ARH missense polymorphisms and plasma cholesterol levels.

Mutations in a putative low-density lipoprotein (LDL) receptor adaptor protein called ARH have been recently described in patients with autosomal recessive hypercholesterolemia (ARH). ARH plays a tissue-specific role in determination of LDL receptor function. In the ARH gene three mismatched polymorphisms have been detected: Pro202Ser, Pro202His and Arg238Trp. These are of putative interest in plasma cholesterol level determination. To evaluate the effect of polymorphisms on plasma cholesterol levels, all polymorphisms were analyzed by PCR and restriction enzyme analysis by MnII, HpyCH4IV and SacII in 100 Caucasian males with high (>90%, 6.29 +/- 0.89 mmol/l), and 100 males with low (<10%, 3.60 +/- 0.57 mmol/l), total plasma cholesterol levels. No significant differences were observed in frequencies of ARH genotypes or alleles between these two extreme groups. These results suggest that ARH polymorphisms are unlikely to be important genetic determinants of plasma cholesterol levels.     

A comparison of nutritional intake, functional status and muscle strength between elderly day hospital and day centre attenders in South London

Two sample groups of elderly were compared from a population living in South London. One group attended a local day centre (a socially orientated establishment), and the other attended a local day hospital (a therapeutically orientated establishment).
The aim of the study was to compare nutritional intake, functional status and muscle strength between these two groups.
The mean nutritional intakes of the day hospital and day centre attenders were similar. Intake of macronutrients, with the exception of fibre, met Recommended Daily Allowances (RDAs) in both groups. In take of folic acid, vitamin D and zinc fell below recommendations in both groups.
Low intake of folic acid was improved by supplementation, and some individual blood levels of folate reflected this. Blood folate levels were generally within normal limits. Low intake of vitamin D was improved by supplementation, but blood levels were generally normal anyway. There was, however, a tendency for the more dependent day hospital patients to have lower vitamin D levels. This group also had less sunshine exposure.
Communal dining, whether in the setting of day hospital or day centre, may have been an essential means of bolstering nutritional intake for many 'at risk' elderly.
There were significant differences in functional status and muscle strength in favour of the day centre group and these indicate that anthropometric indices rather than nutritional or biochemical indices were the most reliable markers of disease and disability in this study.
The effect of fortifying local meals-on-wheels was also highlighted, and suggests that this may be one means of preventing nutritional deficiencies in the vulnerable, house-bound elderly.
Alcohol intake was reported as being modest. However, discrepancies were noted on review of biochemical indices known to be influenced by alcohol intake.     

Phylogenetic Analysis of the DNA Polymerase Gene of a Novel Alphaherpesvirus Isolated from an Indian <Emphasis Type="Italic">Gyps</Emphasis> Vulture

The DNA polymerase gene of a novel herpesvirus, vulture herpesvirus (VHV), isolated from an Indian Gyps vulture was completely sequenced using primer walking and transposon insertion strategies. DNA sequencing analysis revealed a single open reading frame (ORF) of 3660 nucleotides (53% G-C content) able to encode 1219 amino acids. Identification was based on a nucleotide sequence identity of approximately 50% to other herpesvirus sequences found in Genbank. Nine motifs were identified that are conserved amongst all known herpesviruses and are found within the 3–5 exonuclease and DNA binding functional domains of the DNA polymerase enzyme. Phylogenetic analysis using Clustal W with neighbour-joining revealed VHV to group within the subfamily Alphaherpesvirinae, more closely related to the avian herpesviruses than to those of other species. Partial sequence data also revealed VHV to contain other genes fundamental to the structure and replication of all herpesvirus genomes. A Real Time PCR Taqman assay specific for the VHV DNA polymerase gene was designed to detect the presence of VHV genomic material in post mortem tissue samples from diseased birds. Positive tissues included the spleen, rectum, thymus, kidney and brain. A herpesvirus specific to vultures may pose a threat to the management of captive breeding programs being established to assist the survival of wild populations of Gyps vultures.     

Tioman virus, a novel paramyxovirus isolated from fruit bats in Malaysia

A search for the natural host of Nipah virus has led to the isolation of a previously unknown member of the family Paramyxoviridae. Tioman virus (TiV) was isolated from the urine of fruit bats (Pteropus hypomelanus) found on the island of the same name off the eastern coast of peninsular Malaysia. An electron microscopic study of TiV-infected cells revealed spherical and pleomorphic-enveloped viral particles (100--500 nm in size) with a single fringe of embedded peplomers. Virus morphogenesis occurred at the plasma membrane of infected cells and morphological features of negative-stained ribonucleoprotein complexes were compatible with that of viruses in the family Paramyxoviridae. Serological studies revealed no cross-reactivity with antibodies against a number of known Paramyxoviridae members except for the newly described Menangle virus (MenV), isolated in Australia in 1997. Failure of PCR amplification using MenV-specific primers suggested that this new virus is related to but different from MenV. For molecular characterization of the virus, a cDNA subtraction strategy was employed to isolate virus-specific cDNA from virus-infected cells. Complete gene sequences for the nucleocapsid protein (N) and phosphoprotein (P/V) have been determined and recombinant N and V proteins produced in baculovirus. The recombinant N and V proteins reacted with porcine anti-MenV sera in Western blot, confirming the serological cross-reactivity observed during initial virus characterization. The lack of a C protein-coding region in the P/V gene, the creation of P mRNA by insertion of 2-G residues, and the results of phylogenetic analyses all indicated that TiV is a novel member of the genus Rubulavirus.     

Phase I/IIa study of cisplatin and gemcitabine as induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine and paclitaxel for locally advanced non-small-cell lung cancer.

PURPOSE: This is a phase I/IIa study to assess tolerance of gemcitabine and paclitaxel with radiotherapy in locally advanced non-small-cell lung cancer after induction chemotherapy. PATIENTS AND METHODS: Fifty-seven patients with stage III non-small-cell lung cancer were treated with cisplatin 80 mg/m2 on days 1 and 22 and gemcitabine 1,250 mg/m2 on days 1, 8, 22, and 28. Chemoradiotherapy began on day 43 as follows: cohort 1 (n = 9), gemcitabine 300 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 2 (n = 9), gemcitabine 150 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 3 (n = 10) and the 25 phase IIa patients, gemcitabine 300 mg/m2 and paclitaxel 135 mg/m2 every 21 days. Patients were treated with three-dimensional thoracic radiotherapy concurrently to 60 Gy. RESULTS: Weekly chemotherapy resulted in grade 4 esophageal and grade 3 or higher pulmonary toxicities. Reduction in dose density (cohort 3) led to a tolerable toxicity profile and was chosen as the phase IIa regimen. The response rate to induction was 49%, with stable disease in 40% of the patients. The response rate after consolidation therapy was 75% (94% for weekly chemotherapy v 82% for every 3 weeks). Median survival was 23 months, and 3-year survival was 45% for eligible patients. Local relapse occurred in 20% of the patients. Performance status of more than 1 predicted for poor outcome, but baseline pulmonary function did not. Dosimetric parameters including V15, V20, V30 (percent lung volume receiving > or = 15, > or = 20, and > or = 30 Gy, respectively), and mean lung dose correlated with pulmonary toxicity. CONCLUSION: Additional investigation with the 3-week schedule is warranted in patients with a good performance status based on the safety profile and preliminary efficacy data observed in this study.     

Secretin Provocation: Gastrin Results in Various Clinical Situations

Our previous secretin provocation studies in normal volunteers and unoperated duodenal ulcer patients suggested that the gastrin rise in gastrinoma may be an exaggeration of the normal response rather than paradoxical. We report further studies in various clinical settings having normogastrinemia (normal, n = 17; unoperated duodenal ulcer, n = 13; primary hyperparathyroidism, n = 7) and hypergastrinemia (postvagotomy, n = 5; hypochlorhydria, n = 7; achlorhydria, n = 10; chronic renal failure, n = 10; gastrinoma, n = 5). Under all nongastrinoma conditions, there were similar gastrin rises of 9-19% between 2 and 5 min after bolus intravenous GIH secretin (2 CU/kg), which fell to baseline by 8 min, except for chronic renal failure. In chronic renal failure, gastrin remained elevated from 7 to 30 min and was significantly different (p less than 0.05) at 10-30 min compared to all other nongastrinoma conditions except hyperparathyroidism. Peak rises occurred within 5 min in all entities, but only three gastrinoma patients had positive secretin provocation tests by the predefined criterion of a gastrin rise greater than 200 pg/ml. The results of secretin provocation in various clinical entities with and without hypergastrinemia further support the hypothesis that the gastrin rise in gastrinoma is an exaggeration of the normal response. The prolonged gastrin rise seen in chronic renal failure may be due to altered renal clearance, inasmuch as other hypergastrinemic states had responses similar to normal and duodenal ulcer.     

Effect of ventilation by high-frequency oscillation on lung and chest wall mechanics in the dog

High-frequency oscillation (HFO) has been shown to be effective in maintaining gas exchange, but the effects of high-frequency, small-volume ventilation on the mechanical properties of the respiratory system are unknown. A volume displacement plethysmograph was used to study lung volumes and static pressure-volume (PV) curves during HFO in pentobarbital-anesthetized dogs. During long-term studies, adequate gas exchange was maintained with a stroke volume of 2.5 ml/kg and frequencies between 15 and 30 Hz. The effect of 5–7 hours of HFO on lung and chest wall mechanics was studied in 8 dogs. In another 8 dogs the relationship of volume history and respiratory muscle tone to occlusion airway pressure and lung volume during short-term HFO was investigated. With prolonged HFO, a small but significant decrease in total lung capacity occurred by 5 hours and the static respiratory system PV curve shifted slightly to the right. These changes were reversed by muscle paralysis and may be explained by a change in respiratory muscle tone. Static lung compliance and the hysteresis ratio (an index of tissue properties) remained unchanged. The relationship of occlusion airway pressure and lung volume during short-term HFO was dependent on the lung volume history and was influenced by respiratory muscle tone only at low airway pressures. These findings suggest that during prolonged HFO a small increase in chest wall stiffness may result. However, occlusion airway pressure and lung volume at the onset of HFO are mainly dependent on the volume history of the lung. Presented in part at the Fall Meeting of the American Physiological Society, Toronto, Canada, October 12–17, 1980     

Solubility,speciation and local environment of chlorine in zirconolite glass–ceramics for the immobilisation of plutonium residues

The immobilisation and disposal of fissile materials from civil and defence nuclear programmes requires compatible, passively safe and proliferation resistant wasteforms. In this study, we demonstrate the application of an albite glass–zirconolite ceramic material for immobilisation of chloride contaminated plutonium oxide residues in the United Kingdom. The chlorine solubility limit in the albite glass phase was determined to be 1.0 ± 0.1 wt%, above the maximum envisaged chorine inventory of 0.5 wt%, attainable at a 20 wt% PuO₂ incorporation rate within the ceramic. Cl K-edge of X-ray Absorption Near Edge Spectroscopy (XANES) was exploited to confirm partitioning of Cl to the glass phase, speciated as the chloride anion, with exsolution of crystalline NaCl above the chlorine solubility limit. Combinatorial fitting of Cl XANES data, utilising a library of chemically plausible reference spectra, demonstrated the association of Cl with Na and Ca modifier cations, with environments characteristic of the aluminosilicate chloride minerals eudialyte, sodalite, chlorellestadite and afghanite. Adventitious incorporation of Ca, Zr and Ti within the albite glass phase apparently assists chlorine solubility, by templating a local chemical environment characteristic of the mineral reference compounds. The partitioning of Ce, as a Pu analogue, within the glass–ceramic was not adversely impacted by incorporation of Cl. The significance of this research is in demonstrating the compatibility of the glass–ceramic wasteform toward Cl solubility at the expected incorporation rate, below the determined solubility limit. Thus, an upstream heat treatment facility to remove chloride contamination, as specified in the current conceptual flowsheet, would not be required from the perspective of wasteform compatibility, thus providing scope to de-risk the technology roadmap and reduce the projected capital and operational plant costs.

Understanding chlorine speciation and incorporation in glass ceramic wasteforms underpins future treatment of contaminated plutonium residues.