Synthesis of 3-Substituted-clavams: Antifungal Properties, DD-Peptidase and beta-Lactamase Inhibition

The [2+2]cycloaddition of chlorosulfonyl isocyanate to vinyl and (Z)-propenyl ethers derived from the 2-O-sulfonylated (R)- and (S)-1-(furyl-2')-1,2-ethanediols furnished the 4-alkoxy-azetidin-2-ones with a good to moderate stereoselectivity. The intramolecular alkylation of the beta-lactam nitrogen atom led to the corresponding 3-(furyl-2')- and 6-methyl-3-(furyl-2')-clavams. The transformation of the furyl residue into an alkoxycarbonyl group led to clavams related to the natural compounds. The synthesized clavams exhibited moderate inhibitory activities against DD-peptidase 64-575 and beta-lactamase (penase) as well as antifungal activities.     

THE USE OF KNOCKOUT MICE TO UNDERSTAND THE ROLE OF CYTOKINES IN FEVER

1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques. 2. Interleukin (IL)-lβ appears to be critically involved in fever caused by some routes of infectiodinflammation (e.g. localized inflammation with turpentine). This cytokine has only a small role in fevers caused by i.p. injection of lipopolysaccharide (LPS). These IL-lβ-induced fevers in knockout mice appear to be via the induction of IL-6, similar to LPS-induced fevers in rats. Interleukin-6 also appears to be critically involved in turpentine-induced fever. 3. The precise role of tumour necrosis factor (TNF) in fever is controversial. Data obtained from knockout mice lacking both TNF receptors do not support a pyrogenic role for TNF in fever either to i.p. injection of LPS, s.c. injection of turpentine or following caecal ligation and puncture. 4. The roles of these cytokines in fevers induced by injection of LPS, IL-lβ, turpentine and caecal ligation and puncture are summarized. The data show the complexity of the febrile response. Depending on the types of inflammatoryhnfectious stimuli, different cytokines play important roles. Because other cytokines are thought to be involved in fever (e.g. macrophage inflammatory protein, interferons), considerable work is still needed to dissect the precise roles of cytokines in fever.     

Pre-pregnancy dietary vitamin A intake may alleviate the adverse birth outcomes associated with prenatal pollutant exposure: epidemiologic cohort study in Poland

A cohort study assessed the relationship between dietary intake of vitamin A in 493 healthy mothers before and around conception and adverse birth outcomes associated with environmental toxicant exposures. The cohort, non-smoking women with singleton pregnancies, aged 18-35 years, gave birth at 34-43 weeks of gestation. The women were asked about their diets over one year preceding pregnancy. Measurements of PM2.5 were carried out during the second trimester. Birth outcomes were adjusted for potential confounding factors, including gestational age. Standardized beta regression coefficients confirmed an inverse association between PM2.5 and birth weight (beta = -172.4, p = 0.02), but the effect of vitamin A on birth weight was positive (beta = 176.05, p = 0.05), when the two were adjusted for each other. The negative effect of higher prenatal PM2.5 exposures (above third tertile) on birth weight was significant in women below the third tertile of vitamin A intakes (beta = -185.1, p = 0.00), but not in women with higher intakes (beta = 38.6, p = 0.61). The negative effect of higher PM2.5 exposure on length at birth was significant with lower vitamin A intakes (beta = -1.1, p = 0.00) but not with higher intakes (beta = -0.3, p = 0.56). Prepregnancy nutrition of mothers may modulate the harmful effects of prenatal exposures to pollutants on birth outcomes.     

Assessing the efficacy of allogeneic hematopoietic stem cells transplantation (allo‐HSCT) by analyzing survival end points in defined groups of acute myeloid leukemia patients: A retrospective,multicenter Polish Adult Leukemia Group study

The importance of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo‐HSCT. These consisted of leukemia‐free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non‐relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during 1999–2008. The Mantel–Byar approach was used to assess allo‐HSCT on survival endpoints, accounting for a changing transplant status. Undergoing allo‐HSCT significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged 41–60. The CIR demonstrated that allo‐HSCT reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo‐HSCT significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged 41–60. The allo‐HSCT treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis. Am. J. Hematol. 90:904–909, 2015. © 2015 Wiley Periodicals, Inc.     

Programmable Bio-Nano-Chip Technology for the Diagnosis of Cardiovascular Disease at the Point-of-Care

Cardiovascular disease remains the leading cause of death in the world and continues to serve as the major contributor to healthcare costs. Likewise, there is an ever-increasing need and demand for novel and more efficient diagnostic tools for the early detection of cardiovascular disease, especially at the point-of-care (POC). This article reviews the programmable bio-nanochip (P-BNC) system, a new medical microdevice approach with the capacity to deliver both high performance and reduced cost. This fully integrated, total analysis system leverages microelectronic components, microfabrication techniques, and nanotechnology to noninvasively measure multiple cardiac biomarkers in complex fluids, such as saliva, while offering diagnostic accuracy equal to laboratory-confined reference methods. This article profiles the P-BNC approach, describes its performance in real-world testing of clinical samples, and summarizes new opportunities for medical microdevices in the field of cardiac diagnostics.     

Impact of barbecued meat consumed in pregnancy on birth outcomes accounting for personal prenatal exposure to airborne polycyclic aromatic hydrocarbons: Birth cohort study in Poland

ObjectiveWe previously reported an association between prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAH) and lower birth weight, birth length, and head circumference. The main goal of the present analysis was to assess the possible impact of coexposure to PAH-containing barbecued meat consumed during pregnancy on birth outcomes.Materials and methodsThe birth cohort consisted of 432 pregnant women who gave birth at term (>36 wk of gestation). Only non-smoking women with singleton pregnancies, 18–35 y of age, and who were free from chronic diseases such as diabetes and hypertension, were included in the study. Detailed information on diet over pregnancy was collected through interviews and the measurement of exposure to airborne PAHs was carried out by personal air monitoring during the second trimester of pregnancy. The effect of barbecued meat consumption on birth outcomes (birth weight, length, and head circumference at birth) was adjusted in multiple linear regression models for potential confounding factors such as prenatal exposure to airborne PAHs, child's sex, gestational age, parity, size of mother (maternal prepregnancy weight, weight gain in pregnancy), and prenatal environmental tobacco smoke.ResultsThe multivariable regression model showed a significant deficit in birth weight associated with barbecued meat consumption in pregnancy (coeff = ?106.0 g; 95%CI: ?293.3, ?35.8). The effect of exposure to airborne PAHs was about the same magnitude order (coeff. = ?164.6 g; 95%CI: ?172.3, ?34.7). Combined effect of both sources of exposure amounted to birth weight deficit of 214.3 g (95%CI: ?419.0, ?9.6). Regression models performed for birth length and head circumference showed similar trends but the estimated effects were of borderline significance level. As the intake of barbecued meat did not affect the duration of pregnancy, the reduced birth weight could not have been mediated by a shortened gestation period.ConclusionIn conclusion, the study results provided epidemiologic evidence that prenatal PAH exposure from diet including grilled meat might be hazardous for fetal development.     

Pineal cysts in childhood

INTRODUCTION: Little is known about the incidence and symptomatology of pineal cysts in children. Until now, the proper management of this group of patients has not been established. PURPOSE: The purpose of this study was to evaluate the epidemiological and clinical features of pineal cysts in children and adolescents and to try to find guidelines for their management. METHODS AND RESULTS: We analyzed 24 patients (17 girls, mean age 9, and 7 boys, mean age 14) with pineal cysts found as the only pathology on MRI. Six patients were treated surgically (excision of the cysts via a supracerebellar-infratentorial approach) because of the progression of neurological symptoms or the enlargement of the cyst at follow-up. In this group of patients, no surgery-related complications were noted, nor was residual cyst observed on postoperative MRI. In 4 cases, histological examination revealed simple cysts, but in 2 cases pineocytomas were diagnosed. Preoperative symptoms disappeared except light headache in 2 cases and in 1 case no improvement was obtained. The remaining 18 patients had a mean follow-up of 38 months (range 24-60 months). None of the cysts diminished or collapsed. We also measured the circadian pattern of melatonin secretion as well as beta-HCG and AFP levels in serum before surgery. We found very high night levels of melatonin in both of the patients with pineocytomas, while the patients with pineal cysts showed normal or depressed melatonin secretion profile. CONCLUSION: We concluded that though most pineal cysts were clinically benign they should be followed up for many years. If the cyst grows larger in follow-up MRI study and neurological symptoms are progressive, surgical treatment should be performed. In the authors' opinion, one of the markers discriminating benign and neoplastic lesions may be melatonin.