Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain

More and more elderly subjects are offered for pulmonary resection. The object of this study was to review the results of excision for cancer in octogenarians. PATIENTS: 51 consecutive patients (44 men, 7 women) with a mean age of 82 years (80-91) were operated on. 31 lobectomies, 2 bilobectomies, 13 pneumonectomies, 1 segmental resection and 4 exploratory thoracotomies were carried out. 17 tumours were classed as stage I, 15 as stage II and 15 as stage III. RESULTS: 38 patients (75%) had uncomplicated post-operative periods; the predicted factors for complication were the existence of weight loss and alteration of respiratory function. 2 patients (4%) died in the post-operative phase. Neither the type of operation, the staging or the existence of cardiovascular dysfunction had any influence on the post-operative phase. The level of the survival at 3 and 5 years was 39% and 16% respectively. 30% of the late deaths were related to intercurrent events. CONCLUSIONS: Pulmonary excision may be envisaged in an octogenarian who is in good physical and intellectual state with a limited tumour. This surgery in general is applied to a population which probably only marginally consists of octogenarians but the results here justify their inclusion in the indications for selection.     

Morbillivirus downregulation of CD46

There is evidence that CD46 (membrane cofactor protein) is a cellular receptor for vaccine and laboratory-passaged strains of measles virus (MV). Following infection with these MV strains, CD46 is downregulated from the cell surface, and consequent complement-mediated lysis has been shown to occur upon infection of a human monocytic cell line. The MV hemagglutinin (H) protein alone is capable of inducing this downregulation. Some wild-type strains of MV fail to downregulate CD46, despite infection being prevented by anti-CD46 antibodies. In this study we show that CD46 is also downregulated to the same extent by wild-type, vaccine, and laboratory-passaged strains of rinderpest virus (RPV), although CD46 did not appear to be the receptor for RPV. Expression of the RPV H protein by a nonreplicating adenovirus vector was also found to cause this downregulation. A vaccine strain of peste des petits ruminants virus caused slight downregulation of CD46 in infected Vero cells, while wild-type and vaccine strains of canine distemper virus and a wild-type strain of dolphin morbillivirus failed to downregulate CD46. Downregulation of CD46 can, therefore, be a function independent of the use of this protein as a virus receptor.     

Primary nonampullary/periampullary adenocarcinoma of the duodenum

Primary duodenal adenocarcinoma not involving the ampullary region is rare. Our aim was to review the outcome of these patients and determine the factors that affect survival. We performed a retrospective review of all patients with primary, nonampullary duodenal adenocarcinoma at the Cleveland Clinic Foundation from January 1986 through December 1996. Twenty-six patients with primary, nonampullary duodenal malignancies were identified. There were 16 adenocarcinomas, 3 gastrinomas, 3 stromal tumors, 3 leiomyosarcomas, and 1 carcinoid tumor. Patients with adenocarcinoma had symptoms present an average of 6.1 months. Tumors were identified by upper gastrointestinal contrast study and esophagogastroduodenoscopy in 90 per cent and 87 per cent of patients, respectively. Twelve of 13 (93%) cancers found in the third or fourth portion of the duodenum were adenocarcinomas. Seven of the 16 adenocarcinomas were resectable on exploration. Those that were contained within the serosa have not recurred (mean, 6 years); one of the two patients with locally invasive adenocarcinoma remains disease free. The average survival for patients with unresectable disease was 6.7 months. The 5-year survival rates were: all adenocarcinoma, 38 per cent; resectable, 86 per cent; and unresectable, 0 per cent. All patients presenting with weight loss or obstructive symptoms died of disease; those with melena survived long term. Patients with tumors other than adenocarcinoma had a 90 per cent 5-year survival. We conclude that patients typically present with a long history of symptoms. Distal duodenal malignancies are most frequently adenocarcinomas. Upper gastrointestinal contrast study or endoscopy is often diagnostic. Patients with weight loss and/or obstructive symptoms had invasive disease and a morbid prognosis. Aggressive surgery is warranted, and most with resectable disease (86%) had long-term survival.     

High PCO does not alter pHi, but raises [Ca2+]i in cultured rat carotid body glomus cells in the absence and presence of CdC12

We measured the effect of high PCO (500-550 Torr) on the pHi and [Ca2+]i in cultured glomus cells of adult rat carotid body (CB) as a test of the two models currently proposed for the mechanism of CB chemoreception. The metabolic model postulates that the rise in glomus cell [Ca2+]i, the initiating reaction in the signalling pathway leading to chemosensory neural discharge, is due to [Ca2+] release from intracellular Ca2+ stores. The membrane potential model postulates that the rise in [Ca2+]i comes from influx of extracellular Ca2+ through voltage-dependent Ca2+ channels (VDCC) of the L-type. High PCO did not change pHi at PO2 of 120-135 Torr, showing that CO-induced changes in [Ca2+]i are not due to changes in pHi. High PCO caused a highly significant rise in [Ca2+]i from 90+/-12 nM to 675+/-65 nM, both in the absence and in the presence of 200 microM CdCl2, a potent blocker of L-type VDCCs. This result is fully consistent with release of Ca2+ from glomus cell intracellular stores according to metabolic model, but inconsistent with influx of extracellular Ca2+ through VDCCs according to the membrane potential model.     

The metabolism of phytanic acid and pristanic acid in man: a review

The branched-chain fatty acid phytanic acid is a constituent of the diet, present in diary products, meat and fish. Degradation of this fatty acid in the human body is preceded by activation to phytanoyl-CoA and starts with one cycle of alpha-oxidation. Intermediates in this pathway are 2-hydroxy-phytanoyl-CoA and pristanal; the product is pristanic acid. After activation, pristanic acid is degraded by peroxisomal beta-oxidation. Several disorders have been described in which phytanic acid accumulates, in some cases in combination with pristanic acid. In classical Refsum disease, the enzyme that converts phytanoyl-CoA into 2-hydroxyphytanoyl-CoA--phytanoyl-CoA hydroxylase--is deficient, resulting in highly elevated levels of phytanic acid in blood and tissues. Also in rhizomelic chondrodysplasia punctata, phytanic acid accumulates, owing to a deficiency in the peroxisomal import of proteins with a peroxisomal targeting sequence type 2. In patients affected with generalized peroxisomal disorders, degradation of both phytanic acid and pristanic acid is impaired owing to absence of functional peroxisomes. In bifunctional protein deficiency, the disturbed oxidation of pristanic acid results in elevated levels of this fatty acid and a secondary elevation of phytanic acid. In addition, several variant peroxisomal disorders with unknown aetiology have been described in which phytanic acid and/or pristanic acid accumulate. This review describes the discovery of phytanic acid and pristanic acid and the initial attempts to elucidate the origins and fates of these fatty acids. The current knowledge on the alpha-oxidation and beta-oxidation of these branched-chain fatty acids is summarized. The disorders in which phytanic acid and/or pristanic acid accumulate are described and some remarks are made on the pathogenic mechanisms of elevated levels of phytanic acid and pristanic acid.     

A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation

The hydrophilic bile salt ursodeoxycholic acid (UDCA) protects against the membrane-damaging effects associated with hydrophobic bile acids. This study was undertaken to (a) determine if UDCA inhibits apoptosis from deoxycholic acid (DCA), as well as from ethanol, TGF-beta1, Fas ligand, and okadaic acid; and to (b) determine whether mitochondrial membrane perturbation is modulated by UDCA. DCA induced significant hepatocyte apoptosis in vivo and in isolated hepatocytes determined by terminal transferase-mediated dUTP-digoxigenin nick end-labeling assay and nuclear staining, respectively (P < 0.001). Apoptosis in isolated rat hepatocytes increased 12-fold after incubation with 0.5% ethanol (P < 0.001). HuH-7 cells exhibited increased apoptosis with 1 nM TGF-beta1 (P < 0. 001) or DCA at >/= 100 microM (P < 0.001), as did Hep G2 cells after incubation with anti-Fas antibody (P < 0.001). Finally, incubation with okadaic acid induced significant apoptosis in HuH-7, Saos-2, Cos-7, and HeLa cells. Coadministration of UDCA with each of the apoptosis-inducing agents was associated with a 50-100% inhibition of apoptotic changes (P < 0.001) in all the cell types. Also, UDCA reduced the mitochondrial membrane permeability transition (MPT) in isolated mitochondria associated with both DCA and phenylarsine oxide by > 40 and 50%, respectively (P < 0.001). FACS(R) analysis revealed that the apoptosis-inducing agents decreased the mitochondrial transmembrane potential and increased reactive oxygen species production (P < 0.05). Coadministration of UDCA was associated with significant prevention of mitochondrial membrane alterations in all cell types. The results suggest that UDCA plays a central role in modulating the apoptotic threshold in both hepatocytes and nonliver cells, and inhibition of MPT is at least one pathway by which UDCA protects against apoptosis.     

Correlation of fine needle aspiration biopsy and fluoride-18 fluorodeoxyglucose positron emission tomography in the assessment of locally recurrent and metastatic head and neck neoplasia

OBJECTIVE: Patients with primary head and neck neoplasia can present during follow-up with suspected recurrence, and both fine needle aspiration biopsy (FNAB) and fluoride-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan are available methodologies for evaluating these patients. Our objective was to retrospectively correlate patients who underwent both FNAB and FDG-PET scan in order to assess the possibility of recurrent neoplasia. STUDY DESIGN: The cytopathology files at Saint Louis University Health Sciences Center were retrospectively searched for patients with known primary head and neck malignancies beginning in 1995. Suspected recurrence and local metastases evaluated by both FNAB and FDG-PET scan were correlated. RESULTS: Twenty-eight patients received a combined total of 37 FNABs with concurrent FDG-PET scans. The majority of patients had primary oropharyngeal squamous cell carcinoma with intermixed, single cases of other primary head and neck neoplasms. Thirty of the 32 aspirates with recurrent or locally metastatic disease had combined positive findings by both FNAB and FDG-PET scan, yielding a sensitivity of 94%. One nonspecific and one negative FDG-PET scan came from a patient who had disease confirmed by FNAB. Five patients had negative findings by both methods that were supported by the subsequent clinical course. CONCLUSION: FNAB can provide confirmatory evidence of disease in a clinically suspicious abnormality with nonspecific FDG-PET results. FNAB and FDG-PET are highly sensitive for tumors in cases of clinically suspected recurrence and locally metastatic disease.