Enhanced Transmural Dispersion of Repolarization in Patients with J Wave Syndromes

J Wave Syndromes . Introduction: Recently, great attention has been paid to the risk stratification of asymptomatic patients with an electrocardiographic early repolarization (ER) pattern. We investigated several repolarization parameters including the Tpeak‐Tend interval and Tpeak‐Tend/QT ratio in healthy individuals and patients with J wave syndrome who were aborted from sudden cardiac death. Methods and Results: Ninety‐two subjects were enrolled: 12 patients with ventricular fibrillation associated with J waves, 40 healthy subjects with an uneventful ER pattern and 40 healthy control subjects (C) without any evident J waves. Using ambulatory electrocardiogram recordings, the average QT interval, corrected QT interval (QTc), Tpeak‐Tend (Tp‐e) interval, which is the interval from the peak to the end of the T wave, and Tp‐e/QT ratio were calculated. Using ANOVA and post hoc analysis, there was no significant difference in the average QT and QTc in all 3 groups (QT; 396 ± 27 vs 405 ± 27 vs 403 ± 27 m, QTc; 420 ± 26 vs 421 ± 21 vs 403 ± 19 milliseconds in the C, ER pattern and J groups, respectively). The Tp‐e interval and Tp‐e/QT ratio were significantly more increased in the J wave group than the ER Pattern group (Tp‐e: 86.7 ± 14 milliseconds vs 68 ± 13.2 milliseconds, P < 0.001, Tp‐e/QT; 0.209 ± 0.04 vs 0.171 ± 0.03, P < 0.001), but they did not significantly differ between the C and ER pattern groups (Tp‐e: 68.6 ± 7.5 vs 68 ± 13.2, P = 0.97, Tp‐e/QT 0.174 ± 0.02 vs 0.171 ± 0.03, P = 0.4). Conclusion: As novel markers of heterogeneity of ventricular repolarization, Tpeak‐Tend interval and Tp‐Te/QT ratio are significantly increased in patients with J wave syndromes compared to age and sex‐matched uneventful ER. (J Cardiovasc Electrophysiol, Vol. 23 pp. 1109‐1114, October 2012)     

Frequency of Spontaneous Axial Skeletal Variations Detected by the Double Staining Technique for Ossified and Cartilaginous Skeleton in Rat Fetuses

The purpose of the present study was to determine the frequency of spontaneous axial skeletal variations detectable by the double staining technique in Crj: CD (SD) and Crj: Wistar rat fetuses. In addition, the frequencies of unossified skeletal variations were compared between SD and Wistar rats, and between same strain male and female rat fetuses. Fifteen types of the variations were detected. There were strain differences (4 types) and sex differences (3 types) in the frequencies of the variations. With the aid of double staining technique, skeletal variations such as supernumerary ribs or deformed ossification centers detected by the single staining technique could be classified in detail into many types. This study showed that the double staining technique improved detectability of skeletal variations and facilitated their evaluation in developmental toxicity studies.     

Late Radiation Injury of the Large Intestine

Abstract: Late radiation injury of the colon and rectum after radiotherapy for a pelvic malignancy is a not uncommon complication. Although the colonoscopic appearance of radiation injury is well known, few reports have focused on the progression of radiation proctocolitis. The colonoscopic examinations of 103 patients with late radiation injuries were reviewed. The radiotherapy had originally been administered for carcinoma of the uterine cervix (79 patients), prostate (13), uterine corpus (3), ovaries (3), urinary bladder (2), vagina (2), and pelvic metastasis of breast cancer (1). In 31 patients, changes in colonoscopic appearance were followed-up. Anal bleeding was the major initial symptom, with more than half experiencing bleeding within 2 years of radiotherapy. Lesions were limited to the rectum and sigmoid colon. The incidence of late radiation injury, according to cancer site, was calculated to be 3.8% for the cervix uteri, 5.1% for the prostate, 0.60% for the corpus uteri, 0.80% for the ovary and 0.35% for the bladder. Seventeen patients underwent colostomy. Between eight and 37 years after radiotherapy, six patients developed a second colorectal cancer. As to radiation injury, two response types, bleeding and stricture, occurred. Virtually no resolution of the strictures was observed in this series. The grade of radiation injury did not correlate with radiotherapy dosage.     

FAMILY STUDY SHOWING A CLOSE ASSOCIATION OF HLA DPB1*0202/0901 WITH ULCERATIVE COLITIS

Genetic disposition and environmental factors are closely related to the occurrence of ulcerative colitis (UC). The HLA haplotypes of major histocompatibility complex (MHC) Class II are considered to be the most important genetic factors in UC. The current report focuses on the genetic human leukocyte antigen (HLA) of a family in which UC crises have occurred in five of six members with identical MHC Class II haplotypes. Haplotypes A24/26 (A24/‐), BW4/6 (BW4/‐) and DQ1/3 (DQ1/‐) were found in all six members of the family. In DNA typing, characteristic loci common to this family were seen in DRB11502 and DQB10601. From the genetic investigation of this family, we concluded that HLA haplotypes are the most important genetic factors in the occurrence of UC.     

Solid-state compatibility studies using a high-throughput and automated forced degradation system

As the number of pharmaceutical candidate compounds increases, so does the need for development workflow that is capable of handling more compounds in shorter times. In this paper, the establishment of a high-throughput automated powder compatibility testing system is reported. The integrated robotic system automatically dispenses, weighs, and stores powder samples, and extracts and analyses drug substance using ultra-performance liquid chromatography (UPLC). Although automation of powder testing systems is generally accompanied by difficulties in accuracy and precision, mass tracking at every unit operation allowed the system to be validated. In a standard procedure, drug substance and an excipient were dispensed 1:1 (w/w), stored at 70 degrees C for 9 days, dissolved in solvents, and analyzed to examine the degradation of drug substance and the increases in related substances. The robot quantitatively discriminate between initial conditions of the incompatible powder mixtures of aspirin and magnesium stearate (Mg-St) prepared with or without the use of a whisk and shaker system, demonstrating the capability for evaluating powder mixtures with varying degrees of homogeneity where the contact area between excipient and drug substance differs. Differential scanning calorimetry (DSC), however, did not clearly distinguish between those powder samples, indicating that DSC is less sensitive to powder conditions. The incompatibility results of aspirin and Mg-St were comparable to those reported previously, demonstrating that the automated testing system is reliable. The robot reduced manual work to one sixth and cut down on the costs of outsourcing. An extensive impact is anticipated on development workflows because this system is applicable not only to compatibility testing but also to analytical method development for drug products.     

Trisomy 10p and translocation of 10q to 4p associated with selective dysgenesis of IgA-producing cells in lymphoid tissue

A combined chromosomal abberation trisomy of the short arm of chromosome 10 associated with translocation of 10q to chromosome 4p was found in a 14-month-old boy, who died after repeated bouts of pneumonia. The translocation involved the target region 4p16.3 of Wolf-Hirschhorn syndrome and/or Pitt-Rogers-Danks syndrome. The karyotype was 46,XY,der(4)t(4;10)(p16;q11.2),i(10)(p10),ish der(4)t(4;10)(p16.3;q11.2) (D4S96+,D4Z1+),i(10) (pter ++). In addition to growth retardation and external as well as internal dysmorphism, the patient had abnormalities of the immune system, such as thymic involution, generalized lymph node enlargement, unusual distribution of T cells in lymphoid follicles, and selective IgA deficiency. The IgA-producing cells were rarely found in lymph nodes but normally in intestinal mucosa. In contrast, in the lymph nodes, the paracortical T-lymphocytes were hyperplastic, but they rarely entered the primary follicles. It is assumed that the chromosomal abnormality may lead to the dysfunction of T lymphocytes and, further, to the dysgenesis of IgA-producing cells in lymph nodes but not in intestinal mucosa. This suggests that the thymus may differentially control the subsets of IgA-producing cells in lymph nodes and intestinal mucosa.     

Clinical and immunologic assessment of patients with psoriasis in a randomized,double-blind,placebo-controlled trial using recombinant human interleukin 10

BACKGROUND: In several open-label studies, recombinant human interleukin 10 (rhIL-10), a type 2 anti-inflammatory cytokine, has been reported to improve psoriasis, a disease characterized by type 1 cytokine inflammation. OBJECTIVE: To evaluate the safety, efficacy, and immunologic parameters in individuals with psoriasis treated with rhIL-10. DESIGN AND INTERVENTION: Patients received rhIL-10 (20 micro g/kg) or placebo subcutaneously 3 times weekly for 12 weeks in a randomized, double-blind manner. SETTING AND PATIENTS: National Institutes of Health Clinical Center in Bethesda. Twenty-eight patients with moderate-to-severe psoriasis as defined by a Psoriasis Area Severity Index (PASI) score of 10 or higher. MAIN OUTCOME MEASURE: The primary clinical end point was the mean percentage change in the PASI score comparing baseline and week 12 scores. Intracellular cytokine production by peripheral blood mononuclear cells (PBMCs) was measured by flow cytometry. RESULTS: There was no significant difference in the mean percentage change in the PASI score from baseline to week 12 between the rhIL-10-treated group and control patients (17% vs 13% improvement, respectively; P =.69), although a modest trend toward improvement in patients receiving rhIL-10 was documented at both the 6- and 8-week points. Interestingly, proinflammatory and type 1 cytokine production by PBMCs progressively declined in the rhIL-10-treated patients during the entire 12-week study period. CONCLUSIONS: Treatment with rhIL-10 resulted in only temporary clinical improvement in psoriasis, despite sustained systemic decreases in proinflammatory and type 1 cytokine production. These data suggest that immunotherapy that decreases the ratio of systemic type 1 and type 2 cytokine production does not necessarily lead to improvement of type 1 cytokine-mediated disease.