Both ANT and ATPase are essential for mitochondrial permeability transition but not depolarization.

An increase in permeability of the mitochondrial inner membrane, mitochondrial permeability transition (PT), is the central event responsible for cell death and tissue damage in conditions such as stroke and heart attack. PT is caused by the cyclosporin A (CSA)-dependent calcium-induced pore, the permeability transition pore (PTP). The molecular details of PTP are incompletely understood. We utilized holographic and fluorescent microscopy to assess the contribution of ATP synthase and adenine nucleotide translocator (ANT) toward PTP. In cells lacking either ATP synthase or ANT, we observed CSA-sensitive membrane depolarization, but not high-conductance PTP. In wild-type cells, calcium-induced CSA-sensitive depolarization preceded opening of PTP, which occurred only after nearly complete mitochondrial membrane depolarization. We propose that both ATP synthase and ANT are required for high-conductance PTP but not depolarization, which presumably occurs through activation of the low-conductance PT, which has a molecular nature that is different from both complexes.

Point-source modelling using matched case-control data.

We describe an extension to matched case-control studies of the parametric modelling framework developed by Diggle (1990) and Diggle and Rowlingson (1994) to investigate raised risk around putative sources of environmental pollution. We use a conditional likelihood approach for the family of risk functions considered in Diggle and Rowlingson (1994). We show that the likelihood surface that results from these models may be highly irregular, and provide a Bayesian analysis in which we investigate the posterior distribution using Markov chain Monte Carlo. An analysis of one-one matched data that were collected to investigate the relationship between respiratory disease and distance to roads in East London is presented.

Tracheal venous blood and lymph collection: a model to study airway injury in sheep.

Airway injury is a frequent result of the inhalation or aspiration of toxic material. Although upper airway damage can be identified endoscopically, pathophysiological changes are difficult to evaluate. This paper describes an animal model in which changes in tracheal blood and lymph flow rates, wet-to-dry weight ratios, and lymph-to-plasma protein ratios can be evaluated after injury. In this model, 12 cm of the cervical trachea were isolated using a double-cuffed endotracheal tube and injured with cotton smoke at near room temperature. Injury to the trachea was evaluated in twenty-five anesthetized sheep 4 (n = 3), 8 (n = 3), 24 (n = 3), 48 (n = 3), 96 (n = 3), and 192 (n = 2) h after smoke exposure and compared with sham control animals (n = 8). A significant increase in tracheal venous blood flow from 1.3 +/- 0.4 (SD) ml.min-1.cm-1 for the noninjured trachea to 2.8 +/- 1.2 was noted 24 h after injury (P less than 0.01). Lymph flow significantly increased from 1.3 +/- 0.4 microliters.min-1.cm-1 for the noninjured trachea to 9.8 +/- 3.3 24 h after injury while wet-to-dry weight ratios were elevated from 3.0 +/- 0.2 for noninjured trachea to 4.6 +/- 0.9 from 4 to 24 h after injury (P less than 0.01) and decreased to 3.7 +/- 0.5 by 96 h. Cast material consisting of airway exudate, cellular debris, and intact ciliated epithelial cells was both expectorated and found in the trachea when the animals were killed.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective permeability changes in the lungs and airways of sheep after toxic smoke inhalation.

The effect of toxic smoke inhalation on selective microvascular sieving of macro-molecules and lymph protein flux was assessed in adult sheep to determine whether the time course of microvascular dysfunction differs between the lung and trachea. Protein flux across the lung increased sixfold 48 h after inhalation of the products of incomplete cotton combustion, whereas tracheal protein flux increased fivefold 8 h after exposure and returned to near base line 48 h after exposure. The lung and trachea selectively retained some sieving to three different protein macromolecules with molecular radii of 36, 54, and 123 A. In the lungs the sieving selectivity for these macromolecules was least 48 h after injury, and in the trachea molecular selectivity was least 8 h after injury. These data suggest that the time course of microvascular injury differs for the trachea and the lung; microvascular changes are detected earlier in the trachea than in the lung. The inhalation injury described thus permits the characterization of the time course of airway and lung microvascular changes.

Situational trust and co-operative partnerships between physicians and their patients: a theoretical explanation transferable from business practice.

A model to explain interpersonal trust development, and its consequences for co-operative behaviour in doctor/patient partnerships derived from the context of business relationships is applied to patient/physician relationships. Threshold barriers exist against all human behaviours or actions and trust is the process by which barriers to co-operation and compliance are overcome. Dispositional trust (a psychological trait to be trusting) is dominant in the early stages of a relationship and contributes to the weight of subsequent trust development. Co-operative behaviour or compliance ultimately requires a secure situational trust emerging from consultations, which is carried forward as learnt trust and modified in each subsequent consultation. The model comprises three types of situational trust (calculus-based, knowledge-based, and identification trust) and five co-operation criteria from which to determine an individual's tendency for co- operative behaviour. These model components can be identified and mapped from a range of qualitative data, with the aim of enhancing co-operative behaviour and efficiently achieving optimal patient compliance.

Still hungry in hospital: identifying malnutrition in acute hospital admissions.

We assessed the prevalence, methods for recognition and clinical management of malnutrition in acute admissions in a large academic inner-city hospital. Of a total of 337 patients, it was possible to measure both height and weight in 219 patients (65% of admissions). As an alternative for bed-bound patients, mid-upper arm circumference was not very reliable in predicting BMI (sensitivity 98%; specificity 65%), and waist circumference even less so. Of these, 13% were malnourished (body mass index BMI <18.5 kg/m(2) or BMI 18.5-20 kg/m(2) with reported weight loss >3 kg in the last 3 months). Six patients (31% of those with BMI <18.5 kg/m(2)) and one with BMI 18.5-20 kg/m(2) were recognized as suffering from malnutrition and referred to the dietitian. Review of case records could not establish if the diagnosis was missed in the remainder, or if a conscious decision was taken not to manage malnutrition actively. Malnutrition in acute hospital admissions goes apparently unrecognized and unmanaged in 70% of cases. Since there are serious consequences, and effective simple treatment is readily available, increased awareness is required, with routine assessment of nutritional status in all patients.

Studies on low-dose oral contraceptives: cervical mucus and plasma hormone changes in relation to circulating D-norgestrel and 17alpha ethynyl-estradiol concentrations.

A study was undertaken to determine the effects of a low-dose oral contraceptive comprising 150 mug of D-norgestrel and 30 mug of 17alpha-ethynyl estradiol (Microgynon) on the plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17BETA-ESTRADIOL, AND PROGESTERONE AND ON THE PHYSICAl properties of cervical mucus. Samples of blood and cervical mucus were obtained from three women during a treated cycle and the immediately-following "withdrawal" cycle. Specific radioimmunoassay methods were used to determine LH, FSH, 17beta-estradiol, and progesterone levels in treated and withdrawal cycles, and D-norgestrel and 17alpha-ethynyl estradiol in samples obtained during treated cycles. The concentration of synthetic steroids was also measured in blood samples obtained before and 1 hour after ingestion of the contraceptive to determine the maximal daily variation. The results indicated that the contraceptive action of this combined low-dose oral contraceptive is mediated through suppression of ovulation and by rendering the cervical mucus impenetrable to sperm. Plasma FSH levels appeared to be one of the most sensitive indices of suppression. Determination of D-norgestrel and 17alpha-ethynyl estradiol showed that 3 to 4 days were required to reach maximal plasma levels and that daily fluctuations were considerable. Withdrawal of the pill resulted in an immediate return to ovulatory cycles in all three subjects studied.

Comparison of plasma hormone changes using a "conventional" and a "paper" pill formulation of a low-dose oral contraceptive.

Two formulations of a low-dose oral contraceptive (Microgynon: 150 microgram of levonorgestrel [NG] +30 micrograms of ethynylestradiol [EE2]) were studied. The first was the "conventional" pill; the second was a "paper" pill prepared by evaporation of aliquots of a solution of the component steroids onto squares of edible cellulose separated by perforations, similar to a sheet of postage stamps. The effects of the two formulations on plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-estradiol (E2), and progesterone were compared. Samples of blood were obtained from five women during a treatment period on the "conventional" pill and from five on the "paper" pill. When possible, blood samples were also obtained from a "control" cycle of each of these female subjects. Plasma LH, FSH, E2, and progesterone levels were determined by specific radioimmunoassay methods during control and treatment periods and NG and EE2 levels during treatment periods. Eight-hour plasma profiles for NG and EE2 at the beginning and in the later stage of the treatment periods were obtained and these samples were also analyzed for LH, FSH, E2, and progesterone. Results showed that with one exceptcrogynon were equally effective in suppressing ovulation. As in a previous study, FSH levels appeared to be one of the most sensitive indices of suppression.

P50 suppression in recent-onset schizophrenia: clinical correlates and risperidone effects.

Chronic schizophrenic patients often do not suppress the auditory P50 component of the event-related potential to the second of 2 clicks, presented 500 ms apart, suggesting a loss of normal inhibition. This study attempted to replicate the P50 suppression deficit in patients with recent-onset schizophrenia and to examine whether P50 is related to clinical symptoms or is affected by an atypical antipsychotic medication. Data from 22 recent-onset schizophrenia patients and 11 normal controls revealed that disruption in P50 suppression is present during the early stages of illness. In addition, impaired P50 suppression covaried with clinical ratings of anxiety, depression, and anergia; results also suggested that the P50 inhibitory deficit may be related to the degree of patients' attentional impairment. Finally, risperidone, compared with a typical antipsychotic medication, improved inhibition of P50 to the second click. These results support P50 suppression as a measure of disordered neurocognition in schizophrenia.

Etiology and consequences of respiratory failure in thermally injured patients.

Inhalation injury predisposes burn patients to pneumonia, respiratory failure, and death, but the incidence and consequences of respiratory failure in the absence of inhalation injury are not well known. In a review of 529 burn patients admitted over a 4-year period, patients with inhalation injury had a 73% incidence of respiratory failure (hypoxemia, multiple pulmonary infections, or prolonged ventilator support) and a 20% incidence of adult respiratory distress syndrome (ARDS). In patients without inhalation injury, respiratory failure developed in 5% of patients and ARDS in 2% (both p < 0.001). Patients with respiratory failure display a high incidence of multiple organ failure and mortality (27% to 50%), regardless of the presence of inhalation injury. All patients who died had multiple organ failure. This review demonstrates that respiratory failure, regardless of its cause, frequently leads to multiple organ failure and death. Inhalation injury, in the absence of respiratory failure, does not appear to contribute to mortality.

Necrotizing group A streptococcal infections associated with streptococcal toxic shock syndrome.

BACKGROUND: Group A streptococci (GAS) cause a variety of life-threatening infectious complications, including necrotizing fasciitis (NF), purpura fulminans (PF), and streptococcal toxic shock syndrome (strepTSS), in which bacteremia is associated with shock and organ failure. METHODS: We reviewed our experience in the management of patients with necrotizing GAS infections from 1991 to 1995. RESULTS: Eight adult patients (6 NF, 2 PF) were identified. Patients presented with fever, leukocytosis, and severe pain, and rapidly developed shock and organ dysfunction. The diagnosis of strepTSS was confirmed in 6 cases. A total of 54 surgical procedures were required, including widespread debridements and amputations. Two patients died (25%). CONCLUSIONS: Recognition of the need for aggressive diagnosis and surgical treatment of this most rapidly progressive surgical infection is necessary for successful management.

Burn center management of necrotizing soft-tissue surgical infections in unburned patients.

BACKGROUND: Patients with necrotizing soft-tissue infections present great challenges in management from initial presentation through definitive care. Because burn centers concentrate expertise in critical care, wound management, and rehabilitation, we examined the effectiveness of burn center care for patients with necrotizing infections. METHODS: We reviewed our burn center's experience with all patients admitted from 1990 through 1999 with a primary diagnosis of necrotizing fasciitis (NF) or Fournier's gangrene (FG). RESULTS: Fifty-seven patients were identified, 18 with FG and 39 with NF. Patients had a high incidence of preexisting medical problems, including diabetes (37%), obesity defined as greater than 20% above ideal body weight (33%), and hypertension (33%). Seven of 57 (12%) patients died. Patients required a mean of 4.1 operative procedures (range 1 to 15) for definitive wound closure. The mean length of stay (survivors only) was 28.5 days, (range 3 to 70). Although costs increased throughout this period, a formal program of cost-containment resulted in no increase in actual charges per day, from a mean of $4,735 in 1991 to $5,202 in 1999. CONCLUSIONS: Burn centers can provide successful and cost-effective acute care, definitive wound closure, and rehabilitation for patients with NF and FG.

Is immediate chest radiograph necessary after central venous catheter placement in a surgical intensive care unit?

BACKGROUND: Current standard of care dictates that central venous catheter (CVC) insertion should be followed by an immediate chest radiograph to confirm appropriate position and rule out complications. We hypothesized that a subset of monitored intensive care unit patients exists that is at low risk for complications and might safely have radiographic evaluation of line placement deferred until the next scheduled radiograph. METHODS: Data regarding patient and procedural characteristics were obtained prospectively for 184 CVC placed between March 1, 1998, and June 30, 1999. Retrospective data regarding complications were obtained by chart review for an additional 174 CVC placed during the study period but for which data sheets were not completed. All procedures were followed by chest radiography. RESULTS: We documented a complication rate of 9% with the vast majority (25 of 31, 81%) of complications consisting of incorrect positioning. The number of needle passes was greater in the group suffering pneumothorax and arterial puncture than the uncomplicated group (5.6 versus 1.9, P = 0.008). "Straightforward" operator gestalt (P = 0.04) and number of needle passes <3 (P = 0.03) were factors correlating with the absence of complications. These factors had negative predictive values of 94% and 96%, respectively. CONCLUSION: Placement of CVC is safe in experienced hands. In monitored intensive care unit patients who undergo a "straightforward" procedure with <3 needle passes, chest radiograph can be safely deferred until the next scheduled examination.

Who gets what treatment for obesity? A survey of GPs in Scotland.

OBJECTIVE: To describe the types and delivery of obesity treatment currently favoured by General Practitioners (GPs) working in Scotland. DESIGN: Representative cross-sectional survey using a postal questionnaire which included case stories as stimuli for questions about the GPs' nutrition guidance to overweight female patients. SUBJECTS: A systematic sample of 1400 general practitioners (GPs) from a total of 3593 GPs working in Scotland in 1997. RESULTS: From 1363 eligible GPs, 609 returned the full questionnaire and a further 132 took part in a telephone mini-interview. Net response was 54.4% (741/1363). Almost half of the GPs (45.6%) reported that they had read the recent national clinical guideline for integrating obesity prevention with weight management (SIGN 1996). The majority of GPs (89.6%) agreed that nutrition has an important role to play in the management of disease and 82.4% agreed that they can offer healthy eating advice to patients. However, only 34.8% of GPs believed that they had been successful in treating overweight patients. Routinely used treatments involve either a dietitian, practice nurse and/or a commercial slimming group and realistic weight loss was considered one criteria of successful treatment by some GPs. Age, year qualified and location of practice were found to have little influence over variations in GP treatment while weak associations between gender of GP and treatment were found. CONCLUSIONS: The readership of the clinical guidelines in Scotland has been moderate so far although a multidisciplinary approach to obesity treatment is recognised. Further investigations of any relationships between nutrition education-obesity treatment are needed.

Studies on low dose oral contraceptives: plasma hormone changes in relation to deliberate pill ('Microgynon 30') omission.

PIP: The effects of deliberate omission of a Microgynon 30 (150 mcg of levonorgestrel and 30 mcg of ethinyl estradiol) tablet in the early and latter course of the pills were investigated by hormonal profiles (published figuratively) of luteinizing hormone, follicle stimulating hormone (FSH), estradiol 17-beta, and progesterone. 3 women deliberately missed Day 19, and blood samples were drawn from Day 17-24; 7 women deliberately omitted Day 4 treatment, and their blood was drawn from Day 1-7. Blood levels, contrary to previous findings which noted a sharp rise in FSH and near zero titers of steroids after omission of a Microgynon 30 tablet unintentionally, did not show any marked rise either early or late in the cycle omission. Cervical mucus examined in 6 of the subjects displayed physical characteristics associated with an uninterrupted ancillary contraceptive effect.^ieng

Second-order analysis of space-time clustering.

We consider the problem of detecting and describing space-time interaction in point process data. We extend existing second-order methods for purely spatial point process data to the spatial-temporal setting. This extension allows us to estimate space-time interaction as a function of spatial and temporal separation, and provides a useful reinterpretation of a popular test, due to Knox, for space-time interaction. Applications to simulated and real data indicate the method's potential.

Glycosaminoglycan hydrogels as supplemental wound dressings for donor sites.

Chemically crosslinked glycosaminoglycan (GAG) hydrogel films were evaluated as biointeractive dressings in a porcine model for donor-site autograft wounds. Multiple 5 x 5 x 0.03 cm wounds were created on the dorsum of pigs. Half of the wounds were treated with a GAG film plus an occlusive dressing (Tegaderm), whereas the other half were treated with Tegaderm alone. At 3, 5, or 7 days after surgery, the partially healed wounds were excised and evaluated histologically for three animals at each time point. By day 3, epithelial cells had proliferated and migrated from wound edges and from epithelial islands associated with residual hair follicles to begin to cover the wound bed. A statistically significant increase in coverage was observed for GAG + Tegaderm-dressed wounds than for those with Tegaderm alone at day 3 and day 5 post-surgery. By day 7, all treatment groups were completely healed. Thus, GAG hydrogels accelerated wound healing by enhancing re-epithelialization.

Return to work as a measure of outcome in adults hospitalized for acute burn treatment.

Rehabilitation of patients with burn injuries is receiving renewed interest because survival has improved, and health reform has mandated outcomes assessment. To determine factors affecting return to work, a survey was conducted among 234 employed patients treated from 1986 through 1993. The mean burn size was 13.3% total body surface area. Patients returned to work in a mean of 14.3 weeks; a number initially returned to light-duty or part-time jobs as a "bridge" to full-time employment. Length of hospitalization, number of surgeries, total and full-thickness burn size, and subjective assessments by patients of their functional ability correlated with time off work. Patients with health insurance were more likely to resume work than was expected, whereas those covered by Medicaid and those involved in injury-related lawsuits were less likely to return to work. It is hoped that this information can be used to design interventions aimed at improving this outcome of burn treatment.

The 1997 Lindberg Award. Effects of burn injury on bone and growth in a mouse model.

Bone growth and remodeling are inhibited by severe burns in adult and pediatric patients, resulting in alterations in linear growth, bone mass, osteoporosis, and increased risk for pathologic fractures. This study of a mouse model of burn injury showed skeletal changes similar to those reported in patients with burn injuries. Baseline, control, sham, and burned mice were injected with fluorescent markers calcein and tetracycline for histomorphometric analysis. Total femur dry and ash weights and total calcium content were significantly lower 10 days after burn injury compared with sham and control animals. There also were decreases in the percentage of fluorochrome-labeled bone surfaces and bone formation rates in the burn-injured mice compared with control and sham mice; however, there were no differences in the mineral apposition rates. This model now provides an opportunity to examine cellular and molecular mechanisms contributing to skeletal pathology in a well-defined burn injury model.

Resuscitation of thermally injured patients with oxygen transport criteria as goals of therapy.

Resuscitation from shock based on oxygen transport criteria has been widely used in trauma and surgical patients, but has not been examined in thermally injured patients. To study the possible efficacy of this type of resuscitation, the oxygen transport characteristics of burn resuscitation were studied in nine adults, of whom six had inhalation injuries, with a mean burn size of 45% total body surface area and a mean age of 33.4 years, who were resuscitated based on oxygen transport criteria. Pulmonary artery balloon flotation catheters were placed and hemodynamic and oxygen transport parameters (Fick method) were measured hourly for 6 hours. Patients received fluid boluses in addition to resuscitation calculated by the Parkland formula, until the pulmonary artery wedge pressure reached 15 mm Hg, after which dobutamine infusions (5 micrograms/kg/min) were initiated. Cardiac index increased from 2.51 to 6.57 L/min/m2 (p < 0.05), whereas systemic vascular resistance fell from 1534 to 584 dyne sec/cm5 (p < 0.05). Oxygen delivery (DO2I) and oxygen consumption (VO2I) indexes increased significantly during the study period (573 +/- 47 to 1028 +/- 57, and 132 +/- 8 to 172 +/- 16 ml/min/m2, respectively; p < 0.05). VO2I appeared dependent on DO2I at levels of DO2I less than 800 ml/min/m2. In this study, depressed cardiovascular function in patients with burn injuries responded to volume loading and inotropic support much as it does in patients with shock of other etiologies. Whether oxygen transport-based resuscitation is effective in improving survival or the incidence of multiple organ failure is unknown and will need to be evaluated in randomized trials.