Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance.

Gram-negative bacteria pose a major threat to human health in an era fraught with multi-drug resistant bacterial infections. Despite extensive drug discovery campaigns over the past decades, no new antibiotic target class effective against gram-negative bacteria has become available to patients since the advent of the carbapenems in 1985. Antibiotic discovery efforts against gram-negative bacteria have been hampered by limited intracellular accumulation of xenobiotics, in large part due to the impermeable cell envelope comprising lipopolysaccharide (LPS) in the outer leaflet of the outer membrane, as well as a panoply of efflux pumps. The biosynthesis and transport of LPS are essential to the viability and virulence of most gram-negative bacteria. Thus, both LPS biosynthesis and transport are attractive pathways to target therapeutically. In this review, we summarize the LPS biosynthesis and transport pathways and discuss efforts to find small molecule inhibitors against targets within these pathways.

Transition from LDR to HDR brachytherapy for cervical cancer: Evaluation of tumor control, survival, and toxicity.

PURPOSE: In 2012, our institution transitioned from low-dose-rate (LDR) brachytherapy to high dose-rate (HDR) brachytherapy. We report clinical outcomes after brachytherapy for cervical cancer at our institution over a continuous 10-year period. METHODS AND MATERIALS: From 2004 to 2014, 258 women (184 LDR and 74 HDR) were treated with tandem and ovoid brachytherapy in the multidisciplinary management of International Federation of Gynecology and Obstetrics Stages IA-IVB cervical cancer. Clinical and treatment-related prognostic factors including age, stage, smoking status, relevant doses, and toxicity data were recorded. RESULTS: Median followup for the LDR and HDR groups was 46 months and 12 months, respectively. The majority of patients (92%) received external beam radiotherapy as well as concurrent chemotherapy (83%) before the start of brachytherapy. For all stages, the 1-year local control and overall survival (OS) rates were comparable between the LDR and HDR groups (87% vs. 81%, p = 0.12; and 75% vs. 85%, p = 0.16), respectively. Factors associated with OS on multivariate analysis include age, stage, and nodal involvement. On multivariate analysis, severe toxicity (acute or chronic) was higher with HDR than LDR (24% vs. 10%, p = 0.04). Additional prognostic factors associated with increased severe toxicity include former/current smokers and total dose to lymph nodes. CONCLUSIONS: This comparative retrospective analysis of a large cohort of women treated with brachytherapy demonstrates no significant difference in OS or local control between the LDR and HDR. Acute and chronic toxicity increased shortly after the implementation of HDR, highlighting the importance of continued refinement of HDR methods, including integrating advanced imaging.

Understanding suicide attempts by adolescent Hispanic females.

This article presents integrative model to aid clinicians in understanding suicide attempts by adolescent Hispanic females. On the basis of knowledge accumulated through clinical and research experience, the model describes a convergence of sociocultural, familial, developmental, and psychological factors that include considerations of family and parental functioning; adolescent female development; and the relationships of fathers, mothers, and daughters.

A multi-state survey of videotaping practices for major trauma resuscitations.

The objective of this study was to determine the prevalence and problems, both perceived and actual, associated with videotaping major trauma resuscitations. A cross-sectional two-part survey of trauma centers was conducted. Part 1 determined demographic information and videotaping status. Part 2 asked trauma centers that were not doing videotaping (NVTCs) about their plans, past experience, and perceived problems. Videotaping trauma centers (VTCs) were asked about mechanics, responsibility, utilization, and problems. A total of 221 centers were surveyed; 20% VTCs, 70% NVTCs, and 10% NVTCs that had videotaped in the past (PVTC). Among VTCs, 53% reported problems with videotaping including lack of personnel (40%) and time (40%) to administer the program. Videotaping, however, was found to be an effective quality improvement tool in 95% of the VTCs. Of the NVTCs, 70% perceived problems with implementing a videotaping program; these included medicolegal (34%) and patient confidentiality (22%) concerns. Of the PVTCs, 90% stated that they had problems with videotaping including lack of staff support (33%) and lack of personnel to assist with the program (24%). In conclusion, staff participation and adequate personnel outweigh medicolegal concerns as actual videotaping problems. Videotaping is perceived to be an effective performance improvement tool.

Upper-extremity arterial injury.

Current experience in the management of upper-extremity arterial injury in a Level I trauma center between 1992 and 1994 is reported. Arterial trauma was seen in 21 of 643 (3.3%) patients admitted with upper-extremity injury. The mechanism of injury was penetrating in 15 of 21 and blunt in 6 cases. Patient characteristics were: 18 of 21 male, mean age 28, left upper extremity 12 of 21, and 4 patients in shock. Preoperative angiography was performed in 12 of 21 cases (5 of 6 blunt and 7 of 15 penetrating). Involved arteries included: brachial (10), axillary (5), radial (3), and subclavian (3). Associated injuries were common: nerve (9), bone (7), and vein (5). Twenty patients were explored; 18 of 20 underwent arterial repair (16 graft, 2 primary repair), and two proximal arteries were ligated. One intimal flap in the subclavian artery was observed, with a good result. Nerves were repaired in four cases, all with transection, and in four cases there was neurologic deficit without focal transection and no repair was performed. One patient died before his nerve injury could be repaired. Most venous injuries (four of five) were ligated, and three patients with blunt arterial injury underwent forearm fasciotomy. Immediate limb salvage was 100 per cent; there was one in-hospital mortality (4.7%) from exsanguination, and there was one persistent clinically significant late motor nerve deficit. Mean follow-up was 94 days (range, 0-305 days). Upper-extremity arterial injury often can be managed without angiography, particularly in cases of penetrating trauma. Good results can be anticipated with prompt arterial and nerve repair combined with selective use of venous reconstruction and fasciotomy.

A targetted intervention research on traditional healer perspectives of sexually transmitted illnesses in urban Zambia. Current research.

PIP: Interviews with 81 traditional healers from 4 Copperbelt towns in Zambia (Chililabombwe, Chingola, Luanshya, and Mufulira) investigated healers' understanding of, attitudes toward, and management of sexually transmitted diseases (STDs). In general, Zambian traditional healers had detailed constructs of the physiology and infective processes underlying syphilis, gonorrhea, chancroid, and AIDS. STDs were considered to be caused by "dirt" or contamination residing in sperm or vaginal fluids and were closely linked to violations of moral codes. Healers shared complex nosologies based on distinctions between symptoms of different STD pathologies that were more inclusive than biomedical categories. Although condom use was not promoted, healers understood the importance of preventing an infective agent from passing from one person to another. Except for AIDS, STDs were considered curable by expelling the dirt through purgatives or emetics. Modern medicine was perceived as treating only STD symptoms, not curing. Most traditional healers insisted that the infected partner bring the other partner for consultation or treatment was withheld. Since these findings identified some areas of compatibility between indigenous and biomedical models of STDs, the Traditional Medicine Unit of the Ministry of Health and the HIV/AIDS Prevention Project of the Morehouse School of Medicine (Lusaka) established a program in which traditional healers receive AIDS training and learn to counsel clients on safer sex behaviors. Follow-up entails monthly meetings between health professionals and traditional healers. Since program initiation in June 1994, 800 traditional healers and 70 health professionals have participated. Traditional healers now sell condoms to their clients through a social marketing program.^ieng