Synthesis and in-vitro antimicrobial activity of secondary and tertiary amines containing 2-chloro-6-methylquinoline moiety

A number of secondary and tertiary amines bearing 2-chloro-6-methylquinoline were synthesized by nucleophilic substitution reaction of 3-(chloromethyl)-2-chloro-6-methylquinoline with substituted aromatic primary and secondary amines in presence of catalytic amount of triethylamine (TEA) and K(2)CO(3). All the compounds were characterized by combined use of IR, (1)H-NMR, (13)C-NMR, mass spectral data, and microanalyses. The newly synthesized quinolinyl amines were screened in vitro for their antifungal activity against Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, Monascus purpureus MTCC 369, Penicillium citrinum NCIM 768 and for antibacterial activity strains viz. Escherichia coli NCTC 10418, Staphylococcus aureus NCTC 65710, and Pseudomonas aeruginosa NCTC 10662 by agar diffusion technique. Results of the preliminary screening revealed that some of the compounds mainly those with electron withdrawing groups in the phenyl ring showed promising antifungal activity.     

Evaluation of the use of digital images for a national prostate core external quality assurance scheme

Harnden P, Coleman D, Moss S, Kodikara S, Griffin N R & Melia J

(2011) Histopathology 59 , 703–709 Evaluation of the use of digital images for a national prostate core external quality assurance scheme Aims: To evaluate the use of virtual images as an alternative to glass slides to expand the number of participants in the External Quality Assurance Scheme for prostatic biopsies. Methods and results: Benign and neoplastic cases, previously circulated as glass slides, were selected to include cases that had demonstrated a high level of agreement (n = 10) and a lesser degree of agreement (n = 10). Whole slide virtual images were circulated to 68 pathologists; 51 responses were returned. The levels of agreement for the primary diagnosis and for Gleason grading of cancers were analysed using kappa statistics. Responses for glass slides versus images were compared for the 24 pathologists for whom data were available. Levels of agreement for diagnostic categories using virtual slides were moderate to substantial, comparable to those found using glass slides. The level of agreement for Gleason grades 8–10 was substantial, but for lower grades was fair or moderate, poorer than for the glass slide circulation. Conclusions: Circulation of virtual images of biopsy material is a suitable alternative to glass slide‐based schemes for the evaluation of diagnostic consistency. The majority of participants agreed that the ability to evaluate limited diagnostic material outweighed the disadvantages of a virtual system.     

Diclofenac-induced biochemical and histopathological changes in white leghorn birds (Gallus domesticus)

Objective:

Objective: To evaluate diclofenac-induced biochemical and histopathological changes in White Leghorn birds.

Materials and Methods:

Six-week-old birds were equally divided into three groups of six birds each. Group I served as control and received vehicle orally. The birds of Group II and III were orally administered with a single low (2 mg/kg) and high dose (20 mg/kg) of diclofenac sodium, respectively, and were observed for 7 days. The acute toxicity was assessed by observing the clinical signs and symptoms, mortality, alterations in blood biochemistry, and necropsy findings.

Results:

The birds of Group II showed only mild symptoms of diarrhea. In Group III, 50% of birds died in between 24 and 36 h post-treatment showing the symptoms of segregatory behavior, lethargy, terminal anorexia, and severe bloody diarrhea. The birds of Group II and the surviving birds of Group III showed a significantly (P<0.05) increased plasma uric acid, creatinine and plasma glutamic pyruvic transaminase (PGPT), and decreased total protein and albumin at 12 and 24 h post-treatment which returned to the normal levels at 36 h post-treatment. The dead birds of the high-dose group also showed similar pattern of biochemical changes at 12 and 24 h post-treatment and revealed extensive visceral gout with characteristic histopathological lesions in liver, kidney, heart, spleen, and intestine on post-mortem.

Conclusion:

The results indicate that diclofenac sodium has hepatotoxic, nephrotoxic, and visceral gout inducing potentials in White Leghorn birds, especially at higher dose.     

Disappearance of Vaccine-Type Invasive Pneumococcal Disease and Emergence of Serotype 19A in a Minority Population with a High Prevalence of Human Immunodeficiency Virus and Low Childhood Immunization Rates

We analyzed the epidemiology of invasive pneumococcal disease (IPD) following introduction of pneumococcal conjugated vaccine in an urban population with a 2% human immunodeficiency virus (HIV) prevalence and history of low childhood immunization rates. We observed near-elimination of vaccine-type IPD. Substantial disease remains due to non-vaccine-type pneumococci, highlighting the need to increase pneumococcal immunization among HIV-infected adults.Following the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in mid-2000, declines in invasive pneumococcal disease (IPD) were documented across all age groups in the United States (1, 4, 20) and in vulnerable populations (4, 7, 17). Subsequently, increases in IPD caused by nonvaccine serotypes, particularly 19A, were observed (4, 7, 8, 9, 13, 14, 17).Newark, NJ, is a mid-sized U.S. city with a predominantly black and Hispanic population (19), a high human immunodeficiency virus (HIV)/AIDS prevalence (2%) (11), and a history of low childhood immunization rates (2). Potential PCV7-related direct and indirect effects in such populations have not been fully studied. Statewide, passive surveillance of IPD began in mid-2003. We previously described a single Newark medical center''s experience with IPD (18). In the current study, we conducted active, population-based surveillance to complement these efforts and to better understand the contemporary epidemiology of IPD in Newark, specifically, PCV7''s impact and the roles of HIV/AIDS and race/ethnicity in IPD incidence.Multicenter, active surveillance of all Newark IPD cases was conducted from 1 December 2007 through 30 November 2008. Cases were identified at the clinical microbiology laboratories of the four major hospitals serving Newark residents. Case ascertainment was augmented by comparisons with passive reports to New Jersey''s Communicable Disease Reporting and Surveillance System. A case was defined as any Newark resident during the study period with Streptococcus pneumoniae isolated from either blood or cerebrospinal fluid (CSF).Patient demographics and medical information were abstracted from hospital medical charts. Collected isolates were serotyped with sequential multiplex PCR molecular methods developed by the Centers for Disease Control and Prevention (3, 12). DNA sequencing was used for resolution of serotypes 6A, 6B, and 6C. Vaccine serotypes (VT) were defined as those included in PCV7: 4, 6B, 9V, 14, 18C, 19F, and 23F. All others, including vaccine-related serotypes, were defined as nonvaccine serotypes (NVT). We separately considered the additional serotypes included in the 10- and 13-valent vaccines currently under development (6, 21).Race/ethnicity was dichotomized as black, not Hispanic (abbreviated as “black”) versus “all others.” The “all others” category included “Hispanic, all races,” “not Hispanic, white,” “not Hispanic, other,” and “unknown.” HIV status was categorized as either HIV infected or HIV uninfected/status unknown. For most incidence analyses, results are presented using the age intervals in the U.S. Census 2000 (19): <5, 5 to 17, 18 to 44, 45 to 64, and 65 years or older. For HIV-stratified analyses, results are presented using the age intervals in Newark''s HIV/AIDS prevalence reports (11): <13, 13 to 54, and 55 years or older. The χ² test of independence and Fisher''s exact test were used, as appropriate, in univariate analyses (16).During the study period 87 cases of IPD were identified among Newark residents. A total of 81 (93%) occurred at study centers, of which 72 (89%) were collected for serotyping and are described in detail in this report. Three isolates had no extractable DNA, and of the remaining 69, 5 were nontypeable. Ten cases that had not been reported through passive surveillance were identified using the study''s active surveillance methods.Considering all 87 cases during the study period, the reported 1-year incidence of IPD per 100,000 in Newark was 32 (95% confidence interval [CI], 25 to 38). The age distribution was bimodal with peaks in the under-5-years age group and the 45- to 64-years age group (Fig. ​(Fig.1).1). Considering the 72 cases for which full data were available, the relative risk (RR) of IPD for black cases versus all other cases was 2.2 (95% CI, 1.4 to 3.7) and was highest among persons 18 to 44 years old (6.4; 95% CI, 1.4 to 29) (Fig. ​(Fig.1).1). The RR of IPD for HIV-infected patients was 24 (95% CI, 15 to 38), with an incidence of 414 per 100,000 (95% CI, 268 to 611) among HIV-infected patients versus 18 (95% CI, 13 to 24) among HIV-uninfected/status unknown cases and was highest among persons 18 to 54 years old (RR, 47; 95% CI, 25 to 89). The RRs for HIV infected versus HIV uninfected/status unknown, stratified by black and all other race/ethnicity groups, were 19 (95% CI, 11 to 33) and 31 (95% CI, 12 to 85), respectively.Open in a separate windowFIG. 1.Age distribution of invasive pneumococcal disease incidence (per 100,000) by race/ethnicity, Newark, NJ, December 2007 to November 2008. Age- and race-stratified incidences were calculated based on the 72 cases for which full data were available.Table ​Table11 describes the demographic and clinical characteristics of the 72 collected cases. Of the adult cases, 25/63 (40%) were known to be HIV infected. There were no documented HIV-infected pediatric cases. The case fatality ratio was 19% (12/63) in adults and 11% (1/9) in children. Among HIV-infected adults for whom vaccination status was known, 13/21 (62%) had received the 23-valent pneumococcal polysaccharide vaccine (PPV23). Among children whose PCV7 status was known, 3/5 (60%) were up-to-date with PCV7.

TABLE 1.

Demographic and clinical characteristics of Newark IPD cases by HIV status

Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited.