Citations

Little is known about the fate of the lipolytic products produced by the action of lipoprotein lipase (LPL) on circulating triglyceride-rich lipoproteins in humans. We studied eight lean, healthy male subjects after an overnight fast. Subjects received infusions of lipid emulsions containing triolein labeled with 3H on both the glycerol backbone and the fatty acid portion of the molecule; 14C glycerol and 14C oleate were coinfused to quantify the systemic and forearm release of 3H glycerol and 3H oleate resulting from LPL action. There was significant forearm uptake of both whole plasma triglyceride (presumed to represent primarily VLDL; extraction fraction 2.6 ± 0.6%, P < 0.005 vs. zero) and radiolabeled triglyceride derived from the lipid emulsion (a surrogate for chylomicrons; extraction fraction 31 ± 4%, P < 0.005 vs zero). Systemic clearance and forearm fractional extraction of glycerol was greater than that of oleate (P < 0.001 and P < 0.02, respectively). The systemic and forearm fractional release of LPL-generated glycerol were similar at 51 ± 4 and 59 ± 1%, respectively (NS). In contrast, the forearm fractional release of LPL-generated oleate was less than systemic fractional release (14 ± 2 vs. 36 ± 4%, P < 0.0001). These results indicate that there is escape, or spillover, of the lipolytic products of LPL action on triglyceride-rich lipoproteins in humans. They further suggest that LPL-mediated fatty acid uptake is an inefficient process, but may be more efficient in muscle than in adipose tissue.

Abstract Anal canal pressure gradient and ileal pouch motor activity were studied in continent and incontinent patients after ileal pouch-anal anastomosis. A multichannel microtransducer catheter was positioned in eight continent and eight incontinent patients 15 months or more after operation and 24-h ambulatory motor activity recorded. Resting anal pressures were significantly lower for incontinent patients during the day and night. The frequency of high-pressure waves was identical in both groups, but peak pressures were higher for incontinent patients. For continent patients, each high-pressure wave was accompanied by a rapid increase in anal canal pressure such that pressure in the pouch was always less than that in the anal canal. For incontinent patients this response was often absent. Incontinent patients had lower resting pressure, more prolonged anal canal relaxation, higher amplitude high-pressure waves and a non-responsive anal canal; the anal canal pressure gradient was therefore frequently reversed.

Abstract Of 500 consecutive patients who underwent cervical exploration for presumed primary hyperparathyroidism, 461 (92·2 per cent) were cured, as judged by an immediate return of serum calcium levels to normal. Thirty-nine patients (7·8 per cent) had persistent hypercalcaemia after the initial operation. The clinical profiles, operative and pathologic findings, surgical procedures performed and subsequent management of these 39 patients were reviewed. At re-evaluation, 4 patients were noted to have been cured of their hyperparathyroidism: Twenty-one patients had persistent hyperparathyroidism: in 6, all 4 parathyroid glands had not been identified at the initial operation and in 15, hypercalcaemia persisted after the identification of 4 glands. One patient had recurrent hyperparathyroidism after the removal of a 720 mg adenoma and the identification of 3 normal parathyroid glands. Nine patients had non-parathyroid causes for the hypercalcaemia: 2 had occult malignant neoplasms, 6 had benign familial hypocalciuric hypercalcaemia and 1 had immobilization hypercalcaemia. In 4 patients the reason for the persistent hypercalcaemia remained unclear. We suggest a schema that may be used as a guideline in the investigation and management of patients with persistent hypercalcaemia after primary neck exploration for presumed hyperparathyroidism.

Abstract A group of 500 patients with a presumptive diagnosis of primary hyperparathyroidism (HPT) was operated upon at the Mayo Clinic between September 1974 and May 1980 using a standardized operative strategy. Clinical profiles, biochemical data, operative findings and pathological changes are reviewed. Of the 500 patients, 461 (92·2 per cent) were cured after primary cervical exploration. One patient died during the postoperative period, 1 had a permanent unilateral vocal cord paralysis and 10 (2 per cent) had protracted hypoparathyroidism. Owing to the continuing controversy regarding the appropriate therapeutic management of asymptomatic, uncomplicated and mild (‘biochemical’) primary HPT, we further evaluated this surgical experience by comparing the results of operation in two groups of patients: those with (‘biochemical’) HPT (serum calcium < 11 mg/dl) and those with ‘non-biochemical’ HPT (symptomatic or complicated disease or serum calcium > 11 mg/dl). The cure rate in each patient group was greater than 90 per cent. A statistically significant increase in the incidence of negative cervical exploration (4 normal parathyroid glands identified and biopsied) was noted in the ‘biochemical’ group. However, parathyroid disease was found at operation in 92 per cent of these patients. We conclude that cervical exploration in all patients with primary HPT, including those with ‘biochemical’ disease only, is safe and that such an aggressive management policy is justified.

Abstract Among the best-characterized genetic alterations in gliomas is the amplification of the epidermal growth factor receptor (EGFR) gene, present in ∼40% of glioblastoma multiforme, and frequently associated with the EGFRvIII gene rearrangement. We have previously shown that attenuated vaccine strains of measles virus have potent antitumor activity against gliomas, and identified H protein mutations, which ablate recognition of the natural measles virus receptors CD46 and SLAM. Retargeted recombinant viruses were generated from the measles Edmonston-NSe vaccine strain displaying a single-chain antibody against EGFRvIII at the COOH terminus of H and containing the marker green fluorescent protein (GFP) gene in position 1. Two different H mutants were employed: HSNS (V451S, Y481N, and A527S)-CD46 blind, and HAA (Y481A and R533A)-CD46 and SLAM blind. MV-GFP virus was used as a positive control. Both EGFRvIII-retargeted viruses had significant antitumor activity against EGFRvIII-expressing glioblastoma multiforme but no cytopathic effect against normal cells. In an orthotopic model of EGFRvIII-expressing GBM39 xenografts, there was comparable therapeutic efficacy between retargeted strains and unmodified MV-GFP and statistically significant prolongation of survival in treated animals compared with the control group (P = 0.001). Formation of syncytia was observed in tumors treated with retargeted viruses, with a surrounding infiltrate consisting of macrophages and natural killer cells. In summary, EGFRvIII-retargeted oncolytic measles virus strains have comparable therapeutic efficacy with the unmodified MV-GFP strain against EGFRvIII-expressing glioma lines and xenografts with improved therapeutic index, a finding with potential translational implications in glioma virotherapy. (Cancer Res 2006; 66(24): 11840-50)

Background— Nearly half of patients with heart failure have a preserved ejection fraction (HFpEF). Symptoms of exercise intolerance and dyspnea are most often attributed to diastolic dysfunction; however, impaired systolic and/or arterial vasodilator reserve under stress could also play an important role. Methods and Results— Patients with HFpEF (n=17) and control subjects without heart failure (n=19) generally matched for age, gender, hypertension, diabetes mellitus, obesity, and the presence of left ventricular hypertrophy underwent maximal-effort upright cycle ergometry with radionuclide ventriculography to determine rest and exercise cardiovascular function. Resting cardiovascular function was similar between the 2 groups. Both had limited exercise capacity, but this was more profoundly reduced in HFpEF patients (exercise duration 180±71 versus 455±184 seconds; peak oxygen consumption 9.0±3.4 versus 14.4±3.4 mL · kg −1 · min −1 ; both P <0.001). At matched low-level workload, HFpEF subjects displayed ≈40% less of an increase in heart rate and cardiac output and less systemic vasodilation (all P <0.05) despite a similar rise in end-diastolic volume, stroke volume, and contractility. Heart rate recovery after exercise was also significantly delayed in HFpEF patients. Exercise capacity correlated with the change in cardiac output, heart rate, and vascular resistance but not end-diastolic volume or stroke volume. Lung blood volume and plasma norepinephrine levels rose similarly with exercise in both groups. Conclusions— HFpEF patients have reduced chronotropic, vasodilator, and cardiac output reserve during exercise compared with matched subjects with hypertensive cardiac hypertrophy. These limitations cannot be ascribed to diastolic abnormalities per se and may provide novel therapeutic targets for interventions to improve exercise capacity in this disorder.

Estrogen deficiency results in increased bone turnover and net bone loss in rats as well as humans. The respective roles of bone turnover and mechanical strain in mediating estrogen deficiencyinduced cancellous bone loss were investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in long bones. However, cancellous bone was preferentially lost in the metaphysis, a site that experiences low strain energy during normal physical activity. No bone loss was observed in the epiphysis, a site experiencing higher strain energy, despite a similar increase in bone turnover. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased or decreased in long bones of ovariectomized rats by treadmill exercise or functional unloading, respectively. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing weight bearing accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in unloaded limbs and prevented bone loss in the loaded limbs. These results suggest that estrogen alters the mechanosensory (mechanostat) set point for skeletal adaptation, effectively reducing the minimum strain energy levels at which bone is added. Additionally, these studies suggest that physical activity as well as endocrine status play an important role in maintenance of the female skeleton during aging.