YC-1, a novel activator of platelet guanylate cyclase

YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] inhibited the aggregation of and ATP release from washed rabbit platelets induced by arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), and thrombin in a concentration-dependent manner. YC-1 also disaggregated the clumped platelets caused by these inducers. The thromboxane B2 formation caused by collagen, PAF, and thrombin was inhibited by concentrations of YC-1 that did not affect formation of thromboxane B2 and prostaglandin D2 caused by AA. YC-1 suppressed the increase of intracellular Ca2+ concentration and generation of inositol 1,4,5-trisphosphate caused by these five aggregation inducers. Both the cAMP and cGMP contents of platelets were increased by YC-1 in a concentration- and time-dependent manner. Like sodium nitroprusside, YC- 1 potentiated formation of cAMP caused by prostaglandin E1 but not that by 3-isobutyl-1-methylxanthine. Adenylate cyclase and cAMP phosphodiesterase activities were not altered by YC-1. Activity of cGMP phosphodiesterase was unaffected by YC-1. Activities of guanylate cyclase in platelet homogenate and cytosolic fraction were activated by YC-1, whereas particulate guanylate cyclase activity was unaffected. The antiplatelet effect of sodium nitroprusside but not that of YC-1 was blocked by hemoglobin and potentiated by superoxide dismutase. After intraperitoneal administration for 30 minutes, YC-1 prolonged the tail bleeding time of conscious mice. These data indicate that YC-1 is a direct soluble guanylate cyclase activator in rabbit platelets. It may also possess antithrombotic potential in vivo.     

The Use of Cervical Auscultation to Predict Oropharyngeal Aspiration in Children: A Randomized Controlled Trial

In this study, we aimed to determine if the use of cervical auscultation (CA) as an adjunct to the clinical feeding evaluation (CFE + CA) improves the reliability of predicting oropharyngeal aspiration (abbreviated to aspiration) in children. The design of the study is based on open label, randomized controlled trial with concealed allocation. Results from children (<18 years) randomized to either CFE or CFE + CA were compared to videofluoroscopic swallow study (VFSS), the reference standard data. Aspiration was defined using the Penetration-Aspiration Scale. All assessments were undertaken at a single tertiary pediatric hospital. 155 children referred for a feeding/swallowing assessment were randomized into the CFE n = 83 [38 males; mean age = 34.9 months (SD 34.4)] or CFE + CA n = 72 [43 males; mean age = 39.6 months (SD 39.3)] group. kappa statistic, sensitivity, and specificity values, area under receiver operating curve (aROC). No significant differences between groups were found, although CFE + CA (kappa = 0.41, 95 % CI 0.2–0.62) had higher agreement for aspiration detection by VFSS, compared to the clinical feeding exam alone (kappa = 0.31, 95 % CI 0.10–0.52). Sensitivity was 85 % (95 % CI 62.1–96.8) for CFE + CA and 63.6 % (95 % CI 45.1–79.6) for CFE. aROC was not significantly greater for CFE + CA (0.75, 95 % CI 0.65–0.86) than CFE (0.66, 95 % CI 0.55–0.76) across all age groups. Although using CA as an adjunct to the clinical feeding evaluation improves the sensitivity of predicting aspiration in children, it is not sensitive enough as a diagnostic tool in isolation. Given the serious implications of missing the diagnosis of aspiration, instrumental assessments (e.g., VFSS), remain the preferred standard.     

High prevalence of coeliac disease in Danish children with type I diabetes mellitus

The purpose of this population-based study was to determine the prevalence of coeliac disease (CD) in 106 Danish children (age 2-18 y) with type I diabetes mellitus compared with 106 ageand sex-matched healthy controls. Serum samples were analysed for immunoglobulin A (IgA) and IgG gliadin antibodies by enzyme-linked immunosorbent assay (ELISA), for IgA endomysium antibodies (EMA) by immunofluorescence and for IgA tissue transglutaminase antibodies (tTGA) by ELISA. None of the controls had EMA or tTGA. Two diabetics previously diagnosed with CD were antibody negative on a gluten-free diet. Ten diabetics had both EMA and tTGA. Intestinal biopsy was performed in nine of them. All biopsies showed a histological picture of partial or total villous atrophy confirming the diagnosis of CD. Diabetics with CD were significantly younger ( p = 0.026), had an earlier onset of diabetes ( p = 0.005), had a lower height standard deviation score ( p = 0.019) and more often had thyroid antibodies ( p = 0.040) compared with diabetics without CD.

Conclusion: A high prevalence of CD of 10.4% (95% confidence interval 4.6-16.2%) was found in young Danish diabetics. Early onset of diabetes may predispose to CD. Routine serological screening for CD may be valuable in patients with type I diabetes mellitus.     

PLATELET STORAGE POOL DEFICIENCY IN PREGNANCY

SUMMARY A case of inherited platelet storage pool deficiency is described which was successfully managed with prophylactic platelet transfusion at delivery.     

Morning headache in sleep apnoea: clinical and polysomnographic evaluation and response to nasal continuous positive airway pressure

Morning headache is accepted as part of clinical findings of obstructive sleep apnoea syndrome (OSAS). The prevalence of morning headache is at variable levels from 18% to 74% in patients with OSAS. However, there is controversy over the association of morning headache and OSAS. We studied morning headache prevalance and characteristics in 101 controls with apnoea–hypnoea index (AHI) < 5 and 462 OSAS patients with AHI ≥ 5. Morning headache was reported by only nine (8.9%) subjects in a control group compared with 156 (33.6%) of OSAS patients ( P  < 0.01). Morning headache prevalance was significantly higher in severe and moderate OSAS groups. AHI was significantly higher in OSAS patients with morning headache compared with patients without morning headaches. Oxygen saturation nadir during rapid eye movement and non-rapid eye movement sleep as well as mean oxygen saturation value during total sleep time were also found to be significantly lower in morning headache group. However, none of the sleep parameters was found to be determinants of morning headache. Morning headache was more frequently reported by patients of female gender and with primary headache history. Morning headache was totally resolved in 90% of patients treated with nasal continuous positive airway pressure. The history of OSAS should be considered in the differential diagnosis of morning headache.     

Epidemiology of colorectal cancer in Asia

The prevalence of colorectal cancer is increasing in Asia. However, the age‐standardized rate has reached a plateau in some countries. Some studies have shown a male predominance difference and increasing risk in the elderly, but not in the younger population. ‘Right shifting’ of colorectal cancer, not accountable by difference in age or the indications for endoscopic examination, has also been noted. Westernized diet is associated with colorectal cancer, but controversy remains on how it causes colorectal cancer. Alcohol consumption, obesity, diabetes mellitus, consumption of red and processed meat and cigarette smoking are linked to bowel cancer epidemiologically. Only high dietary calcium has a consistent negative (or ‘protective’) effect. The efficacy of fish oil, vitamin D, soy, phytoestrogens, folate, methionine, riboflavin and vitamin B6 has not been established. Aspirin and non‐steroidal anti‐inflammatory drugs use decrease risk of colorectal cancer after 5–10 years of use. There is no evidence for a detrimental effect of proton pump inhibitors or benefit of statins in colorectal cancer. In conclusion, there is a rising trend and prevalence of colorectal cancer in Asia. Dietary modification or supplementation may not be effective in preventing colorectal cancer. Surveillance of colorectal cancer in high‐risk groups, according to current recommendation, is probably most effective.     

Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia

In patients with B-cell chronic lymphocytic leukemia (B-CLL), the absolute number of T cells is increased. Although it has been suggested that these T cells might be tumor specific, concrete evidence for this hypothesis is lacking. We performed a detailed immunophenotypic analysis of the T-cell compartment in the peripheral blood of 28 patients with B-CLL (Rai 0, n = 12; Rai I-II, n = 10; Rai III-IV, n = 6) and 12 healthy age-matched controls and measured the ability of these patients to mount specific immune responses. In all Rai stages a significant increase in the absolute numbers of CD3+ cells was observed. Whereas the number of CD4+ cells was not different from controls, patients with B-CLL showed significantly increased relative and absolute numbers of CD8+ cells, which exhibited a CD45RA+CD27- cytotoxic phenotype. Analysis of specific immune responses with tetrameric cytomegalovirus (CMV)-peptide complexes showed that patients with B-CLL had significantly increased numbers of tetramer-binding CMV-specific CD8+ T cells. The rise in the total number of CD8+ cytotoxic T cells was evident only in CMV-seropositive B-CLL patients. Thus, our data suggest that in patients with B-CLL the composition of T cells is shifted toward a CD8+ cytotoxic cell type in an effort to control infections with persistent viruses such as CMV. Moreover, they offer an explanation for the high incidence of CMV reactivation in CLL patients treated with T cell-depleting agents, such as the monoclonal antibody (mAb) alemtuzumab (Campath; alpha-CD52 mAb). Furthermore, because in CMV-seronegative patients no increase in cytotoxic CD8+ T cells is found, our studies do not support the hypothesis that tumor-specific T cells account for T-cell expansion in B-CLL.     

PRURITUS AND HLA IN HEMODIALYSIS PATIENTS

Hepatitis C virus (HCV) infection is known to increase morbidity and mortality in the dialysis population. Renal transplantation is an offered treatment option after a careful pretransplant evaluation. This study assessed the impact of HCV infection on patient and allograft survival rates in a selected group of dialysis patients and kidney transplant recipients.
The study included 252 end-stage renal disease patients who were receiving hemodialysis (HD) treatment or who received renal transplantation at our centre in 1995–96. Of the total, 116 [94 HCV (–) and 22 HCV (+)] underwent transplantation and 134 [106 HCV (–) and 30 HCV (+)] remained on HD. We retrospectively investigated 5 years of follow-up findings in the records of these patients. All 22 HCV (+) individuals underwent liver biopsy to ensure there was no advanced liver disease before transplantation. None of the recipients or HD patients showed decompensation related to liver disease during follow up.
The overall 5-year patient survival rates for the kidney recipient and HD groups were 85.2% and 74.5%, respectively. Comparison of outcomes for the HCV (+) recipients had a significantly higher 5-year survival rate than the HCV (+) HD patients ( P <0.04). The 3-year graft survival rates for the HCV (+) and HCV (–) transplant recipients were comparable, but the risks of chronic rejection and graft loss at 5 years were higher in the HCV (+) group ( P <0.02, P <0.006, respectively). In conclusion, renal transplantation should be the preferred therapy in HCV-infected dialysis patients because it improves the survival rates. HCV infection is associated with increased rates of chronic rejection and graft loss at 5 years post-transplantation.