Nutrition-induced catch-up growth increases hypoxia inducible factor 1alpha RNA levels in the growth plate.

Although catch-up growth is a well-known phenomenon, the local pathways at the epiphyseal growth plate that govern this process remain poorly understood. To study the mechanisms governing catch-up growth in the growth plate, we subjected prepubertal rats to 10 days of 40% food restriction, followed by a renewal of the regular food supply to induce catch-up growth. The animals were weighed daily, and their humeral length was measured at sacrifice. The proximal tibial epiphyseal growth plates (EGPs) were studied, and findings were compared with EGPs from animals fed ad libitum and animals under food restriction. The gene expression profile in the growth plates was examined using DNA microarrays, and the expression levels of selected genes were validated by real-time polymerase chain reaction. To localize gene expression in different growth plate zones, microdissection was used. Protein levels and localization were examined using immunohistochemistry. We showed that the expression level of 550 genes decreased during food restriction and increased during catch-up growth, starting already one day after refeeding. HIF-1alpha, as well as several of its downstream targets, was found among these genes. Immunohistochemistry showed a similar pattern for HIF-1alpha protein abundance. Additionally, HIF-1alpha mRNA and protein levels were higher in the proliferating than in the hypertrophic zone, and this distribution was unaffected by nutritional status. These findings indicate that nutrition has a profound effect on gene expression level during growth plate growth, and suggest an important role for HIF-1alpha in the growth plate and its response to nutritional manipulation.

Laparoscopic versus open liver resection for metastatic colorectal cancer.

BACKGROUND: Application of minimally invasive surgery for oncologic liver resection is still limited to expert centers. We describe our experience in laparoscopic liver resection (LLR) for colorectal liver metastases (CLM). PATIENTS AND METHODS: Between February 2010 and February 2015, 174 patients underwent resection of CLM. LLR was chosen according to surgeon's preferences. Data was retrieved from the institutes' electronic charts and retrospectively analyzed. RESULTS: LLR was performed in 42 patients (24.5%) and OLR in 132. Increased number of metastases were found in OLR (2.82 ± 2.81 versus 1.78 ± 1.16, P = 0.02), with no difference in maximal lesion size (33.1 ± 22 versus 34.9 ± 27.5 cm, P = 0.7). Altogether 55 patients underwent major hepatectomy, and 50 of the OLR group (37.8%, 37 right hepatectomy and 7 left hepatectomy) (P = 0.02). In 5 patients (11.6%) a conversion to open surgery was indicated. Operative time was longer in LLR. Estimated blood loss was decreased in laparoscopic minor resections. One OLR patient died during the postoperative period (0.7%). Eight patients in the OLR group had major complications, versus 1 in the LLR group (P = 0.0016). Reoperation within 30 days was performed in 4 OLR patients and none in the LLR group. Patients in the LLR group had shorter length of stay (LOS) (6.78 ± 2.75 versus 8.39 ± 5.64 days, P = 0.038). R0 resection was 88% in both groups. CONCLUSIONS: In selected patients with CLM, LLR is feasible, safe and may achieve shorter LOS without inferior oncologic outcome.

Computational redesign of a protein-protein interface for high affinity and binding specificity using modular architecture and naturally occurring template fragments.

A new method is presented for the redesign of protein-protein interfaces, resulting in specificity of the designed pair while maintaining high affinity. The design is based on modular interface architecture and was carried out on the interaction between TEM1 beta-lactamase and its inhibitor protein, beta-lactamase inhibitor protein. The interface between these two proteins is composed of several mostly independent modules. We previously showed that it is possible to delete a complete module without affecting the overall structure of the interface. Here, we replace a complete module with structure fragments taken from nonrelated proteins. Nature-optimized fragments were chosen from 10(7) starting templates found in the Protein Data Bank. A procedure was then developed to identify sets of interacting template residues with a backbone arrangement mimicking the original module. This generated a final list of 361 putative replacement modules that were ranked using a novel scoring function based on grouped atom-atom contact surface areas. The top-ranked designed complex exhibited an affinity of at least the wild-type level and a mode of binding that was remarkably specific despite the absence of negative design in the procedure. In retrospect, the combined application of three factors led to the success of the design approach: utilizing the modular construction of the interface, capitalizing on native rather than artificial templates, and ranking with an accurate atom-atom contact surface scoring function.

Human action and God's will: a problem of consistency in Jewish bioethics.

The religious legitimacy of medical practice was an issue of serious contention amongst medieval Jewish scholars. For Nahmanides, altering the patient's fate through manipulation of natural causality amounts to circumventing divine judgment. For Maimonides, however, human accomplishment is part of God's providential design; this view generally prevails in contemporary Jewish bioethics. But the doctrine of deligitimizing human intervention continues, even while unacknowledged, the underlie certain contemporary positions. These include arguments within Jewish bioethics about end-of-life decisions, which are therefore imbued with inconsistencies. It is suggested that, given the overall endorsement of modern medicine, the Nahmanidean approach must be explicitly confronted.