Enzymatic phosphorylation of muscle glycogen synthase: a mechanism for maintenance of metabolic homeostasis.

We recently analyzed experimental studies of mammalian muscle glycogen synthesis using metabolic control analysis and concluded that glycogen synthase (GSase) does not control the glycogenic flux but rather adapts to the flux which is controlled bv the activity of the proximal glucose transport and hexokinase steps. This model did not provide a role for the well established relationship between GSase fractional activity, determined by covalent phosphorylation, and the rate of glycogen synthesis. Here we propose that the phosphorylation of GSase, which alters the sensitivity to allosteric activation by glucose 6-phosphate (G6P), is a mechanism for controlling the concentration of G6P instead of controlling the flux. When the muscle cell is exposed to conditions which favor glycogen synthesis such as high plasma insulin and glucose concentrations the fractional activity of GSase is increased in coordination with increases in the activity of glucose transport and hexokinase. This increase in GSase fractional activity helps to maintain G6P homeostasis by reducing the G6P concentration required to activate GSase allosterically to match the flux determined by the proximal reactions. This role for covalent phosphorylation also provides a novel solution to the Kacser and Acarenza paradigm which requires coordinated activity changes of the enzymes proximal and distal to a shared intermediate, to avoid unwanted flux changes.     

Differential use of endoplasmic reticulum membrane for phagocytosis in J774 macrophages

Sustained phagocytosis requires the continuous replacement of cell-surface membrane from intracellular sources. Depending on the nature of the engulfed particles, a variety of endocytic compartments have been demonstrated to contribute membranes needed for the formation of phagosomes. It has recently been reported that the endoplasmic reticulum (ER) can also fuse with the plasma membrane during phagocytosis [Gagnon, E., Duclos, S., Rondeau, C., Chevet, E., Cameron, P. H., Steele-Mortimer, O., Paiement, J., Bergeron, J. J. & Desjardins, M. (2002) Cell 110, 119-131]. However, there is currently no known mechanistic basis for this fusion process to occur. Here we report that direct ER-plasma membrane fusion during phagocytosis requires the ER resident soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein ERS24/Sec22b and that J774-macrophages react toward the challenge of large (3.0-microm) but not small (0.8-microm) particles by triggering this fusion mechanism, allowing them to access the most abundant endogenous membrane source in the cell, the ER.     

Emergency surgical revascularisation for coronary angioplasty complications.

OBJECTIVES--To evaluate trends in referrals for emergency operations after percutaneous transluminal coronary angioplasty (PTCA) complications; to analyse morbidity and mortality and assess the influence of PTCA backup on elective surgery. DESIGN--A retrospective analysis of patients requiring emergency surgical revascularisation within 24 hours of percutaneous transluminal coronary angioplasty. PATIENTS--Between January 1980 and December 1990, 75 patients requiring emergency surgery within 24 hours of percutaneous transluminal coronary angioplasty. SETTING--A tertiary referral centre and postgraduate teaching hospital. RESULTS--57 patients (76%) were men, the mean age was 55 (range 29-73) years, and 30 (40%) had had a previous myocardial infarction. Before PTCA, 68 (91%) had severe angina, 59 (79%) had multivessel disease, and six (8%) had a left ventricular ejection fraction of less than 40%. A mean of 2.1 grafts (range one to five) were performed; the internal mammary artery was used in only one patient. The operative mortality was 9% and inhospital mortality was 17%. There was a need for cardiac massage until bypass was established in 19 patients (25%): this was the most important outcome determinant (P = 0.0051) and was more common in those patients with multivessel disease (P = 0.0449) and in women (P = 0.0388). In 10 of the 19 cases a vacant operating theatre was unavailable, the operation being performed in the catheter laboratory or anaesthetic room. These 19 patients had an operative mortality of 32% and inhospital mortality of 47%, compared with 2% and 7% respectively for the 56 patients who awaited the next available operating theatre. Complications included myocardial infarction, 19 patients (25%); arrhythmias, 10 patients (3%); and gross neurological event, two patients (3%). The mean intensive care unit stay was 2.6 days (range 1 to 33 days) and the mean duration of hospital admission was 13 days (range 5-40 days). CONCLUSIONS--Patients undergoing emergency surgery after PTCA complications have a substantially increased inhospital mortality and morbidity. PTCA in this unit continues to require surgical cover. Delays in operating on stable patients in centres which operate a "next available theatre" backup policy may not differ from some units performing PTCA with offsite cover for PTCA complications. Particularly in the presence of multivessel disease, however, PTCA complications may be associated with the need for "crash" bypass and such patients are unlikely to survive hospital transfer. The proportion of patients requiring "crash" bypass has increased during the period reviewed because of the extent of disease in the emergency surgical group increased. These results indicate that surgery should not be denied to these patients.     

Active immunization of murine allogeneic bone marrow transplant donors with B-cell tumor-derived idiotype: a strategy for enhancing the specific antitumor effect of marrow grafts

Persistence of the underlying malignancy remains the major obstacle limiting the success of high-dose chemoradiotherapy with allogeneic bone marrow transplantation (BMT) for lymphomas and multiple myeloma. We used the C3H 38C13 murine B-cell lymphoma, which expresses and secretes clonally derived Ig, the idiotype of which can serve as a tumor-specific antigen, to test the principle of transfer of tumor idiotype-specific immunity with BM. BALB/c marrow donors were twice immunized with 38C13-derived Ig, or with an isotype-matched control Ig, conjugated to keyhole limpet hemocyanin. Lethally irradiated C3H recipients reconstituted with marrow from idiotype immune, but not nonspecifically immune, donors demonstrated protection against subsequent lethal tumor challenge. The immunoprotective effect of immune allogeneic marrow was abrogated by T-cell depletion of the marrow graft before infusion. Low levels of serum anti-idiotypic antibody remained unaltered in recipients of T-cell-depleted immune marrow, consistent with a primary role for T-cell immunity in the cellular mechanism of this phenomenon. A modest therapeutic effect of immune allogeneic marrow was observed against 10 day, 1 cm established subcutaneous tumors, but only in combination with a booster immunization of the recipient post-BMT. These results provide the rationale for a novel strategy for enhancing the specific antitumor effect of allogeneic marrow grafts.     

Estimation of expected number of rare alleles of a locus and calculation of mutation rate

An approach is described for the estimation of the number of rare variants in the population from the number in a sample drawn at random from the population. This quantity is used to derive an estimate of the mutation rate. The data required are the number of rare variants in the sample and the distribution of offspring within a population of well-defined size with little or no immigration. Application of this approach to data on 28 loci assayed in the Yanamamo, a tribe of South American Indians, yields an average mutation rate of 0.1 ~ 0.2 × 10^-5. Determination of this figure is subject to several assumptions concerning the nature of the rare variants and the structure of the population. Violation of these assumptions will generally result in the underestimate of the true mutation rate.     

Response to 2'-deoxycoformycin after failure of interferon-alpha in nonsplenectomized patients with hairy cell leukemia

Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN- alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients.     

Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation.

Brain lactate concentration is usually assumed to be stable except when pathologic conditions cause a mismatch between glycolysis and respiration. Using newly developed 1H NMR spectroscopic techniques that allow measurement of lactate in vivo, we detected lactate elevations of 0.3-0.9 mM in human visual cortex during physiologic photic stimulation. The maximum rise appeared in the first few minutes; thereafter lactate concentration declined while stimulation continued. The results are consistent with a transient excess of glycolysis over respiration in the visual cortex, occurring as a normal response to stimulation in the physiologic range.     

Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy.

Glucose is the main fuel for energy metabolism in the normal human brain. It is generally assumed that glucose transport into the brain is not rate-limiting for metabolism. Since brain glucose concentrations cannot be determined directly by radiotracer techniques, we used 13C NMR spectroscopy after infusing enriched D-[1-13C]glucose to measure brain glucose concentrations at euglycemia and at hyperglycemia (range, 4.5-12.1 mM) in six healthy children (13-16 years old). Brain glucose concentrations averaged 1.0 +/- 0.1 mumol/ml at euglycemia (4.7 +/- 0.3 mM plasma) and 1.8-2.7 mumol/ml at hyperglycemia (7.3-12.1 mM plasma). Michaelis-Menten parameters of transport were calculated to be Kt = 6.2 +/- 1.7 mM and Tmax = 1.2 +/- 0.1 mumol/g.min from the relationship between plasma and brain glucose concentrations. The brain glucose concentrations and transport constants are consistent with transport not being rate-limiting for resting brain metabolism at plasma levels greater than 3 mM.     

Pregnancy,birth and risk: an introduction

In this introduction, I use my nearly 40 years of work in the area to reflect on the total medicalisation of pregnancy and childbirth that informs even the critical sociology that purports to examine the issue. The risks that are faced in pregnancy and birth are not only the inherent dangers that midwives have worked with across time and space but also those particular risks introduced by medicalisation itself. Medicalisation blinds us to those risks on the one hand, while it blinds us to the skills and knowledge that midwives and birthing women themselves have on the other. The women and midwives researched in these articles show us that in pregnancy and birth, as in most of life, it is not just a matter of ‘real risk’ versus ‘perceived risk’ as risk theorists (too) often describe it. There is rather an intelligent balancing of risks, weighing of risks and contextualising of risks. What we see in this issue is a glimpse into the ways in which people intelligently, creatively and determinedly balance risks.     

【特刊综述】雄激素对骨骼肌的作用：对乏力的发展和治疗的意义

雄激素对骨骼肌合成有明显影响,随着年龄增大,雄激素的下降常伴随肌量和肌力的下降。这种肌量和肌功能的下降,被称为少肌症或肌体老化,是老年人体质弱化（男性化减退）进展的关键事项。也是导致快速机能衰退及其不良后果的关键。雄激素水平下降对老年男性体质弱化（男性化减退）的潜在影响和对躯体功能的促进治疗作用无疑已经引起了相当的关注。本综述概述了近期关于肌肉老化、少肌症、老年体质弱化的概念、定义,并评估了关于雄激素和老年体质弱化的研究进展。近期源于观测性和介入性研究的证据强烈支持雄激素对老年男性肌量的作用,但雄激素对肌力和特有的躯体功能的效用并不明确。研究显示,雄激素治疗在老年男性中通常有良好的耐受性,而近期的研究则关注于雄激素的高剂量治疗和对于心血管风险较高人群的治疗。雄激素受体调节剂（SARMs）的初期试验研究显示传统雄激素治疗对于老年患者在肌量和肌功能方面有相同的效用。将来的重要研究方向包括利用这类雄激素治疗并结合适用于不同老年患者群体促进躯体功能的运动训练,同时将更多地关注近期关于激素水平、身体成分及躯体功能间关系的观测性（回顾性）研究。