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Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.

Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.

BACKGROUND: A growing body of literature on Roux-en-Y gastric bypass surgery (RYGB) has generated inconclusive results on the mechanism underlying the beneficial effects on weight loss and glycaemia, partially due to the problems of designing clinical studies with the appropriate controls. Moreover, RYGB is only performed in obese individuals, in whom metabolism is perturbed and not completely understood.METHODS: In an attempt to isolate the effects of RYGB and its effects on normal metabolism, we investigated the effect of RYGB in lean pigs, using sham-operated pair-fed pigs as controls. Two weeks post-surgery, pigs were subjected to an intravenous glucose tolerance test (IVGTT) and circulating metabolites, hormones and lipids measured. Bile acid composition was profiled after extraction from blood, faeces and the gallbladder.RESULTS: A similar weight development in both groups of pigs validated our experimental model. Despite similar changes in fasting insulin, RYGB-pigs had lower fasting glucose levels. During an IVGTT RYGB-pigs had higher insulin and lower glucose levels. VLDL and IDL were lower in RYGB- than in sham-pigs. RYGB-pigs had increased levels of most amino acids, including branched-chain amino acids, but these were more efficiently suppressed by glucose. Levels of bile acids in the gallbladder were higher, whereas plasma and faecal bile acid levels were lower in RYGB- than in sham-pigs.CONCLUSION: In a lean model RYGB caused lower plasma lipid and bile acid levels, which were compensated for by increased plasma amino acids, suggesting a switch from lipid to protein metabolism during fasting in the immediate postoperative period.

BACKGROUND: A growing body of literature on Roux-en-Y gastric bypass surgery (RYGB) has generated inconclusive results on the mechanism underlying the beneficial effects on weight loss and glycaemia, partially due to the problems of designing clinical studies with the appropriate controls. Moreover, RYGB is only performed in obese individuals, in whom metabolism is perturbed and not completely understood.METHODS: In an attempt to isolate the effects of RYGB and its effects on normal metabolism, we investigated the effect of RYGB in lean pigs, using sham-operated pair-fed pigs as controls. Two weeks post-surgery, pigs were subjected to an intravenous glucose tolerance test (IVGTT) and circulating metabolites, hormones and lipids measured. Bile acid composition was profiled after extraction from blood, faeces and the gallbladder.RESULTS: A similar weight development in both groups of pigs validated our experimental model. Despite similar changes in fasting insulin, RYGB-pigs had lower fasting glucose levels. During an IVGTT RYGB-pigs had higher insulin and lower glucose levels. VLDL and IDL were lower in RYGB- than in sham-pigs. RYGB-pigs had increased levels of most amino acids, including branched-chain amino acids, but these were more efficiently suppressed by glucose. Levels of bile acids in the gallbladder were higher, whereas plasma and faecal bile acid levels were lower in RYGB- than in sham-pigs.CONCLUSION: In a lean model RYGB caused lower plasma lipid and bile acid levels, which were compensated for by increased plasma amino acids, suggesting a switch from lipid to protein metabolism during fasting in the immediate postoperative period.

The most frequently used, and effective, treatment for morbid obesity is Roux-en-Y gastric bypass surgery (RYGB), which results in rapid remission of T2D in most cases. To what extent this is accounted for by weight loss or other factors remains elusive. To gain insight into these mechanisms, we investigated the effects of RYGB on ß-cell function and ß-cell mass in the pig, a species highly reminiscent of the human. RYGB was performed using linear staplers during open surgery. Sham-operated pigs were used as controls. Both groups were fed a low calorie diet for 3 weeks after surgery. Intravenous glucose-tolerance tests were performed 2 weeks after surgery. Body weight in RYGB-pigs and sham-operated, pair-fed control pigs developed similarly. RYGB-pigs displayed improved glycaemic control, which was attributed to increases in ß-cell mass, islet number and number of extra-islet ß-cells. Pancreatic expression of insulin and glucagon was elevated, and cells expressing the GLP-1-receptor were more abundant in RYGB-pigs. Our data from a pig model of RYGB emphasize the key role of improved ß-cell function and ß-cell mass to explain the improved glucose tolerance after RYGB as food intake and body weight remained identical.

BACKGROUND & AIMS: Dietary chloroplast thylakoids have previously been found to reduce food intake and body weight in animal models, and to change metabolic profiles in humans in mixed-food meal studies. The aim of this study was to investigate the modulatory effects of thylakoids on glucose metabolism and appetite-regulating hormones during an oral glucose tolerance test in pigs fed a high fat diet.METHODS: Six pigs were fed a high fat diet (36 energy% fat) for one month before oral glucose tolerance test (1 g/kg d-glucose) was performed. The experiment was designed as a cross-over study, either with or without addition of 0.5 g/kg body weight of thylakoid powder.RESULTS: The supplementation of thylakoids to the oral glucose tolerance test resulted in decreased blood glucose concentrations during the first hour, increased plasma cholecystokinin concentrations during the first two hours, and decreased late postprandial secretion of ghrelin.CONCLUSION: Dietary thylakoids may be a novel agent in reducing the glycaemic responses to high carbohydrate and high glycaemic index foods. Thylakoids may in the future be promising for treatment and prevention of diabetes, overweight and obesity.

BACKGROUND & AIMS: Dietary chloroplast thylakoids have previously been found to reduce food intake and body weight in animal models, and to change metabolic profiles in humans in mixed-food meal studies. The aim of this study was to investigate the modulatory effects of thylakoids on glucose metabolism and appetite-regulating hormones during an oral glucose tolerance test in pigs fed a high fat diet.METHODS: Six pigs were fed a high fat diet (36 energy% fat) for one month before oral glucose tolerance test (1 g/kg d-glucose) was performed. The experiment was designed as a cross-over study, either with or without addition of 0.5 g/kg body weight of thylakoid powder.RESULTS: The supplementation of thylakoids to the oral glucose tolerance test resulted in decreased blood glucose concentrations during the first hour, increased plasma cholecystokinin concentrations during the first two hours, and decreased late postprandial secretion of ghrelin.CONCLUSION: Dietary thylakoids may be a novel agent in reducing the glycaemic responses to high carbohydrate and high glycaemic index foods. Thylakoids may in the future be promising for treatment and prevention of diabetes, overweight and obesity.

The study employed mechanical stretching in vitro of sections of abdominal aorta of elderly mice to investigate any benefits of oral treatment with alpha-ketoglutarate (AKG) on arterial elasticity. Eighteen female mice (50-weeks-old) were assigned to a control (2% w/v) Na2-AKG or (2% w/v) a Ca-AKG group, and treated for 182 days before being humanely killed. Aorta sections were exposed to increases in force (0.09 N) giving approx. 6 kPa of pressure, after which elastic recoil (N ms-1 wet wt.) was measured. Na2-AKG treatment for 182 days induced a 30% (P <0.01) improvement, while Ca-AKG induced a 93% (P <0.001) improvement in the elastic recoil compared to controls (3.30 ± 0.08 x 10-5 N ms-1 mg-1 wet wt.). AKG administered orally improved arterial elasticity in elderly mice, a change that occurred despite an increase in total collagen content. Alpha-ketoglutarate warrants further investigation as a candidate for therapies targeting arterial stiffening with age.

The study employed mechanical stretching in vitro of sections of abdominal aorta of elderly mice to investigate any benefits of oral treatment with alpha-ketoglutarate (AKG) on arterial elasticity. Eighteen female mice (50-weeks-old) were assigned to a control (2% w/v) Na2-AKG or (2% w/v) a Ca-AKG group, and treated for 182 days before being humanely killed. Aorta sections were exposed to increases in force (0.09 N) giving approx. 6 kPa of pressure, after which elastic recoil (N ms-1 wet wt.) was measured. Na2-AKG treatment for 182 days induced a 30% (P <0.01) improvement, while Ca-AKG induced a 93% (P <0.001) improvement in the elastic recoil compared to controls (3.30 ± 0.08 x 10-5 N ms-1 mg-1 wet wt.). AKG administered orally improved arterial elasticity in elderly mice, a change that occurred despite an increase in total collagen content. Alpha-ketoglutarate warrants further investigation as a candidate for therapies targeting arterial stiffening with age.

The aim of the study was to evaluate the effect of both phytohaemagglutinin (PHA) alone, and in combination with alpha-ketoglutaric acid (AKG), on nitrogen elimination via the urinary tract as opposed to the gastrointestinal tract of rats. In experiment 1, rats were assigned to one of two experimental groups, (1) Control and (2) PHA, whilst in experiment 2, rats were assigned to one of three experimental groups, (1) Control, (2) AKG, and (3) AKG+PHA. AKG was administered via drinking water, while PHA was administered via a stomach tube. The stock solution of crude PHA in 0.9 % NaCl, was (20 % w/v) in water: 50 mg PHA/ml, 20 ml/kg body wt. Rats were 7 weeks old at the start of the experiments. Significantly lower daily weight gains in the AKG+PHA and PHA groups (p<0.05) were observed compared to the Control and AKG groups. Increased duodenal crypt depth (138 % ; p<0.05) was noticeable in the AKG+PHA group cf Controls; however, there was no significant difference in the thickness of the tunica mucosa. In the AKG+PHA group, the expression of neuropeptide Y (NPY) in the granula of neuronal cells of the submucosal parasympathetic ganglia was noticeable, although no expression was found in goblet cells. Finally, significant reduction in N excretion in urine was observed in the AKG+PHA, compared with the Control groups (p< 0.05). It is concluded that a combined PHA and AKG treatment stimulated the small bowel growth via enhanced epithelial turnover, reduced the N excreted in urine and increased the N in faeces.

The aim of the study was to evaluate the effect of both phytohaemagglutinin (PHA) alone, and in combination with alpha-ketoglutaric acid (AKG), on nitrogen elimination via the urinary tract as opposed to the gastrointestinal tract of rats. In experiment 1, rats were assigned to one of two experimental groups, (1) Control and (2) PHA, whilst in experiment 2, rats were assigned to one of three experimental groups, (1) Control, (2) AKG, and (3) AKG+PHA. AKG was administered via drinking water, while PHA was administered via a stomach tube. The stock solution of crude PHA in 0.9 % NaCl, was (20 % w/v) in water: 50 mg PHA/ml, 20 ml/kg body wt. Rats were 7 weeks old at the start of the experiments. Significantly lower daily weight gains in the AKG+PHA and PHA groups (p<0.05) were observed compared to the Control and AKG groups. Increased duodenal crypt depth (138 % ; p<0.05) was noticeable in the AKG+PHA group cf Controls; however, there was no significant difference in the thickness of the tunica mucosa. In the AKG+PHA group, the expression of neuropeptide Y (NPY) in the granula of neuronal cells of the submucosal parasympathetic ganglia was noticeable, although no expression was found in goblet cells. Finally, significant reduction in N excretion in urine was observed in the AKG+PHA, compared with the Control groups (p< 0.05). It is concluded that a combined PHA and AKG treatment stimulated the small bowel growth via enhanced epithelial turnover, reduced the N excreted in urine and increased the N in faeces.

The aim of the study was to evaluate the effect of both phytohaemagglutinin (PHA) alone, and in combination with alpha-ketoglutaric acid (AKG), on nitrogen elimination via the urinary tract as opposed to the gastrointestinal tract of rats. In experiment 1, rats were assigned to one of two experimental groups, (1) Control and (2) PHA, whilst in experiment 2, rats were assigned to one of three experimental groups, (1) Control, (2) AKG, and (3) AKG+PHA. AKG was administered via drinking water, while PHA was administered via a stomach tube. The stock solution of crude PHA in 0.9 % NaCl, was (20 % w/v) in water: 50 mg PHA/ml, 20 ml/kg body wt. Rats were 7 weeks old at the start of the experiments. Significantly lower daily weight gains in the AKG+PHA and PHA groups (p<0.05) were observed compared to the Control and AKG groups. Increased duodenal crypt depth (138 % ; p<0.05) was noticeable in the AKG+PHA group cf Controls; however, there was no significant difference in the thickness of the tunica mucosa. In the AKG+PHA group, the expression of neuropeptide Y (NPY) in the granula of neuronal cells of the submucosal parasympathetic ganglia was noticeable, although no expression was found in goblet cells. Finally, significant reduction in N excretion in urine was observed in the AKG+PHA, compared with the Control groups (p< 0.05). It is concluded that a combined PHA and AKG treatment stimulated the small bowel growth via enhanced epithelial turnover, reduced the N excreted in urine and increased the N in faeces.

The aim of the study was to evaluate the effect of both phytohaemagglutinin (PHA) alone, and in combination with alpha-ketoglutaric acid (AKG), on nitrogen elimination via the urinary tract as opposed to the gastrointestinal tract of rats. In experiment 1, rats were assigned to one of two experimental groups, (1) Control and (2) PHA, whilst in experiment 2, rats were assigned to one of three experimental groups, (1) Control, (2) AKG, and (3) AKG+PHA. AKG was administered via drinking water, while PHA was administered via a stomach tube. The stock solution of crude PHA in 0.9 % NaCl, was (20 % w/v) in water: 50 mg PHA/ml, 20 ml/kg body wt. Rats were 7 weeks old at the start of the experiments. Significantly lower daily weight gains in the AKG+PHA and PHA groups (p<0.05) were observed compared to the Control and AKG groups. Increased duodenal crypt depth (138 % ; p<0.05) was noticeable in the AKG+PHA group cf Controls; however, there was no significant difference in the thickness of the tunica mucosa. In the AKG+PHA group, the expression of neuropeptide Y (NPY) in the granula of neuronal cells of the submucosal parasympathetic ganglia was noticeable, although no expression was found in goblet cells. Finally, significant reduction in N excretion in urine was observed in the AKG+PHA, compared with the Control groups (p< 0.05). It is concluded that a combined PHA and AKG treatment stimulated the small bowel growth via enhanced epithelial turnover, reduced the N excreted in urine and increased the N in faeces.

The aim of the study was to evaluate the effect of both phytohaemagglutinin (PHA) alone, and in combination with alpha-ketoglutaric acid (AKG), on nitrogen elimination via the urinary tract as opposed to the gastrointestinal tract of rats. In experiment 1, rats were assigned to one of two experimental groups, (1) Control and (2) PHA, whilst in experiment 2, rats were assigned to one of three experimental groups, (1) Control, (2) AKG, and (3) AKG+PHA. AKG was administered via drinking water, while PHA was administered via a stomach tube. The stock solution of crude PHA in 0.9% NaCl, was (20% w/v) in water: 50 mg PHA/ml, 20 ml/kg body wt. Rats were 7 weeks old at the start of the experiments. Significantly lower daily weight gains in the AKG+PHA and PHA groups (p<0.05) were observed compared to the Control and AKG groups. Increased duodenal crypt depth (138%; p<0.05) was noticeable in the AKG+PHA group of Controls; however, there was no significant difference in the thickness of the tunica mucosa. In the AKG+PHA group, the expression of neuropeptide Y (NPY) in the granula of neuronal cells of the submucosal parasympathetic ganglia was noticeable, although no expression was found in goblet cells. Finally, significant reduction in N excretion in urine was observed in the AKG+PHA, compared with the Control Groups (p<0.05). It is concluded that a combined PHA and AKG treatment stimulated the small bowel growth via enhanced epithelial turnover, reduced the N excreted in urine and increased the N in feces.

Muscle contraction studies often focus solely on myofibres and the proteins known to be involved in the processes of sarcomere shortening and cross-bridge cycling, but skeletal muscle also comprises a very elaborate ancillary network of capillaries, which not only play a vital role in terms of nutrient delivery and waste product removal, but are also tethered to surrounding fibres by collagen "wires". This paper therefore addresses aspects of the ancillary network of skeletal muscle at both a microscopic and functional level in order to better understand its role holistically as a considerable contributor to force transfer within muscular tissue.

Introduction:Phytomaemagglutinin (PHA) and alpha-ketoglutaric acid (AKG) in growing rats stimulate a change in the proportion of N excretion via urine and faeces, in favour of faecal excretion. The aim of the study was to investigate the effect oforal supplementation of PHA and AKG on pathways of nitrogen excretion and serum levels of urea in uraemic conditions induced by nephrectomy. Material and methods: Experiment 1 - 12 rats were assigned to one of two groups, control and PHA. Experiment 2 - PHA was administered to 36 male rats which were assigned to 4 groups: 1) uraemic control, 2) uraemic + AKG, 3) Shap-operated, 4) Sham-operated + AKG. AKG was administered via drinking water, while PHA was administered via a stomach tube. Results: Lower daily weight gain (P<0.05), increase in small intestine and total Gl tract weight (P<0.05) as well as significant reduction in N excretion in urine in the PHA group were observed (P<0.05). Significantly higher daily weight loss in the uraemic rats, compared to that of the sham-operated rats, was observed (P<0.05). A significant increase in N excretion in faeces was observed in the AKG group, compared to the uraemic rats (P<0.05). In both sham-operated and uraemic rats, AKG treatment led to a significant reduction in the urea levels (P<0.05). Conclusions: The change in the proportion of N excretion via urine and faeces caused by PHA due to increasing the rate of protein production in the intestinal wall, apparently favouring faecal excretion, can be enhanced by the oral administration of AKG.

The aim of the study was to evaluate the effect of both phytohaemagglutinin (PHA) alone, and in combination with alpha-ketoglutaric acid (AKG), on nitrogen elimination via the urinary tract as opposed to the gastrointestinal tract of rats. In experiment 1, rats were assigned to one of two experimental groups, (1) Control and (2) PHA, whilst in experiment 2, rats were assigned to one of three experimental groups, (1) Control, (2) AKG, and (3) AKG+PHA. AKG was administered via drinking water, while PHA was administered via a stomach tube. The stock solution of crude PHA in 0.9% NaCl, was (20% w/v) in water: 50 mg PHA/ml, 20 ml/kg body wt. Rats were 7 weeks old at the start of the experiments. Significantly lower daily weight gains in the AKG+PHA and PHA groups (p<0.05) were observed compared to the Control and AKG groups. Increased duodenal crypt depth (138%; p<0.05) was noticeable in the AKG+PHA group of Controls; however, there was no significant difference in the thickness of the tunica mucosa. In the AKG+PHA group, the expression of neuropeptide Y (NPY) in the granula of neuronal cells of the submucosal parasympathetic ganglia was noticeable, although no expression was found in goblet cells. Finally, significant reduction in N excretion in urine was observed in the AKG+PHA, compared with the Control Groups (p<0.05). It is concluded that a combined PHA and AKG treatment stimulated the small bowel growth via enhanced epithelial turnover, reduced the N excreted in urine and increased the N in feces.

Muscle contraction studies often focus solely on myofibres and the proteins known to be involved in the processes of sarcomere shortening and cross-bridge cycling, but skeletal muscle also comprises a very elaborate ancillary network of capillaries, which not only play a vital role in terms of nutrient delivery and waste product removal, but are also tethered to surrounding fibres by collagen "wires". This paper therefore addresses aspects of the ancillary network of skeletal muscle at both a microscopic and functional level in order to better understand its role holistically as a considerable contributor to force transfer within muscular tissue.

Introduction:Phytomaemagglutinin (PHA) and alpha-ketoglutaric acid (AKG) in growing rats stimulate a change in the proportion of N excretion via urine and faeces, in favour of faecal excretion. The aim of the study was to investigate the effect oforal supplementation of PHA and AKG on pathways of nitrogen excretion and serum levels of urea in uraemic conditions induced by nephrectomy. Material and methods: Experiment 1 - 12 rats were assigned to one of two groups, control and PHA. Experiment 2 - PHA was administered to 36 male rats which were assigned to 4 groups: 1) uraemic control, 2) uraemic + AKG, 3) Shap-operated, 4) Sham-operated + AKG. AKG was administered via drinking water, while PHA was administered via a stomach tube. Results: Lower daily weight gain (P<0.05), increase in small intestine and total Gl tract weight (P<0.05) as well as significant reduction in N excretion in urine in the PHA group were observed (P<0.05). Significantly higher daily weight loss in the uraemic rats, compared to that of the sham-operated rats, was observed (P<0.05). A significant increase in N excretion in faeces was observed in the AKG group, compared to the uraemic rats (P<0.05). In both sham-operated and uraemic rats, AKG treatment led to a significant reduction in the urea levels (P<0.05). Conclusions: The change in the proportion of N excretion via urine and faeces caused by PHA due to increasing the rate of protein production in the intestinal wall, apparently favouring faecal excretion, can be enhanced by the oral administration of AKG.

Muscle weakness is a prominent feature of end-state renal failure. While the cause of this strongly disabling muscle condition is at present unknown, there are suggestions that metabolic factors may play a role in this type of muscle fatigue. In vitro measurements of muscle function of the fast-twitch extensor digitorum longus (EDL) muscle of adult rats was performed. Isolated muscles were exposed to either a normal ionic environment, a uremic environment - with and without alpha-ketoglutarate (AKG), or with and without succinate, before being field stimulated until they were almost totally fatigued. The addition of AKG to the uremic environment was found to restore muscle performance so that the muscles no longer differed significantly from those incubated in a normal ionic environment. Similar effects to those noted for AKG were observed for succinate. It is concluded that DKG and succinate have a positive and restorative effect on muscle fatigue in uremic fast skeletal muscles in vitro. This beneficial form of treatment is proposed to act at the in vitro isolated muscle level by means of phosphate-binding, as the literature shows that an elevated plasma Pi concentration with renal failure disrupts normal muscle function.

The aim of the study was to evaluate the influence of a-ketoglutarate (AKG), at pH 2 or 5, combined with vitamin B6 (AKG 2B, AKG 5B) or C (AKG 2C, AKG 5C), on the performance and haemoglobin and amino acid levels in growing rats. Eighty rats were divided into 5 treatment groups and stayed on trial for 9 d (n=16) or 18 d (n=10). No significant differences in average daily gain (ADG), average daily feed intake (ADFI), or feed efficiency were seen between the dextrose-treated control group and the AKG treated groups. The highest ADG and ADFI were seen in the AKG 2B rats. The AKG 2B and AKG 2C treated rats had the highest Hb levels. The Hb levels were positively correlated with a better performance. The free glutamine (Glu) increased over time in all the groups. The arginine (Arg) levels significantly increased in the AKG 2B and AKG 5B groups. An increase in free Glu had a positive impact on the growth performance.

Muscle weakness is a prominent feature of end-state renal failure. While the cause of this strongly disabling muscle condition is at present unknown, there are suggestions that metabolic factors may play a role in this type of muscle fatigue. In vitro measurements of muscle function of the fast-twitch extensor digitorum longus (EDL) muscle of adult rats was performed. Isolated muscles were exposed to either a normal ionic environment, a uremic environment - with and without alpha-ketoglutarate (AKG), or with and without succinate, before being field stimulated until they were almost totally fatigued. The addition of AKG to the uremic environment was found to restore muscle performance so that the muscles no longer differed significantly from those incubated in a normal ionic environment. Similar effects to those noted for AKG were observed for succinate. It is concluded that DKG and succinate have a positive and restorative effect on muscle fatigue in uremic fast skeletal muscles in vitro. This beneficial form of treatment is proposed to act at the in vitro isolated muscle level by means of phosphate-binding, as the literature shows that an elevated plasma Pi concentration with renal failure disrupts normal muscle function.

The aim of the study was to evaluate the influence of a-ketoglutarate (AKG), at pH 2 or 5, combined with vitamin B6 (AKG 2B, AKG 5B) or C (AKG 2C, AKG 5C), on the performance and haemoglobin and amino acid levels in growing rats. Eighty rats were divided into 5 treatment groups and stayed on trial for 9 d (n=16) or 18 d (n=10). No significant differences in average daily gain (ADG), average daily feed intake (ADFI), or feed efficiency were seen between the dextrose-treated control group and the AKG treated groups. The highest ADG and ADFI were seen in the AKG 2B rats. The AKG 2B and AKG 2C treated rats had the highest Hb levels. The Hb levels were positively correlated with a better performance. The free glutamine (Glu) increased over time in all the groups. The arginine (Arg) levels significantly increased in the AKG 2B and AKG 5B groups. An increase in free Glu had a positive impact on the growth performance.

Enteric bacteria execute, via lipopolysaccharide (LPS), a pathogenic role in intestinal inflammation. The effects of LPS on survival and neurotransmitter expression in cultured porcine myenteric neurons were investigated. Myenteric neurons were isolated and cultured for 6 days in medium, in LPS (100 ng/ml) with or without α-ketoglutarate or the nitric oxide synthase (NOS) inhibitor L-NAME, in α-ketoglutarate or in the NO donor SNAP. Neuronal survival and expression of vasoactive intestinal peptide (VIP) and NOS were evaluated by immunocytochemistry. Addition of LPS significantly decreased neuronal survival; only 40% survived, compared to controls run in parallel. The LPS-induced neurotoxic effect was not counteracted by the simultaneous presence of α-ketoglutarate or L-NAME. Either SNAP or α-ketoglutarate influenced neuronal survival. Culturing, particularly in the presence of LPS, markedly increased the proportion of VIP-immunoreactive neurons; NOS-immunoreactive neurons were unchanged. The reported LPS-induced neurotoxicity indicates loss of enteric neurons as a consequence of intestinal inflammation.

The relation between supraphysiologic circulating testosterone levels and prostatic diseases is unclear and difficult to study in men. Animal models may be advantageous. Based on a pilot study, testosterone enantate 50 mg (n=12) or 25 mg (n=12) was administered to guinea-pigs intramuscularly every 3 weeks, for either 7 or 14 months. The histopathology of the prostate was described. Epithelial hyperplasia was found in 14/21 animals receiving testosterone and in 7/12 very old animals, but no such changes were found in the sham or castrated animals. Testosterone stimulation seems to induce epithelial hyperplasia, but not cancer, in the guinea-pig prostate.