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PubMed2002

Anemia and blood transfusion in critically ill patients.

CONTEXT: Anemia is a common problem in critically ill patients admitted to intensive care units (ICUs), but the consequences of anemia on morbidity and mortality in the critically ill is poorly defined. OBJECTIVES: To prospectively define the incidence of anemia and use of red blood cell (RBC) transfusions in critically ill patients and to explore the potential benefits and risks associated with transfusion in the ICU. DESIGN: Prospective observational study conducted November 1999, with 2 components: a blood sampling study and an anemia and blood transfusion study. SETTING AND PATIENTS: The blood sampling study included 1136 patients from 145 western European ICUs, and the anemia and blood transfusion study included 3534 patients from 146 western European ICUs. Patients were followed up for 28 days or until hospital discharge, interinstitutional transfer, or death. MAIN OUTCOME MEASURES: Frequency of blood drawing and associated volume of blood drawn, collected over a 24-hour period; hemoglobin levels, transfusion rate, organ dysfunction (assessed using the Sequential Organ Failure Assessment score), and mortality, collected throughout a 2-week period. RESULTS: The mean (SD) volume per blood draw was 10.3 (6.6) mL, with an average total volume of 41.1 (39.7) mL during the 24-hour period. There was a positive correlation between organ dysfunction and the number of blood draws (r = 0.34; P<.001) and total volume drawn (r = 0.28; P<.001). The mean hemoglobin concentration at ICU admission was 11.3 (2.3) g/dL, with 29% (963/3295) having a concentration of less than 10 g/dL. The transfusion rate during the ICU period was 37.0% (1307/3534). Older patients and those with a longer ICU length of stay were more commonly transfused. Both ICU and overall mortality rates were significantly higher in patients who had vs had not received a transfusion (ICU rates: 18.5% vs 10.1%, respectively; chi(2) = 50.1; P<.001; overall rates: 29.0% vs 14.9%, respectively; chi(2) = 88.1; P<.001). For similar degrees of organ dysfunction, patients who had a transfusion had a higher mortality rate. For matched patients in the propensity analysis, the 28-day mortality was 22.7% among patients with transfusions and 17.1% among those without (P =.02); the Kaplan-Meier log-rank test confirmed this difference. CONCLUSIONS: This multicenter observational study reveals the common occurrence of anemia and the large use of blood transfusion in critically ill patients. Additionally, this epidemiologic study provides evidence of an association between transfusions and diminished organ function as well as between transfusions and mortality.

APACHE↗

PubMed2001

Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats.

The substituted amphetamine 3,4 methylenedioxyamphetamine (MDA) is a popular recreational drug of abuse. Administration of MDA to experimental animals has been shown to induce damage to serotonergic axons and nerve terminals. However, there is a lack of information on whether these treatments can produce any long-term changes in behavioural performance particularly under stressful conditions. In the present study, MDA (7.5 mg/kg; i.p.) was administered twice daily to adult male Sprague Dawley rats for four days. Four weeks following the last dose, spontaneous behaviors of these animals were tracked and scored in a novel "open field" environment using an automated video registration and computer interpretation system. Changes in behavior were observed in MDA treated animals including reductions in exploratory oriented behaviors (locomotion and rearing) and increases in grooming behavior when compared to vehicle treated controls. MDA-treated animals also displayed an enhanced locomotor and stereotyped response to d-amphetamine (12 mg/kg; i.p.). Significant reductions in 5-HT concentrations (20-30%) were observed in the frontal cortex, amygdala, striatum, and hypothalamus as a result of MDA treatment. In addition, [3H] paroxetine binding was reduced by (40%) in the cortex of MDA treated rats indicating that the decrease in 5-HT concentrations were accompanied by a reduction in intact presynaptic 5-HT nerve terminals. Changes in behavioural performance in a novel "open field" environment and following d-amphetamine challenge might be considered as a behavioural model of serotonergic deficit induced by MDA. The findings of this study also suggest that MDA use may increase both the abuse potential, and the propensity to develop psychosis as a result of abusing other psychostimulants such as d-amphetamine.

Animals↗

PubMed2002

Bone density and metabolism in children and adolescents with moderate to severe cerebral palsy.

OBJECTIVES: Diminished bone density and a propensity to fracture with minimal trauma are common in children and adolescents with moderate to severe cerebral palsy (CP). The purpose of this study was to provide a detailed evaluation of bone mineral density (BMD) and metabolism in this population and to assess the relationship of these measures to multiple other clinical, growth, and nutrition variables. METHODS: The study group consisted of 117 subjects ages 2 to 19 years (mean: 9.7 years) with moderate to severe CP as defined by the Gross Motor Functional Classification scale. Population-based sampling was used to recruit 62 of the participants, which allows for estimations of prevalence. The remaining 55 subjects were a convenience sampling from both hospital- and school-based sources. The evaluation included measures of BMD, a detailed anthropometric assessment of growth and nutritional status, medical and surgical history, the Child Health Status Questionnaire, and multiple serum analyses. BMD was measured in the distal femur, a site specifically developed for use in this contracted population, and the lumbar spine. BMD measures were converted to age and gender normalized z scores based on our own previously published control series (n > 250). RESULTS: Osteopenia (BMD z score <-2.0) was found in the femur of 77% of the population-based cohort and in 97% of all study participants who were unable to stand and were older than 9 years. BMD was not as low in the lumbar spine (population-based cohort mean +/- standard error z score: -1.8 +/- 0.1) as in the distal femur (mean z score: -3.1 +/- 0.2). Fractures had occurred in 26% of the children who were older than 10 years. Multiple clinical and nutritional variables correlated with BMD z scores, but interpretation of these findings is complicated by covariance among variables. In stepwise regression analyses, it was found that severity of neurologic impairment as graded by Gross Motor Functional Classification level, increasing difficulty feeding the child, use of anticonvulsants, and lower triceps skinfold z scores (in decreasing order of importance) all independently contribute to lower BMD z scores in the femur. CONCLUSIONS: Low BMD is prevalent in children with moderate to severe CP and is associated with significant fracture risk. The underlying pathophysiology is complex, with multiple factors contributing to the problem and significant variation between different regions of the skeleton.

Adolescent↗

PubMed2002

Apolipoprotein E4 is associated with reduced calcaneal quantitative ultrasound measurements and bone mineral density in elderly women.

Some studies have reported an association between the apolipoprotein E4 (APOE4) allele and reduced bone density and increased propensity to fracture, but this remains controversial as other studies have not found an association between APOE4 and bone density or fracture. No information is available concerning the effect of the APOE4 allele on quantitative ultrasound (QUS) parameters. We therefore examined this issue in a population-based study of 1332 healthy elderly women, examining the effect of the APOE4 allele on QUS parameters at the calcaneus and comparing this to dual-energy X-ray absorptiometry (DEXA) bone mineral density (BMD) at the hip. In addition, we examined the effect of the APOE4 allele on fracture. Subjects who had at least one APOE4 allele (n = 308) had lower calcaneal QUS parameters and lower hip BMD at the total hip, trochanter, and intertrochanter, but not the femoral neck, compared to subjects without an APOE4 allele (n = 1024) after adjustment for age, body mass index (BMI), and smoking. The decrement in QUS parameters and BMD was approximately 2%. Those subjects having an APOE4 allele were also more likely to fall into a low bone density group, defined by a T score of <1 SD below the young normal range (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.08-2.22). We compared both prevalent and incident nontraumatic fractures over 2 years in the APOE4-present group compared with the APOE4-absent group. There were 354 subjects who entered the study with a history of one or more prevalent fractures, and 104 subjects sustained a nontraumatic fracture during the study. These fractures were not associated with the presence of the APOE4 allele, but a 2% decrement in BMD was unlikely to be associated with a statistically observable increase in fractures in this study. The APOE4 allele was not associated with a difference in any biochemical measures of bone formation or resorption, or in estrogen concentration, nor was it associated with a difference in BMI. Therefore, we conclude that the APOE4 allele is associated with a consistent decrease in both QUS parameters at the calcaneus and BMD at the clinically important hip site, and that this is not associated with differences in biochemical measures of bone formation or resorption.

Aged↗

PubMed2005

[Sudden cardiac death in familial hypertrophic cardiomyopathy. Identification of high-risk patients].

Hypertrophic cardiomyopathy (HCM) is a relatively frequent, genetically determined primary cardiomyopathy, characterized by most often asymmetric hypertrophy of the ventricular septum with or without systolic obstruction of the left ventricular outflow tract. HCM is a genetically heterogeneous disease, with 12 different disease-causing genes beeing indentified to date. Histologically the disease is characterized by hypertophy and disarray of myofibrils as well as by an increase in myocardial fibrosis. Clinically, these changes may lead to palpitations, dyspnoe on exertion, and/or angina pectoris. However, they also lead to an increased propensity to the development of severe ventricular tachyarrhythmias and sudden cardiac death. The incidence of sudden death is significantly increased in HCM, particularly in affected young subjects. Risk stratification in HCM should include a complete clinical-cardiological evaluation that should also consider new diagnostic features, e. g. MR imaging. Major risk factors for sudden cardiac death include a survived cardiac arrest (ventricular fibrillation), non-sustained and sustained ventricular tachycardia, a history of premature familial sudden death, unexplained syncope, an abnormal blood pressure response on exercise, and left ventricular thickness greater than or equal to 3 cm. Ideally, risk stratification should also include genetic testing, since some gene mutations seem to be associated with a higher risk for sudden cardiac death than others. However, genetic testing in HCM in not yet available on a routine basis. The implantation of a cardioverter/defibrillator is first-line therapy in patients with documented ventricular tachycardia/fibrillation or patients who have survived sudden cardiac death. These devices also play an important role in the primary prevention of sudden cardiac death in HCM. Algorithms and scores are available to estimate the risk of sudden death, however, the decision to implant a cardioverter/defibrillator remains an individual decision in every single patient.

Blood Pressure↗

PubMed1992

Detrimental effect of alcohol intoxication on severity of injuries in male traffic accident victims: a cross-sectional study.

A cross-sectional emergency room study was performed among traffic accident victims aged 16 to 75 years in order to investigate the prevalence of alcohol intoxication (blood alcohol concentration (BAC greater than or equal to 0.8 g/kg) and its potential detrimental effect on injury severity. A BAC greater than or equal to 0.8 g/kg was present in 29% of the male patients. Intoxicated patients had a similar propensity to require inpatient hospital care (65 versus 60%) but had significantly longer hospital stays than the non-intoxicated patients (36 versus 20 days; p less than 0.05), observations which may be explained by the higher prevalence of serious injuries (head and internal injuries) among the intoxicated cohort. This study supports and emphasizes the detrimental effect of alcohol intoxication on the severity of injuries in traffic accident victims, and reinforces the need for further legal and public health measures in preventing alcohol-related traffic accidents.

Accidents, Traffic↗

PubMed1995

Effects of alcohol, at two times of day, on EEG-derived indices of physiological arousal.

Effects of alcohol consumption (0.8 ml/kg) on sleep propensity, spectral characteristics of the EEG and self-rated activation in 16 young male subjects, were investigated during sessions at each of two times of day (08.00 and 16.00). Within-session, time-related changes in the pattern of stage-1 sleep occurrence, and of spectral power in different EEG bands indicated that, irrespective of time of day, physiological arousal increased as estimated blood alcohol concentration (BAC) was rising, and decreased as BAC was falling. Subjective activation was reduced by alcohol during both phases of the BAC curve. A pattern of reduced stage-1 sleep occurrence, higher absolute high alpha power and higher ratings of activation suggested that, irrespective of alcohol condition, physiological and subjective arousal was higher during sessions starting at 16.00 than during those starting at 08.00. There were no significant interactions between alcohol and time of day in respect of any dependent variable. However, the degree to which effects reflecting circadian variation may have been masked by effects of limited sleep restriction prior to morning sessions remains unclear. Subjects reported having slept on only 23.5% of occasions when sleep was scored. Comparison of patterns of statistically significant changes in absolute and relative power in different bands indicated that the two indices do not provide exactly equivalent information about changes in the EEG.

Adult↗

PubMed2005

Short-term homeostasis of REM sleep throughout a 12:12 light:dark schedule in the rat.

STUDY OBJECTIVES: Intervals extending from the end of a rapid eye movement (REM) sleep episode until the triggering of the next tend to be longer when they follow a longer REM sleep episode. A short-term REM sleep homeostatic process has been hypothesized to explain this effect. The present study assessed and modeled the REM sleep episode-interval relationship and compared its expression at different phases of a 12:12 light: dark schedule. DESIGN: Chronically implanted rats were continuously recorded for 3 consecutive days. Automated state scoring in 15-second epochs determined lengths of REM sleep episodes and intervals and non-rapid eye movement sleep and wakefulness content of intervals. SETTING: Individual sound-attenuated temperature-regulated boxes. PARTICIPANTS: 16 Sprague-Dawley rats. INTERVENTIONS: Scheduled 12:12 light:dark cycle. MEASUREMENTS AND RESULTS: The effect of REM sleep episode length is evidenced by a rising trend in the means and robust means of intervals and non-rapid eye movement content that follow REM sleep episodes of a given length. The relationship of robust means of intervals and REM sleep episode length was best fitted by a Gompertz sigmoid function. The parameters of the Gompertz equation were modulated throughout the 24 hours, presenting the highest amplitude and earliest rise in hours 1 to 4 after lights on and the lowest amplitude at the start of lights off. The modulation was also evident when only intervals with less than 3 minutes of wakefulness were considered. CONCLUSIONS: Short-term REM sleep homeostasis is modulated throughout the 24 hours under a 12:12 light:dark regime. Its assessment may provide a useful measure of REM sleep propensity, regulation, and recurrence.

Animals↗

PubMed2004

Sweet liking, novelty seeking, and gender predict alcoholic status.

BACKGROUND: The relationship between a hedonic response to sweet taste and a propensity to excessive alcohol drinking is supported by both animal and human studies. There is evidence indicating that the tendency to rate more concentrated sweet solutions as the most pleasurable (i.e., sweet liking) is associated with the genetic vulnerability to alcoholism. However, sweet liking by itself is insufficient to predict the alcoholic status of the individual. Our previous study indicated that alcoholic status can be predicted by a combination of hedonic response to sweet taste and personality profile as measured by the Tridimensional Personality Questionnaire (TPQ). This study was designed to further test this hypothesis. METHODS: Participants were 165 patients admitted to a residential treatment program for the treatment of alcoholism, drug dependence and/or interpersonal problems secondary to substance-abusing family members. In addition to a routine medical examination, on the 24th day after admission, patients completed the TPQ, the standard sweet taste test was conducted, and paternal family history of alcoholism was evaluated. RESULTS: Sweet liking was strongly associated with a paternal history of alcoholism. The odds of receiving an alcohol dependence diagnosis were shown to increase, on the average, by 11% for every one-point increase in the TPQ novelty-seeking score in sweet-liking but not in sweet-disliking subjects. Gender contributed independently to the probability of alcohol dependence, with males exhibiting higher rates of alcoholism than females. CONCLUSIONS: These findings support the hypothesis that a hedonic response to sweet taste is associated with a genetic risk for alcoholism. Alcoholic status may be predicted by a combination of sweet liking, the TPQ novelty-seeking score, and gender in a mixed group of alcoholic, polysubstance-dependent, and psychiatric patients.

Adult↗

PubMed2005

Neurosurgical coverage: essential, desired, or irrelevant for good patient care and trauma center status.

SUMMARY AND BACKGROUND DATA: As a result of many factors, the availability of neurosurgeons (NS) to care for trauma patients (TP) is increasingly sparse. This has precipitated a crisis in access to neurosurgical support in many trauma systems, often placing undue burden on level I centers. This study examines the profile of head-injured (HI) trauma patients and their actual need for the specific expertise of a neurosurgeon. METHODS: The National Trauma Data Bank (NTDB) was queried for specific information relating to the volume, nature, timeliness, and outcome of HI TP. Study patients were identified by reported International Classification of Diseases, 9th Edition (ICD-9) codes denoting open (OHI) or closed head injury (CHI) in isolation or in combination with other injuries. RESULTS: Total number of NTDB patients studied was 731,823, of which 213,357 (29%) had a reported HI. CHI represented 22% of all TP and 74% of HI. OHI was reported in 8% of all TP and was 26% of HI. Craniotomy (crani) was performed in 3.6% of all HI (1% of all TP). This was in 2.8% of OHI and 2.6% of CHI. Mean Glasgow Coma Scale score (GCS) of crani patients was 9, and 13 for the noncrani group. Subdural hematoma occurred in 18% of HI (5% of TP), with 13% undergoing crani. Epidural hematoma occurred in 10% of HI (3% of all TP), with 17% undergoing crani. Median time to OR for all cranis was 195 minutes (195 for CHI; 183 for OHI). Of all cranis, 6.5% were performed within 1 hour of hospital admission. Intracranial pressure (ICP) monitoring was reportedly used in 0.7% of TP and 2.2% of HI. CONCLUSIONS: Care of TP with HI rarely requires the explicit expertise and immediate presence of a neurosurgeon due to volume and nature of care. HI was diagnosed in <30% of TP reported to the NTDB. Over 95% required nonoperative management alone, with only 1% of all TP and 2%-4% of HI TP requiring crani and/or ICP monitoring. Immediate availability of NS is not essential if a properly trained and credentialed trauma surgeon or other health care provider can appropriately monitor patients for neurologic demise and effect early transfer to a center capable of, and committed to, operative and postoperative neurosurgical care. A subgroup of patients known to have a high propensity for the specific expertise of a neurosurgeon may be able to be identified for direct transport to these committed centers.

Craniocerebral Trauma↗

PubMed2001

Mortality after coronary artery occlusion in different models of cardiac hypertrophy in rats.

Chronic treatment with minoxidil induces cardiac trophic and sympathetic responses, which may increase the propensity for lethal arrhythmias. To test this hypothesis, acute coronary artery occlusion was performed in conscious normotensive rats treated for 2 or 5 weeks with minoxidil with the use of a 2-stage approach to cause a myocardial infarction. For comparison, rats with aortocaval (A-V) shunts and spontaneously hypertensive rats (SHR) were studied. Minoxidil increased left ventricular and right ventricular weights by 15% to 20%, and the A-V shunt increased these weights by 30% to 40%. In SHR, left ventricular weight was increased by 50%, and right ventricular weight was increased by 25%. In rats treated with minoxidil for 5 weeks, coronary artery occlusion caused a rapid and marked mortality, and 4 hours after myocardial infarction, only 18% of these rats were alive versus 61% of the control rats. In rats with the A-V shunt, coronary artery occlusion was also associated with increased mortality, and after 6 hours, 33% were still alive compared with 59% of the control rats. In contrast, SHR with marked hypertension and cardiac hypertrophy showed only a minor increase in mortality (survival rates were 53% versus 60% in SHR versus Wistar-Kyoto rats, respectively). Mortality was preceded by high arrhythmia scores, and ventricular fibrillation was the cause of death. Discontinuation of minoxidil for 1 week, sympathetic blockade with nadolol or clonidine, or blockade of the renin-angiotensin system with enalapril or losartan did not improve minoxidil-induced excess mortality. We conclude that ventricular stretch and other mechanisms (eg, cardiac vagal activity) in rats appear to be more potent than hypertension-induced left ventricular hypertrophy in predisposing for lethal arrhythmias in the setting of acute ischemia.

Animals↗

PubMed2001

Treatment for amphetamine withdrawal.

BACKGROUND: Amphetamine withdrawal has been less studied although it is a common problem with a prevalent rate of 87% among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse of amphetamine use. In clinical practice, treatment for cocaine withdrawal has been recommended for the management of amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two substances are not the same. OBJECTIVES: To search and determine risks, benefits, and costs of a variety of treatments for the management of amphetamine withdrawal. SEARCH STRATEGY: Electronic searches of MEDLINE (1966 - December 2000), EMBASE (1980 - February 2001), CINAHL (1982 - January 2001) and Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4) were undertaken. References to the articles obtained by any means were searched. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were included. Participants were people with amphetamine withdrawal, diagnosed by any set of criteria. Any kinds of biological and psychological treatments both alone and combined were examined. A variety of outcomes, for example, number of treatment responders, score changes, were considered. DATA COLLECTION AND ANALYSIS: Two reviewers evaluated and extracted the data independently. The dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assessed the continuous data. MAIN RESULTS: The results of two studies have shown some benefits of amineptine in the treatment of amphetamine withdrawal. Those benefits can be seen in the respects of discontinuation rate and global state, as measured by Clinical Global Impression Scale. However, no direct benefit of amineptine on amphetamine withdrawal symptoms or craving was shown. REVIEWER'S CONCLUSIONS: The evidence about the treatment for amphetamine withdrawal is very limited. Amineptine has limited benefits on some amphetamine withdrawal symptoms. Due to a number of reports of amineptine abuse, it has been withdrawn from the market for a few years. At present, no available treatment has been demonstrated to be effective in the treatment of amphetamine withdrawal. The medications that should be considered for further treatment studies may be those with the propensities to increase dopamine, norepinephrine and/or serotonin activities of the brain. Naturalistic studies of amphetamine withdrawal symptoms and course are also crucial for the development of study designs appropriate for further treatment studies of amphetamine withdrawal.

Amphetamine↗

PubMed2006

Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation.

BACKGROUND: Late-stage prostate cancer patients are refractory to hormone therapy and exhibit a high propensity to develop skeletal metastasis. In this regard, the role of a novel cytokine system belonging to the tumor necrosis factor (TNF) family that is critical for osteoclastic osteolysis and that consists of receptor activator of NF-kappaB ligand (RANKL), its receptor (RANK), and decoy receptor osteoprotegerin (OPG) is of potential interest. METHODS: Reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical analysis was used to examine the expression of RANKL, RANK, and OPG in human prostate cancer cell lines and in 89 archival samples of primary and metastatic (lymph nodes, skeleton) prostate cancer patients. Expression of these proteins was correlated with clinicopathogic parameters of the prostate cancer. RESULTS: Expression of RANKL/RANK/OPG was low in normal but markedly higher in prostate cancer cell lines. Analysis of surgical biopsy specimens showed the expression of RANKL (31%), RANK (38%), and OPG (19%) in primary carcinoma. The expression frequency was significantly higher (RANKL [44%], RANK [49%], and OPG [73%]) in metastatic prostate cancer. OPG (83%) production was more common in skeletal as compared with lymph node metastases (46%), whereas the expression of RANKL expression was less discordant in bone (47%) and lymph node metastases (36%). The increased expression of RANKL/RANK/OPG observed correlated with Gleason score, TNM stage, androgen status, and serum prostate-specific antigen (PSA) levels in the prostate cancer patients. CONCLUSIONS: Expression of RANKL/RANK/OPG correlates with more aggressive, advanced, metastatic prostate carcinoma to suggest their role as diagnostic, prognostic, and therapeutic targets for prostate cancer.

Aged↗

PubMed2003

Ethiopian-born and native Israeli school children have different growth patterns.

OBJECTIVE: Nutrition status of preschool children in Azezo, North West Ethiopia, and Ethiopian-born and native Israeli children aged 7 to 11 y and 12 to 15 y was studied. The aim of the study was to determine the growth patterns of immigrant children after changes in their nutritional habits. METHODS: The Ethiopian-born and native school children were recruited from a caravan-dwelling site and a boarding school and from a town adjacent to the caravan site and a boarding school, respectively. RESULTS: Weight for age was lower than -2 standard deviations of the Z score in 40.5%, 55.6%, 31.9%, and 61% of children aged 1 to 24, 25 to 36, 37 to 48, and 49 to 60 mo, respectively. Similarly, 18.9%, 59.3%, 39.1%, and 19.5% of children aged 1 to 24, 25 to 36, 37 to 48, and 49 to 60 mo had a height for age lower than -2 standard deviations of the Z score. The Ethiopian-born boys aged 7 to 11 y had lower body weight (P < 0.03), mean arm muscle circumference, plasma transthyretin and magnesium (P < 0.0001), and higher triceps skinfold thickness (P < 0.01) compared with the controls. Similarly, the Ethiopian-born girls had lower body weight (P < 0.006), weight-to-height ratio (P < 0.02), mean arm muscle circumference and plasma transthyretin, calcium, and magnesium (P < 0.0001), and higher triceps skinfold thickness (P < 0.0001) than their Israeli counterparts. Weight, weight-to-height ratio, mean arm muscle circumference, plasma calcium and magnesium (P < 0.0001), and transthyretin (P < 0.01) were lower and triceps skinfold thickness (P < 0.0001) was higher in the Ethiopian-born boarding school children than in the native Israelis of the same age range. CONCLUSIONS: The Azezo study confirmed that malnutrition-induced developmental impairment in preschool children is a major problem in Ethiopia. It is a manifestation of a rural economic and educational poverty and cannot be eradicated by palliative short-term nutritional programs. Although ethnicity and prenatal and postnatal malnutrition may have contributed, an insufficiency or imbalance of vital nutrients appeared to be the determinant factor for the lower relative growth of the Ethiopian-born children. The children from Ethiopia may have a propensity to avoid certain foods because of digestive intolerance or early childhood dietary habituation. Parental financial constraint may have been a factor in the younger group. These findings have implications for nutrition and welfare policies for children emigrating from developing countries.

Adolescent↗

PubMed1998

A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia.

Quetiapine (Seroquel, ICI 204,636) is an atypical antipsychotic that is effective in the treatment of both positive and negative symptoms of schizophrenia, and has a low propensity to cause extrapyramidal symptoms. The compound has a relatively short plasma elimination half-life (approximately 7 h). However, since dopamine D2 receptor occupancies correlate poorly with plasma concentrations of antipsychotics, plasma elimination half-life may not predict either duration of clinical effect or dosing frequency. Accordingly, the efficacy and tolerability of three dosing regimens (450 mg/day given in two or three divided doses daily, and 50 mg/day given twice daily) were compared in a 6-week, double-blind, randomized, multicentre, parallel-group study. The study recruited hospitalized men and women aged 18-65 years meeting DSM-IIIR criteria for acute exacerbation of chronic or subchronic schizophrenia. Six hundred and eighteen patients were randomly assigned to treatment with quetiapine 150 mg tid (n = 209), 225 mg bd (n = 200), or a comparator dose of 25 mg bd (n = 209). At day 42, the last day of randomized treatment and the primary timepoint for efficacy, quetiapine 450 mg/day was more effective than 50 mg/day: 225 mg bd was consistently superior to 25 mg bd in all measures of efficacy (total BPRS, P = 0.006; CGI severity, CGI improvement and SANS, P < 0.03), and 150 mg tid was statistically significantly superior to 25 mg bd with respect to BPRS total score (P = 0.05). The 225 mg bd and 150 mg tid groups were not significantly different from each other with respect to any efficacy measure. Quetiapine was generally well tolerated. Extrapyramidal symptom (EPS) adverse events were generally rare, and occurred with similar frequencies in the two 450 mg/day groups. Quetiapine was not associated with sustained increases in plasma prolactin at any dose. These data support the atypical profile developed from preclinical studies and show that quetiapine is an effective, well tolerated antipsychotic that can be given twice daily.

Adolescent↗

PubMed1999

Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia.

Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the DRD3ser-gly genotype in the schizophrenia patients with TD. The difference between the schizophrenia patients with TD and the controls was highly significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for multiple testing, as was the difference between the combined group of schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002). Comparing the schizophrenia patients with and without TD, genotypes containing the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02). DRD3 genotype and age at first antipsychotic treatment contributed significantly to total score on the Abnormal Involuntary Movements Scale (AIMS). The contribution of DRD3 to the variance in AIMS total was 5.2% and the total proportion of the variance accounted for by these two variables together was 11.9%. These results support and extend the report by Steen et al (1997) of an association between DRD3 and TD in schizophrenia patients.

Adult↗

PubMed1994

Enhanced cancer growth in mice administered daily human-equivalent doses of some H1-antihistamines: predictive in vitro correlates.

BACKGROUND: Present studies of drug-induced tumor growth promotion have evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy[ethanamine.HCl, a tamoxifen derivative which potently inhibits lymphocyte mitogenesis in vitro and stimulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (HIC), some of which are on cytochromes P450, may correlate with tumor growth-promoting activity. PURPOSE: We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine. METHODS: Potency of each agent was ranked 1-5 in each of the following in vitro assays: 1) inhibition of [3H]histamine binding to microsomal HIC, 2) inhibition of histamine binding to microsomal P450, 3) inhibition of the P450-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. Two laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous injection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C-3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly assigned to treatment groups, then received a single, daily intraperitoneal injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being killed. Tumors were surgically removed and wet weights compared statistically among groups. RESULTS: The cumulative potency of each drug in affecting tumor growth or growth mechanisms in the five in vitro assays ranked as follows: Loratidine and astemizole ranked highest and were equally potent, followed in decreasing order by hydroxyzine, doxylamine, and cetirizine. A significant correlation (r = .97; P < .02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth in vivo: Loratidine and astemizole significantly (P < .001) promoted the growth of both melanoma and fibrosarcoma, hydroxyzine significantly (P < .001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote the growth of either tumor. CONCLUSION: Data demonstrate that the in vitro assays predicted the propensity of each H1-antihistamine to stimulate cancer growth in vivo. IMPLICATION: These in vitro tests may prove valuable to screen potential tumor growth promoters.

Animals↗

PubMed2000

Capsaicin induced cough in cryptogenic fibrosing alveolitis.

BACKGROUND: Cough is a common and troublesome symptom in cryptogenic fibrosing alveolitis (CFA) but the mechanisms responsible are not known. The cough threshold to inhaled capsaicin is increased in asthma and chronic obstructive pulmonary disease (COPD) where lung volumes are increased, but the relationship between cough response and symptom intensity has not been studied in CFA where lung volumes are reduced. METHODS: Capsaicin challenge tests were performed on 15 subjects with proven CFA and 96 healthy controls. Symptoms, as assessed by daily diary card cough score and by visual analogue scale (VAS), were related to the capsaicin sensitivity (C5) and compared with lung volumes. Volume restriction was produced in a group of 12 normal healthy subjects by a plastic shell tightly strapped to the chest wall. Capsaicin challenge tests were performed in these subjects, both strapped and unstrapped, to determine whether volume restriction altered the cough reflex. RESULTS: The median C5 response in normal subjects was more than 500 microM compared with 15.6 microM in those with CFA (p<0.001). The C5 response of the CFA patients was not related to symptoms of cough (whether measured by diary card or by VAS), nor was it related to percentage predicted total lung capacity (TLC) or forced vital capacity (FVC). Volume restriction of normal subjects with chest strapping successfully restricted lung volumes to levels similar to that of the CFA patients but did not change the sensitivity to capsaicin. CONCLUSIONS: The cough reflex measured using capsaicin is markedly increased in patients with CFA. This increase is not the result of alterations in the deposition of inhaled particles of capsaicin brought about by volume restriction. It could be related to reduced lung compliance leading to sensitisation of rapidly adapting receptors, other mechanical changes, or to destruction of pulmonary C fibres secondary to interstitial inflammation. The capsaicin test may be a useful method of objectively monitoring cough propensity in CFA.

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