Bone resorption is decreased postprandially by intestinal factors and glucagon-like peptide-2 is a possible candidate

OBJECTIVE: Food intake inhibits bone resorption by a mechanism thought to involve gut hormones, and the intestinotrophic glucagon-like peptide 2 (GLP-2) is a candidate because exogenous GLP-2 inhibits bone resorption in humans. The purpose of the study was to investigate patients with short-bowel syndrome (SBS) or total gastrectomy in order to elucidate whether the signal for the meal-induced reduction of bone resorption is initiated from the stomach or the intestine. MATERIAL AND METHODS: Bone resorption was assessed from the serum concentration of collagen type I C-telopeptide cross-links (s-CTX) and compared with the plasma concentrations of GLP-2. Bone formation was assessed from serum osteocalcin concentrations. Seven SBS patients with a preserved colon and 7 with SBS and colectomy and 7 healthy controls were given a breakfast test meal (936 kcal). Eight patients who had undergone total gastrectomy had an oral glucose load (75 g in 150 ml). RESULTS: The SBS patients without a colon showed no reduction in bone resorption (s-CTX) to a meal, whereas SBS patients with a colon had an intermediate response with a 27% (p<0.05) reduction of s-CTX from baseline after 120 min as compared with 66% (p<0.001) for normal controls. A significant reduction of 53% (p<0.001) was seen in gastrectomized patients after receiving oral glucose, which is comparable with the published data for the oral glucose tolerance test (OGGT) in healthy subjects (50% reduction over 120 min). Bone formation was unchanged for both SBS and gastrectomy patients. GLP-2 concentrations increased significantly in all groups with the exception of the SBS plus colectomy group. CONCLUSIONS: An intestinal factor is responsible for the postprandial reduction in bone resorption, and our findings are compatible with such a function for GLP-2.     

Growth factors in short-bowel syndrome patients

Malabsorption is a key finding in patients with short-bowel syndrome. Malabsorption of nonessential and essential nutrients, fluids, and electrolytes, if not compensated for by increased intake, leads to diminished body stores and subclinical and (eventually) clinical deficiencies. After intestinal resection, adaptation (a spontaneous progressive recovery from the malabsorptive disorder) may be evident. This article describes selected factors responsible for the morphologic and functional changes in the adaptive processes and presents results of clinical trials that use either growth hormone or glucagon-like peptide-2 to facilitate a condition of hyperadaptation in short-bowel patients.     

ESPEN Guidelines on Parenteral Nutrition: Gastroenterology

Undernutrition as well as specific nutrient deficiencies has been described in patients with Crohn's disease (CD), ulcerative colitis (UC) and short bowel syndrome. In the latter, water and electrolytes disturbances may be a major problem.The present guidelines provide evidence-based recommendations for the indications, application and type of parenteral formula to be used in acute and chronic phases of illness.Parenteral nutrition is not recommended as a primary treatment in CD and UC. The use of parenteral nutrition is however reliable when oral/enteral feeding is not possible.There is a lack of data supporting specific nutrients in these conditions.Parenteral nutrition is mandatory in case of intestinal failure, at least in the acute period.In patients with short bowel, specific attention should be paid to water and electrolyte supplementation. Currently, the use of growth hormone, glutamine and GLP-2 cannot be recommended in patients with short bowel.

Summary of statements: Parenteral nutrition in Crohn's disease
Subject	Recommendations	Grade	Number
Indication	PN is indicated for patients who are malnourished or at risk of becoming malnourished and who have an inadequate or unsafe oral intake, a non (or poorly) functioning or perforated gut, or in whom the gut is inaccessible. Specific reasons in patients with CD include an obstructed gut, a short bowel, often with a high intestinal output or an enterocutaneous fistula.	B	4.1
Active disease	Parenteral nutrition (PN) should not be used as a primary treatment of inflammatory luminal CD.	A	3.5
	Bowel rest has not been proven to be more efficacious than nutrition per se.
Maintenance of remission	In case of persistent intestinal inflammation there is rarely a place for long-term PN.	B	3.7
	The most common indication for long-term PN is the presence of a short bowel.
Perioperative	Use of PN in the perioperative period in CD patients is similar to that of other surgical procedures.	B	3.6
Application	When indicated, PN improves nutritional status and reduces the consequences of undernutrition, providing there is not continuing intra-abdominal sepsis	B	1
	Specific deficits (trace elements, vitamins) should be corrected by appropriate supplementation.	B	1
	The use of PN in patients with CD should follow general recommendations for parenteral nutrition.	B	1
Route	Parenteral nutrition is usually combined with oral/enteral food unless there is continuing intra-abdominal sepsis or perforation. Central and peripheral routes may be selected according to the expected duration of PN	C	3.2
Type of formula	Although there are encouraging experimental data, the present clinical studies are insufficient to permit the recommendation of glutamine, n-3 fatty acids or other pharmaconutrients in CD.	B	4.3
Undernutrition	Parenteral nutrition may improve the quality of life in undernourished CD patients.	C	3.4
Summary of statements: PN in ulcerative colitis
Subject	Recommendations	Grade	Number
Indication	Parenteral nutrition should only be used in patients with UC who are malnourished or at risk of becoming malnourished before or after surgery if they cannot tolerate food or an enteral feed	B	9
Active disease	There is no place for PN in acute inflammatory UC as means of enabling bowel rest.	B	10
Maintenance of remission	Parenteral nutrition is not recommended.	B	11
Application	Treat specific deficiencies when oral route is not possible.	C	5
Type of formula	The value of specific substrates (n-3 fatty acids, glutamine) is not proven.	B	10.2
Summary of statements: Short bowel syndrome (intestinal failure)
Subject	Recommendations	Grade	Number
Indication	Maintenance and/or improvement of nutritional status, correction of water and electrolyte balance, improvement in quality of life.	B	15
Route
Post-op period	Predictions on the route of nutritional support needed can be made from knowledge of the remaining length of small bowel and the presence or absence of the colon. PN is likely to be needed if the remaining small bowel length is very short (e.g., less than 100 cm with a jejunostomy and less than 50 cm with a remaining colon in continuity). With longer lengths parenteral nutrition, water and electrolytes may be needed until oral/enteral intake is adequate to maintain nutrition, water and electrolyte status.	B	17.1
Adaptation phase	Patients with a jejunostomy have little change in their nutritional/fluid requirements with time. Patients with a colon in continuity with the small bowel have an improvement in absorption over 1–3 years and parenteral nutrition can often be reduced or stopped.	B	17.2
	Dietary counseling is important for those with a retained colon and may facilitate intestinal adaptation. In patients with a jejunostomy and a high output stoma advice on oral fluid intake and drug treatments are vital.
Maintenance/Stabilization	Parenteral nutrition, water and electrolytes (especially sodium and magnesium should be continued when oral/enteral intake is insufficient to maintain a normal body weight/hydration or when the intestinal/stool output is so great as to severely reduce the patient's quality of life. Assuming strict compliance with dietary/water and electrolyte advice, after 2 years, dependency on PN is likely to be long-term.	B	17.3
Type of formula	No specific substrate composition of PN is required per se.	B	16
	Specific attention should be paid to electrolyte supplementation (especially sodium and magnesium).	B	16, 17
	Currently, the use of growth hormone, glutamine or GLP-2 cannot be recommended.	B	18

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Assessment of the psychological effects of genetic screening for hereditary hemochromatosis

Discovery of genetic variants of the HFE gene has made it possible to screen for hereditary hemochromatosis. However, genetic screening raises ethical, legal, social, and psychological questions, which need to be addressed. To assess the psychological impact on individuals undergoing genetic screening for hereditary hemochromatosis and to determine the effects of providing different levels of information to the participants. Male residents, aged 30–50 years (n = 10,993) were invited to a genetic screening for hereditary hemochromatosis. Carriers of the gene variants H63D, S65C, and C282Y were offered additional biochemical screening using serum ferritin and transferrin saturation. Psychological factors were evaluated through questionnaires before and after genetic and biochemical screening. According to genotype, participants were divided into three groups with different risks profiles for having/developing clinical hemochromatosis (at-risk, uncertain risk, no risk). Before completion of the questionnaires, 929 participants received only genetic information and 366 received both genetic and biochemical information. At-risk participants receiving only genetic information generally displayed negative reactions to the test result, whereas participants receiving both genetic and biochemical information were more satisfied and had fewer negative psychological reactions to the test result. Genetic screening is more readily accepted by subjects when genetic information is supported by biochemical measurements, especially in participants with a risk of clinical disease. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Synthesis and structure-activity relationship studies of 2-(N-substituted)-aminobenzimidazoles as potent negative gating modulators ofsmall conductance Ca2+-activated K+ channels

Small conductance Ca2+-activated K+ channels (SK channels) participate in the control of neuronal excitability, in the shaping of action potential firing patterns, and in the regulation of synaptic transmission.SK channel inhibitors have the potential of becoming new drugs for treatment of various psychiatric and neurological diseases such as depression, cognition impairment, and Parkinson's disease. In the present study we describe the structure-activity relationship (SAR) of a class of 2-(N-substituted)-2-aminobenzimidazoles that constitute a novel class of selective SK channel inhibitors that, in contrast to classical SK inhibitors, do not block the pore of the channel. The pore blocker apamin is not displaced by these compounds in binding studies, and they still inhibit SK channels in which the apamin binding site has been abolished by point mutations. These novel SK inhibitors shift the concentration-response curve for Ca2+ toward higher values and represent the first example of negative gating modulation as a mode-of-action for inhibition of SK channels. The first described compound in this class is NS8593 (14), and the most potent analogue identified in this study is the racemic compound 39 (NS11757), which reversibly inhibits SK3-mediated currents with a K(d) value of 9 nM.     

Health literacy levels in outpatients with liver cirrhosis

Abstract

Objective: Health literacy (HL) is a concept covering a range of cognitive and social skills that comprises aspects necessary for patients to navigate in the healthcare system. Our study aimed to investigate HL in patients with liver cirrhosis and determine factors associated with low HL.

Methods: Data were collected among outpatients with cirrhosis (n?=?108), using three dimensions from the Health Literacy Questionnaire. The selected dimensions were: ‘Social support for health’ (Social support scale), ‘Ability to actively engage with healthcare providers’ (Engagement scale), and ‘Understand health information well enough to know what to do’ (Information scale). Unpaired t-test was used to investigate differences on the HLQ scale scores. The effect sizes (ES) were calculated between groups using Cohen’s d.

Results: A total of 105 patients completed the questionnaire. Mean age of respondents was 60.6 years (45.5% females). A majority had alcoholic liver cirrhosis (64.8%) and 36.2% were living alone. Males had a low level of Social support HL (p?p?Conclusions: Male outpatients with liver cirrhosis were found to have low levels of HL, so were patients with low education. In order to effectively communicate and support patients to self-manage their disease, healthcare providers can benefit from including a focus on HL in planning and delivering health care to patients with liver cirrhosis.     

Extrinsic factors modifying expressivity of the HFE variant C282Y, H63D, S65C phenotypes in 1,294 Danish men

This study analysed the influence of extrinsic factors on the phenotypic expression of HFE gene variants in ethnic Danish men. A cohort of 6,020 men aged 30-53 years was screened for HFE C282Y, H63D and S65C variants. Serum iron, serum transferrin, transferrin saturation, and serum ferritin were analysed in 1,452 men and 1,294 men completed a questionnaire on factors, which could influence iron balance. The C282Y allele was present in 5.6%, H63D in 12.8% and S65C in 1.8% of the men. In the entire series, 3% had elevated iron status markers (transferrin saturation ≥50%, ferritin ≥300 μg/L). Self-reported liver disease had an elevating effect and peptic ulcer a lowering effect on iron status markers. Age increased the fraction of men with elevated ferritin from 8.3% at 32-38 years to 16.2% at 46-53 years of age (p = 0.002). Blood donation had a lowering effect on iron status markers (p = 0.0001). Alcohol consumption elevated serum iron and serum ferritin (p = 0.001). Meat consumption had an elevating effect (p = 0.02) and milk consumption a lowering effect (p = 0.03) on serum ferritin. There was no influence of vitamin-mineral tablets on iron status markers. In adjusted logistic regression analysis, the HFE genotype had the highest impact on iron status markers; high alcohol consumption was significantly associated with elevated transferrin saturation. High age and high alcohol consumption were significantly associated with elevated ferritin and high egg consumption and blood donation was significantly associated with normal ferritin levels. In conclusion, the expressivity of HFE variant phenotypes in Danish men was enhanced by alcohol and meat consumption and decreased by milk and egg consumption and blood donation.     

Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis

The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged.     

Implant surface preparation in the surgical treatment of experimental peri-implantitis with autogenous bone graft and ePTFE membrane in cynomolgus monkeys

The aim of the present investigation was to assess the effect of four implant surface preparation methods used in the surgical treatment of experimental peri-implantitis with autogenous bone graft and expanded polytetrafluoroethylene (ePTFE) membrane. The methods were air-powder abrasive unit+citric acid, air-powder abrasive unit, gauze soaked in saline+citric acid, and gauze soaked alternately in chlorhexidine and saline. A total of 64 implants with a titanium plasma-sprayed (TPS) surface was placed in eight cynomolgus monkeys (Macaca fascicularis). After a 3-month period with plaque control, experimental peri-implantitis was induced. A bone loss of 4-6 mm was established after 9-17 months and plaque control was re-implemented. The peri-implantitis defects were surgically exposed, granulation tissue was removed, and each implant surface was prepared by one of the above-mentioned procedures. The defects were then filled with autogenous bone graft particles and covered by an ePTFE membrane. The animals were sacrificed after 6 months. Evaluation by clinical parameters, radiography including quantitative digital subtraction radiography, histology, and stereology did not reveal significant differences between the methods. Almost total bone regeneration and considerable re-osseointegration were obtained irrespective of the method applied. A mean bone-to-implant contact of 39-46% was observed within the defects. Therefore, the present study of implants with a TPS surface in cynomolgus monkeys indicates that the simplest method involving gauze soaked alternately in chlorhexidine and saline should be the preferred implant surface preparation method in the surgical treatment of peri-implantitis involving autogenous bone graft and ePTFE membrane.     

Autogenous bone graft and ePTFE membrane in the treatment of peri-implantitis. I. Clinical and radiographic observations in cynomolgus monkeys

The purpose of the study was to examine the effect of autogenous bone graft particles and expanded polytetrafluoroethylene (ePTFE) membrane in the treatment of peri-implantitis. The treatment outcome was evaluated by clinical and radiographic methods including quantitative digital subtraction radiography. A total of 64 implants with a titanium plasma-sprayed (TPS) surface was inserted in eight cynomolgus monkeys (Macaca fascicularis). After a 3-month healing period with plaque control, experimental peri-implantitis characterized by a bone loss of 4-6 mm was established during 14-22 months. Plaque control was then re-implemented and surgical treatment involving autogenous bone+membrane (B+M), autogenous bone (B), membrane (M), or a conventional flap procedure alone (control) (C) was performed. The animals were killed 6 months after treatment. Healthy peri-implant tissue was established irrespective of the applied surgical procedure. A mean bone gain of 4.7 mm was identified around implants treated with B+M, while, respectively, 4.0, 3.0, and 1.9 mm were recorded within the B, M, and C groups. Quantitative digital subtraction radiography confirmed considerable bone gain within defects treated with autogenous bone with or without membrane coverage. The bone gain, especially for defects treated with B+M, seemed to be almost to the level before development of peri-implantitis. By contrast, 38 and 25% of the defect was on average characterized by bone gain when, respectively, M or C was used alone. The present study of implants with a TPS surface in cynomolgus monkeys thus demonstrates considerable bone regeneration after treatment of experimental peri-implantitis with autogenous bone graft particles with or without ePTFE membrane coverage. Further stereologic and histologic evaluation of the treatment outcome is necessary before final conclusions about the effect of autogenous bone graft and ePTFE membrane can be made.