Nonconvulsive status epilepticus in the critically ill elderly

PURPOSE: To describe the electrographic and clinical features of nonconvulsive status epilepticus (NCSE) in the critically ill elderly and to identify potential predictors of outcome. METHODS: We prospectively identified 25 episodes of altered mentation and NCSE in 24 critically ill elderly patients associated with generalized, focal, or bihemispheric epileptiform EEG patterns. Patients with anoxic encephalopathy were excluded. RESULTS: Of 25 hospitalizations, 13 (52%) resulted in death, and 12 (48%) patients survived to discharge. Death was associated with the number of acute, life-threatening medical problems on presentation (survivors, 1.8; fatalities, 2.8; p = 0.013) and with generalized EEG pattern (p = 0.017). Higher doses or greater number of antiepileptic drugs (AEDs) did not improve outcome. Treatment with intravenous benzodiazepines was associated with increased risk of death (p = 0.033). Ten patients with advance directives were managed outside the intensive care unit (ICU). Mean hospitalization was 39 days in the ICU group and 22 for those with advance directives (p = 0.017). CONCLUSIONS: Severity of illness correlates with mortality in critically ill elderly patients with NCSE. Treatment with intravenous benzodiazepines may increase their risk of death. Aggressive ICU management may prolong hospitalization at considerable cost, without improving outcome. It is unclear whether NCSE affects outcome in the critically ill elderly or is merely a marker for severity of disease in predisposed patients. The benefits of aggressive therapy are unclear. Carefully controlled, prospective trials will be necessary to determine the best therapies for NCSE in the critically ill elderly and the appropriate role of the ICU in their management.     

Transurethral microwave thermotherapy: what role should it play versus medical management in the treatment of benign prostatic hyperplasia?

Both transurethral microwave thermotherapy (TUMT) and medical management by alpha-blockade or 5-alpha-reductase inhibition are increasingly being considered as alternatives to surgery for treatment of patients with benign prostatic hyperplasia (BPH). We review current evidence supporting the effectiveness and safety of TUMT and medical management. Factors for consideration in appropriately selecting patients for TUMT versus medical management are suggested. Available data indicate that TUMT confers greater long-term benefits than medical management as judged by symptom score and peak urinary flow rate improvements. TUMT-associated morbidity is comparatively low. Alpha-blockade affords more rapid relief than TUMT for patients with BPH; however, other strategies such as the use of temporary intraurethral endoprostheses during the acute post-TUMT recovery period may diminish or abolish the differences in time-course of symptom and flow rate improvement between TUMT and alpha-blockade. 5-Alpha-reductase inhibition with finasteride offers a favorable side-effect profile, although the magnitude of symptom and flow rate improvements is modest, and maximal effects of finasteride do not become manifest until after several months of treatment. As TUMT continues to evolve, increasing attention is being accorded the delivery of high thermal doses and precise targeting of the thermal energy delivered. The development of alpha-blockers with a more favorable side-effect profile continues to be a major focus of investigation. The potential clinical utility of combination therapy with TUMT and alpha-blockade is currently under investigation.     

International bank for foot-and-mouth disease vaccine: assessment of Montanide ISA 25 and ISA 206, two commercially available oil adjuvants

The International Vaccine Bank at Pirbright has recently installed large-scale vaccine formulation equipment for the preparation of oil-adjuvanted vaccines. Such vaccines are claimed to offer a number of advantages over Al(OH)3, particularly their ability to raise better immunity in pigs. This paper reports on the potency in pigs, cattle and guinea-pigs of foot-and-mouth disease vaccines prepared with two novel oil adjuvants, Montanide ISA 25 and 206 (Seppic, Paris). The results indicate that vaccines adjuvanted with these oils retain potency for a longer period than our conventional aqueous formulation, following storage at +4 degrees C, and elicit good antibody responses in both pigs and cattle regardless of injection route. In addition they gave no evidence of toxicity or prolonged pyrexia following their administration. Local reactions at the site of inoculation were not observed in cattle vaccinated intramuscularly, even following a booster dose. Pigs vaccinated intramuscularly only showed local reactions if the volume administered exceeded the 2.0 ml dose or the animals received a second vaccination. These observations on the efficacy of such oil formulated vaccines suggest that they have potential as an alternative to the current aqueous formulation.     

In vivo model of adeno-associated virus vector persistence and rescue

Gene therapy vectors based on human DNA viruses could be mobilized or rescued from individuals who are subsequently infected with the corresponding wild-type (wt) helper viruses. This phenomenon has been effectively modeled in vitro with both adenovirus (Ad) and adeno-associated virus (AAV) vectors but has not previously been studied in vivo. In the current study, we have developed an in vivo model to study the interactions of a recombinant AAV vector (AAV-CFTR) with wt AAV type 2 (AAV2) and a host range mutant Ad (Ad2HR405) for which monkey cells are permissive (D.E.Brough, S.A.Rice, S.Sell, and D.F.Klessig, J. Virol. 55:206-212, 1985). AAV-CFTR was administered to the respiratory epithelium of the nose or lung of rhesus macaques. Primary cells were harvested from the infusion site at time points up to 3 months after vector administration to confirm vector DNA persistence. Vector DNA was present in episomal form and could be rescued in vitro only by addition of wt AAV2 and Ad. In in vivo rescue studies, vector was administered before or after wt-AAV2 and Ad2HR405 infection, and the shedding of AAV-CFTR was examined. Ad2HR405 and wt-AAV2 infections were established in the nose with concomitant administration. wt-AAV2 replication occurred in the lung when virus was administered directly at a high titer to the lower respiratory tract. AAV-CFTR vector rescue was also observed in the latter setting. Although these studies were performed with small numbers of animals within each group, it appears that AAV-CFTR DNA persists in the primate respiratory tract and that this model may be useful for studies of recombinant AAV vector rescue.     

The distribution of the matricellular protein thrombospondin 2 in tissues of embryonic and adult mice

Mice that lack the matricellular protein thrombospondin 2 (TSP2) develop a pleiotropic phenotype characterized by morphological changes in connective tissues, an increase in vascular density, and a propensity for bleeding. Furthermore, dermal cells derived from TSP2-null mice display adhesion defects, a finding that implicates TSP2 in cell-matrix interactions. To gain a better understanding of the participation of TSP2 in the development and maturation of the mouse, we examined its distribution in embryonic and adult tissues. Special attention was paid to the presence of TSP2 in collagen fibers, because collagen fibrils in the TSP2-null mouse appear to be irregular in size and contour by electron microscopy. Immunohistochemical analysis of Day 15 and Day 18 embryos revealed TSP2 in areas of chondrogenesis, osteogenesis, and vasculogenesis, and in dermal and other connective tissue-forming cells. Distinctly different patterns of deposition of TSP2 were observed in areas of developing cartilage and bone at Days 15 and 18 of embryonic development. A survey of adult tissues revealed TSP2 in dermal fibroblasts, articular chondrocytes, Purkinje cells in the cerebellum, Leidig cells in the testis, and in the adrenal cortex. Dermal fibroblasts were also shown to synthesize TSP2 in vitro. The distribution of TSP2 during development is in keeping with its participation in the formation of a variety of connective tissues. In adult tissues, TSP2 is located in the pericellular environment, where it can potentially influence the cell-matrix interactions associated with cell movement and tissue repair.     

On bracket slot height: a methodologic study

The present study examined the prevalence of comorbid anxiety symptoms in 44 children with pervasive developmental disorders. Parents of the children were interviewed using the Anxiety Disorders section of the Diagnostic Interview Schedule for Children. Results indicated that severe anxiety symptoms are highly prevalent in children with pervasive developmental disorders: 84.1% of the children met the full criteria for at least one anxiety disorder. Furthermore, 72.7% of the children displayed ritualistic behaviors. Implications of the findings are discussed.     

Dysplasia in Barrett's esophagus: diagnosis, surveillance and treatment

Barrett's esophagus is a premalignant metaplastic change in the lining of the distal esophagus. It represents a peculiar form of healing which occurs in response to chronic gastroesophageal reflux disease. The condition should be considered in all patients undergoing endoscopy for symptoms of reflux disease and is confirmed when any biopsy shows the presence of specialized intestinal metaplasia irrespective of the macroscopic appearance of the distal esophagus. Endoscopic surveillance with multiple biopsy sampling of the esophageal mucosa is indicated for all medically fit patients with Barrett's esophagus. The diagnosis of dysplastic change within this abnormal mucosa requires histological examination of the biopsies by 2 independent but experienced pathologists. Identification of high-grade dysplasia heralds the development of invasive cancer and offers the physician an opportunity to intervene. Despite extensive endoscopic sampling of the esophageal mucosa the differentiation between high-grade dysplasia and invasive adenocarcinoma is unreliable. Esophagectomy remains the treatment of choice for patients with high-grade dysplasia since adenocarcinoma of the esophagus carries such a poor prognosis.     

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice

Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.     

In vitro selection of the Naegleria GIR1 ribozyme identifies three base changes that dramatically improve activity

NanGIR1 is a member of a new class of group I ribozymes whose putative biological function is site-specific hydrolysis at an internal processing site (IPS). We have previously shown that NanGIR1 requires 1 M KCl for maximal activity, which is nevertheless slow (0.03 min(-1)). We used in vitro selection and an RNA pool with approximately nine mutations per molecule to select for faster hydrolysis at the IPS in 100 mM KCl. After eight rounds of selection, GIR1 variants were isolated that catalyzed hydrolysis at 300-fold greater rates than NanGIR1 RNA. Although not required by the selection, many of the resultant RNAs had increased thermal stability relative to the parent RNA, and had a more compact structure as evidenced by their faster migration in native gels. Although a wide spectrum of mutations was found in generation 8 clones, only two mutations, U149C and U153C, were common to greater than 95% of the molecules. These and one other mutation, G32A, are sufficient to increase activity 50-fold. All three mutations lie within or proximal to the P15 pseudoknot, a structural signature of GIR1 RNAs that was previously shown to be important for catalytic activity. Overall, our findings show that variants of the Naegleria GIR1 ribozyme with dramatically improved activity lie very close to the natural GIR1 in sequence space. Furthermore, the selection for higher activity appeared to select for increased structural stability.     

Talc pleurodesis: talc slurry versus thoracoscopic talc insufflation in a porcine model

BACKGROUND: Pleurodesis using both talc slurry and thoracoscopic talc insufflation has been shown to be clinically effective. This study compares these two modalities of pleural talc instillation in an animal model. METHODS: Eleven immature pigs underwent general endotracheal anesthesia. On one side, a slurry of 5 g sterile United States Pharmacopeia talc in 50 mL of saline solution was instilled through a thoracostomy tube. On the other side, the lung was deflated and 5 g of dry talc was insufflated under thoracoscopic visualization. The animals were sacrificed 30 days later, and the quality of pleural adhesions was graded from 0 to 2 (0 = absent; 1 = light; 2 = dense) in each of six regions of each hemithorax. The distribution of adhesions on each side was graded from 0 to 6, according to the number of areas that contained adhesions. RESULTS: One animal died of anesthetic complications. Among the survivors, adhesions produced by both methods were dense and diffuse in 8 of 10 animals, and light and diffuse in 1 animal. One animal had light or absent adhesions on the talc slurry side, and dense and diffuse adhesions on the thoracoscopic talc insufflation side. There was no difference between the techniques for density of adhesion scores (talc slurry, 9.9 +/- 2.2; thoracoscopic talc insufflation, 10.0 +/- 2.5) or distribution of adhesion scores (talc slurry, 5.5 +/- 1.0; thoracoscopic talc insufflation, 5.8 +/- 0.4) (p > 0.1). CONCLUSIONS: Effective pleurodesis in a porcine model can be obtained with either talc slurry or thoracoscopic talc insufflation.