Acetylcholinesterase inhibition in dementia with Lewy bodies: results of a prospective pilot trial

OBJECTIVE: Dementia with Lewy bodies (DLB) is the second commonest form of dementia. The response to acetylcholinesterase inhibition (AChEI) could be greater in DLB than in Alzheimer's disease (AD) because cholineacetyl-transferase levels are more reduced in the former. This preliminary trial seeks to compare performances in cognitive tasks before and after tacrine administration in DLB and AD subjects. METHODS: Six DLB and 6 AD patients were enrolled in an open, nonrandomized, intervention trial using 80 mg/day tacrine. Patients met ADRDA or DLB consortium criteria for probable diseases. Subjects were matched for Mini Mental State Examination (MMSE) score, age and sex. Mattis Dementia Rating Scale (DRS), Controlled Oral Word Association Test (FAS) and Boston Naming tests were administered at baseline and at 6 months into treatment. RESULTS: AD and DLB groups did not differ in initial mean total DRS scores. In the primary analysis, both groups declined during the course of treatment (-7.3 +/- 4.2 and -16.8 +/- 39.2 DRS points, respectively). Due to the large variability in DLB posttreatment scores, this group was divided post hoc into responders (DLBr) and nonresponders (DLBnr). The DLBr group outperformed the DLBnr group at baseline (p < 0.05) and, notably, in follow-up DRS test scores (p < 0.001). Two-way MANOVA comparing both DLB subgroups with either the entire AD cohort or similarly stratified AD subgroups showed a significant interaction (F = 7.6; p < 0.015), attributed mostly to declines in DLBnr group scores (p < 0.01). Surprisingly, on DRS memory subscale and FAS tests, there were significant improvements in DLBr scores (p < 0.02). A baseline MMSE (or DRS memory) score >/=15 predicted a positive response to tacrine in DLB. Acceleration of parkinsonism occurred in all DLB subjects. CONCLUSION: Results from a primary analysis of the therapeutic effect of 80 mg/day tacrine in DLB and AD were negative. However, post hoc analysis showed that mild to moderate DLB responds favorably to AChEI relative to AD through stabilization of global cognitive decline and improvements in specific cognitive areas. These results could be useful in the planning of a more definitive study.     

Relationships: importance for patients with cerebral tumours

OBJECTIVE: To investigate the influence of relationships on psychosocial status in patients with Stage III and IV brain tumours. PATIENTS AND METHODS: Thirty-three outpatients at a university medical centre were referred to the study by their treating physician prior to the initiation of aggressive chemotherapy. All subjects underwent a comprehensive psychosocial assessment. RESULTS: Depressive and anxious complaints were common, but not related to gender. Single/divorced status suggested greater vulnerability to anxiety as 88% of singles and only 48% of patients with partners reported clinical levels of anxiety. Single patients' anxiety was related to inactivity (r = 0.78, p < 0.05) and fears of financial difficulties (r = 0.72, p < 0.05). State and trait anxiety related differently to married patients' complaints. Married patients more frequently reported clinical levels of depressive symptoms (44% partnered vs 28% singles). Depression among married patients was predicted by problems with sex, finances, marital difficulties, and inactivity [R2 = 0.803; F = 20.420, df(4,20), p < 0.0001)]. Problems with relationships were disassociated from problems with sex. Married patients' problematic relationships were predicted by overprotection, inactivity, concerns of bodily deterioration, depression, and anxiety [R2 = 0.775, F = 13.060, df(5, 19) < 0.0001]. CONCLUSIONS: Married neuro-oncology patients may experience depressive symptoms arising from the marriage, but appear to be buffered from anxiety when compared with single/divorced patients. The prevalence of anxiety among single patients suggests modifications of interventions by relationship status.     

Allograft loss in renal transplant recipients with Fabry's disease and activated protein C resistance

INTRODUCTION: Fabry's disease is associated with an increased incidence of thrombotic events and rejection. Spontaneous thrombosis of a functioning cadaveric renal allograft in a recipient with Fabry's disease prompted prospective evaluation of all transplant candidates with Fabry's disease for hypercoagulability. MATERIALS AND METHODS: Transplant candidates with Fabry's disease were tested for hypercoagulability, analyzed for HLA-type and ABO group, and comorbid conditions suggestive of hypercoagulability. RESULTS: A unique association of Fabry's disease with activated protein C Resistance was documented in a cohort of Caucasian male renal transplant recipients with Fabry's disease. Four of five patients were blood group A and had no significant comorbid conditions suggestive of hypercoagulability. The resistance to activation of protein C (APCR)(+) patients shared HLA loci-B8 and Dr3, although the APCR(-) patients shared HLA loci-B27 and -B38. CONCLUSIONS: Due to the observed increase in the incidence of APCR in our Fabry's cohort, we suggest screening all patients with Fabry's disease for APCR. Because factor V and factor Va receptors are found on vascular endothelium and peripheral blood monocytes, APCR in the presence of Fabry's disease may be a nonimmunological stimulus for rejection. Analysis of HLA typing in patients with Fabry's disease may further elucidate HLA-based association of Fabry's disease and resistance to activated protein C with the risk of thrombosis and rejection.     

Reconstruction of a parotidectomy defect using a paraumbilical perforator flap without deep inferior epigastric vessels

A 37-year-old woman who underwent a parotidectomy for acinic cell carcinoma was referred for correction of the resulting defect. As an assistant principal, the patient was often in public and, because she was somewhat self-conscious about her facial deformity, she sought reconstruction. Physical examination revealed a pre-auricular soft-tissue defect that measured approximately 5 x 5 cm. After consultation with the patient, microsurgical transfer of fat from the lower abdomen based on branches of the deep inferior epigastric vessels, rather than the deep inferior epigastric artery and vein itself, was planned. A vertical skin ellipse measuring 6 x 5 cm was raised from the right lower abdomen with a pedicle consisting of only a branch of the deep inferior epigastric artery and vein. The donor vessels were then microsurgically anastomosed to the superficial temporal artery and vein on the left side of the face. Two weeks postoperatively the flap was defatted, with removal of the skin-monitoring island. The patient continues to do well with a normal contour of the face and decreased anxiety secondary to correction of her facial deformity.     

Participation of patients 65 years of age or older in cancer clinical trials.

PURPOSE: Although 61% of new cases of cancer occur among the elderly, recent studies indicate that the elderly comprise only 25% of participants in cancer clinical trials. Further investigation into the reasons for low elderly participation is warranted. Our objective was to evaluate the participation of the elderly in clinical trials sponsored by the National Cancer Institute (NCI) and assess the impact of protocol exclusion criteria on elderly participation. PATIENTS AND METHODS: We conducted a retrospective analysis using NCI data, analyzing patient and trial characteristics for 59,300 patients enrolled onto 495 NCI-sponsored, cooperative group trials, active from 1997 through 2000. Our main outcome measure was the proportion of elderly patients enrolled onto cancer clinical trials compared with the proportion of incident cancer patients who are elderly. RESULTS: Overall, 32% of participants in phase II and III clinical trials were elderly, compared with 61% of patients with incident cancers in the United States who are elderly. The degree of underrepresentation was more pronounced in trials for early-stage cancers than in trials for late-stage cancers (P <.001). Furthermore, protocol exclusion criteria on the basis of organ-system abnormalities and functional status limitations were associated with lower elderly participation. We estimate that if protocol exclusions were relaxed, elderly participation in cancer trials would be 60%. CONCLUSION: The elderly are underrepresented in cancer clinical trials relative to their disease burden. Older patients are more likely to have medical histories that make them ineligible for clinical trials because of protocol exclusions. Insurance coverage for clinical trials is one step toward improvement of elderly access to clinical trials. Without a change in study design or requirements, this step may not be sufficient.     

Long-term effects on feeding and body weight after stimulation of forebrain or hindbrain CRH receptors with urocortin

Research on the contribution of CRH receptor stimulation to energy homeostasis has focused on forebrain substrates. In this study, we explored the effects of caudal brainstem administration of the CRH receptor agonist, urocortin, on food intake and body weight, and on plasma glucose and corticosterone (CORT) in non-deprived rats. Urocortin (0, 0.3, 1, 3 microg) delivered, respectively, to the fourth and lateral ventricles yielded substantial suppression of food intake measured 2, 4 and 24 h later. A significant but more modest anorexia was observed between 24 and 48 h after injection. Intake responses did not differ between the injection sites, but body weight loss measured 24 h after lateral-i.c.v. injection was substantially greater than that after fourth-i.c.v. injection. Fourth-i.c.v. urocortin administration (3 microg) produced substantial elevations in plasma glucose and CORT that were not distinguishable in magnitude and duration from responses to lateral-i.c.v. delivery. Unilateral microinjection of urocortin into the dorsal vagal complex significantly reduced 24-h food intake at a dose (0.1 microg) that was subthreshold for the response to ventricular administration, suggesting that fourth-i.c.v. effects are mediated in part by stimulation of CRH receptors in this region of the caudal brainstem. The results indicate that similar effects can be obtained from stimulation of anatomically disparate populations of CRH receptors, and that interactions between forebrain and hindbrain structures should be considered in the evaluation of CRH contributions to food intake and body weight control.     

Post-phototherapy neonatal bilirubin rebound: a potential cause of significant hyperbilirubinaemia.

AIM: To determine the incidence of post-phototherapy neonatal plasma total bilirubin (PTB) rebound. METHODS: A prospective clinical survey was performed on 226 term and near-term neonates treated with phototherapy in the well baby nursery of the Shaare Zedek Medical Center from January 2001 to September 2002. Neonates were tested for PTB 24 hours (between 12 and 36 hours) after discontinuation of phototherapy, with additional testing as clinically indicated. The main outcome measure, significant bilirubin rebound, was defined as a post-phototherapy PTB > or =256 micromol/l. Phototherapy was not reinstituted in all cases of rebound, but rather according to clinical indications. RESULTS: A total of 30 (13.3%) neonates developed significant rebound (mean (SD) PTB 287 (27) micromol/l, upper range 351 micromol/l). Twenty two of these (73%) were retreated with phototherapy at mean PTB 296 (29) micromol/l. Multiple logistic regression analysis showed significant risk for aetiological risk factors including positive direct Coombs test (odds ratio 2.44, 95% CI 1.25 to 4.74) and gestational age <37 weeks (odds ratio 3.21, 95% CI 1.29 to 7.96). A greater number of neonates rebounded among those in whom phototherapy was commenced < or =72 hours (26/152, 17%) compared with >72 hours (4/74, 5.4%) (odds ratio 3.61, 95% CI 1.21 to 10.77). CONCLUSION: Post-phototherapy neonatal bilirubin rebound to clinically significant levels may occur, especially in cases of prematurity, direct Coombs test positivity, and those treated < or =72 hours. These risk factors should be taken into account when planning post-phototherapy follow up.     

Disorders of sexual impulse control in neuropsychiatric conditions

This article reviews hypersexuality in individuals with neuropsychiatric disorders and its psychopharmacologic treatment. A brief review of the neurology, neuroendocrinology, and neuropharmacology of sexual behavior is presented. Literature describing the occurrence and treatment of hypersexuality in individuals with neuropsychiatric disorders is reviewed along with literature which discusses the pharmacologic treatment of individuals with hypersexual disorders in nonneuropsychiatric populations. Finally, a clinical algorithm for approaching and treating such disorders in a neuropsychiatric population is presented.     

Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder.

Post-traumatic stress disorder (PTSD) affects about 20-30% of exposed individuals. Clinical studies of PTSD generally employ stringent criteria for inclusion in study populations, and yet in animal studies the data collection and analysis are generally expressed as a function of exposed vs nonexposed populations, regardless of individual variation in response. Prior data support an approach to animal models analogous to inclusion criteria in clinical studies. This series of studies sought to assess prevalence rates of maladaptive vs adaptive responses determined according to a more stringent approach to the concept of inclusion/exclusion criteria (cutoff behavioral criteria-CBC), consisting of two successive behavioral tests (elevated plus maze and acoustic startle response tests). The rats were exposed to stressors in two different paradigms; exposure to a predator and underwater trauma. The prevalence rates of maladaptive responses to stress in these two distinct models dropped over time from 90% in the acute phase to 25% enduring/maladaptive response at 7 days, to remain constant over 30 days. As setting the affected individuals apart from the unaffected approximates clinical studies, it might also help to clarify some of the pending issues in PTSD research.