Perceptions of surgical specialists in general surgery, orthopaedic surgery, urology and gynaecology on teaching endoscopic surgery in The Netherlands

BACKGROUND: Specific training in endoscopic skills and procedures has become a necessity for profession with embedded endoscopic techniques in their surgical palette. Previous research indicates endoscopic skills training to be inadequate, both from subjective (resident interviews) and objective (skills measurement) viewpoint. Surprisingly, possible shortcomings in endoscopic resident education have never been measured from the perspective of those individuals responsible for resident training, e.g. the program directors. Therefore, a nation-wide survey was conducted to inventory current endoscopic training initiatives and its possible shortcomings among all program directors of the surgical specialties in the Netherlands. METHODS: Program directors for general surgery, orthopaedic surgery, gynaecology and urology were surveyed using a validated 25-item questionnaire. RESULTS: A total of 113 program directors responded (79%). The respective response percentages were 73.6% for general surgeons, 75% for orthopaedic surgeon, 90.9% for urologists and 68.2% for gynaecologists. According to the findings, 35% of general surgeons were concerned about whether residents are properly skilled endoscopically upon completion of training. Among the respondents, 34.6% were unaware of endoscopic training initiatives. The general and orthopaedic surgeons who were aware of these initiatives estimated the number of training hours to be satisfactory, whereas the urologists and gynaecologists estimated training time to be unsatisfactory. Type and duration of endoscopic skill training appears to be heterogeneous, both within and between the specialties. Program directors all perceive virtual reality simulation to be a highly effective training method, and a multimodality training approach to be key. Respondents agree that endoscopic skills education should ideally be coordinated according to national consensus and guidelines. CONCLUSIONS: A delicate balance exists between training hours and clinical working hours during residency. Primarily, a re-allocation of available training hours, aimed at core-endoscopic basic and advanced procedures, tailored to the needs of the resident and his or her phase of training is in place. The professions need to define which basic and advanced endoscopic procedures are to be trained, by whom, and by what outcome standards. According to the majority of program directors, virtual reality (VR) training needs to be integrated in procedural endoscopic training course

Spontaneous Abortion and Preterm Labor and Delivery in Nonhuman Primates: Evidence from a Captive Colony of Chimpanzees (Pan troglodytes)

Preterm birth is a leading cause of perinatal mortality, yet the evolutionary history of this obstetrical syndrome is largely unknown in nonhuman primate species.We examined the length of gestation during pregnancies that occurred in a captive chimpanzee colony by inspecting veterinary and behavioral records spanning a total of thirty years. Upon examination of these records we were able to confidently estimate gestation length for 93 of the 97 (96%) pregnancies recorded at the colony. In total, 78 singleton gestations resulted in live birth, and from these pregnancies we estimated the mean gestation length of normal chimpanzee pregnancies to be 228 days, a finding consistent with other published reports. We also calculated that the range of gestation in normal chimpanzee pregnancies is approximately forty days. Of the remaining fifteen pregnancies, only one of the offspring survived, suggesting viability for chimpanzees requires a gestation of approximately 200 days. These fifteen pregnancies constitute spontaneous abortions and preterm deliveries, for which the upper gestational age limit was defined as 2 SD from the mean length of gestation (208 days).The present study documents that preterm birth occurred within our study population of captive chimpanzees. As in humans, pregnancy loss is not uncommon in chimpanzees, In addition, our findings indicate that both humans and chimpanzees show a similar range of normal variation in gestation length, suggesting this was the case at the time of their last common ancestor (LCA). Nevertheless, our data suggest that whereas chimpanzees' normal gestation length is ∼20-30 days after reaching viability, humans' normal gestation length is approximately 50 days beyond the estimated date of viability without medical intervention. Future research using a comparative evolutionary framework should help to clarify the extent to which mechanisms at work in normal and preterm parturition are shared in these species

Inhibition of the receptor‐binding function of clathrin adaptor protein AP‐2 by dominant‐negative mutant μ2 subunit and its effects on endocytosis

Although interactions between the mu2 subunit of the clathrin adaptor protein complex AP-2 and tyrosine-based internalization motifs have been implicated in the selective recruitment of cargo molecules into coated pits, the functional significance of this interaction for endocytosis of many types of membrane proteins remains unclear. To analyze the function of mu2-receptor interactions, we constructed an epitope-tagged mu2 that incorporates into AP-2 and is targeted to coated pits. Mutational analysis revealed that Asp176 and Trp421 of mu2 are involved in the interaction with internalization motifs of TGN38 and epidermal growth factor (EGF) receptor. Inducible overexpression of mutant mu2, in which these two residues were changed to alanines, resulted in metabolic replacement of endogenous mu2 in AP-2 complexes and complete abrogation of AP-2 interaction with the tyrosine-based internalization motifs. As a consequence, endocytosis of the transferrin receptor was severely impaired. In contrast, internalization of the EGF receptor was not affected. These results demonstrate the potential usefulness of the dominant-interfering approach for functional analysis of the adaptor protein family, and indicate that clathrin-mediated endocytosis may proceed in both a mu2-dependent and -independent manner

Eps15 is constitutively oligomerized due to homophilic interaction of its coiled-coil region

Eps15 is a member of an emerging family of proteins containing a novel protein/protein interaction domain, the EH domain, of as yet unknown function. Recent findings of Eps15 association with clathrin adaptor complex AP-2 and its localization in clathrin-coated pits have implicated Eps15 in the regulation of vesicle trafficking. Here we show that Eps15 exists in several multimeric states in vivo. When purified recombinant Eps15 or lysates of NIH 3T3 cells were treated with cross-linking reagents, covalent dimers of Eps15 and larger covalent multimers were detected in high yield. Large Eps15 oligomers co-immunoprecipitated with AP-2 at an efficiency higher than that of Eps15 dimers. Furthermore, cross-linking of the membrane-bound fraction of Eps15 in mildly permeabilized cells was as efficient as that of the cytosolic fraction. Size-exclusion column chromatography of recombinantly produced Eps15 and of total cell lysates was performed to examine the equilibrium ratio of the monomers versus the aggregated forms of Eps15. These experiments showed that essentially all the Eps15 was aggregated, whereas monomers of Eps15 could be obtained only under strong denaturing conditions. To map the region of Eps15 responsible for dimerization, fusion proteins corresponding to the three structural domains of Eps15 were prepared. Cross-linking analysis revealed that the central portion of Eps15, which possesses a coiled-coil region (residues 321-520), serves as the interacting interface. The possibility that hetero-oligomeric complexes of Eps15 dimers and AP-2 function during the recruitment of proteins into coated pits is discussed

Association between resting heart rate across the life course and all-cause mortality: longitudinal findings from the Medical Research Council (MRC) National Survey of Health and Development (NSHD)

BACKGROUND: Resting heart rate (RHR) is an independent risk factor for mortality. Nevertheless, it is unclear whether elevations in childhood and mid-adulthood RHR, including changes over time, are associated with mortality later in life. We sought to evaluate the association between RHR across the life course, along with its changes and all-cause mortality. METHODS: We studied 4638 men and women from the Medical Research Council (MRC) National Survey of Health and Development (NSHD) cohort born during 1 week in 1946. RHR was obtained during childhood at ages 6, 7 and 11, and in mid-adulthood at ages 36 and 43. Using multivariable Cox regression, we calculated the HR for incident mortality according to RHR measured at each time point, along with changes in mid-adulthood RHR. RESULTS: At age 11, those in the top fifth of the RHR distribution (≥97 bpm) had an increased adjusted hazard of 1.42 (95% CI 1.04 to 1.93) for all-cause mortality. A higher adjusted risk (HR, 95% CI 2.17, 1.40 to 3.36) of death was also observed for those in the highest fifth (≥81 bpm) at age 43. For a > 25 bpm increased change in the RHR over the course of 7 years (age 36–43), the adjusted hazard was elevated more than threefold (HR, 95% CI 3.26, 1.54 to 6.90). After adjustment, RHR at ages 6, 7 and 36 were not associated with all-cause mortality. CONCLUSIONS: Elevated RHR during childhood and midlife, along with greater changes in mid-adulthood RHR, are associated with an increased risk of all-cause mortality

Enzymatic hydroxylation in p-hydroxybenzoate hydroxylase: A case study for QM/MM molecular dynamics

We investigate the OH transfer step of the hydroxylation reaction of p-hydroxybenzoate in the enzyme p-hydroxybenzoate hydroxylase (PHBH) using QM/MM molecular dynamics methods. The QM region (49 atoms) is treated at the AM1 level, while the MM part (ca. 23000 atoms) is described by the GROMOS force field. Performing pointwise thermodynamic integration from 10 starting structures, we have obtained an average value of the free-energy barrier for this reaction of 101 kJ mol-1. The simulations provide insight into the dynamics of the hydrogen bonding network in the active site along the course of the reaction. In addition, we describe statistical techniques to analyze molecular dynamics data that assess the convergence of averages and yield an error measure. We discuss the effect of different error sources on the free energy