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Autoimmune encephalitides constitute an emerging group of diseases for which the diagnosis and management may be challenging, and are usually associated with antibodies against neuroglial antigens used as biomarkers. In this review, we aimed to clarify the diagnostic approach to patients with encephalitis of suspected autoimmune origin in order to initiate early immunotherapy, and to summarize the evidence of current immunotherapies and alternative options assessed for refractory cases. Currently, the general therapeutic approach consists of steroids, IVIG, and/or plasma exchange as first-line medications, which should be prescribed once a diagnosis of possible autoimmune encephalitis is established. For patients not responding to these treatments, rituximab and cyclophosphamide are used as second-line immunotherapy. Additionally, alternative therapies, chiefly tocilizumab and bortezomib, have been reported to be useful in particularly refractory cases. Although the aforementioned approach with first and second-line immunotherapy is widely accepted, the best therapeutic strategy is still unclear since most available evidence is gathered from retrospective non-controlled studies. Moreover, several predictors of good long-term prognosis have been proposed such as response to first-line therapies, modified Rankin score lesser than 4 at the worst neurologic status, no need for admission in intensive care unit, and early escalation to second-line immunotherapy. Thus, the lack of solid evidence underlines the necessity of future well-conducted trials addressing both the best therapeutic regimen and the outcome predictors, but since autoimmune encephalitides have a relatively low incidence, international collaborations seem imperative to reach a reasonable study population size.

© 2017 American College of Neuropsychopharmacology. All rights reserved. The use of cigarettes delivering different nicotine doses allows evaluation of the contribution of nicotine to the smoking experience. We compared responses of 46 young adult smokers to research cigarettes, delivering 0.027, 0.110, 0.231, or 0.763 mg nicotine, and conventional cigarettes. On five separate days, craving, withdrawal, affect, and sustained attention were measured after overnight abstinence and again after smoking. Participants also rated each cigarette, and the nicotine metabolite ratio (NMR) was used to identify participants as normal or slow metabolizers. All cigarettes equally alleviated craving, withdrawal, and negative affect in the whole sample, but normal metabolizers reported greater reductions of craving and withdrawal than slow metabolizers, with dose-dependent effects. Only conventional cigarettes and, to a lesser degree, 0.763-mg nicotine research cigarettes increased sustained attention. Finally, there were no differences between ratings of lower-dose cigarettes, but the 0.763-mg cigarettes and (even more so) conventional cigarettes were rated more favorably than lower-dose cigarettes. The findings indicate that smoking-induced relief of craving and withdrawal reflects primarily non-nicotine effects in slow metabolizers, but depends on nicotine dose in normal metabolizers. By contrast, relief of withdrawal-related attentional deficits and cigarette ratings depend on nicotine dose regardless of metabolizer status. These findings have bearing on the use of reduced-nicotine cigarettes to facilitate smoking cessation and on policy regarding regulation of nicotine content in cigarettes. They suggest that normal and slow nicotine metabolizers would respond differently to nicotine reduction in cigarettes, but that irrespective of metabolizer status, reductions to

OBJECTIVES: To evaluate the hospital multistay rate to determine if it has the attributes necessary for a performance indicator that can be applied to administrative databases. DATA SOURCES/STUDY SETTING: The fiscal year 1994 Veterans Affairs Patient Treatment File (PTF), which contains discharge data on all VA inpatients. STUDY DESIGN: Using a retrospective study design, we assessed cross-hospital variation in (a) the multistay rate and (b) the standardized multistay ratio. A hospital's multistay rate is the observed average number of hospitalizations for patients with one or more hospital stays. A hospital's standardized multistay ratio is the ratio of the geometric mean of the observed number of hospitalizations per patient to the geometric mean of the expected number of hospitalizations per patient, conditional on the types of patients admitted to that hospital. DATA COLLECTION/EXTRACTION METHODS: Discharge data were extracted for the 135,434 VA patients who had one or more admissions in one of seven disease groups. PRINCIPAL FINDINGS: We found that 17.3 percent (28,300) of the admissions in the seven disease categories were readmissions. The average number of stays per person (multistay rate) for an average of seven months of follow-up ranged from 1.15 to 1.45 across the disease categories. The maximum standardized multistay ratio ranged from 1.12 to 1.39. CONCLUSIONS: This study has shown that the hospital multistay rate offers sufficient ease of measurement, frequency, and variation to potentially serve as a performance indicator.

Udgivelsesdato: 1999-null The two porphyrias, familial porphyria cutanea tarda (fPCT) and hepatoerythropoietic porphyria (HEP), are associated with mutations in the gene encoding the enzyme uroporphyrinogen decarboxylase (UROD). Several mutations, most of which are private, have been identified in HEP and fPCT patients, confirming the heterogeneity of the underlying genetic defects of these diseases. We have established a denaturing gradient gel electrophoresis (DGGE) assay for mutation detection in the UROD gene, enabling the simultaneous screening for known and unknown mutations. The established assay has proved able to detect the underlying UROD mutation in 10 previously characterized DNA samples as well as a new mutation in each of six previously unexamined PCT patients. The six novel UROD mutations comprise three missense mutations (M01T, F229L, and M324T), two splice mutations (IVS3-2A-->T and IVS5-2A-->G) leading to exon skipping, and a 2-bp deletion (415-416delTA) resulting in a frameshift and the introduction of a premature stop codon. Heterologous expression and enzymatic studies of the mutant proteins demonstrate that the three mutations leading to shortening or truncation of the UROD protein have no residual catalytic activity, whereas the two missense mutants retained some residual activity. Furthermore, the missense mutants exhibited a considerable increase in thermolability. The six new mutations bring to a total of 29 the number of disease-related mutations in the UROD gene. The DGGE assay presented greatly improves the genetic diagnosis of fPCT and HEP, thereby facilitating the detection of familial UROD deficient patients as well as the discrimination between familial and sporadic PCT cases.

A two-compartment system for approximating five successive steady-state levels of gadopentetate dimeglumine (Gd-DTPA) concentration in pigs was developed. The method of calculating Gd-DTPA concentration was based on a simultaneous reference determination of 99mTc-DTPA. Experimental and theoretical results showed a steady state after 25 min. The nuclear magnetic resonance (NMR) relaxivities of Gd-DTPA were determined in vivo in pig kidneys during steady-state levels. T1 relaxivity (R1) and T2 relaxivity (R2) in the kidney cortex were found to be 1.1+/-0.03 and 2.0+/-0.2 (s(-1) mM(-1)), respectively. R1 and R2, in in vitro human plasma solutions at 25 degrees C were 5.3+/-0.02 and 5.8+/-0.06 s-1 mM-1 and at 37 degrees C 4.3+/-0.04 and 4.9+/-0.01 s(-1) mM(-1). Thus, the in vivo relaxivities were reduced 3.9 and 2.5 times for R1 and R2, respectively, compared to the in vitro relaxivities. This marked difference in relaxivities between tissue and plasma may be the result of the difference in steric relations. In plasma, the mobility and distribution of the Gd-DTPA complex are unrestricted, whereas they may be reduced in the tissues because of the close proximity to the cell wall, to the proteins and to other extracellular elements and compartments.

A finger prick-swab method of blood specimen collection was qualitatively and quantitatively compared with the conventional venipuncture method for HBsAg and anti-HBs determinations by radioimmunoassay (RIA). The new method consisted of pricking the finger, collecting 0.1-0.2 ml of blood with a cotton-wool swab, and eluting the swab in 1 ml of 1% bovine albumin in saline containing 0.1% sodium azide. Using chimpanzees seropositive for HBsAg or anti-HBs, comparisons were made of RIA results of: (a) whole blood, haemolysed blood, serum, and plasma; (b) paired finger prick samples and serum; (c) dilutions of finger prick samples and serum; and (d) different volumes of blood on swabs. Field studies were carried out at two institutions where hepatitis B was hyperendemic to compare results from paired finger prick and serum specimens assayed by the RIA and haemagglutination techniques. The laboratory studies showed that swab RIA values for anti-HBs were significantly lower than serum values and that for HBsAg, swab values were significantly higher than serum values. In HBsAg tests, the field studies showed 100% agreement between the two methods; in anti-HBs tests, the finger prick method showed 85% agreement with positive sera. Because of the logistics of collecting and processing blood serum, the finger prick-swab technique may be a valuable aid in large-scale seroepidemiological surveys for hepatitis B.

When blood samples were analyzed for seroconversion after measles vaccination, it was discovered that the vaccine had been ineffective for a certain period. During the 2 years between vaccination and the time of seroanalysis, nonseroconverters had a significantly higher mortality than seroconverters (P less than 0.05). The incidence of measles among nonseroconverters was 30% during the period. Between 9 months and 3 years of age, cumulative mortality was 15.1% for nonseroconverters and 4.5% for seroconverters. The difference in mortality was larger when high risk groups (twins, motherless children) were excluded from the analysis (P less than 0.01). The difference in mortality was particularly marked among children vaccinated in the age group 9 to 11 months. This as well as other community studies suggest that measles vaccination reduces child mortality from the age of vaccination by at least 30%.

Porphyria cutanea tarda (PCT), the most common porphyria disease, is characterized by blistering and skin fragility of sun-exposed skin. The symptoms are caused by lowered activity of uroporphyrinogen decarboxylase (URO-D) resulting in accumulation of water-soluble porphyrins in the skin. Most PCT cases are sporadic but can be familiar due to mutations in the URO-D gene located on chromosome number 1. The disease may be exacerbated by environmental factors. Iron accumulation is a characteristic finding and there is an association to hereditary haemochromatosis. Therapeutic venesection reduces the iron load and the uroporphyrins are mobilized by treatment with hydroxychloroquine. An increased risk of liver cirrhosis and hepatocellular carcinoma may presumably be reduced by early diagnosis and treatment. Udgivelsesdato: 2000-Apr-3

Posterolateral fractures of the tibial plateau are difficult to address. Malunion can lead to early posttraumatic arthritis of the knee due to instability and elevated joint reaction forces. Arthroscopically assisted percutaneous reduction facilitates visualization and avoids open approaches either directly from posterolateral or from lateral with optional extension via a lateral epicondylus osteotomy. We describe and illustrate a minimal invasive technique using an arthroscopic posterolateral viewing portal. Using this technique, we demonstrated very good clinical outcome with excellent patient satisfaction. Key words: Schatzker, tibia head fracture, knee arthroscopy, multiligamentary injury.

Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)‐4, IL‐5 and IL‐13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL‐5R and IL‐5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late‐onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non‐response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL‐5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non‐response.

OTC splicing mutations are generally associated with the severest and early disease onset of ornithine transcarbamylase deficiency (OTCD), the most common urea cycle disorder. Noticeably, splicing defects can be rescued by spliceosomal U1snRNA variants, which showed their efficacy in cellular and animal models. Here, we challenged an U1snRNA variant in the OTCD mouse model (spf/ash) carrying the mutation c.386G &gt, A (p.R129H), also reported in OTCD patients. It is known that the R129H change does not impair protein function but affects pre-mRNA splicing since it is located within the 5&prime, splice site. Through in vitro studies, we identified an Exon Specific U1snRNA (ExSpeU1O3) that targets an intronic region downstream of the defective exon 4 and rescues exon inclusion. The adeno-associated virus (AAV8)-mediated delivery of the ExSpeU1O3 to mouse hepatocytes, although in the presence of a modest transduction efficiency, led to increased levels of correct OTC transcripts (from 6.1 &plusmn, 1.4% to 17.2 &plusmn, 4.5%, p = 0.0033). Consistently, this resulted in increased liver expression of OTC protein, as demonstrated by Western blotting (~3 fold increase) and immunostaining. Altogether data provide the early proof-of-principle of the efficacy of ExSpeU1 in the spf/ash mouse model and encourage further studies to assess the potential of RNA therapeutics for OTCD caused by aberrant splicing.