Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice

Aims/hypothesis 1,25-dihydroxyvitamin D₃, the active form of vitamin D, prevents Type 1 diabetes in non-obese diabetic (NOD) mice. Epidemiological data show a threefold increase in human Type 1 diabetes when vitamin D deficiency was present in the first months of life. To evaluate whether a similar dietary deficiency affects diabetes incidence in NOD mice, we generated NOD mice with vitamin D deficiency in early life.Methods Breeding pairs of NOD mice, as well as their offspring (test mice), were kept in surroundings devoid of ultraviolet light and were fed a vitamin D-depleted diet for 100 days. Mice were followed for 250 days.Results At 250 days, 35% (12/35) male and 66% (22/33) female vitamin D-deficient mice were diabetic compared to 15% (6/40, p=0.05) and 45% (13/29, p<0.01) of the control mice. At 100 days no difference in insulitis was seen, but more vitamin D-deficient mice were glucose intolerant. Higher IL1 expression was detected in islets of vitamin D-deficient mice and their peritoneal macrophages had an aberrant cytokine profile (low IL1 and IL6, high IL15). Thymus and lymph nodes of vitamin D-deficient mice contained less CD4⁺CD62L⁺ cells.Conclusion/interpretation Vitamin D status increases the expression of Type 1 diabetes in NOD mice. Our data in NOD mice, as well as human epidemiological data, point to the importance of preventing vitamin D deficiency in early childhood. Controlling this dietary factor could be an easy and safe way to reduce the incidence of Type 1 diabetes in subjects who are genetically at risk.Abbreviations 1,25(OH)₂D₃ 1,25-dihydroxyvitamin D₃ - 25(OH)D₃ 25-hydroxyvitamin D₃ - BW body weight - HBSS Hanks balanced salt solution - IP interferon-inducible protein - IPGTT intra-peritoneal glucose tolerance test - iNOS inducible nitric oxide synthase - LPS lipopolysaccharide - MCP monocyte chemo-attractant protein - MIP macrophage inflammatory protein - MLR mixed lymphocyte reaction - NOD non-obese diabetic - RPMI Roswell Park Memorial Institute - UV ultraviolet     

Gastric Antisecretory Effects of Compound BP 2-94 (A Histamine H3-Receptor Agonist Prodrug)

Compound BP 2-94 is an orally available prodrugof the histamine H₃-receptor agonist(R)--methylhistamine, which was found to producehigher plasma levels than the parent drug in humans. In the present study radioimmunoassay wascarried out in dogs to investigate the generation of(R)--methylhistamine in vivo after intragastricadministration of the prodrug. The effects of BP 2-94 on gastric acid secretion and on histamine,gastrin, and somatostatin release were alsoinvestigated. After intragastric administration of BP2-94 (10 mg/kg), both the prodrug and(R)--methylhistamine were detected in plasma: plasma levels of(R)--methylhistamine decayed with aT_1/2 of about 1 hr and displayedconcentrations as high as 50-fold the EC₅₀ ofthe drug at the H₃ receptor for at least 2 hr. In conscious dogsprovided with gastric fistula BP 2-94, administered at10 and 30 mg/kg intragastrically, caused adose-dependent inhibition (maximum reduction was about80%) of the acid secretion stimulated by2-deoxy-D-glucose, whereas (R)--methylhistamine(20 mg/kg, intragastrically) was ineffective. BP 2-94(30 mg/kg, intragastrically) significantly reduced theacid secretion stimulated by bombesin, while leavingunaffected that induced by histamine. The increase inplasma gastrin levels induced by 2-deoxy-D-glucose,bombesin or a test meal was not significantly modified by BP 2-94 (30 mg/kg, intragastrically). Inanesthetized dogs BP 2-94 (30 mg/kg, intragastrically)significantly reduced histamine release detected in theportal vein under bombesin infusion, whereas it did not modify gastrin and somatostatin plasmalevels. These data indicate that BP 2-94 is a goodprodrug of (R)--methylhistamine in the dog,causing an efficacious reduction of acid secretioninduced by both 2-deoxy-D-glucose and bombesin.Moreover, the study of paracrine and hormonal mediatorsof acid secretion confirms that the main mechanismunderlying inhibition of acid production induced byH₃-receptor activation is the impairment of histaminerelease from gastric histaminocytes (possiblyenterochromaffin-like cells).     

Prevention and therapy of osteoporosis: the roles of plain vitamin D and alfacalcidol

Severe vitamin D deficiency was identified only in the first decades of the last century as the most common aetiology of rickets in children and osteomalacia in adults. It was later shown that vitamin D is not, as had been supposed, the biologically active principle for healing bone disease but must be hydroxylated in the liver and then finally in the kidney to become 1,25-dihydroxy-cholecalciferol, a biologically highly active renal hormone. This study reviews the various principles, mechanisms, and approaches to the treatment of different forms of osteoporosis using vitamin D, alfacalcidol, and calcitriol therapy regimens.     

Serumglykoproteine beim Diabetes mellitus; quantitative immunologische Bestimmung von saurem α1-Glykoprotein,Gc, α2-Makroglobulin und Hämopexin bei Diabetikern mit und ohne Angiopathien

Zusammenfassung 1. Bei Diabetikern mit und ohne Gefäßkomplikationen wurden die Serumkonzentrationen des sauren ₁-Glykoproteins, der gruppen-spezifischen Komponente (Gc), des ₂-Makroglobulins und des Hämopexins mit der Immuno-Diffusions-Methode nachMancini und Mitarb. quantitativ bestimmt. — 2. Das ₂- Makroglobulin ist bei Diabetikern vermehrt, bei 276 Patienten fand sich ein Mittelwert von 242 mg% gegenüber einem Mittelwert von 186 mg% bei 98 nicht-diabetischen Blutspendern. Diese Differenz ist statistisch hochsignifikant. Der Konzentrationsanstieg ist bei jugendlichen Diabetikern stärker ausgeprägt als bei Altersdiabetikern. Bei Patienten mit Retinopathie findet sich eine deutlichere Vermehrung als bei Patienten ohne Retinopathie. Auch geht der Anstieg des ₂-Makroglobulins mit dem Schweregrad arteriosklerotischer Veränderungen der peripheren Gefäße parallel. — 3. Die Konzentrationen des sauren ₂-Glykoproteins und der gruppen-spezifischen Komponente sind in Seren von Diabetikern gegenüber gesunden Blutspendern nur unwesentlich vermehrt. — 4. Die Hämopexin Konzentration ist bei Diabetikern mit einem Mittelwert von 92 mg% gegenüber gesunden Blutspendern mit einem Mittelwert von 77 mg% gering erhöht; dieser geringe Unterschied ist statistisch hochsignifikant.

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Serum, glycoproteins in diabetes mellitus; quantitative immunological determination of acid ₁-glycoprotein, Gc, ₂-macroglobulin and haemopexin in diabetics with and without angiopathy

Summary 1. Serum concentrations of acid ₁-glycoprotein, Gc, ₂-macroglobulin and haemopexin were determined in diabetics with and without vascular complications by the immunological assay method ofMancint and co-workers. — 2. ₂-macroglobulin concentrations were increased in sera of diabetics. The mean value was 242 mg% in 276 patients compared with the mean value of 186 mg% in a sample of 98 healthy blood-donors. This difference is statistically highly significant. The increase was more pronounced in juvenile diabetes than in late-onset diabetes. The increase was also more pronounced in patients with retinopathy than in patients without retinopathy. There was also an increase of ₂- macroglobulin concentrations in relation to the degree of arteriosclerotic changes of the peripheral vessels. — 3. Serum concentrations of acid ₁-glycoprotein and Gc were only slightly increased in diabetics compared with blood-donors. — 4. There was a small, but statistically highly significant increase of haemopexin concentrations in sera of diabetics. The mean value in 243 diabetics was 92 mg%, in 15 healthy blood-donors a mean value of only 77 mg% was found.

Mit Unterstützung durch die Deutsche Forschungsgemeinschaft     

Cooperative effects of gamma-interferon and 1α, 25-dihydroxyvitamin D3 on in vitro differentiation of the blast cells of RAEB and RAEB-T

Summary We added recombinant human gammainterferon (-IFN) and 1 , 25-dihydroxyvitamin D₃ (1 , 25 (OH)₂D₃) to the bone marrow cells from six patients with RAEB or RAEB-T in liquid suspension cultures. After cultivation for 7 to 9 days, numerical, morphological and functional changes of the cells were assessed. -IFN and 1 , 25 (OH)₂D₃ additively suppressed cell growth, especially the number of blast cells decreased. The expression of -naphthylbutyrate esterase (NBE) activity appeared to be promoted but that of naphthol AS-D chloroacetate esterase (NAE) activity was apparently suppressed by the addition of -IFN and/or 1 , 25 (OH)₂D₃. The percentage of NBT reduction-positive cells and latex-phagocytizing cells was only slightly increased by both agents. These results indicate that -IFN and 1 , 25 (OH)₂D₃ cooperate to induce monocytoid differentiation of the patients' blast cells. Combination therapy with both agents merits further study.     

Reversion of the steroid-induced decrease of serum osteocalcin with sodium fluoride

Summary Osteopenia observed in corticotherapy is due, among other causes, to a decrease in bone formation as can be shown by a steroid-induced osteocalcin decrease. Although various treatments have been proposed there is no agreement as to which one is the best. Two such treatments, sodium fluoride and vitamin D administration increase osteocalcin levels. We treated a group of 12 patients under corticoid therapy (mean dose 16 mg per day) with 50 mg/day p.o. sodium fluoride, and determined osteocalcin levels before and two weeks after sodium fluoride treatment. Similarly, another group of 9 patients with a similar mean steroid dose was treated with 0.5 /day of 1(OH)₂D3 in order to assess the effect of this vitamin on osteocalcin and to determine which was the best treatment. Both groups were compared with respective control groups. A significant osteocalcin increase was observed in the control groups (p<0.001); similar significance was observed in the sodium fluoride group, whereas a lower significance (p<0.01) was observed in the vitamin D group. These results suggest that sodium fluoride could be more effective than vitamin D in the treatment of steroid-induced osteopenia.     

α1-antitrypsin deficiency and liver disease

Summary ₁-Antitrypsin (₁AT) deficiency, one of the most common lethal hereditary disorders among Caucasians, is associated with emphysema in adults, while in children it is associated with liver disease. Produced in the liver and released into the plasma, ₁AT serves as the body's major inhibitor of neutrophil elastase, a powerful proteolytic enzyme capable of degrading extracellular structural proteins. The pathogenesis of the liver disease associated with ₁AT deficiency is not as well understood, but is clearly linked to specific mutations in coding exons of the ₁AT gene, and the resulting accumulation of ₁AT within hepatocytes. At present, therapy for the liver disease associated with ₁AT deficiency is symptomatic, with liver transplantation as a last resort. New strategies are being developed to suppress the accumulation of ₁AT by transferring the normal gene into the liver.     

Plasma 6-keto-PGF1α, thromboxane B2 and PGE2 in Type 1 (insulin-dependent) diabetic patients during exercise

Summary The capacity of prostacyclin production determined as plasma 6-keto-PGF₁ was investigated in 12 Type 1 (insulin-dependent) diabetic patients with a median duration of diabetes of 14 years during ordinary metabolic control. Using high pressure liquid chromatography preceding radioimmunoassay, the plasma concentration of 6-keto-PGF₁, the stable metabolite of prostacyclin, was determined at rest and after a standardised bicycle exercise test. The plasma 6-keto-PGF₁ in diabetic patients at rest did not differ from that of 25 healthy volunteers; 2.9 pg/ml (range<0.2–15.3) versus 1.7 pg/ml (range<0.2–16.6). During the exercise test plasma 6-keto-PGF₁ increased significantly in the diabetic patients as well as in the control group (p< 0.05). The increment of 6-keto-PGF₁ in the diabetic patients was neither related to the metabolic regulation, duration of diabetes nor to changes in platelet volume, platelet number or the production of thromboxane B₂ and prostaglandin E₂. Our results do not support the hypothesis that Type 1 diabetic patients have a decreased capacity of prostanoid production, as suggested from in vitro studies.     

Serum Levels of α1-Antitrypsin Predict Phenotypic Expression of the α1-Antitrypsin Gene

We conducted a retrospective analysis to determine if both ₁-antitrypsin serum level and phenotype need be studied when evaluating children for ₁-AT deficiency. We collected data from patients less than 19 years old who had both serum ₁-AT level and phenotype determined over a 9-year period (January 1992–December 2000). Eighty-eight patients were identified and 15 had the PiZZ phenotype. The serum ₁-AT level was below normal (normal 85–215 mg/dl) in all 15 PiZZ patients. Seventy-two of 73 non-PiZZ patients had normal or above normal serum levels. The sensitivity of the serum ₁-AT level was 100%, and the specificity was 99%. The serum ₁-AT level had a positive predictive value of 94% and a negative predictive value of 100%. We conclude that serum ₁-AT levels are highly predictive of the PiZZ phenotype. Determination of the serum ₁-AT level alone should be the initial test when evaluating for ₁-AT deficiency.     

Differential Effect of Nitric Oxide Inhibition as a Function of Preservation Period in Pancreas Transplantation

The role of nitric oxide, produced duringreperfusion as a function of preservation time, in thedevelopment of the inflammatory process in pancreastransplantation has been explored. For this purpose, the effect of nitric oxide synthase inhibition,as well as 6-keto-prostaglandin F₁,leukotriene B₄, and lipoperoxidation levelswere evaluated in an experimental model of rat pancreastransplantation after different periods of cold preservation.The results show posttransplantation increases in6-keto-prostaglandin F₁, leukotrieneB₄, and lipoperoxidation levels in pancreatictissue and in plasma lipase. When ischemia was induced for 30 min, nitricoxide synthase inhibition prevented these increases, andL-arginine was able to reverse this effect. By contrast,nitric oxide synthase inhibition has no effect when ischemia was prolonged for 12 hr. Insummary, this study suggests that, during reperfusion,nitric oxide modulates 6-keto-prostaglandinF₁ synthesis, lipoperoxidation levels,and the development of pancreatic injury but only whenthe ischemic period is quite short.     

Prevention of post-menopausal bone loss with 1α-hydroxy vitamin D3 a three-year prospective study

Summary An open and controlled prospective study was used to assess the preventive efficiency of 1-hydroxy vitamin D₃ (1 (OH) Vit. D₃) on post-menopausal vertebral bone loss. Of the 36 patients included in the study, 25 completed two years of treatment with 1 g/day of 1 (OH) Vit. D₃ and 500 mg of calcium. The vertebral bone mineral density measured by dual photon absorptiometry did not vary in the treated group, whereas it decreased significantly in the control group at the end of the 2 years. At two years, withdrawal of treatment led to a signficant bone loss, whereas bone mass remained stable in a subgroup of patients who underwent a third year of treatment with 1 (OH) Vit. D₃. Overall, tolerance was satisfactory. However, urinary calcium increased significantly during treatment and one third of the patients developed hypercalciuria 7.5 mmoles/24 h. No variation in either serum calcium or creatinine levels was noted. These results indicate that 1 (OH) Vit. D₃ could be useful in preventing post-menopausal bone loss provided it was complemented by regular monitoring of urinary calcium excretion.     

Evaluation of the relationship between serum apelin levels and vitamin D and mean platelet volume in diabetic patients

Objectives

It was reported that Vitamin D deficiency was associated with a greater risk of cardiometabolic diseases, obesity, impaired glucose tolerance and diabetes mellitus type 2, arterial hypertension, and dyslipidemia. Apelin is an adipocytokine suspected to have a role in skeletal muscle glucose utilization and glycemic regulation which may be a promising treatment modality for diabetes. It was recently reported that increased mean platelet volume (MPV) was emerging as an independent risk factor for thromboembolism, stroke, and myocardial infarction. In patients with diabetes, MPV was higher compared with the normal glycemic controls; in addition, it has been proposed that an increase in MPV may play a role in the micro- and macro-vascular complications related to diabetes. We postulated that deficiency in Vitamin D levels might be associated with higher MPV and lower serum apelin levels leading a further increase in insulin resistance in diabetic patients. So, we aimed to investigate Vitamin D levels, MPV and serum apelin levels in diabetic patients and their correlations between each other.

Materials and method

This is a cross-sectional study design. Seventy-eight patients with Diabetes Mellitus type 2, admitted to our outpatient clinic of internal medicine department at Bezmialem Vakif University, were included in our study. Forty-one patients were female; 37 patients were male. Serum apelin levels, fasting glucose levels, urea, creatinine, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting serum insulin level, HbA1_c, free T3, free T4, TSH, vitamin D (25-OH Vitamin D) and complete blood counts were analyzed in all subjects.

Results

Each sex was analyzed separately. We found that a positive correlation existed between serum apelin levels and BMI in female patients. (r: 0.380, P: 0.014) There was also a significant positive correlation between MPV and HbA1_c and fasting glucose levels and a negative correlation between MPV and PLT. (r: 0.377, P: 0.021; r: 0.395, P: 0.014; r: −0.401, P: 0.011; respectively) We failed to show a significant relationship between serum vitamin D levels, serum apelin levels and MPV in patients with diabetes mellitus type 2.

Conclusion

We failed to show an association between vitamin D, apelin and MPV higher volumes of which may have a role in cardiovascular complications related to diabetes by increasing platelet activation.     

Effects of analogs of 1,25(OH)2 Vitamin D3 on the proliferation and differentiation of the human chronic myelogenous leukemia cell line,RWLeu-4

Summary We evaluated the proliferative and differentiative effects of analogs of 1,25(OH)₂ vitamin D₃ [1,25(OH)₂D₃] on a chronic myelogenous leukemia cell line, RWLeu-4, which is growth-inhibited and differentiates in response to 1,25(OH)₂D₃ (ED₅₀-3-10 nM). Side-chain-fluorinated analogs were more potent (ED₅₀=0.7–2 nM) while most of those with altered saturation of the D ring or side-chain carbon-carbon bonds were equally or less effective than 1,25(OH)₂D₃. However, the two analogs with either two additional double bonds or an extra double and triple bond in the D ring had greater antiproliferatiive activity [1,25(OH)₂-16,23-diene D₃ (ED₅₀=2.7 nM) and 1,25(OH)₂-16-ene-23-yne D₃ (ED₅₀=0.7 nM)]. Since the latter of these has been reported to be less potent at mobilizing calcium than 1,25(OH)₂D₃, it (or a similar compound) may be a candidate for clinical use as an antineoplastic agent.Abbreviations 1,25(OH)₂D₃ 1,25-(OH)₂ vitamin D₃ - CML chronic myelogenous leukemia - NBT nitroblue tetrazolium - ED₅₀ 50% effective dose - IC₅₀ 50% inhibitory concentration     

Isolierung und Charakterisierung des schwangerschafts-assoziierten α2-Glykoproteins (α2PAG)

Zusammenfassung Eine Methode zur Isolierung des schwangerschafts-assoziierten ₂-Glykoproteins ( ₂PAG) aus dem Extrakt menschlicher Plazenten mit Hilfe von Immunadsorbentien wird beschrieben.Von dem gereinigten Protein sind die physikalischen Eigenschaften und die chemische Zusammensetzung ermittelt worden: ₂PAG, sedimentiert mit 11,5 S, hat offensichtlich ein Molekulargewicht von 360000 und ist aus Untereinheiten aufgebaut, die ein Molekulargewicht von 180000 haben und durch Schwefelbrücken zusammengehalten werden. Der isoelektrische Punkt liegt um pH 4,7 und der Extinktionskoeffizient (E _1cm ^1% ) beträgt 9,7 bei 277 nm. Der Anteil der Kohlenhydrate im Molekül wurde zu 12,1% bestimmt (Hexosen 6%, Hexosamin 3,7%, Fucose 0,06% Neuraminsäure 2,4%). Auch eine Analyse der Aminosäuren wird mitgeteilt. Das durch Immunadsorption gereinigte ₂PAG ist zur Eichung eines Standards und zur Absolutbestimmung der Konzentration des Proteins in Seren verwendet worden.

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Summary A method using immunoadsorbents for the isolation of pregnancy-associated ₂-glycoprotein ( ₂PAG) from the extract of human placentae is described.The physical properties and the chemical composition of the purified protein are determined: ₂PAG sediments with 11,5 S, has a molecular weight of 360000 daltons and is composed of subunits having a molecular weight of 180000, which are held together by disulfide bonds. The isoelectric point was found to be pH 4,7 and the extinction coefficient (E _1cm ^1% ) was determined to be 9,7 at 277 nm. The carbohydrate content of the molecule amounts to 12,1% (hexose 6,0%, hexosamine 3,7%, fucose 0,06%, sialic acid 2,4%). An analysis of the amino acids is reported, too. The purified ₂PAG was used to determine the absolute concentrations of this protein in a reference standard and in sera.

     

Vitamin D deficiency, vitamin D receptor gene polymorphisms and cardiovascular risk factors in Caribbean patients with type 2 diabetes

Aim

The prevalence of diabetes in the French West Indies is three times higher than in mainland France. We aimed to assess the associations between vitamin D deficiency, vitamin D receptor (VDR) gene polymorphisms and cardiovascular risk factors in Caribbean patients with type 2 diabetes (T2D).

Methods

In this cross-sectional study of 277 patients, 25-hydroxyvitamin D was measured by radioimmunoassay. FokI, BsmI, ApaI and TaqI single nucleotide polymorphisms (SNPs) of the VDR gene were genotyped. Analysis of covariance and logistic regression were performed.

Results

The study included 76 patients of Indian descent and 201 patients of African descent. The prevalence of vitamin D deficiency (< 20 ng/mL) was 42.6%. When patients were classified into groups with (G1) and without (G2) vitamin D deficiency, there were no significant differences in age, systolic blood pressure, low-density lipoprotein cholesterol and HbA_1c, although body mass index was significantly higher in G1. Vitamin D deficiency was significantly associated with increased diastolic blood pressure and triglyceride levels, and reduced high-density lipoprotein cholesterol (P < 0.05). Prevalence of vitamin D deficiency was decreased in patients carrying the f allele of FokI (OR: 0.52; P = 0.02) and the aa genotype of ApaI (OR: 0.46; P = 0.05). BsmI and TaqI SNPs were not associated with vitamin D deficiency.

Conclusion

The rate of vitamin D deficiency was high in our T2D patients, and was associated with the VDR gene FokI and ApaI polymorphisms and cardiovascular risk profile. Measurements of vitamin D may help to detect T2D patients with cardiovascular risk, and VDR polymorphisms might explain why vitamin D deficiency is so frequently seen in some T2D patients.     

β1-Antitrypsin deficiency and chronic pancreatitis

Summary ₁-Antitrypsin deficiency is a genetic disorder commonly associated with pulmonary and hepatic injury. Low serum levels of this glycoprotein result in an imbalance between circulating protease and protease inhibitors, which is thought to play a role in the development of emphysema. In recent studies, a protease-to-protease inhibitor imbalance in patients with ₁-antitrypsin deficiency was thought to be a mechanism contributing to the development of chronic pancreatitis. The heterozygous phenotype and low levels of this glycoprotein have been reported to occur more frequently in patients with chronic pancreatitis than in healthy controls. We report a patient with Pi-SS phenotype ₁-antitrypsin deficiency and chronic pancreatitis complicated by recurrent pancreatic pseudocysts and chronic abdominal pain. Our case supports the association between chronic pancreatitis and ₁-antitrypsin deficiency. Furthermore, this case provides support for the use of pancreatic stent drainage in the management of intractable abdominal pain in patients with chronic pancreatitis and a dominant stricture.     

Should we monitor vitamin B<Subscript>12</Subscript> levels in patients who have had end-ileostomy for inflammatory bowel disease?

Background and aims We examined whether vitamin B₁₂ levels are low following surgery in those patients who have had end-ileostomy for inflammatory bowel disease.Patients and methods This prospective observational study used the database of a university teaching hospital to identify patients with inflammatory bowel disease with an end-ileostomy constructed more than 30 months previously. Precise diagnosis, disease distribution and details of their surgery were collected from case notes of the 39 eligible patients (18 Crohns disease, 17 ulcerative colitis, 4 indeterminate colitis). Mean duration since ileostomy formation was 12.53 years. Patients found to be vitamin B₁₂ deficient underwent further investigations to ascertain the cause of their vitamin B₁₂ deficiency (<150 ng/l).Results There was no significant difference between serum vitamin B₁₂ levels in patients with Crohns disease and those in patients with ulcerative colitis following end ileostomy formation. Two patients (5.1%) were identified as having vitamin B₁₂ deficiency. One of these had had a panproctocolectomy for Crohns disease, followed by subsequent resection for ileal obstruction and ongoing small intestinal disease. The other had had colectomy for ulcerative colitis, in whom no cause other than the ileostomy was found for the vitamin B₁₂ deficiency. There was no significant correlation between serum vitamin B₁₂ levels and duration of ileostomy overall or in the disease subgroups.Conclusion We do not recommend routine screening for vitamin B₁₂ deficiency in this group of patients unless they have undergone additional small bowel resection or have ongoing small bowel inflammation.     

Low Endogenous Prostaglandin E2 Predisposes to Relapsing Inflammation in Experimental Rat Enterocolitis

Intramural injection ofpeptidoglycan-polysaccharide (PG-PS) induces acuteenterocolitis that spontaneously relapses in Lewis butnot Fischer rats. Interleukin-1 (IL-1) and tumornecrosisfactor- (TNF-) induce prostaglandin E₂(PGE₂) secretion, which inhibits secretion ofthese cytokines by macrophages, suggesting an inhibitoryfeedback mechanism. We postulate that Lewis ratsusceptibility to relapse is due to an imbalance betweenprotective prostaglandins and cytokines. Female Fischerand Lewis rats were injected with PG-PS (37.5 g/g)or human serum albumin intramurally. Tissue IL-1 and PGE₂ immunoreactivities andmyeloperoxidase (MPO) activity were determined.Relapsing rats had lower PGE₂ andPGE₂:IL-1 ratios than nonrelapsingrats (P < 0.05). In Fischer rats, 2 mg/kg/day indomethacinpotentiated cecal MPO and IL-1 concentrationsabove PG-PS alone (P < 0.05). Misoprostol treatmentblocked PG-PS-induced IL-1 and MPO and inhibited the potentiating effect of indomethacin on MPOand IL-1 (P < 0.05). In conclusion, increasedendogenous PG may be protective against relapsinginflammation in PG-PS induced enterocolitis, at least partially via inhibition of proinflammatorycytokines. An imbalance between protectiveprostaglandins and proinflammatory cytokines may beinvolved in the pathogenesis of chronic relapsinginflammation in genetically susceptible hosts.     

Vitamin D deficiency amongst minority ethnic groups in the UK: a cross sectional study

Background

Vitamin D deficiency is common amongst minority groups in Britain but its magnitude amongst South Asian (SA) and Black African-Caribbean (AC) groups is not well defined. The steroidal, endocrine nature of vitamin D provides it with a putative link with cardiovascular disease (CVD), and we hypothesised that aberrant levels of this hormone would reflect a heightened risk of CVD in these ethnic groups.

Methods

SA (n = 1105, 57% male) and AC (n = 748, 51% male) were recruited as part of a community heart failure study from 20 primary care practices, Birmingham, UK. Vitamin D₂/D₃ levels were measured to determine rates of total vitamin D status, which were age/sex adjusted.

Results

The majority of SAs had severe vitamin D deficiency (42.2%, 95% CI: 39.2–45.1), which was more frequent than in AC (12.5%, 10.2–14.9, p < 0.001. Vitamin status in SA and AC was unrelated to the presence of osteoporosis, and on multivariate analysis of SA, vitamin D levels were independently associated with age (β = 0.18, p < 0.001), haemoglobin (β = 0.12, p = 0.002), and negatively with alkaline phosphatase (a marker of bone mineralisation, β = − 0.11, p = 0.022). Amongst AC, vitamin D was independently associated with having ever smoked (β = − 0.13, p = 0.006) and systolic blood pressure (β = 0.10, p = 0.038).

Conclusions

Vitamin D deficiency is a frequent biochemical observation amongst minority groups in Britain but the clinical significance is unclear, and ethnically specific. A proportionate susceptibility to bone disease is not apparent in either minority group.     

Regulation of hepatocyte albumin and α1-acid glycoprotein secretion by monokines,dexamethasone, and nitric oxide synthase pathway: Significance of activated liver nonparenchymal cells

To clarify the mechanism involved in regulating the secretion of albumin and ₁-acid glycoprotein by rat hepatocytes, we studied hepatocyte culture and cocultures of hepatocyte and liver nonparenchymal cells. The secretion of ₁-acid glycoprotein by hepatocytes was stimulated and that of albumin was inhibited by combinations of dexamethasone and monokines, especially by dexamethasone and interleukin-6. The secretion of these proteins was equally inhibited during stimulation by lipopolysaccharide in cocultures. The inhibitory effect of sinusoidal endothelial cells was smaller than that of Kupffer cells. This inhibition was partially aboslished by blocking the nitric oxide synthase pathway in cocultured cells and was completely abolished by dexamethasone. In conclusion, the secretion of albumin and ₁-acid glycoprotein by hepatocytes was regulated by monokines, dexamethasone, and the inducible nitric oxide synthase pathway in hepatocytes and liver nonparenchymal cellsin vitro.