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 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.

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.

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.

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.

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.

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.

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.

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.

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.

Evolução clínica pós-stent coronariano em pacientes submetidos a transplante de rim / Clinical outcome of renal transplant patients after coronary stenting

OBJETIVO: Avaliar a evolução clínica de pacientes submetidos a transplante de rim, portadores de doença arterial coronariana, que foram tratados com implante de stent coronariano (ATC-ST). MÉTODOS: Entre julho de 1998 e novembro de 2004, foram realizados, no total, 3.334 transplantes de rim em nossa Instituição (Hospital do Rim e Hipertensão). Desse total, 33 pacientes previamente submetidos a transplante de rim fizeram ATC-ST para o tratamento de 62 estenoses graves em 54 artérias coronárias, nos quais foi realizada análise retrospectiva. O registro dos eventos clínicos foi feito por meio de análise do prontuário médico, consulta médica e ligações telefônicas. RESULTADOS: No seguimento clínico de 30 meses, após a ATC-ST, observou-se que 67 por cento dos pacientes permaneceram assintomáticos, 18 por cento dos pacientes apresentaram quadro de angina estável, 6 por cento apresentaram síndrome coronariana aguda sem supra de ST e 3 por cento apresentaram síndrome coronariana aguda com supra de ST. Não houve pacientes com acidente vascular cerebral, insuficiência cardíaca congestiva ou morte cardíaca. Houve três mortes não-cardíacas. Foi observado índice de reestenose de 9 por cento, que é comparável ao dos estudos de stent farmacológico. CONCLUSÃO: Concluímos que pacientes submetidos a transplante de rim que desenvolveram doença arterial coronariana e que foram tratados com stent coronariano tiveram baixo porcentual de reestenose clínica, provavelmente relacionado ao regime de imunossupressão administrado para evitar rejeição renal.

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 percent of the patients remained asymptomatic, 18 percent presented stable angina, 6 percent presented acute coronary syndrome without ST-segment elevation (ACSWSTE), and 3 percent 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 percent 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.

An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination.

BACKGROUND: The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects. METHODS: Between June 1999 and February 2000, 70 recipients of primary one-haplotype living-related donor renal allografts were randomized to receive SRL (2 mg/d) or azathioprine (AZA) (2 mg/kg/d) combined with cyclosporine and prednisone. The primary end-point was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 3 months after transplantation. RESULTS: From week 4 to month 12, SRL patients received lower cyclosporine (week 4: 364 mg/d vs. 455 mg/d, p = 0.004; month 12: 195 mg/d vs. 255 mg/d, p = 0.038) doses and showed lower cyclosporine concentrations (week 4: 247 ng/mL vs. 309 ng/mL, p = 0.04; month 12: 143 ng/mL vs. 188 ng/mL, p = 0.045). Compared with AZA, SRL patients showed reduced 3-month primary end point (0% vs. 17.1%, p = 0.025), and reduced incidence of biopsy-confirmed acute rejection at 3 months (0% vs. 14.3%, p = 0.01) but not at 12 months (11.4% vs. 14.3%, NS). Mean creatinine at 12 months were not different (1.8 +/- 0.6 vs. 1.6 +/- 0.6, p = 0.23). Hyperlipidemia was the only adverse event more frequent among SRL patients (49% vs. 17%, p = 0.01). There were no differences in infections and no malignancies in both groups. CONCLUSIONS: The combination of 2 mg fixed doses of SRL, reduced cyclosporine exposure and prednisone was associated with a low incidence of acute rejection and did not result in significantly impaired graft function compared with patients receiving AZA, standard doses of cyclosporine and prednisone.

CARD15 frameshift mutation in patients with CROHN disease is associated with immune dysregulation.

BACKGROUND: Mutations in the caspase-activating recruitment domain 15 (CARD15) gene are associated with Crohn disease (CD). CARD15 is an intracellular receptor for bacterial lipopolysaccharides (LPS). LPS-induced activation of transfectants containing the frameshift mutation (1007fs) of CARD15 is impaired. The aim of this study was to investigate whether the presence of CARD15 1007fs affects activation of CD patients' own cells. Patients (4 homozygotes, 6 heterozygotes, and 6 wild-type) were matched according to clinical picture and medication. METHODS: Immune inflammatory status was evaluated by measuring monocyte HLA-DR and CD11b densities and the proportion of CD14dimCD16+ monocytes, and was found to be comparable in the three groups. Blood mononuclear cells were cultured overnight in serum-free medium alone, or the medium supplemented with LPS (0.1-10.0 ng/mL), a combination of IFN-gamma (100 IU/mL) and granulocyte-macrophage colony stimulating factor (GM-CSF) (5 ng/mL), or both. TNF and IL-10 levels in the culture supernatant were determined. RESULTS: LPS 0.1 or 1.0 ng/mL alone did not increase TNF levels. IFN-gamma/GM-CSF induced TNF release, and co-culture with LPS 1.0 or 10.0 ng/mL was strongly synergistic. CARD15 1007fs mutation was linked in a gene-dose-dependent manner to low TNF release induced by IFN-gamma/GM-CSF (P value for linear trend = 0.001). The degree of synergism in co-culture was normal or high, suggesting that 1007fs did not depress responses to LPS. IL-10 levels were not related to CARD15 1007fs. CONCLUSIONS: In CD patients, CARD15 1007fs is associated in a gene-dose-dependent manner to low mononuclear cell TNF release by IFN-gamma/GM-CSF but does not impair TNF release by LPS. This type of immune dysregulation may influence susceptibility to and/or phenotype of CD.

CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn's disease.

BACKGROUND: Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn's disease (CD). AIM: Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD. PATIENTS AND METHODS: We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs. RESULTS: In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery. CONCLUSIONS: The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.

The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring.

UNLABELLED: The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. We sought to determine the influence of ethnic miscegenation on tacrolimus pharmacokinetics and trough concentrations during the first 6 months after transplantation. METHODS: Tacrolimus concentrations were measured in blood samples obtained from 22 transplant recipients during the first week of transplant, within pharmacokinetic profiles, and throughout the first 6 months post-transplant, using the Pro Tac II ELISA method. Pharmacokinetic parameters and between- and within-subject blood concentration variability were compared stratifying the total population in two distinct ethnic groups of white (W) and non-white (NW) patients, according to a stringent criterion. RESULTS: Between-subject variability in dose-adjusted concentrations during dosing interval varied from 38.8 to 69.5%. Compared with W patients, NW patients showed higher variability in blood tacrolimus concentrations during dosing interval (37.40 +/- 5.64 vs. 56.95 +/- 11.49, p < 0.001) and lower drug exposures (AUC: 229.4 +/- 55.5 vs. 66.9 +/- 67.1 ng x h/mL, p=0.036). The correlation coefficients (r2) between C0, C12 or Cmax and AUC were 0.83, 0.91 and 0.5, respectively. An equation derived from early time concentrations (C0, C1.5 and C4) accounted for 94% of the variability observed in AUC. Compared with W patients, a higher proportion of tacrolimus blood determinations during the first week were below 10 nug/mL in NW patients (24% vs. 62%, p=0.028). Tacrolimus absorption increased from week 1-4 (1.1 +/- 0.53 vs. 1.73 +/- 0.97 nug/mL/mg, p < 0.0001) but was still showed high between- (41.6-70.4%) and within-subject (18.2-32.5%) variability, regardless of ethnicity, after stabilization. CONCLUSION: Non-white patients show higher tacrolimus variability and lower drug exposures after transplantation compared with W patients. Therefore, higher initial tacrolimus doses and intensive monitoring are recommended when administering tacrolimus-based immunosupressive therapy to NW patients of this transplant population.

Familial and sporadic inflammatory bowel disease: comparison of clinical features and serological markers in a genetically homogeneous population.

BACKGROUND: The familial occurrence of inflammatory bowel disease (IBD) and the clinical features of familial and sporadic IBD in the genetically homogeneous Finnish population are evaluated. METHODS: 257 patients with Crohn disease (CD) and 436 with ulcerative colitis (UC) participated in the study. They were asked whether IBD was present (familial IBD) or absent (sporadic IBD) in their first-degree relatives. Data on the clinical course of the disease were collected from the patient records. Antibodies to Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) were determined from serum samples. RESULTS: Affected first-degree relatives were found in 15.6% of patients with CD and in 13.8% of patients with UC. In familial cases CD was more often located in the ileum (38% versus 21%) and less often in the ileocolon (35% versus 50%) (P< 0.05) than in sporadic cases. A greater percentage of CD patients than UC patients were smokers (47% versus 13%; P < 0.01). An elevated level of IgA and/or IgG antibodies for ASCA was found more often in CD patients than in UC patients (59% versus 14%; P < 0.01), while pANCA were found more often in UC than in CD patients (48% versus 12%; P < 0.01). The combination of pANCA-ASCA+ yielded a sensitivity, specificity and positive predictive value of 48%, 92% and 90%, respectively, for CD, and the combination of pANCA + ASCA- of 55%, 94% and 90%, respectively, for UC. CONCLUSIONS: The percentage of familial IBD cases in Finland is comparable to that reported elsewhere in Europe. No important clinical differences between patients with familial and sporadic forms of the disease were found. ASCA is associated with both familial and sporadic CD and pANCA with UC, but low sensitivity diminishes their value as a serological marker of IBD or as a differential diagnostic test between CD and UC.