Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins

Commitment of cells to apoptosis is governed largely by the interaction between members of the Bcl-2 protein family. Its three subfamilies have distinct roles: The BH3-only proteins trigger apoptosis by binding via their BH3 domain to prosurvival relatives, while the proapoptotic Bax and Bak have an essential downstream role involving permeabilization of organellar membranes and induction of caspase activation. We have investigated the regulation of Bak and find that, in healthy cells, Bak associates with Mcl-1 and Bcl-x(L) but surprisingly not Bcl-2, Bcl-w, or A1. These interactions require the Bak BH3 domain, which is also necessary for Bak dimerization and killing activity. When cytotoxic signals activate BH3-only proteins that can engage both Mcl-1 and Bcl-x(L) (such as Noxa plus Bad), Bak is displaced and induces cell death. Accordingly, the BH3-only protein Noxa could bind to Mcl-1, displace Bak, and promote Mcl-1 degradation, but Bak-mediated cell death also required neutralization of Bcl-x(L) by other BH3-only proteins. The results indicate that Bak is held in check solely by Mcl-1 and Bcl-x(L) and induces apoptosis only if freed from both. The finding that different prosurvival proteins have selective roles has notable implications for the design of anti-cancer drugs that target the Bcl-2 family.     

Marek's disease virus-induced transient paralysis in chickens. 3. Differentiation of field cases from classical Marek's disease by central nervous system lesions

Vasculitis with intramural pseudocyst formation primarily in the cerebellar white matter, but also in nuclei of the medulla, resulted in leakage of IgG and albumin and vacuolation of the neuropil (vasogenic oedema) in brains from chickens with clinical signs of Marek's disease virus (MDV)-induced transient paralysis (TP). Demyelination was absent. Chickens that had recovered from TP had a restored blood-brain-barrier, indicated by the rarity of vasculitis and vascular intramural pseudocysts in the cerebellum. In addition, the vacuolation and protein leakage were greatly decreased. The minor vacuolation resulted primarily from intramyelinic (cytotoxic) oedema. The small quantity of extravascular protein was being removed by microglial cells and astrocytes. In one chicken which failed to fully recover from TP (TP-prolonged) there was neither vasogenic oedema, cytotoxic oedema, nor vasculitis in the cerebellum. The medulla of the TP-prolonged chicken had a severe lymphocytosis, swollen axons, neuronal degeneration, secondary demyelination and some associated serum protein leakage. All TP-affected and TP-recovered chickens, and the TP-prolonged chicken, had perivascular mononuclear cell cuffs within all brain sections. Chickens with classical Marek's disease (MD) generally lacked CNS vacuolation, perivascular mononuclear cell cuffs, vasculitis and serum protein leakage. However, in a few cases of MD with severe perivascular mononuclear cell cuffs, focal demyelinating plaques were seen. These plaques had associated vacuolation, serum protein leakage, axonal spheroids and neuronal degeneration.     

Effects of tibolone on lipoprotein(a) and HDL subfractions

Objective: To determine the effects of tibolone, a synthetic steroid used to alleviate climacteric symptoms and prevent osteoporosis, on lipoprotein metabolism, with particular reference to lipoprotein(a) levels and HDL subfraction profiles.Design: Thirty nine postmenopausal women were treated with tibolone (Livial) 2.5 mg/day for 6 months and fasting serum lipoprotein levels were estimated at 0, 2, 4 and 6 months. Results: Lipoprotein(a) levels were reduced significantly over the 6 months from a median level of 245 (range <60–780) mg/I to 152 (range <60–530) mg/l, a reduction of 39% in the median level. A decrease was observed in approximately two thirds of the women. Reductions were noted in all 6 subjects whose pretreatment levels were high, although concentrations remained at a level associated with increased risk in all but one. There were significant decreases in triglycerides and VLDL cholesterol and no significant change in LDL cholesterol. There was a significant reduction of 18% in HDL cholesterol and a 26% reduction in the HDL₂:HDL₃ ratio. Conclusion: The reduction in lipoprotein(a) levels may have a beneficial effect on cardiovascular risk, which could go some way towards balancing the potentially adverse effect on the cardiovascular system caused by the reduction in HDL cholesterol.     

Nocturnal oxyhemoglobin desaturation following tracheostomy for obstructive sleep apnea

Eleven obese men with coexistent obstructive sleep apnea and chronic obstructive pulmonary disease underwent tracheostomy. Nocturnal polysomnography prior to tracheostomy revealed oxyhemoglobin desaturation associated with obstructive apnea. Following surgery, repeated polysomnography was performed to assess the effect of tracheostomy on nocturnal oxygen saturation. Non-apneic desaturation characteristic of that previously described in patients with "type B" chronic obstructive pulmonary disease was noted in six subjects. Oxyhemoglobin saturation in these six fell more than 8 percent below baseline waking and non-rapid-eye-movement (REM) sleep levels. These episodes usually lasted five minutes or longer, occurred almost uniformly during REM sleep, and were acutely ameliorated by low-flow (4 liters per minute) supplemental oxygen. The subjects with REM-associated desaturation did not differ from the subjects without desaturation by preoperative anthropomorphic, blood gas, or pulmonary function criteria. However, subjects with REM-associated desaturation tended to have lower right and left ventricular ejection fractions by pooled gated wall studies. It is concluded that patients with obstructive sleep apnea and chronic obstructive pulmonary disease should be re-evaluated after tracheostomy, since they may be at risk for continued oxyhemoglobin desaturation and progressive right ventricular deterioration despite adequate treatment of their apneic condition.     

Social Security disability determinations. Knowledge and attitudes of consultative physicians

Social Security spends $135 million yearly, contracting with physicians to provide consultative examinations for disability applicants. However, little is known about who these physicians are or how they view the determination of impairment. We surveyed a random sample of 153 physicians from North Carolina who performed consultative examinations for the North Carolina Disability Determinations Agency in 1983 (the consultative group), and a randomly selected group of 165 physicians of similar medical specialties (the comparison group). Response rates were 75% for the consultative group and 66% for the comparison group. Most consultative physicians (63%) performed fewer than 6 examinations per month. Characteristics of the consultative physicians were similar to the comparison group. Both groups were skeptical of the claims of disability applicants; 48% of the consultative and 55% of the comparison group thought that a majority of applicants could be employed. Of the consultative physicians, 53% indicated that they had learned little about disability programs from any source. Most consultative physicians (58%) judged it "almost impossible" to determine impairment on the basis of a single office examination. However, consultative physicians were less likely than the comparison group to view Social Security as difficult to work with (25% vs. 54%; P less than 0.01). Agencies that determine disability ask physicians to perform a task for which they feel ill prepared and have little special knowledge.     

Validation and application of single breath cardiac output determinations in man

Cardiac outputs by single breath (Qsb) and Fick (Qf) procedures were compared in five healthy males during supine rest and exercise with Qf ranging from 6-19 L X min-1. The prolonged exhalation (SB) was not controlled. The Qsb calculations incorporated an equation of the CO2 dissociation curve and a "moving spline" sequential curve-fitting technique to calculate the instantaneous R from points on the original expirogram. The resulting linear regression equation for all 38 comparisons obtained (r = +0.76, p less than 0.001, mean difference +/- S.D. = 2.93 +/- 2.72 L X min-1) indicated a 24% underestimation of Qf. A substantial portion of the variability during exercise (n = 28) was due to a difference in alveolar ventilation between the time of the mixed expired (E) gas collection and the SB maneuver. When Qsb was corrected (Qsb) by a linear regression based on the difference between Re and Rsb during exercise and by adding 2.44 L X min-1 at rest (the mean difference), the relationship was greatly improved (Qsb = 0.14 + 0.99 Qf, r = +0.93, mean difference +/- S.D. = 0 +/- 1.47 L X min-1). A subsequent study during upright rest and exercise to 80% of VO2max in 6 subjects indicated a close linear relationship between Q'sb and VO2 for all 95 values obtained (r = +0.94), with slope and intercept close to published studies utilizing invasive cardiac output measurements. Considerations of measured blood gases in relation to estimated values suggested that underestimates of Qf arose, at least in part, from arterial desaturation during the SB maneuver. Detailed computational procedures are provided for implementing this improved Qsb procedure.     

The complications of extracorporeal shockwave lithotripsy: management and prevention

Extracorporeal shockwave lithotripsy has been shown to be a safe and effective method of treating most upper urinary tract stones. Major complications, although few, include haemorrhage, septicaemia, "Steinstrasse" formation and cardiac arrhythmias. The experience from 600 consecutive cases is reviewed and methods of prevention are discussed.     

The incidence and effect of resternotomy following cardiac surgery on morbidity and mortality: a 1-year national audit on behalf of the Association of Cardiothoracic Anaesthesia and Critical Care

Over 30,000 adult cardiac operations are carried out in the UK annually. A small number of these patients need to return to theatre in the first few days after the initial surgery, but the exact proportion is unknown. The majority of these resternotomies are for bleeding or cardiac tamponade. The Association of Cardiothoracic Anaesthesia and Critical Care carried out a 1-year national audit of resternotomy in 2018. Twenty-three of the 35 centres that were eligible participated. The overall resternotomy rate (95%CI) within the period of admission for the initial operation in these centres was 3.6% (3.37–3.85). The rate varied between centres from 0.69% to 7.6%. Of the 849 patients who required resternotomy, 127 subsequently died, giving a mortality rate (95%CI) of 15.0% (12.7–17.5). In patients who underwent resternotomy, the median (IQR [range]) length of stay on ICU was 5 (2–10 [0–335]) days, and time to tracheal extubation was 20 (12–48 [0–2880]) hours. A total of 89.3% of patients who underwent resternotomy were transfused red cells, with a median (IQR [range]) of 4 (2–7 [1–1144]) units of red blood cells. The rate (95%CI) of needing renal replacement therapy was 23.4% (20.6–26.5). This UK-wide audit has demonstrated that resternotomy after cardiac surgery is associated with prolonged intensive care stay, high rates of blood transfusion, renal replacement therapy and very high mortality. Further research into this area is required to try to improve patient care and outcomes in patients who require resternotomy in the first 24 h after cardiac surgery.