Amyloid beta-peptide(1-42) contributes to the oxidative stress and neurodegeneration found in Alzheimer disease brain

Oxidative stress is extensive in Alzheimer disease (AD) brain. Amyloid beta-peptide (1-42) has been shown to induce oxidative stress and neurotoxicity in vitro and in vivo. Genetic mutations that result in increased production of Abeta1-42 from amyloid precursor protein are associated with an early onset and accelerated pathology of AD. Consequently, Abeta1-42 has been proposed to play a central role in the pathogenesis of AD as a mediator of oxidative stress. In this review, we discuss the role of Abeta1-42 in the lipid peroxidation and protein oxidation evident in AD brain and the implications of such oxidative stress for the function of various proteins that we have identified as specifically oxidized in AD brain compared to control, using proteomics methods. Additionally, we discuss the critical role of methionine 35 in the oxidative stress and neurotoxic properties exhibited by Abeta1-42.     

Comparative genomic hybridization of 49 primary retinoblastoma tumors identifies chromosomal regions associated with histopathology,progression, and patient outcome

Forty-nine primary retinoblastoma (Rb) tumors were analyzed by the use of comparative genomic hybridization (CGH), and clinical/histological correlations were performed. Adverse histological factors were present in 13 patients. Chromosomal imbalance was a frequent phenomenon, seen in 96% of the tumors. Gain of 6p represented the most frequent event (69% of the tumors), whereas +1q was observed in 57%, confirming that these abnormalities are key secondary events in retinoblastoma tumor progression. Loss of 13q and 16 was significantly associated with tumors displaying adverse histo-prognostic factors, whereas -16q was significantly associated with tumors without adverse features. In three patients who developed an extra-ocular relapse, the tumors showed -13q and 2/3 had -5q, suggesting that these abnormalities may be associated with metastasis. Children >or= 36 months of age at enucleation tended to have more CGH abnormalities per tumor than children < 12 months (median numbers 11 vs. 3). In addition, +1q, +13q, -16, and -16q were more frequent in children with an older age at enucleation. Identical CGH changes were found in both tumors from one patient with bilateral tumors, suggesting a common origin. It is possible that tumors displaying loss of 13q and 5q indicate those patients who may suffer an adverse outcome and who would require alternative or more intensive therapy. CGH analysis on larger cohorts and in prospective clinical trials will be invaluable in determining whether a genetic classification of retinoblastoma represents a reliable measure of prognosis.     

LcrV plague vaccine with altered immunomodulatory properties

Yersinia pestis, the causative agent of plague, secretes LcrV (low-calcium-response V or V antigen) during infection. LcrV triggers the release of interleukin 10 (IL-10) by host immune cells and suppresses proinflammatory cytokines such as tumor necrosis factor alpha and gamma interferon as well as innate defense mechanisms required to combat the pathogenesis of plague. Although immunization of animals with LcrV elicits protective immunity, the associated suppression of host defense mechanisms may preclude the use of LcrV as a human vaccine. Here we show that short deletions within LcrV can reduce its immune modulatory properties. An LcrV variant lacking amino acid residues 271 to 300 (rV10) elicited immune responses that protected mice against a lethal challenge with Y. pestis. Compared to full-length LcrV, rV10 displayed a reduced ability to release IL-10 from mouse and human macrophages. Furthermore, the lipopolysaccharide-stimulated release of proinflammatory cytokines by human or mouse macrophages was inhibited by full-length LcrV but not by the rV10 variant. Thus, it appears that LcrV variants with reduced immune modulatory properties could be used as a human vaccine to generate protective immunity against plague.     

Intestinal Spirochetosis and Acquired Immunodeficiency Syndrome: Ultrastructural Studies of Two Cases

Two cases of intestinal spirochetosis (IS) with acquired immunodeficiency syndrome are reported. In case 1, a 48-year-old homosexual black man presented with a 1-month history of alternating watery diarrhea and constipation, which dissipated following the removal of two colonic hyperplastic polyps containing IS. In case 2, a 26-year-old homosexual black man presented with a 3-month history of persistent bloody diarrhea and was found to have chronic shigellosis and IS. Pathologic findings of IS were similar in both cases. Basophilic fringes typical of IS covered the surfacing colonic epithelium and consisted of dense growths of spirochetes adherent to and oriented perpendicular to the plasma membranes of the surfacing epithelium. The spirochetes measured 3 to 5 μm in length and 0.2 (im in width, contained four to eight axial fibrils, and closely resembled Brachyspira aalborgi ultrastructurally. These cases are notable because the histopathologic changes of IS were more extensive than generally described. There was involvement of both the right colon and rectum by IS in case 2, and in both cases there was extension of the IS down into the crypts of Lieberkiihn, spirochetal invasion of the colonic mucosa, and a conspicuous inflammatory response by macrophages in the underlying lamina propria.     

Phagocytosis of Live Versus Heat-Killed Bacteria by Human Polymorphonuclear Leukocytes

Heat-killed Pseudomonas aeruginosa are phagocytized much more slowly by human polymorphonuclear leukocytes than are the live organisms. The post-phagocytic increase in hexose monophosphate shunt activity (HMS) parallels the ingestion of the bacteria. The addition of serum to the live organisms causes a marked increase in both ingestion and cellular HMS activity; serum actually causes an inhibition of both uptake and HMS activity when added to the heat-killed organisms. Differences in postphagocytic HMS activity between live and heat-killed organisms were observed with three different species of bacteria, indicating that the phenomenon is not restricted to P. aeruginosa. These data emphasize that the influence of the particle on the phagocytic process is considerable.     

A method for real-time, evidence-based general medical attending rounds.

PURPOSE: To assess the utility and practicality of an evidence-based format in internal medicine attending rounds. METHOD: Two randomly selected teams of residents and medical students in the internal medicine program at the Montefiore Medical Center participated in "Evidence-Based Medicine Attending Month." The process entailed the development of patient-based, searchable questions, a search for the evidence, the critical appraisal of the retrieved literature, and the application of the evidence to the care of the patient. At the last meeting, participants evaluated each case by answering three questions about whether the process (1) had changed the medical management of the patient during the admission, (2) had changed the way they would manage similar patients in the future, and (3) had informed them about the disease process in general. RESULTS: A total of 12 of 16 formal EBM questions were developed and assessed (75% completion rate) during the four-week period, in addition to the standard background literature reviews usually performed. Twenty-two articles were retrieved and critically appraised. The evaluation demonstrated that 50% of the participants felt the process had changed the active management of patients currently treated by the team, 75% reported that the process would affect the care of future patients with comparable medical problems, and over 90% believed the program had informed them about the disease process. CONCLUSIONS: The formal EBM approach was conveniently implemented and enhanced the learning experience of the participants. It helped inform students' and residents' patient care at the time and their attitudes towards future patients. Hence, it is both practical and useful to perform formal EBM attending rounds.     

Quantification of HIV-1 p24 by a highly improved ELISA: an alternative to HIV-1 RNA based treatment monitoring in patients from Abidjan, C?te d'Ivoire.

BACKGROUND: Quantification of HIV-1 RNA remains difficult to implement in Africa. Simple and inexpensive tests for antiretroviral treatment (ART) monitoring are needed. OBJECTIVE: To evaluate an HIV-1 p24 ELISA, which combines efficient virus disruption, heat-denaturation and signal amplification, in a West African setting. STUDY DESIGN: Eighty-six HIV-1 infected patients from Abidjan, C?te d'Ivoire, were tested for p24, HIV-1 RNA, and CD4+ count at baseline, and twice within 8 months after ART initiation. RESULTS: All patients responded to ART with a minimal HIV-1 RNA drop of 0.5 log(10) at first follow-up. Forty-one (47.7%) then rebounded >0.5 log(10) or persisted above 1000 copies/mL by week 24. The predicted baseline concentration of p24 corresponding to 100,000 copies/mL of HIV-1 RNA, above which ART is recommended, was 4546 fg/mL (95% confidence interval 3148-6566). A prediction model of virologic failure, occurring after an initial response to ART, correctly classified 84% of patients using baseline p24, p24 change on therapy, and achievement of undetectable p24 as explanatory variables. The model and further bootstrap evaluation suggested a good ability to discriminate between sustained or failing virologic response to ART. CONCLUSION: HIV-1 p24 and RNA based-ART monitoring in a low-resource country dominated by HIV-1 CRF02 AG appeared comparable.     

Estradiol effects on the growth hormone/insulin-like growth factor-1 axis in amenorrheic athletes.

Disruption of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis has been reported and studied in menopause, hypothalamic amenorrhea, and anorexia nervosa, but not in weight-stable amenorrheic athletes. We investigated the effects of short-term transdermal estradiol on basal and exercise-stimulated serum GH, IGF-1, and associated binding proteins (IGFBP-1 and IGFBP-3) in seven weight-stable female amenorrheic athletes with percentage body fats greater that 12%. Each subject received a 72 h placebo patch followed by 144 h of transdermal estradiol. Serum samples for GH, IGF-1, IGFBP-1, and IGFBP-3 were obtained at baseline (t1), 72 hr (t2), 144 hr (t3), and during three 90-minute trials of aerobic exercise. Basal, and exercise GH, IGF-1, and IGFBP-1 were not different between trials. Baseline IGFBP-3 decreased from t1 to t2 (p = 0.04) and serum free fatty acids increased from t1 to t2, and t1 to t3 (p = 0.04, and 0.02 respectively). These findings differ from postmenopausal women, and women having weightloss-associated amenorrhea, suggesting that estrogen, exercise, and nutritional deficiencies may have independent effects on the GH/IGF-1 axis.     

Blood pressure in adults with short stature skeletal dysplasias

Hypertension, compounded by obesity, contributes to cardiovascular disease and mortality. Data describing hypertension prevalence in adults with short stature skeletal dysplasias are lacking, perhaps due to poor fit of typical adult blood pressure cuffs on rhizomelic or contracted upper extremities. Through health screening research, blood pressure was measured in short stature adults attending support group meetings and skeletal dysplasia clinics. Blood pressure was measured with a commercially available, narrower adult cuff on the upper and/or lower segment of the arm. Height, weight, age, gender, diagnosis, exercise, and medications were collected. Subjects were classified as normotensive, prehypertensive, or hypertensive for group analysis; no individual clinical diagnoses were made. In 403 short stature adults, 42% were hypertensive (systolic >140, diastolic >90 OR taking antihypertensive medications). For every BMI unit and 1 kg weight increase in males, there was a 9% and an 8% increase, respectively, in the odds of hypertension versus normotension. In females, the increase was 10% and 6%, respectively. In those with achondroplasia, the most common short stature dysplasia, males (n = 106) had 10% greater odds of hypertension versus normotension for every BMI unit and kilogram increase. In females with achondroplasia (n = 128), the odds of hypertension versus normotension was 8% greater for each BMI unit and 7% for each additional kilogram. These data suggest a high population prevalence of hypertension among short stature adults. Blood pressure must be monitored as part of routine medical care, and measuring at the forearm may be the only viable clinical option in rhizomelic short stature adults with elbow contractures.