometric study. In PA from rats with compensated HF, (1) blood pressure and wall tensile stress increased, whereas blood velocity and wall shear stress decreased; (2) contractions to KCl were not altered, but maximal contraction to phenylephrine and EC(50) decreased; (3) endothelium-dependent relaxation to acetylcholine and basal NO activity were blunted, whereas endothelium-independent relaxation was preserved; (4) eNOS mRNA levels and eNOS transcription in lung nuclei decreased; and (5) medial cross-sectional area, thickness, smooth muscle cell number, elastin, and collagen contents increased. Conversely, no such changes were found in TA from rats with compensated HF. CONCLUSIONS: In compensated HF induced by small myocardial infarction, hemodynamics, vascular wall function, and structure are altered in PA but preserved in TA. These results indicate that the pulmonary vascular bed is an early target of regional circulatory alterations in HF.