Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.

BACKGROUND AND PURPOSE: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. METHODS: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. RESULTS: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. CONCLUSION: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

Inhaled short-acting bronchodilators for managing emergency childhood asthma: an overview of reviews.

International guidelines provide conflicting recommendations on how to use bronchodilators to manage childhood acute wheezing conditions in the emergency department (ED), and there is variation within and among countries in how these conditions are managed. This may be reflective of uncertainty about the evidence. This overview of systematic reviews (SRs) aimed to synthesize, appraise, and present all SR evidence on the efficacy and safety of inhaled short-acting bronchodilators to treat asthma and wheeze exacerbations in children 0-18 years presenting to the ED. Searching, review selection, data extraction and analysis, and quality assessments were conducted using methods recommended by The Cochrane Collaboration. Thirteen SRs containing 56 relevant trials and 5526 patients were included. Results demonstrate the efficacy of short-acting beta-agonist (SABA) delivered by metered-dose inhaler as first-line therapy for younger and older children (hospital admission decreased by 44% in younger children, and ED length of stay decreased by 33 min in older children). Short-acting anticholinergic (SAAC) should be added to SABA for older children in severe cases (hospital admission decreased by 27% and 74% when compared to SABA and SAAC alone, respectively). Continuous nebulization, addition of magnesium sulfate to SABA, and levosalbutamol compared to salbutamol cannot be recommended in routine practice.

Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder.

Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDECONT: F[1,41]=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t[40]=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.

Differences in structural geometrical outcomes at the neck of the proximal femur using two-dimensional DXA-derived projection (APEX) and three-dimensional QCT-derived (BIT QCT) techniques.

UNLABELLED: Structural geometric parameters at neck of the proximal femur were obtained using DXA-derived hip structural analysis (APEX 3) and quantitative computed tomography-derived (BIT QCT) techniques in 237 elderly females. Linear correlations for parameters ranged from 0.45 to 0.90. The average value of the subperiosteal width, as determined by the two techniques, was the same; variables dependent on mass measurements were different. INTRODUCTION: There has been increasing interest in using bone structural geometry to assess bone fragility to complement bone mineral mass. The objective of this study is to compare structural geometrical differences between "2D" DXA-derived and "3D" QCT-derived techniques in unselected clinical cases. METHODS: All 237 females had both DXA and QCT assessments of femoral neck structural geometry. Variables compared were areal bone mineral density, cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), averaged cortical thickness (Ct), endosteal width (ESW), subperiosteal width (W), and buckling ratio (BR). RESULTS: Correlation of femoral neck variables ranged from 0.45 for ESW to 0.90 for CSA. APEX 3 and BIT QCT-derived femoral neck W values were numerically similar. However CSA, CSMI, Z and Ct values measured by APEX 3 were higher and ESW and BR values were lower than corresponding BIT QCT. CONCLUSIONS: 2D DXA structural analysis of neck of femur is related to but different from same parameters calculated from true 3D images obtained by CT. Femoral neck size values are similar for DXA and QCT, but structural geometrical variables dependent on mass calibration standards, location of neck ROI and mathematical derivation techniques are different.

Do fathead minnows, Pimephales promelas Rafinesque, alter their club cell investment in responses to variable risk of infection from Saprolegnia?

Fish in the Superorder Ostariophysi possess large epidermal club cells that release chemical cues warning nearby conspecifics of danger. Despite the long-held assumption that such club cells evolved under the selective force of predation, recent studies demonstrated that predation has no effect on club cell investment. Rather, club cells have an immune function and cell production may be stimulated by skin-penetrating pathogens and parasites. The current work investigates whether fathead minnows, Pimephales promelas, alter their club cell characteristics based on variation in infection risk. In a 2 × 3 design, we exposed minnows to infective cysts of two oomycete species (Saprolegnia ferax and S. parasitica) at three different concentrations (2, 20 or 200 cysts L(-1)). Club cell characteristics (number and size) were quantified 12 days after exposure. Saprolegnia parasitica is thought to be more pathogenic than S. ferax, hence we predicted greater club cell investment and a larger turnover rate of cells by minnows exposed to S. parasitica than S. ferax. We also predicted that minnows exposed to higher numbers of cysts should invest more in club cells and have a higher turnover rate of cells. We found no difference in club cell density or size between fish exposed to the two Saprolegnia species; however, fish exposed to high concentrations of pathogens had smaller club cells than those exposed to low concentrations, indicating a higher rate of turnover of cells in the epidermis.

Detection of herpes viruses in respiratory secretions of patients undergoing artificial ventilation.

The significance of detection of herpes viruses in respiratory secretions of critically ill patients is controversial. The study aim was to determine the prevalence of herpes virus DNA in respiratory secretions in patients on artificial ventilation. Respiratory secretions taken thrice weekly from 174 patients in a tertiary center intensive therapy unit (ITU) were tested for herpes simplex virus (HSV) by nested PCR. Samples from 61 patients in ITU for 4 days or more were also tested for Epstein Barr Virus (EBV) and cytomegalovirus (CMV) using real-time PCR. HSV positivity increased with ITU stay with 18.6% admission samples positive, 32.5% day 2-5 samples, and 65.9% day 6-39 samples. Being HSV positive on admission did not influence mortality (9/27, 33.3% vs. 38/118, 32.2%) however, subsequently, mortality of those negative but becoming positive was higher than in those remaining negative (10/35, 29% vs. 5/24 21%). At least one sample was EBV positive in 61% and CMV positive in 19% of patients tested. Of 63 patients tested for all three viruses, 4 were positive for three viruses, 23 patients for two viruses, 24 for one virus and 12 were negative for all the above viruses. Detection of HSV, EBV and CMV is common in ITU patients. Becoming HSV positive while in ITU may increase mortality.

Amygdaloid kindling is anxiogenic but fails to alter object recognition or spatial working memory in rats.

Kindling in rats produces enduring behavioral changes that parallel the psychobehavioral disturbances frequently accompanying temporal lobe epilepsy. Some evidence suggests that the site of kindling is an important determinant of the type of behavioral changes observed following kindling, although this variable has not been systematically investigated. In the present experiments, the effects of amygdaloid kindling were assessed on a battery of behavioral tests we used previously to assess the effects of kindling in dorsal hippocampus or perirhinal cortex. Three generalized seizures were kindled with stimulation in or near the basolateral amygdala. One week later, rats were tested successively on measures of anxiety, activity, object recognition memory, and spatial working memory over a period of 3 weeks. Amygdaloid kindling produced increased anxiety, but spared all other behaviors assessed. This pattern of results is partially distinct from the previously described effects of perirhinal cortical kindling, which increases anxiety but also impairs object recognition memory, and is completely distinct from dorsal hippocampal kindling, which selectively increases activity and impairs spatial working memory. The observations suggest that kindling of distinct highly interconnected temporal lobe sites produces distinct patterns of behavioral comorbidity. The underlying mechanisms are thus most likely localized to intrinsic circuits at the site of seizure origination.

Choice of antenatal testing significantly effects a patient's work obligations.

OBJECTIVE: We sought to compare two approaches to antenatal testing for their impact on the workforce. STUDY DESIGN: This is a prospective observational study of women who presented for antenatal testing. All women were given a survey upon presentation. As per hospital protocol, nonstress testing (NST) was performed semiweekly and biophysical profile (BPP) was performed weekly. The choice of testing was determined by the attending physician. chi2- and Student's t-tests were performed where appropriate. A P-value of <0.05 was considered significant. RESULT: A total of 195 women were surveyed. Among them, 94 women had an NST and 101 had a BPP. Overall, 59.2% were multiparous, 33.1% had to arrange for child care and 97.2% felt reassured by the testing. There were no differences in demographic characteristics, education, type of insurance or employment status between the groups. Women who had NSTs were more likely to lose time from work than those who had BPPs (218.4 versus 68.9 min; P<0.001). Of the women who had semiweekly NSTs, 80.6% would have preferred weekly testing. If the 94 women who received semiweekly testing had weekly testing, a total of 534.4 h would have been available for the workforce. CONCLUSION: Twice-weekly NST results in a significant increase in time lost from the workforce compared with weekly BPP.

Dorsal hippocampal kindling produces a selective and enduring disruption of hippocampally mediated behavior.

Kindling produces enduring neural changes that are subsequently manifest in enhanced susceptibility to seizure-evoking stimuli and alterations in some types of behavior. The present study investigated the effects of dorsal hippocampal (dHPC) kindling on a variety of behaviors to clarify the nature of previously reported effects on spatial task performance. Rats were kindled twice daily with dHPC stimulation until three fully generalized seizures were evoked. Beginning 7 d later and on successive days, rats were tested in an elevated plus maze, a large circular open field, an open field object exploration task, and a delayed-match-to-place (DMTP) task in a water maze to assess anxiety-related and activity-related behavior (tasks 1 and 2), object recognition memory (task 3), and spatial cognition (task 4). Kindling disrupted performance on the DMTP task in a manner that was not delay dependent and produced a mild enhancement of activity-related behaviors in the open field task but not the elevated plus maze. All other aspects of testing were spared. These findings indicate that dHPC kindling produces enduring and selective effects on behavior that are consistent with a restricted disruption of hippocampally mediated functions. Possible bases for these effects are changes in local NMDA receptor function and/or changes in local inhibition, which might alter the optimal conditions for experience-dependent induction of intrahippocampal plasticity. This preparation may be useful for studying the mechanisms of mnemonic dysfunction associated with temporal lobe epilepsy and may offer unique insights into the mechanisms underlying normal hippocampal function.

Photosensitization of experimental atheromas by porphyrins.

Arteriosclerotic arteries have been shown to fluoresce when treated with hematoporphyrin derivative. This study investigates the incorporation and distribution of a partially purified form of hematoporphyrin derivative (Photofrin II) in normal and arteriosclerotic rabbit aortas. A thoracoabdominal exploration was performed in 15 rabbits. Group I comprised normal rabbits, Group II normal rabbits given 5 mg/kg Photofrin II 48 hours before surgery, Group III arteriosclerotic rabbits and Group IV arteriosclerotic rabbits given 5 mg/kg Photofrin II 48 hours before surgery. Multiple aortic biopsy specimens for frozen section were taken from all rabbits. In addition, open laser endarterectomy (with an argon ion laser) was performed on Group III and Group IV rabbits. Frozen sections were studied by digital video fluorescence microscopy to determine the distribution of Photofrin II within the layers of the aortic wall. The fluorescence of the intima of Group IV rabbits was found to be significantly greater than that of the intima, internal elastic lamina, media or adventitia of the other groups (p less than 0.01) and significantly greater than that of the internal elastic lamina, media or adventitia of Group IV rabbits (p less than 0.01). When open laser endarterectomy was performed, Group III rabbits required 103 +/- 14 J/cm2 and Group IV required 33 +/- 3 J/cm2 (p less than 0.01). It is concluded that porphyrins are selectively localized within the intima of arteriosclerotic arteries. This localization sensitizes atheromas to argon ion laser light and facilitates laser endarterectomy.

Resistance exercise training restores bone mineral density in heart transplant recipients.

OBJECTIVES: This was a prospective, randomized, controlled study designed to determine the effect of resistance exercise training on bone metabolism in heart transplant recipients. BACKGROUND: Osteoporosis frequently complicates heart transplantation. No preventative strategy is generally accepted for glucocorticoid-induced bone loss. METHODS: Sixteen male heart transplant recipients were randomly assigned to a resistance exercise group that trained for 6 months (mean [+/- SD] age 56 +/- 6 years) or a control group (mean age 52 +/- 10 years) that did not perform resistance exercise. Bone mineral density (BMD) of the total body, femur neck and lumbar spine (L2 to L3) was measured by dual-energy X-ray absorptiometry before and 2 months after transplantation and after 3 and 6 months of resistance exercise or a control period. The exercise regimen consisted of lumbar extension exercise (MedX) performed 1 day/week and variable resistance exercises (Nautilus) performed 2 days/week. Each exercise consisted of one set of 10 to 15 repetitions performed to volitional fatigue. RESULTS: Pretransplantation baseline values for regional BMD did not differ in the control and training groups. Bone mineral density of the total body, femur neck and lumbar vertebra (L2 to L3) were significantly decreased below baseline at 2 months after transplantation in both the control (-3.3 +/- 1.3%, -4.5 +/- 2.8%, -12.7 +/- 3.2%, -14.8 +/- 3.1%, respectively). Six months of resistance exercise restored BMD of the whole body, femur neck and lumbar vertebra to within 1%, 1.9% and 3.6% of pretransplantation levels, respectively. Bone mineral density of the control group remained unchanged from the 2-month posttransplantation levels. CONCLUSIONS: Within 2 months after heart transplantation, approximately 3% of whole-body BMD is lost, mostly due to decreases in trabecular bone (-12% to -15% of lumbar vertebra). Six months of resistance exercise, consisting of low back exercise that isolates the lumbar spine and a regimen of variable resistance exercises, restores BMD toward pretransplantation levels. Our results suggest that resistance exercise is osteogenic and should be initiated early after heart transplantation.

Exercise-induced hypoxemia in heart transplant recipients.

OBJECTIVES: The purpose of this study was to determine whether heart transplantation has an adverse effect on pulmonary diffusion and to investigate the potentially deleterious effects of impaired pulmonary diffusion on arterial blood gas dynamics during exercise in heart transplant recipients. BACKGROUND: Abnormal pulmonary diffusing capacity is reported in patients after orthotopic heart transplantation. Abnormal diffusion may be caused by cyclosporine or by the persistence of preexisting conditions known to adversely affect diffusion, such as congestive heart failure and chronic obstructive pulmonary disease. METHODS: Eleven patients (mean age 50 +/- 14 years) performed pulmonary function tests 3 +/- 1 months before and 18 +/- 12 (mean +/- SD) months after heart transplantation. Transplant patients were assigned to groups with diffusion > 70% (n = 5) or diffusion < 70% of predicted values (n = 5). The control group and both subsets of patients performed 10 min of cycle exercise at 40% and 70% of peak power output. Arterial blood gases were drawn every 30 s during the 1st 5 min and at 6, 8 and 10 min. RESULTS: Significant improvements in forced vital capacity (17.4%), forced expiratory volume in 1 s (11.7%) and diffusion capacity (6.6%) occurred in the patients; however, posttransplantation vital capacity, forced expiratory volume and diffusion were lower (p < or = 0.05) compared with values in 11 matched control subjects. Changes in blood gases were similar among groups at 40% of peak power output. At 70% of peak power output, arterial blood gases and pH were significantly (p < or = 0.05) lower in transplant patients with low diffusion (arterial oxygen pressure 15 to 38 mm Hg below baseline) than in patients with normal diffusion and control subjects. Cardiac index did not differ (p > or = 0.05) between transplant patients with normal and low diffusion at rest or during exercise. Posttransplantation mean pulmonary artery pressure was significantly related to exercise-induced hypoxemia (r = 0.71; p = 0.03). CONCLUSIONS: Abnormal pulmonary diffusion observed in patients before heart transplantation persists after transplantation with or without restrictive or obstructive ventilatory defects. Heart transplant recipients experience exercise-induced hypoxemia when diffusion at rest is < 70% of predicted. Our data also suggest that abnormal pulmonary gas exchange possibly contributes to diminished peak oxygen consumption in some heart transplant recipients; however, direct testing of this hypothesis was beyond the scope of the present study. This possibility needs to be investigated further.

An intragenic suppressor of a calmodulin mutation in Paramecium: genetic and biochemical characterization.

We describe a suppressor of the calmodulin mutant cam1 in Paramecium tetraurelia. The cam1 mutant, which has a SER----PHE change at residue 101 of the third calcium-binding domain, inhibits the activity of the Ca(2+)-dependent K+ current and causes exaggerated behavioral responses to most stimuli. An enrichment scheme, based on an increased sensitivity to Ba2+ in cam1 cells, was used to isolate suppressors. One such suppressor, designated cam101, restores both the activity of the Ca(2+)-dependent K+ current and behavioral responses of the cells. We show that the cam101 mutant is an intragenic suppressor of cam1, based on genetic and microinjection data. The cam101 calmodulin is shown to be similar to wild-type calmodulin in terms of its ability to stimulate calmodulin-dependent phosphodiesterase at low concentrations of free calcium. However, the cam101 calmodulin has a reduced affinity for a monoclonal antibody to wild-type Paramecium calmodulin, as does the parental cam1 calmodulin, and a different mobility on acid-urea gels relative to both wild-type and cam1 calmodulin. We have been able to demonstrate that the isolation of intragenic suppressors of a calmodulin mutation is possible, which allows for the further genetic analysis of structure-function relationships in the calmodulin molecule.

A controlled prospective study of DSM-III adjustment disorder in childhood. Short-term prognosis and long-term predictive validity.

OBJECTIVES: Using DSM-III criteria for adjustment disorder (AD), further operationalized by requiring at least three clinically significant symptoms, we sought to characterize this diagnosis in terms of presenting features, recovery, and predictive validity among juveniles. DESIGN: The samples included clinically referred, 8- to 13-year-old patients with the research diagnosis of AD (N = 30) and a high rate of comorbid disorders and age-and comorbid disorder-matched psychopathologic controls (N = 26). As part of a naturalistic, longitudinal, nosologic study, patients were repeatedly examined during an average follow-up interval of 7 to 8 years. RESULTS: Adjustment disorder was associated with six symptoms, on average, and 60% of the patients had other, specific psychiatric disorders. Adjustment disorder had a median episode length of 7 months and a 97% recovery rate. Comorbidity had no appreciable effect on recovery. Patients with adjustment disorder and controls had similar rates of new psychiatric disorders and other dysfunctional outcomes during the follow-up. CONCLUSIONS: Among psychiatrically referred youths, the diagnosis of AD has clinical information value and identifies a syndromatic presentation that can be the focus of concern or treatment. It has a reasonably good short-term prognosis, in spite of the fact that patients with this diagnosis typically present with comorbid specific psychiatric disorders. Controlling for the effects of comorbidity, AD does not predict later dysfunction. To achieve a convergence of findings from research and clinical practice, it would be important to ensure a uniform application of specific, operational diagnostic criteria for AD.

A controlled family history study of childhood-onset depressive disorder.

BACKGROUND: We studied the family psychiatric history of 125 youths with childhood-onset depressive disorder (a portion of whom developed bipolar disorder) and 55 psychiatric controls with nonaffective disorder. METHODS: Probands were classified according to prospectively observed clinical course in childhood. Family psychiatric history was determined by interviewers blind to probands' diagnosis, with mothers typically informing about themselves and about remaining first- and a all second-degree adult relatives. RESULTS: Families of affectively ill juveniles had 5-fold greater odds of lifetime depressive disorder and 2-fold greater odds of recurrent unipolar depressive disorder than did families of psychiatric controls. The higher risk of depression was most evident in first-degree and female relatives. Mothers of affectively ill youths were younger at onset of depression than were mothers of controls. Alcoholism and substance use disorders were more prevalent in relatives of affectively ill probands than in controls and cosegregated with familial depression. However, other covariates were more important at predicting patterns of familial depression. Familial illness patterns also varied somewhat with proband characteristics. CONCLUSIONS: Child probands with affective disorder identify families enriched with affective disorder (even compared with families of psychiatric controls), suggesting that juvenile- and adult-onset forms of this condition share the same diathesis. Rates of affective illness in the families of depressed youngsters also are notably higher than population-based estimates. The findings therefore indicate that very-early-onset affective disorder is familial and that pedigrees ascertained through affectively ill children are good candidates for family and genetic studies.

Depressive disorders in childhood. II. A longitudinal study of the risk for a subsequent major depression.

As part of a longitudinal nosologic study of major depressive disorder, dysthymic disorder (DD), and adjustment disorder with depressed mood ( ADDM ) in a school-aged cohort, the predictive validity of each diagnosis was examined. Using all available data on the course of the disorders, the criterion was the first subsequent major depressive episode. Major depressive disorder and DD signaled a similarly high risk of a new bout of depressive illness. For the children who recovered from their first episode of major depression and then had their second one (40%), the free interval did not exceed two years; an underlying dysthymia increased the risk of recurrence. Major depression and dysthymia were distinct from ADDM and a set of control disorders; the latter two diagnostic groups were associated with a minimal risk for major depression.

Initial psychologic responses of parents to the diagnosis of insulin-dependent diabetes mellitus in their children.

As part of a prospective, longitudinal study of school-aged children with newly diagnosed insulin-dependent diabetes mellitus (IDDM), we examined how the parents adjusted to the illness. The present article documents this process for the first year of IDDM. We found no support for earlier claims that most parents resort to blatantly neurotic or psychopathologic behavior to cope. Instead, the initial strain of living with IDDM generally elicited mild and subclinical depression, anxiety, and overall distress. Mothers were more affected than fathers: they were more symptomatic (about one of four developed a mild grief reaction) and the bulk of them worried considerably about their children. However, the parents' initial emotional upheaval resolved in approximately equal to 6 mo; most mothers came to terms with IDDM by the end of the first year; and other areas of parental functioning (e.g., quality of their marriage) were not affected. Therefore, along with our previous report on how the children coped initially, the findings document the emotional resiliency of families during the first year of IDDM.

The effect of heat shock on primary cultures of brain capillary endothelium: inhibition of assembly of zonulae occludentes and the synthesis of heat-shock proteins.

Subjecting primary cultures of bovine brain microvessel endothelial cells to thermal stress (heat shock) results in: (1) an inhibition of further tight junction assembly, (2) the disappearance and/or disassembly of tight junctions, (3) a 30-fold increase in the number of plasmic fracture (PF)-face intramembrane particles, and (4) the new and/or enhanced synthesis of at least three heat-shock polypeptides (HSPs) with molecular masses of approximately 100,000, 90,000 and 70,000. Endothelial cells which are heat-shocked and allowed to recover at 37 degrees C exhibit, within the first 2 h, a marked depression in the synthesis of HSPs and the new and/or enhanced synthesis of a 47,000 dalton "recovery" polypeptide. In later periods of recovery (2-4 h), the synthesis of this polypeptide is even more pronounced and is accompanied by the new and/or enhanced synthesis of a polypeptide(s) with a molecular mass of 35 to 37,000. The appearance of these "recovery protein(s)" in the endothelial cells is concomitant with a decrease in the number of PF-face intramembrane particles and the resumption of tight junction assembly. Results of this study suggest that some of the HSPs synthesized by thermally-stressed cultures of brain endothelial cells may activate or be directly involved in a mechanism(s) to ensure survival of these cells by decreasing membrane fluidity and stabilizing the plasma membrane of these cells. Moreover, our results also suggest that the recovery of these cells from the stress of heat shock is accompanied by the synthesis of "recovery" proteins which, in some manner, may be directly involved in, or necessary for, rapidly reversing the membrane-stabilizing effect of heat shock by promoting membrane fluidity and the apparent amplified synthesis and assembly and/or reassembly of tight junctions.

Criterion and predictive validity of the diagnosis of adjustment disorder: a prospective study of youths with new-onset insulin-dependent diabetes mellitus.

OBJECTIVE: The authors examined the criterion and predictive validity of the diagnosis of adjustment disorder in a pediatric study group. METHOD: Ninety-two school-age children with new-onset insulin-dependent diabetes mellitus were evaluated repeatedly and were diagnosed by using DSM-III. The criteria for adjustment disorder were further operationalized by requiring four clinically significant symptoms or signs; the time frame for its onset was extended to 6 months after the diagnosis of insulin-dependent diabetes. Predictive validity was assessed in terms of new psychiatric disorders other than adjustment disorder during the next 5 years. RESULTS: Of the 92 children, 33 developed adjustment disorder and five developed other psychiatric disorders in response to the diagnosis of insulin-dependent diabetes mellitus. Mean time from diabetes diagnosis to onset of adjustment disorder was 29 days, the average episode length was 3 months, and the recovery rate was 100%. Among youths with adjustment disorder in response to the medical diagnosis, the 5-year cumulative probability of a new psychiatric disorder was 0.48, compared to 0.16 among the other youths. CONCLUSIONS: The findings generally support the criterion validity of the diagnosis of adjustment disorder. However, episode duration and the predictive validity of the diagnosis appear to be functions of the study group being examined. In nonpsychiatrically referred pediatric patients, early problems in adaptation to the stress of changed health status, as evidenced by adjustment disorder, appear to signal vulnerability to later psychopathology.