Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis.

BACKGROUND: An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)-mediated catabolism of endogenous all-trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866). OBJECTIVES: To study the effects of topical talarozole on retinoid biomarkers in normal skin in a randomized phase I trial. METHODS: Gels containing talarozole (0.35% or 0.07%) and vehicle were applied once daily for 9 days on either buttock of 16 healthy volunteers. Epidermal shave biopsies (for mRNA analysis) and punch biopsies (for histology and immunofluorescence analysis) were collected from the treatment areas. Genes encoding the following were studied by quantitative real-time polymerase chain reaction: cellular retinoic acid binding protein 2 (CRABP2), cytokeratins (KRT2 and KRT4), CYP26A1, CYP26B1, CYP26C1 and CYP2S1, two enzymes in the retinol metabolism (retinal dehydrogenase-2 and retinol acyltransferase) and two proinflammatory cytokines [interleukin (IL)-1alpha and tumour necrosis factor-alpha]. RESULTS: Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1alpha compared with vehicle-treated skin. No mRNA change in retinol-metabolizing enzymes was obtained. There was no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. Immunofluorescence analysis confirmed an upregulation of KRT4 protein, but no upregulation of CYP26A1 and CYP26B1 expression was detected. CONCLUSIONS: Talarozole influences the biomarker pattern consistently with increased retinoic acid stimulation. The low irritancy of talarozole at the two examined dosages is a possible advantage over topical retinoids.

The ability of YSR scales to predict DSM/DISC-C psychiatric disorders among incarcerated male adolescents.

OBJECTIVE: To investigate whether the empirical or DSM-oriented scales of the Youth Self-Report (YSR) can be used to screen for DSM psychiatric disorders among incarcerated boys. DSM-oriented scales have recently been developed by Achenbach to enhance comparability of YSR results with DSM diagnostic categories. METHOD: A representative sample (N = 196) of incarcerated boys aged 12-18 was assessed with the child version of the Diagnostic Interview Schedule for Children (DISC-C) to diagnose DSM psychiatric disorders, and with the Youth Self-Report (YSR). RESULTS: Only 22% had YSR total problem scores in the clinical range, whereas 90 % met criteria of at least one DSM/DISC-C psychiatric disorder. Weak associations between both empirical and DSM-oriented YSR scale scores and DSM/DISC-C diagnoses were found. CONCLUSIONS: Neither the empirical nor the DSM-oriented YSR scales adequately screen for DSM/DISC-C psychiatric disorders among incarcerated boys. The use of the YSR and the DISC-C to assess DSM constructs results in, at least partially, different diagnostic information.

Activity of the triazole antifungal r126638 as assessed by corneofungimetry.

BACKGROUND: R126638 is a novel triazole exhibiting potent in vitro and in vivo antifungal activity against fungal pathogens including dermatophytes and yeasts. OBJECTIVE: To determine the antifungal activity in time in the stratum corneum of healthy volunteers after oral intake of R126638 at a daily dose of 100 or 200 mg for 1 week. METHOD: Sixteen male volunteers were randomly allocated to oral treatment with either 100 or 200 mg of R126638 once daily for 1 week. Five cyanoacrylate skin surface strippings (CSSS) were obtained from the forearm of each subject before drug intake at day 1. CSSS were also collected during treatment at day 2 (24 h after the first drug intake, before the second drug intake), at day 4 (before the fourth drug intake) and at day 7 (10 h after the last drug intake). The post-treatment lingering effect was assessed at day 10 (3 days after treatment) and at day 14 (7 days after treatment). The corneofungimetry bioassay was performed on these CSSS to assess the antifungal profile of R126638. Cells of different fungal species (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Candida albicans and Malassezia globosa) were deposited and cultured for 10 days on CSSS in a sterile and controlled environment. The extent of fungal growth on the stratum corneum was determined using computerized image analysis. RESULTS: R126638 clearly reduced the growth of all tested fungal species. The onset of effects of R126638 was evidenced at day 4 when it reached statistical significance for 3 of 5 species. At day 7, significance was reached for 4 of 5 species. During the posttreatment period, R126638 remained effective for 4 of 5 species at day 10, and this activity persisted until day 14 for 2 of 5 species. CONCLUSION: A broad spectrum antifungal activity was rapidly expressed in the stratum corneum after oral intake of R126638. The drug likely reached the upper layers of the stratum corneum by diffusion and persisted in this location for at least 7 days after treatment.

What patient characteristics make clinicians recommend brief treatment?

OBJECTIVE: Assessing self-rated items that might have an impact on clinicians recommending brief treatment (BT) over unlimited or long-term treatment (ULT). METHOD: On the basis of patient self-report data we compared patients referred by clinicians to BT (n=71) with those referred to ULT (n=145). RESULTS: The final multiple logistic regression model indicates that the chance of being allocated to BT increases with: more satisfaction with support, higher self-esteem, primary education or less, and high desire for support as an intervention. With regard to desire to confess in treatment, low and high scores make the chance of being allocated to BT lower. This is also the case for daily hassles. Finally, some specific target complaints, in particular anxiety, lower the chance of being allocated to BT. CONCLUSION: Using data about patient's complaints and symptoms, stress and support, personality and coping, and request for type of intervention, we built a regression-model that classified 80% of the patients correctly with regard to allocation to BT or ULT.

Priorities and satisfaction on the help needed and provided in a first episode of psychosis. A survey in five European Family Associations.

In the case of a first episode of psychosis among members of different associations of families of mentally ill people, little is known about their priorities and how satisfied they are with the help provided to them. A survey was conducted in five European family associations. Respondents emphasized the need for early (ambulant) intervention through outreach with very practical goals directed at creating stability and social functioning. About one-third of the respondents are unsatisfied or very unsatisfied. The highest percentage of unsatisfied respondents was in the following five areas of care: advice on how to handle specific problems; help with preserving or regaining social functioning; help with regaining structure and routine; information; prompt assistance preferably in patients own environment. The agreement of these findings with findings from earlier studies underlines the importance of suggesting specific changes in the delivery of care.

[A study of the incidence and a descriptive analysis of adult non-tuberculous primary bacterial meningitis in a population in Argentina]. / Estudio de incidencia y análisis descriptivo de la meningitis bacteriana primaria no tuberculosa del adulto en una población argentina.

INTRODUCTION: Adult non tuberculous primary bacterial meningitis (PBM) represents an important cause of morbidity and mortality in hospitals. The shortage of studies based on the population in Latin America provided the motivation for this work. AIMS: To determine the incidence of PBM in the captive population of our hospital and carry out a descriptive analysis of the cases detected. PATIENTS AND METHODS: We performed an epidemiological study of the captive population (CP) of the hospital (an average of 85,200 patients in 11 years) and a retrospective descriptive examination of patients who had been admitted. The clinical histories of all patients over the age of 18 who had been admitted with PBM between 1 January 1988 and 31 December 1998 were studied. RESULTS AND CONCLUSIONS: A total number of 87 cases of primary bacterial meningitis were registered, of which 70 belonged to the CP. The overall gross rate of PBM incidence in the CP was 8.6/100,000 per year. The annual incidence rate, adjusted to the 1991 National Census on the Argentinean Population, was 5.4/100,000 per year, with a greater frequency between the ages of 70 and 79: 21/100,000 per year. Median age: 73 (lower quartile, 66; upper quartile, 78). Clinical manifestations included high temperatures (90%), consciousness disorders (87%), and a stiff neck (81%). The frequency with which it appeared remained constant over the 11 year period, without showing any seasonal variations. The most frequent etiological agent was pneumococcus (50%). No cases of PBM by Listeria were reported. Overall fatality during the stay in hospital was 23%, without any type of modification over the period we studied.

Psychometric properties of the Subjective Well-Being Under Neuroleptics scale and the Subjective Deficit Syndrome Scale.

RATIONALE: Subjective experience of antipsychotic drugs is relevant for medication compliance and quality of life. There is, however, sparse knowledge about the assessment of subjective experience. OBJECTIVES: To examine the internal consistency, test-retest reliability, sensitivity to medication change and concurrent validity of two test instruments: the Subjective Well-Being Under Neuroleptics (SWN) and the Subjective Deficit Syndrome Scale (SDSS). METHODS: Both instruments were used at admission and after 6 weeks of medication stabilization in 105 consecutively admitted patients diagnosed with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edn) diagnoses of recent-onset schizophrenia, schizophreniform disorder or schizoaffective disorder. RESULTS: Almost all patients were capable of reproducing their subjective experience in a consistent way both before and after medication stabilization. The internal consistency of both instruments was high. The test-retest reliability was high if medication was not changed, especially for the SWN. The SWN was sensitive for changes in medication and dosage. The short form of the SWN (SWN-20 items) had comparable psychometric qualities to the original instrument (SWN-38 items). The concurrent validity of the SWN and the SDSS was good, indicating that both tests measure the same concept. CONCLUSIONS: The assessment of subjective experience with the SWN (both versions) may be used in evaluating differential effects of anti-psychotics and dose on subjective well-being.

Time course of atrial fibrillation-induced cellular structural remodeling in atria of the goat.

BACKGROUND: Previously we documented cellular structural changes of a non-degenerative nature in atrial myocytes after atrial fibrillation (AF) in the goat. The time course of these changes was not studied. METHODS AND RESULTS: Cellular structural changes were studied by light- and electron microscopy and immunohistochemistry in goat atria after 0-16 weeks AF. The first sign of cellular structural remodeling was a more homogeneous chromatin distribution, at 1 week of AF. Sub-structural changes in mitochondria and sarcoplasmic reticulum occurred gradually. Cellular degeneration was absent. The degree of myolysis and glycogen accumulation increased till 8 weeks of AF and did not increase further from thereon. After 16 weeks of AF, 42% of the myocytes in the right atrial free wall were affected by myolysis. The diameter of the atrial myocytes increased. Dedifferentiation of the atrial myocytes was suggested by altered expression patterns of structural proteins, such as the disappearance of cardiotin (1 week), the A-I junctional part of titin (4 weeks), desmin at the intercalated disk (ID) (8 weeks) and a gradual re-expression of alpha-smooth muscle actin. CONCLUSION: Remodeling of the cellular ultrastructure in atrial myocardium of the goat develops progressively during AF. Re-expression of fetal proteins indicate dedifferentiation of atrial myocytes, analogous to observations in hibernating myocardium of the ventricle.

Physical inactivity as a determinant of the physical activity level in the elderly.

OBJECTIVE: To assess the relationship between the mean physical activity level (PAL) and the time spent on activities of three different intensity levels in an elderly population. Data was compared with previously obtained data from a group of younger adults. SUBJECTS: Fourteen elderly women and 14 elderly men (61+/-4 y; 27+/-5 kg/m(2); 33+/-7% body fat), and 14 young women and 16 young men (27+/-5 y, 24+/-2 kg/m(2)). MEASUREMENTS: PAL was determined as average daily metabolic rate (ADMR) combined with a measurement of basal metabolic rate (BMR): PAL=ADMR/BMR. ADMR was measured with the doubly labeled water method. BMR was measured with a ventilated hood system. Time spent on activity and activity intensity was measured by using a tri-axial accelerometer (7x2x0.8 cm, 30 g) over a 2 week interval. RESULTS: Mean PAL was 1.65+/-0.14. PAL was inversely related to the percentage of time spent on low-intensity activity (lying, sitting and standing), r= -0.43; P<0.05. Older subjects spent significantly more time at these activities than 20 to 35-y-old subjects (82+/-7% vs 65+/-7%; P<0.0001). A significant relation was not observed between PAL and the percentage of time spent on moderate (walking) or high (household activities, exercise and sports) intensity activity, or activity monitoring time (14.4+/-1.2 h/day). CONCLUSION: In the elderly, spending relatively more time on low-intensity activities affects the mean PAL negatively. To obtain a higher PAL does not necessarily imply high-intensity activities like sports.

Preferences for treatment during a first psychotic episode.

Psychiatric services providing care for patients and their families confronted with a first psychotic episode need to be sensitive towards patients' and families' preferences. Ten patients, ten family members and ten professional caregivers composed a list of 42 preferences in the treatment for a first psychotic episode. In total 99 patients, 100 family members and 263 professional caregivers evaluated these preferences, thus producing an order of priorities. There appears to be considerable agreement among the groups of respondents regarding their top ten priorities, especially concerning information on diagnosis and medication. However, we found important differences between groups of respondents. The results suggest that in psychiatric services great attention should be given to psycho-education and early outpatient intervention.

Impaired autoregulation of cerebral blood flow in an experimental model of traumatic brain injury.

In order to study the pathophysiology and the intracranial hemodynamics of traumatic brain injury, we have developed a modified closed-head injury model of impact-acceleration that expresses several features of severe head injury in humans, including acute and long-lasting intracranial hypertension, diffuse axonal injury, neuronal necrosis, bleeding, and edema. In view of the clinical relevance of impaired autoregulation of cerebral blood flow after traumatic brain injury, and aiming at further characterization of the model, we investigated the autoregulation efficiency 24 h after experimental closed-head injury. Cortical blood flow was continuously monitored with a laser-Doppler flowmeter, and the mean arterial blood pressure was progressively decreased by controlled hemorrhage. Relative laser-Doppler flow was plotted against the corresponding mean arterial blood pressure, and a two-line segmented model was applied to determine the break point and slopes of the autoregulation curves. The slope of the curve at the right hand of the break point was significantly increased in the closed head injury group (0.751 +/- 0.966%/mm Hg versus -0.104 +/- 0.425%/mm Hg,p = 0.028). The break point tended towards higher values in the closed head injury group (62.2 +/- 20.8 mm Hg versus 46.9 +/- 12.7 mm Hg; mean +/- SD, p = 0.198). It is concluded that cerebral autoregulation in this modified closed head injury model is impaired 24 h after traumatic brain injury. This finding, in addition to other characteristic features of severe head injury established earlier in this model, significantly contributes to its clinical relevance.

[Spontaneous infectious spondylodiscitis in adults. Analysis of 30 cases]. / Espondilodiscitis infecciosas espontáneas en adultos. Análisis de 30 casos.

We revised retrospectively 30 cases of Spontaneous Infectious Spondylodiskitis (SIS) in adults, diagnosed between 1986 and 1997. The mean age of the patients was 68.8 years; 56.7% were males. The identifiable causes were infectious endocarditis 13 (43.3%); tuberculosis 7 (23.3%); urinary tract infection 4 (13.3%); bacteremia with focus 2 (6.7%) and without focus 2 (6.7%). The cause was not identified in other 2 cases (6.7%). Infections were due to pyogenic bacteriae in 19 (63.3%); tuberculosis 6 (20%) and unknown 5 (16.7%). All patients had localized pain, 70% fever, 36.7% irradiated pain and 23.3% paraparesis. Fever was more frequent in patients with pyogenic etiology than in those with tuberculous SIS (p = 0.004). Blood cultures were positive in 70.4%. Percutaneous aspiration of the disc was performed in 13 patients; cultures were positive in 7. Causal germs were Streptococcus spp. 33.3%; Mycobacterium tuberculosis 20%; Staphylococcus spp. 16.6%; Escherichia coli 6.6%; Pseudomonas aeruginosa 6.6%. There was no bacteriological recovery in 5 (16.7%). Localization was lumbar in 18 (60%), dorsal in 8 (26.6%) and cervical in 4 (13.3%). X-ray of the spine was positive in 63.3% of the cases. Technetium scan in 90.5%, CT in 85.7% and MRI in 100% of cases in which it was carried out. All patients received antibiotic treatment with a median duration of 6 weeks for pyogenic SIS and one year for tuberculous SIS. Eighty three percent required immobilizing brace and 10% surgery for stabilization. Thirty six percent of patients presented complications, most of them related to the causal disease. There was a statistically significant association between mortality and diabetes.

Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat.

BACKGROUND: After cardioversion of sustained atrial fibrillation (AF), the electrical and contractile functions of the atria are impaired, and recurrences of AF frequently occur. Whether remodeling of the structure of atrial myocardium is the basis for this problem is not known. METHODS AND RESULTS: Sustained AF was induced by electrical pacing in 13 goats instrumented long-term. The goats were killed after 9 to 23 weeks, and the atrial myocardium was examined by light and electron microscopy. The changes were quantified in left and right atrial free walls, appendages, trabeculae, the interatrial septum, and the bundle of Bachmann. A substantial proportion of the atrial myocytes (up to 92%) revealed marked changes in their cellular substructures, such as loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were accompanied by an increase in size of the myocytes (up to 195%). There were virtually no signs of cellular degeneration, and the interstitial space remained unaltered. The duration of sustained AF did not significantly affect the degree of myolytic cell changes. CONCLUSIONS: Sustained AF in goats leads to predominantly structural changes in the atrial myocytes similar to those seen in ventricular myocytes from chronic hibernating myocardium. These structural changes may explain the depressed contractile function of atrial myocardium after cardioversion. This goat model of AF offers a new approach to study the cascade of events leading to sustained AF and its maintenance.

Isolation of Candida species on media with and without added fluconazole reveals high variability in relative growth susceptibility phenotypes.

Mouthwashes from human immunodeficiency virus-positive individuals were sampled for yeasts by direct plating on a differential agar medium with and without added fluconazole and via enrichment broths with and without added fluconazole. The colonies of the yeasts isolated were tested for relative growth in the presence of single concentrations of itraconazole and fluconazole. Among 258 culture plates containing yeasts obtained via different isolation routes from 86 yeast-positive samples, 33 (12.7%) of the plates showed unexpectedly high colony-to-colony variation in relative growth. Intercolony variation was seen in 41 (47.7%) of the 86 isolates when relative growth data were analyzed for all colonies of an isolate tested, regardless of the medium used for isolation. The prevalence of relative growth variability with the azoles was highest for Candida glabrata (100% of 13 isolates), followed by Candida krusei (60% of 5 isolates) and Candida albicans (40% of 53 isolates), and the visual patterns of variability seen in scatter plots of the data showed species specificity. Relative growth phenotypes generally tended to be stable for each yeast colony in subcultures, whether or not the medium used for subculture contained antifungal agents. DNA fingerprinting of stable and variable C. albicans isolates showed changes in band patterns detected with the probe Ca3, suggesting that the variability may have resulted from selection of different subtypes of the yeasts during the isolation procedure. These findings suggest that the yeasts isolated from single clinical samples were often not clonal in nature. The relative growth test revealed colony variability more readily than conventional susceptibility testing.

125I-Tyr0-hCRH labelling characteristics of corticotropin-releasing hormone receptors: differences between normal and adenomatous corticotrophs.

The presence of corticotropin-releasing hormone (CRH) receptors has been previously demonstrated in corticotrophs from normal pituitaries using a method combining immunocytochemistry and liquid emulsion autoradiography. The aim of this study was to compare the characteristics of the 125I-Tyr0-hCRH binding in corticotrophs from normal pituitaries (three obtained at autopsy and one obtained at surgery) with corticotrophs from pituitary adenomas (six corticotroph adenomas responsible for Cushing's disease and two silent corticotroph adenomas secreting a biologically inactive ACTH molecule). In normal corticotrophs, the larger part of the 125I-Tyr0-hCRH binding was localised in patchy conglomerates at the centre of the cell and, to a much lesser degree, in a diffuse pattern at the cell periphery. In adenomatous corticotrophs, CRH receptor expression is disturbed both quantitatively and qualitatively. Except for a minority of cells in one adenoma, all adenomatous corticotrophs showed only peripherally bound 125I-Tyr0-hCRH and no centrally localised binding. Furthermore, adenomatous corticotrophs revealed a statistically significant lower signal intensity when compared to normal corticotrophs and a strongly negative correlation was found between the labelling area in adenomatous corticotrophs and both the basal and CRH-stimulated plasma ACTH levels. These findings suggest defective processing of CRH receptors and could be relevant to the sustained ACTH secretion by adenomatous corticotrophs in Cushing's disease and, more generally, provide an explanation to its pathology. The silent corticotrophs secreting a biologically inactive ACTH molecule were characterised by a very faint signal intensity, although present on almost every cell.

Protection with lubeluzole against delayed ischemic brain damage in rats. A quantitative histopathologic study.

BACKGROUND AND PURPOSE: Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an N-methyl-D-aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus. METHODS: Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group). RESULTS: Posttreatment with lubeluzole (0.31 mg/kg i.v. bolus at 5 minutes and 0.31 mg/kg i.v. infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left (P = .002) and 113 in the right hemisphere (P = .013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons. CONCLUSIONS: Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.

Sabeluzole stabilizes the neuronal cytoskeleton.

There is growing evidence that cytoskeletal instability of neuronal cells is an important step towards tangle formation and subsequent functional disconnection in the AD brain. Sabeluzole, a new drug in clinical trials for Alzheimer's disease (AD), has been shown to slow down the clinical progression of the disease. In a search for the mechanism of action of this compound, the effect of sabeluzole on the neuronal cytoskeleton was investigated. Previous studies have shown that in human TR14 neuroblastoma cells and in rat hippocampal neurons a hyperstimulating medium of kinase activators leads to induction of aberrant tau phosphorylation followed by neurotoxicity. This report documents the attenuation of this neurotoxicity by sabeluzole. By selective permeabilization procedures and quantitative immunocytochemistry we show that the compound is found to preferentially increase the fraction of polymerized tubulin. Evidence is presented that the compound differentially modulates a nocodazole-induced depolymerization in contrast to a cold-induced depolymerization. In the mouse, N4 neuroblastoma cells sabeluzole decreases the spontaneous retraction frequency of neurites and lowers the lateral mobility of the cells. We, therefore, propose that sabeluzole exerts its neuroprotective effect by a stabilization of the neuronal cytoskeleton and that this mechanism provides a completely new approach for treatment in Alzheimer's disease.

Water balance and acute mountain sickness before and after arrival at high altitude of 4,350 m.

The present study is a first attempt to measure water balance and its components at altitude by using labeled water and bromide dilution and relating the results with acute mountain sickness (AMS). Water intake, total water output, and water output in urine and feces were measured over a 4-day interval before and a subsequent 4-day interval after transport to 4,350 m. Total body water and extracellular water were measured at the start and at the end of the two intervals. There was a close relationship between energy intake and water intake, and the relationship was unchanged by the altitude intervention. Subjects developing AMS reduced energy intake and water intake cor respondingly. The increase in total body water (TBW) in subjects developing AMS was accompanied by a reduction in total water loss. They did not show the increased urine output, compensating for the reduced evaporative water loss at altitude. Subjects showed a significant increase in TBW after 4 days at altitude. Subjects with AMS showed the biggest shifts in extracellular water relative to TBW. In conclusion, fluid retention in relation to AMS is independent of a change in water requirements due to altitude exposure. Subjects developing AMS were those showing a fluid shift of at least 1 liter from the intracellular to the extracellular compartment or from the extracellular to the intracellular compartment.