Association analysis of chromosome 1 migraine candidate genes

Background  

Migraine with aura (MA) is a subtype of typical migraine. Migraine with aura (MA) also encompasses a rare severe subtype Familial Hemiplegic Migraine (FHM) with several known genetic loci. The type 2 FHM (FHM-2) susceptibility locus maps to chromosome 1q23 and mutations in the ATP1A2 gene at this site have recently been implicated. We have previously provided evidence of linkage of typical migraine (predominantly MA) to microsatellite markers on chromosome 1, in the 1q31 and 1q23 regions. In this study, we have undertaken a large genomic investigation involving candidate genes that lie within the chromosome 1q23 and 1q31 regions using an association analysis approach.     

Multiple Genetic Mutations Associated with Polymyxin Resistance in Acinetobacter baumannii

We studied polymyxin B resistance in 10 pairs of clinical Acinetobacter baumannii isolates, two of which had developed polymyxin B resistance in vivo. All polymyxin B-resistant isolates had lower growth rates than and substitution mutations in the lpx or pmrB gene compared to their parent isolates. There were significant differences in terms of antibiotic susceptibility and genetic determinants of resistance in A. baumannii isolates that had developed polymyxin B resistance in vivo compared to isolates that had developed polymyxin B resistance in vitro.     

Laparoscopic total mesorectal excision: a consecutive series of 100 patients

OBJECTIVE: To analyze total mesorectal excision (TME) for rectal cancer by the laparoscopic approach during a prospective nonrandomized trial. SUMMARY BACKGROUND DATA: Improved local control and survival rates in the treatment of rectal cancer have been reported after TME. METHODS: The authors conducted a prospective consecutive series of 100 laparoscopic TMEs for low and mid-rectal tumors. All patients had a sphincter-saving procedure. Case selection, surgical technique, and clinical and oncologic results were reviewed. RESULTS: The distal limit of rectal neoplasm was on average 6.1 (range 3-12) cm from the anal verge. The mean operative time was 250 (range 110-540) minutes. The conversion rate was 12%. Excluding the patient who stayed 104 days after a severe fistula and reoperation, the mean postoperative stay was 12.05 (range 5-53) days. The 30-day mortality was 2% and the overall postoperative morbidity was 36%, including 17 anastomotic leaks. Of 87 malignant cases, 70 (80.4%) had a minimum follow-up of 12 months, with a median follow-up of 45.7 (range 12-72) months. During this period 18.5% (13/70) died of cancer and 8.5% (6/70) are alive with metastatic disease. The port-site metastasis rate was 1.4% (1/70): a rectal cancer stage IV presented with a parietal recurrence at 17 months after surgery. The locoregional pelvic recurrence rate was 4.2% (3/70): three rectal cancers stage III at 19, 13, and 7 postoperative months. CONCLUSIONS: Laparoscopic TME is a feasible but technically demanding procedure (12% conversion rate). This series confirms the safety of the procedure, while oncologic results are at present comparable to the open published series with the limitation of a short follow-up period. Further studies and possibly randomized series will be necessary to evaluate long-term clinical outcome in cancer patients.     

A qualitative study investigating the meaning of participation to improve the measurement of this construct

Quality of Life Research - The purpose of this study was to improve the measurement of participation. Research questions were as follows: (1) What constitutes participation according to adults? (2)...     

Identification and characterization of UK-201844, a novel inhibitor that interferes with human immunodeficiency virus type 1 gp160 processing

More than 10(6) compounds were evaluated in a human immunodeficiency virus type 1 (HIV-1) high-throughput antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (UK-201844). UK-201844 exhibited antiviral activity against HIV-1 NL4-3 in MT-2 and PM1 cells, with 50% effective concentrations of 1.3 and 2.7 microM, respectively, but did not exhibit measurable antiviral activity against the closely related HIV-1 IIIB laboratory strain. UK-201844 specifically inhibited the production of infectious virions packaged with an HIV-1 envelope (Env), but not HIV virions packaged with a heterologous Env (i.e., the vesicular stomatitis virus glycoprotein), suggesting that the compound targets HIV-1 Env late in infection. Subsequent antiviral assays using HIV-1 NL4-3/IIIB chimeric viruses showed that HIV-1 Env sequences were critical determinants of UK-201844 susceptibility. Consistent with this, in vitro resistant-virus studies revealed that amino acid substitutions in HIV-1 Env are sufficient to confer resistance to UK-201844. Western analysis of HIV Env proteins expressed in transfected cells or in isolated virions showed that UK-201844 inhibited HIV-1 gp160 processing, resulting in the production of virions with nonfunctional Env glycoproteins. Our results demonstrate that UK-201844 represents the prototype for a unique HIV-1 inhibitor class that directly or indirectly interferes with HIV-1 gp160 processing.     

Crepuscular flight activity of Culex erraticus (Diptera: Culicidae)

Circadian patterns of flight activity in mosquitoes can influence pathogen transmission by regulating dispersal potential of vectors and contact rates between vectors and reservoir and/or dead-end hosts. We investigated circadian activity patterns of Culex erraticus (Dyar and Knab) at a wetland field site in central Alabama, by aspirating resting adults and questing females in the morning and evening hours, respectively. Mosquitoes were aspirated at regular time intervals to determine the time of day during which peak resting site-seeking and host-seeking activities occurred. Day-to-day variation in activity patterns due to wind, humidity, and temperature was examined using stepwise linear regression. We found a distinct peak in flight activity during the morning hours (2 h before and 2 h after sunrise) for females and males of Culex erraticus, the most commonly encountered species at the site. The exact time of the peak varied from day to day, and was largely a function of temperature. A less distinct peak in activity was observed for questing females in the evening, although flights generally commenced just after sunset and peaked 30-60 min after sunset. A significant amount of day-to-day variation in the number of questing females was attributable to relative humidity. Our study demonstrates predictable patterns of circadian activity for Cx. erraticus, a suspected bridge vector of eastern equine encephalitis virus. Moreover, these patterns are modulated by environmental conditions. This information may be used to develop vector control strategies and make predictions about factors that affect the spread of mosquito-vectored pathogens.     

Community-wide Implementation of Health Information Technology: The Massachusetts eHealth Collaborative Experience

The Massachusetts eHealth Collaborative (MAeHC) was formed to improve patient safety and quality of care by promoting the use of health information technology through community-based implementation of electronic health records (EHRs) and health information exchange. The Collaborative has recently implemented EHRs in a diverse set of competitively selected communities, encompassing nearly 500 physicians serving over 500,000 patients. Targeting both EHR implementation and health information exchange at the community level has identified numerous challenges and strategies for overcoming them. This article describes the formation and implementation phases of the Collaborative, focusing on barriers identified, lessons learned, and policy issues.     

Cell-free DNA as a potential marker to predict carbon tetrachloride-induced acute liver injury in rats

Purpose

Finding an optimal biomarker for the noninvasive evaluation of acute liver injury (ALI) may be of great value in predicting clinical outcomes and investigating potential treatments. We investigated cell-free DNA (CFD) as a potential biomarker to predict carbon tetrachloride-induced ALI in rats.

Methods

Forty-five Sprague–Dawley rats were randomly assigned to three groups. ALI was induced by carbon tetrachloride via a nasogastric tube at 1, 2.5, or 5 ml/kg of a 50 % solution. Fifteen additional rats underwent a sham procedure. Blood samples were drawn at time t which was 0 (baseline), 3, 6, 12, 24, 48, 72, 96, and 120 h for the measurements of CFD, glutamate–pyruvate transaminase (GPT), glutamate–oxaloacetate transaminase (GOT), and total bilirubin. Prothrombin time and histology were examined at 24 and 120 h following injection of 5 ml/kg carbon tetrachloride in 18 additional rats and in 10 control rats.

Results

CFD levels in rats subjected to carbon tetrachloride-induced ALI were significantly increased in all blood samples starting at 12 h after the induction of ALI (p < 0.001), reaching peak levels at 24 h. Blood GOT, GPT, and total bilirubin were elevated in all blood samples starting at 3 h after the induction of ALI (p < 0.0001), reaching peak levels by 48 h. A positive correlation was demonstrated between CFD levels and GOT (R ² = 0.92), GPT (R ² = 0.92), and total bilirubin (R ² = 0.76). CFD levels correlated with liver damage seen on histological examination, as well as predicted liver damage, at 24 h after ALI.

Conclusions

CFD may be a useful biomarker for the prediction and measurement of ALI. There is no evidence to suggest that CFD is superior to other available noninvasive biomarkers.     

Nanoparticles for Improved Local Retention after Intra-Articular Injection into the Knee Joint

Purpose

To evaluate using cationic polymeric nanoparticles that interact with hyaluronate to form ionically cross-linked hydrogels to increase the intra-articular retention time of osteoarthritis drugs in the synovial cavity.

Methods

In vitro tests included nanoparticle release from cross-linked hydrogels using syringe and membrane dissolution tests, viscosity measurement of synovial fluid containing hydrogels, and release-rate measurement for a model active conjugated to a cationically substituted dextran using a hydrolyzable ester linkage in a sink dissolution test. Nanoparticle retention after intra-articular injection into rat knees was measured in vivo using fluorescence molecular tomography.

Results

Diffusional and convective transport of cationic nanoparticles from ionically cross-linked hydrogels formed in synovial fluid was slower in vitro than for uncharged nanoparticles. Hydrogels formed after the nanoparticles were mixed with synovial fluid did not appreciably alter the viscosity of the synovial fluid in vitro. In vitro release of a conjugated peptide from the cationic nanoparticles was approximately 20% per week. After intra-articular injection in rat knees, 70% of the nanoparticles were retained in the joint for 1 week.

Conclusions

This study demonstrates the feasibility of using cationic polymeric nanoparticles to increase the retention of therapeutic agents in articular joints for indications such as osteoarthritis.