Citations

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 Seven patients with major liver injury initially assessed and managed elsewhere, and then referred to the Hepatobiliary Unit at Hammersmith Hospital, London, are reported. Six of the 7 patients had been operated upon and 4 had undergone two laparotomies before referral. All were seriously ill as a result of bleeding or liver necrosis and infection. Further laparotomy was carried out for the control of bleeding, débridement of dead tissue and drainage of infected material. Hepatic resection was performed in all patients and 3 of the 7 died in the postoperative period. Liver resection is necessary for the control of bleeding and removal of dead tissue in severe shattering injuries. Should temporary packing be instituted in order to obtain control, then early referral for definitive treatment is necessary. Delay is dangerous and extension of necrosis with secondary infection is inevitable.

Summary In 4 dogs a 75-cm segment of jejunum was isolated from the intestinal stream. Stimulating electrodes were implanted at each end of the segment and recording electrodes at intervals between. The two ends of the segment were fashioned as stomas on the anterior abdominal wall. After recovery, the electrical activity of the segment was continuously recorded, whilst a solution of 100 mmol/l glucose and 90 mmol/l NaCl was infused into the proximal stoma at 2.9 ml/min. Effluent from the distal stoma was collected in 5-min aliquots for three consecutive 30-min periods. In the second period electrical stimuli were given via either the proximal or the distal bipolar electrodes to entrain pacesetter potentials. Both forward and backward electrical pacing decreased the output of water, glucose and sodium from the jejunal segment, but the decrease was significantly greater with backward pacing. We conclude that pacing a segment of jejunum backwards with electrical stimuli produces a greater increase in absorption from the segment than pacing it forwards, a finding which has therapeutic implications in patients with the short bowel syndrome.

Abstract Gastric emptying of solids and liquids was measured in 12 dogs with and without corporal or antral gastrojejunostomy. Both types of stoma hastened the onset but did not alter the time from onset to complete emptying of 40 small plastic spheres. Corporal gastrojejunostomy slowed the emptying of 400 ml. of 154 mM NaCl but not of 500 mM glucose, whereas antral gastrojejunostomy slowed the emptying of both.

Abstract Aberrant patterns of pre-mRNA processing are typical of human malignancies, yet the mechanisms responsible for these changes remain undefined. We have recently shown overexpression of a core splice regulatory protein, serine-arginine protein kinase 1 (SRPK1), in dysplastic and neoplastic pancreatic ductular cells. In the present study, we have established that SRPK1 levels are similarly up-regulated in breast and colonic tumors where its expression increases coordinately with tumor grade. Targeting SRPK1 for inhibition using small interfering RNA in breast and colonic tumor cell lines in vitro resulted in both increased apoptotic potential and enhanced cell killing after treatment with gemcitabine and cisplatin. Recent reports have described multifaceted interactions between the mitogen-activated protein kinase (MAPK) and AKT signaling networks and the splice regulatory machinery. Consequently, we have shown that targeted inhibition of SRPK1 in tumor cells results in reduced phosphorylation of MAPK3, MAPK1, and AKT. Alterations in the splice pattern and resulting expression of MAPK kinase are implicated in mediating the antitumoral effects resulting from SRPK1 down-regulation. The up-regulation of SRPK1 in multiple cancers and its ability to regulate multiple relevant signaling pathways provide support for developing agents to inhibit this kinase for possible broad application to treat epithelial cancers. [Cancer Res 2007;67(5):2072–80]

Abstract A policy of supportive treatment is frequently adopted for patients with metastatic disease to the adrenal glands. This study reports an experience with adrenalectomy for adrenal metastasis. Between 1983 and 1993, adrenalectomy was performed in 52 patients for metastasis to the adrenal glands. Survival was calculated by the Kaplan- Meier method and compared with the log rank test. Primary tumour sites included kidney (n = 15), lung (n = 11), colon (n = 7), unknown (n = 5), stomach (n = 3), melanoma (n = 3) and other (n = 8). Adenocarcinoma (69 per cent) was the most common histological cell type. Thirty-two patients were asymptomatic on initial evaluation. Symptomatic adrenal pain relief was achieved in 11 of 13 patients. Overall survival rates were 73 per cent at 1 year and 40 per cent at 2 years. Patients with potentially curative resection had better survival than those who had a palliative procedure. Patients with adrenal metastases due to adenocarcinoma had improved survival compared with that in those with other histological cell types. Although long-term survival is generally poor, highly selected patients with adrenal metastasis (symptomatic disease or adenocarcinoma) may benefit from surgical resection.

Background and Purpose— Thrombolysis for acute ischemic stroke saves societal costs, but hospitals that practice acute stroke care appear to shoulder the burden of the cost, which exceeds reimbursement. With creation of the diagnosis-related group (DRG) 559, the US Centers for Medicare and Medicaid Services pays hospitals approximately US $6000 more per case when thrombolysis is administered. We sought to determine the total cost of, and reimbursement for, acute stroke treatment with thrombolysis at a single stroke center and the economic impact of DRG 559. Methods— Between September 2001 and December 2004, we collected data on all patients with acute stroke who received thrombolysis. We identified all hospital costs and reimbursement per patient. Financial results were expressed as a cost-reimbursement ratio: average total cost to average total reimbursement per patient. We then reanalyzed data using the projected Medicare hospital reimbursement with DRG 559. Results— Sixty-seven patients with stroke (mean age, 72 years) were treated (mean length of stay, 4.4 days; mean stroke severity, National Institutes of Health Stroke Scale score of 15; and symptomatic intracranial hemorrhage rate, 7%). The cost-reimbursement ratio was 1.41 (95% CI=0.98 to 2.28) before DRG 559 and estimated to be 0.82 (95% CI=0.66 to 0.97) after DRG 559. Conclusions— Our hospital costs have traditionally exceeded Medicare reimbursement for the acute care of thrombolyzed patients with ischemic stroke, but with DRG 559, a new economically favorable cost-reimbursement ratio for hospitals will be established.

Background and Purpose— Genetic factors influence risk for ischemic stroke and likely do so at multiple steps in the pathogenic process. Variants in genes related to inflammation contribute to risk of stroke. The purpose of this study was to confirm our earlier finding of an association between allele 2 of a variable number tandem repeat of the IL-1 receptor antagonist gene ( IL1RN ) and cerebrovascular disease. Methods— An association study of the variable number tandem repeat genotype with ischemic stroke and stroke subtypes was performed on samples from a North American study of affected sibling pairs concordant for ischemic stroke and 2 North American cohorts of prospectively ascertained ischemic stroke cases and unrelated controls. DNA analysis was performed on cases and controls, stratified by race. Results— After adjustment for age, sex, and stroke risk factors, the odds ratio for association of allele 2 and ischemic stroke was 2.80 (95% confidence interval, 1.29 to 6.11; P =0.03) for the white participants. The effect of allele 2 of IL1RN on stroke risk most closely fits a recessive genetic model ( P =0.009). For the smaller sample of nonwhite participants, the results were not significant. Conclusions— Allele 2 of IL1RN , present in nearly one-quarter of stroke patients, may contribute to genetic risk for ischemic stroke and confirm the previously identified association with cerebrovascular disease. These results are driven by the association in the white participants. Further exploration in a larger nonwhite sample is warranted.

Abstract Bcl family members Bcl-2, Bcl-xL, and Mcl-1, are frequently expressed and implicated in the survival of myeloma cells. Obatoclax (GX015-070) is a novel, small-molecule antagonist of the BH3-binding groove of the Bcl family of proteins. We show that GX015-070 inhibits the binding of Bak to Mcl-1, up-regulates Bim, induces cytochrome c release, and activates capase-3 in human myeloma cell lines (HMCLs), confirming the predicted mechanism of action. Consequently, GX015-070 potently inhibited the viability of 15 of 16 HMCLs (mean IC50 of 246 nM), including those resistant to melphalan and dexamethasone. In combination studies, GX015-070 enhanced the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib. Sensitivity to GX015-070 correlated with the absence or near absence of Bcl-xL. Coculture with interleukin-6 or adherence to bone marrow stroma conferred modest resistance; however, it did not overcome GX015-070–induced cytotoxicity. Of importance, GX015-070 as a single agent induced potent cytotoxic responses against patient-derived tumor cells. GX015-070 inhibited normal bone marrow–derived colony formation; however, cytotoxicity to human blood lymphocytes was not observed. Taken together, these studies describe a novel BH3 mimic with selectivity for Mcl-1, and support the therapeutic application of GX015-070 for diverse neoplasias including multiple myeloma.