Hypertensive action of 18-hydroxydeoxycorticosterone.

18-Hydroxydeoxycorticosterone is an adrenal steroid hormone causing salt and water retention and is secreted in greatly increased amounts in response to the pituitary hormone adrenocorticotropic hormone. Its production is abnormally high in some forms of hypertension in man and rat. Direct proof that 18-hydroxydeoxycorticosterone is capable of causing hypertension is present. Daily subcutaneous injections of 200 micrograms, a low physiological dose, significantly increase the blood pressure of unilaterally nephrectomized saline-treated rats after 2 weeks. This strengthens the hypothesis that 18-hydroxydeoxycorticosterone contributes to the etiology of hypertension, possibly by a mechanism involving stressinduced release of adrenocorticotropic hormone.

Restricted diastolic opening of the mitral leaflets in patients with left ventricular dysfunction: evidence for increased valve tethering.

OBJECTIVES: We tested the hypothesis that patients with incomplete systolic mitral leaflet closure (IMLC: apically displaced coaptation) also have restricted diastolic leaflet opening that is independent of mitral inflow volume and provides evidence supporting increased leaflet tethering. BACKGROUND: Competing hypotheses for functional mitral regurgitation (MR) with IMLC include global left ventricular (LV) dysfunction per se (reduced leaflet closing force) versus geometric distortion of the mitral apparatus by LV dilation (augmented leaflet tethering). These are inseparable in systole, but restricted leaflet motion has also been observed in diastole, and attributed to reduced mitral inflow. METHODS: Diastolic mitral leaflet excursion and orifice area were measured by two-dimensional echocardiography in 58 patients with global LV dysfunction, 36 with and 22 without IMLC, compared with 21 normal subjects. The biplane Simpson's method was used to calculate LV ejection volume, which equals mitral inflow volume in the absence of aortic regurgitation. RESULTS: The diastolic mitral leaflet excursion angle was markedly reduced in patients with IMLC compared with those without IMLC, whose ventricles were smaller, and normal subjects (17 +/- 10 degrees vs. 58 +/- 13 degrees vs. 67 +/- 8 degrees, p < 0.0001). Excursion angle was dissociated from mitral inflow volume (r2 = 0.04); excursion was reduced in patients with IMLC despite a normal inflow volume in the larger ventricles with MR (60 +/- 25 vs. 61 +/- 12 ml in normal subjects, p = NS), and excursion was nearly normal in patients without IMLC despite reduced inflow volume (40 +/- 10 ml, p < 0.001 vs. normal subjects). The anterior leaflet when maximally open coincided well with the line connecting its attachments to the anterior annulus and papillary muscle tip (angular difference = 3 +/- 7 degrees vs. 25 +/- 9 degrees vs. 32 +/- 10 degrees in patients with and without IMLC vs. normal subjects, p < 0.0001). In patients with IMLC, the leaflet tip orifice was smaller in an anteroposterior direction but wider than in the other groups, giving a normal total area (6.8 +/- 1.8 vs. 7.1 +/- 1.2 vs. 6.9 +/- 0.8 cm2, p = NS). CONCLUSIONS: Patients with LV dysfunction and systolic IMLC also have restricted diastolic leaflet excursion that is independent of inflow volume, coincides with the tethering line connecting the annulus and papillary muscle and reflects limitation of anterior motion relative to the posteriorly placed papillary muscles without a decrease in total orifice area. These observations are consistent with increased tethering by displaced mitral leaflet attachments in the dilated ventricles of patients with IMLC that can restrict both diastolic opening and systolic closure.

How best to estimate the global burden of pertussis?

In most countries, pertussis surveillance is inadequate for accurately estimating numbers of cases or deaths. Good estimates are needed to help set priorities for vaccination programmes. We aimed to develop a simple, reliable, and explicit method for estimating pertussis cases and deaths for children under 15 years to calculate the global disease burden in 1999. We estimated the proportion of susceptible children becoming infected in countries with poor vaccination coverage (<70%) in 1999 at 30% by 1 year, 80% by 5 years, and 100% by 15 years of age and for countries with good coverage (> or =70%) at 10% by 1 year, 60% by 5 years, and 100% by 15 years. Vaccine efficacy was estimated at 80% for preventing infection and 95% for preventing deaths. We used UN population estimates and vaccination coverage reported to WHO (adjusted for specific survey data if available). Case fatality ratios for countries with high and low child mortality were derived from published and unpublished work. For some countries with good vital events registration we used reported deaths adjusted for underascertainment. In 1999 there were an estimated 48.5 million pertussis cases in children worldwide. Deaths from pertussis were estimated at 390000 and at 295000 after adjustment for local data sources. Based on this approach, disability-adjusted life years from pertussis (12.7 million) in 2000 exceeded those of other preventable diseases such as lung cancer (11.4 million) and meningitis (5.8 million). This simple approach yields estimates that can be used for setting vaccination programme priorities. Better data are needed on the public health importance of pertussis in high mortality countries, the benefits of incomplete vaccination, and the harm from delayed vaccination.

Diagnosis of pericardial effusions from routine gated blood-pool imaging.

Gated blood-pool scintigraphy (GBPS) is often obtained as the initial test to evaluate symptoms suggestive of left ventricular dysfunction. Since large pericardial effusions may also cause such symptoms, the ability to recognize them on routine GBPS is of clinical importance. Characteristic features of the "halo" sign surrounding the cardiac blood pool were developed, based on the GBPS of patients with known pericardial effusions. These criteria were then applied blindly to 154 consecutive patients who underwent both GBPS and echocardiography. All five patients with large effusions (approximately greater than 500 ml) were correctly identified by GBPS (sensitivity 100%); for patients with moderate effusions (approximately 150-500 ml), the sensitivity was only 33% (3/9). There were three false positives (specificity 98%). We conclude that large pericardial effusions can be identified with high sensitivity and specificity on routine GBPS. Although echocardiography remains the method of choice for the diagnosis of effusions, inspection for characteristics suggesting their presence on GBPS should be part of routine interpretations.

Poliomyelitis eradication.

Since the poliomyelitis eradication program began in 1988, the number of poliovirus infected continents and countries have decreased from five to two and from greater than 100 to 53, respectively. A nearly 90% reduction in the incidence of polio has been achieved with a corresponding decrease in virus genomic heterogeneity. Major challenges to eradication remain in south Asia and Africa in those areas with hot and humid climates, high population density, and high birth rates. Of particular concern are countries with ongoing social unrest and poor health infrastructure. With the approaching eradication of polio, post-eradication issues are now being addressed. The World Health Organization (WHO) draft plan for containment of wild polioviruses has been published for comment. Commissions and committees for certification of eradication have been established. Still under discussion is the question of the appropriate strategy for stopping oral polio vaccine (OPV) immunization. Studies are underway to determine whether vaccine-derived polioviruses will continue to circulate after OPV cessation and the potential disease consequences of that circulation.

Reduction by 9-tetrahydrocannabinol in the blood pressure of hypertensive rats bearing regenerated adrenal glands.

A suspension of (-)-Delta(9)-trans-tetrahydrocannabinol (Delta(9)-THC) (3 mg/kg body wt) was administered daily for one week by i.p. injection to female rats showing the syndrome of adrenal regeneration hypertension (ARH). Other ARH rats received no injections or injections of vehicle only. On the first day, Delta(9)-THC decreased the average blood pressure by 38+/-6 mmHg 1 h, 31+/-5 mmHg 3 h, and 11+/-5 mmHg 5 h after injection (n=0). On subsequent days the acute effect disappeared, but statistically highly significant decreases were observed between the blood pressures of the Delta(9)-THC-treated group and those of the other two groups. Plasma corticosterone concentrations, measured on the eighth day of treatment, one hour after injection time, averaged 26.+/-2.7 mug/100 ml in the untreated animals, 26.6+/-2.0 mug/100 ml in the vehicle-injected animnals, and 21.3+/-2.4 mug/100 ml in the animals injected with Delta(9)-THC. The findings indicate that Delta(9)-THC, at a moderate dose for the rat, is capable of lowering the blood pressure in rats suffering from adrenal regeneration hypertension and that chronic administration of Delta(9)-THC does not appear to stimulate the pituitary-adrenal axis, in contrast to reported effects of acute administration (Barry, Perhach & Kubena, 1970).

ACTH and adrenal aerobic glycolysis. I: Effects of O-nitrophenylsulphenyl and other ACTH analogues, vasoactive intestinal peptide and human parathyroid hormone(1-34) on lactic acid, steroid and cyclic AMP production by mouse adrenocortical cells.

The structural requirements in the ACTH molecule for evocation of the glycolytic response in suspensions of mouse adrenal cells were investigated by examining the effects of analogues containing modifications at positions 8, 9 and 10 and of peptides containing homologies with the amino-terminal segment of ACTH. Introduction of a nitrophenylsulphenyl (NPS) group into the tryptophan moiety at position 9 of ACTH(1-24) greatly reduced both the potency and the capacity for maximal glycolytic response. It also virtually abolished cyclic AMP formation. In contrast, the capacity for a maximal steroidogenic response remained unimpaired in the NPS derivative, although steroidogenic potency was reduced to 0.4% of that of ACTH(1-24). Replacement of the tryptophan moiety with phenylalanine had intermediate inhibitory effects on glycolysis and steroid output; replacement with alanine virtually abolished both these responses. Replacement of arginine in position 8 with lysine in the Phe9 analogue caused a fifty-fold increase in glycolytic potency, but rendered it steroidogenically inactive. Cyclic AMP production was abolished in the Ala9 analogue and greatly impaired in the Phe9 and Lys8,Phe9 analogues. Replacement of the glycine moiety in position 10 with L-alanine, D-alanine, beta-alanine or alpha-aminoisobutyric acid had little or no effect on steroidogenic or glycolytic capacity, although potency was reduced with all substitutions excepting L-alanine.(ABSTRACT TRUNCATED AT 250 WORDS)

ACTH and adrenal aerobic glycolysis. II: Effects of aminoterminal peptide fragments on lactic acid and steroid production by mouse adrenocortical cells.

The effects of shortening the ACTH molecule from either end of the peptide chain on adrenal glycolysis and steroidogenesis were examined in mouse adrenal cell suspensions. Shortening the (1-24) sequence to (1-17), (1-16) and (1-14), thereby interfering with the basic tetrapeptide (15-18) assigned to the address message, progressively reduced both glycolytic and steroidogenic potencies by four, six and ten orders of magnitude respectively, without impairing the capacity for maximal excitation. The glycolytic potency of the (1-18) sequence, which was amidated at the C-terminal, equalled that of ACTH (1-24), but the steroidogenic potency was reduced by an order of magnitude. The (1-13) sequence of alpha-MSH, which contains substitutions at both terminals, had glycolytic and steroidogenic potencies intermediate between those of ACTH(1-16) and ACTH(1-17). Deletion of Ser1,Tyr2 from ACTH(1-18)-NH2 reduced both potencies by an order of magnitude. ACTH(11-24) and (7-38) were inactive or inhibitory. The capacity for excitation was further examined by comparing responses to peptide fragments (1-4), (1-10), (1-13), (4-10), (4-11), (5-10), (5-14), (7-13) and (11-24) at a concentration of 1 mmol/l. All fragments, excepting (1-4), (5-10) and (11-24) were active. The activities of fragments (5-14) and (7-13), as opposed to (5-10), suggest that the requirements for methionine in position 4 may be replaced by the (11-13) tripeptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of sodium transport by toad skin incubated with natural derivatives of corticosterone and deoxycorticosterone.

The effects on sodium transport of several steroids physiologically secreted or possibly involved in pathological disorders were compared with those of aldosterone in the isolated toad skin. The 18-hydroxylated derivatives of deoxycorticosterone and corticosterone, in contrast to their parent compounds, significantly enhanced sodium transport at a concentration of 50 nmol/l. In the presence of glucose, 18-hydroxydeoxycorticosterone increased transepithelial potential difference, as did aldosterone. The 19-nor derivative of deoxycorticosterone, recently implicated in the aetiology of adrenal regeneration hypertension, stimulated sodium transport, unlike 19-nor-corticosterone and 16-oxo-androstenediol. Insulin significantly increased sodium transport in aldosterone-treated skin and lowered the resistance. The natriferic response to vasopressin was potentiated fivefold by exposure of the skin to aldosterone and was doubled in skin exposed to 19-nor-deoxycorticosterone. We conclude that 18-hydroxylated adrenocortical steroids can play a physiological role in salt retention; furthermore, these steroids, as well as 19-nor-deoxycorticosterone, could be involved in pathological conditions such as low renin hypertension. Caution should be exercised in evaluating mineralocorticoid potency solely in terms of the urinary sodium to potassium ratio.

Lactic acid and steroid production by intact mouse adrenal glands and cell suspensions: effects of nucleotide derivatives and substrates.

The effects of the dibutyryl derivatives of cyclic GMP and cyclic AMP on lactic acid and steroid production were compared in intact mouse adrenal glands at concentrations of 0.5-1 mmol/l and in mouse adrenal cell suspensions at concentrations of 0.01-1 mmol/l. The dibutyryl derivative of cyclic GMP had little or no effect on lactic acid production in either tissue preparation. It caused a slight stimulation of corticosteroid output in intact glands at a concentration of 1 mmol/l, amounting to one-tenth of the response observed with 1 mM-dibutyryl cyclic AMP. Dose-dependent increases in lactic acid and steroid production were obtained with dibutyryl cyclic AMP in cell suspensions. AMP and GMP increased lactic acid but not steroid production. All the substrates tested (glucose, glucose-6-phosphate, fructose, fructose-6-phosphate, fructose-1,6-diphosphate, 10 mmol/l; pyruvate and glycerol, 20 mmol/l) stimulated basal glycolysis in intact glands and cell suspensions and none affected basal steroid production significantly. By far the greatest increase in lactic acid production was noted with fructose-1,6-diphosphate. However, only glucose and, in unsectioned glands, pyruvate exerted a potentiating effect on the glycolytic response to ACTH. Glucose potentiated the steroidogenic response to ACTH also, but only in intact glands. The relative ineffectiveness of dibutyryl cyclic GMP is in accord with the species-dependent differing responses to the free form of the cyclic nucleotides noted in mouse and rat adrenal glands. The substrate requirements are in keeping with a rate-limiting role of phosphofructokinase and an action of ACTH at some site between the entry of glucose into the cell and the formation of fructose-1,6-diphosphate.

Changing the infection control paradigm from off-line to real time: the experience at Millard Fillmore Health System.

In 1993, several departments at Millard Fillmore Health System joined efforts to initiate a new approach to infection control. The main emphasis of this program is to move infection control to a real-time mode to manage patient outcomes daily. The principal objective was to decrease the number of nosocomial infections by 10%, with a particular emphasis on surgical-site infections. Besides real-time surveillance, we are critically evaluating several aspects of the management of nosocomial infections. High-level computer support has been the frame-work upon which this program was built. We have microcomputers that are linked directly to microbiology, pharmacy, billing, and admissions, downloading data several times daily. An expert software system merges all of the data, and from this we can target patients for real-time interventions. The computer system allows all inpatients to be screened for either infection control or antibiotic management interventions on a daily basis, with minimal time being spent on data collection and maximal efforts devoted to interventions at the bedside. Additionally, the infection management program will assist in maintaining the extraordinarily low expenditures on antimicrobial agents. During 1993, the Millard Fillmore Health System spent $924,884 on antibiotics, an amount approximately 50% that of comparably sized hospitals.

Effects of adrenal steroids and their reduced metabolites on hippocampal long-term potentiation.

We studied the effects of steroid hormones on the hippocampal long-term potentiation (LTP), a putative mechanism of neuronal plasticity and memory storage in the CNS. In vivo experiments were performed in rats under chloral hydrate anesthesia (0.4 mg/kg i.p.). All animals were adrenalectomized 48 h before recording. LTP was induced after priming tetanic stimulation at the perforant pathway (PP) and single pulse field potentials were obtained from the dentate gyrus (DG). The excitatory post-synaptic potential (EPSP) slope and population spike (PS) amplitude were analyzed before and after the i.v. injection of the steroids and after the induction of LTP, and followed up to 1 h. Results obtained with the hormones were compared with matched control animals injected with vehicle alone, Nutralipid 10%. Previous results from our laboratory showed that deoxycorticosterone (DOC) decreased the magnitude of the EPSP at all times after priming stimulation and the PS decreased during the first 30 min of the LTP. Corticosterone decreased the EPSP in the first 15 min and the PS during the first 30 min after priming stimuli. In these experiments the mineralocorticoids aldosterone and 18-OH-DOC elicited a decrease of the EPSP at all times post-train; and no significant difference against vehicle was observed in the PS. Post-injection values were not changed except for 18-OH-DOC at a dose of 1 mg, where a decrease of both the EPSP (P less than 0.01) and the PS (P less than 0.02) was observed against vehicle. ATH-progesterone at 0.1 mg/rat also decreased the EPSP values significantly after priming stimulation and no significant changes against vehicle were observed in the PS. These results show that adrenal steroids can modulate hippocampal LTP, that they can act at different neuronal loci and with different time courses in the development of the phenomena.

Modulation by adrenal steroids of limbic function.

The effects of various steroid hormones on the long-term potentiation (LTP) of the rat hippocampus were evaluated. LTP was elicited in the dentate gyrus of adrenalectomized animals with priming tetanic stimulation (200 Hz-0.03 cps) of its main afferent, the perforant pathway. Single pulse EPSP (excitatory post-synaptic potential) slope, and PS (population spike) amplitude values were compared before and after the i.v. injection of the hormones and subsequently after the priming stimulation every 15 min up to 1 h. 18-OH-deoxycorticosterone (18-OH-DOC) produced a significant decrease of the EPSP LTP and arrested the PS enhancement in comparison with vehicle at every time post-tetanic stimulation. Its 21-acetate derivative produced a moderate decrease of the EPSP and had no effect on the PS LTP in comparison with vehicle. Deoxycorticosterone (DOC) exhibited similar effects on the EPSP although less marked than with 18-OH-DOC while the PS only decreased in the first 30 min post-train. Corticosterone decreased both EPSP and PS for the first 15 and 30 min after priming stimulation, respectively, matching values with those of vehicle afterwards. Its 21-acetate produced an initial decrease of the EPSP and had no effect on the PS LTP. Allo-tetrahydro-DOC produced little, if any, initial enhancement of the PS LTP in comparison with vehicle. These results show that the adrenal steroids tested can modulate hippocampal LTP, a plastic phenomenon in the mammalian CNS which is known to be related to memory and learning processes. Moreover, adrenal steroids can independently modify the PS or EPSP components of the LTP, suggesting different loci of action at the neuronal level.

Assessing antibacterial pharmacoeconomics in the intensive care unit.

Intensive care units (ICUs) represent areas of high use of antibacterials and other pharmacy goods and services. Many institutions view their ICUs as a target for drug-use surveillance and cost-containment programmes. Economic assessment of antibacterial interventions in the ICU should include all direct costs and patient outcomes. Nonetheless, many of these institutions focus their efforts at reducing antibacterial costs without considering the consequences of these actions. It is possible that devoting more resources to antibacterials can have an overall positive economic impact if more appropriate antibacterial use reduces length of stay, decreases bacterial resistance or lowers frequency of adverse complications. Two consequences of antibacterial use which can result in substantial economic burdens to institutions are drug-induced complications (toxicities and adverse events) and the development of antibacterial-resistant organisms. These events are logical targets for performing pharmacoeconomic studies to evaluate appropriate and inappropriate antibacterial use. Either of these problems can increase length of stay, which is the single most important variable influencing the overall cost of patient care. The primary goal of patient care is to hasten patients' clinical improvement. This will result in decreased antibacterial acquisition costs, decreased lengths of ICU and hospital stays, and ultimately decreased consumption of hospital resources. These can be accomplished by using strategies to guide antibacterial use in order to reduce failures, adverse events, toxicity and antimicrobial resistance.

Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus.

Treatment factors predictive of clinical and microbiological outcomes and the relationship between a pneumonia scoring system and clinical outcomes in vancomycin-treated patients with a Staphylococcus aureus-associated lower-respiratory-tract infection (LRTI) were studied. A computer database review identified patients for whom S. aureus was isolated from a respiratory-tract specimen between January 1 and December 31, 1998, and who had antimicrobials ordered within 72 hours of isolation of that organism. Through further review of individual patient charts, this group was restricted to those treated with vancomycin for a documented S. aureus-associated LRTI. Classification-and-regression-tree (CART) modeling was performed to determine which clinical variables were correlated with clinical outcomes and microbiological outcomes. Median changes in clinical pneumonia scores from baseline in two patient groups (those with clinical success and those with clinical failure) were compared. Seventy patients met the study criteria. CART modeling found that both outcomes were associated with area under the inhibitory curve (AUIC). The pneumonia scoring system was predictive of eventual clinical success as early as day 3 of treatment; having at least a 4-point decrease in the pneumonia score by day 3 was correlated with an 87% clinical success rate. Both AUIC and a pneumonia scoring system were useful for predicting clinical and microbiological outcomes of vancomycin therapy in patients with LRTIs caused by S. aureus.

Use of benchmarking techniques to justify the evolution of antibiotic management programs in healthcare systems.

OBJECTIVE: To apply basic benchmarking techniques to hospital antibiotic expenditures and clinical pharmacy personnel and their duties, to identify cost savings strategies for clinical pharmacy services. DESIGN: Prospective survey of 18 hospitals ranging in size from 201 to 942 beds. Each was asked to provide antibiotic expenditures, an overview of their clinical pharmacy services, and to describe the duties of clinical pharmacists involved in antibiotic management activities. Specific information was sought on the use of pharmacokinetic dosing services, antibiotic streamlining, and oral switch in each of the hospitals. RESULTS: Most smaller hospitals (< 300 beds) did not employ clinical pharmacists with the specific duties of antibiotic management or streamlining. At these institutions, antibiotic management services consisted of formulary enforcement and aminoglycoside and/or vancomycin dosing services. The larger hospitals we surveyed employed clinical pharmacists designated as antibiotic management specialists, but their usual activities were aminoglycoside and/or vancomycin dosing services and formulary enforcement. In virtually all hospitals, the yearly expenses for antibiotics exceeded those of Millard Fillmore Hospitals by $2,000-3,000 per occupied bed. In a 500-bed hospital, this difference in expenditures would exceed $1.5 million yearly. Millard Fillmore Health System has similar types of patients, but employs clinical pharmacists to perform streamlining and/or switch functions at days 2-4, when cultures come back from the laboratory. CONCLUSIONS: The antibiotic streamlining and oral switch duties of clinical pharmacy specialists are associated with the majority of cost savings in hospital antibiotic management programs. The savings are considerable to the extent that most hospitals with 200-300 beds could readily cost-justify a full-time clinical pharmacist to perform these activities on a daily basis. Expenses of the program would be offset entirely by the reduction in the actual pharmacy expenditures on antibiotics.