Paediatric gastro-oesophageal reflux: prognostic indicators from pH monitoring

The original diagnostic 24 hour pH monitoring data in 57 children with gastro-oesophageal reflux (GOR) were retrospectively reviewed after a minimum of one year follow up. The tracings of children who responded to medical treatment were compared with those who failed to respond and required a fundoplication. Children with GOR secondary to oesophageal atresia/tracheo-oesophageal fistula and neurological conditions (n = 12) were analysed separately from those with primary GOR (n = 45). Children with primary GOR requiring a fundoplication (n = 9) had increased daytime reflux. The percentage time pH < 4 was the best discriminator (21% v 7%) with a threshold of 18% giving a 92% specificity and a 70% sensitivity. For children with secondary GOR the percentage time pH < 4 at night was significantly higher (29% v 3.7%) in those requiring a fundoplication (n = 5). A threshold of 18% gave an 80% specificity and an 86% sensitivity. These results show that both daytime and night time pH monitoring data can be of prognostic value in different subgroups of children with GOR. A percentage time pH < 4 of greater than 18% was a useful threshold to apply when evaluating the pH monitoring data.     

Ligand binding and covalent structure of an oxygen-binding heme protein from Rhodobacter sphaeroides, a representative of a new structural family of c-type cytochromes

The amino acid sequence of an oxygen-binding heme protein (SHP) from Rhodobacter sphaeroides has been determined. The cysteines, which bind the single heme group in the 112-residue protein, are located at positions 43 and 46. SHP is similar in size to the large membrane-bound form of the class I cytochrome c5 of Azotobacter vinelandii (116 residues) and in the location of the heme binding site at positions 48 and 51. Two extra cysteines in SHP (residues 89 and 97) are located in positions similar to those of cytochrome c5 (residues 98 and 101) and form a disulfide bridge in both proteins. In total, four regions of alpha-helix are predicted, covering 46% of the protein, which is comparable to that in other small cytochromes. SHP is thus distantly related to small class I c-type cytochromes but is representative of a distinct family by virtue of its high-spin nature, the lack of a strong sixth ligand, and its capacity to bind oxygen. Potentially, the most important characteristic of SHP is its ability to transiently bind oxygen during autoxidation, which occurs with a half-life of 3 min with a 4-fold excess of O2. SHP also binds carbon monoxide, azide, and cyanide. The kinetics of reduction by free flavins indicate that SHP is less reactive than other class I cytochromes c and that the heme is less accessible to solvent. There is localized positive charge (+3) at the site of reduction of SHP, although the overall protein charge is -2. This may account in part for the ability of SHP to bind anions.     

Clinical presentation and prognostic factors in sodium monofluoroacetate intoxication

From 1970 to 1992 a total of 63 patients underwent operation for ampullary tumor: 40 pancreatoduodenectomies (PDs), 3 total PDs, 8 ampullectomies, and 12 bypass or exploratory laparotomies. The resectability rate was 68%. There were 9 benign tumors, 1 anaplastic tumor, and 53 adenocarcinomas. According to Martin's classification, there were 7 stage I, 11 stage II, 14 stage III, and 21 stage IV tumors. All patients with stage I, II, and III tumors underwent resection. Patients with stage IV tumors had either resection (n = 11) or bypass (n = 10). The mean duration of hospital stay was 20.6 days. Operative mortality was 12.7% for the whole series and 7.5% after PD (2.5% for the last 10 years). Overall survival was 40% at 5 years (85% for stage I, 65% for stage II, 44% for stage III, and 8% for stage IV). Survival was better for stages I, II, and III after PD than after ampullectomy. For stage IV patients survival was 70% after PD versus 20% after bypass at 1 year and 25% versus 0% after 2 years. In our opinion, PD should be proposed even for benign lesions because two of our patients had to undergo repeat operation (PD) 4 and 22 years later, respectively, for stage IV disease. PD is our choice for all tumors of the ampulla.     

Complications of care in a pediatric intensive care unit: a prospective study

OBJECTIVES: (a) To examine the frequency, type, and severity of complications occurring in a pediatric intensive care unit; (b) to identify populations at risk; and (c) to study the impact of complications on morbidity and mortality. DESIGN: Prospective survey. SETTING: Pediatric intensive care unit (PICU) of a university-affiliated hospital. PATIENTS: 1035 consecutive admissions over an 18-month period. RESULTS: 115 complications occurred during 83 (8.0%) admissions, for 2.7 complications per 100 PICU-days; 48 (42%) complications were major, 45 (39%) moderate, and 22 (19%) minor. Sixty complications (52%) were ventilator-related, 14 were drug-related, 13 procedure-related, 24 infectious, and 22 involved invasive devices (18 vascular catheters). Human error was involved in 41 (36%) cases, 21 of which were major (18%). Treatments included reintubation < 24 h (28), intravenous antimicrobials (24), and invasive bedside procedures (14). Cardiopulmonary resuscitation was required in 6 patients. Thirteen patients with complications died (15.7%); 2 deaths were directly due to complications. Patients with complications were younger, had longer lengths of stay, and had a higher mortality. Length of stay was a positive risk factor for complication risk (odds ratio = 1.09, 95% confidence interval: 1.05 to 1.13; p = 0.0001); other patient characteristics had no predictive effect. Kaplan-Meier estimates showed that the most severe complications occurred early in the PICU stay. The best indicators of patient mortality were number of complications (odds ratio = 2.96, 95% confidence interval 1.72 to 5.08; p = 0.0001), and mortality risk derived from the Pediatric Risk of Mortality Score (odds ratio = 1.08, 95% confidence interval 1.06 to 1.10; p = 0.0001). Mortality was correlated with increasing severity of complications. CONCLUSION: Complications have a significant impact on patient care. Patients may be at increased risk earlier in their PICU course, when the number of interventions may be greatest. Complications may increase patient mortality and predict patient death better than other patient variables.     

Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates

Resistance-modifying agents (RMAs) such as Verapamil have been proved to be effective in reversing multi-drug resistance (MDR) in many in vitro assays. In this study we have investigated the efficacy of Dex-Verapamil, the R-isomer of Verapamil, as a chemosensitizer in a murine leukemia cell line (P388) and in its resistant counterpart (P388/Dx) expressing a typical MDR phenotype. We have examined in vivo the effect of the co-administration of Dex-Verapamil and Doxorubicin in mice transplanted with P388 or P388/Dx cells. Mice treated with the combination of Doxorubicin plus RMA had a significant increase in survival rate as compared to controls; however, the effect was modest. On the contrary, in vitro Dex-Verapamil can enhance Doxorubicin cytotoxicity in P388/Dx cells with a much greater effect depending on the treatment scheme used, by increasing the intracellular content of drug. Taken together our data indicate that Dex-Verapamil can indeed increase the sensitivity to Doxorubicin in resistant cells, but the limited efficacy shown in vivo demonstrates that this phenomenon is strongly dependent on the treatment scheme used and on the maintenance of constantly elevated serum levels.     

Informing consumer decisions in health care: implications from decision-making research

Despite the wider dissemination of health plan report cards, little is known about whether consumers will use this information in making plan and provider choices. Studies of human judgment and decision making are reviewed, as are their implications for devising strategies to inform consumers. The limitations of human information processing suggest that many consumers will not use performance information in making choices. Strategies are needed to support consumers who prefer to rely on intermediaries as well as those who wish to apply the information for their own use. Many current strategies are based on assumptions not supported by existing decision-making research. Although there is much to learn about assisting consumers in making informed choices, a great deal is known from decision-making research. Our approaches and our research agenda must be based on this existing foundation of knowledge.     

Metabolic impact of adenovirus-mediated overexpression of the glucose-6-phosphatase catalytic subunit in hepatocytes

Glucose-6-phosphatase (G6Pase) catalyzes the hydrolysis of glucose 6-phosphate (Glu-6-P) to free glucose and, as the last step in gluconeogenesis and glycogenolysis in liver, is thought to play an important role in glucose homeostasis. G6Pase activity appears to be conferred by a set of proteins localized to the endoplasmic reticulum, including a glucose-6-phosphate translocase, a G6Pase phosphohydrolase or catalytic subunit, and glucose and inorganic phosphate transporters in the endoplasmic reticulum membrane. In the current study, we used a recombinant adenovirus containing the cDNA encoding the G6Pase catalytic subunit (AdCMV-G6Pase) to evaluate the metabolic impact of overexpression of the enzyme in primary hepatocytes. We found that AdCMV-G6Pase-treated liver cells contain significantly less glycogen and Glu-6-P, but unchanged UDP-glucose levels, relative to control cells. Further, the glycogen synthase activity state was closely correlated with Glu-6-P levels over a wide range of glucose concentrations in both G6Pase-overexpressing and control cells. The reduction in glycogen synthesis in AdCMV-G6Pase-treated hepatocytes is therefore not a function of decreased substrate availability but rather occurs because of the regulatory effects of Glu-6-P on glycogen synthase activity. We also found that AdCMV-G6Pase-treated-cells had significantly lower rates of lactate production and [3-3H]glucose usage, coupled with enhanced rates of gluconeogenesis and Glu-6-P hydrolysis. We conclude that overexpression of the G6Pase catalytic subunit alone is sufficient to activate flux through the G6Pase system in liver cells. Further, hepatocytes treated with AdCMV-G6Pase exhibit a metabolic profile resembling that of liver cells from patients or animals with non-insulin-dependent diabetes mellitus, suggesting that dysregulation of the catalytic subunit of G6Pase could contribute to the etiology of the disease.