Rag mutations reveal robust alternative end joining.

Mammalian cells repair DNA double-strand breaks (DSBs) through either homologous recombination or non-homologous end joining (NHEJ). V(D)J recombination, a cut-and-paste mechanism for generating diversity in antigen receptors, relies on NHEJ for repairing DSBs introduced by the Rag1-Rag2 protein complex. Animals lacking any of the seven known NHEJ factors are therefore immunodeficient. Nevertheless, DSB repair is not eliminated entirely in these animals: evidence of a third mechanism, 'alternative NHEJ', appears in the form of extremely rare V(D)J junctions and a higher rate of chromosomal translocations. The paucity of these V(D)J events has suggested that alternative NHEJ contributes little to a cell's overall repair capacity, being operative only (and inefficiently) when classical NHEJ fails. Here we find that removing certain portions of murine Rag proteins reveals robust alternative NHEJ activity in NHEJ-deficient cells and some alternative joining activity even in wild-type cells. We propose a two-tier model in which the Rag proteins collaborate with NHEJ factors to preserve genomic integrity during V(D)J recombination.

A Case Report on Breast Implant Illness.

In this case report, we discuss the case of a 64-year-old woman who presented with an unusual complaint of a chronic cough associated with pleuritic chest pain of 15 years following a saline-filled breast implant surgery. Initially, these were minimally abated by acid reflux medications. However, her cough worsened despite other interventions. In the work-up to determine the etiology of her complaints, the most common causes of a chronic cough were considered. The history ruled out post-nasal drip, and pulmonary function tests excluded asthma and chronic obstructive pulmonary disease (COPD), although she had a family history. An IgE allergy panel and an Aspergillus antibody test were also normal. However, an esophagram revealed a significant finding of mild to moderate Gastroesophageal reflux disease (GERD). Ultimately, the subsequent removal of the implants led to a dramatic resolution of her symptoms. It is worth noting that breast implants, like any other medical device, carry certain risks. Complications such as infections, implant rupture, capsular contracture, and changes in breast sensations are known risks associated with breast augmentation surgery.

Correction: Vancomycin Flushing Syndrome Due to Oral Vancomycin in Chronic Kidney Disease Patients: A Case Report.

[This corrects the article DOI: 10.7759/cureus.28024.].

Red Man Syndrome Due to Oral Vancomycin in Chronic Kidney Disease Patients: A Case Report.

The red man syndrome is a known complication of vancomycin. It is commonly seen with intravenous (IV) use but is also documented with oral use. We aim to describe a case of a chronic kidney disease (CKD) patient who developed red man syndrome secondary to oral vancomycin use. Our case is about an immunosuppressed 68-year-old man who received oral vancomycin for pseudomembranous colitis, which was caused by Clostridium difficile. On the eighth day of the treatment, the patient experienced pruritus and an erythematous rash, which was diagnosed as red man syndrome, and the oral vancomycin was immediately discontinued. Upon the discontinuation of the drug, the rash disappeared, thus confirming the diagnosis. The patient's status of chronic kidney disease stage four resulted in reduced clearance of the drug, thus causing the adverse effect. This case highlights the importance of prophylaxis to prevent red man syndrome in a chronic kidney disease patient. Red man syndrome is commonly seen after the initiation of vancomycin, ciprofloxacin, or amphotericin B. Prompt diagnosis and management are required to prevent the complications due to this condition.

Superior Vena Cava Syndrome Due to Right Anterior Mediastinal Hematoma: A Case Report.

The superior vena cava syndrome (SVCS) has been frequently reported to be secondary to malignancy, specifically, small cell bronchogenic carcinoma and non-Hodgkin's lymphoma. There is some data suggesting causes like postprocedural hematomas. We aim to describe a case of a patient who developed SVCS secondary to a mediastinal hematoma secondary to epicardial pacer leads (postprocedural). Our case is about a 75-year-old male with a past medical history of coronary artery disease and coronary artery bypass graft (CABG) who presented to the Emergency Department (ED) with moderate-to-severe right axillary pain radiating to the ipsilateral side of the neck, arm, and chest, associated to right temporal headache. A computed tomography angiography (CTA) of the chest was indicated at the time and revealed a hematoma with an active extravasation within the right superior anterior mediastinum, outside the pericardium. The patient was admitted to the Cardiovascular Intensive Care Unit (CVICU) and was started on nicardipine as his blood pressure in the ED was 217/125 and remained elevated despite proper pain management. A repeat CT scan of the chest showed a regressing hematoma that coincided with an improvement of the symptoms. This case highlights the importance of the complications of anterior mediastinal hematoma. The superior vena cava syndrome can develop after cardiologic procedures, after the implantation of devices. Prompt clinical diagnosis, including imaging, and treatment are necessary to manage this condition.

Multimodality imaging findings in image-guided biopsy proven splenic littoral cell angioma: series of three cases.

Littoral cell angioma (LCA) is a rare primary splenic vascular tumor arising from the littoral cells that line the splenic sinuses of the red pulp. Definitive diagnosis of this entity depends on histology and immunochemical studies, for which splenectomy is usually performed. We present three image-guided percutaneous core biopsy proven cases of splenic LCA and also discuss imaging features of these rare tumors on CT, MR, and US findings.

Prevalence of carotid stenosis in a high-risk Caribbean population.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the prevalence of carotid stenosis among patients presenting to the University Hospital of West Indies (UHWI) Accident and Emergency Department (A&E) with an ischemic stroke or transient ischemic attack (TIA). METHODS: Beginning in August 2006, all patients presenting to the UHWI A&E with an acute stroke or TIA were screened for enrollment. Patients were excluded if they had a hemorrhagic stroke or if informed consent could not be obtained. Demographic and clinical information were collected by chart review and interviewer-administered questionnaires. All participants had noncontrast head computed tomography (CT) and bilateral carotid duplex ultrasounds. RESULTS: 133 patients were enrolled in the study. 90% presented with a stroke and 10% with a TIA. Mean age was 64 years, 52% were male, 96% self-identified as black. 78% had diabetes mellitus or hypertension or both, 27% were current or past smokers. 65.1% had a normal carotid ultrasound, 28.5% had <50% stenosis, 1.6% had 50% to 69% stenosis, 0.8% had >or=70% stenosis to near occlusion, 1.6% had near occlusion and 1.6% total occlusion. CONCLUSIONS: The prevalence of moderate or high-grade carotid stenosis in this high-risk black Caribbean population presenting with an ischemic stroke or a TIA is 5.6%. This is lower than that described in other populations. Further studies are needed to determine the cost-effectiveness of routine screening for carotid stenosis in this population.

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors.

We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K(i) <1nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.

Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.

The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.

A FRET-based assay platform for ultra-high density drug screening of protein kinases and phosphatases.

Protein phosphorylation is one of the major regulatory mechanisms involved in signal-induced cellular events, including cell proliferation, apoptosis, and metabolism. Because many facets of biology are regulated by protein phosphorylation, aberrant kinase and/or phosphatase activity forms the basis for many different types of pathology. The disease relevance of protein kinases and phosphatases has led many pharmaceutical and biotechnology companies to expend significant resources in lead discovery programs for these two target classes. The existence of >500 kinases and phosphatases encoded by the human genome necessitates development of methodologies for the rapid screening for novel and specific compound inhibitors. We describe here a fluorescence-based, molecular assay platform that is compatible with robotic, ultra-high throughput screening systems and can be applied to virtually all tyrosine and serine/threonine protein kinases and phosphatases. The assay has a coupled-enzyme format, utilizing the differential protease sensitivity of phosphorylated versus nonphosphorylated peptide substrates. In addition to screening individual kinases, the assay can be formatted such that kinase pathways are re-created in vitro to identify compounds that specifically interact with inactive kinases. Miniaturization of this assay format to the 1-microl scale allows for the rapid and accurate compound screening of a host of kinase and phosphatase targets, thereby facilitating the hunt for new leads for these target classes.

Overcoming obstacles to establish a multidisciplinary team approach to hepatobiliary diseases: a working model in a Caribbean setting.

INTRODUCTION: By providing a structured forum to exchange information and ideas, multidisciplinary team meetings improve working relationships, expedite investigations, promote evidence-based treatment, and ultimately improve clinical outcomes. METHODS: This discursive paper reports the introduction of a multidisciplinary team approach to manage hepatobiliary diseases in Jamaica, focusing on the challenges encountered and the methods used to overcome these obstacles. CONCLUSION: Despite multiple challenges in resource-limited environments, a multidisciplinary team approach can be incorporated into clinical practice in developing nations. Policy makers should make it a priority to support clinical, operational, and governance aspects of the multidisciplinary teams.

Endoscopic transmural drainage of pancreatic pseudocysts: technical challenges in the resource poor setting.

Although surgical drainage of pancreatic pseudocysts has been superseded by less invasive options, the requirement for specialized equipment, technical expertise, and consumables limits the options available in low resource settings. We describe the challenges experienced during endoscopic transmural drainage in a low resource setting and the methods used to overcome these barriers. Despite operating in a low resource environment, endoscopic drainage of pancreatic pseudocysts can be incorporated into our armamentarium with minimal change to the existing hardware. Careful patient selection by a dedicated multidisciplinary team should be observed in order to achieve good outcomes.

Laparoscopic Inguinal Hernia Repair in a Developing Nation: Short-term Outcomes in 103 Consecutive Procedures.

BACKGROUND: There are no published data on the outcomes of inguinal hernia repair from the Anglophone Caribbean. To the best of our knowledge, this is the first report of a series of laparoscopic inguinal hernia repairs from the region. MATERIALS AND METHODS: Data was extracted from a prospectively maintained database of consecutive trans abdominal pre-peritoneal (TAPP) repairs done between June 1, 2005 and May 30, 2012. Perioperative data collected included patient demographics, hernia type, operative technique, duration of surgery, intra-operative details, morbidity, analgesia requirements, and duration of hospitalization. A telephone survey was also performed to identify late recurrences and complications. Descriptive statistics were generated using Statistical Package for Social Sciences (SPSS) Ver 12.0. RESULTS: There were 103 consecutive TAPP procedures in 88 patients at an average age of 35.4 years ± 12.9 (standard deviation; SD) and average body mass index (BMI) of 28.9 Kg/m(2) ± 2.23 (SD). The indications were bilateral (30), recurrent unilateral (24), and primary unilateral (49) inguinal hernias. The mean duration of operation was 68.5 minutes (SD ± 10.4; Range: 55-95; Median 65; Mode 65) minutes for unilateral TAPP and 89 minutes (SD ± 7.61; Range: 80-105; Median 90; Mode 90) for bilateral repairs. Post-operatively, 65/70 patients required ≤1 dose of parenteral opioid analgesia and 74 (84.1%) patients discontinued oral analgesia within 48 hours of operation. Complications were recorded in six (5.8%) cases and a recurrence in one (0.97%) case after a mean follow-up period of 3.2 years (SD ± 1.8; Range: 0.5-7). CONCLUSION: Laparoscopic inguinal hernia repair is a safe and effective operation in this setting.

Vascular supply to the liver: a report of a rare arterial variant.

In the classic description of hepatic arterial supply, the common hepatic artery originates from the coeliac trunk. However, there are numerous variations to this classic pattern. We report a rare variant pattern of hepatic arterial supply and discuss the clinical significance of this variation.

Accessory renal arteries in a Caribbean population: a computed tomography based study.

INTRODUCTION: The commonest variation to the classic anatomic description of renal arterial supply is the presence of accessory renal arteries. The incidence varies widely according to ethnicity. There is no data on the prevalence of these anomalies in persons of Caribbean ethnicity. METHODS: All CT scans done over two years from July 1, 2010 to June 30, 2012 were retrospectively evaluated. The anatomy of the renal arterial supply was reported from these studies and the anatomy of accessory renal arteries was documented. RESULTS: There were 302 CT scans evaluated and accessory renal arteries were present in 109/302 (36.1%) CT scans, 95% confidence interval 30.6%, 41.4%. There were 71/309 (23.5%) patients with accessory arteries on the left and 54/309 (17.9%) had them on the right (p 0.087). Of these, 16 (14.7%) patients had bilateral accessory renal arteries present. The most common origin for the accessory arteries was the abdominal aorta in 108 (99.1%) cases and in 1 case the accessory artery arose from the coeliac trunk. There were 80 left sided accessory renal arteries: 17 (21.3%) upper polar and 27 (33.8%) lower polar arteries. Of 62 right sided accessory arteries, 14 (22.6%) were upper polar and 26 (42%) were lower polar arteries. CONCLUSION: This is the first population-based report of anatomic anomalies in renal arterial supply in a Caribbean population. These are important findings that may affect vascular and urologic procedures on persons of Caribbean ethnicity.

Scrotal pearls and pitfalls: ultrasound findings of benign scrotal lesions.

Scrotal symptoms including palpable mass or pain often bring men to medical attention. Ultrasound serves as an extension of the physical examination in these patients and, in most cases, allows definitive diagnosis. Although the diagnosis of malignancy is of greatest concern both to the patient and clinician, a number of benign scrotal pathologies exist and most have characteristic imaging features. Knowledge of these imaging findings can help the radiologist to confidently identify common benign scrotal conditions. Location and imaging characteristics of uncommon lesions help to establish a rational differential diagnosis and appropriate recommendations for patient management.