A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign.

BACKGROUND: PPKs represent a heterogeneous group of disorders with hyperkeratosis of palmar and/or plantar skin. PPK, hair shaft abnormalities, cardiomyopathy and arrhythmias can be caused by mutations in desmosomal genes, e.g. desmoplakin (DSP). PPK should trigger genetic testing to reveal mutations with possible related cardiac disease. OBJECTIVES: To report a large multigenerational family with a novel DSP mutation associated with early-onset PPK and adult-onset cardiomyopathy and arrhythmias. METHODS: A custom-designed in-house panel of 35 PPK related genes was used to screen mutations in the index patient with focal PPK. The identified DSP mutation was verified by Sanger sequencing. DNA samples from 20 members of the large multigenerational family were sequenced for the DSP mutation. Medical records were reviewed. Clinical dermatological evaluation was performed, including light microscopy of hair samples. Cardiac evaluation included clinical examination, echocardiography, cardiac magnetic resonance imaging (CMR), electrocardiogram (ECG), Holter monitoring and laboratory tests. RESULTS: We identified a novel autosomal dominant truncating DSP c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated cardiomyopathy (DCM) with arrhythmia susceptibility and focal PPK as an early cutaneous sign. The mutation was found in nine affected family members, but not in any unaffected members. Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age. CONCLUSIONS: We report a novel truncating DSP mutation causing focal PPK with varying severity and left ventricular dilatation and ventricular extrasystoles. This finding emphasizes the importance of genetic diagnosis in patients with PPK for clinical counselling and management of cardiomyopathies and arrhythmias.

A randomized trial comparing dual axis rotational versus conventional coronary angiography in a population with a high prevalence of coronary artery disease.

OBJECTIVES: To compare the safety, radiation dose, and contrast volume between dual axis rotational coronary angiography (DARCA) and conventional coronary angiography (CCA). BACKGROUND: CCA is performed in multiple, predefined stationary views, at different angulations around the patient, for both the left and right coronary arteries. DARCA (AlluraXperSwing™, Philips, the Netherlands) involves a pre-set rotation of the C-arm around the patient and allows for the visualization of each coronary artery in different views, using a single automatic pump contrast injection. METHODS: From November 2012 to February 2013, 201 patients were randomly assigned to either CCA (n = 100) or DARCA (n = 101). Exclusion criteria included acute coronary syndrome (ACS), prior PCI or CABG. CCAs were performed in 4 acquisition runs for the left coronary artery and 2 to 3 acquisition runs for the right coronary artery, whereas DARCAs were performed in a single run for each coronary artery. RESULTS: Baseline demographics and clinical characteristics were similar for both groups. The overall prevalence of CAD was 77.6%. The DARCA group had a significant reduction in the amount of contrast, 60 ml (IQR: 52.5-71.5 ml) versus 76 ml (IQR: 68-87 ml), P < 0.0001; and radiation dose by Air Kerma, 269.5 mGy (IQR: 176-450.5) versus 542.1 mGy (IQR: 370.7-720.8), P < 0.0001. There were fewer patients requiring additional projections in the DARCA group: 54.0% versus 75.0%; P = 0.002. CONCLUSIONS: In a population with a high prevalence of CAD, DARCA was safe and resulted in a significant decrease in contrast volume and radiation dose.

A Stentless Modified Lich-Gregoir Technique for Safe Early Bladder Catheter Removal in Living and Deceased Kidney Transplants.

OBJECTIVES: To describe a stentless modified Lich-Gregoir technique (mLG) for ureteroneocystostomy in renal transplantation (RT), with early bladder catheter (BC) removal (under 48 hours), and compare the postoperative results with those of the traditional technique (LG) with routine bladder catheter removal (4 to 5 days). The modification consists of maintaining a thin layer of detrusor fibers covering the bladder mucosa during dissection, which is incorporated into the anastomosis to reinforce the ureteroneocystostomy. MATERIALS AND METHODS: This retrospective cohort study compared the postoperative outcomes of 100 consecutive patients who underwent mLG with early removal of BC between October 2018 to November 2019 with those of a historical cohort of 165 consecutive patients transplanted using stentless LG and routine removal of BC, who underwent surgery between July 2017 and September 2018. All transplants were performed by the same surgeon. Follow-up was 6 months. RESULTS: Demographic characteristics were comparable, although patients in the mLG group had a higher mean preoperative urine volume (911 ± 753.8mL vs 629 ± 638.6mL, P =.016). Patients in the mLG group successfully underwent early BC removal (2.2 ± 0.9 vs 4.8 ± 4.8 days, P <.001), with no differences in the incidence of surgical or clinical complications, including urine leaks (1% vs 3%, P =.284). In addition, mLG patients presented a shorter mean length of hospital stay (6.5 ± 5.0 vs 7.1 ± 6.2 days, P =.023). CONCLUSION: This stentless modified Lich-Gregoir technique enables safe early bladder catheter removal and is associated with reduced hospital length of stay.

Optical Absorption Exhibits Pseudo-Direct Band Gap of Wurtzite Gallium Phosphide.

Definitive evidence for the direct band gap predicted for Wurtzite Gallium Phosphide (WZ GaP) nanowires has remained elusive due to the lack of strong band-to-band luminescence in these materials. In order to circumvent this problem, we successfully obtained large volume WZ GaP structures grown by nanoparticle-crawling assisted Vapor-Liquid-Solid method. With these structures, we were able to observe bound exciton recombination at 2.14 eV with FHWM of approximately 1 meV. In addition, we have measured the optical absorption edges using photoluminescence excitation spectroscopy. Our results show a 10 K band gap at 2.19 eV and indicate a weak oscillator strength for the lowest energy band-to-band absorption edge, which is a characteristic feature of a pseudo-direct band gap semiconductor. Furthermore, the valence band splitting energies are estimated as 110 meV and 30 meV for the three highest bands. Electronic band structure calculations using the HSE06 hybrid density functional agree qualitatively with the valence band splitting energies.

Author Correction: Optical Absorption Exhibits Pseudo-Direct Band Gap of Wurtzite Gallium Phosphide.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A network approach to discerning the identities of C. elegans in a free moving population.

The study of C. elegans has led to ground-breaking discoveries in gene-function, neuronal circuits, and physiological responses. Subtle behavioral phenotypes, however, are often difficult to measure reproducibly. We have developed an experimental and computational infrastructure to simultaneously record and analyze the physical characteristics, movement, and social behaviors of dozens of interacting free-moving nematodes. Our algorithm implements a directed acyclic network that reconstructs the complex behavioral trajectories generated by individual C. elegans in a free moving population by chaining hundreds to thousands of short tracks into long contiguous trails. This technique allows for the high-throughput quantification of behavioral characteristics that require long-term observation of individual animals. The graphical interface we developed will enable researchers to uncover, in a reproducible manner, subtle time-dependent behavioral phenotypes that will allow dissection of the molecular mechanisms that give rise to organism-level behavior.

Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation : a prospective cohort study in men in eastern Finland.

Background-Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated (HFE) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study. Methods and Results-Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1. 1 to 4.8; P=0.03) risk of acute myocardial infarction compared with noncarriers. Conclusions-Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.

Post-transplant soluble CD30 levels are associated with early subclinical rejection in kidney transplantation.

Several studies have shown association of high pre- or post-transplant levels of soluble CD30 (sCD30) with acute rejection and poor late kidney transplant outcome. Our goal was to investigate whether sCD30 levels at month-3 post-transplant are associated with subclinical rejection, presence of CD30(+) cells within the graft, and expression of immune response genes in peripheral blood mononuclear cells. The study comprised 118 adult first kidney graft recipients, transplanted at a single center, receiving tacrolimus in low concentration. All were submitted to a protocol biopsy at month-3. Subclinical rejection was identified in 10 biopsies and sCD30 levels ≥ 61.88 ng/mL (P = 0.004), younger recipient age (P = 0.030) and non-Caucasian ethnicity (P = 0.011) were independently associated with this outcome. Rare CD30(+) cells were present in only two biopsies. There was a correlation between sCD30 levels and CD30 gene expression in peripheral blood mononuclear cells (r = 0.385, P = 0.043). These results show that high sCD30 levels are independent predictors of graft dysfunction and may contribute to patient selection protocols by indicating those who could benefit from a more thorough evaluation.

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21.

In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor alpha-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.

The effects of the apolipoprotein B signal peptide (ins/del) and XbaI polymorphisms on plasma lipid responses to dietary change.

There is interindividual variation in plasma lipid response to dietary changes. The polymorphisms which are associated with plasma lipid levels could possibly explain part of this variation. Therefore, the apolipoprotein B (apo B) signal peptide insertion/deletion (ins/del) and XbaI restriction fragment length polymorphisms are possible regulators of plasma lipid responses. We examined their role in the regulation of plasma lipid responses in 87 North Karelians (43 men, 44 women). The dietary study consisted of a 2-week baseline period (34-35% of energy from fat), followed by an 8-week low-fat (24 En%), low-cholesterol (279 mg/d) diet period and an 8-week switchback period. In this study population the apo B ins/del and XbaI polymorphisms exhibited mainly similar and partly significant effects on the responses of plasma very low-density lipoprotein (VLDL) and high density lipoprotein2 (HDL2) cholesterol to dietary changes. After consumption of the low saturated fat, low-cholesterol diet, ins/ins X - /X - homozygotes showed the greatest increase in VLDL cholesterol (p < 0.05 for differences between ins/del genotypes) and the greatest fall in HDL2 cholesterol (p = 0.01 for ins/del and p = 0.05 for XbaI), while only minimal alterations were seen in the del/del and X + /X + groups. After returning to the original diet, the changes of these lipids were reversed, ins/ins and X -/X - homozygotes having the greatest reductions in VLDL cholesterol (p < 0.05 for XbaI) and the greatest increases in HLDL2 cholesterol (p < 0.001 for XbaI). The findings suggest that plasma VLDL and HDL2 cholesterol responsiveness to diet may be partly explained by variation at the apo B gene.

Gingival overgrowth among patients medicated with cyclosporin A and tacrolimus undergoing renal transplantation: a prospective study.

BACKGROUND: The aim of this study is to make a longitudinal evaluation of the incidence and severity of gingival overgrowth (GO) induced by immunosuppressive agents, such as tacrolimus (Tcr) and cyclosporin A (CsA), in the absence of calcium channel blockers in patients undergoing renal transplantation (RT). METHODS: This longitudinal study is conducted in 49 patients with RT who were divided into a CsA group (n = 25) and Tcr group (n = 24). The individuals were assessed at four time intervals: before transplant and 30, 90, and 180 days after RTs. Demographic data and periodontal clinical parameters (plaque index, cemento-enamel junction to the gingival margin, probing depth, clinical attachment level, bleeding on probing [BOP], and GO) were collected at all time intervals. RESULTS: The mean GO index was significantly lower in the Tcr group compared to the CsA group after 30 (P = 0.03), 90 (P = 0.004), and 180 (P = 0.01) days of immunosuppressive therapy. One hundred eighty days after RTs, a clinically significant GO was observed in 20.0% of individuals in the CsA group and 8.3% of individuals in the Tcr group. However, this difference was not statistically significant (P = 0.41). There was a reduction in periodontal clinical parameters regarding the time of immunosuppressive therapy for PI and BOP (P <0.001) in both groups. CONCLUSION: Although there was no statistical difference in the incidences of clinically significant GO after 180 days of immunosuppressive therapy, it was observed that GO occurred later in the Tcr group, and the severity of GO in this group was lower than in patients who used CsA.

Pregnancy after renal transplantation: an evaluation of the graft function.

OBJECTIVES: To evaluate pregnancy outcomes and graft function in renal transplant recipients. STUDY DESIGN: Thirty-four pregnancies in 31 patients were evaluated. Graft dysfunction was defined as an increase of 0.3mg/dL (215 µmol/L) or more in serum creatinine (SCr) during pregnancy. Twenty-eight patients were also evaluated at one, six and twelve months after delivery to analyze the evolution of the graft function. RESULTS: Fifteen patients experienced graft dysfunction during pregnancy, 10 related to preeclampsia, two related to rejection, one related to allograft obstruction and one related to urinary tract infection. One patient did not have an identified cause. In one patient, graft rejection ended in graft loss. The mean SCr level in the first trimester was 0.9 mg/dL (range: 0.5-2.1) among women who did not have graft dysfunction and 1.1mg/dL (range: 0.5-1.9) among patients who had graft dysfunction (P=0.66). The mean SCr level one year after delivery was 1.18 mg/dL in the first group and 1.21 mg/dL in the second group (P=0.74). There was no difference in SCr level from the first trimester of pregnancy to one year after delivery in both groups evaluated (P=0.35 and P=0.13). CONCLUSIONS: Although graft dysfunction may occur during pregnancy, it seems to be temporary in the majority of the cases. It is important to emphasize that rejection is still a cause of graft loss during pregnancy.

Clinical outcome of renal transplant patients after coronary stenting.

OBJECTIVE: To assess the clinical outcome of renal transplant patients who developed coronary artery disease and were treated with coronary stenting (TCA-ST). METHODS: A total of 3,334 renal transplants were performed in our service--Hospital do Rim e Hipertensão--HRH (Kidney and Hypertension Hospital) from July, 1998 to November, 2004. During this period, 33 of the renal transplant patients underwent TCA-ST to treat 62 severe stenoses in 54 coronary arteries. A retrospective analysis was performed with renal transplant patients undergoing TCA-ST at HRH. The clinical events were registered using medical charts, medical visits and phone calls. RESULTS: During the 30-month clinical follow-up after TCA-ST, 67% of the patients remained asymptomatic, 18% presented stable angina, 6% presented acute coronary syndrome without ST-segment elevation (ACSWSTE), and 3% presented acute coronary syndrome with ST-segment elevation (ACSSTE). No strokes, CHF or cardiac deaths were observed. Three non-cardiac deaths occurred. A restenosis rate of 9% was observed, which is comparable to those found in studies on drug-eluting stents. CONCLUSION: In conclusion, renal transplant patients who developed CAD and were treated with coronary stenting had a low rate of in-stent restenosis, probably related to the immunosuppressive regimen given to prevent kidney rejection.

Evaluation of subgingival bacterial plaque changes and effects on periodontal tissues in patients with renal transplants under immunosuppressive therapy.

OBJECTIVE: The purpose of this study was to identify the presence of periodontal microrganisms in 35 renal transplant patients before the transplant procedure. STUDY DESIGN: At each time point, clinical parameters were recorded and subgingival plaque samples were collected from 4 different sites at days 30 and 90 after surgery. Samples were plated onto selective and nonselective media to determine total colony counts and the presence of putative periodontal pathogens. After transplant surgery, patients received immunosuppressive therapy. RESULTS: Statistical analysis of the microbiologic data showed significant changes between time points. An increase in total counts of microrganisms was observed on day 90 after surgery. As a side effect of cyclosporine, 14 patients developed gingival overgrowth. Beta-hemolytic Streptococcus was more frequently detected in patients who did not present gingival overgrowth 90 days after surgery. CONCLUSION: Quantitative and qualitative changes of the subgingival microflora can occur 90 days after transplant surgery, while patients are still under immunosupressive drugs.

Structural analysis of the Pimelodus maculatus (Lacépède, 1803) embryogenesis (Siluriformes: Pimelodidae)

The fish embryonic development comprises the events between the egg fertilization up to larvae hatching, being useful for the identification of viable eggs in productivity and survival studies as well as in raising experiments of several species. The goal of the present study was to characterize the embryonic development of Pimelodus maculatus (Siluriformes; Pimelodidae). The embryogenesis was typical of teleosteans, but with differences in relation to other species such as duration of development, type of blastocoel, moment of somite segmentation among others. Six stages of embryonic development were defined: zygote, cleavage, blastula, gastrula, organogenesis (divided in phases: early segmentation and late segmentation) and hatching with a period of incubation equal to 13 hours at 29 ºC and 17 hours at 25 ºC. The extruded oocytes presented a mean diameter of 812 µm before and 1066 µm after hydration. When fertilized, they presented a yellowish coloration and a gelatinous layer surrounding the chorion. The cleavage pattern is described as: 2; 4; 8 (4x2); 16 (4x4); 32 (4x8) and 64 (2x4x8) blastomeres up to morula phase (+64 cells). It was also possible to observe at this phase, the beginning of the formation of the yolk syncyctial layer (YSL). Afterwards, the blastula and gastrula stages followed. The end of gastrula was characterized by the formation of the yolk plug. Subsequently, the differentiation between cephalic and caudal regions began, along with the embryo elongation, structuring of optic, Kupffer's and otic vesicles besides a previously unidentified structure in the yolk syncyctial layer. The end of this stage is typified by the tail detachment. The late segmentation phase was distinguished by a free tail, presence of more than 30 somites, optic and otic vesicles, development of posterior intestine, pigmentation of cephalic and caudal regions of yolk sac and embryo growth. The recently-hatched larvae presented a primordial digestive tract, quite evident and pigmented eyes, closed mouth, encephalic vesicles and a mean length of 3410 µm.

O desenvolvimento embrionário de peixes compreende eventos que ocorrem desde o ovo fertilizado à eclosão das larvas, podendo auxiliar na identificação dos ovos viáveis em estudos de produtividade e sobrevivência, como também nas pesquisas de cultivo desses animais. O objetivo do presente estudo foi caracterizar o desenvolvimento embrionário do Pimelodus maculatus (Siluriformes; Pimelodidae). A embriogênese foi característica de teleósteos, apresentando variações que difere de outras espécies como, tempo de desenvolvimento, tipo da blastocele, momento de segmentação dos somitos, entre outros. Seis estágios de desenvolvimento embrionário foram definidos: zigoto, clivagem, blástula, gástrula, organogênese (dividido em fases: segmentação inicial e segmentação final) e eclosão com período de incubação de 13 horas à 29ºC e de 17 horas à 25ºC. Os ovócitos extrusados apresentaram diâmetro médio de 812 µm antes da hidratação e após 1066 µm. Após a fertilização, apresentaram coloração amarelada e uma camada gelatinosa envolvendo o córion. O padrão de clivagens foi descrito como segue: 2; 4; 8 (4x2); 16 (4x4); 32 (4x8) e 64 (2x4x8) blastômeros até a fase de mórula (+64 células). Também foi possível observar nesta fase, o início da formação da camada sincicial do vitelo (CSV). Em seguida foram observados os estágios de blástula e gástrula. O final da gástrula caracterizou-se pela formação do tampão vitelino. A seguir, iniciou-se a diferenciação das regiões cefálica e caudal, o alongamento do embrião, estruturação das vesículas ópticas, de Kufper, óticas e de uma estrutura não identificada na literatura localizada na camada sincicial do vitelo. O final deste estágio é demarcado pelo desprendimento da cauda. A fase de segmentação final caracterizou-se pela cauda livre, presença de mais de 30 somitos, vesícula óptica e ótica, desenvolvimento do intestino posterior, pigmentação nas regiões cefálica e caudal do saco vitelino e crescimento do embrião. As larvas recém-eclodidas apresentaram esboço do trato digestório, olhos bem evidentes e pigmentados, boca fechada, presença das vesículas encefálicas e com comprimento médio de 3410 µm.