Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Randomized trial of allergen-induced asthmatic response in smokers and non-smokers: effects of inhaled corticosteroids.

BACKGROUND: It is thought that asthmatics who smoke cigarettes respond less well to inhaled corticosteroid (ICS) therapy than asthmatics who do not smoke. OBJECTIVE: To evaluate the effects of smoking on allergen-induced airway responses in asthmatics treated with ICS. METHODS: Randomized, double-blind, crossover study evaluating twice daily fluticasone propionate (FP) 100 µg, FP 500 µg and placebo, for 7 days, on allergen-induced asthmatic responses in 18 non-smoking and 17 smoking atopic asthmatics (NCT01400906). At 1 h post-morning dose on Day 6, forced expiratory volume in 1 sec (FEV1 ) was measured up to 10 h post-challenge. Exhaled nitric oxide (eNO), induced sputum cell counts, and responsiveness to methacholine were assessed the following day. RESULTS: The late asthmatic response (LAR) was suppressed by FP in smokers and non-smokers; with placebo, the LAR was also attenuated in smokers versus non-smokers (adjusted mean minimum change in FEV1 (L) over 4-10 h [95% CI] in non-smokers: placebo -1.01 [1.31, 0.70], FP 100 µg -0.38 [0.54, 0.22], FP 500 µg -0.35 [0.54-0.22]; and in smokers: placebo -0.63 [0.84, 0.43]; FP 100 µg -0.44 [0.65, 0.23]; FP 500 µg -0.46 [0.59-0.32]). The Early AR was suppressed by FP treatment in non-smokers, but was not impacted in smokers. The reduction in methacholine hyperresponsiveness after FP was greater in non-smokers (1.5- and twofold doubling dose difference from placebo after FP 100 µg and FP 500 µg) than smokers (1.0 and 1.3 difference, respectively). Allergen-induced increases in eNO and sputum eosinophils were lower in smokers than non-smokers and were suppressed in both groups by FP. CONCLUSION AND CLINICAL RELEVANCE: Allergen-induced LARs were of a similar amplitude in both smoking and non-smoking atopic asthmatics at the end of ICS treatment, but attenuation of the LAR in smokers was only partly associated with ICS treatment. The marked attenuation of the LAR observed in smokers in the absence of ICS treatment is a novel observation.

Risk factors of overweight and obesity in childhood and adolescence in South Asian countries: a systematic review of the evidence.

OBJECTIVE: To assess and synthesize the published evidence on risk factors of overweight and obesity in childhood and adolescence in South Asia. STUDY DESIGN: A systematically conducted narrative review. METHODS: A systematic review was conducted of all primary studies published between January 1990 and June 2013 from India, Pakistan, Nepal, Bangladesh, Sri Lanka, Bhutan, and Maldives located through the following data bases: PubMed, PubMed central, EMBASE, MEDLINE, BioMed central, Directory of Open Access Journals (DOAJ) and electronic libraries of the authors' institutions. Data extraction and quality appraisal of included studies was done independently by two authors and findings were synthesized in a narrative manner as meta-analysis was found to be inappropriate due to heterogeneity of the included studies. RESULTS: Eleven primary studies were included in the final review, all of which were conducted in school settings in India, Pakistan and Bangladesh. Prevalence of overweight and obesity showed wide variations in the included studies. The key individual risk factors with statistically significant associations to overweight and obesity included: lack of physical activities reported in six studies; prolonged TV watching/playing computer games reported in four studies; frequent consumption of fast food/junk food reported in four studies; and frequent consumption of calorie dense food items reported in two studies. Family level risk factors included higher socioeconomic status reported in four studies and family history of obesity reported in three studies. CONCLUSION: This review provides evidence of key contributors to the increasing burden of obesity and overweight among children and adolescents in South Asia, and demonstrates the nutritional transition that characterizes other developing countries and regions around the world. The findings have implications for policy, practice and the development of interventions at various levels to promote healthy eating and physical activity among children and adolescents in the region as well as more globally.

One-year safety and efficacy of ustekinumab and results of dose adjustment after switching from inadequate methotrexate treatment: the TRANSIT randomized trial in moderate-to-severe plaque psoriasis.

BACKGROUND: There are limited long-term, 'real-world' data on ustekinumab, or the effect of dose adjustment in suboptimal responders. OBJECTIVES: We describe 52-week data from TRANSIT, which initiated ustekinumab by licensed regimen and investigated exploratory dose adjustment. METHODS: Patients with moderate-to-severe psoriasis and inadequate methotrexate response received ustekinumab, with immediate or gradual methotrexate withdrawal. Outcomes were similar between treatment arms at week 12 (primary endpoint), so week 52 data were pooled. Patients weighing ≤ 100 kg or > 100 kg were administered ustekinumab 45 or 90 mg, respectively. Patients weighing ≤ 100 kg without 75% improvement in Psoriasis Area and Severity Index (PASI 75) response at weeks 28 or 40 received a dose adjustment to 90 mg. The primary analysis used observed data. RESULTS: Overall, 391 and 98 patients received ustekinumab 45 and 90 mg, respectively. Forty-four patients (9%) discontinued before week 52 (0·4% due to adverse events). At week 52 (in the overall population), 369 patients (83%) achieved a PASI score ≤ 5, and 341 patients (77%) achieved PASI 75; the median PASI score decreased from 15 at baseline to 1·8. At weeks 28 and 40, 84 and 31 patients, respectively, did not achieve PASI 75 and received a dose adjustment; by week 52, 35/82 (43%) and 15/31 (48%) of these patients, respectively, achieved PASI 75 (two discontinued between weeks 28 and 40). CONCLUSIONS: Ustekinumab showed sustained 1-year efficacy and was well tolerated when initially administered according to label. Adjusting the ustekinumab dose to 90 mg may result in clinically meaningful improvement in response in patients weighing ≤ 100 kg with suboptimal initial response.

Transition to ustekinumab in patients with moderate-to-severe psoriasis and inadequate response to methotrexate: a randomized clinical trial (TRANSIT).

BACKGROUND: Limited data exist on transitioning patients with psoriasis from conventional systemic agents to biologics. OBJECTIVES: The TRANSIT study aimed to assess the efficacy and safety of two methotrexate-to-ustekinumab transition strategies. METHODS: Patients with moderate-to-severe psoriasis and inadequate methotrexate response were randomized 1 : 1 to receive ustekinumab with immediate (arm 1) or 4-week gradual (arm 2) methotrexate withdrawal. Patients weighing ≤ 100 kg or > 100 kg received ustekinumab 45 mg or 90 mg, respectively. The primary endpoint was the frequency of adverse events (AEs) at week 12. Secondary endpoints included additional safety, efficacy and patient-reported outcomes. We report the 12-week efficacy and safety results. RESULTS: Overall, 244 patients in arm 1 and 245 in arm 2 were randomized and received ustekinumab. Four patients per arm discontinued the trial by week 12. At week 12 in arms 1 and 2, respectively, 61% and 65% of patients experienced an AE, 2·9% and 2·4% had a serious AE, and 1·2% and 0·4% had an AE leading to ustekinumab discontinuation. In arms 1 and 2, respectively, median Psoriasis Area and Severity Index (PASI) score decreased from 15·2 and 15·4 at baseline to 2·9 and 2·8 at week 12; 58% and 62% of patients achieved a 75% reduction from baseline in PASI score (PASI 75) at week 12; median baseline Dermatology Life Quality Index fell from 8 and 9 at baseline to 1 (both arms) at week 16. CONCLUSIONS: Ustekinumab was well tolerated and effective in patients who had an inadequate response to methotrexate. Both transition strategies resulted in similar week 12 safety and efficacy outcomes.

The value of antifungal therapy in allergic fungal rhinosinusitis.

BACKGROUND: Allergic fungal rhinosinusitis (AFS) is considered to part of the disease spectrum of chronic rhinosinusitis, which affects between five to fifteen per cent of the population. Currently, there is uncertainty relating to the pathological process and therefore optimal management of AFS. Studies assessing antifungal use have shown mixed results. The aim of this review is to assess the effect of antifungals on patients with AFS. METHODS: A systematic review of the literature to include all published trials searching Pubmed, Medline (Ovid), CINAHL (EBSCO) and the Cochrane central register of controlled trials (CENTRAL) databases. RESULTS: Sixteen studies (two systematic reviews, two meta-analysis, four randomised controlled trials, five prospective cohort studies and three retrospective studies) were included in this review. There was found to be no overall benefit of topical or oral antifungals upon endoscopic findings or patient reported outcome measures in AFS. There were no statistically significant differences in adverse effect profiles between treatment and control groups. CONCLUSION: There is limited evidence to support the use of topical or oral antifungal agents in patients with AFS. Future research recommendations include large multicentre randomised trials with better matched patient groups and appropriate dosage and timing of antifungals.

Untangling the physics of water transport in boron nitride nanotubes.

Carbon nanotubes (CNTs) have long been heralded as the material of choice for next-generation membranes. Some studies have suggested that boron nitride nanotubes (BNNTs) may offer higher transport of pure water than CNTs, while others conclude otherwise. In this work, we use a combination of simulations and experimental data to uncover the causes of this discrepancy and investigate the flow resistance through BNNT membranes in detail. By dividing the resistance of the nanotube membranes into their contributing components, we study the effects of pore end configuration, membrane length, and BNNT atom partial charges. Most molecular simulation studies of BNNT membranes use short membranes connected to high and low pressure reservoirs. Here we find that flow resistances in these short membranes are dominated by the resistance at the pore ends, which can obscure the understanding of water transport performance through the nanotubes and comparison between different nanotube materials. In contrast, it is the flow resistance inside the nanotubes that dominates microscale-thick laboratory membranes, and end resistances tend to be negligible. Judged by the nanotube flow resistance alone, we therefore find that CNTs are likely to consistently outperform BNNTs. Furthermore, we find a large role played by the choice of partial charges on the BN atoms in the flow resistance measurements in our molecular simulations. This paper highlights a way forward for comparing molecular simulations and experimental results.

Plasma CRP levels in premenopausal women with major depression: a 12-month controlled study.

C-reactive protein (CRP), an inflammatory marker of cardiovascular risk, is often elevated in major depressive disorder (MDD). The magnitude and consistency of this elevation have not been previously characterized in premenopausal women with MDD. The aim of the study was to prospectively assess plasma CRP levels, body composition, endocrine and metabolic parameters, and depressive status in premenopausal women with MDD (n=77) and controls (n=41), aged 21 to 45. Women were enrolled in a 12-month, controlled study of bone turnover, the P.O.W.E.R. ( Premenopausal, Osteoporosis, Women, Al Endronate, Dep Ression) Study. Blood samples were taken at Baseline, Month 6, and Month 12. Most subjects with MDD were in clinical remission. These women tended to have consistently higher CRP levels than controls over 12 months (p=0.077). BMI was positively related to log[CRP] in women with MDD only. Nine women with MDD had CRP levels greater than 10 mg/l, a value associated with a very high cardiovascular risk. This subset was obese and had significantly higher triglycerides, total cholesterol, LDL-cholesterol, fasting insulin, and HOMA-IR than the rest of women with MDD. The variations in CRP levels over time were high (intra- and inter-individual coefficients of variations of approximately 30-50% and approximately 70-140%, respectively). No control had CRP levels greater than 10 mg/l. Depression was associated with increased plasma CRP in women with MDD. The clinical significance of abnormal plasma CRP for cardiovascular risk needs to be assessed in large prospective studies of women with depression.

Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses.

Recent findings demonstrate that chemokines, and more specifically CC chemokine ligand 2 (CCL2 or monocyte chemoattractant protein-1), play a major role in pain processing. In the present study, we assess nociceptive responses of mice that overexpressed CCL2 under control of glial fibrillary acidic protein promoter (CCL2 tg). In models of acute nociception CCL2 tg mice demonstrated significantly enhanced nociceptive behavior relative to wild-type controls in responses to both thermal (hot plate) and chemical (formalin test) stimulus modalities. There were no differences in mechanical allodynia in the partial sciatic nerve ligation model, in terms of either magnitude or duration of the allodynic response; however, both groups responded to the maximal extent measurable. In a model of inflammatory pain, elicited by intraplantar administration of complete Freund's adjuvant (CFA), CCL2 tg mice displayed both greater edema and thermal hyperalgesia compared with control mice. In control mice, edema and hyperalgesia returned to baseline values 5-7 days post CFA. However, in CCL2 tg mice, thermal hyperalgesia was significantly different from baseline up to 3 weeks post CFA. Parallel to these enhanced behavioral responses CCL2 serum levels were significantly greater in CCL2 overexpressing mice and remained elevated 7 days post CFA. Consequently, proinflammatory cytokine mRNA expression (IL-1beta, IL-6, and TNFalpha) levels were greater in skin, dorsal root ganglia (DRG), and spinal cord, whereas the anti-inflammatory cytokine (IL-10) level was lower in skin and DRG in CCL2 overexpressing mice than in control mice. Taken together with data from CCR2-deficient mice, these present data confirm a key role of CCL2/CCR2 axis in pain pathways and suggest that inhibiting this axis may result in novel pain therapies.

Angioplasty and STent for Renal Artery Lesions (ASTRAL trial): rationale, methods and results so far.

Atherosclerotic renovascular disease (ARVD) is a relatively common condition which may lead to progressive renal dysfunction, and eventually to end-stage renal failure. Revascularization has been used in an attempt to prevent progression of ARVD, despite a lack of evidence for a benefit on kidney function. Therefore, large-scale randomized trials are needed to determine reliably whether or not there is any worthwhile benefit. The Angioplasty and STent for Renal Artery Lesions (ASTRAL) trial comparing renal function in ARVD patients randomized to either revascularization or medical management alone was designed to provide this evidence. ASTRAL started recruiting in November 2000 and, as of the end of 2006, 731 patients have been randomized into the trial (19 patients short of its minimum target of 750 patients). A pooled analysis (not split by treatment arm) of all patients shows that serum creatinine increased in the first 6 months then remained relatively steady, whereas blood pressure has decreased from baseline. The trial is due to close to recruitment in April 2007, with the first presentation of the results of the randomized treatment comparison planned for the spring of 2008. To date ASTRAL is by far the largest randomized trial in ARVD, and will provide the most reliable and timely evidence on the role, if any, of revascularization in ARVD with which to guide the treatment of future patients.

Analysis of vertebrate SCL loci identifies conserved enhancers.

The SCL gene encodes a highly conserved bHLH transcription factor with a pivotal role in hemopoiesis and vasculogenesis. We have sequenced and analyzed 320 kb of genomic DNA composing the SCL loci from human, mouse, and chicken. Long-range sequence comparisons demonstrated multiple peaks of human/mouse homology, a subset of which corresponded precisely with known SCL enhancers. Comparisons between mammalian and chicken sequences identified some, but not all, SCL enhancers. Moreover, one peak of human/mouse homology (+23 region), which did not correspond to a known enhancer, showed significant homology to an analogous region of the chicken SCL locus. A transgenic Xenopus reporter assay was established and demonstrated that the +23 region contained a new neural enhancer. This combination of long-range comparative sequence analysis with a high-throughput transgenic bioassay provides a powerful strategy for identifying and characterizing developmentally important enhancers.

Did the 'croaky voice' public health campaign have any impact on the stage of laryngeal cancer at presentation in 84 cases from the Humber and Yorkshire Coast Cancer Network?

BACKGROUND: A public health campaign on laryngeal cancer was conducted in 2011 in the Humber and Yorkshire Coast Cancer Network. This study evaluated its subsequent impact (if any) upon the stage of laryngeal cancer at presentation. METHODS: Cases of laryngeal cancer diagnosed in the Humber and Yorkshire Coast Cancer Network from January 2009 to July 2014 were identified from cancer registries and were dichotomised into early (tumour stage T1-2) and late (T3-4) disease. Statistical analysis using segmented regression analysis of interrupted time series data was performed. RESULTS: There were no statistically significant changes in laryngeal cancer cases immediately after the intervention for both early (p = 0.191) and late (p = 0.680) stage disease. There were also no significant changes to monthly detection rates in both groups on follow up. CONCLUSION: Findings of the first public health campaign on laryngeal cancer in the UK are described. Such processes are complex; the implications for future study are discussed.

Short stretches of rare codons regulate translation of the transcription factor ZEB2 in cancer cells.

Two proteins comprising the ZEB family of zinc finger transcription factors, ZEB1 and ZEB2, execute EMT programs in embryonic development and cancer. By studying regulation of their expression, we describe a novel mechanism that limits ZEB2 protein synthesis. A protein motif located at the border of the SMAD-binding domain of ZEB2 protein induces ribosomal pausing and compromises protein synthesis. The function of this protein motif is dependent on stretches of rare codons, Leu(UUA)-Gly(GGU)-Val(GUA). Incorporation of these triplets in the homologous region of ZEB1 does not affect protein translation. Our data suggest that rare codons have a regulatory role only if they are present within appropriate protein structures. We speculate that pools of transfer RNA available for protein translation impact on the configuration of epithelial mesenchymal transition pathways in tumor cells.

Assessing the temporal reproducibility of human esophageal motor-evoked potentials to transcranial magnetic stimulation.

BACKGROUND: Although the electrophysiological properties and reproducibility of somatic limb motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) are well characterized, little is known about the reproducibility of MEPs for viscerosomatic structures such as the esophagus. AIM: To determine the temporal reproducibility of esophageal MEPs to TMS. METHODS: MEPs to TMS were recorded from the proximal esophagus, using a swallowed catheter housing a pair of electrodes, in eight healthy subjects at five stimulus intensities (SI) (motor threshold [MT] to 20% above MT). For each SI, 20 consecutive TMS stimuli at 5-second intervals were delivered over a single scalp site (dominant hemisphere at site exhibiting MT at lowest SI) and repeated 40 and 80 minutes thereafter. MEP amplitudes and latencies were measured, and means were sequentially calculated for each SI and then log-transformed. The repeatability coefficients (RC) for the three time points were calculated across each set of 20 stimuli and presented as an exponential ratio. RESULTS: Best RC (amplitude/latency) were achieved at 120% SI relative to MT, being 1.8/1.2 (optimal = 1.0). For lower intensities of 115%, 110%, 105%, and 100% SI, the RC were 2.1/1.2, 2.1/1.1, 2.4/1.2, and 2.6/1.4, respectively. For all SI, the greatest reductions in RC occurred over the first 10 stimuli, with little additional gain beyond this number. CONCLUSIONS: Latencies of esophageal MEP to TMS across intensities are highly reproducible, whereas amplitudes are more stimulus intensity-dependent, being most reliable and reproducible at the highest stimulus strengths. SIGNIFICANCE: Using careful parameters, TMS can be used reliably in future studies of viscerosomatic structures, although the size of the response variability needs to be taken into account when assessing changes in cortico-fugal activity.

Taxol and anti-stathmin therapy: a synergistic combination that targets the mitotic spindle.

Stathmin is an abundant cytosolic phosphoprotein that plays an important role in the regulation of cellular proliferation. Its major function is to promote depolymerization of the microtubules that make up the mitotic spindle. Taxol is an effective chemotherapeutic agent whose activity is mediated through stabilization of the microtubules of the mitotic spindle. We demonstrate that antisense inhibition of stathmin expression chemosensitizes K562 leukemic cells to the antitumor effects of Taxol and results in a synergistic inhibition of their growth and clonogenic potential. In the presence of stathmin inhibition, exposure to Taxol results in more severe mitotic abnormalities (hypodiploidy and multinucleation). This, in turn, results in increased apoptosis of the aneuploid cells during subsequent cell division cycles. This novel molecular-based therapeutic approach may provide an effective form of cancer therapy that would avoid the severe toxicities associated with the use of multiple chemotherapeutic agents with overlapping toxicity profiles.

Improving paranasal sinus computed tomography reporting prior to functional endoscopic sinus surgery - an ENT-UK panel perspective.

BACKGROUND: Functional endoscopic sinus surgery is recognised to have a significant complication profile (e.g. blindness, cerebrospinal fluid leak and intracranial sepsis). Pre-operative computed tomography imaging is considered mandatory for surgical planning to reduce intra-operative risk. A radiological report is the 'gold standard' in image interpretation; however, because of a lack of otolaryngological or radiological guidance, its contents may be variable. By surveying practising otolaryngologists, this study aimed to provide some guidance which may be used by radiologists to produce more surgically relevant radiological reports. METHOD: A prospective questionnaire was distributed to the ENT-UK panel. RESULTS: A total of 117 consultant members of the panel completed the survey. Twenty-nine per cent indicated that they were uncomfortable interpreting all areas of the computed tomography scan. Greatest importance was given to areas including the ethmoid roof (dehiscence, asymmetry and angle), lamina papyracea (dehiscence) and sphenoid sinus (carotid canal dehiscence and optic nerve relationships). CONCLUSION: Functional endoscopic sinus surgery is commonly performed by non-subspecialist rhinologists. The information obtained from this study can be used by radiologists to improve report relevance, particularly for the generalist ENT surgeon. This contributes to improving patient safety and helps avoid medicolegal litigation when complications arise.

Multifocal extraparotid Warthin's tumours mimicking metastatic squamous cell carcinoma of the upper neck.

BACKGROUND: Warthin's tumours can show features of pseudo-neoplasia. They do not usually cause problems for diagnosis and management when present within the parotid gland. However, extraparotid Warthin's tumours that are associated with pseudo-neoplasia upon cytological analysis can mimic metastatic malignant disease. The case of a patient presenting with multifocal extraparotid Warthin's tumours is described. CASE REPORT: A 57-year-old male smoker presented with rapidly growing upper neck lumps. Fine needle aspiration cytology, magnetic resonance imaging and positron emission tomography findings were compatible with metastatic squamous cell carcinoma secondary to either an unknown primary upper aerodigestive or a parotid malignancy. The patient subsequently underwent total conservative parotidectomy and modified radical neck dissection. Final histology findings revealed multifocal benign Warthin's tumours with four extraparotid components. CONCLUSION: Warthin's tumours may present outside the parotid gland, present with multifocal lesions and mimic metastatic disease. Frozen section examination prior to radical resection should be considered to guide management.

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.

BACKGROUND AND PURPOSE: Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. EXPERIMENTAL APPROACH: We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. KEY RESULTS: Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E). CONCLUSIONS AND IMPLICATIONS: The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.

Purification and partial characterization of rat liver pyruvate dehydrogenase kinase activator protein (free pyruvate dehydrogenase kinase).

Rat liver pyruvate dehydrogenase (PDH) kinase activator protein (KAP), a free PDH kinase readily separable from PDH complex and its intrinsic kinase, has been purified to apparent homogeneity from liver mitochondria of fed and 48-h starved rats. On SDS-PAGE an apparently single band of M(r) 45 kDa was obtained. N-Terminal amino acid sequence analyses (8-10 cycles) confirmed the presence of a single peptide in each case. The specific activity of the purified KAP from 48-h starved rats (14,413 U/mg protein) was 4.5-fold greater than that from fed rats.

Neonatal carnitine palmitoyltransferase-2 deficiency: a case presenting with myopathy.

Mitochondria were isolated from liver, heart and skeletal muscle of a 34-day-old female infant who died from a myopathic illness. Muscle biopsy showed lipid accumulation and no obvious pathology in any other organ. Enzymatic analysis of skeletal muscle extracts revealed normal activities of the markers pyruvate dehydrogenase and citrate synthase. Malonyl-CoA-sensitive carnitine palmitoyltransferase (CPT1) was detected but malonyl-CoA-insensitive carnitine palmitoyltransferase (CPT2) appeared to be absent. Quantitative immunoblotting revealed the presence of a normal abundance of CPT2 protein in the patient's muscle. It is concluded that enzymically inactive CPT2 protein was present.