Conotoxin GIIIA: selective inhibition of 22Na influx via voltage-dependent Na channels in adrenal medullary cells

Summary Conotoxin GIIIA and GIIIB from the marine snail Conus geographus have been reported to inhibit voltage-dependent Na channels in skeletal muscle and postganglionic sympathetic neuron, but have no effect on Na channels in brain, giant axon and heart. In eel electroplax, conotoxins were also shown to share the common binding sites with saxitoxin (see review Gray et al. 1988).In bovine adrenal medullary cells, conotoxin GIIIA inhibited veratridine-induced influx of ²²Na, ⁴⁵Ca and secretion of catecholamines with an IC₅₀ of 6 mol/l, while saxitoxin suppressed veratridine-induced responses with an IC₅₀ of 6.3 nmol/l. [³H]Saxitoxin binding to the cells was inhibited by unlabeled saxitoxin with an IC₅₀ of 5.1 nmol/l, but was slightly reduced by 10 mol/l conotoxin GIIIA. Conotoxin GIIIA, at 10 mol/l, did not alter carbachol-induced influx of ²²Na, ⁴⁵Ca and secretion of catecholamines as well as high K-induced ⁴⁵Ca influx and catecholamine secretion.These results indicate that conotoxin GIIIA, at concentrations 950 fold higher than saxitoxin, inhibits Na influx via voltage-dependent Na channels, but has no effect on the nicotinic receptor-ion channel complex or the voltage-dependent Ca channels. Conotoxin GIIIA seems to bind at the sites which are distinct from saxitoxin, but are functionally linked to the voltage-dependent Na channels. Conotoxins may be useful for the classification of Na channels in excitable cell membranes. Send offprint requests to A. Wada at the above address     

Acute promyelocytic leukemia: an unusual cause showing prolonged disseminated intravascular coagulation after placental abruption

Background Disseminated intravascular coagulation (DIC) caused by placental abruption usually improves rapidly after prompt delivery and adequate anti-DIC treatment. Case A 30-year-old nulliparous woman suffered from placental abruption at the 25th week of pregnancy, and emergent cesarean section was done immediately. She exhibited DIC, which continued even after termination of the pregnancy and anti-DIC treatment. She also showed neutropenia. We closely observed her, and at the 58th day postpartum, blast cells appeared in the peripheral blood and she was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy was done successfully. The close observation after delivery enabled us to make the prompt diagnosis/treatment, leading to the complete remission. Conclusion APL should be added to the list of differential diagnosis when DIC persists even after prompt delivery and appropriate anti-DIC treatment after placental abruption.     

Femur fracture during abdominal breech delivery

BACKGROUND: While vaginal breech delivery, although rare, can cause femur fracture, abdominal breech delivery is not expected to cause it. CASE: A 2,490-g female infant was delivered at term by elective cesarean section for breech presentation. She sustained a fracture of the femur shaft. A simple splinting led to a complete healing of the fracture without sequelae. CONCLUSION: Although abdominal breech delivery reduces the risk of birth trauma, we must be aware that femur fracture can occur regardless of the mode of delivery.     

Soy isoflavone aglycones are absorbed faster and in higher amounts than their glucosides in humans

Isoflavones are contained in soybean or soy foods in two chemical forms, i.e., aglycones and glucosides. We investigated the difference in the absorption of soy isoflavone aglycones and glucosides in humans. After a single, low dose intake (0.11 mmol), the highest isoflavone concentrations in plasma were reached 2 and 4 h after ingestion of aglycones and glucosides, respectively; subjects were four men (41 y old) and four women (45 y old). The highest plasma concentration after aglycone intake was more than two times greater than that after glucoside ingestion. In a similar manner, we then compared the plasma isoflavone concentration profiles after intake of a single, high dose of isoflavones (1.7 mmol) in eight subjects (four men, 40 y old; four women, 47 y old) and found the highest plasma concentration after aglycone intake was more than five times higher than that after glucoside intake. In both high and low dose intake tests, the plasma concentration of genistein was significantly higher than that of daidzein despite the similar levels of intake. After long-term (4 wk) intakes (0.30 mmol/d), we also measured the plasma concentration of isoflavones (eight men, 45 y old). After 2 and 4 wk, these concentrations remained >100% higher after ingestion of aglycones than of glucosides. The isoflavone aglycones were absorbed faster and in greater amounts than their glucosides in humans. Isoflavone aglycone-rich products may be more effective than glucoside-rich products in preventing chronic disease such as coronary heart disease.     

Surveillance study for creating the national clinical database relating to ECG-gated myocardial perfusion SPECT of asymptomatic ischemic heart disease in patients with type-2 diabetes mellitus: J-ACCESS 2 study design

Objective Diabetes mellitus is an independent risk factor for acute myocardial infarction. Thus, a surveillance study was conducted as part of studies to create a national database related to electrocardiogram (ECG)-gated myocardial perfusion single-photon emission computed tomography (SPECT) of ischemic heart disease. Methods Single-photon emission computed tomography was conducted in patients with type 2 diabetes mellitus and their prognoses will be followed for 3 years, stratified by patients’ clinical background and SPECT findings. Results A total of 513 patients from 50 institutions were enrolled in this study, 297 of whom were men (age 66.2 ± 0.4 years, mean ± SEM) and 261 women (age 67.8 ± 0.5 years). They have a history of retinopathy (25.3%), neuropathy (19.9%), cerebrovascular disorder, chronic obstructive pulmonary disease, and photocoagulation. Major risk factors for present disease were hypertension (82.3%) and hyperlipidemia (79.7%). In 244 patients (129 men and 115 women), body mass index (BMI) was 25 or more. Fifty-two of them (10.1%) underwent coronary angiography; of these, 26 (50.0%) had no coronary artery lesions with 75% or more stenosis, and only 1 (1.9%) had a left main trunk with 50% or more stenosis. An overwhelming majority of patients (94.3%) underwent SPECT imaging by a 1-day stress-followed-by-rest procedure. Stress procedure was exercise in most (70.8%) patients, followed by dipyridamole infusion in 14.6%, adenosine infusion in 6.6%, and adenosine triphosphate infusion in 5.7%. Endpoint of stress examination was most often fatigue in lower limbs (40.7%), followed by completion of pharmacological stress protocol (28.7%), and achievement of target heart rate (26.3%). The largest number of patients (198, 38.6%) received ^99mTc-tetrofosmin at an initial dosage of 200–300 MBq (mean 331 ± 3 MBq) followed by a second dosage of 700–800 MBq (mean 748 ± 8 MBq). Among them, 491 (95.7%) received some kind of therapeutic drug: hypoglycemic drugs were used by the largest number (83.2%), followed by hypotensive (66.7%), hypolipidemic (40.7%), and antiplatelet drugs (27.7%), vasodilators (5.5%), and antioxidants and others (2.3%). Conclusions This study was designed to clarify the correlation between coronary artery disease and diabetes mellitus as its risk factor based on the clinical and imaging findings. Patient enrollment was closed on September 30, 2005, and follow-up is now under way.     

Increased insulin sensitivity and hypoinsulinemia in APS knockout mice

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.     

Prognostic Factors in Endodontic Surgery Using an Endoscope: A 1 Year Retrospective Cohort Study

This retrospective study clarified the success rate of endoscopic endodontic surgeries and identified predictors accounting for successful surgeries. In this retrospective study, 242 patients (90 males, 152 females) who underwent endoscopic endodontic surgery at a single general hospital and were diagnosed through follow-up one year later were included. Risk factors were categorized into attributes, general health, anatomy, and surgery. Then, the correlation coefficient was calculated for the success or failure of endodontic surgery for each variable, the odds ratio was calculated for the upper variable, and factors related to the surgical prognosis factor were identified. The success rate of endodontic surgery was 95.3%, showing that it was a highly predictable treatment. The top three correlation coefficients were post, age, and perilesional sclerotic signs. Among them, the presence of posts was the highest, compared with the odds ratio, which was 9.592. This retrospective study revealed the success rate and risk factors accounting for endoscopic endodontic surgeries. Among the selected clinical variables, the presence of posts was the most decisive risk factor determining the success of endodontic surgeries.     

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001).Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.Clinical Trial Registration ClinicalTrials.gov, REACH ({"type":"clinical-trial","attrs":{"text":"NCT01140347","term_id":"NCT01140347"}}NCT01140347) and REACH-2 ({"type":"clinical-trial","attrs":{"text":"NCT02435433","term_id":"NCT02435433"}}NCT02435433).Subject terms: Oncology, Biomarkers     

Mumbai disease in far western Nepal: HIV infection and syphilis among male migrant-returnees and non-migrants

OBJECTIVE: To measure the seroprevalence of human immunodeficiency virus (HIV) infection and syphilis, and to assess the behavioural risk factors for these infections among migrant-returnees and non-migrants in far western Nepal. METHODS: In April 2001, we recruited 97 male migrant-returnees and 40 non-migrants from five rural villages in Doti district where migration to Mumbai is common. For data collection, we conducted a serological examination for HIV and syphilis, and a perception and behaviour survey on HIV and other sexually transmitted infections. RESULTS: We found that 11 of 137 men (8%) were positive for HIV infection and 30 men (22%) for syphilis. The respondents, especially the migrant-returnees from Mumbai, were engaging in risky behaviours such as pre- or extramarital sex, and sex with multiple partners, including sex workers. CONCLUSIONS: This study revealed high HIV and syphilis prevalence among the male migrant-returnees and non-migrants in far western Nepal where migration to Mumbai is common. The prevalent behaviours, particularly among the migrant-returnees, imply urgent needs of the behavioural modification programme in this area to prevent the spread of HIV infection to general population.     

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Summary. We report a case of aplastic anaemia (AA) treated with granulocyte colony-stimulating factor (G-CSF) terminating as acute myeloblastic leukaemia (AML). Because of severe pneumonia, 250 μg of G-CSF was administered for 30d to promote neutrophil recovery. Following G-CSF therapy, myeoblasts appeared, and the diagnosis of AML was then made. The myeloblasts proliferated in response to G-CSF in vitro and in vivo. In AA. development of AML, after treatment with G-CSF is rate. Therefore a careful observation for leukaemic transformation is necessary in long-term administration of G-CSF for AA.