Conjugation of trypsin by temperature-sensitive polymers containing a carbohydrate moiety: thermal modulation of enzyme activity

Given the substantial increase in the numbers of community psychiatric nurses (CPNs) in England in the last 15 years this paper asks the question: is CPN activity where it should be? In-other words is activity distributed around the country according to need? Various indicators of need are suggested including population age structure, deprivation indices and suicide rates. We find no evidence -- based on information from scatterplots, Spearman correlations and more innovative measures of inequality -- that CPNs are distributed according to need. If this is confirmed by further research it is cause for alarm -- CPNs should be where they are most needed.     

Double patch closure of ventricular septal defect with increased pulmonary vascular resistance

BACKGROUND: Closure of a large ventricular septal defect (VSD) in children with elevated pulmonary vascular resistance is associated with significant morbidity and mortality. Pulmonary hypertensive episodes continue to be a major cause of postoperative morbidity and mortality. We designed a fenestrated flap valve double VSD patch in an effort to decrease the morbidity and mortality associated with the closure of a large VSD with elevated pulmonary vascular resistance. METHODS: Eighteen children (mean age, 5.7 years) with a large VSD and elevated pulmonary vascular resistance (mean, 11.4 Wood units) underwent double patch VSD closure using moderately hypothermic cardiopulmonary bypass and cardioplegic arrest. The routine VSD patch was fenestrated (4 to 6 mm) and on the left ventricular side of the patch, a second, smaller patch was attached to the fenestration along its superior margin before closure of the VSD. RESULTS: All children survived operation and were weaned from inotropic and ventilator support within 48 hours postoperatively. Postoperative pulmonary artery pressures were significantly lower than preoperative values. One child died 9 months postoperatively. CONCLUSIONS: Closure of a large VSD in children with elevated pulmonary vascular resistance can be performed with low morbidity and mortality when a flap valve double VSD patch is used.     

Bacillary generalized angiomatosis in HIV infection

A unique case of generalized bacillary angiomatosis (BA) in a patient who died of HIV infection is described. Apart from widely spread skin lesions there were also manifestations in the brain, lungs, heart, esophagus and intestine. Gram-negative bacteria were found in the histological sections. Oval and roundish bacteria with a predominantly perivascular location were found electron microscopically in the archives material.     

Impaired awareness and employment outcome after traumatic brain injury

Inaccurate self-awareness is a common finding after traumatic brain injury. Such impaired awareness has been hypothesized to limit patients' eventual functional outcomes by decreasing motivation for treatment and resulting in selection of inappropriate long-term goals. Previous investigations of the association between impaired awareness and employment outcome have produced inconsistent results. The present article reviews these studies and presents the results of our new investigation of this issue. In addition, we studied the comparability of two methods of measuring impaired awareness. Results provided strong support for a positive relationship between accurate self-awareness and favorable employment outcome at follow-up.     

Effect of lipectomy on growth and development of hyperinsulinemia and hyperlipidemia in the Zucker rat

The Zucker fat rat inherits obesity and hyperinsulinemia, exhibits insulin resistance, and is, therefore, a model of adult onset, or type II, diabetes. The purpose of this study was to determine if excision of fat depots from the infant Zucker (fa+/fa+) rat would affect growth, fat cell number, hyperinsulinism, and hyperlipidemia. In the experimental design, 10 percent of the total body weight (inguinal and interscapular depots) was excised at 6 weeks of age from 18 fat and 18 lean (fa+/fa-) litter mates, with 18 fat and 18 lean rats serving as nonoperated controls. At intervals, serum glucose, insulin, cholesterol, and triglycerides were measured. Initially, the operated fat group was significantly (p < 0.01) lighter than the nonoperated group. By 9 weeks postoperatively, the operated fat rat group had regained weight and continued to grow at the same rate as the nonoperated fat rats because of intra-abdominal fat depots. Lipectomy had no effect on growth rate of the lean rat group. Although lipectomy caused no consistent change in serum glucose or insulin levels, it caused a significant decrease in lipid levels. For example, the operated fat rats had a reduction in cholesterol from 876 to 171 mg/dl by 15 weeks postoperatively, and serum cholesterol persisted at about 50 percent of the nonoperated group throughout the rest of the study (38 weeks postoperatively). Even a greater reduction in triglyceride levels occurred, for example, from 7415 to 1082 mg/dl at 24 weeks postoperatively. Lipectomy did not cause a change in lipid levels in the lean group. It is concluded that the lipectomy in the Zucker fat group is an excellent model to evaluate the effects of changes in fat cell number on lipid metabolism.     

Gene amplification in a p53-deficient cell line requires cell cycle progression under conditions that generate DNA breakage

Amplification of genes involved in signal transduction and cell cycle control occurs in a significant fraction of human cancers. Loss of p53 function has been proposed to enable cells with gene amplification to arise spontaneously during growth in vitro. However, this conclusion derives from studies employing the UMP synthesis inhibitor N-phosphonacetyl-L-aspartate (PALA), which, in addition to selecting for cells containing extra copies of the CAD locus, enables p53-deficient cells to enter S phase and acquire the DNA breaks that initiate the amplification process. Thus, it has not been possible to determine if gene amplification occurs spontaneously or results from the inductive effects of the selective agent. The studies reported here assess whether p53 deficiency leads to spontaneous genetic instability by comparing cell cycle responses and amplification frequencies of the human fibrosarcoma cell line HT1080 when treated with PALA or with methotrexate, an antifolate that, under the conditions used, should not generate DNA breaks. p53-deficient HT1080 cells generated PALA-resistant variants containing amplified CAD genes at a frequency of >10(-5). By contrast, methotrexate selection did not result in resistant cells at a detectable frequency (<10(-9)). However, growth of HT1080 cells under conditions that induced DNA breakage prior to selection generated methotrexate-resistant clones containing amplified dihydrofolate reductase sequences at a high frequency. These data demonstrate that, under standard growth conditions, p53 loss is not sufficient to enable cells to produce the DNA breaks that initiate amplification. We propose that p53-deficient cells must proceed through S phase under conditions that induce DNA breakage for genetic instability to occur.     

Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients

This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 mL/min/kg and 0.74 +/- 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics.     

Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloromethane in liver and kidney

Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation between species was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/rat > hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.     

Lead poisoning from drinking Kombucha tea brewed in a ceramic pot

Kombucha tea is an alternative therapy that is gaining popularity as a remedy for a diverse range of ailments. We report two cases of symptomatic lead poisoning requiring chelation therapy in a married couple who had been drinking Kombucha tea for six months, brewing the tea in a ceramic pot. We postulate that acids in the tea eluted lead from the glaze pigment used in the ceramic pot, in a manner analogous to elution of lead from crystal decanters by wine and spirits.     

Efficacy of low-dose dopamine in preventing amphotericin B nephrotoxicity in bone marrow transplant patients and leukemia patients

This study evaluated the efficacy of low-dose dopamine for prevention of amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Seventy-one patients undergoing cytoreductive therapy who required amphotericin B were randomly assigned in an unblinded fashion to a group receiving continuous-infusion low-dose dopamine (3 microgram/kg/min) or a group receiving no dopamine. Amphotericin B was dosed at 0.5 or 1.0 mg/kg/day based on computerized tomography scan results or presence of positive blood cultures. No patient received saline boluses. The rate of nephrotoxicity, severity as graded by Southwest Oncology Group toxicity criteria, and time to each grade of nephrotoxicity were compared between the two groups. Eighty percent of the no-dopamine group and 66.7% of the dopamine group developed nephrotoxicity, defined as a 1.5-fold or greater increase in baseline serum creatinine level (P = 0.20). No statistical difference was noted at any grade of nephrotoxicity between the two groups. Thirty-four percent of patients in the no-dopamine group versus 17.6% in the dopamine group had a 2.5-fold or greater increase in serum creatinine level, which was not statistically significant (P = 0.0888). Ten patients developed grade IV nephrotoxicity and were withdrawn from the study, 7 in the no-dopamine group and 3 in the dopamine group (P = 0.19). The time to each grade of nephrotoxicity was also not significantly different for the two groups. Eleven adverse drug reactions were reported in the dopamine group in comparison to one in the no-dopamine group. Thus, dopamine offers little in the way of prevention of nephrotoxicity associated with amphotericin B therapy. Although the significance of drug reactions in the dopamine group is not clearly established due to lack of cardiac monitoring in the no-dopamine group, dopamine therapy is not without complications.