The control structure of the nematode Caenorhabditis elegans: Neuro-sensory integration and proprioceptive feedback.

We develop a biophysically realistic model of the nematode C. elegans that includes: (i) its muscle structure and activation, (ii) key connectomic activation circuitry, and (iii) a weighted and time-dynamic proprioception. In combination, we show that these model components can reproduce the complex waveforms exhibited in C. elegans locomotive behaviors, chiefly omega turns. This is achieved via weighted, time-dependent suppression of the proprioceptive signal. Though speculative, such dynamics are biologically plausible due to the presence of neuromodulators which have recently been experimentally implicated in the escape response, which includes an omega turn. This is the first integrated neuromechanical model to reveal a mechanism capable of generating the complex waveforms observed in the behavior of C. elegans, thus contributing to a mathematical framework for understanding how control decisions can be executed at the connectome level in order to produce the full repertoire of observed behaviors.

First Observation of P-odd γ Asymmetry in Polarized Neutron Capture on Hydrogen.

We report the first observation of the parity-violating gamma-ray asymmetry A_{γ}^{np} in neutron-proton capture using polarized cold neutrons incident on a liquid parahydrogen target at the Spallation Neutron Source at Oak Ridge National Laboratory. A_{γ}^{np} isolates the ΔI=1, ^{3}S_{1}→^{3}P_{1} component of the weak nucleon-nucleon interaction, which is dominated by pion exchange and can be directly related to a single coupling constant in either the DDH meson exchange model or pionless effective field theory. We measured A_{γ}^{np}=[-3.0±1.4(stat)±0.2(syst)]×10^{-8}, which implies a DDH weak πNN coupling of h_{π}^{1}=[2.6±1.2(stat)±0.2(syst)]×10^{-7} and a pionless EFT constant of C^{^{3}S_{1}→^{3}P_{1}}/C_{0}=[-7.4±3.5(stat)±0.5(syst)]×10^{-11} MeV^{-1}. We describe the experiment, data analysis, systematic uncertainties, and implications of the result.

Restricting feeding to the active phase in middle-aged mice attenuates adverse metabolic effects of a high-fat diet.

Time-restricted feeding ameliorates the deleterious effects of a high-fat diet on body weight and metabolism in young adult mice. Because obesity is highly prevalent in the middle-aged population, this study tested the hypothesis that time-restricted feeding alleviates the adverse effects of a high-fat diet in male middle-aged (12months) mice. C57BL6/J mice were fed one of three diets for 21-25weeks: 1) high-fat diet (60% total calories from fat) ad-libitum (HFD-AL), 2) HFD, time-restricted feeding (HFD-TRF), and 3) low-fat diet (10% total calories from fat) ad-libitum (LFD-AL) (n=15 each). HFD-TRF mice only had food access for 8h/day during their active period. HFD-TRF mice gained significantly less weight than HFD-AL mice (~20% vs 55% of initial weight, respectively). Caloric intake differed between these groups only during the first 8weeks and accounted for most but not all of their body weight difference during this time. TRF of a HFD lowered glucose tolerance in terms of incremental area under the curve (iAUC) (p<0.02) to that of LFD-AL mice. TRF of a HFD lowered liver weight (p<0.0001), but not retroperitoneal or epididymal fat pad weight, to that of LFD-AL mice. Neither HFD-AL nor HFD-TRF had any effect on performance in the novel object recognition or object location memory tests. Circulating corticosterone levels either before or after restraint stress were not affected by diet. In conclusion, TRF without caloric restriction is an effective strategy in middle-aged mice for alleviating the negative effects of a HFD on body weight, liver weight, and glucose tolerance.

[Complete resection of urothelial cancer metastases with curative intent]. / Metastasenchirurgie in kurativer Absicht beim Urothelkarzinom.

BACKGROUND: Recent publications suggest that a subgroup of patients can benefit from surgical removal of transitional cell carcinoma (TCC) metastases in addition to systemic chemotherapy. We report the combined experience and outcome of patients undergoing resection of TCC metastases at 15 uro-oncologic centers in Germany. MATERIALS AND METHODS: Forty-four patients with distant metastatic TCC of the bladder or upper urinary tract underwent resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008 in an attempt to be rendered free of disease. RESULTS: The resected metastatic sites consisted of retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). The treatment sequence included systemic chemotherapy in 35/44 (79.5%) patients before and/or after surgery. Median survival times from initial diagnosis of metastatic TCC and subsequent resection were as follows: overall survival, 35 and 27 months, respectively; cancer-specific survival, 38 and 34 months, respectively; and progression-free survival, 19 and 15 months, respectively. Overall 5-year survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up time of 8 months. Seven patients without disease progression survived for more than 2 years and remain free from tumor progression at a median of 63 months. CONCLUSION: The results in this selected cohort confirm that long-term cancer control and possibly cure can be achieved in a subgroup of patients following surgical removal of TCC metastases. However, prospective data to identify patients most likely to benefit from this aggressive therapeutic approach are lacking. Therefore, metastasectomy in patients with disseminated TCC remains investigational and should be offered only to those with limited disease as a combined-modality approach with systemic chemotherapy.

An amino acid-based peritoneal dialysis fluid buffered with bicarbonate versus glucose/bicarbonate and glucose/lactate solutions: an intraindividual randomized study.

OBJECTIVE: In order to study acute metabolic changes and peritoneal transport, amino acids as osmotic agent and bicarbonate as buffer were tested as new agents in peritoneal dialysis (PD) solutions. DESIGN: In a prospective, cross-over, randomized, intraindividual study, we investigated the acute metabolic changes following the application of three different PD fluids: (1) a 1% amino acid-based PD solution buffered with bicarbonate (34 mmol/L) (Amino/Bic); (2) a 1.5% glucose anhydrous-containing bicarbonate-buffered solution (34 mmol/L) (Glu/Bic); and (3) a conventional 1.5% glucose anhydrous-based dialysis solution with lactate (35 mmol/L) (Glu/Lac). SETTING: University medical center. PATIENTS: Ten nondiabetic patients stable on continuous ambulatory peritoneal dialysis (time on dialysis, 42.5 +/- 21.5 months) were treated and monitored with the test solutions over a 6-hour dwell. Three different study days followed in a randomized order for each patient (interval of 1-3 weeks). Blood and dialysate samples were taken at 0.25, 0.5, 1, 2, 4, and 6 hours. Immediately after the 1-hr dwell (and after sampling), the patients received a standardized breakfast, thereby simulating usual food intake. RESULTS: Following the application of Amino/Bic a significant increase in plasma amino acids occurred, with peak levels (maximum 250% increase) after either the 1-hr or the 2-hr dwell. Before taking the standard meal (0.5 hr, 1 hr), the mean serum glucose level with Amino/Bic was 8% +/- 13% lower than with Glu/Bic (p = 0.06) and 14% +/- 8% lower than with Glu/Lac (p < 0.01). This difference was still significant after the standard breakfast and also for the whole dwell (average serum glucose 0.5-6 hr: Amino/Bic, 91 +/- 6 mg/dL; Glu/Bic, 100 +/- 8 mg/dL; Glu/Lac, 102 +/- 7 mg/dL; p < 0.01 MANOVA). The serum insulin profiles did not differ between the fluids. A transperitoneal protein- and amino acid-related nitrogen loss of 0.49 +/- 0.18 g and 0.48 +/- 0.12 g per dwell was measured using Glu/Bic and Glu/Lac, while a positive balance of 1.80 +/- 0.43 g was achieved with Amino/Bic. The parameters of acid-base status (pH, HCO3, pCO2) remained nearly unchanged in the blood, irrespective of the solution used, while dialysate values differed markedly. No significant differences with respect to ultrafiltration (Amino/Bic, -68 +/- 199 mL/6 hr; Glu/Bic, -51 +/- 89 mL/6 hr; Glu/ Lac, -2 +/- 134 mL/6 hr) and peritoneal creatinine clearance (Amino/Bic, 4.9 +/- 0.6 mL/min; Glu/Bic, 5.1 +/- 0.6 mL/min; Glu/ Lac, 4.8 +/- 0.5 mL/min) were measured. CONCLUSIONS: Our results demonstrate that ultrafiltration and small solute clearance over a 6-hour dwell with a 1% Amino/Bic solution were comparable to those of 1.5% Glu/Bic and 1.5% Glu/Lac. Reduced serum glucose concentrations were found with Amino/Bic and this fluid compensated the transperitoneal protein-nitrogen loss of about three glucose dwells. Bicarbonate buffering (34 mmol/L) did not change blood acid-base status combined with either glucose or amino acids.

In vivo and in vitro effects of amino-acid-based and bicarbonate-buffered peritoneal dialysis solutions with regard to peritoneal transport and cytokines/prostanoids dialysate concentrations.

BACKGROUND: Increasing evidence suggests that conventional PD solutions are detrimental to host defence mechanisms of peritoneal cells. We tested a new amino-acid-based and bicarbonate-buffered PD solution under in vivo and in vitro conditions. METHODS: During a prospective, cross-over randomized, intraindividual study 10 CAPD patients were investigated with three different solutions: Amino/Bic, 1% amino acid, 34 mmol/l bicarbonate; Glu/Bic, 1.5% glucose, 34 mmol/l bicarbonate; and Glu/Lac, 1.5% glucose, 35 mmol/l lactate. A PET was performed and transport properties (clearance, D/P ratio, MTAC) were calculated. Prostanoid and cytokine concentrations were measured in serum and the 6 h effluent. Using an in vitro model, mononuclear leukocytes of healthy donors were also incubated with the test fluids. In vivo results. Peritoneal clearance and MTAC of small solutes (creatinine, urea) were not significantly altered by amino acids or bicarbonate. Peritoneal permeability and transperitoneal excretion of higher-weight protein molecules (beta 2-microglobulin, albumin, IgG) were increased with Amino/Bic compared to Glu/Lac (P < 0.05) (D/P ratio albumin: Amino/Bic, 0.027 +/- 0.003; Glu/Bic, 0.023 +/- 0.003; Glu/Lac, 0.022 +/- 0.002). Application of Amino/Bic was accompanied by an increased effluent concentration of Il-6, Il-8, TNF alpha, PGE2, and 6-keto-PGF1a (P < 0.05). Dialysate nitrite/nitrate and cGMP concentrations (as indicators of NO generation) did not differ between the solutions. In vitro results. Both bicarbonate fluids demonstrated a better preservation of the mitochondrial dehydrogenases activity (MTT assay) compared to Glu/ Lac (P < 0.01) (Amino/Bic: 80.6 +/- 3.2%; Glu/Bic: 86.0 +/- 1.8%; Glu/Lac, 64.9 +/- 2.3%, referred to RPMI as control). Constitutive and LPS stimulated release of Il-1 beta and Il-6 was less suppressed with both bicarbonate fluids (P < 0.05) (LPS-stim. Il-6 release: Amino/Bic, 33.0 +/- 6.6%; Glu/Bic, 65.5 +/- 10.3%; Glu/Lac, 1.5 +/- 0.7% referred to RPMI). CONCLUSION: Application of an amino-acid/bicarbonate solution resulted in a small but significant increase in peritoneal permeability. Also increased concentrations of various cytokines/prostanoids were measured in the effluent. According to in vitro testing with mononuclear phagocytes both bicarbonate-buffered fluids were to the same extent less inhibitory to certain cell functions than lactate-buffered solution.

Managing overuse injuries: a systematic approach.

Cumulative, repetitive microtrauma can cause tissue damage that leads to overuse injuries, which constitute a large share of sports-related disorders. The authors explain their five-step approach to treating overuse injuries: establishing a pathoanatomic diagnosis, controlling inflammation, promoting healing, increasing fitness, and controlling tissue abuse. The case of a 28-year-old male runner with heel pain demonstrates their management of overuse injuries.

Patient profile, referral sources, and consultant utilization in a primary care sports medicine clinic.

BACKGROUND: Sports medicine has matured as a focused discipline within primary care with the number of primary care sports medicine physicians growing annually. The practices of these physicians range from "part-time" sports medicine as a part of a broader practice in their primary specialty, to functioning as a full-time team physician for a university or college. Managed care organizations are increasingly incorporating primary care sports medicine providers into their organizations. The optimal role of these providers in a managed care system has not been described. METHODS: A descriptive analysis was made of patient contacts in a referral-based, free-standing primary care sports medicine clinic associated with a large managed care system. This study describes patient information including demographic data, referral source, primary diagnosis, specialized diagnostic testing, and subsequent specialty consultation. RESULTS: A total of 1857 patient contacts were analyzed. New patients were referred from a full range of physicians both primary care (family practice, internal medicine, pediatrics, and emergency physicians) and other specialists, with family practice clinic providers (physicians, physician assistants, and nurse practitioners) accounting for the largest percentage of new referrals. The majority of patient visits were for orthopedic injuries (95.4%); the most frequently involved injury sites were: knee (26.5%), shoulder (18.2%), back (14.3%), and ankle (10%). The most common types of injury were: tendinitis (21.3%), chronic anterior knee pain (10.6%), and ligament sprains (9.9%). Specialized testing was requested for 8% of all patients. The majority of patients were treated at the Ft Belvoir Sports Medicine Clinic by primary care sports medicine physicians without further specialty referral. CONCLUSIONS: Primary care sports medicine physicians offer an intermediate level of care for patients while maintaining a practice in their primary care specialty. This dual practice is ideal in the managed care setting. This study demonstrates the complementary nature of primary care sports medicine and orthopedics, with the primary care sports medicine physician reducing the demand on orthopedists for nonsurgical treatment. This study also demonstrates the need for revision in the orthopedic curriculum for primary care physicians.

Special considerations for the female runner.

There are a number of physiologic and anatomic differences between males and females which affect performance and the rate of injury. In addition, there are several disorders which occur with some frequency in female runners - eating disorders and amenorrhea, which warrant review. Most pregnant runners should be encouraged to remain active, with appropriate medical supervision. Providing good medical care for female runners requires a working knowledge of their unique features.