Pharmacokinetic Modeling of Optimized Midazolam and Pentobarbital Dosing Used in Treatment Protocols of Refractory Status Epilepticus.

OBJECTIVES: To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status epilepticus (RSE). DESIGN: One- and two-compartment in silico pharmacokinetic models of midazolam and pentobarbital. SETTING: Not applicable. SUBJECTS: Not applicable. INTERVENTIONS: We compared the model variables used in midazolam and pentobarbital protocols for standard RSE. MEASUREMENTS AND MAIN RESULTS: Standard RSE treatment protocols result in steady-state serum concentrations that are 6.2-9.0-fold higher for the one-compartment model and 2.3-4.7-fold higher for the two-compartment model. In the model, not including bolus doses delays the achievement of serum steady-state concentration by 0.5 and 2.7 hours for midazolam and pentobarbital, respectively. Abrupt discontinuation of these medications reduces modeled medication exposure by 1.1 and 6.4 hours, respectively. CONCLUSIONS: Our in silico pharmacokinetic modeling of standard midazolam and pentobarbital dosing protocols for RSE suggests potential variables to optimize in future clinical studies.

International peritoneal dialysis training practices and the risk of peritonitis.

BACKGROUND: The effects of training practices on outcomes of patients receiving peritoneal dialysis (PD) are poorly understood and there is a lack of evidence informing best training practices. This prospective cohort study aims to describe and compare international PD training practices and their association with peritonitis. METHODS: Adult patients on PD <3 months participating in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) were included. Training characteristics (including duration, location, nurse affiliation, modality, training of family members, use of individual/group training and use of written/oral competency assessments) were reported at patient and facility levels. The hazard ratio (HR) for time to first peritonitis was estimated using Cox models, adjusted for selected patient and facility case-mix variables. RESULTS: A total of 1376 PD patients from 120 facilities across seven countries were included. Training was most commonly performed at the facility (81%) by facility-affiliated nurses (87%) in a 1:1 setting (79%). In the UK, being trained by both facility and third-party nurses was associated with a reduced peritonitis risk [adjusted HR 0.31 (95% confidence interval 0.15-0.62) versus facility nurses only]. However, this training practice was utilized in only 5 of 14 UK facilities. No other training characteristics were convincingly associated with peritonitis risk. CONCLUSIONS: There was no evidence to support that peritonitis risk was associated with when, where, how or how long PD patients are trained.

Childhood Infectious Encephalitis: An Overview of Clinical Features, Investigations, Treatment, and Recent Patents.

BACKGROUND: Infectious encephalitis is a serious and challenging condition to manage. This overview summarizes the current literature regarding the etiology, clinical manifestations, diagnosis, management, and recent patents of acute childhood infectious encephalitis. METHODS: We used PubMed Clinical Queries as a search engine and used keywords of "encephalitis" AND "childhood" Patents were searched using the key term "encephalitis" in google.patents.- com and patentsonline.com. RESULTS: Viral encephalitis is the most common cause of acute infectious encephalitis in children. In young children, the clinical manifestations can be non-specific. Provision of empiric antimicrobial therapy until a specific infectious organism has been identified, which in most cases includes acyclovir, is the cornerstone of therapy. Advanced investigation tools, including nucleic acid-based test panel and metagenomic next-generation sequencing, improve the diagnostic yield of identifying an infectious organism. Supportive therapy includes adequate airway and oxygenation, fluid and electrolyte balance, cerebral perfusion pressure support, and seizure control. Recent patents are related to the diagnosis, treatment, and prevention of acute infectious encephalitis. CONCLUSION: Viral encephalitis is the most common cause of acute infectious encephalitis in children and is associated with significant morbidity. Recent advances in understanding the genetic basis and immunological correlation of infectious encephalitis may improve treatment. Third-tier diagnostic tests may be incorporated into clinical practice. Treatment is targeted at the infectious process but remains mostly supportive. However, specific antimicrobial agents and vaccines development is ongoing.

Meaning of Intracranial Pressure-to-Blood Pressure Fisher-Transformed Pearson Correlation-Derived Optimal Cerebral Perfusion Pressure: Testing Empiric Utility in a Mechanistic Model.

OBJECTIVES: Time-averaged intracranial pressure-to-blood pressure Fisher-transformed Pearson correlation (PRx) is used to assess cerebral autoregulation and derive optimal cerebral perfusion pressure. Empirically, impaired cerebral autoregulation is considered present when PRx is positive; greater difference between time series median cerebral perfusion pressure and optimal cerebral perfusion pressure (ΔCPP) is associated with worse outcomes. Our aims are to better understand: 1) the potential strategies for targeting optimal cerebral perfusion pressure; 2) the relationship between cerebral autoregulation and PRx; and 3) the determinants of greater ΔCPP. DESIGN: Mechanistic simulation using a lumped compartmental model of blood pressure, intracranial pressure, cerebral autoregulation, cerebral blood volume, PaCO2, and cerebral blood flow. SETTING: University critical care integrative modeling and precision physiology research group. SUBJECTS: None, in silico studies. INTERVENTIONS: Simulations in blood pressure, intracranial pressure, PaCO2, and impairment of cerebral autoregulation, with examination of "output" cerebral perfusion pressure versus PRx-plots, optimal cerebral perfusion pressure, and ΔCPP. MEASUREMENTS AND MAIN RESULTS: In regard to targeting optimal cerebral perfusion pressure, a shift in mean blood pressure or mean intracranial pressure with no change in mean blood pressure, with intact cerebral autoregulation, impacts optimal cerebral perfusion pressure. Second, a positive PRx occurs even with intact cerebral autoregulation. In relation to ΔCPP, for a given input blood pressure profile, with constant intracranial pressure, altering the degree of impairment in cerebral autoregulation or the level of PaCO2 maintains differences to within ±5 mm Hg. Change in intracranial pressure due to either an intermittently prolonged pattern of raised intracranial pressure or terminal escalation shows ΔCPP greater than 10 mm Hg and less than -10 mm Hg, respectively. CONCLUSIONS: These mechanistic simulations provide insight into the empiric basis of optimal cerebral perfusion pressure and the significance of PRx and ΔCPP. PRx and optimal cerebral perfusion pressure deviations do not directly reflect changes in cerebral autoregulation but are, in general, related to the presence of complex states involving well-described clinical progressions with raised intracranial pressure.

Management protocols for status epilepticus in the pediatric emergency room: systematic review article.

OBJECTIVE: This systematic review of national or regional guidelines published in English aimed to better understand variance in pre-hospital and emergency department treatment of status epilepticus. SOURCES: Systematic search of national or regional guidelines (January 2000 to February 2017) contained within PubMed and Google Scholar databases, and article reference lists. The search keywords were status epilepticus, prolonged seizure, treatment, and guideline. SUMMARY OF FINDINGS: 356 articles were retrieved and 13 were selected according to the inclusion criteria. In all six pre-hospital guidelines, the preferred route of medication administration was to use alternatives to the intravenous route: all recommended buccal and intranasal midazolam; three also recommended intramuscular midazolam, and five recommended using rectal diazepam. All 11 emergency department guidelines described three phases in therapy. Intravenous medication, by phase, was indicated as such: initial phase - ten/11 guidelines recommended lorazepam, and eight/11 recommended diazepam; second phase - most (ten/11) guidelines recommended phenytoin, but other options were phenobarbital (nine/11), valproic acid (six/11), and either fosphenytoin or levetiracetam (each four/11); third phase - four/11 guidelines included the choice of repeating second phase therapy, whereas the other guidelines recommended using a variety of intravenous anesthetic agents (thiopental, midazolam, propofol, and pentobarbital). CONCLUSIONS: All of the guidelines share a similar framework for management of status epilepticus. The choice in route of administration and drug type varied across guidelines. Hence, the adoption of a particular guideline should take account of local practice options in health service delivery.

Management protocols for status epilepticus in the pediatric emergency room: systematic review article / Protocolos de manejo de estado de mal epiléptico no pronto socorro pediátrico: análise sistemática

Abstract Objective: This systematic review of national or regional guidelines published in English aimed to better understand variance in pre-hospital and emergency department treatment of status epilepticus. Sources: Systematic search of national or regional guidelines (January 2000 to February 2017) contained within PubMed and Google Scholar databases, and article reference lists. The search keywords were status epilepticus, prolonged seizure, treatment, and guideline. Summary of findings: 356 articles were retrieved and 13 were selected according to the inclusion criteria. In all six pre-hospital guidelines, the preferred route of medication administration was to use alternatives to the intravenous route: all recommended buccal and intranasal midazolam; three also recommended intramuscular midazolam, and five recommended using rectal diazepam. All 11 emergency department guidelines described three phases in therapy. Intravenous medication, by phase, was indicated as such: initial phase - ten/11 guidelines recommended lorazepam, and eight/11 recommended diazepam; second phase - most (ten/11) guidelines recommended phenytoin, but other options were phenobarbital (nine/11), valproic acid (six/11), and either fosphenytoin or levetiracetam (each four/11); third phase - four/11 guidelines included the choice of repeating second phase therapy, whereas the other guidelines recommended using a variety of intravenous anesthetic agents (thiopental, midazolam, propofol, and pentobarbital). Conclusions: All of the guidelines share a similar framework for management of status epilepticus. The choice in route of administration and drug type varied across guidelines. Hence, the adoption of a particular guideline should take account of local practice options in health service delivery.

Resumo Objetivo: Esta análise sistemática de diretrizes nacionais ou regionais publicadas em inglês tem como objetivo entender melhor a diferença no tratamento do estado de mal epiléptico pré-hospitalar e no departamento de emergência. Fontes: Pesquisa sistemática de diretrizes nacionais ou regionais (janeiro de 2000 a fevereiro de 2017) contidas nas bases de dados do Pubmed e do Google Acadêmico e listas de referência de artigos. As palavras-chave da busca foram estado de mal epiléptico, convulsão prolongada, tratamento e diretriz. Resumo dos achados: Foram identificados 356 artigos e 13 foram selecionados de acordo com os critérios de inclusão. Em todas as seis diretrizes pré-hospitalares, o caminho preferencial de administração da medicação foi usar opções à via intravenosa: todas recomendaram midazolam bucal e intranasal; três também recomendaram midazolam intramuscular; e cinco recomendaram usar o diazepam via retal. Todas as 11 diretrizes de departamento de emergência descreveram três fases na terapia. No que diz respeito à medicação intravenosa, por fase, temos: fase inicial - 10/11 diretrizes recomendaram lorazepam e 8/11 recomendaram diazepam; segunda fase - a maioria (10/11) das diretrizes recomendou fenitoína, porém outras opções foram fenobarbital (9/11), ácido valproico (6/11) e fosfenitoína ou levetiracetam (individualmente, 4/11); terceira fase - 4/11 diretrizes incluíram a opção de repetir a terapia da segunda fase, ao passo que as outras diretrizes recomendaram usar diversos agentes anestésicos intravenosos (tiopental, midazolam, propofol e pentobarbital). Conclusões: Todas as diretrizes compartilham uma estrutura semelhante para manejo do estado de mal epiléptico. A escolha da via de administração e do tipo de medicamento variou em todas as diretrizes. Assim, a adoção de uma diretriz específica deve levar em consideração as opções da prática local na prestação de serviços de saúde.

Acute Whole-Body Vibration does not Facilitate Peak Torque and Stretch Reflex in Healthy Adults.

The acute effect of whole-body vibration (WBV) training may enhance muscular performance via neural potentiation of the stretch reflex. The purpose of this study was to investigate if acute WBV exposure affects the stretch induced knee jerk reflex [onset latency and electromechanical delay (EMD)] and the isokinetic knee extensor peak torque performance. Twenty-two subjects were randomly assigned to the intervention or control group. The intervention group received WBV in a semi-squat position at 30° knee flexion with an amplitude of 0.69 mm, frequency of 45 Hz, and peak acceleration of 27.6 m/s(2) for 3 minutes. The control group underwent the same semii-squatting position statically without exposure of WBV. Two-way mixed repeated measures analysis of variance revealed no significant group effects differences on reflex latency of rectus femoris (RF) and vastus lateralis (VL; p = 0.934 and 0.935, respectively) EMD of RF and VL (p = 0.474 and 0.551, respectively) and peak torque production (p = 0.483) measured before and after the WBV. The results of this study indicate that a single session of WBV exposure has no potentiation effect on the stretch induced reflex and peak torque performance in healthy young adults. Key PointsThere is no acute potentiation of stretch reflex right after whole body vibration.Acute whole body vibration does not improve mus-cle peak torque performance in healthy young adults.

High quality de novo sequencing and assembly of the Saccharomyces arboricolus genome.

BACKGROUND: Comparative genomics is a formidable tool to identify functional elements throughout a genome. In the past ten years, studies in the budding yeast Saccharomyces cerevisiae and a set of closely related species have been instrumental in showing the benefit of analyzing patterns of sequence conservation. Increasing the number of closely related genome sequences makes the comparative genomics approach more powerful and accurate. RESULTS: Here, we report the genome sequence and analysis of Saccharomyces arboricolus, a yeast species recently isolated in China, that is closely related to S. cerevisiae. We obtained high quality de novo sequence and assemblies using a combination of next generation sequencing technologies, established the phylogenetic position of this species and considered its phenotypic profile under multiple environmental conditions in the light of its gene content and phylogeny. CONCLUSIONS: We suggest that the genome of S. arboricolus will be useful in future comparative genomics analysis of the Saccharomyces sensu stricto yeasts.

OriDB, the DNA replication origin database updated and extended.

OriDB (http://www.oridb.org/) is a database containing collated genome-wide mapping studies of confirmed and predicted replication origin sites. The original database collated and curated Saccharomyces cerevisiae origin mapping studies. Here, we report that the OriDB database and web site have been revamped to improve user accessibility to curated data sets, to greatly increase the number of curated origin mapping studies, and to include the collation of replication origin sites in the fission yeast Schizosaccharomyces pombe. The revised database structure underlies these improvements and will facilitate further expansion in the future. The updated OriDB for S. cerevisiae is available at http://cerevisiae.oridb.org/ and for S. pombe at http://pombe.oridb.org/.

Prognostic value of renal function in patients with cardiac resynchronization therapy.

BACKGROUND: Renal insufficiency is prevalent in patients with heart failure and indicates poor prognosis. We examine (i) the relationship between left ventricular (LV) reverse remodeling (RR) and renal function and (ii) the prognostic value of renal function in patients receiving cardiac resynchronization therapy (CRT). METHODS: The relationship between LV-RR, defined as a 10% reduction in LV end-systolic volume, and renal function was examined in 85 consecutive patients receiving CRT. Echocardiographic assessment and renal function tests were performed before and 3 months after CRT. All-cause mortality and the composite of mortality or heart failure hospitalization between those with preserved or deteriorated renal function at 3 months were assessed by Kaplan Meier analysis. RESULTS: There was a slight improvement in glomerular filtration rate (GFR) in those with LV-RR (n=44; 51.7+/-20.4 vs. 54.2+/-19.1 ml/min/1.73 m2; p=0.024) while a significant deterioration (n=41; 61.9+/-17 vs. 48.8+/-13.0 ml/min/1.73 m2; p<0.001) was observed in those without LV-RR. The change (Delta) in GFR was significantly correlated with DeltaLV end-systolic/diastolic volumes and DeltaLV ejection fraction. After follow up of 856.4+/-576.8 days, patients with preserved renal function had significant lower all-cause mortality (log rank chi2=4.82, p=0.029) and the composite endpoints (log rank chi2=5.04, p=0.025). CONCLUSION: Preservation of renal function was observed in patients with systolic heart failure and renal insufficiency responding to CRT and provided prognostic information. A rapid decline in renal function after CRT was associated with worse clinical outcomes.

Prevalence of sleep disturbances in Chinese patients with end stage renal failure on maintenance hemodialysis.

BACKGROUND: Sleep disorders, such as daytime sleepiness, insomnia, restless legs syndrome (RLS) and obstructive sleep apnea syndrome (OSAS) have been reported as prevalent among patients with end stage renal failure(ESRF). MATERIAL/METHODS: As there is little published data from Southeast Asia, a sleep questionnaire was administered to all patients (N=43, 27 males) on chronic hemodialysis (HD) at the Prince of Wales Hospital, Hong Kong, to assess their sleep complaints. RESULTS: The mean age was 49.5 +/- 11.3 years (mean I SD) with mean body mass index (BMI) of 22.6 +/- 3.6 kg/m2. Frequent awakenings and sleep onset insomnia were the most frequent complaints (79% each), while daytime sleepiness occurred in 74% of patients. Sleep maintenance insomnia and pruritus occurred in 64% and 60% of patients respectively. Symptoms of RLS were reported by 70% of patients. The prevalence of OSAS was estimated by the frequency of observed choking (4.7% of cases), witnessed apnea (14%), snoring and witnessed apnea (9.3%), disruptive snoring (14%), disruptive snoring and witnessed apnea (2.3%), extremely loud snoring (4.7%). CONCLUSIONS: Our questionnaire survey revealed a high prevalence of sleep complaints such as frequent awakenings, daytime sleepiness, insomnia and RLS in patients with ESRF on maintenance HD, but a relatively low prevalence of OSAS, which may be related to the low BMI of our ESRF patients.

A 3.0-kDa low molecular weight heparin promotes gastric ulcer healing in rats.

BACKGROUND: Previous studies have shown that intragastric administration of unfractionated heparin enhances gastric ulcer healing in rats. As the large molecule of heparin may be partially degraded in the upper gastrointestinal tract, it is likely that fragments of heparin, derived from the unfractionated parent compound, are involved in the anti-ulcer action in the stomach. Therefore, it is possible that low molecular weight heparin may have a similar ulcer healing effect. METHODS: Male Sprague-Dawley rats with acetic acid-induced gastric ulcers were given a 3.0-kDa low molecular weight heparin (0.6-6.0 mg/kg) intravenously or intragastrically once daily for 4 days. Ulcer healing, mucosal histological changes, angiogenesis and gastric mucus production both in vivo and in vitro were determined. The bleeding time was measured to indicate the anticoagulation activity. RESULTS: Both intravenous and intragastric low molecular weight heparin dose dependently accelerated gastric ulcer healing, which was accompanied by a significant increase in mucosal regeneration and proliferation, angiogenesis and mucus content in the stomach. The drug also stimulated the mucus production in MKN-28 cells. Drug administration by either route did not alter the bleeding time in rats. CONCLUSIONS: A 3.0-kDa low molecular weight heparin possesses an ulcer healing effect similar to that of unfractionated heparin in the stomach of the rat. This smaller molecular drug is superior to the unfractionated form, does not affect the coagulation activity and may show better absorption in the gastrointestinal tract.

Trephine bone grafting technique for the treatment of scaphoid nonunion.

A simple, minimally invasive trephine bone grafting technique for the treatment of scaphoid fracture nonunions is described. The method has a short surgical time, good results, and minimal donor site morbidity.

A novel cDNA encoding for a LIM domain protein located at human chromosome 14q32 as a candidate for leukemic translocation.

A full-length cDNA clone encoding a zinc finger protein was isolated and sequenced. This full-length clone consists of 728 bp and has a predicted open reading frame (ORF) encoding 208 amino acids. The ORF of this polypeptide codes for the human cysteine-rich protein 2 (HCRP2) and has an amino acid sequence that is 92.8% identical to its rat homolog (RCRP2). HCRP2 was mapped to chromosome 14q32, which is a hot spot of translocation in tumor development, by fluorescent in situ hybridization (FISH).

Medial preoptic microimplants of the antiestrogen, keoxifene, affect luteinizing hormone-releasing hormone mRNA levels, median eminence luteinizing hormone-releasing hormone concentrations and luteinizing hormone release in ovariectomized, estrogen-treated rats.

Abstract We examined the temporal changes in plasma luteinizing hormone (LH) levels, median eminence luteinizing hormone-releasing hormone (LHRH) concentrations and LHRH mRNA levels in estrogen-treated, ovariectomized rats with empty or antiestrogen- containing microcannulae stereotaxically implanted into the medial preoptic area. Neither treatment disrupted the negative feedback effects of estrogen on LH secretion, but antiestrogen (Keoxifene) blocked the afternoon LH surges. In rats exhibiting LH surges, median eminence LHRH concentrations were similar at 0800, 1200 and 1600 h, but they were significantly elevated by 2000 h. In contrast, no alterations in LHRH concentrations occurred in the Keoxifene-treated group. LHRH mRNA levels in control rats were significantly elevated at 1200, 1600 and 2000 h compared with 0800 h, but LHRH mRNA levels in Keoxifene-treated rats did not change significantly over the time period examined. When we compared treatment effects over time we saw that serum LH levels were significantly higher in control than Keoxifene-treated rats only at 1600 and 2000 h. Median eminence LHRH concentrations did not differ between treatment groups until 2000 h when control animals had significantly higher levels than those of Keoxifene-treated animals. LHRH mRNA levels in Keoxifene-treated rats were significantly higher than those of controls at 0800 hand significantly lower at 1600 h. No differences in LHRH mRNA levels were detected between groups at either 1200 h or 2000 h. In summary, although it was not clear on which neuronal system estrogen acted, depriving medial preoptic neurons of this steroid in systemically estrogenized rats certainly disrupted the neural mechanisms involved in surge, but not basal LH release. In addition, neither LHRH mRNA levels nor median eminence LHRH concentrations showed variations within the period studied when the estrogen-sensitive mechanisms involved in LH release were disrupted. Therefore, the changes in LHRH mRNA levels and LHRH concentrations in the median eminence seen in surging animals probably resulted from the same neural events which triggered LH release.

Estimation of tumor promoting activity and structure-function relationships of aplysiatoxins.

Twelve aplysiatoxin compounds have been evaluated as possible tumor promoters in vivo by means of three biological tests: viz. irritation of mouse ear, induction of ornithine decarboxylase in dorsal skin of mice, and inhibition of specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to an epidermal particulate fraction. The potencies of these three biological activities correlate well for each derivative. Bromoaplysiatoxin shows biological activities that are similar to those of the strong tumor promoter, aplysiatoxin. The present studies suggest that the C-3, C-20 and C-30 hydroxyl groups of the aplysiatoxins are involved in binding to the specific receptor of TPA.