Cellular Targeting in Autoimmunity

Many biologic agents that were first approved for the treatment of malignancies are now being actively investigated and used in a variety of autoimmune diseases such as rheumatoid arthritis (RA), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, systemic lupus erythematosus (SLE), and Sjogren??s syndrome. The relatively recent advance of selective immune targeting has significantly changed the management of autoimmune disorders and in part can be attributed to the progress made in understanding effector cell function and their signaling pathways. In this review, we will discuss the recent FDA-approved biologic therapies that directly target immune cells as well as the most promising investigational drugs affecting immune cell function and signaling for the treatment of autoimmune disease.     

First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer

Purpose  

Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.     

Changes of smooth muscle contractile filaments in small bowel atresia

AIM: To investigate morphological changes of intestinal smooth muscle contractile fibres in small bowel atresia patients.METHODS: Resected small bowel specimens from small bowel atresia patients (n = 12) were divided into three sections (proximal, atretic and distal). Standard histology hematoxylin-eosin staining and enzyme immunohistochemistry was performed to visualize smooth muscle contractile markers α-smooth muscle actin (SMA) and desmin using conventional paraffin sections of the proximal and distal bowel. Small bowel from age-matched patients (n = 2) undergoing Meckel’s diverticulum resection served as controls.RESULTS: The smooth muscle coat in the proximal bowel of small bowel atresia patients was thickened compared with control tissue, but the distal bowel was unchanged. Expression of smooth muscle contractile fibres SMA and desmin within the proximal bowel was slightly reduced compared with the distal bowel and control tissue. There were no major differences in the architecture of the smooth muscle within the proximal bowel and the distal bowel. The proximal and distal bowel in small bowel atresia patients revealed only minimal differences regarding smooth muscle morphology and the presence of smooth muscle contractile filament markers.CONCLUSION: Changes in smooth muscle contractile filaments do not appear to play a major role in postoperative motility disorders in small bowel atresia.     

Reversible skeletal disease and high fluoride serum levels in hematologic patients receiving voriconazole

We here investigate the occurrence of fluoride intake-associated alterations in patients with hematologic disease on triazol antifungal medication. Clinical, laboratory, and radiology data of overall 43 patients with hematologic malignancies taking voriconazole (n = 20), posaconazole (n = 8), and itraconazole (n = 4), and a hematologic patient control group (n = 11) are described. Bone pain and radiologic evidence of periostitis were exclusively observed in patients receiving long-term voriconazole. Cessation of treatment led to clinical improvement in all cases. In line with clinical evidence, fluoride serum concentration was elevated in patients receiving voriconazole (median, 156.5 μg/L; interquartile range, 96.8 μg/L; normal < 30 μg/L) but not in the other treatment groups (P < .001 for all comparisons vs voriconazole). We conclude that serum fluoride levels were elevated on average 5-fold above normal levels in hematologic patients receiving voriconazole. Clinically relevant skeletal disease was associated with renal insufficiency and above 10-fold elevated fluoride levels, and was reversible on termination of voriconazole treatment.     

Bacterial rheotaxis

The motility of organisms is often directed in response to environmental stimuli. Rheotaxis is the directed movement resulting from fluid velocity gradients, long studied in fish, aquatic invertebrates, and spermatozoa. Using carefully controlled microfluidic flows, we show that rheotaxis also occurs in bacteria. Excellent quantitative agreement between experiments with Bacillus subtilis and a mathematical model reveals that bacterial rheotaxis is a purely physical phenomenon, in contrast to fish rheotaxis but in the same way as sperm rheotaxis. This previously unrecognized bacterial taxis results from a subtle interplay between velocity gradients and the helical shape of flagella, which together generate a torque that alters a bacterium's swimming direction. Because this torque is independent of the presence of a nearby surface, bacterial rheotaxis is not limited to the immediate neighborhood of liquid-solid interfaces, but also takes place in the bulk fluid. We predict that rheotaxis occurs in a wide range of bacterial habitats, from the natural environment to the human body, and can interfere with chemotaxis, suggesting that the fitness benefit conferred by bacterial motility may be sharply reduced in some hydrodynamic conditions.     

Anomalous coronary circulation: left anterior descending and left circumflex coronary arteries arising from the right sinus of valsalva

Approximately 1% of adults who undergo cardiac catheterization have coronary anomalies. Patients may present with chest pain, arrhythmias, presyncope, and sometimes sudden cardiac death. Multidetector computed tomography (MDCT) is an excellent tool for identifying coronary artery anomalies and defining their course and relationship to the great vessels and surrounding structures; its value is incremental to conventional angiography. We present a rare case of a coronary anomaly involving three separate ostia at the right sinus of Valsalva for the left and right coronary vessels.     

Does a blood pressure J curve exist for patients with chronic kidney disease?

Aggressive reduction of blood pressure may increase cardiovascular events (the J‐curve phenomenon) in certain populations. In this regard, most studies in patients with chronic kidney disease have shown a J curve for cardiovascular morbidity and mortality, and this phenomenon persists after adjusting for confounding factors. Since there is no evidence that a straighter blood pressure target (<130/70 mm Hg) could improve renal outcomes, the increased cardiovascular risk associated with extreme blood pressure reduction should be seen as undesirable. Moreover, the intensive control of blood pressure may induce an unintended reduction of renal function and this decrease, in turn, may increase cardiovascular risk.     

Recruitment and retention in academic medicine--what junior faculty and trainees want department chairs to know

Attracting and retaining bright and motivated physicians remains a high priority for academia. Historically, the recruitment of trainees into academia and the retention of junior faculty have been suboptimal. To learn more about the perceived obstacles that discourage the pursuit of academic careers, a Workshop on Academic Career Pathways was conducted during the 2011 Southern Regional Meetings held in New Orleans. The audience included mainly residents and fellows as well as junior and senior faculties. Speakers described career options in academic medicine focusing on the clinician-investigator and the clinician-educator tracks. Afterward, the audience was asked to identify perceived obstacles to recruitment and retention in academic medicine. The group identified 10 major obstacles in 3 categories: financial challenges, personal mentoring and academic skills acquisition. This article summarizes the workshop proceedings and ends with recommendations to chairs and department leaders for improving recruitment and retention in academic medicine based on the discussion.