Case report: meningitis as a presenting feature of anti-NMDA receptor encephalitis

BACKGROUND:Meningitis is a very rare atypical presenting feature of anti-NMDA receptor encephalitis. In our case report, we describe an unusual clinical presentation of anti-NMDA receptor encephalitis with a biphasic pattern of meningitis followed by encephalitis and discuss potential mechanisms underlying this presentation. We aim to widen the differential diagnosis to be considered in a patient presenting with clinical meningitis and pyrexia. CASE PRESENTATION:This is a case of a 33-year old Caucasian woman who initially presented with a lymphocytic meningitis attributed to a viral infection. She subsequently developed fluctuating consciousness, agitation, visual hallucinations, dyskinetic movements, a generalized tonic-clonic seizure, and autonomic instability. Investigations revealed a diagnosis of anti-NMDA receptor encephalitis secondary to a previously unidentified ovarian teratoma. She made an excellent recovery with immunotherapy and removal of the teratoma. CONCLUSION:Clinicians should consider autoimmune encephalitides in individuals with meningitis, particularly where extensive investigations fail to identify a causative pathogen and there is rapid development of an encephalitic phenotype

Activated plasma coagulation β-Factor XII-induced vasoconstriction in rats

By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the β-fragment of activated plasma coagulation Factor XII (β-FXIIa) transiently elevates BP (blood pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of β-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n=10); (ii) β-FXIIa (85 ng/min per kg of body weight; n=9); or (iii) β-FXIIa after 2ADX (bilateral adrenalectomy; n=9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. β-FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, β-FXIIa infusion increased MAP by 6% (5±2 mmHg) and TPR by 45% (0.50±0.12 mmHg/ml per min), despite falls in SV (−38±8 μl) and HR [−18±5 b.p.m. (beats/min)] (all P<0.05). In 2ADX rats, β-FXIIa had no HR effect, but decreased SV (−89±9 μl) and MAP (−4±1 mmHg), and increased TPR by 66% (0.59±0.15 mmHg/ml per min) (all P<0.05). After infusion, adrenally intact rats exhibited persistent vasoconstriction (MAP, 10±1 mmHg; TPR, 0.55±0.07 mmHg/ml per min; both P<0.05), whereas in 2ADX rats, MAP remained 5±1 mmHg below baseline (P<0.05) and TPR returned to baseline. End-study arterial adrenaline (epinephrine) concentrations in the three groups were 1.9±0.6, 9.8±4.1 and 0.6±0.2 nmol/l respectively. Thus, in neurally intact lightly anaesthetized untreated rats, β-FXIIa infusion induces both adrenal catecholamine-mediated and adrenally independent increases in peripheral resistance

Observation of Fundamental Mechanisms in Compression-Induced Phase Transformations Using Ultrafast X-ray Diffraction

As theoretically hypothesized for several decades in group IV transition metals, we have discovered a dynamically stabilized body-centered cubic (bcc) intermediate state in Zr under uniaxial loading at sub-nanosecond timescales. Under ultrafast shock wave compression, rather than the transformation from alpha-Zr to the more disordered hex-3 equilibrium omega-Zr phase, in its place we find the formation of a previously unobserved nonequilibrium bcc metastable intermediate. We probe the compression-induced phase transition pathway in zirconium using time-resolved sub-picosecond x-ray diffraction analysis at the Linac Coherent Light Source. We also present molecular dynamics simulations using a potential derived from first-principles methods which independently predict this intermediate phase under ultrafast shock conditions. In contrast with experiments on longer timescale (> 10 ns) where the phase diagram alone is an adequate predictor of the crystalline structure of a material, our recent study highlights the importance of metastability and time dependence in the kinetics of phase transformations

Clinical trials in amyotrophic lateral sclerosis:a systematic review and perspective

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of phase II, phase II/III and phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15000 people with amyotrophic lateral sclerosis. 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis

Unagreement is an illusion

This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11049-015-9311-yThis paper proposes an analysis of unagreement, a phenomenon involving an apparent mismatch between a definite third person plural subject and first or second person plural subject agreement observed in various null subject languages (e.g. Spanish, Modern Greek and Bulgarian), but notoriously absent in others (e.g. Italian, European Portuguese). A cross-linguistic correlation between unagreement and the structure of adnominal pronoun constructions suggests that the availability of unagreement depends on whether person and definiteness are hosted by separate heads (in languages like Greek) or bundled on a single head (i.e. pronominal determiners in languages like Italian). Null spell-out of the head hosting person features high in the extended nominal projection of the subject leads to unagreement. The lack of unagreement in languages with pronominal determiners results from the interaction of their syntactic structure with the properties of the vocabulary items realising the head encoding both person and definiteness. The analysis provides a principled explanation for the cross-linguistic distribution of unagreement and suggests a unified framework for deriving unagreement, adnominal pronoun constructions, personal pronouns and pro

Identification of Contractile Vacuole Proteins in Trypanosoma cruzi

Contractile vacuole complexes are critical components of cell volume regulation and have been shown to have other functional roles in several free-living protists. However, very little is known about the functions of the contractile vacuole complex of the parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, other than a role in osmoregulation. Identification of the protein composition of these organelles is important for understanding their physiological roles. We applied a combined proteomic and bioinfomatic approach to identify proteins localized to the contractile vacuole. Proteomic analysis of a T. cruzi fraction enriched for contractile vacuoles and analyzed by one-dimensional gel electrophoresis and LC-MS/MS resulted in the addition of 109 newly detected proteins to the group of expressed proteins of epimastigotes. We also identified different peptides that map to at least 39 members of the dispersed gene family 1 (DGF-1) providing evidence that many members of this family are simultaneously expressed in epimastigotes. Of the proteins present in the fraction we selected several homologues with known localizations in contractile vacuoles of other organisms and others that we expected to be present in these vacuoles on the basis of their potential roles. We determined the localization of each by expression as GFP-fusion proteins or with specific antibodies. Six of these putative proteins (Rab11, Rab32, AP180, ATPase subunit B, VAMP1, and phosphate transporter) predominantly localized to the vacuole bladder. TcSNARE2.1, TcSNARE2.2, and calmodulin localized to the spongiome. Calmodulin was also cytosolic. Our results demonstrate the utility of combining subcellular fractionation, proteomic analysis, and bioinformatic approaches for localization of organellar proteins that are difficult to detect with whole cell methodologies. The CV localization of the proteins investigated revealed potential novel roles of these organelles in phosphate metabolism and provided information on the potential participation of adaptor protein complexes in their biogenesis

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist

"Background Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. Methods Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. Findings Mean serum IGF-1 concentrations fell by at least 50%: 467 μg/L (SE 24), 526 μg/L (29), and 523 μg/L (40) in patients treated for 6, 12 and 18 months, respectively (p less than 0·001), whereas growth hormone increased by 12·5 μg/L (2·1), 12·5 μg/L (3·0), and 14·2 μg/L (5·7) (p less than 0·001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8·0 μg/L (2·5) at baseline, rose to 15·2 μg/L (2·4) on drug, and fell back within 30 days of withdrawal to 8·3 μg/L (2·7). Antibodies to growth hormone were detected in 27 (16·9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p less than 0·05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11·46 months (0·70) decreased by 0·033 cm3(0·057; p=0·353). Interpretation Pegvisomant is an effective medical treatment for acromegaly.