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Aim: Image-guided surgery (IGS) allows for accurate, real-time localization of subsurface critical structures during surgery. No prior IGS systems have described a feasible method of intraoperative reregistration after manipulation of the kidney during robotic partial nephrectomy (PN). We present a method for seamless reregistration during IGS and evaluate accuracy before and after tumor resection in two validated kidney phantoms. Materials and Methods: We performed robotic PN on two validated kidney phantoms-one with an endophytic tumor and one with an exophytic tumor-with our IGS system utilizing the da Vinci Xi robot. Intraoperatively, the kidney phantoms' surfaces were digitized with the da Vinci robotic manipulator via a touch-based method and registered to a three-dimensional segmented model created from cross-sectional CT imaging of the phantoms. Fiducial points were marked with a surgical marking pen and identified after the initial registration using the robotic manipulator. Segmented images were displayed via picture-in-picture in the surgeon console as tumor resection was performed. After resection, reregistration was performed by reidentifying the fiducial points. The accuracy of the initial registration and reregistration was compared. Results: The root mean square (RMS) averages of target registration error (TRE) were 2.53 and 4.88 mm for the endophytic and exophytic phantoms, respectively. IGS enabled resection along preplanned contours. Specifically, the RMS averages of the normal TRE over the entire resection surface were 0.75 and 2.15 mm for the endophytic and exophytic phantoms, respectively. Both tumors were resected with grossly negative margins. Point-based reregistration enabled instantaneous reregistration with minimal impact on RMS TRE compared with the initial registration (from 1.34 to 1.70 mm preresection and from 1.60 to 2.10 mm postresection). Conclusions: We present a novel and accurate registration and reregistration framework for use during IGS for PN with the da Vinci Xi surgical system. The technology is easily integrated into the surgical workflow and does not require additional hardware.

Introduction: The da Vinci Skills Simulator (DVSS) is an effective platform for robotic skills training. Novel training methods using expert gaze patterns to guide trainees have demonstrated superiority to traditional instruction. Portable head-mounted eye-trackers (HMET) offer the opportunity for eye tracking technology to enhance surgical robotic simulation training. Objective: To evaluate if training guided by expert gaze patterns can improve trainee performance over standard movement training techniques during robotic simulation. Methods: Medical students were recruited and randomized into gaze training (GT, n  = 9) and movement training (MT, n  = 8) groups. First, the participants reviewed an instructional video, with the GT group emulating expert gaze patterns and the MT group ( n  = 8) standard movement-based instruction. Training consisted of 10 repetitions of "Suture Sponge 3" on the DVSS while wearing HMET; the first three repetitions were followed by group-appropriate video coaching (gaze vs movement feedback), while the remaining repetitions were without feedback. Finally, two multitasking repetitions with a secondary bell-counting task were completed. Primary outcomes included DVSS scores during training and multitasking. Secondary outcomes included metrics collected from the HMET (gaze patterns and gaze entropy). Results: Total score, efficiency, and penalties improved significantly over the training in both groups; the GT group achieved higher scores on every attempt. Total scores in the GT group were higher than the MT group postvideo review (20.3 ± 21.8 vs 3.0 ± 6.2, p  = 0.047), after coaching repetitions (61.8 ± 18.8 vs 30.1 ± 26.2, p  = 0.01), and at the last training attempt (73.0 ± 16.5 vs 63.1 ± 17.4, p  = 0.247). During multitasking, the GT group maintained higher total scores (75 ± 10.1 vs 63.3 ± 15.3, p  = 0.01), efficiency (86.3 ± 7.4 vs 77.4 ± 11.2, p  = 0.009), and superior secondary task performance (error: 6.3% ± 0.06 vs 10.7% ± 0.11, p  = 0.20). Gaze entropy (cognitive-load indicator) and gaze pattern analysis showed similar trends. Conclusion: Gaze-augmented training leads to more efficient movements through adoption of expert gaze patterns that withstand additional stressors.

Background: There is a significant need for a non-biohazardous, educational platform to equip and maintain the surgical skills required by urology trainees and low-volume implanters for inflatable penile prosthetic (IPP) placement., Aim: To design and develop an anatomic, hydrogel-based simulation platform for training and evaluate IPP placement using modern education theory., Methods: The backward design concept was used as a framework in the design and development of an IPP simulation platform. Steps included delineating requirements from a physicians' perspective, translating requirements into engineering tasks (deliverables), developing a prototype, and pilot validation. Using a combination of 3-dimensional printing and hydrogel casting, a genitourinary tract model was constructed to replicate the appropriate steps of IPP placement guided by expert feedback. Full-immersion IPP simulations were performed through both infrapubic and penoscrotal approaches by 4 expert surgeons under operative conditions. Questionnaires evaluating the simulation's realism, value as a training tool, and further recommendations were completed., Outcomes: Using backward design educational pedagogy, a high-fidelity, full-procedural IPP simulation was fabricated and verified as an adequate educational tool for training and assessment., Results: An expert consensus on the anatomic landmarks, steps and substeps, instruments, and errors to be included in the model was reached using a hierarchical task analysis and was successfully translated into a prototype hydrogel model. Experts performed all appropriate steps of IPP surgery and rated the simulation highly in terms of its realism and value as a training tool. On average, experts agreed that the model could function as a training tool, assessment tool, prerequisite for IPP accreditation, and requirement before live surgery. Experts stated they would have their trainees ideally complete an average of 1.75 models before live surgical training. All experts believed an operative checklist would be an ideal assessment tool. Witthaus MW, Saba P, Melnyk R, et al. The Future of Penile Prosthetic Surgical Training Is Here: Design of a Hydrogel Model for Inflatable Penile Prosthetic Placement Using Modern Education Theory. J Sex Med 2020;17:2299-2306., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction and Objective: Despite the adoption of robotic donor nephrectomy, the steep learning curve of robotic recipient transplantation has hindered the implementation of a complete robot-assisted kidney transplantation (RAKT). We sought to develop a high-fidelity perfused full immersion nonbiohazardous platform for RAKT simulation training. Methods: A three-dimensional (3D) computer-aided design (CAD) model consisting of a kidney, pelvicaliceal system, renal artery, and vein was created from a CT scan of a donor patient. 3D printed casts designed from the CAD model were injected with various polyvinyl alcohol hydrogel formulations to fabricate an anatomical kidney phantom and surrounding abdominal cavity. The process was repeated using a recipient's CT scan to create the recipient pelvic model containing a bony pelvis, pelvic musculature, iliac arteries and veins, and bladder. Donor and recipient models each contained structures to simulate the perfused vascular and ureterovesical anastomosis. A board-certified transplant surgeon completed a robotic training curriculum, including four RAKT simulation procedures, from procurement of the donor kidney to final retroperitonealization. Metrics from the simulations (e.g., arterial, venous, ureterovesical, and total anastomosis times) were recorded and compared with surgical times from published data. Results: The average time for the nephrectomies was 67.33 (±31.58) minutes. The average total anastomosis time was 60.85 (±9.73) minutes with 20.37 (±3.87), 20.17 (±4) and 15.1 (±2.35) minutes for arterial, venous, and ureterovesical anastomosis, respectively. The recorded arterial and venous anastomosis times were within published times for competency (Δ = 2.47 and Δ = 2.87, respectively), whereas the uterovesical time was within the mastery range (Δ = 0.45). Conclusions: Using a combination of 3D printing and hydrogel casting technologies, a high fidelity perfused full-immersion nonbiohazardous simulation platform for RAKT was developed. The utilization of this platform has the potential to replace the early cases in a learning curve while decreasing the barriers to utilization for transitioning transplant surgeons.

Introduction and Objectives: There is a scarcity of high-fidelity, life-like, standardized and anatomically correct polymer-based kidney models for robot-assisted partial nephrectomy (RAPN) simulation training. The purpose of this technical report is to present mechanical and functional testing data as evidence for utilizing a perfused hydrogel kidney model created utilizing 3D printed injection casts for RAPN simulation and training., Methods: Anatomically correct, tumor-laden kidney models were created from 3D-printed casts designed from a patient's CT scan and injected with poly-vinyl alcohol (PVA). A variety of testing methods quantified Young's modulus in addition to comparing the functional effects of bleeding and suturing among fresh porcine kidneys and various formulations of PVA kidneys., Results: 7% PVA at three freeze-thaw cycles (7%-3FT) was found to be the formula that best replicates the mechanical properties of fresh porcine kidney tissue, where mean(± SD) values of Young's modulus of porcine tissue vs 7%-3FT samples were calculated to be 85.97(± 35) kPa vs 80.97(± 9.05) kPa, 15.7(± 1.6) kPa vs 74.56(± 10) kPa and 87.46(± 2.97) kPa vs 83.4(± 0.7) kPa for unconfined compression, indentation and elastography testing, respectively. No significant difference was seen in mean suture tension during renorrhaphy necessary to achieve observable hemostasis and capsular violation during a simulated perfusion at 120 mmHg., Conclusions: This is the first study to utilize extensive material testing analyses to determine the mechanical and functional properties of a perfused, inanimate simulation platform for RAPN, fabricated using a combination of image segmentation, 3D printing and PVA casting.

We consider the effect of atomic impurities on the energy spectrum and electrical conductance of graphene. As is known, the ordering of atomic impurities at the nodes of a crystal lattice modifies the graphene spectrum of energy, yielding a gap in it. Assuming a Fermi level within the gap domain, the electrical conductance diverges at the ordering of graphene. Hence, we can conclude about the presence of a metal-dielectric transition. On the other hand, for a Fermi level occurring outside of the gap, we see an increase in the electrical conductance as a function of the order parameter. The analytic formulas obtained in the Lifshitz one-electron strong-coupling model, describing the one-electron states of graphene doped with substitutional impurity atoms in the limiting case of weak scattering, are compared to the results of numerical calculations. To determine the dependence of the energy spectrum and electrical conductance on the order parameter, we consider both the limiting case of weak scattering and the case of finite scattering potential. The contributions of the scattering of electrons on a vapor of atoms to the density of states and the electrical conductance of graphene with an admixture of interstitial atoms are studied within numerical methods. It is shown that an increase in the electrical conductance with the order parameter is a result of both the growth of the density of states at the Fermi level and the time of relaxation of electron states. We have demonstrated the presence of a domain of localized extrinsic states on the edges of the energy gap arising at the ordering of atoms of the admixture. If the Fermi level falls in the indicated spectral regions, the electrical conductance of graphene is significantly affected by the scattering of electrons on clusters of two or more atoms, and the approximation of coherent potential fails in this case.

Background: The development of technical skills for a cervical laminectomy are traditionally acquired through intraoperative learning and cadaveric courses. These methods provide little objective assessment, involve financial and biohazard considerations, and may not incorporate desired pathology., Objective: To develop an inexpensive cervical spine laminectomy simulator capable of measuring operative performance and to assess its face, content, and construct validity., Methods: A virtual model was generated and 3D printed into negative molds. A multilayered surgical phantom was fabricating by filling molds with hydrogels, plaster, and fiberglass. A pressure transducer measured simulated spinal cord manipulation. Participants completed full-procedural laminectomy simulations. Post-simulation surveys assessed face and content validity. Construct validity was assessed by comparing expert and novice procedural metrics., Results: Twelve surgeons participated. The simulator received median face and content validity ratings of 4/5. Differences between experts and novices were found in mean intrathecal pressure wave count (84 vs 153, P = .023), amplitude (4 vs 12% > 2SD above expert mean, P < .001), area under curve (4 vs 12% > 2SD above expert mean, P < .001), procedure time (35 vs 69 min P = .003), and complication rates (none vs 3 incorrect levels decompressed and 1 dural tear, P = .06). Insignificant differences were found in mean pressure wave slope and blood loss., Conclusion: This inexpensive cervical laminectomy simulator received favorable face and content validity ratings, and distinguished novice from expert participants. Further studies are needed to determine this simulator's role in the training and assessment of novice surgeons., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Objectives: To incorporate and validate clinically relevant performance metrics of simulation (CRPMS) into a hydrogel model for nerve-sparing robot-assisted radical prostatectomy (NS-RARP)., Materials and Methods: Anatomically accurate models of the human pelvis, bladder, prostate, urethra, neurovascular bundle (NVB) and relevant adjacent structures were created from patient MRI by injecting polyvinyl alcohol (PVA) hydrogels into three-dimensionally printed injection molds. The following steps of NS-RARP were simulated: bladder neck dissection; seminal vesicle mobilization; NVB dissection; and urethrovesical anastomosis (UVA). Five experts (caseload >500) and nine novices (caseload <50) completed the simulation. Force applied to the NVB during the dissection was quantified by a novel tension wire sensor system fabricated into the NVB. Post-simulation margin status (assessed by induction of chemiluminescent reaction with fluorescent dye mixed into the prostate PVA) and UVA weathertightness (via a standard 180-mL leak test) were also assessed. Objective scoring, using Global Evaluative Assessment of Robotic Skills (GEARS) and Robotic Anastomosis Competency Evaluation (RACE), was performed by two blinded surgeons. GEARS scores were correlated with forces applied to the NVB, and RACE scores were correlated with UVA leak rates., Results: The expert group achieved faster task-specific times for nerve-sparing (P = 0.007) and superior surgical margin results (P = 0.011). Nerve forces applied were significantly lower for the expert group with regard to maximum force (P = 0.011), average force (P = 0.011), peak frequency (P = 0.027) and total energy (P = 0.003). Higher force sensitivity (subcategory of GEARS score) and total GEARS score correlated with lower nerve forces (total energy in Joules) applied to NVB during the simulation with a correlation coefficient (r value) of -0.66 (P = 0.019) and -0.87 (P = 0.000), respectively. Both total and force sensitivity GEARS scores were significantly higher in the expert group compared to the novice group (P = 0.003). UVA leak rate highly correlated with total RACE score r value = -0.86 (P = 0.000). Mean RACE scores were also significantly different between novices and experts (P = 0.003)., Conclusion: We present a realistic, feedback-driven, full-immersion simulation platform for the development and evaluation of surgical skills pertinent to NS-RARP. The correlation of validated objective metrics (GEARS and RACE) with our CRPMS suggests their application as a novel method for real-time assessment and feedback during robotic surgery training. Further work is required to assess the ability to predict live surgical outcomes., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Introduction and Objectives: The restriction of resident hours with an increasing focus on patient safety and a reduced caseload has impacted surgical training. A complex and complication prone procedure such as percutaneous nephrolithotomy (PCNL) with a steep learning curve may create an unsafe environment for hands-on resident training. In this study, we validate a high fidelity, inanimate PCNL model within a full-immersion simulation environment., Methods: Anatomically correct models of the human pelvicaliceal system, kidney, and relevant adjacent structures were created using polyvinyl alcohol hydrogels and three-dimensional-printed injection molds. All steps of a PCNL were simulated including percutaneous renal access, nephroscopy, and lithotripsy. Five experts (>100 caseload) and 10 novices (<20 caseload) from both urology (full procedure) and interventional radiology (access only) departments completed the simulation. Face and content validity were calculated using model ratings for similarity to the real procedure and usefulness as a training tool. Differences in performance among groups with various levels of experience using clinically relevant procedural metrics were used to calculate construct validity., Results: The model was determined to have an excellent face and content validity with an average score of 4.5/5.0 and 4.6/5.0, respectively. There were significant differences between novice and expert operative metrics including mean fluoroscopy time, the number of percutaneous access attempts, and number of times the needle was repositioned. Experts achieved better stone clearance with fewer procedural complications., Conclusions: We demonstrated the face, content, and construct validity of an inanimate, full task trainer for PCNL. Construct validity between experts and novices was demonstrated using incorporated procedural metrics, which permitted the accurate assessment of performance. While hands-on training under supervision remains an integral part of any residency, this full-immersion simulation provides a comprehensive tool for surgical skills development and evaluation before hands-on exposure.

One of the most critical challenges to full integration of unmanned aircraft systems (UAS) into the National Airspace System (NAS) is the requirement to comply with CFR 14 Part 91.113 to "see and avoid" other aircraft. Various attempts have been made to develop systems to "sense and avoid" other aircraft so UAS can comply with the intent of the regulation. This article proposes a framework to develop effectiveness requirements for any SAA system by linking UAS characteristics and operating environments to midair collision risk quantified by a fatality rate. The framework consists of a target level of safety (TLS) approach using an event tree format. Safety has been identified as the most important consideration in the UAS integration process. While safety can be defined in many ways, the authors propose using a fatality rate metric that follows other statistics used in the industry. This metric allows for the use of a TLS approach to the development of SAA requirements for system certification. Failure to adequately link system requirements to safety could result in the implementation of SAA systems that either do not adequately mitigate the risk associated with UAS operations or are overdesigned, resulting in increased cost and complexity. This article demonstrates the use of the proposed framework to develop specific SAA effectiveness standards based on UAS weight and airspace class combinations., (© 2014 Society for Risk Analysis.)

Triglyceride lipases such as lipoprotein lipase, endothelial lipase, and hepatic lipase play key roles in controlling the levels of plasma lipoprotein. Accordingly, small-molecule modulation of these species could alter patient lipid profiles with corresponding health effects. Screening of these enzymes for small-molecule therapeutics has historically involved the use of lipid-based particles to mimic native substrates. However, particle-based artifacts can complicate the discovery of therapeutic molecules. As a simplifying solution, the authors sought to develop an approach involving a soluble and monomeric lipase substrate. Using purified bovine lipoprotein lipase as a model system, they show that the hydrolysis of resorufin butyrate can be fluorescently monitored to give a robust assay (Z' > 0.8). Critically, using parallel approaches, they show that resorufin butyrate is soluble and monomeric under assay conditions. The presented assay should be useful as a simple and inexpensive primary or secondary screen for the discovery of therapeutic lipase modulators.

A two-Yukawa representation of the EXP6 fluids at supercritical temperatures and high pressures has been developed and examined using molecular simulations. A uniquely defined mapping of the repulsive part of the EXP6 potential curve onto the two-Yukawa potential is used. Two ranges of temperatures, one encountered in geochemical applications (T(geo) range) and the other at conditions of detonations (T(det) range), are considered and it is shown that the local structures of both fluids are practically identical. Deviations between the EXP6 and two-Yukawa potential functions at intermediate separations lead to differences in the thermodynamic properties of the two fluids at lower temperatures of the T(geo) range; at higher temperatures and in the high T(det) temperature range both the structural and thermodynamic properties of the EXP6 and two-Yukawa fluids are practically identical.

The liquid-vapor phase diagram and surface tension for the Sutherland fluids with a variable range of interaction have been determined by canonical Monte Carlo simulations and compared with the augmented van der Waals analytic theory. The theory, based on a short-range Yukawa reference, performs well for medium-range models but its accuracy deteriorates with the shortening range due to deteriorating accuracy of the underlined analytic mean spherical approximation solution for the reference Yukawa potential. The simulation results are also analyzed from the point of the extended principle of corresponding states and it is shown that the surface tension and also, to a certain degree of accuracy, the vapor-liquid coexistence curve satisfy the principle.

A novel perturbation approach for the structure factor S(k) of the Lennard-Jones-type Yukawa fluid with z=1.8 is presented. An approach is based on a new reference system, that is, the short-range Yukawa model with z0>z=1.8. By choosing for the reference system the value z0=6, it is shown that (i) the proposed approach for S(k) performs much better than the traditional hard-sphere reference perturbation method does; (ii) the use of an approximate mean spherical (MSA) description of the reference structure factor provides the results for S(k) that are more accurate as those obtained from the direct MSA computations; and (iii) the results obtained for S(k) tend to reproduce "exact" simulation results when accurate simulation data for the reference system are used.

The detector presampling modulation transfer function (MTF) of a 576-channel variable resolution x-ray (VRX) computed tomography (CT) scanner was evaluated in this study. The scanner employs a VRX detector, which provides increased spatial resolution by matching the scanner's field of view (FOV) to the size of an object being imaged. Because spatial resolution is the parameter the scanner promises to improve, the evaluation of this resolution is important. The scanner's pre-reconstruction spatial resolution, represented by the detector presampling MTF, was evaluated using both modeling (Monte Carlo simulation) and measurement (the moving slit method). The theoretical results show the increase in the cutoff frequency of the detector presampling MTF from 1.39 to 43.38 cycles/mm as the FOV of the VRX CT scanner decreases from 32 to 1 cm. The experimental results are in reasonable agreement with the theoretical data. Some discrepancies between the measured and the modeled detector presampling MTFs can be explained by the limitations of the model. At small FOVs (1-8 cm), the MTF measurements were limited by the size of the focal spot. The obtained results are important for further development of the VRX CT scanner.

Efforts to improve the spatial resolution of CT scanners have focused mainly on reducing the source and detector element sizes, ignoring losses from the size of the secondary-ionization charge "clouds" created by the detected x-ray photons, i.e., the "physics limit." This paper focuses on implementing a technique called "projective compression." which allows further reduction in effective cell size while overcoming the physics limit as well. Projective compression signifies detector geometries in which the apparent cell size is smaller than the physical cell size, allowing large resolution boosts. A realization of this technique has been developed with a dual-arm "variable-resolution x-ray" (VRX) detector. Accurate values of the geometrical parameters are needed to convert VRX outputs to formats ready for optimal image reconstruction by standard CT techniques. The required calibrating data are obtained by scanning a rotating pin and fitting a theoretical parametric curve (using a multi-parameter minimization algorithm) to the resulting pin sinogram. Excellent fits are obtained for both detector-arm sections with an average (maximum) fit deviation of ~0.05 (0.1) detector cell width. Fit convergence and sensitivity to starting conditions are considered. Pre- and post-optimization reconstructions of the alignment pin and a biological subject reconstruction after calibration are shown.

Biophysical study of the transmembrane (TM) domains of integral membrane proteins has traditionally been impeded by their hydrophobic nature. As a result, an understanding of the details of protein-protein interactions within membranes is often lacking. We have demonstrated previously that model TM segments with flanking cationic residues spontaneously fold into alpha-helices upon insertion into membrane-mimetic environments. Here, we extend these studies to investigate whether such constructs consisting of TM helices from biological systems retain their native secondary structures and oligomeric states. Single-spanning TM domains from the epidermal growth factor receptor (EGFR), glycophorin A (GPA), and the influenza A virus M2 ion channel (M2) were designed and synthesized with three to four lysine residues at both N- and C-termini. Each construct was shown to adopt an alpha-helical conformation upon insertion into sodium dodecyl sulfate micelles. Furthermore, micelle-inserted TM segments associated on SDS-PAGE gels according to their respective native-like oligomeric states: EGFR was monomeric, GPA was dimeric, and M2 was tetrameric. This approach was then used to investigate whether one or both of the TM segments (Tar-1 and Tar-2) from the Escherichia coli aspartate receptor were responsible for its homodimeric nature. Our results showed that Tar-1 formed SDS-resistant homodimers, while Tar-2 was monomeric. Furthermore, no heterooligomerization between Tar-1 and Tar-2 was detected, implicating the Tar-1 helix as the oligomeric determinant for the Tar protein. The overall results indicate that this approach can be used to elucidate the details of TM domain folding for both single-spanning and multispanning membrane proteins.

This paper describes a simple method for the analysis of tocopherols in tissues by which frozen tissues-70 degrees C were pulverized at dry ice temperatures (-70 degrees C) and immediately extracted with hexane. There was no need to remove the coeluting lipids from tissues by saponification, since at that level of neutral lipids in the sample, there was no reduction in fluorescence response. For the analysis of oil, in which large amounts of neutral lipids were coextracted, a 20% reduction of fluorescence response was observed, but the response was equal for all tocopherol forms, and was appropriately corrected. Saponification was used only when tocopherol esters were present, and only after an initial hexane extraction to remove the free tocopherols in order to avoid their loss by saponification, particularly non alpha-tocopherol and tocotrienols. All the tocopherols and tocotrienols were separated on a normal-phase diol (epoxide) column that gave consistent and reproducible results, without the disadvantages of nonreproducibility with silica columns, or the lack of separation with reversed-phase columns. The tocopherols were quantitated by using a tocopherol form not present in the sample as an internal tocopherol standard, or using an external tocopherol standard if all forms were present, or when the sample was saponified. Piglet heart and liver samples showed the presence of mainly alpha-tocopherol, with minor amounts of beta- and gamma-tocopherol and alpha-tocotrienol, but no delta-tocopherol. Only small amounts of tocopherol esters were present in the liver but not in the heart.

The attitudes of a sample of spinal cord injured outpatients toward a range of sexual behaviors were measured before and after participation in a counseling program. In comparison to the sexual attitudes of an untreated control group those of the sample group were found to be more permissive after than before the program. In addition, the counseling program, which operated in a workshop format over a period of 6 weeks, was favorably evaluated by participants on a number of criteria.

In order to determine whether insulin binding to receptors in the central nervous system can be modified by changes in energy balance, hypothalami from 48 h food deprived and 14 day food restricted (8 or 4 g chow/day) rats were removed and insulin binding to partially purified membranes from both medial and lateral hypothalamic regions was studied. Hypothalamic insulin concentration was measured in similarly treated animals. Although hypothalamic insulin concentration did not vary, insulin binding to lateral receptors was significantly lower than that obtained from the medial region. After prolonged food restriction, binding to medial receptors was significantly reduced in comparison to controls, whereas binding in the lateral region remained unchanged; differences were most pronounced at near-physiological insulin concentrations. Changes in per cent specific [125I]insulin binding were associated with corresponding changes in maximal insulin-binding capacity, the latter being inversely related to receptor affinity for this hormone. These results are consistent with the hypothesis that insulin, acting via hypothalamic receptors, may serve as a metabolic feedback signal linking the periphery with central body weight regulatory mechanisms.

During spontaneous body weight gain in dormice, Glis glis, progressive increases in the efficiency of food utilization as defined by weight gain (g)/food intake (g), and parallel increases in mean daily food intake were observed. Towards the end of the weight gain period, there was an abrupt drop in feeding efficiency with no significant change in food intake even when the latter was expressed relative to an index of each animal's "metabolic mass" (body weightkg0.62). Animals whose body weight increases followed a return to ad lib feeding after prolonged food restriction showed marked decreases in feeding efficiency from initially high values which were independent of changes in food intake. These results are discussed in relation to the sliding set point concept of body weight regulation in hibernators.

We have previously shown that [125I]insulin binding to medial hypothalamic receptors is attenuated following 14 days of food restriction. Such rats are characterized by considerably reduced circulating insulin levels with unchanged hypothalamic insulin concentration. The present data demonstrate that, in contrast to the effects of starvation, [125I]insulin binding to hypothalamic receptors from rats made hyperinsulinaemic by daily injections of protamine zinc insulin (4-6 U/rat/day for 14 days) is unaffected by this manipulation, even though hypothalamic insulin concentration in insulin-injected animals was significantly higher than in saline-injected controls. Insulin binding to partially purified membranes from the medial hypothalamic region was significantly greater than that from the lateral area, confirming a finding in our earlier study. Insulin treatment was associated with slight reductions in maximal insulin-binding capacity of medial hypothalamic receptors, a tendency which appeared to be compensated by reciprocal changes in receptor affinity for this hormone. The data indicate that hypothalamic insulin receptors are not regulated by peripheral or even central insulin levels per se; it appears, rather, that some other, as yet unidentified, correlate(s) of significantly altered food intake and/or body weight can modify hypothalamic insulin receptor function. Perhaps such modifications could, in turn, participate in the activation of regulatory mechanisms involved in correcting energy imbalance.

Pituitary beta-endorphin content was measured in dormice during several distinct phases of the infradian body weight cycle. No significant differences in opiate content among groups were found. It appears unlikely that pituitary concentrations of beta-endorphin have etiological significance in the development of spontaneous obesity in hibernators.

[125I]insulin binding to partially purified hypothalamic membranes is reduced during prolonged starvation, and changes in hypothalamic insulin binding capacity correlate well with spontaneous variations in energy balance in ground squirrels. To determine whether an insulin binding impairment in the central nervous system can be observed during the early expression of genetic obesity, both obese (fa/fa) and phenotypically lean (Fal-) Zucker rats were studied at 6 weeks of age. Hypothalamic tissue from fa/fa rats bound significantly less hormone than that from the lean animals, but binding was not changed in tissue from cerebral cortex. It is concluded that a defect in insulin binding to hypothalamic receptors in Zucker fatty rats may contribute to the development of weight gain in these animals.