Ana Rubio

Sibutramine in weight control : a dose-ranging, efficacy study

We tested the safety and efficacy of sibutramine, 5 and 20 mg, and placebo on weight loss. Medication was added to caloric restriction, behavior modification, and exercise in a parallel‐group, double‐blind clinical trial. Participants were 130% to 180% of ideal body weight and in good health. The study lasted 12 weeks over Thanksgiving, Christmas, and New Years Day. Weight loss during 8 weeks of study medication was: placebo, 1.4 ± 2.1 kg (n = 19); 5 mg sibutramine, 2.9 ± 2.3 kg (n = 18); and 20 mg sibutramine, 5.0 ± 2.7 kg (n = 18) (p < 0.05 sibutramine, 5 and 20 mg, versus placebo; p < 0.05 sibutramine, 20 mg versus 5 mg). There is a significant dose‐effect relationship. Five participants left the study before completion, all because of adverse events: placebo (one patient), 5 mg sibutramine (one patient), and 20 mg sibutramine (three patients). Sleep difficulties were noted by eight participants (20 mg sibutramine, seven patients; 5 mg, one patient; and placebo, no patients). Six of 21 participants receiving 20 mg complained of irritability, unusual impatience, or “excitation.” Sibutramine, 5 and 20 mg, added to a multimodal program assisted participants in losing weight.

Suicide and Alzheimer's pathology in the elderly: A case-control study

BACKGROUND The single most important risk factor for Alzheimers pathology is age. Elderly individuals are also at increased risk for suicide, but comprehensive studies of the association between Alzheimers pathology and suicide are lacking. We designed the current study to determine if Alzheimers disease changes are overrepresented in elderly people committing suicide. METHODS The design is a case-control study. Cases (n = 28) were subjects older than 60 years of age who completed suicide. For each case, two age- and gender-matched individuals who died naturally were selected as control subjects (n = 56). Neuropathologic examination of hippocampal sections was performed blindly and included a modified Braak scoring system and semiquantitative assessment of neurofibrillary tangles, amyloid deposition, Lewy bodies, and Lewy-associated neurites. Data were analyzed by conditional logistic regression. RESULTS The brains of individuals who committed suicide had higher modified Braak scores than those of matching control subjects (p =.0028). The number of neurofibrillary tangles in CA1 was not an independent predictor of suicide status in the statistical analysis (p =.16), although the distribution was more highly skewed among the cases (75th percentile of 10.5 for cases, vs. 2 for control subjects). CONCLUSIONS Severe Alzheimers disease pathology is overrepresented in elderly patients who complete suicide.

Parkinson's disease and dementia with Lewy bodies: One disease or two?

Parkinsons disease (PD) and dementia with Lewy bodies (DLB) have clinical features in common and are both characterized neuropathologically by the presence of Lewy bodies (LBs). We conducted a clinicopathological correlation pilot study to better understand whether PD and DLB represent two distinct nosological entities or rather exist along the spectrum of a single LB disease. A neuropathologist blinded to clinical diagnoses evaluated brains with largely pure LB pathology to determine LB distribution and frequency. Research clinicians blinded to LB distribution and frequency determined consensus clinical diagnoses. Clinical features separated cases into two groups, one having features most compatible with PD and the other with DLB. The groups were distinguishable mainly by the time course of clinical symptoms. Although the presence of neocortical LBs was more common in the group of patients with clinical features of DLB, neocortical LBs were also present in 1 member of the PD group and even in the clinically normal control subject. Thus, there appear to be two clinical syndromes, distinguished mainly by the time course of symptoms. The mechanisms responsible for the different clinical presentations are not known, and the issue of whether PD and DLB represent two distinct diseases remains unsettled.

Phenotypic variability of CADASIL and novel morphologic findings

Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-arterio-atherosclerotic, non-amyloidotic arteriopathy affecting preferentially the small arteries and arterioles of the brain. The morphologic hallmark is the presence of a characteristic granular alteration of the arterial media that ultrastructurally corresponds to the accumulation of electron-dense material surrounding the smooth muscle cells. Although the presence of this granular osmiophilic material (GOM) was originally described as limited to brain vessels, identical electron microscopic findings have been demonstrated in the media of peripheral tissue arteries, allowing for a pathologic diagnosis of the disease by a simple skin, muscle or nerve biopsy. We report some atypical features identified in our CADASIL patients that broaden the phenotypic expression of this disease. Firstly, we identified a cortical infarct in an otherwise typical CADASIL patient. Secondly, we observed GOM in skin arteries of a 30-year-old man with hemiplegic migraine, the son of a woman who had died with CADASIL. This confirms that it may be possible to diagnose the disease at a preclinical stage by the ultrastructural evaluation of peripheral tissue biopsy material, particularly for individuals for whom there is a supporting family history. Thirdly, ultrastructural examination of the skin, and subcutaneous and striated muscle of an unrelated and apparently sporadic patient with neuropathologic and neuroradiologic evidence of CADASIL in meningeal and cerebral vessels failed to reveal diagnostic lesions in peripheral arteries. Thus, the possibility of a false-negative pathologic diagnosis in patients with a clinicoradiologic diagnosis of CADASIL, if one relies solely on a peripheral tissue biopsy, does exist. Additionally, we have identified heat shock proteins (Hsp70 and αB crystallin) and ubiquitin in the vascular myocytes of affected arteries. αB crystallin also seemed to be deposited extracellularly, which suggests that GOM also might be immunoreactive for αB crystallin.

Fibro-osseous lesions of the central nervous system: Report of four cases and literature review

Fibro-osseous lesions, also reported as calcifying pseudoneoplasms of the neural axis, are uncommon lesions of the CNS. We report four additional cases: two extraaxial and two intraaxial, in patients ages 33, 47, 49, and 59 years at presentation. Fibro-osseous lesions involving the CNS demonstrate variable proportions of fibrous stroma, bone, palisading spindle to epithelioid to multinucleated cells in association with a highly distinctive, perhaps pathognomonic, chondromyxoid-like matrix often distributed in a nodular pattern. This histopathologically distinctive lesion can be seen in many regions of the neuraxis, often with a dural association, and most commonly along the vertebral column. It appears to be a slow-growing lesion and, with wide excision, the prognosis is excellent. The etiology remains unclear, but the preponderance of data favors a reactive rather than neoplastic process. If this putative pseudotumor is not recognized histopathologically, a neoplastic or infectious differential might result in inappropriate investigations and potentially harmful therapies.

Prediction of Diltiazem Plasma Concentration Curves From Limited Measurements Using Compliance Data

SummaryThis analysis illustrates the importance of compliance in understanding intrapatient variation in plasma drug concentrations during 2 weeks of repeated (4 times daily) administration. Plasma concentration data are presented from 4 illustrative patients enrolled in a dose-ranging randomised clinical trial comparing diltiazem with placebo for the prevention of painful vaso-occlusive crises in sickle cell disease. Nonlinear regression was used to fit a 1-compartment model (using 1 elimination constant for the first dose and another for subsequent doses) to the observed diltiazem concentration curves for individual patients, taking into account the time of administration of each dose. Actual dosage intervals were obtained from an electronic device (the Medication Event Monitoring System®). The parameters estimated from fitting the actual compliance curves were then used to predict the curves obtained if compliance had been as prescribed (perfect compliance curves). Comparison of the actual and perfect compliance curves shows that within-patient variation in plasma diltiazem concentrations over time can only be understood when the timing of drug administration is included in the analysis. We conclude that dynamic compliance data are important in those situations where close monitoring of treatment is required and may be important in population pharmacokinetic modelling when limited data are available from each patient.

Hemangioblastoma of the optic nerve

A 43-year-old woman presented with progressive loss of vision in the right eye. Magnetic resonance imaging (MRI) showed a prominently enhancing lesion of the optic nerve, thought preoperatively to represent an optic nerve meningioma or optic neuritis. Histological examination of the excised tumor showed this lesion to be hemangioblastoma. Her family history was unremarkable. However, subsequent review of the preoperative MRIs and postoperative imaging studies showed two small cerebellar lesions, probably hemangioblastomas, and renal, pancreatic, and adnexal cysts, establishing the diagnosis of von Hippel-Lindau disease.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (cadasil)

Summary: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described neurovascular disease affecting young to middle age individuals. The disease is caused by mutations in the Notch3 gene located in the short arm of chromosome 19. Clinically, the disease is characterized by migrainous headaches (with or without aura), mood disturbances, focal neurologic deficits, transient ischemic attacks, strokes, and dementia. Pathologically, the disease is characterized by a stereotypic degeneration of the arterial walls (especially in the intracranial compartments) with deposition in the media of a nonatheromatous, nonamyloidotic substance that under the electron microscope (EM) appears as a granular osmiophilic material (GOM), pathognomonic for the disease. The nature of the GOM is undetermined and the pathogenesis remains to be elucidated. A review of current literature in English language is presented on the clinical, radiologic, pathologic, and genetic features of CADASIL.

Alzheimer lesions in the autopsied brains of people 30 to 50 years of age

Objective:To test the hypothesis that asymptomatic Alzheimer disease lesions may appear before 50 years of age. Background:Alzheimer disease has an asymptomatic stage during which people are cognitively intact despite having substantial pathologic changes in the brain. While this asymptomatic stage is common in older people, how early in life it may develop has been unknown. Methods:We microscopically examined the postmortem brains of 154 people aged 30 to 39 years (n=59) and 40 to 50 years (n=95) for specific Alzheimer lesions: beta-amyloid plaques, neurofibrillary tangles, and tau-positive neurites. We genotyped DNA samples for the apolipoprotein E gene (APOE). Results:We found beta-amyloid lesions in 13 brains, all of them from people aged 40 to 49 with no history of dementia. These plaques were of the diffuse type only and appeared throughout the neocortex. Among these 13 brains, five had very subtle tau lesions in the entorhinal cortex and/or hippocampus. All individuals with beta-amyloid deposits carried one or two APOE4 alleles. Among the individuals aged 40 to 50 with genotype APOE3/4, 10 (36%) had beta-amyloid deposits but 18 (64%) had none. Conclusions:Our study demonstrates that beta-amyloid deposits in the cerebral cortex appear as early as 40 years of age in APOE4 carriers, suggesting that these lesions may constitute a very early stage of Alzheimer disease. Future preventive and therapeutic measures for this disease may have to be stratified by risk factors like APOE genotype and may need to target people in their 40s or even earlier.

The prevalence of Alzheimer neuropathologic lesions is similar in blacks and whites.

Alzheimer disease is the most common dementia in older Americans, but its impact on blacks is not clearly understood. We examined prospectively 200 autopsy brains at the Office of the Chief Medical Examiner in Maryland and compared the frequency and severity of Alzheimer lesions in blacks and whites. Histologic sections of the hippocampus and entorhinal and neocortices were immunostained for A&bgr; and tau proteins. Subjects were genotyped for ApoE. A&bgr; deposits were rated as none, sparse, moderate, or frequent; tau lesions were rated into 4 groups corresponding to Braak scores; and A&bgr; angiopathy was classified as present or absent. Outcome scores were treated as ordinal variables and analyzed by proportional odds logistic regression. A&bgr; plaques were present in 60% of black males, 58% of white males, 74% of black females, and 74% of white females. Tau lesions were present in 96% of black males, 88% of white males, 96% of black females, and 96% of white females. Neither race nor gender was a significant factor in the frequency or severity of Alzheimer lesions, and ApoE4 increased the risk for Alzheimer lesions similarly in blacks and whites.