A case of pure gelastic seizures due to hypothalamic hamartoma with a benign course.

Hypothalamic hamartoma is a potentially complex entity with diverse clinical manifestations. We report a case of gelastic seizures associated with a hypothalamic hamartoma, which followed a benign course. A 31-year-old woman with episodes of laughter was referred for diagnostic evaluation. Her initial MRI and EEG were reported as normal. However, her episodes of laughter were typical of gelastic seizures from history and video review. Repeat MRI revealed a small HH. She declined any medical treatment and was medication free until last follow-up. This benign course of HH-associated epilepsy, not necessitating treatment, to our knowledge, has not been previously reported.

Status epilepticus results in persistent overproduction of reactive oxygen species, inhibition of which is neuroprotective.

Epilepsy and seizure activity result in the generation of reactive oxygen species (ROS), which contribute to seizure-induced neuronal damage. Recent in vitro evidence indicates that NADPH oxidase contributes significantly to seizure-induced ROS. We further tested this in rat glio-neuronal cultures and in ex vivo chronic epileptic rat brain tissue using live cell-imaging techniques. Here, we show that ROS are upregulated in chronic epilepsy and that ROS production contributes to cell death, which is seen after status epilepticus (SE) and chronic seizures. Inhibition of ROS production by AEBSF, a NADPH oxidase inhibitor, markedly reduced seizure-induced cell death in the perforant path model of epilepsy. These findings demonstrate a critical role for ROS, generated by NADPH oxidase, contributing to seizure-induced cell death. These findings point to NADPH oxidase inhibition as a novel treatment strategy to prevent brain injury in SE and chronic epilepsy.

Antiviral medication use in a cohort of pregnant women during the 2009-2010 influenza pandemic.

Preventing influenza-like illness (ILI) during pregnancy with antiviral medication use (AVMU) can mitigate serious health risks to mother and foetus. We report on AVMU in pregnant women in Ontario, Canada, and describe characteristics of AVMU during the 2009-2010 H1N1 pandemic. Rates and risk estimates of AVMU were compared across multiple categories and stratified across ILI infection status. Increased AVMU was observed in women with influenza infections, active smokers, those vaccinated against influenza, and those with pre-existing co-morbidities. Decreased AVMU was observed in women with multiple gestations, and those in neighbourhoods of high immigrant concentrations. Our stratified analysis indicated that the observed patterns differed by ILI infection status. We demonstrated that once infected, women across multiple groups were equally likely to use antiviral medications. In this report we also propose possible clinical explanations for the observed differences in AVMU, which will be useful in planning prevention initiatives for future pandemics.

Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?

BACKGROUND: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. METHODS: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). RESULTS: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). CONCLUSION: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.

Association of caesarean delivery for first birth with placenta praevia and placental abruption in second pregnancy.

OBJECTIVE: To quantify the risk of placenta praevia and placental abruption in singleton, second pregnancies after a caesarean delivery of the first pregnancy. DESIGN: Retrospective cohort study. SETTING: Linked birth and infant mortality database of the USA between 1995 and 2000. POPULATION: A total of 5,146,742 singleton second pregnancies were available for the final analysis after excluding missing information. METHODS: Multiple logistic regressions were used to describe the relationship between caesarean section at first birth and placenta praevia and placental abruption in second-birth singletons. MAIN OUTCOME MEASURES: Placenta praevia and placental abruption. RESULTS: Placenta praevia was recorded in 4.4 per 1000 second-birth singletons whose first births delivered by caesarean section and 2.7 per 1000 second-birth singletons whose first births delivered vaginally. About 6.8 per 1000 births were complicated with placental abruption in second-birth singletons whose first births delivered by caesarean section and 4.8 per 1000 birth in second-birth singletons whose first births delivered vaginally. The adjusted odds ratio (95% CIs) of previous caesarean section for placenta praevia in following second pregnancies was 1.47 (1.41, 1.52) after controlling for maternal age, race, education, marital status, maternal drinking and smoking during pregnancy, adequacy of prenatal care, and fetal gender. The corresponding figure for placental abruption was 1.40 (1.36, 1.45). CONCLUSION: Caesarean section for first live birth is associated with a 47% increased risk of placenta praevia and 40% increased risk of placental abruption in second pregnancy with a singleton.

Postprandial venous ammonia concentrations in the diagnosis of hepatobiliary disease in dogs.

A postprandial ammonia tolerance test (PPATT) was performed on normal dogs and dogs with signs that suggested they may have liver disease. All dogs underwent transcolonic scintigraphy, liver biopsy, or both and were assigned to extrahepatic disease, primary hepatocellular, and congenital portosystemic vascular anomalies (PSVA) groups. Each dog was fed a chicken and rice diet providing 25% of its estimated daily metabolizable energy requirement (MER) as an ammonia challenge. This is practical in patients with liver disease because ammonium chloride administration often causes vomiting or ammonia toxicity. Venous ammonia concentrations were measured before feeding and every 2 hours after feeding for 8 hours. No difference in mean ammonia concentrations between dogs with extrahepatic disease and control dogs was found. Therefore, the specificity of the PPATT was 100%. Dogs with hepatocellular disease showed no change in mean ammonia concentration at any time point, before or after feeding, but sensitivity was greatest when venous ammonia was measured 6 hours after feeding (sensitivity before feeding, 28%, and after feeding, 36%). Among dogs with congenital PSVA, mean ammonia concentrations were higher than the reference range at all time points before and after feeding, and peak mean ammonia concentration occurred 6 hours after feeding. In this group, the sensitivity of the PPATT was 81% before feeding and 91% 6 hours after feeding. This study demonstrates that the measurement of venous ammonia concentration is a useful test to detect congenital PSVA, and the sensitivity of the test may be improved by sampling 6 hours after feeding. The PPATT has poor sensitivity in detecting primary hepatocellular disease.

Multiple endocrine neoplasia type 1 in a crossbred dog.

Multiple endocrine neoplasia type 1 was diagnosed in a 12-year-old male crossbred dog. Relevant history included polyuria and polydipsia of four months' duration. Physical examination revealed abdominal enlargement, seborrhoea and polypnoea. Diagnostic tests indicated hypercalcaemia, elevated serum alkaline phosphatase and alanine aminotransferase, an exaggerated response to adrenocorticotropic stimulation of the adrenal gland, lack of cortisol suppression with a low dose dexamethasone suppression test and suppression of cortisol secretion with a high dose dexamethasone test. An enlarged right parathyroid gland was removed surgically and confirmed histopathologically to be a parathyroid adenoma. The pituitary-dependent hyperadrenocorticism was treated successfully with mitotane for 14 months before the patient was euthanased for an unrelated problem.

Rapid onset transverse myelitis in adolescence: implications for pathogenesis and prognosis.

Five adolescents with transverse myelitis were reviewed. All presented with a rapid onset paralysis of the lower limbs and impairment of bladder control. The maximum disability developed between 10 minutes and six hours. There was no history of trauma, asthma, or prodromal illness. Investigations failed to demonstrate a vascular cause. Extensive spinal cord abnormalities were observed on magnetic resonance imaging. Electrophysiological investigations, performed in four cases, were all consistent with anterior horn cell damage. In all five adolescents there was poor recovery. The underlying pathogenesis of this rapid onset condition remains a subject of debate. Similarities with both transverse myelitis and fibrocartilaginous emboli are evident, widening the spectrum of conditions within the transverse myelitis umbrella. These observations suggest that in rapid onset "transverse myelitis" the combination of extensive hyperintensity on spinal cord neuroimaging with electrophysiological evidence of anterior horn cell involvement might have adverse prognostic significance.

Vertebral physitis with epiphyseal sequestration and a portosystemic shunt in a Pekingese dog.

Vertebral physitis with bone sequestration and a portosystemic shunt were diagnosed in an 18-month-old female Pekingese dog. The latter was determined by the presence of low blood urea nitrogen, elevated serum bile acids, microhepatica and an increased portosystemic shunt fraction. It was managed with a home-cooked low protein diet. Vertebral physitis and bone sequestration was diagnosed by the presence of thoracolumbar hyperaesthesia, radiographic and scintigraphic changes, isolation of Staphylococcus intermedius from blood and the third lumbar vertebra, and histopathological examination of a surgical biopsy. A partial sequestrectomy was performed and a six-month course of amoxycillin-clavulanate was prescribed. The dog was pain-free and showed partial resolution of the radiographic signs four months after the discontinuation of antibiotics.

Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation Group.

A safety and immunogenicity trial was conducted in vaccinia-immune and vaccinia-naive human immunodeficiency virus (HIV)-uninfected adults who were randomized to receive 10(6) or 10(7) TCID50 of canarypox (ALVAC) vector expressing HIV-1MN gp160 or 10(5.5) TCID50 of ALVAC-rabies virus glycoprotein control at 0 and 1 or 2 months and ALVAC-gp160 or 50 microg of HIV-1SF2 recombinant (r) gp120 in microfluidized emulsion at 9 and 12 months; others received rgp120 at 0, 1, 6, and 12 months. All vaccines were well-tolerated. Neither vaccinia-immune status before vaccination nor ALVAC dose affected HIV immune responses. HIV-1MN and HIV-1SF2 neutralizing antibodies were detected more often (100%) in ALVAC-gp160/rgp120 recipients than in recipients of ALVAC-gp160 (<65%) or rgp120 (89%) alone. ALVAC-gp160/rgp120 also elicited more frequent HIV V3-specific and fusion-inhibition antibodies, antibody-dependent cellular cytotoxicity, lymphoproliferation, and cytotoxic CD8+ T cell activity than did either vaccine alone. Trials with ALVAC expressing additional HIV components and rgp120 are underway.

Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group.

Phase I studies of volunteers not infected with human immunodeficiency virus type 1 (HIV-1) have shown that immunization with envelope subunit vaccine products elicits antibodies that neutralize laboratory-adapted (prototype) HIV-1 strains in vitro. Prototype strains are adapted to grow in continuous (neoplastic) cell lines and are more susceptible to neutralization than are primary isolates cultured in human peripheral blood mononuclear cells. In this study, 50 sera from nine phase I vaccine trials and 16 from HIV-1-infected persons were evaluated for neutralizing antibody activity against 3 laboratory-adapted and 5 primary HIV-1 isolates. Of 50 sera, 49 neutralized at least 1 of the prototype strains; however, none displayed neutralizing activity against primary isolates of HIV-1. Serum from most HIV-1-infected persons neutralized both laboratory-adapted and primary HIV-1 isolates. These data demonstrate a qualitative, or large quantitative, difference in the neutralizing antibody response induced by envelope subunit vaccination and natural HIV-1 infection.

Muscle fructose-2,6-bisphosphate and glucose-1,6-bisphosphate during insulin-induced hypoglycemia.

Glucose production during insulin-induced hypoglycemia in the fasted state is heavily dependent on the process of hepatic gluconeogenesis. Skeletal muscle glycogen is one possible source of lactate for hepatic gluconeogenesis. Fructose 2,6-bisphosphate (F-2,6-P2) and glucose 1,6-bisphosphate (G-1,6-P2) are two allosteric activators of muscle glycolysis. To investigate their putative role in the control of muscle lactate production during hypoglycemia, fasted rats were infused via jugular catheters with insulin in 0.9% NaCl or with 0.9% NaCl alone for 60 or 120 min. Muscles were removed and clamp frozen in liquid nitrogen. The insulin infusion produced plasma insulin values of 97 +/- 13 microU/ml after 1 h and 100 +/- 9 microU/ml after 2 h. Blood glucose in the saline-infused rats was 4.6 +/- 0.2 mM after 1 h and 5.1 +/- 0.1 mM after 2 h compared with 1.5 +/- 0.01 and 1.0 +/- 0.1 mM after 1 and 2 h, respectively, in the insulin-infused rats. The hypoglycemic rats had significantly elevated plasma epinephrine and blood lactate levels compared with the saline-infused rats. F-2,6-P2 and G-1,6-P2 were increased two- to five-fold in white quadriceps of hypoglycemic rats compared with that of saline-infused rats. The results are consistent with F-2,6-P2 and G-1,6-P2 playing a role in stimulating muscle lactate production as a source of gluconeogenic substrate during insulin-induced hypoglycemia.

Summary report: workshop on the potential risks of antibody-dependent enhancement in human HIV vaccine trials.

Concern that ADE of HIV infection could occur in vivo, as a result of HIV immunization, has arisen for several reasons. Immune-mediated disease enhancement occurs in several human and animal viral diseases, including lentiviral diseases. Tropism for host M/M cells is a common characteristic in these diseases. Sera from naturally infected, and possibly HIV-immunized, individuals have been shown to contain infection enhancing antibodies in vitro. Finally, there is considerable genetic, and potentially antigenic, diversity among HIV-1 isolates. This workshop was convened to evaluate these concerns regarding ADE of HIV infection in human HIV vaccine trials and to propose studies that would address this potential risk. Although there is currently no evidence that immune-mediated enhancement of disease occurs in HIV, there is clearly a need for carefully designed experiments to further evaluate this issue. As there are several notable diseases for which in vitro ADE does not correlate with ADE in vivo, in vitro data are insufficient to deter development of current HIV-1 vaccine candidates. In vivo correlates of protection/enhancement are necessary to evaluate the ADE risk accurately. The development of an HIV animal model that would allow testing of vaccine candidates is of primary importance.

Hypersensitivity of human testis-tumour cell lines to chemotherapeutic drugs.

Metastatic testis tumours, in contrast to most other types of cancer, can be cured by drugs. To investigate which classes of chemotherapeutic drug are differentially toxic to testis-tumour cells, we compared the in vitro dose-response curves of 5 human testis and 5 bladder-cancer cell lines to 12 compounds. The testis cells were hypersensitive to drugs that interact directly with DNA (m-amsa, bleomycin, cisplatin, doxorubicin, methylnitrosourea, mitozolomide, etoposide, mitomycin-C), but little or no difference between the 2 cell types was seen following exposure to drugs whose mechanisms of action do not involve direct interaction with DNA (methotrexate, 5-fluorouracil, colchicine, vinblastine). We conclude that testis tumour cells are either less tolerant of, or have a reduced capacity to repair, DNA damage.

O6-alkylguanine-DNA-alkyltransferase activity and nitrosourea sensitivity in human cancer cell lines.

The DNA repair enzyme, O6-alkylguanine-DNA-alkyltransferase (ATase), is thought to be the principal mechanism controlling resistance to nitrosoureas and related alkylating agents. We compared the sensitivities of five human testis and five bladder tumour cell lines to two nitrosoureas (N-nitroso-N-methylurea (MNU) and mitozolomide) with cellular levels of ATase. Enzyme levels ranged from 3 to 206 fmol mg-1 protein (0.1 x 10(4) to 5.1 x 10(4) molecules/cell) in the testis lines and from 11 to 603 fmol mg-1 (0.4 x 10(4) to 9.1 x 10(4) molecules/cell) in the bladder lines. Based on IC50s in an MTT assay, the testis tumour cell lines were, on average, four times more sensitive to MNU and six times more sensitive to mitozolomide than the bladder cell lines. The cytotoxicities of MNU and mitozolomide were closely related (R = 0.9). In the testis cell lines ATase activity (molecules/cell) was related to IC50s for mitozolomide (R = 0.97) but not MNU (R = 0.78). In the bladder cell lines and overall, ATase activity correlated with cellular sensitivity to neither agent. Relatively high levels of resistance occurred in cells expressing low levels of ATase, and amongst cell lines expressing high levels of ATase, large differences in IC50s were observed. These results support the suggestion that resistance to nitrosoureas can be mediated by mechanisms other than ATase and that at relatively high levels of expression, ATase does not confer resistance in proportion to its activity.

Relationship between topoisomerase II level and chemosensitivity in human tumor cell lines.

Patients with metastatic testis tumors are generally curable using chemotherapy, whereas those with disseminated bladder carcinomas are not. We have compared levels of the nuclear enzyme topoisomerase II in three testis (SuSa, 833K, and GH) and three bladder (RT4, RT112, and HT1376) cancer cell lines which differ in their sensitivity to chemotherapeutic agents. The testis cell lines were more sensitive than the bladder lines to three drugs whose cytotoxicity is mediated in part by inhibiting topoisomerase II: amsacrine; Adriamycin; and etoposide (VP16). The frequency of DNA strand breaks induced by amsacrine was higher (1.5- to 13-fold) in the testis cells than in the bladder cells. The level of topoisomerase II-mediated DNA strand breakage in vitro, measured by filter trapping of amsacrine-induced protein:DNA cross-links, was similarly higher in nuclear extracts from the testis than the bladder cells. Western blot analysis showed a generally higher level of topoisomerase II protein in testis than in bladder cell nuclear extracts. Topoisomerase II protein expression broadly correlated with drug-induced strand breakage in both protein extracts and whole cells, but not with population doubling time. However, despite a 2- to 20-fold increased sensitivity to the different topoisomerase II inhibitors, the testis line 833K had a less than 2-fold higher level of topoisomerase II protein than that of the bladder line RT4. These results indicate that the level of expression of topoisomerase II is an important determinant of the relative chemosensitivity of testis and bladder tumor cell lines, but that additional factors must contribute to the extreme chemosensitivity of testis cells.

Inherent sensitivity and induced resistance to chemotherapeutic drugs and irradiation in human cancer cell lines: relationship to mutation frequencies.

Metastatic nonseminomatous testicular germ cell tumors are curable using combination chemotherapy in approximately 80% of patients. In contrast, most other patients with other types of cancer either present with or acquire drug-resistant disease following chemotherapy. Cell lines derived from testis tumors retain hypersensitivity to both drugs and radiation in vitro, thus providing a model system with which to investigate the genetic basis of hypersensitivity to these agents. This study compared the spontaneous and both ethyl methanesulfonate- and cisplatin-induced frequencies of mutation of 6-thioguanine resistance in 3 human bladder and 3 testis tumor cell lines and a bladder and a testis cell line with cisplatin resistance induced in vitro. The two tumor types showed similar frequencies of both spontaneous and induced mutation frequencies at this locus. Therefore, we failed to provide evidence for the hypothesis that the curability of testis tumors is associated with a low frequency of mutation to drug resistance.

5-azacytidine and 5-azadeoxycytidine inhibit human immunodeficiency virus type 1 replication in vitro.

Chemotherapeutic agents which affect the integration, stability, or inducibility of the human immunodeficiency virus (HIV) provirus would have considerable value in treating acquired immunodeficiency syndrome. Two nucleoside analogs of cytosine, 5-azacytidine and 5-azadeoxycytidine, which seem to have such value because of their capabilities to affect both the stability and the methylation patterns of the nucleic acids into which they are incorporated, were tested for their ability to inhibit the replication of HIV type 1 (HIV-1) in human CEM T cells in vitro. 5-Azadeoxycytidine (1 microM) completely inhibited HIV replication in CEM cells, by the criteria of reduced viral antigen expression and decreased supernatant reverse transcriptase activity, with little toxicity for the treated cells. 5-azacytidine (1 microM) also inhibited HIV replication, but less effectively. When added 2 or more h after CEM cells were infected with HIV-1, both 5-azacytosine derivatives were less effective than they were when added at the time of infection. Even 2 h of exposure to 5-azadeoxycytidine was sufficient for inhibition of HIV replication. Although long exposure to either analog at concentrations of 1 microM would result in pronounced cellular cytotoxicity, the the fact that short exposures to the same dose of drug inhibit HIV replication but are not toxic for the cells implies that cellular toxicity itself is not an important mechanism of the antiviral action of the analogs.