Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies

BACKGROUND: There have been no previous studies on the role of inflammation in the brain for the second most common dementing disorder, dementia with Lewy bodies. OBJECTIVE: To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains. DESIGN AND MAIN OUTCOME MEASURES: Post-mortem tissue collection from a brain donor program using standardized diagnostic criteria. Brains collected from January 1, 1993, through December 31, 1996, were screened and selected only for the presence or absence of tau neuritic plaques. Results of immunohistochemistry for HLA-DR were quantified using area fraction counts. Counts were performed by investigators who were unaware of the diagnosis. Results were compared across groups using analysis of variance and posthoc testing. SETTING: A medical research institute in Sydney, Australia. PATIENTS: Eight brains with DLB and without the tau neuritic plaques typical of AD, 10 brains with AD and no Lewy bodies, and 11 nondemented controls without significant neuropathological features were selected from a consecutive sample. RESULTS: Compared with AD, DLB demonstrated significantly less inflammation in the form of HLA-DR-reactive microglia in all cortical regions (P<.001, posthoc). The level of inflammation in DLB was comparable to that seen in controls (P=.54, post hoc). CONCLUSIONS: Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.     

A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide,ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced solid tumours

Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.Methods We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.Results Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10–300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1–2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3–18) weeks. Four of 18 evaluable patients (22%) had stable disease.Conclusions Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.Subject terms: Drug development, Drug safety     

Prenatal exposure to polychlorinated biphenyls and asthma,eczema/hay fever,and frequent ear infections

Objectives: The effects of prenatal exposure to Polychlorinated biphenyls (PCBs) on the development of asthma, frequent ear infections, and eczema/hay fever are not well understood. We aim to investigate associations between prenatal PCB exposure and these health outcomes in the offspring of women who worked at the LaSalle Electrical Utilities Company (EUC). Methods: A retrospective cohort with at least one live birth and known employment time at EUC was eligible for this analysis. Exposure was defined and categorized by the number of fiscal quarters worked during the PCB era (1952–1981). A total of 288 women with 800 live births were included. A Chi-Square test was used to compare maternal and child characteristics across exposure groups and repeated measures logistic regression, controlling for clustering among siblings, was used to assess the associations between prenatal PCB exposure and these outcomes. Results: After adjustment for confounding and independent maternal predictors, 1–4 quarters of prenatal exposure to PCBs increased the odds for asthma (OR 3.24[1.30–8.09]), eczema/hay fever (OR 3.29[1.54–7.04]), and frequent ear infections (OR 2.24[1.19–4.22]) when compared with persons unexposed/exposed only to naphthalenes. The significance of the associations varied by exposure period and level of exposure, with the strongest associations in those employed exclusively after 1952 when PCBs were introduced. Conclusions: These results support previous findings of associations of prenatal exposure to PCBs with asthma, eczema/hay fever, and frequent ear infections. Additional prospective studies are needed to confirm these findings. Also required are more precise PCB exposures to separate them from other exposures in occupational settings.     

Insights into capacity-constrained optimal transport

A variant of the classical optimal transportation problem is the following: among all joint measures with fixed marginals and that are dominated by a given density, find the optimal one. Existence and uniqueness of solutions to this variant were established by Korman and McCann. In the present article, we expose an unexpected symmetry leading to explicit examples in two and more dimensions. These are inspired in part by simulations in one dimension that display singularities and topology and in part by two further developments: the identification of all extreme points in the feasible set and an approach to uniqueness based on constructing feasible perturbations.     

Adhesive strips versus subcuticular suture for mediansternotomy wound closure

Abstract Background and Aim: This prospective randomized study was undertaken to compare the use of the 3M™ Steri‐Strip™ S Surgical Skin closure system with a running absorbable subcuticular suture technique for skin closure following a mediansternotomy for cardiac surgical procedures. Methods: Thirty‐six patients undergoing a mediansternotomy for a cardiac surgical procedure were prospectively randomized to either Steri‐Strip S or subcuticular suture for wound closure. The wounds were evaluated on postoperative days 7 and 21 for erythema, edema, pain, cosmesis, and the time taken to close the incision. Results: Skin closure with Steri‐Strip S was faster (5.33 ± 1.32 minutes steri‐strips vs. 6.07 ± 0.91 sutures; p = 0.06) and resulted in significantly less erythema and edema, but no difference in pain or cosmesis after seven days. Following 21 days, there was no difference in pain, edema, or cosmesis between the groups. However, patients receiving steri‐strips continue to have less erythema. Conclusions: Both Steri‐Strip S and absorbable sutures are effective techniques for skin closure following a mediansternotomy incision for cardiac surgical procedures. Steri‐Strip S can decrease the amount of erythema, but results in no significant difference in pain, cosmesis, or edema compared to the traditional subcuticular wound closure technique. (J Card Surg 2011;26:344‐347)     

Desflurane confers neurologic protection for deep hypothermic circulatory arrest in newborn pigs

BACKGROUND: Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), as used for infant heart surgery, carry a risk of ischemic neurologic injury. Volatile anesthetics have neuroprotective properties against both global and focal ischemia at normothermia. The authors examined the hemodynamic and neuroprotective effects of desflurane in a piglet CPB-DHCA model. METHODS: Twenty piglets aged 5-10 days received a desflurane- (6-9% expired) or fentanyl-based anesthetic before and during CPB (before and after DHCA). DHCA lasted 90 min at 19 degrees C brain. Cardiovascular variables (heart rate, arterial pressure, blood gases, glucose, brain temperature) were monitored. On postoperative day 2, neurologic and histologic outcomes were determined. RESULTS: Cardiovascular variables before, during, and after CPB were physiologically similar between groups. The desflurane group had better neurologic performance (P = 0.023) and greater postoperative weight gain (P = 0.04) than the fentanyl group. In neocortex, the desflurane group had less tissue damage (P = 0.0015) and fewer dead neurons (P = 0.0015) than the fentanyl group. Hippocampal tissue damage was less in the desflurane group (P = 0.05), but overall, neuronal cell counts in the CA1 sector of the right hippocampus were similar to those in the fentanyl group. CONCLUSIONS: Desflurane-based anesthesia yields hemodynamics during CPB with DHCA that are similar to those with fentanyl-based anesthesia. However, desflurane-based anesthesia improves neurologic and histologic outcomes of CPB-DHCA in comparison with outcomes with fentanyl-based anesthesia.