Extended Resections for Advanced Gallbladder Cancer: Results from a Nationwide Cohort Study.

BACKGROUND: Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC. METHODS: Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed. RESULTS: The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5-19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion. CONCLUSION: The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice.

Recently, there has been considerable interest in using 4-methylumbelliferone (4-MU) to inhibit hyaluronan (HA) synthesis in mouse models of cancer, autoimmunity and a variety of other inflammatory disorders where HA has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration and metabolism of 4-MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4-MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after 1 week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a 1-week loading period on the drug is required for most protocols. At steady state, more than 90% of the drug is present in plasma as the glucuronidated metabolite 4-methylumbelliferyl glucuronide (4-MUG), with the sulphated metabolite, 4-methylumbelliferyl sulphate (4-MUS) comprising most of the remainder. Chow containing 5% but not 0·65% 4-MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, as well as in the DORmO mouse model of autoimmune diabetes. While oral 4-MU was effective at preventing EAE, daily intraperitoneal injections of 4-MU were not. Factors potentially affecting 4-MU uptake and plasma concentrations in mice include its taste, short half-life and low bioavailability. These studies provide a practical resource for implementing oral 4-MU treatment protocols in mice.

Value of routine intraoperative frozen sections of proximal bile duct margins in perihilar cholangiocarcinoma, a retrospective multicenter and matched case-control study.

BACKGROUND: Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and oncological outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA. MATERIALS AND METHODS: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality. RESULTS: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influenced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348). CONCLUSION: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival.

Blood testing in sport: hematological profiling.

Hemoglobin concentration and percent reticulocytes (%retics) were analyzed in blood samples taken pre-competition, post-competition, and during out of competition testing in elite speed skaters. Percent reticulocytes during screening was not different from the values obtained post-race, and no significant gender difference was found. Mean hemoglobin concentration both in males and females was slightly higher at 1 425 m altitude compared to <750 m altitude (0.23 g/dl increase in males and 0.48 g/dl increase in females; p<0.05 and p<0.01, respectively). Mean %retics at 1 425 m altitude is higher (0.24% in males and 0.27% in females, respectively, p<0.01) compared to blood sampled <750 m altitude. The distribution of percent reticulocytes shows 11 out of 11 500 samples with %reticulocytes below 0.4%. From the 171 samples with a values >2.4% in 52 skaters at least two consecutive samples yielded a percent reticulocytes above 2.4%. In 50 individuals with generally normal values but at least in two consecutive samples values above 2.4% the pattern required additional testing. In conclusion, percent reticulocytes are a robust hematological parameter, including acute exercise.

Resistance training in cancer survivors: a systematic review.

This systematic review summarizes the research of previous studies that used resistance training in the post-treatment phase of cancer patients with a focus on methodological quality, training methods and physical outcome measures. We found twenty-four studies (10 RCTs, 4 controlled clinical trials and 10 uncontrolled trials) that met all inclusion criteria. The studies were of moderate methodological quality. The majority of studies involved breast cancer patients (54%), followed by prostate cancer patients (13%). Most studies used a combination of resistance and aerobic training, which was mostly supervised. Resistance training involved large muscle groups, with 1-3 sets of 8-12 repetitions. The duration of the resistance training programs varied from 3-24 weeks, with a training frequency of 1-5 sessions per week. The training intensity ranged from 25% to 85% of the one-repetition maximum. Overall, positive training effects were observed for cardiopulmonary and muscle function, with significant increases in peak oxygen uptake (range: 6-39%), and in the one-repetition maximum (range: 11-110%). In general, there were no effects of training on body composition, endocrine and immune function, and haematological variables. No adverse effects of the resistance training were reported. Based upon these results, we recommend to incorporate resistance training in cancer rehabilitation programmes.

Four weeks' corticosteroid inhalation does not augment maximal power output in endurance athletes.

OBJECTIVE: To assess possible ergogenic properties of corticosteroid administration. DESIGN: A balanced, double-blind, placebo-controlled design was used. PARTICIPANTS: 28 well-trained cyclists and rowers. INTERVENTION: 4 weeks' daily inhalation of 800 microg budesonide or placebo. MAIN OUTCOME MEASUREMENTS: The subjects performed three incremental cycle ergometer tests until exhaustion, before and after 2 and 4 weeks of placebo or budesonide administration, to measure maximal power output (W(max)). Once a week they filled in a profile of mood state (POMS) questionnaire. RESULTS: There was no significant difference in W(max) between the placebo (376 (SD 25) W) and the corticosteroid group (375 (36) W) during the preintervention test, and there were no significant changes in either group after 2 and 4 weeks of intervention. No effect of the intervention on mood state was found. CONCLUSION: 4 weeks of corticosteroid or placebo inhalation in healthy, well-trained athletes did not affect maximal power output or mood state. Hence no ergogenic properties of 4 weeks' corticosteroid administration could be demonstrated, which corroborates previous studies of short-term corticosteroid administration.

Cardiac remodelling: concentric versus eccentric hypertrophy in strength and endurance athletes.

Cardiac remodelling is commonly defined as a physiological or pathological state that may occur after conditions such as myocardial infarction, pressure overload, idiopathic dilated cardiomyopathy or volume overload. When training excessively, the heart develops several myocardial adaptations causing a physiological state of cardiac remodelling. These morphological changes depend on the kind of training and are clinically characterised by modifications in cardiac size and shape due to increased load. Several studies have investigated morphological differences in the athlete's heart between athletes performing strength training and athletes performing endurance training. Endurance training is associated with an increased cardiac output and volume load on the left and right ventricles, causing the endurance-trained heart to generate a mild to moderate dilatation of the left ventricle combined with a mild to moderate increase in left ventricular wall thickness. Strength training is characterised by an elevation of both systolic and diastolic blood pressure. This pressure overload causes an increase in left ventricular wall thickness. This may or may not be accompanied by a slight raise in the left ventricular volume. However, the development of an endurancetrained heart and a strength-trained heart should not be considered an absolute concept. Both forms of training cause specific morphological changes in the heart, dependent on the type of sport. (Neth Heart J 2008;16:129-33.).

Corticotroph axis sensitivity after exercise: comparison between elite athletes and sedentary subjects.

Strenuous exercise activates the hypothalamic-pituitary-adrenal (HPA) axis. Several reports showed that physical training is associated with a decreased efficiency of the feedback control of HPA axis. The aims of the present study were: 1) to evaluate the differences in the mechanical, hormonal, and lactate responses to a high-intensity isokinetic exercise among different groups of competitive athletes (CA, no.=20) of power and endurance disciplines and sedentary controls (SED, no.=10); 2) to determine the effects of the training status on the HPA axis responsiveness following exercise, as indirectly evaluated by the rates of ACTH, cortisol, and DHEA recovery after exercise. CA and SED fulfilled eight sets of twenty concentric contractions of the knee extensors at 180 degrees/sec angular velocity throughout a constant range of motion (100 degrees). There was a rest period of 30 sec between each set and a 3-min rest period between the two legs. Before, immediately after the isokinetic exercise and at different times in the subsequent 120 min of recovery, blood and saliva were sampled to determine plasma ACTH, salivary cortisol, serum DHEA, and serum lactate concentrations. CA showed a higher cortisol response to exercise than SED, whereas no differences were found in the responses of ACTH, DHEA and lactate. In the athlete group the exercise-induced increases of ACTH, cortisol, and lactate were higher in power athletes with respect to endurance athletes. No differences were observed between athletes and SED in the rates of hormonal recovery after exercise: this finding does not support the concept that a reduced feedback control of HPA axis can represent a feature of trained individuals.

The effects of creatine supplementation on selected factors of tennis specific training.

BACKGROUND: Creatine supplementation is popular among tennis players but it is not clear whether it actually enhances tennis performance. OBJECTIVES: To examine the effects of creatine supplementation on tennis specific performance indices. METHODS: In a randomised, double blind design, 36 competitive male tennis players (24 creatine, mean (SD) age, 22.5 (4.9) years; 12 placebo, 22.8 (4.8) years) were tested at baseline, after six days of creatine loading, and after a maintenance phase of four weeks (14 creatine, 10 placebo). Serving velocity (10 serves), forehand and backhand velocity (three series of 5x8 strokes), arm and leg strength (bench press and leg press), and intermittent running speed (three series of five 20 metre sprints) were measured. RESULTS: Compared with placebo, neither six days nor five weeks of creatine supplementation had a significant effect on serving velocity (creatine: +2 km/h; placebo: +2 km/h, p = 0.90); forehand velocity (creatine: +4 km/h; placebo: +4 km/h, p = 0.80), or backhand velocity (creatine: +3 km/h; placebo: +1 km/h, p = 0.38). There was also no significant effect of creatine supplementation on repetitive sprint power after 5, 10, and 20 metres, (creatine 20 m: -0.03 m/s; placebo 20 m: +0.01 m/s, p = 0.18), or in the strength of the upper and lower extremities. CONCLUSIONS: Creatine supplementation is not effective in improving selected factors of tennis specific performance and should not be recommended to tennis players.

[Putative effects of doping in cycling]. / Vermeende effecten van doping in de wielersport.

After recent scandals in cycling involving doping, it has been asserted that top-level cycling is impossible without pharmacological support. An important prerequisite for successfully completing the Tour de France is maintaining energy balance. To compensate for the daily caloric expenditure of 23-25 MJ, conventional food must be supplemented with liquid food. Quick administration of liquid carbohydrates is essential for optimal recovery of glycogen stores in the liver and skeletal muscle. Androgenic anabolic steroids are a frequently used form of doping. In endurance sports, these drugs have not been shown to affect endurance performance, and there is little evidence to suggest that they enhance recovery. Although epoetin use can increase maximal oxygen uptake, its effects on maximal power output are less pronounced than what is generally assumed. A relationship between haemoglobin concentration and sport performance has not been proved. It has been found that growth hormone rather has a negative than a positive influence on the sport performance. The doping problem is due in part to superstition, hearsay and insufficient knowledge among the athlete's support personnel, which frequently leads to medical malpractice in sport. Education and quality control for sport professionals, including sports physicians, may help to control the doping problem.

Accidental breaches of the doping regulations in sport: is there a need to improve the education of sportspeople?

OBJECTIVES: To identify educational needs of elite sportspeople with respect to the doping laws. METHODS: A questionnaire survey of 196 Olympic level sportspeople from the fields of athletics, cycling, rowing, and sailing. The questionnaire addressed the date and source of the last doping educational update, the usefulness of current resources, sources of help, and possible ways of improving the system. The questionnaire also sought to estimate the use of nutritional supplements in these sports. RESULTS: Seventy four (38%) athletes responded to the questionnaire. Over 90% of responders had received a doping educational update in the last six months, and most agreed with the statement "I have received the information I need to avoid getting into trouble with the doping laws". Despite this, more than half of responders agreed with the statements "I should receive reminders more often" and "The authorities should do more to educate sportspeople". In addition, there were four people who admitted taking a banned substance by accident. Forty one (55%) reported taking supplements. The team doctor was the most popular source if information on a substance or product was required, with 62% and 66% of subjects stating that they would contact their team doctor when based in the United Kingdom and abroad respectively. The UK Sports website was often suggested in relation to ways of improving knowledge. CONCLUSIONS: There is a need to alter the educational process, particularly with respect to contingency planning for minor illness. The use of internet based resources for up to date information about banned substances needs to be promoted, and access to the internet improved. The educational needs of team doctors with respect to the doping laws need to be assessed.

HLA and other host factors in transfusion-acquired HIV-1 infection.

The host and viral factors that underlie infection with HIV-1 vary considerably with some individuals progressing to AIDS within 3 to 5 years after infection, whereas others remain clinically asymptomatic for over 10 years. Host factors that may contribute to disease progression include HLA and allelic variants of the chemokine receptors CCR5 and CCR2, which have been shown to influence both long-term survival and rapid progression. In this study, we have examined the contribution of HLA and polymorphisms in CCR5 and CCR2 to long-term survival in transfusion-acquired HIV-1-infected individuals. We have found a higher number of HLA-A32 and -A25 alleles but a lower number of the HLA-B8 allele in the study group compared with the frequencies seen in the HIV-1-negative Australian caucasian population. However, there was no apparent contribution by allelic variants of CCR5 and CCR2 to long-term survival and the combined influence of HLA and CCR polymorphisms could not be evaluated in this relatively small (n = 20) group of study subjects. The results of this work support a role for HLA in long-term nonprogression though the presence in the Sydney Blood bank Cohort of nef-defective HIV-1 may confound associations between certain HLA alleles and long-term survival in the face of infection with HIV-1.

Meniscal tissue regeneration in porous 50/50 copoly(L-lactide/epsilon-caprolactone) implants.

Porous materials of a high-molecular-weight 50/50 copolymer of L-lactide and epsilon-caprolactone with different compression moduli were used for meniscal repair. In contrast to the previously used 4,4'-diphenylmethane and 1,4-trans-cyclohexane diisocyanates containing polyurethanes, degradation products of the copolymer are non-toxic. Two series of porous materials with compression moduli of 40 and 100 kPa respectively were implanted in the knees of dogs using a new, less traumatizing suturing technique. A porous aliphatic polyurethane series with compression modulus of 150 kPa was implanted for comparison. Adhesion of the implant to meniscal tissue was found to be essential for healing of the longitudinal lesion. Copolymer implants showed better adhesion, probably due to the higher degradation rate of the copolymer. Fibrocartilage formation was found to be affected by the compression modulus of the implant. Implants with a modulus of 40 kPa did not show ingrowth of fibrocartilage, whereas implants with compression moduli of 100 and 150 kPa yielded 50-70 and 80-100% fibrocartilage respectively. During degradation the copolymer phase separated into a crystalline phase containing mainly L-lactide and an amorphous phase containing mainly epsilon-caprolactone. The copolymer degraded through bulk degradation.

The influence of food temperature on postprandial blood pressure reduction and its relation to substance-P in healthy elderly subjects.

Blood pressure (BP) in the elderly may decrease after a meal or oral glucose loading. The mechanism of this phenomenon is still unclear. In addition, the effect of the temperature of a meal on postprandial BP is unknown. However, it has been suggested that vasoactive gastrointestinal peptides are involved in the etiology of postprandial BP reduction. Therefore, we studied the effects of a cold and a warm glucose solution on BP, heart rate, plasma glucose, insulin, and substance-P levels in 15 healthy elderly subjects with a mean age of 74 +/- 3 (SD) years. With an interval of at least 2 days, a warm (50 degrees C) and a cold (5 degrees C) solution (75 g glucose/300 mL water) were given in random order. After the cold glucose loading mean arterial pressure increased by a maximum of 3.9 +/- 1.3 mmHg (P less than 0.01). In contrast, BP decreased after the warm solution by a maximum of 8.0 +/- 1.1 mmHg (P less than 0.001). Neither test had an influence on plasma substance-P levels. Our data suggest that postprandial blood pressure reduction in the elderly is dependent on food temperature. Substance-P does not seem to play a role in this phenomenon.

Rapid visuomotor preparation in the human brain: a functional MRI study.

An important feature of human motor behaviour is anticipation and preparation. We report a functional magnetic resonance imaging study of the neuronal activation patterns in the human brain that are associated with the rapid visuomotor preparation of discrete finger responses. Our imaging results reveal a large-scale distributed network of neural areas involved in fast visuomotor preparation, including specific areas in the frontal cortex (middle frontal gyrus, premotor and supplementary motor cortex), the parietal cortex (intra-parietal sulcus, inferior and superior parietal lobe) and the basal ganglia. Our reaction time results demonstrate that it is easier to prepare two fingers on one hand than on two hands. This hand-advantage phenomenon was associated with relatively enhanced levels of activity in the basal ganglia and relatively reduced levels of activity in the parietal cortex. These findings provide direct evidence for differential activity in a distributed brain system associated with specific neuro-computational operations subserving fast visuomotor preparation.

Adaptation and overtraining in horses subjected to increasing training loads.

To evaluate markers for overtraining, seven male race horses were subjected to 272 days of training consisting of daily exercise bouts of either endurance running (heart rate 140/min) or interval training (maximal heart rate), both increasing in duration and intensity. An incremental exercise test was held every 4 wk, and from day 187 it was held every 2 wk. Muscle glycogen, muscle lactate, energy-rich phosphates, adrenal response to adrenocorticotropic hormone, plasma and red blood cell volumes, and a number of blood chemical variables were measured. The horses showed symptoms of weight loss, irritability, and an inability to complete the training after the intensity of the endurance exercise was increased. Test performance was not decreased. The adrenal response to adrenocorticotropic hormone was not changed during overtraining. The decline in muscle ATP concentration during maximal exercise was less during the period of staleness, whereas plasma volume, red blood cell volume, and blood chemical variables were unchanged. It was concluded that as long as exhaustive training is alternated by light exercise, overtraining is unlikely to occur. Furthermore, no single parameter can be used to detect early overtraining.

Relationship between exercise-induced muscle damage and enzyme release in rats.

The relationship between the amount of exercise-induced muscle damage and the release of creatine kinase (CK), aspartate aminotransferase (AST), and lactate dehydrogenase (LD) was studied. Gender differences in enzyme release and histological damage were also studied. Serial pre- and postexercise blood samples were drawn from untrained male and female catheterized Wistar rats that ran 1.5 or 2.5 h on a treadmill (incline 10 degrees). Three days postexercise, muscle damage was quantified morphometrically in five different hindlimb and forearm muscles. The 1.5 and 2.5 h of exercise elicited histological damage only in the soleus muscle. Significant plasma CK, AST, and LD elevations were found immediately postexercise both in male and female rats. However, the enzyme release was significantly greater in males than in females. Part of this could be explained by differences in clearance rates between males and females. No gender difference in amount of histological damage was found. The actual volume of histological muscle damage was significantly less than the calculated muscle damage based on enzyme release. An increase in the exercise duration from 1.5 to 2.5 h resulted in a disproportional increase in both histological muscle damage and muscle enzyme release. From the present study it is concluded that muscle enzyme release is not clearly reflected in histological muscle damage.

Glucose feeding and exercise in trained rats: mechanisms for glycogen sparing.

This investigation studied the effect of an oral glucose feeding on glycogen sparing during exercise in non-glycogen-depleted and glycogen-depleted endurance-trained rats. The non-glycogen-depleted rats received via a stomach tube 2 ml of a 20% glucose solution labeled with [U-14C]glucose just prior to exercise (1 h at 25 m/min). Another group of rats ran for 40 min at higher intensity to deplete glycogen stores, after which they received the same glucose feeding and continued running for 1 h at 25 m/min. The initial 40-min run depleted glycogen in heart, skeletal muscle, and liver. In the non-glycogen-depleted rats the glucose feeding spared glycogen in the liver, primarily from the oxidation of blood-borne glucose in muscle. In the glycogen-depleted rats, muscle glycogen was repleted after the feeding, but sources other than the administered glucose also contributed to glycogen synthesis. The results suggest that glycogen depletion rather than the glucose feeding per se stimulates glycogen resynthesis in muscle during exercise in endurance-trained rats.

Exercise-induced swelling of rat soleus muscle: its relationship with intramuscular pressure.

Exercise-induced tissue swelling and its possible consequence for tissue pressure were studied in rat soleus muscle. Rats ran for 75 min on a belt with a 10 degree positive incline. Wet weights of cryofixed soleus muscles were increased at 3 (16%), 6 (28%), 9 (16%), and 24 (16%) h after running compared with those of nonexercised controls. The transient increase in muscle wet weight correlated in time with an increase in muscle volume. Muscle fiber swelling accounted for most of the muscle swelling in absolute terms because of the large proportion (approximately 90%) of the muscle volume composed of fibers, but swelling of the interstitium was about twofold larger than fiber swelling per unit area. Muscle fiber degeneration was most frequently found at the end of the observation period, i.e., 24 h after running. The muscle swelling was not associated with an increase in intramuscular pressure. During the postexercise measuring period (18 min to 24 h after exercise), intramuscular pressures of exercised rats (1.3 +/- 0.3 mm Hg) did not differ significantly from control values (1.0 +/- 0.2 mm Hg). These findings indicate that increased intramuscular pressure is not responsible for the muscle fiber degeneration found in rat soleus muscle 24 h after endurance running.