Risk of stroke with antivenom usage after venomous snakebite in Taiwan: a population-based cohort study.

BACKGROUND AND PURPOSE: Stroke is a rare complication of snakebites, but may lead to serious sequelae. We aimed to explore the relationship between venomous snakebite and the risk for acute stroke, in a nationwide population-based cohort study. METHODS: This retrospective cohort study used claims data between 1 January 2000 and 31 December 2012, from the Taiwan National Health Insurance Research Database. The study included data of patients aged 18 years or older with venomous snakebite (n = 535), matched for propensity score with controls without venomous snakebite (n = 2140). The follow-up period was the duration from the initial diagnosis of venomous snakebite and administration of antivenom to the date of an acute stroke, or until 31 December 2013. The competing risk model was used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of stroke, ischemic stroke and hemorrhagic stroke, after adjusting for demographic and other possible stroke risk factors. RESULTS: The adjusted HR for the venomous snakebite group compared with the control group was 2.68 for hemorrhagic stroke (95% CI = 1.35-5.33). Stratified analysis showed that the older age group (>65 years old) had a higher risk of hemorrhagic stroke. A 2.72-fold significant increase in the risk for hemorrhagic stroke was observed following venomous snakebite with antivenom usage (95% CI = 1.41-5.26). CONCLUSION: Venomous snakebite is associated with an increased risk of hemorrhagic stroke after the use of antivenom. Further study of the underlying mechanism is warranted.

Hydroxychloroquine was associated with reduced risk of new-onset diabetes mellitus in patients with Sjögren syndrome.

OBJECTIVES: To determine whether taking hydroxychloroquine (HCQ) could prevent the development of new-onset diabetes mellitus (DM) among patients with Sjögren syndrome (SS). METHODS: This is a nationwide, population-based, retrospective cohort study utilizing the Taiwan National Health Insurance Research Database (NHIRD). Data were collected from 1 January 1999, through 31 December 2013, using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. In total, 7774 patients newly diagnosed with SS by at least three outpatient visits or one inpatient admission were selected from the NHIRD as participants. Patients who had previously been diagnosed with DM and whose follow-up durations shorter than 90 days were excluded. HCQ exposure group includes patients who had been diagnosed with SS no longer than 180 days previously, and had been prescribed HCQ for the first time for at least 90 days. The diagnosis of DM was defined as at least two outpatient visits or one inpatient admission with anti-diabetic medication prescription. RESULTS: Patients with SS treated with HCQ had a significantly lower cumulative incidence of new-onset DM than those not treated with HCQ (adjusted hazard ratio: 0.51, 95% confidence interval: 0.28-0.96, P < 0.05). HCQ use for 3 years or more had favorable protective effects (adjusted hazard ratio: 0.22, CI: 0.05-0.92). CONCLUSIONS: HCQ reduced the incidence of DM in a time and dose-dependent manner. Patients with SS who had taken HCQ for 3 years or more exhibited significant protective effects against developing new-onset DM.

Yam bean seed poisoning mimicking cyanide intoxication.

BACKGROUND: Yam bean is a common food in southern Taiwan. However, its seeds are rarely consumed. We describe five patients of yam bean seed poisoning in Taiwan, one of them life-threatening. CLINICAL PRESENTATION: The five patients presented with perioral numbness, nausea and vomiting after eating a same soup made from yam bean seeds. One of them, a 54-year-old woman, had difficulty breathing and lost consciousness. Physical examination showed dilated pupils and coma with no focal neurological signs. The initial blood pressure was normal. Laboratory data showed a severe anion gap metabolic acidosis, with a serum lactate level of 185 mg/dL. An initial diagnosis of cyanide intoxication was considered and she was given sodium nitrite and sodium thiosulfate i.v. Hypotension ensued shortly afterwards and pulmonary artery catheterization showed a decreased cardiac index. Aggressive fluid and inotropic therapy were given and the patient eventually recovered. The other four patients suffered only minor gastrointestinal and neurological symptoms and received supportive treatment. Cyanide levels were negative in all five patients. CONCLUSION: Yam bean seed poisoning can cause acute metabolic acidosis and altered mental status, which could be confused with acute cyanide intoxication from a cyanogenic glycoside-containing plant. To our knowledge, this is the first outbreak of yam bean seed poisoning reported in the English published work.

Secondary erythrocytosis in distal renal tubular acidosis: report of one case.

The wide spectrum of distal renal tubular acidosis (RTA) has been reported. Children with distal RTA can present with failure to thrive, gastrointestinal symptoms, nephrocalcinosis, and renal failure, etc. So far, secondary erythrocytosis in pediatric patients with distal RTA has not been reported. Here we report a case of distal RTA with failure to thrive and nephrocalcinosis accompanied by secondary erythrocytosis in a 3-year-old boy. He has been followed up for 2 years and is under treatment with NaHCO3 and potassium citrate. The treatment contributes to the improvement of metabolic acidosis and his growth. There is normal renal function and constant erythrocytosis during the follow-up period. Further studies are needed to clarify the relationship between erythrocytosis and distal RTA.

Involvement of Fas (CD95/APO-1) and Fas ligand in apoptosis induced by ganciclovir treatment of tumor cells transduced with herpes simplex virus thymidine kinase.

Transduction of cancer cells with herpes simplex virus thymidine kinase gene (HSVtk) followed by prodrug ganciclovir (GCV) treatment has been shown to induce apoptosis. In this study, four murine tumors including B16F10 melanoma, NG4TL4 sarcoma, H6 hepatoma and 1MEA 7R.1 hepatoma were found to vary in sensitivity to this gene therapy strategy in vitro but, at effective doses of GCV, the HSVtk-transduced cells of all four tumors showed similar kinetics of early rise in p53 protein levels, then cell cycle S-/G2-phase arrest and finally signs of apoptosis. Immunoblot analyses revealed that Fas (CD95/APO-1), Fas ligand (FasL) and two downstream mediators, RIP and caspase-3, (CPP32, YAMA, Apopain) were increased in GCV-treated HSVtk-transduced tumor cells the cell cycle arrest and before apoptosis. Increased expression of FasL could also be observed in vivo in HSVtk-transduced tumors induced to regress by GCV treatment. Enzyme measurements using specific substrate showed that the caspase-3 activation followed kinetically the FasL expression. More than half of the HSVtk/GCV-induced cell death could be abrogated by addition to the cell culture medium of a specific antisense oligonucleotide to block FasL synthesis, a recombinant Fas/Fc chimeric protein to compete with Fas receptor for FasL binding, or cell-permeable specific tetrapeptide inhibitors of caspase-3 or caspase-8.

S- and G2-phase cell cycle arrests and apoptosis induced by ganciclovir in murine melanoma cells transduced with herpes simplex virus thymidine kinase.

Mechanism of cell killing by transfer of Herpes simplex virus type-1 thymidine kinase (HSVtk) and subsequent ganciclovir (GCV) treatment was examined in B16F10 murine melanoma model. While parental B16F10 melanoma cells were resistant to GCV at 100 microM or higher, HSVtk-transduced B16F10 melanoma cell clones became susceptible to GCV with IC50 of 0.1 to 0.3 microM. By means of various parameters including characteristic morphological changes, in situ DNA end-labeling, DNA ladder pattern, flow cytometric detection of sub-G1 DNA content, and annexin V binding of inverted cell surface phosphatidylserine, apoptosis was shown to be associated with the cell killing of ganciclovir on HSVtk-transduced melanoma B16F10 cells. Kinetic analysis showed that the signs of apoptosis were observed not until 60 h of continued GCV treatment and preceded first by a rise in p53 protein level in 12 h and then by S-phase/G2-phase cell cycle arrest associated with corresponding increases in the level of cyclin B1 protein but no apparent change in protein level of Bax or Cdc2. These results suggest that apoptosis occurred as a result of ganciclovir-induced cell cycle arrests rather than direct chemical effect on HSVtk-transduced B16F10 melanoma cells.

Restoration of the immunocompetence by IL-2 activation and TCR-CD3 engagement of the in vivo anergized tumor-specific CTL from lung cancer patients.

The present study investigates the nature of the immunosuppressed state of the lymphocytes obtained from the malignant pleural effusion (effusion associated lymphocytes, EAL) of lung cancer patients. The immunocompetence of EAL from 13 patients was assessed by determining their T-helper cell phenotype, proliferative response to alpha CD3-activation, and their cytolytic activity against three tumor targets: the autologous tumor, Daudi, and K562. Flow cytometry analysis showed that the lymphocytes in EAL were predominantly T cells with < 1% natural killer cells. The T-helper cell phenotype was found to be predominantly of Th2 type, but could be readily converted to Th1 type by culturing the EAL in vitro, and this conversion was augmented by interleukin-2 (IL-2) or IL-2 plus alpha CD3. To test the cytolytic activity of EAL, it was found that after 6-day culturing, the EAL remained in an immunosuppressed state so that they failed to kill any of the three tumor targets. Stimulation with IL-2 partially restored the immunocompetence of EAL. Further engagement of TCR-CD3 by alpha CD3 fully restored the cytolytic activity of the EAL to kill the autologous tumor target but not Daudi or K562 tumor cells, and thus seemed to be tumor specific. The specificity was further confirmed by testing the activated EAL and normal donor peripheral blood lymphocytes against a variety of tumor targets and control targets. Furthermore, the killing by EAL against the autologous tumor target seemed to be major histocompatibility complex-restricted and was inhibited by anti-human leukocyte antigen class I antibody. The EAL from lung cancer patients also showed much reduced responsiveness to the alpha CD3 stimulation to induce proliferation, and addition of IL-2 restored the responsiveness. These results suggest that, through close contact with tumor cells, anergy of cytotoxic T lymphocytes (CTLs) was induced in vivo at a localized site. IL-2 stimulation and TCR-CD3 engagement could reverse the anergic state and restored the full competence of CTLs in EAL to mediate the specific anti-tumor killing against the autologous tumor. Proper manipulation of EAL may prove useful as a source of anti-tumor effectors for cancer adoptive immunotherapy.

Lack of NK cells and related cytokines in pleural effusion.

BACKGROUND: Relatively low number and activity of natural-killer (NK) cells have been reported in malignant pleural effusions. However, there has been no report on NK cells related cytokines. METHODS: Lymphocyte subpopulations were studied in 30 cases of pleural effusion with various etiologies, along with peripheral blood, by using flow cytometry. The related cytokine levels in peripheral blood and pleural fluid, including IL-1 alpha, IL-4 and IL-12, were also analyzed with ELISA assays. RESULTS: The results showed significant increase of T-helper cell subpopulation in pleural effusion of various etiologies. No obvious change of B-lymphocyte subpopulation between peripheral blood and pleural effusion was found. IL-4 was undetectable in both peripheral blood and pleural fluid in most cases. IL-1 alpha was detectable in some cases and the level was highest in pleural fluid of empyema. Decreased NK cells were found in most cases of pleural effusion and accompanied by undetectable IL-12 both in pleural fluid and peripheral blood. The only one case with detectable IL-12 concentration in pleural fluid was the one with tuberculous pleurisy. CONCLUSIONS: Increased T-helper cell subpopulation and decreased NK cell subpopulation were found in pleural effusion of various etiologies. In spite of the small series of our patients, the decrease of NK cell subpopulation and the undetectable IL-12 concentration in pleural effusion deserves further investigations.