Novel TULP1 mutation causing leber congenital amaurosis or early onset retinal degeneration

PURPOSE: To report a large, consanguineous Algerian family affected with Leber congenital amaurosis (LCA) or early-onset retinal degeneration (EORD). METHODS: All accessible family members underwent a complete ophthalmic examination, and blood was obtained for DNA extraction. Homozygosity mapping was performed with markers flanking 12 loci associated with LCA. The 15 exons of TULP1 were sequenced. RESULTS: Seven of 30 examined family members were affected, including five with EORD and two with LCA. All patients had nystagmus, hemeralopia, mild myopia, and low visual acuity without photophobia. Fundus features were variable among EORD patients: typical spicular retinitis pigmentosa or clumped pigmented retinopathy with age-dependent macular involvement. A salt-and-pepper retinopathy with midperipheral retinal pigment epithelium (RPE) atrophy was present in the older patients with LCA, whereas the retina appeared virtually normal in the younger ones. Both scotopic and photopic electroretinograms were nondetectable. Fundus imaging revealed a perifoveal ring of increased fundus autofluorescence (FAF) in the proband, and optical coherence tomography disclosed a thinned retina, mainly due to photoreceptor loss. Linkage analysis identified a region of homozygosity on chromosome 6, region p21.3, and mutation screening revealed a novel 6-base in-frame duplication, in the TULP1 gene. CONCLUSIONS: Mutation in the TULP1 gene is a rare cause of LCA/EORD, with only 14 mutations reported so far. The observed intrafamilial phenotypic variability could be attributed to disease progression or possibly modifier alleles. This study provides the first description of FAF and quantitative reflectivity profiles in TULP1-related retinopathy.

Risk factors for early catheter-related infections in cancer patients

BACKGROUND: Early catheter-related infection is a serious complication in cancer treatment, although risk factors for its occurrence are not well established. The authors conducted a prospective study to identify the risk factors for developing early catheter-related infection. METHODS: All consecutive patients with cancer who underwent insertion of a central venous catheter were enrolled and were followed prospectively during 1 month. The study endpoint was occurrence of early catheter-related infection. RESULTS: Over 10,392 catheter-days of follow-up, 14 of 371 patients had early catheter-related infections (14 patients in 10,392 catheter-days or 1.34 per 1000 catheter-days). The causative pathogens were gram positive in 11 of 14 patients. In univariate analysis, the risk factors for early catheter-related infection were aged <10 years (P = .0001), difficulties during insertion (P < 10(-6)), blood product administration (P < 10(-3)), parenteral nutrition (P < 10(-4)), and use >2 days (P < 10(-6)). In multivariate analysis, 3 variables remained significantly associated with the risk of early catheter-related infection: age <10 years (odds ratio [OR], 18.4; 95% confidence interval [95% CI], 1.9-106.7), difficulties during insertion procedure (OR, 25.6; 95% CI, 4.2-106), and parenteral nutrition (OR, 28.5; 95% CI, 4.2-200). CONCLUSIONS: On the day of insertion, 2 variables were identified that were associated with a high risk of developing an early catheter-related infection: young age and difficulties during insertion. The results from this study may be used to identify patients who are at high risk of infection who may be candidates for preventive strategies.

Differential effects of captopril and nitrates on muscle sympathetic nerve activity in volunteers

BACKGROUND The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Activation of SNS plays an important role in the pathophysiology and the prognosis of cardiovascular diseases such as heart failure, acute coronary syndromes, arrhythmia, and possibly hypertension. Vasodilators such as adenosine and sodium nitroprusside are known to activate SNS via baroreflex mechanisms. Because vasodilators are widely used in the treatment of patients with cardiovascular diseases, the aim of the present study was to assess the influence of clinically used dosages of isosorbide dinitrate and captopril on sympathetic nerve activity at rest and during stimulatory maneuvers. METHODS AND RESULTS Twenty-eight healthy volunteers were included in this double-blind placebo-controlled study, and muscle sympathetic nerve activity (MSA; with microelectrodes in the peroneal nerve), blood pressure, heart rate, and neurohumoral parameters were measured before and 90 minutes after the oral administration of 40 mg isosorbide dinitrate or 6.25 mg captopril. Furthermore, a 3-minute mental stress test and a cold pressor test were performed before and 90 minutes after drug administration. Resting MSA did not change after captopril and decreased compared with placebo (P < .05 versus placebo), whereas isosorbide dinitrate led to a marked increase in MSA (P < .05). Systolic blood pressure was reduced by isosorbide dinitrate (P < .05), whereas captopril decreased diastolic blood pressure (P < .05). The increases in MSA, blood pressure, and heart rate during mental stress were comparable before and after drug administration regardless of the medication. During cold pressor test, MSA and systolic and diastolic blood pressures increased to the same degree independent of treatment, but after isosorbide dinitrate, the increase in MSA seemed to be less pronounced. Heart rate did not change during cold stimulation. Plasma renin activity increased after captopril and isosorbide dinitrate (P < .05), whereas placebo had no effect. Endothelin-1 increased after placebo and isosorbide dinitrate (P < .05) but not after captopril. CONCLUSIONS Thus, captopril suppressed MSA despite lowering of diastolic blood pressure but allowed normal adaptation of the SNS during mental or physical stress. In contrast, the nitrate strongly activated the SNS under baseline conditions. These findings demonstrate that vasodilators differentially interact with the SNS, which could be of importance in therapeutic strategies for the treatment of patients with cardiovascular diseases.

Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials

A system for screening of nutritional risk is described. It is based on the concept that nutritional support is indicated in patients who are severely ill with increased nutritional requirements, or who are severely undernourished, or who have certain degrees of severity of disease in combination with certain degrees of undernutrition. Degrees of severity of disease and undernutrition were defined as absent, mild, moderate or severe from data sets in a selected number of randomized controlled trials (RCTs) and converted to a numeric score. After completion, the screening system was validated against all published RCTs known to us of nutritional support vs spontaneous intake to investigate whether the screening system could distinguish between trials with a positive outcome and trials with no effect on outcome.

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in 7 unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits thereby interfering with integrin maturation and/or function. Our study extends knowledge of Glanzmann thrombasthenia and the pathophysiology of an integrin. This article is protected by copyright. All rights reserved.

Home parenteral nutrition is beneficial in systemic sclerosis patients with gastrointestinal dysfunction

OBJECTIVES To assess 12-month changes in nutritional status and quality of life (QoL) in systemic sclerosis (SSc) patients requiring home parenteral nutrition (HPN). METHOD We conducted a retrospective, single-centre database analysis of SSc patients regarding a 12-month period of HPN at an interdisciplinary University Unit/team for nutrition and rheumatic diseases. Nutritional status was analysed by nutritional risk screening (NRS) and body mass index (BMI). QoL was evaluated using Short-Form Health Survey (SF-36) questionnaires. RESULTS Between 2008 and 2013, daily nocturnal HPN was initiated in five consecutive SSc patients (four females and one male, mean age 62.2 years) suffering severe malnutrition due to gastrointestinal tract (GIT) involvement. After 12 months of HPN, the mean NRS score decreased from 4.4 (range 4-5) to 1.4 (range 1-2), the mean BMI increased from 19.1 (range 17.4-20.3) to 21.0 kg/m(2) (range 18.3-23.4). QoL improved in all patients, reflected by the summary of physical components with 33.92 points before vs. 67.72 points after 12 months of HPN, and the summary of mental components with 49.66 points before vs. 89.27 points after 12 months of HPN. Two patients suffered one catheter-related infection each with subsequent surgical removal and reinsertion. CONCLUSIONS HPN is a feasible method for improving anthropometric parameters and QoL in SSc patients severely affected by GIT dysfunction. We recommend HPN in malnourished, catabolic SSc patients unable to otherwise maintain or improve their nutritional status.

Screening renal artery angiography in hypertensive patients undergoing coronary angiography and 6-month follow-up after ad hoc percutaneous revascularization

OBJECTIVE: To determine the prevalence and independent predictors of significant atherosclerotic renal artery stenosis (RAS) in unselected hypertensive patients undergoing coronary angiography and to assess the 6-month outcome of those patients with a significant RAS. METHODS: One thousand, four hundred and three consecutive hypertensive patients undergoing drive-by renal arteriography were analyzed retrospectively. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of RAS. In patients with significant RAS (>or=50% luminal narrowing), 6-month follow-up was assessed and outcome was compared between patients with or without renal revascularization. RESULTS: The prevalence of significant RAS was 8%. After multivariate analysis, coronary [odds ratio 5.3; 95% confidence interval (CI) 2.7-10.3; P < 0.0001], peripheral (odds ratio 3.3; 95% CI 2.0-5.5; P < 0.0001), and cerebral artery (odds ratio 2.8; 95% CI 1.5-5.3; P = 0.001) diseases, and impaired renal function (odds ratio 2.9; 95% CI 1.8-4.5; P < 0.0001) were found as independent predictors. At least one of these predictors was present in 96% of patients with RAS. In 74 patients (66%) with significant RAS, an ad hoc revascularization was performed. At follow-up, creatinine clearance was significantly higher in revascularized than in nonrevascularized patients (69.2 vs. 55.5 ml/min per 1.73 m, P = 0.029). By contrast, blood pressure was comparable between both groups, but nonrevascularized patients were taking significantly more antihypertensive drugs as compared with baseline (2.7 vs. 2.1, follow-up vs. baseline; P = 0.0066). CONCLUSION: The prevalence of atherosclerotic RAS in unselected hypertensive patients undergoing coronary angiography was low. Coronary, peripheral, and cerebral artery diseases, and impaired renal function were independent predictors of RAS. Ad hoc renal revascularization was associated with better renal function and fewer intake of antihypertensive drugs at follow-up.

Mild cognitive impairment in medical inpatients: the mini-mental state examination is a promising screening tool

AIM: To assess the prevalence of mild cognitive impairment (MCI) in medical inpatients aged 55-85 years without known cognitive deficits, and how often ward physicians mentioned MCI in their discharge notes. Moreover, we aimed to identify variables associated with MCI and to assess the sensitivity and specificity of the Mini-Mental State Examination (MMSE) for MCI. METHODS: Two neuropsychologists administered a 60-min battery of validated tests to evaluate different cognitive domains. The diagnosis of MCI was based on a prespecified algorithm. The sensitivity and specificity of the MMSE for MCI were calculated. RESULTS: Fifteen patients showed a normal cognitive profile (21.4%), while 55 patients (78.6%) showed MCI. Ward physicians, blinded to the results of the neuropsychological evaluation, did not mention MCI in their discharge notes of any of the evaluated patients. The only variable independently associated with MCI was the MMSE. A MMSE score of < or =28 showed a sensitivity of 85.5% and a specificity of 66.7% for MCI. CONCLUSION: MCI is frequent albeit overlooked in elderly medical inpatients without previously known cognitive deficits. In view of therapies preventing the progression of MCI to dementia, MCI screening will be crucial. The MMSE represents a promising screening tool for MCI in medical inpatients.

Screening for lupus anticoagulant: improving the performance of the lupus-sensitive PTT-LA

Introduction: The aim of the present work was to verify whether calculating a ratio between clotting times obtained with the sensitive PTT-LA and a less sensitive activated partial thromboplastin time (aPTT)-reagent may represent a valuable aPTT-based screening strategy for lupus anticoagulants (LA). Methods: For the pilot study, plasma samples from normal subjects (n = 15) and from patients with LA (n = 10), therapeutic anticoagulation with vitamin K-antagonists (VKA) (n = 15) or unfractionated heparin (n = 15), coagulation factors deficiency (n = 16), and inhibitory antibodies against factor VIII or IX (n = 11) were studied. For the evaluation study, 1553 consecutive plasma samples from nonanticoagulated patients investigated for LA between January 2005 and December 2007 at our institution were studied. Following screening strategies were employed: Pathromtin-SL (aPTT-SL), PTT-LA (aPTT-LA), ratio aPTT-LA/aPTT-SL (aPTT-ratio), and Russell's viper venom (RVV) based LA-Check. LA positive samples were identified by mixing studies and diluted RVV confirmation test (LA-Check/LA-Sure). Results: Pilot study: All screening strategies had a 100% sensitivity, and the aPTT-ratio reached the highest specificity (82%; 95%CI: 74-90%). Within the evaluation study, following sensitivities for LA screening were observed: aPTT-SL 59.0% (95%CI: 57-61%), aPTT-LA 82.1% (95%CI: 80-84%), aPTT-ratio 92.3% (95%CI: 91-94), and LA-Check 83.3% (95%CI: 82-85%). Conclusion: Calculating a ratio between the LA-sensitive PTT-LA and the less sensitive Pathromtin-SL improves the performance of the PTT-LA itself and represents a simple and sensitive aPTT-based integrated strategy for LA screening.

The role of reinfection and partner notification in the efficacy of Chlamydia screening programs

Repeated Chlamydia trachomatis infections after treatment are common. One reason is reinfection from untreated partners in ongoing sexual partnerships. Mathematical models that are used to predict the impact of screening on reducing chlamydia prevalence often do not incorporate reinfection and might overestimate the expected impact. We describe a pair compartmental model that explicitly incorporates sexual partnership duration and reinfection. The pair model predicts a weaker impact of screening when compared directly with a model that does not accommodate partnerships. Effective management of sex partners to prevent reinfection might need to be strengthened in chlamydia control programs.

Transmission dynamics of Chlamydia trachomatis affect the impact of screening programmes

To assess the impact of screening programmes in reducing the prevalence of Chlamydia trachomatis, mathematical and computational models are used as a guideline for decision support. Unfortunately, large uncertainties exist about the parameters that determine the transmission dynamics of C. trachomatis. Here, we use a SEIRS (susceptible-exposed-infected-recovered-susceptible) model to critically analyze the turnover of C. trachomatis in a population and the impact of a screening programme. We perform a sensitivity analysis on the most important steps during an infection with C. trachomatis. Varying the fraction of the infections becoming symptomatic as well as the duration of the symptomatic period within the range of previously used parameter estimates has little effect on the transmission dynamics. However, uncertainties in the duration of temporary immunity and the asymptomatic period can result in large differences in the predicted impact of a screening programme. We therefore analyze previously published data on the persistence of asymptomatic C. trachomatis infection in women and estimate the mean duration of the asymptomatic period to be longer than anticipated so far, namely 433 days (95% CI: 420-447 days). Our study shows that a longer duration of the asymptomatic period results in a more pronounced impact of a screening programme. However, due to the slower turnover of the infection, a substantial reduction in prevalence can only be achieved after screening for several years or decades.

LC-MS/MS screening method for designer amphetamines, tryptamines, and piperazines in serum

Since the late 1990s and early 2000s, derivatives of well-known designer drugs as well as new psychoactive compounds have been sold on the illicit drug market and have led to intoxications and fatalities. The LC-MS/MS screening method presented covers 31 new designer drugs as well as cathinone, methcathinone, phencyclidine, and ketamine which were included to complete the screening spectrum. All but the last two are modified molecular structures of amphetamine, tryptamine, or piperazine. Among the amphetamine derivatives are cathinone, methcathinone, 3,4-DMA, 2,5-DMA, DOB, DOET, DOM, ethylamphetamine, MDDMA, 4-MTA, PMA, PMMA, 3,4,5-TMA, TMA-6 and members of the 2C group: 2C-B, 2C-D, 2C-H, 2C-I, 2C-P, 2C-T-2, 2C-T-4, and 2C-T-7. AMT, DPT, DiPT, MiPT, DMT, and 5MeO-DMT are contained in the tryptamine group, BZP, MDBP, TFMPP, mCPP, and MeOPP in the piperazine group. Using an Applied Biosystems LC-MS/MS API 365 TurboIonSpray it is possible to identify all 35 substances. After addition of internal standards and mixed-mode solid-phase extraction the analytes are separated using a Synergi Polar RP column and gradient elution with 1 mM ammonium formate and methanol/0.1% formic acid as mobile phases A and B. Data acquisition is performed in MRM mode with positive electro spray ionization. The assay is selective for all tested substances. Limits of detection were determined by analyzing S/N-ratios and are between 1.0 and 5.0 ng/mL. Matrix effects lie between 65% and 118%, extraction efficiencies range from 72% to 90%.

Screening the Structural Space of Bicyclo-DNA: Synthesis and Properties of Bicyclo-DNA Functionalized at C(6’)

The synthesis of a novel bicyclo-thymidine nucleoside bearing an ester functionality at C(6') (bc(alpha-alk)-nucleosides) is reported. This nucleoside was incorporated into oligodeoxynucleotides via solid phase phosphoramidite chemistry, and the ester moiety was post-synthetically converted to an amide or a carboxy group, or was left unchanged. Thermal melting data (T-m) with complementary DNA and RNA were collected and compared to natural DNA and to bc- and bc(ox)-DNA. It was found that single incorporations of bc(alpha-alk)-nucleosides in DNA duplexes were destabilizing by 0.5 to 2.5 degrees C/mod, whereas two consecutive bc(alpha-alk)-residues were less destabilizing, and in some cases even stabilizing by 0.5 degrees C/mod. In duplexes with complementary RNA, isolated bc(alpha-alk)-residues destabilized the duplex by -1.0 to -4.0 degrees C/mod, depending on the chemical nature of the substituent, whereas two consecutive modifications were only destabilizing by 0.3-1.0 degrees C/mod. The pairing selectivity was similar to that of unmodified or bc-DNA.