Synthesis of new triazole fused imidazo[2,1-b]thiazole hybrids with emphasis on Staphylococcus aureus virulence factors.

A series of new triazole fused imidazo[2,1-b]thiazole hybrids (9a-u) were designed, synthesized and evaluated as antimicrobial agents. Compounds 9c, 9d, 9e, 9j and 9l showed promising broad spectrum antimicrobial activity. Further, compound 9c exhibited significant anti-biofilm activity with single and mixed biofilm disruption demonstrated by Field Emission Scanning Electron Microscope (FE-SEM). Furthermore, molecular docking studies revealed that they interact with the virulence factor, Staphylococcus aureus dehydrosqualene synthase (CrtM) (PDB ID: 2ZCS). Overall, the findings suggest compound 9c as potential lead for further development of novel antibacterial and anti-biofilm agents.

Is It Painful to Manage Chronic Pain? A Cross-Sectional Study of Physicians In-Training in a University Program.

BACKGROUND: Prescribing opioids for chronic non-cancer pain (CNCP) is a challenge due to associated risks from abuse, addiction and adverse effects. We surveyed resident physicians on their knowledge, attitude and practices in opioid prescription practices in the ambulatory setting and conducted an educational module to address their knowledge gaps. METHODS: A phase 1 survey assessed knowledge, attitudes and practices of residents in the out-patient management of CNCP with opioids. Demographics, numbers of patients seen, those with concerns for risky behaviors, adverse effects and the reasons for concern were also recorded. In Phase 2, an educational module in the form of didactics and case based discussions addressed the perceived deficiencies noted from results of phase 1 survey. Pre and post module surveys assessed the effectiveness of the educational module. RESULTS: In the phase 1 study (45/49, 92% response rate, M:F = 30:15) 33.3% (15/45) were in Post-Graduate Year (PGY) 1, 35.6% (16/45) PGY2s and 31.1% (14/45) PGY3s; 80% (36/45) saw more than one patient with CNCP in the previous 3 months; 62.2% (28/45) had at least one patient with concerns for misuse and addiction; 77.8% (35/45) and 86.7% (39/45) reported a lack of training and consistent documentation respectively, and 82.2% (37/45) were uncomfortable to refill for other provider's patients. All (100%, 45/45) consulted the clinical pharmacist; 86.7% (39/45) believed that either focused education would be beneficial. In the phase 2 study (44/49, 89.7% response rate, M: F = 29: 15), the pre- and post-module responses showed that > 90% of the residents perceived improvement in knowledge and confidence in management of CNCP with opioids after the educational module. CONCLUSIONS: Internal medicine residents perceived deficits in their ability to manage CNCP. Following a focused educational training, residents' knowledge and confidence in prescription of opioids improved, demonstrating the need to include management of CNCP with opioids into their curriculum.

Feeding after percutaneous endoscopic gastrostomy: experience of early versus delayed feeding.

BACKGROUND: Multiple studies have demonstrated that feeding ≤4 hours after placement of a percutaneous endoscopic gastrostomy (PEG) tube is a reasonable option. Many physicians, however, continue to delay feedings until the next day or 24 hours; therefore, we evaluated the safety and effect of early feeding (≤4 hours) after PEG placement in our tertiary care center. METHODS: A retrospective study of 444 patients who underwent PEG between June 2006 and December 2011 was performed. Early feeding was defined as feeding ≤4 hours and delayed feeding was defined as feeding >4 hours. Statistical analysis was performed using the Fisher exact test and the Student t test. RESULTS: A total of 444 patients underwent PEG between June 2006 and December 2011. A majority of PEGs were performed on inpatients by gastroenterologists. The mean time of feeding after PEG was 3.2 ± 0.9 hours for the early group (n = 197) and 17.0 ± 10.0 hours for the delayed group (n = 247). No statistically significant differences were noted between the early (≤4 hours) feedings versus the delayed (>4 hours) feedings for overall morality within 30 days (P = 0.72) and overall complications (P = 1.00). Furthermore, no statistically significant differences were noted between early versus delayed feeding for 24-hour mortality (P = 1.00), 24- to 72-hour mortality (P = 0.20), and 3-30 days mortality (P = 0.86). For each complication, there were no statistically significant differences noted between the two groups for wound infection (P = 0.52), melena (P = 0.26), vomiting (P = 0.42), leakage (P = 0.41), stomatitis (P = 0.13), aspiration pneumonia (P =1.00), and other complications (P = 0.47). CONCLUSIONS: Feeding ≤4 hours after PEG appears to be as safe as delayed feeding. Based on this study and the literature, strong consideration for the majority of patients should be undertaken to begin feeding within 4 hours after PEG.

Mutations in NLRP7 are associated with diploid biparental hydatidiform moles, but not androgenetic complete moles.

BACKGROUND: NLRP7 (NALP7) has been identified as the major gene involved in the inherited predisposition to recurrent molar pregnancies, a rare recessive condition in which affected individuals have complete hydatidiform moles of diploid biparental origin (BiCHM). The role of NLRP7 in other types of molar pregnancy and reproductive wastage has not been conclusively demonstrated. The purpose of this study was to clarify this by identifying NLRP7 variation in two clinically well-defined groups of patients: women with recurrent BiCHM, and women with three or more recurrent complete hydatidiform moles of proven androgenetic origin (AnCHM). METHODS: Fluorescent microsatellite genotyping of molar tissue was used to establish a diagnosis of recurrent BiCHM (four novel cases) or recurrent AnCHM (nine women with multiple CHM). These two groups were subsequently screened for mutations in NLRP7 using DNA sequencing. Additional screening for non-pathological variants was performed in 21 previously published cases of recurrent BiCHM. Taqman genotyping was used to determine the frequency of novel NLRP7 variants in two control cohorts of Caucasian and Asian women with no adverse reproductive outcomes. RESULTS: Of the four novel cases with recurrent BiCHM, two were homozygous for mutations in NLRP7 while one was a compound heterozygote for a nonsense mutation and a pathological variant. No NLRP7 mutations or pathological variants were identified in the fourth case. None of the women with AnCHM carried any mutations or pathological variants of NLRP7. A single case of AnCHM was found to be heterozygous for a novel variant (R413Q). CONCLUSION: NLRP7 mutations do not represent a major cause of AnCHM.

Interactions of mouse glycophorin A with the dRTA-related mutant G719D of the mouse Cl-/HCO3- exchanger Ae1.

The AE1 mutation G701D, associated with recessive distal renal tubular acidosis (dRTA), produces only minimal erythroid phenotype, reflecting erythroid-specific expression of stimulatory AE1 subunit glycophorin A (GPA). GPA transgene expression could theoretically treat recessive dRTA in patients and in mice expressing cognate Ae1 mutation G719D. However, human (h) GPA and mouse (m) Gpa amino acid sequences are widely divergent, and mGpa function in vitro has not been investigated. We therefore studied in Xenopus oocytes the effects of coexpressed mGpa and hGPA on anion transport by erythroid (e) and kidney (k) isoforms of wild-type mAe1 (meAe1, mkAe1) and of mAe1 mutant G719D. Coexpression of hGPA or mGpa enhanced the function of meAe1 and mkAe1 and rescued the nonfunctional meAe1 and mkAe1 G719D mutants through increased surface expression. Progressive N-terminal truncation studies revealed a role for meAe1 amino acids 22-28 in GPA-responsiveness of meAe1 G719D. MouseN-cyto/humanTMD and humanN-cyto/mouseTMD kAE1 chimeras were active and GPA-responsive. In contrast, whereas chimera mkAe1N-cyto/hkAE1 G701DTMD was GPA-responsive, chimera hkAE1N-cyto/mkAe1 G719DTMD was GPA-insensitive. Moreover, whereas the isolated transmembrane domain (TMD) of hAE1 G701D was GPA-responsive, that of mAe1 G719D was GPA-insensitive. Thus, mGpa increases surface expression and activity of meAe1 and mkAe1. However, the G719D mutation renders certain mAe1 mutant constructs GPA-unresponsive and highlights a role for erythroid-specific meAe1 amino acids 22-28 in GPA-responsiveness.

Misdiagnosis of occult hip fracture is more likely in patients with poor mobility and cognitive impairment.

The diagnosis of occult hip fracture is frequently missed. We wished to investigate if patients in whom occult hip fracture was initially misdiagnosed had any distinct features, and their outcome. We reviewed 297 patients who presented with hip fractures over a two-year period. There were 24 occult hip fractures, the diagnosis was initially missed in 9 patients and correctly made in the other 15. Of the correctly identified patients, 8/15 were independently mobile and 9/15 were living in their own home compared to 0/9 independently mobile and 2/9 living in own home among those with missed diagnosis (p < 0.001). Seven of nine patients with a missed diagnosis had mental confusion but none in the other 15 (p < 0.001). Eight of the nine patients with missed diagnosis of fracture had intra-capsular fractures, of which 6 secondarily displaced. Three of those nine patients died within one year from their fracture. We suggest a low threshold of investigation for occult hip fracture in the elderly, infirm and mentally confused who present to the accident department with suspected occult hip fracture.

Angiotensin II type 1 and 2 receptors gene polymorphisms in pre-eclampsia and normal pregnancy in three different populations.

OBJECTIVES: To investigate a possible association between pre-eclampsia (PE) and the genotype for the angiotensin II type-1 receptor (AT1R) and the angiotensin type-2 receptor (AT2R) in various population groups. DESIGN: The study was retrospective in a case-controlled design. SAMPLES: Two hundred thirty-six pregnant women with PE/eclampsia (E) and 426 non-hypertensive pregnant women were included. METHOD: Polymorphic sites of AT1R (A1166C) and AT2R (A1675G) were amplified by polymerase chain reaction, digested with a restriction enzyme that differentiated between the alternative alleles, and analyzed. MAIN OUTCOME MEASURES: Maternal genotypes and their correlation with clinical parameters. RESULTS: The frequency of the AT2R-GG genotype (A1675G) in the PE group was significantly greater than in controls for Afro-Caribbean women (49.3% vs 26.9%, p=0.004), but the frequency difference in Asian or Caucasian women was not significant (23.0% vs 25.4%, p=0.63; 27.7% vs 14.8%, p=0.17, respectively). The highly significant difference in Afro-Caribbean women was maintained after controlling for the effects of age, BMI and parity (p=0.005). There was no significant association of the molecular variant of AT1R (A1166C) with PE in Afro-Caribbean, Caucasian or Asian women. However, in the whole PE group compared to the controls there was a higher proportion of the AT2R-GG genotype with AT1R-AC (56% vs 44%, OR 2.37; 95% CI: 1.06-5.32). In Afro-Caribbean women, the combination of AT1R-AC with AT2R-AG genotypes was significantly higher in controls compared to PE group (93.8% vs 6.3%, OR 0.11; 95% CI: 0.01-0.81). CONCLUSION: There is an association between PE/E and the GG-genotype of AT2R in Afro-Caribbean women.

Aspiration and tetracycline sclerotherapy of primary vaginal hydrocoele of testis in adults.

BACKGROUND: Primary Vaginal Hydrocoele of Testis is a common condition which is primarily treated surgically. Many patients with Hydrocoele of testis are either not willing or are unfit for surgery. This study was done to know the safety, efficacy and out come of tetracycline induced sclerotherapy of Primary Vaginal Hydrocoele of Testis in adults. METHODS: This quasi experimental study was done in Shahina Jamil Hospital, attached with Frontier Medical College and Ayub Teaching Hospital, Abbottabad from March 2006 to April, 2007. Thirty-seven patients with primary vaginal hydrocoele were included in the study. Aspiration and instillation of Tetracycline was done after spermatic cord block with 2% lignocaine. Procedure time, Peri and Post-procedure complications, number of injections for cure and patients' satisfaction with the procedure were recorded. Patients were discharged home 3 to 4 hours after the procedure and followed up after one week, one month, three months and six months. Direct admission and re-admissions were recorded. RESULTS: The mean age of patients was 47 years. Mean procedure time was 45 minutes. All patients were cured. Mild postoprocedure pain occurred in 12 (40%), moderate pain in 14 (46%) patients and severe pain in 4 (13.3%) patients. No patient developed haematoma or local infection. One patient (3.3%) had micturition problem. Two (6.6%) patients had minimal recurrence. One injection was sufficient for cure in all patients. 28 (93%) patients were satisfied while 2 (6.6%) patients were not satisfied with this procedure. No patient was admitted in the hospital after the procedure. CONCLUSION: Aspiration and injection of tetracycline in Primary vaginal Hydrocoele of Testis in adults is safe, effective and very economical procedure.

Histoplasmosis-Induced Hemophagocytic Lymphohistiocytosis in an Adult Patient: A Case Report and Review of the Literature.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threating immune dysregulation syndrome characterized by persistent activation of the mononuclear phagocytic system leading to uncontrolled systemic hyperinflammatory response. The proliferation and activation of histiocytes and lymphocytes lead to production of large amounts of cytokines, also called cytokine storm. Hematopoietic and lymphoid tissues are directly involved while other organs are damaged by circulating cytokines. Primary HLH is attributed to genetic defects of the immune system and secondary HLH is usually seen in adults secondary to malignancy, infection, or autoimmune diseases. Zoonotic diseases including fungal infections are an important cause of HLH. Secondary HLH can delay the recognition of the underlying zoonoses. We report the case of a 61-year-old female with history of rheumatoid arthritis with histoplasmosis associated hemophagocytic lymphohistiocytosis.

Management of Lung Cancer in the Elderly.

Lung cancer disproportionately affects the elderly. Aging is typically associated with higher risk of comorbidity, declines in physical, organ, and cognitive function, and diminished social support. Hence the management of a disease as complex and potentially lethal as lung cancer in this population is challenging. Despite most patients with lung cancer being elderly, most high-level evidence has been derived from studies that included younger patients and only a minority of the fit elderly. This article reviews the literature on the care of older adults with lung cancer. The evolving role of geriatric assessment in lung cancer is discussed.

Thromboprophylaxis and Incidence of Venous Thromboembolism in Patients With Hemophilia A or B Who Underwent High-Risk Orthopedic Surgeries.

Total hip replacement (THR) and total knee arthroplasty (TKA) carry a high risk of postoperative venous thromboembolism (VTE); therefore, anticoagulation prophylaxis is recommended in these patients. Unfortunately, there are no guidelines about VTE prophylaxis in patients with hemophilia who underwent these high-risk surgeries. To determine whether these patients have high risk of VTE, we conducted a retrospective study on patients with hemophilia who underwent elective THR/TKA at our institute from 2004 to 2012. Postoperatively, we collected information on duration and method of factor VIII/IX infusion, VTE-prophylaxis, and complications. There were 23 patients with hemophilia, 18 (78%) with hemophilia A and 5 (22%) with hemophilia B, who underwent high-risk surgeries (39% THR and 61% TKA). The VTE prophylaxis included sequential compression device, 12 (52%), and prophylactic enoxaparin, 1 (4%). Ten (43%) patients did not receive VTE prophylaxis. At 1-year follow-up, we did not find any evidence of clinical VTE in our patients. Better risk stratification is needed to identify patients who would benefit from pharmacological prophylaxis.

Complications of renal transplantation.

Continued improvements in graft survival have led to widespread acceptance of renal transplantation as the preferred treatment for the majority of patients with end-stage renal disease. The long-term care of these patients is often provided away from transplantation centers. This article presents both the clinical and imaging features of renal transplantation complications and their interventional management. Urologic and vascular complications may occur. Vascular complications include renal artery stenosis and renal artery and renal vein thrombosis. Ultrasound can accurately depict and characterize many of the potential complications of renal transplantation and increasingly magnetic resonance imaging also facilitates this role. In addition, interventional radiologic techniques allow nonsurgical treatment.

Multimodality imaging of paratesticular neoplasms and their rare mimics.

Extratesticular neoplasms are rare but clinically significant lesions that affect patients of all ages. These neoplasms are generally asymptomatic but may have potentially life-threatening sequelae. Lipoma is the most common primary benign paratesticular neoplasm and the most common tumor of the spermatic cord. Adenomatoid tumor is the most common tumor of the epididymis, followed by leiomyoma. In adult patients, it is imperative to consider sarcomas in the differential diagnosis of all solid tumors of the scrotum. The most common sarcomatous tumors in pediatric patients are embryonal sarcoma and rhabdomyosarcoma. Metastases, particularly from testicular, prostatic, renal, and gastrointestinal primary malignancies, can also occur. Mimics of paratesticular neoplasms including polyorchidism and splenogonadal fusion are rare but must also be considered for optimal management. Ultrasonography (US) is currently the imaging modality of choice. However, US findings are often variable and nonspecific and do not usually allow definitive characterization. Specific computed tomographic and magnetic resonance imaging findings with respect to tumor location, morphologic features, and tissue characteristics can aid in the evaluation of paratesticular neoplasms and help narrow the differential diagnosis.

Multidetector CT urography: techniques, clinical applications, and pitfalls.

For two decades, computed tomography (CT) has challenged intravenous urography (IVU) in the evaluation of urinary tract abnormalities. Compared with IVU, CT is more sensitive and specific in the detection and characterization of a variety of urinary tract disorders, including renal masses and urolithiasis. The last purported advantage of IVU has been its ability to depict subtle and mucosal abnormalities of the urothelium. Now, using multidetector CT (MDCT), this challenge has been overcome. In this article, we review the current role of MDCT urography in the evaluation of the urinary tract.

Common operation, uncommon complication. Bleeding from superior haemorrhoidal artery after minimally invasive procedure for hemorrhoids - a case report / Operação comum, complicação incomum. Sangramento de artéria hemorroidária superior após PMIH - um relato de caso

ABSTRACT Minimally invasive procedure for hemorrhoids is one of the commonest new wave operations done for prolapsed hemorrhoids. The diameter of the stapled tissue is critical in this operation, and an increase in the same could include more tissue in the anvil, with disastrous results. This is a case report of a post minimally invasive procedure for hemorrhoids bleed, which was refractory to two local oversewing attempts. When the bleeding was massive, an angiogram was obtained. This revealed a pseudo aneurysm of the left superior haemorrhoidal artery, which was embolized, stopping the bleed. The stapler dimensions were studied and the possible cause of the event was arrived at. The specific stapler used had a diameter of 2 mm more than the regular Medtronic and Ethicon staplers, possibly including more of the rectal wall, and the superior haemorrhoidal artery as well. This case report documents a rare and potentially fatal complication of a simple procedure.

RESUMO O procedimento minimamente invasivo para as hemorroidas (PMIH) é uma das novas operações mais comuns para ao tratamento de hemorroidas prolapsadas. O diâmetro do tecido grampeado é crítico nessa operação; um aumento nesse diâmetro poderia colocar mais tecido na bigorna do grampeador, com resultados desastrosos. Este relato de caso descreve o desfecho de uma hemorragia após PMIH, refratária a duas tentativas locais de sobressutura. Um angiograma foi realizado quando a hemorragia foi considerada intensa. O exame revelou um pseudoaneurisma da artéria hemorroidária superior esquerda, que foi embolizada, interrompendo o sangramento. As dimensões do grampeador foram estudadas e descobriu-se a possível causa do evento. O grampeador específico usado tinha um diâmetro 2 mm maior do que os grampeadores regulares da Medtronic e da Ethicon e possivelmente captou uma área maior da parede retal e a artéria hemorroidária superior. Este relato de caso documenta uma complicação rara e potencialmente fatal de um procedimento simples.

Systemic mastocytosis presenting as acute appendicitis: a case report and review of the literature.

Systemic mastocytosis is characterized by abnormal growth and accumulation of mast cells in various organs. Gastrointestinal (GI) symptoms are common disease manifestations in this disease and can significantly impair the quality of life. Signs of GI systemic mastocytosis include steatorrhea, malabsorption, hepatomegaly, splenomegaly, portal hypertension, and ascites. Acute appendicitis as a presenting feature in systemic mastocytosis has not been reported in the literature previously. In this report, we discuss the case of a female patient with systemic mastocytosis (c-KIT D816V (+)) who was admitted for right-sided acute abdominal pain. Laboratory study revealed an normal white blood cell count with eosinophilia and an elevated serum tryptase level of 23 µg/l. CT of the abdomen and pelvis showed an enlarged appendix of 12 mm in diameter, with minimal wall enhancement. Laparoscopic appendectomy was performed. The appendix was found to be hyperemic and firm, and it was densely adherent to the posterior cecum, the surrounding peritoneal wall, and the overlying mesenteric fat. Pathology revealed acute appendicitis with greater than 30 mast cells per high-power field by immunoperoxidase studies with mast cell tryptase and CD117. The patient subsequently improved and was discharged home. This case is the first reported case with a histological diagnosis of acute appendicitis resulting from mast cell infiltration. Physicians should be aware of acute appendicitis as a manifestation of systemic mastocytosis. Prompt diagnosis and management may prevent potentially fatal complications of appendiceal perforation and peritonitis.

Angiomyogenesis for myocardial repair.

The conventional therapeutic modalities for myocardial infarction have limited success in preventing the progression of left ventricular remodeling and congestive heart failure. The heart cell therapy and therapeutic angiogenesis are two promising strategies for the treatment of ischemic heart disease. After extensive assessment of safety and effectiveness in vitro and in experimental animal studies, both of these approaches have accomplished the stage of clinical utility, albeit with limited success due to the inherent limitations and problems of each approach. Neomyogenesis without restoration of regional blood flow may be less meaningful. A combined stem-cell and gene-therapy approach of angiomyogenesis is expected to yield better results as compared with either of the approaches as a monotherapy. The combined therapy approach will help to restore the mechanical contractile function of the weakened myocardium and alleviate ischemic condition by restoration of regional blood flow. In providing an overview of both stem cell therapy and gene therapy, this article is an in-depth and critical appreciation of combined cell and gene therapy approach for myocardial repair.

Multi-detector row CT urography of normal urinary collecting system: furosemide versus saline as adjunct to contrast medium.

PURPOSE: To retrospectively evaluate whether intravenous furosemide, either alone or in addition to intravenous saline, improved depiction of the normal urinary collecting system at multi-detector row computed tomographic (CT) urography. MATERIALS AND METHODS: Institutional review board approval for review of patient images and medical records was obtained; informed consent was not required for this HIPAA-compliant study. Excretory phase images from multi-detector row CT urography in 87 patients (44 women, 43 men; age range, 21-83 years; mean, 53 years) were reviewed. Examinations were performed with, in addition to intravenous contrast medium, 250 mL of intravenous normal saline alone (n = 35), both 250 mL of normal saline and 10 mg of intravenous furosemide (n = 26), or 10 mg of furosemide alone (n = 26). Three readers, blinded to the imaging technique used, individually assigned opacification scores to each of six urinary collecting system segments. Urinary distention was assessed by one reader by measuring transverse widths of the proximal, middle, and distal ureteral segments. Mean opacification scores for each segment and mean ureteral width measurements for each technique were compared by using the Student t test. RESULTS: Mean opacification scores achieved with furosemide were significantly higher than those achieved with saline for the middle (P