Day: 11/20/2010

The potential benefits of rapamycin on renal function, tolerance, fibrosis, and malignancy following transplantation

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Use of the mammalian target of rapamycin (mTOR) inhibitor rapamycin in organ transplantation has evolved through different phases over the past two decades. After its discovery in the mid 1970s, antifungal and cytotoxic effects were the first of its properties to be explored, but the most significant advancement was found in its use as an immunosuppressive agent to reduce transplant rejection. This was viewed as an important step forward for immunosuppression, as early studies suggested that rapamycin was less nephrotoxic than calcineurin inhibitors (CNIs). Later, detrimental effects of rapamycin on kidney function were found in some patients. Nonetheless, a fascination with the mTOR pathway and its central role in multiple cellular processes has ensued. Among the potential positive clinically relevant effects is rapamycin’s capacity to interfere with fibrotic processes that often accompany transplant rejection, and to influence the preferential development of immunological tolerance. A feature of increasing importance is that the mTOR pathway is central for vital aspects of tumor development, including angiogenesis and cell growth; rapamycin, therefore, has anticancer activities, which may prove critical in the fight against high cancer rates in transplant recipients. The final chapters defining the value of rapamycin have not been written yet, and indeed remain a work in progress. Only further research will reveal the full potential of rapamycin in organ transplantation.

 

Sirolimus for calcineurin inhibitors in organ transplantation

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Sirolimus (SRL) is an antiproliferative agent inhibiting the mammalian target of rapamycin (mTOR) proposed as a non-nephrotoxic alternative to calcineurin inhibitors for the prevention of acute rejection in renal transplantation. Despite initial encouraging results, enthusiasm faded with large trials showing an increased risk of acute rejection with this molecule that did not provide superior graft function over cyclosporin or tacrolimus. Recent data showed that SRL, along with an immunosuppressive activity on CD4+ T cells, exerts a paradoxical stimulatory effect on innate immunity, which may explain its incomplete control of alloimmune response. Moreover, SRL therapy is burdened by a concerning safety profile including high risk of delayed graft function and onset of proteinuria. This adds to many other adverse effects, including dyslipidemia, diabetes, myelosuppression, delayed wound healing, infertility, ovarian cysts, and mouth ulcers, that further limit the use of this molecule. Severe cases of interstitial pneumonia have also been reported with this therapy, raising additional concerns. Incomplete control of immune response, along with a poor tolerability, makes SRL far from being the ideal antirejection drug. Progressive restrictions of SRL indication in renal transplantation have, however, been paralleled by evidence showing mTOR abnormalities involved in many pathogenic conditions, thus opening the avenue to new possible applications of this molecule.

 

Association between Plasma IL-6 Response to Acute Stress and Early-Life Adversity in Healthy Adults

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Increased production of peripheral cytokines and other pro-inflammatory markers has been linked to psychiatric disorders such as major depressive disorder and post-traumatic stress disorder. Recent research has pointed to early-life stress, particularly childhood maltreatment, as an independent and preventable risk factor for systemic inflammation in adulthood. Some data suggest that adults with a history of childhood maltreatment exhibit a heightened inflammatory response to acute stress challenge. To further elucidate the relationship between childhood maltreatment and pro-inflammatory cytokine production, we examined plasma IL-6 response to the Trier Social Stress Test (TSST) in 69 healthy adult subjects without depression or post-traumatic stress disorder. Serial plasma IL-6 concentrations were measured during a standardized psychosocial stressor in n=19 subjects with moderate–severe childhood maltreatment (MAL), and n=50 controls without maltreatment (CTL), as indicated by self-ratings on the childhood trauma questionnaire (CTQ). CTQ total scores were positively correlated with overall change in IL-6 response, as well as the maximum IL-6 concentration during the TSST. Greater acute IL-6 release and higher IL-6 concentrations over time were observed for the MAL group relative to the CTL group. Inflammation may be an important developmental mediator linking adverse experiences in early life to poor adult physical and mental health. The results of this preliminary study warrant further investigation in a larger sample.

Video Capsule Endoscopy: What Is the Future?

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Video capsule endoscopy (VCE) that was launched 10 years ago has become a first-line procedure for examining the small bowel, especially in the case of obscure gastrointestinal bleeding. Other major indications include Crohn disease (CD), celiac disease, and intestinal polyposis syndrome. In the case of small bowel diseases, the use of VCE must be integrated in a global diagnostic and therapeutic approach. More recently, wireless endoscopy has been adapted for examining the colon, opening up larger perspectives for colorectal cancer screening or colon examination. Technologic modifications of the second-generation colon capsule increase the sensitivity of this method for detecting polyps. Other new developments, including remote magnetic manipulation, power management, drug delivery capsule, microbiopsy capsule, and adaptation of technologies such as chromoendoscopy, are sure to enhance the capabilities of wireless endoscopy in gastrointestinal disorders.

Evaluation of the Outcomes of Ice Application for the Control of Pain Associated with Chest Tube Irritation

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The aim of this study was to evaluate the effectiveness of the use of ice for the control of pain associated with chest tube irritation. The randomized and single-blinded study consisted of 40 patients (20 in the control and 20 in the study group) who underwent thoracotomy with chest tube placement. The same general anesthesia protocol was used for all patients, and the procedure was performed by the same surgery team. Procedures such as decortication and thoracic wall resection were not included in the study. Standard postoperative analgesic methods were applied to all patients. Additionally, ice (in flexible and bendable cold gel packs wrapped in fine cloth sheaths) was applied to the chest tube insertion site at the 24th, 28th, 36th, and 40th postoperative hours for 20 minutes. To assess the effectiveness of ice application, Verbal Category Scale and Behavioral Pain Scale methods were used to measure the severity of pain. Average pain severity scores during the mobilization activities, including coughing and walking, were compared and found to be significantly lower in the study group patients who received cold therapy than in the control group patients (p < .05). Additionally, analgesic consumption was lower in the study group than in the control group patients (p < .05). As a result, the application of ice to the chest tube insertion site reduced pain associated with irritation along with the need for analgesics.