Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum

AbstractThis review focuses on muscle disorders and diseases caused by defects in the Ca2+ release channels of the sarcoplasmic reticulum, the ryanodine receptors, and in the luminal, low affinity, high capacity Ca2+-binding proteins, calsequestrins. It provides a time line over the past half century of the highlights of research on malignant hyperthermia (MH), central core disease (CCD) and catecholaminergic polymorphic ventricular tachycardia (CPVT), that resulted in the identification of the ryanodine receptor (RYR), calsequestrin (CASQ) and dihydropyridine receptor (CACNA1S) genes as sites of disease-causing mutations. This is followed by a description of approaches to functional analysis of the effects of disease-causing mutations on protein function, focusing on studies of how mutations affect spontaneous (store overload-induced) Ca2+-release from the sarcoplasmic reticulum, the underlying cause of MH and CPVT. Subsequent sections describe results obtained by analysis of knockin mouse lines carrying MH- and CCD-causing mutations, including a Casq1 knockout. The review concludes with the presentation of two mechanistic models. The first shows how dysregulation of Ca2+ homeostasis can lead to muscle diseases involving both RyR and Casq proteins. The second describes a theory of central core formation wherein non-uniformity of Ca2+ release, resulting in non-uniformity of muscle contraction, is presented as an intrinsic property of the specific tertiary structure of mutant heterotetrameric ryanodine receptors and as the underlying cause of core formation in skeletal muscle. This article is part of a Special Issue entitled: 11th European Symposium on Calcium

Interleukin (IL)–12 and IL-23 Are Key Cytokines for Immunity against Salmonella in Humans

Patients with inherited deficiency of the interleukin (IL)–12/IL-23–interferon (IFN)–g axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23–component deficiency had a history of salmonella disease than did those with IFN-g–component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN-g–independent pathways. Investigation of the IL-12/IL-23–IFN-g axis should be considered in patients with invasive salmonella disease

Charged Higgs phenomenology in the flipped two Higgs doublet model

We study the phenomenology of the charged Higgs boson in the "flipped" two Higgs doublet model, in which one doublet gives mass to up-type quarks and charged leptons and the other gives mass to down-type quarks. We present the charged Higgs branching ratios and summarize the indirect constraints. We extrapolate existing LEP searches for H+H- and Tevatron searches for t tbar with t --> H+ b into the flipped model and extract constraints on MH+ and the parameter tan(beta). We finish by reviewing existing LHC charged Higgs searches and suggest that the LHC reach in this model could be extended for charged Higgs masses below the tb threshold by considering t tbar with t --> H+ b and H+ --> q qbar, as has been used in Tevatron searches.Comment: 23 pages, 7 figures. V2: added refs on H+W- associated productio

Public acceptability of financial incentives for smoking cessation in pregnancy and breastfeeding

Objective To survey public attitudes about incentives for smoking cessation in pregnancy and for breast feeding to inform trial design. Design Cross-sectional survey. Setting and participants British general public. Methods Seven promising incentive strategies had been identified from evidence syntheses and qualitative interview data from service users and providers. These were shopping vouchers for: (1) validated smoking cessation in pregnancy and (2) after birth; (3) for a smoke-free home; (4) for proven breast feeding; (5) a free breast pump; (6) payments to health services for reaching smoking cessation in pregnancy targets and (7) breastfeeding targets. Ipsos MORI used area quota sampling and home-administered computer-assisted questionnaires, with randomised question order to assess agreement with different incentives (measured on a five-point scale). Demographic data and target behaviour experience were recorded. Analysis used multivariable ordered logit models. Results Agreement with incentives was mixed (ranging from 34% to 46%) among a representative sample of 1144 British adults. Mean agreement score was highest for a free breast pump, and lowest for incentives for smoking abstinence after birth. More women disagreed with shopping vouchers than men. Those with lower levels of education disagreed more with smoking cessation incentives and a breast pump. Those aged 44 or under agreed more with all incentive strategies compared with those aged 65 and over, particularly provider targets for smoking cessation. Non-white ethnic groups agreed particularly with breastfeeding incentives. Current smokers with previous stop attempts and respondents who had breast fed children agreed with providing vouchers for the respective behaviours. Up to £40/month vouchers for behaviour change were acceptable (>85%). Conclusions Women and the less educated were more likely to disagree, but men and women of childbearing age to agree, with incentives designed for their benefit. Trials evaluating reach, impact on health inequalities and ethnic groups are required prior to implementing incentive interventions

Perspectives on financial incentives to health service providers for increasing breast feeding and smoking quit rates during pregnancy: a mixed methods study

Objective: To explore the acceptability, mechanisms and consequences of provider incentives for smoking cessation and breast feeding as part of the Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS) study. Design: Cross-sectional survey and qualitative interviews. Setting: Scotland and North West England. Participants: Early years professionals: 497 survey respondents included 156 doctors; 197 health visitors/maternity staff; 144 other health staff. Qualitative interviews or focus groups were conducted with 68 pregnant/postnatal women/family members; 32 service providers; 22 experts/decision-makers; 63 conference attendees. Methods: Early years professionals were surveyed via email about the acceptability of payments to local health services for reaching smoking cessation in pregnancy and breastfeeding targets. Agreement was measured on a 5-point scale using multivariable ordered logit models. A framework approach was used to analyse free-text survey responses and qualitative data. Results: Health professional net agreement for provider incentives for smoking cessation targets was 52.9% (263/497); net disagreement was 28.6% (142/497). Health visitors/maternity staff were more likely than doctors to agree: OR 2.35 (95% CI 1.51 to 3.64; p<0.001). Net agreement for provider incentives for breastfeeding targets was 44.1% (219/497) and net disagreement was 38.6% (192/497). Agreement was more likely for women (compared with men): OR 1.81 (1.09 to 3.00; p=0.023) and health visitors/maternity staff (compared with doctors): OR 2.54 (95% CI 1.65 to 3.91; p<0.001). Key emergent themes were 'moral tensions around acceptability', 'need for incentives', 'goals', 'collective or divisive action' and 'monitoring and proof'. While provider incentives can focus action and resources, tensions around the impact on relationships raised concerns. Pressure, burden of proof, gaming, box-ticking bureaucracies and health inequalities were counterbalances to potential benefits. Conclusions: Provider incentives are favoured by non-medical staff. Solutions which increase trust and collaboration towards shared goals, without negatively impacting on relationships or increasing bureaucracy are required

Analysis of treatment of childhood leukaemia. V. Advantage of reduced chemotherapy during and immediately after cranial irradiation.

This paper compares anti-leukaemic efficiency with toxicity to the patient of chemotherapy during and immediately after central nervous system irradiation. The drug regimen consisted of daily mercaptopurine (MP) and weekly methotrexate (MTX) at the maximum tolerated dose. Of 140 patients with acute lymphoblastic leukaemia allocated to receive this drug regimen during and after cranial irradiation, 8 died in complete remission within 6 months of the end of irradiation. Details of the nature of these deaths are given. This result led the Working Party to modify the chemotherapy scheduled for this stage in treatment. The modified chemotherapy consisted of MP at reduced dosage before and during cranial irradiation and omission of MP and MTX for 3 weeks after irradiation, during which time daily prednisolone with 2 doses of vincristine were substituted. Following that, the treatment reverted to the original schedule of daily MP and weekly MTX at maximum tolerated dose. Of 109 patients allocated to this modified regimen only one died in remission within 24 weeks after cranial irradiation. Analysis of the anti-leukaemic effect of the modified regimen showed that up to 600 days it was at least as effective as the original more intensive regimen. We conclude that there is a definite advantage in keeping chemotherapy to a minimum during and immediately following cranial prophylactic irradiation

Rabbit cardiac and slow-twitch muscle express the same phospholamban gene

AbstractThe nucleotide sequences of cDNAs encoding phospholamban were found to be virtually identical when the cDNA clones were isolated from rabbit slow-twitch (soleus) and rabbit cardiac muscle libraries. These findings demonstrate that both types of muscle express the same phospholamban gene. The deduced amino acid sequences of rabbit and dog phospholamban were identical except for a change from Asp (dog) to Glu (rabbit) at position 2. The nucleotide sequences of the 5′- and the very long 3′-untranslated regions of rabbit and dog phospholamban cDNAs also exhibited a high percentage of identity