Use of High Doses of Quetiapine in Bipolar Disorder Episodes are not Linked to High Activity of Cytochrome P4503A4 and/or Cytochrome P4502D6.

The use of quetiapine for treatment of bipolar disorders at a higher dosage than the licensed range is not unusual in clinical practice. Quetiapine is predominantly metabolised by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2D6. The large interindividual variability of those isozyme activities could contribute to the variability observed in quetiapine dosage. The aim of the present study is to evaluate if the use of high dosages of quetiapine in some patients, as compared to patients treated with a dosage in the licensed range (up to 800 mg/day), could be explained by a high activity of CYP3A4 and/or of CYP2D6. CYP3A4 activities were determined using the midazolam metabolic ratio in 21 bipolar and schizoaffective bipolar patients genotyped for CYP2D6. 9 patients were treated with a high quetiapine dosage (mean ± SD, median; range: 1467 ± 625, 1200; 1000-3000 mg/day) and 11 with a normal quetiapine dosage (433 ± 274, 350; 100-800 mg/day). One patient in the high dose and one patient in the normal dose groups were genotyped as CYP2D6 ultrarapid metabolizers. CYP3A4 activities were not significantly different between the two groups (midazolam metabolic ratio: 9.4 ± 8.2; 6.2; 1.7-26.8 vs 3.9 ± 2.3; 3.8; 1.5-7.6, in the normal dose group as compared to the high dose group, respectively, NS). The use of high quetiapine dosage for the patients included in the present study cannot be explained by variations in pharmacokinetics parameters such as a high activity of CYP3A4 and/or of CYP2D6.

Quetiapine dosage in bipolar disorder episodes and mixed states

OBJECTIVE: Although the maximal quetiapine doses in the published studies were restricted to 800 mg/day, higher quetiapine doses are not unusual in clinical practice. The aim of the present study was to evaluate the effectiveness, tolerability and clinical reasons associated to the use of high dosage of quetiapine (>800 mg), when used under routine clinical conditions, in a sample of bipolar disorder and schizoaffective bipolar inpatients. METHODS: Charts of all bipolar and schizoaffective adult inpatients, who had received quetiapine for a mood episode between 1999 and 2005 were retrospectively reviewed. These charts also included the assessment of manic and depressive symptoms on admission and at discharge using the Beck-Rafaelsen Mania Scale (MAS) and the Montgomery Asberg depression rating scale (MADRS), respectively. RESULTS: Data of 50 patients were analyzed. The overall F in repeated measures ANOVA revealed a significant MAS scores reduction between admission and discharge. MAS scores reduction did not differ between the high and low quetiapine groups. Similarly, a significant MADRS reduction was found. Again, no differences between the high and the low dose group were found. Logistic regression analysis of the 50 patients revealed only mixed episodes predicted high quetiapine dosage. CONCLUSIONS: The present study confirms quetiapine efficiency and tolerability in the treatment of bipolar episodes, even in doses > to 800 mg and found a link between quetiapine doses and mixed episodes

The effect of patient, provider and financing regulations on the intensity of ambulatory physical therapy episodes : a multilevel analysis based on routinely available data

Background: Many studies have found considerable variations in the resource intensity of physical therapy episodes. Although they have identified several patient-and provider-related factors, few studies have examined their relative explanatory power. We sought to quantify the contribution of patients and providers to these differences and examine how effective Swiss regulations are (nine-session ceiling per prescription and bonus for first treatments). Methods: Our sample consisted of 87,866 first physical therapy episodes performed by 3,365 physiotherapists based on referrals by 6,131 physicians. We modeled the number of visits per episode using a multilevel log linear regression with crossed random effects for physiotherapists and physicians and with fixed effects for cantons. The three-level explanatory variables were patient, physiotherapist and physician characteristics. Results: The median number of sessions was nine (interquartile range 6-13). Physical therapy use increased with age, women, higher health care costs, lower deductibles, surgery and specific conditions. Use rose with the share of nine-session episodes among physiotherapists or physicians, but fell with the share of new treatments. Geographical area had no influence. Most of the variance was explained at the patient level, but the available factors explained only 4% thereof. Physiotherapists and physicians explained only 6% and 5% respectively of the variance, although the available factors explained most of this variance. Regulations were the most powerful factors. Conclusion: Against the backdrop of abundant physical therapy supply, Swiss financial regulations did not restrict utilization. Given that patient-related factors explained most of the variance, this group should be subject to closer scrutiny. Moreover, further research is needed on the determinants of patient demand.

Distinct cytokine profiles of circulating mononuclear cells stimulated with Staphylococcus aureus enterotoxin A in vitro during early and late episodes of chronic osteomyelitis

We investigated the cytokine profile of peripheral mononuclear cells from chronic osteomyelitis (OST) patients following in vitro stimulation with staphylococcal enterotoxin A (SEA). We demonstrate that stimulation with SEA induced prominent lymphocyte proliferation and high levels of tumour necrosis factor (TNF)-α, interleukin (IL)-4 and IL-10 secretion in both OST and non-infected individuals (NI). Even though stimulation with SEA had no impact on IL-6 production in either patient group, the baseline level of IL-6 production by cells from OST patients was always significantly less than that produced by cells from NI. After classifying the osteomyelitic episodes based on the time after the last reactivation event as "early" (1-4 months) or "late" osteomyelitis (5-12 months), we found that increased levels of TNF-α and IL-4 in combination with decreased levels of IL-6 were observed in the early episodes. By contrast, increased levels of IL-10, IL-2 and IL-6 were hallmarks of late episodes. Our data demonstrate that early osteomyelitic episodes are accompanied by an increased frequency of "high producers" of TNF-α and IL-4, whereas late events are characterised by increased frequencies of "high producers" of IL-10, IL-6 and IL-2. These findings demonstrate the distinct cytokine profiles in chronic osteomyelitis, with a distinct regulation of IL-6 production during early and late episodes.

Hindsight judgement on ambiguous episodes of suspected infection in critically ill children: poor consensus amongst experts?

Few episodes of suspected infection observed in paediatric intensive care are classifiable without ambiguity by a priori defined criteria. Most require additional expert judgement. Recently, we observed a high variability in antibiotic prescription rates, not explained by the patients' clinical data or underlying diseases. We hypothesised that the disagreement of experts in adjudication of episodes of suspected infection could be one of the potential causes for this variability. During a 5-month period, we included all patients of a 19-bed multidisciplinary, tertiary, neonatal and paediatric intensive care unit, in whom infection was clinically suspected and antibiotics were prescribed ( n=183). Three experts (two senior ICU physicians and a specialist in infectious diseases) were provided with all patient data, laboratory and microbiological findings. All experts classified episodes according to a priori defined criteria into: proven sepsis, probable sepsis (negative cultures), localised infection and no infection. Episodes of proven viral infection and incomplete data sets were excluded. Of the remaining 167 episodes, 48 were classifiable by a priori criteria ( n=28 proven sepsis, n= 20 no infection). The three experts only achieved limited agreement beyond chance in the remaining 119 episodes (kappa = 0.32, and kappa = 0.19 amongst the ICU physicians). The kappa is a measure of the degree of agreement beyond what would be expected by chance alone, with 0 indicating the chance result and 1 indicating perfect agreement. CONCLUSION: agreement of specialists in hindsight adjudication of episodes of suspected infection is of questionable reliability.

Are tax subsidies for private medical insurance self-financing? Evidence from a microsimulation model for outpatient and inpatient episodes

This paper analyses whether or not tax subsidies to private medicalinsurance are self-financing by means of a structural approach. Weconstruct a simulation routine based on a microeconometric discretechoice model that allows us to evaluate the impact of premium changeson the utilisation of outpatient and inpatient health care services. Wesimulate the 1999 Spanish tax reform that abolished the tax deductionfor expenditures on private health insurance using a representativesample of the Catalan population. Prior to this reform, foregone taxrevenue arising from deductions after the purchase of private insuranceamounted to 69.2 M. per year. In contrast, the elimination of thesubsidies to private policies is estimated to generate an extra costfor the public sector of about 8.9 M. per year.

Cumulative frequency-dependent selective episodes allow for rapid morph cycles and rock-paper-scissors dynamics in species with overlapping generations.

Rock-paper-scissors (RPS) dynamics, which maintain genetic polymorphisms over time through negative frequency-dependent (FD) selection, can evolve in short-lived species with no generational overlap, where they produce rapid morph frequency cycles. However, most species have overlapping generations and thus, rapid RPS dynamics are thought to require stronger FD selection, the existence of which yet needs to be proved. Here, we experimentally demonstrate that two cumulative selective episodes, FD sexual selection reinforced by FD selection on offspring survival, generate sufficiently strong selection to generate rapid morph frequency cycles in the European common lizard Zootoca vivipara, a multi-annual species with major generational overlap. These findings show that the conditions required for the evolution of RPS games are fulfilled by almost all species exhibiting genetic polymorphisms and suggest that RPS games may be responsible for the maintenance of genetic diversity in a wide range of species.

Myocardial impairment in chronic hypoxia is abolished by short aeration episodes: involvement of K+ATP channels.

In vivo exposure to chronic hypoxia is considered to be a cause of myocardial dysfunction, thereby representing a deleterious condition, but repeated aeration episodes may exert some cardioprotection. We investigated the possible role of ATP-sensitive potassium channels in these mechanisms. First, rats (n = 8/group) were exposed for 14 days to either chronic hypoxia (CH; 10% O(2)) or chronic hypoxia with one episode/day of 1-hr normoxic aeration (CH+A), with normoxia (N) as the control. Second, isolated hearts were Langendorff perfused under hypoxia (10% O(2), 30 min) and reoxygenated (94% O(2), 30 min) with or without 3 microM glibenclamide (nonselective K(+)(ATP) channel-blocker) or 100 microM diazoxide (selective mitochondrial K(+)(ATP) channel-opener). Blood gasses, hemoglobin concentration, and plasma malondialdehyde were similar in CH and CH+A and in both different from normoxic (P < 0.01), body weight gain and plasma nitrate/nitrite were higher in CH+A than CH (P < 0.01), whereas apoptosis (number of TUNEL-positive nuclei) was less in CH+A than CH (P < 0.05). During in vitro hypoxia, the efficiency (ratio of ATP production/pressure x rate product) was the same in all groups and diazoxide had no measurable effects on myocardial performance, whereas glibenclamide increased end-diastolic pressure more in N and CH than in CH+A hearts (P < 0.05). During reoxgenation, efficiency was markedly less in CH with respect to N and CH+A (P < 0.0001), and ratex pressure product remained lower in CH than N and CH+A hearts (P < 0.001), but glibenclamide or diazoxide abolished this difference. Glibenclamide, but not diazoxide, decreased vascular resistance in N and CH (P < 0.005 and < 0.001) without changes in CH+A. We hypothesize that cardioprotection in chronically hypoxic hearts derive from cell depolarization by sarcolemmal K(+)(ATP) blockade or from preservation of oxidative phosphorylation efficiency (ATP turnover/myocardial performance) by mitochondrial K(+)(ATP) opening. Therefore K(+)(ATP) channels are involved in the deleterious effects of chronic hypoxia and in the cardioprotection elicited when chronic hypoxia is interrupted with short normoxic aeration episodes.

Recurrent left colonic diverticulitis episodes: more severe than the initial diverticulitis?

BACKGROUND: Until recently, it was accepted that the rate of complications and failure of medical therapy were higher during recurrent episodes of diverticulitis. New data and new interpretation of older studies have challenged this opinion. The aim of the present study was to determine whether recurrent diverticulitis in comparison with the initial episode has a different short-term outcome after medical or surgical treatment. METHODS: This was a retrospective cohort study of 271 consecutive patients admitted for diverticulitis confirmed by computed tomography (CT) between 2001 and 2004. Altogether 202 patients had an initial episode (group I), and 69 had recurrent diverticulitis (group R). A total of 20 clinical and 15 radiologic parameters were analyzed and compared between the two groups, including need for surgery, clinical presentation at admission, response to treatment, complications, laboratory parameters, and pathologic CT features (colonic wall thickening, abscess, pneumoperitoneum, free intraperitoneal fluid). An unpaired Student's t-test and Fisher's and Wilcoxon's tests were applied for statistical analysis. RESULTS: None of the clinical or radiologic parameters was statistically different between the two groups. Regarding surgery, 15.8% of the group I patients needed surgery at admission compared to 5.8% in group R (p = 0.04). Conservative treatment failure was similar in the two groups (10.7% vs. 10.0%; p = 0.84). There was 3% mortality at 30 days in group I compared to 0% in group R. CONCLUSIONS: Recurrent episodes of diverticulitis do not lead to more complications and more conservative treatment failure. Moreover, surgery at admission was less frequent among patients who presented with a recurrence.

Characterizing major avalanche episodes in space and time in the twentieth and early twentyfirst centuries in the Catalan Pyrenees

With the aim of better understanding avalanche risk in the Catalan Pyrenees, the present work focuses on the analysis of major (or destructive) avalanches. For such purpose major avalanche cartography was made by an exhaustive photointerpretation of several flights, winter and summer field surveys and inquiries to local population. Major avalanche events were used to quantify the magnitude of the episodes during which they occurred, and a Major Avalanche Activity Magnitude Index (MAAMI) was developed. This index is based on the number of major avalanches registered and its estimated frequency in a given time period, hence it quantifies the magnitude of a major avalanche episode or winter. Furthermore, it permits a comparison of the magnitude between major avalanche episodes in a given mountain range, or between mountain ranges, and for a long enough period, it should allow analysis of temporal trends. Major episodes from winter 1995/96 to 2013/14 were reconstructed. Their magnitude, frequency and extent were also assessed. During the last 19 winters, the episodes of January 22-23 and February 6-8 in 1996 were those with highest MAAMI values,followed by January 30-31, 2003, January 29, 2006, and January 24-25, 2014. To analyze the whole twentieth century, a simplified MAAMI was defined in order to attain the same purpose with a less complete dataset. With less accuracy, the same parameters were obtained at winter time resolution throughout the twentieth century. Again, 1995/96 winter had the highest MAAMI value followed by 1971/72, 1974/75 and 1937/38 winter seasons. The analysis of the spatial extent of the different episodes allowed refining the demarcation of nivological regions, and improving our knowledge about the atmospheric patterns that cause major episodes and their climatic interpretation. In some cases, the importance of considering a major avalanche episode as the result of a previous preparatory period, followed by a triggering one was revealed.