Effects of a psychosocial family-based preventive intervention on cortisol response to a social challenge in preschoolers at high risk for antisocial behavior

CONTEXT: Salivary cortisol levels during social challenge relate to adaptive functioning in children and adults. Low cortisol levels have been related to conduct problems and antisocial behavior. Although studies in rodents implicate early-life social experience in cortisol regulation, no studies with humans have examined the effects of an experimentally manipulated early-life social experience on cortisol regulation. OBJECTIVE: To examine the effects of experimental manipulations of social experience on cortisol response to a social challenge in preschoolers at risk for antisocial behavior. DESIGN: Randomized controlled trial. SETTING: Department of Child and Adolescent Psychiatry, New York University School of Medicine. PARTICIPANTS: Ninety-two preschool-age siblings of youths adjudicated for delinquent acts. Intervention Family-based intervention included 22 weekly group sessions for parents and preschoolers and 10 biweekly home visits conducted during a 6- to 8-month period. MAIN OUTCOME MEASURES: Salivary cortisol levels before and after a social challenge (entry into an unfamiliar peer group). RESULTS: Relative to controls, children in the intervention condition had increased cortisol levels in anticipation of the peer social challenge. Increases were relative to both preintervention cortisol levels during the challenge and cortisol levels in the home, which were not altered by the intervention. CONCLUSIONS: A family-based preventive intervention for children at high risk for antisocial behavior alters stress response in anticipation of a peer social challenge. The experimentally induced change in cortisol levels parallels patterns found in normally developing, low-risk children.     

Use of Boronic Acid Disk Tests To Detect Extended- Spectrum β-Lactamases in Clinical Isolates of KPC Carbapenemase-Possessing Enterobacteriaceae

We evaluated boronic acid (BA)-based methods for their ability to detect extended-spectrum β-lactamases (ESBLs) among clinical isolates of KPC-producing members of the Enterobacteriaceae family. A total of 155 isolates of Klebsiella pneumoniae (n = 141), Escherichia coli (n = 6), Enterobacter aerogenes (n = 6), and Klebsiella oxytoca (n = 2) genotypically confirmed to be KPC producers were analyzed. As many as 118 isolates harbored ESBLs (103 harbored SHV-type ESBLs, 13 harbored CTX-M-type ESBLs, and 2 harbored both SHV- and CTX-M-type ESBLs); the remaining 37 isolates were genotypically negative for ESBL production. The CLSI ESBL confirmatory test was positive for 79 of the 118 ESBL producers (sensitivity, 66.9%), while all 37 non-ESBL producers were negative (specificity, 100%). When a ≥5-mm increase in the zone diameter of either the cefotaxime (CTX)-clavulanate (CA) or the ceftazidime (CAZ)-CA disks containing BA compared with the zone diameter of the CTX or CAZ disks containing BA was considered to be a positive result for ESBL production, the method detected all 118 ESBL producers (sensitivity, 100%) and showed no false-positive results for non-ESBL producers (specificity, 100%). Double-disk synergy tests, in which disks of CTX, CAZ, aztreonam, or cefepime in combination with BA were placed at distances of 20, 25, and 30 mm (center to center) from a disk containing amoxicillin (amoxicilline)-clavulanate-BA, were able to detect 116 (98.3%), 101 (85.6%), and 28 (23.7%) of the ESBL-positive isolates, respectively; no false-positive results for non-ESBL-producing isolates were detected. Our results demonstrate that the modified CLSI ESBL confirmatory test with antibiotic disks containing BA is the most accurate phenotypic method for the detection of ESBLs in Enterobacteriaceae producing KPC carbapenemases.During the last decade, carbapenem resistance has emerged among clinical isolates of the Enterobacteriaceae family, and this is increasingly attributed to the production of β-lactamases capable of hydrolyzing carbapenems (23). Among these enzymes, a new type of Ambler class A β-lactamase, the Klebsiella pneumoniae carbapenemase (KPC), has been rapidly spreading among K. pneumoniae isolates and other Enterobacteriaceae in the northeastern regions of the United States and has now spread to several regions of North and South America, as well as in Israel, China, and Greece (2, 13, 16, 21).The current spread of KPC enzymes makes them a potential threat to currently available antibiotic-based treatments. These enzymes confer various levels of resistance to all β-lactams, including carbapenems, even though cefamycins and ceftazidime are only weakly hydrolyzed (15, 18). KPC-possessing strains frequently carry extended-spectrum β-lactamase (ESBL) genes (1, 3, 8, 13, 24), which could possibly contribute to the expression and dissemination of the β-lactam resistance trait (8, 18, 21). It should be also noted that KPCs and ESBLs are mostly plasmid-encoded determinants that can easily disseminate to other enterobacterial strains (3, 7, 15, 18, 26). Therefore, the phenotypic detection of ESBLs in KPC-producing isolates of the Enterobacteriaceae is of potential interest for epidemiological purposes as well as for limiting the spread of the underlying resistance mechanisms.The CLSI recommends a phenotypic confirmatory test for ESBL production that consists of measuring the growth-inhibitory zones around both cefotaxime (CTX) and ceftazidime (CAZ) disks with or without clavulanate (CA) for K. pneumoniae, Klebsiella oxytoca, Escherichia coli, and Proteus mirabilis (4). Different double-disk synergy tests (DDSTs) based on the synergy of amoxicillin (amoxicilline)-clavulanate (AMC) with extended-spectrum cephalosporins and aztreonam have also been extensively used for the detection of ESBLs (7). However, strategies for the laboratory identification of ESBLs need to be reviewed and adjusted as additional mechanisms of resistance to β-lactams coexist in enterobacterial strains (7). KPCs hydrolyze several β-lactam antibiotics, and hence, the presence of an ESBL can be masked by the expression of a KPC. Moreover, the weak inhibition of KPCs by the β-lactam inhibitors (15, 18, 30) may interfere with the interpretation of ESBL detection methods and KPC enzymes may be mistaken for ESBLs. Thus, there is a need to accurately detect ESBLs in the presence of coexisting KPC expression.Boronic acid (BA) compounds were recently reported to be reversible inhibitors of KPCs (6, 16, 27). In particular, we have shown that BA disk assays are considered positive for the detection of the KPC enzyme when the growth-inhibitory zone diameter around a meropenem, imipenem, or cefepime disk with phenylboronic acid is 5 mm or greater of the growth-inhibitory zone diameter around the disk containing meropenem or cefepime alone (27). The results of this study also showed that BA affected the activity of CAZ in ESBL-negative KPC-producing isolates but not in SHV ESBL-positive KPC-producing isolates, most likely due to the presence of the SHV ESBL, which is not restrained by BA (27). BA-based tests with disks of CAZ and CTX have also been successfully employed for the identification of ESBLs in AmpC producers (11, 25). These observations led us to design a modified CLSI ESBL confirmatory test using antibiotic disks containing BA as well as different DDSTs employing BA for the accurate detection of ESBLs in KPC-producing enterobacterial isolates.     

Strongyloides stercoralis in a bronchial washing specimen processed as conventional and Thin‐Prep smears: Report of a case and a review of the literature

Strongyloidiasis is an opportunistic infection which may result in a fatal hyperinfection syndrome in immunocompromised patients. We report the case of a pulmonary infection with Strongyloides stercoralis in a 61‐year‐old male with a history of a long‐term administration of corticosteroids. Cytologic examination of a bronchial washing specimen, processed both as conventional and as Thin‐Prep smears, revealed an abundance of the typical larvae of Strongyloides stercoralis, amidst a cellular population comprising several acute inflammatory cells as well as bronchial epithelial cells with features of basal cell hyperplasia or regenerative atypia. To the best of our knowledge there is only one previous report describing Strongyloides stercoralis in thin‐layer smears, and there are no previous studies comparing its morphology in conventional and thin‐layer preparations. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Prognostication of the high-risk WM patient

Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these “poor-risk” patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.     

In vitro and in vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine and containing ring incorporated at N(4)-position: synthesis, spectroscopic study and crystal structure of platinum(II) complexes with thiosemicarbazones, potential anticancer agents

Reactions of thiosemicarbazones of 2-formyl and 2-acetyl pyridine and containing an azepane ring (hexamethyleneiminyl ring) incorporated at N(4)-position, HL(1) (1) and HL(2) (2) with platinum(II) afforded the complexes, [Pt(L(1))Cl] (3) and [Pt(L(2))Cl] (4). Characterization of the compounds was accomplished by means of elemental analysis and spectroscopic techniques NMR, UV-vis and IR spectroscopy. The single-crystal X-ray structure of complex [Pt(L(2))Cl] (4) shows that the ligand monoanion coordinates in a planar conformation to the metal via the pyridyl N atom, the imine-N atom, and thiolato S-atom. Compounds 1-4 have been evaluated for antiproliferative activity in vitro against three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). Ligand 2 exhibited high activity as anticancer agent against all four cancer cell lines, while ligand 1 exhibited selectivity against MCF-7, L-929 cell lines and complex 4 against A-549, T-24 cancer cell lines. Also, the acute toxicity and antitumor activity were evaluated on leukemia P388-bearing mice. Complex 3 afforded five to six cures against leukemia P388. The in vivo results of the antitumor activity show the two platinum complexes as very effective chemotherapeutic antileukemic agents.     

Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E₂ (PGE₂), but increasing the biosynthesis of prostacyclin (PGI₂). In low-density lipoprotein receptor–deficient (Ldlr^–/–) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE₂ accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr^–/– mice, whereas, despite the direct vasodilator properties of PGI₂, deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1^–/– mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in Ldlr^–/– mice and in Ipr^–/– Ldlr^–/– mice. Thus, estrogen compensates for a deficiency in PGI₂ to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors.     

Witnessed resuscitation: beneficial or detrimental?

This article explores the existing literature and discusses the benefits and disadvantages of witnessed resuscitation for health professionals, relatives, and patients themselves. Keywords "witnessed resuscitation," "patient perspective," "health professionals," and "resuscitation room" were entered into MEDLINE, Medscape, and Science Direct databases. The issue of witnessed resuscitation, along with the benefits and disadvantages of its implementation, is discussed widely with increasing controversy among health professionals. Many authors accept the existence of benefits of witnessed resuscitation, but they each have reservations on certain aspects of the practice. Although witnessed resuscitation has demonstrable benefits, the dearth of research literature on the subject makes it difficult to come to a concrete conclusion about its value in practice. More studies are needed focusing on the impact of witnessed resuscitation on staff, family members, and patients. Larger sample sizes are needed in future studies, and studies are needed in which geographical, cultural, religious, and sociological factors are taken into consideration.     

Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells

Kaposi's sarcoma (KS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection up-regulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation. A lentiviral library of individual KSHV-encoding genes, comprising the majority of known latent genes and a selection of lytic viral genes, was constructed to investigate the underlying mechanism of this up-regulation. Two lytic genes, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR), up-regulated Ang2 expression in LEC. Both vIL6 and vGPCR are expressed in KSHV-infected LEC and caused up-regulation of Ang2 in a paracrine manner. KSHV, vIL6, and vGPCR up-regulated Ang2 through the mitogen-activated protein kinase (MAPK) pathway. Gene expression microarray analysis identified several other angiogenic molecules affected by KSHV, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, which is also affected by vIL6 and vGPCR in LEC, and matrix metalloproteinases, which could act in concert with Ang2 to contribute to KS development. These findings support the paracrine and autocrine roles of the lytic KSHV-encoded proteins, vIL6 and vGPCR, in KS pathogenesis and identify Ang2 as a potential therapeutic target for this neoplasm.     

Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC)

Alcohol consumption may be associated with risk of colorectal cancer (CRC), but the epidemiological evidence for an association with specific anatomical subsites, types of alcoholic beverages and current vs. lifetime alcohol intake is inconsistent. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 478,732 study subjects free of cancer at enrolment between 1992 and 2000 were followed up for an average of 6.2 years, during which 1,833 CRC cases were observed. Detailed information on consumption of alcoholic beverages at baseline (all cases) and during lifetime (1,447 CRC cases, 69% of the cohort) was collected from questionnaires. Cox proportional hazard models were used to examine the alcohol-CRC association. After adjustment for potential confounding factors, lifetime alcohol intake was significantly positively associated to CRC risk (hazard ratio, HR=1.08, 95%CI=1.04-1.12 for 15 g/day increase), with higher cancer risks observed in the rectum (HR=1.12, 95%CI=1.06-1.18) than distal colon (HR=1.08, 95%CI=1.01-1.16), and proximal colon (HR=1.02, 95%CI=0.92-1.12). Similar results were observed for baseline alcohol intake. When assessed by alcoholic beverages at baseline, the CRC risk for beer (HR=1.38, 95%CI=1.08-1.77 for 20-39.9 vs. 0.1-2.9 g/day) was higher than wine (HR=1.21, 95%CI=1.02-1.44), although the two risk estimates were not significantly different from each other. Higher HRs for baseline alcohol were observed for low levels of folate intake (1.13, 95%CI=1.06-1.20 for 15 g/day increase) compared to high folate intake (1.03, 95%CI=0.98-1.09). In this large European cohort, both lifetime and baseline alcohol consumption increase colon and rectum cancer risk, with more apparent risk increases for alcohol intakes greater than 30 g/day.