Secondary closure of oroantral and oronasal fistulas: a modification of existing techniques

Fifty-three patients, 25 with oroantral and 28 with oronasal fistulas, were treated using a modified technique of peripheral de-epithelialization and overlapping flaps. This technique was used with sliding buccal flaps, palatal rotation flaps, palatal island flaps, tongue flaps, and distant tubed pedicle flaps. The advantage of the flap is that it provides more tissue attachment, which promotes healing and resists the tendency of the flap to return to its original position. A high degree of success can be predicted. Only two failures were observed in 53 cases.     

Transdermal Dual-Controlled Delivery of Contraceptive Drugs: Formulation Development,in Vitro and in Vivo Evaluations,and Clinical Performance

Several transdermal contraceptive device (TCD) formulations were developed to provide a dual-controlled transdermal delivery of levonorgestrel (LN), a potent progestin, and 17-estradiol (E₂), a natural estrogen. Using a sensitive HPLC method, the in vitro release and skin permeation profiles of LN and E₂ from various TCD formulations were simultaneously characterized in the hydrodynamically well-calibrated Valia–Chien skin permeation cells and both were found to follow zero-order kinetics. The rates of drug release and skin permeation were observed to vary significantly depending upon some formulation parameters. Six-month stability studies were performed on seven formulations at room and elevated temperatures (37 and 45°C), and two (Formulations 4 and 5) were found to be acceptable, based on drug recovery, release rate, and skin permeation rate data. Judging from the 6-month accelerated stability studies, it is projected these two formulations will have shelf-life of at least 2 years. As a result of development of an efficient manufacturing process, Formulation 4 was selected for further evaluation. One-week primary skin irritation evaluation in 6 rabbits indicated that Formulation 4 is nonirritating, and it was thus selected for Phase I clinical bioavailability/dose proportionality studies in 12 healthy female volunteers of child-bearing age. Results of pharmacokinetic and pharmacodynamic analyses demonstrated that it is capable of achieving and maintaining a steady-state serum level of LN throughout the 3-week treatment period by weekly applications of one or two TCD patches (10 or 20 cm²). A dose proportionality was obtained in the serum drug levels, daily dose delivered, and contraception efficacy. An excellent correlation was obtained for the rates of transdermal delivery determined by the in vitro studies using human cadaver skin, the in vivo studies in rabbits, and the clinical studies in living subjects.     

Structure-based pharmacophore modeling and virtual screening to identify novel inhibitors for anthrax lethal factor

Inhibition of anthrax lethal factor (LF) has been reported to be a potent strategy for the treatment of anthrax; however, no effective LF inhibitors are currently available. In this study, a structure-based pharmacophore model was developed based on the co-crystallized structure of anthrax LF with the active inhibitor GM6001. The best pharmacophore model (denoted as SB_Hypo1), consisting of two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic, was further validated using Gunner-Henry score method. The well-validated SB_Hypo1 was then used as a 3D-query in virtual screening to identify potential hits from NCI database. These hits were subsequently filtered by ADMET and validated by molecular docking experiments, and their binding stabilities were validated by 10-ns MD simulations. Finally, three hits were identified as potential leads based on their favorable binding interactions.     

Renosplenic Shunting in the Nutcracker Phenomenon: A Discussion and Paradigm Shift in Options? A Novel Approach to Treating Nutcracker Syndrome

The nutcracker syndrome is a rare clinical manifestation of symptoms caused by the compression of the left renal vein by an overriding superior mesenteric artery, an anatomical variant otherwise known as the nutcracker phenomenon. Usually present in women and children, when symptomatic, it commonly presents with hematuria, proteinuria, and chronic pelvic pain. Effective modalities of treatment apart from conservative management, include both invasive surgical procedures such as renal vein transposition and autotransplantation of the kidney and more popular recently, the less invasive endovascular stenting. Both options, however, are not without complications, such as, retroperitoneal hematomas or stent migration, thrombosis and restenosis. We now present a case of spontaneous renosplenic shunting in a 68-year-old lady of Chinese descent with the nutcracker syndrome—the first of such cases to be ever reported in a patient with no preexisting predilection for chronic liver disease and portosystemic shunting. Despite having significant pelvic venous congestion as evident on computed tomography scans, she remained asymptomatic. This may present a novel paradigm shift for the treatment of the nutcracker syndrome —surgical creation of a renosplenic bypass instead of current modalities, an alternative solution which can be performed laparoscopically and is without problems related to stent use. The creation of laparoscopic splenorenal bypass has been reported once thus far in Cleveland Ohio by Chung and Gill with good symptomatic improvement but no further studies since to validate its long-term effectiveness.     

A Novel Target and Approach for Identifying Antivirals against Molluscum Contagiosum Virus

The dermatological disease molluscum contagiosum (MC) presents as lesions restricted solely to the skin. The poxvirus molluscum contagiosum virus (MCV) is responsible for this skin disease that is easily transmitted through casual contact among all populations, with greater frequency in children and immunosuppressed individuals. In addition, sexual transmission of MCV in adolescents and adults is a health concern. Although the skin lesions ultimately resolve in immunocompetent individuals, they can persist for extended periods, be painful, and result in scarring. Treatment is problematic, and there is no drug that specifically targets MCV. The inability of MCV to propagate in cell culture has impeded drug development. To overcome these barriers, we integrated three new developments. First, we identified a new MCV drug target (mD4) that is essential for processive DNA synthesis in vitro. Second, we discovered a small chemical compound that binds to mD4 and prevents DNA synthesis in vitro. Third, and most significant, we engineered a hybrid vaccinia virus (mD4-VV) in which the natural vaccinia D4 (vD4) gene is replaced by the mD4 target gene. This hybrid virus is dependent on mD4 for viral growth in culture and is inhibited by the small compound. This target system provides, for the first time, a platform and approach for the discovery and evaluation of new therapeutics that can be used to treat MC.     

Psychological Comfort of Paramedics with Field Death Pronouncement: A National Asian Study to Prepare Paramedics for Field Termination of Resuscitation

Objectives: Paramedics' decision to terminate field resuscitation without a physician present may depend on personal and external factors. This study investigates factors associated with paramedic psychological comfort with termination of resuscitation (TOR) to inform future training. Methods: We administered an anonymous survey to all practicing paramedics in a large urban Asian Emergency Medical Services system where formal TOR training had not yet been conducted and field TOR was not routinely applied. The survey assessed psychological comfort using the validated Psychological Comfort Total (PCT) scale (summed score of 28 items, with higher scores representing greater comfort). We examined scores associated with four personal (prior resolution of personal loss, knowledge of survival probability, religious affiliation and experience with death pronouncements) and two external (location of patient and perceived trust of family) factors. Data were entered into Excel and analyzed by t-tests and ANOVA. Results: Response rate was 73.6% (254/345). Respondents were 30.3 years (mean, SD 7.1) with 7.2 years (mean, SD 5.54) of practice experience. Over 60% had been involved in 6 or more field death pronouncements in the prior 12 months. Higher PCT scores were associated with prior resolution of personal loss and knowledge of survival probability. Lower PCT scores were associated with patient location in a public place and perceived family lack of trust. PCT scores were not associated with paramedic religious affiliation or number of prior death pronouncements. Conclusions: Paramedic psychological comfort with field death pronouncement is associated with personal and external factors. Since paramedic comfort is important for protocol adoption, TOR education should target not only knowledge, but also public arena management, communication skills for engaging with families, and help paramedics resolve prior personal loss.     

EHR Adoption and Hospital Performance: Time‐Related Effects

Objective

To assess whether, 5 years into the HITECH programs, national data reflect a consistent relationship between EHR adoption and hospital outcomes across three important dimensions of hospital performance.

Data Sources/Study Setting

Secondary data from the American Hospital Association and CMS (Hospital Compare and EHR Incentive Programs) for nonfederal, acute‐care hospitals (2009–2012).

Study Design

We examined the relationship between EHR adoption and three hospital outcomes (process adherence, patient satisfaction, efficiency) using ordinary least squares models with hospital fixed effects. Time‐related effects were assessed through comparing the impact of EHR adoption pre (2008/2009) versus post (2010/2011) meaningful use and by meaningful use attestation cohort (2011, 2012, 2013, Never). We used a continuous measure of hospital EHR adoption based on the proportion of electronic functions implemented.

Data Collection/Extraction Methods

We created a panel dataset with hospital‐year observations.

Principal Findings

Higher levels of EHR adoption were associated with better performance on process adherence (0.147; p < .001) and patient satisfaction (0.118; p < .001), but not efficiency (0.01; p = .78). For all three outcomes, there was a stronger, positive relationship between EHR adoption and performance in 2010/2011 compared to 2008/2009. We found mixed results based on meaningful use attestation cohort.

Conclusions

Performance gains associated with EHR adoption are apparent in more recent years. The large national investment in EHRs appears to be delivering more consistent benefits than indicated by earlier national studies.     

Frequent DNA methylation of MiR‐129‐2 and its potential clinical implication in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis and high mortality due to a lack of effective medical treatment and apparent early stage symptoms. Understanding molecular mechanism of cancer development is crucial for HCC diagnosis, prognosis, and treatment. Recently, microRNAs have been shown to play an important role in carcinogenesis, being regulated by DNA methylation in several cases. In this study, a whole genome approach was used to identify methylation‐regulated miRNAs in HCC, finally focusing on miR‐129‐2. MiR‐129‐2 methylation and reduced expression were observed in all examined HCC cell lines but not in normal liver cells and tissues. In 39 (93%) of 42 HCC, the methylation levels of miR‐129‐2 were significantly increased in tumor tissues compared with adjacent normal tissues. Furthermore, miR‐129‐2 methylation was detectable in plasma samples from HCC patients, but not in plasma samples from healthy individuals or patients with liver cirrhosis. At a cut‐off value of ?2.36 (log2 transformation of methylation level), it was possible to distinguish HCC from healthy and cirrhotic controls with sensitivity and specificity of 88% and 100%, respectively. This study indicates that miR‐129‐2 methylation is highly accurate in distinguishing HCC patients from cirrhosis patients and healthy individuals, implying its potential utility as an early diagnostic marker for HCC. © 2013 Wiley Periodicals, Inc.