Prevalence of vertebral alterations and the effects of calcium and vitamin D supplementation on calcium metabolism and bone mineral density after gastrectomy.

BACKGROUND: Bone disease is common after gastrectomy, resulting in decreased bone mass and an increased risk of fracture. No proven therapy is currently available. METHODS: Serum markers of calcium metabolism in 98 patients after partial or total gastrectomy were compared with those in 30 age- and sex-matched healthy controls. Patients with disorders of calcium metabolism were investigated by conventional radiography and single-energy computed tomography of the spine. Forty patients participated in a 1-year follow-up study to investigate the effects of vitamin D and calcium supplementation on calcium metabolism and bone mineral density. RESULTS: Altered serum markers of calcium and phosphate metabolism were observed in 77 (79 per cent) of 98 patients. Sixty (79 per cent) of these had vertebral alterations. Vertebral fractures were detected in 22 patients, grade I vertebral deformities in 50 patients, grade II deformities in 22 patients and osteopenia (Z-score less than - 1) in 30 patients. Calcium and vitamin D supplementation resulted in an increase in 25-hydroxy-vitamin D (P < 0.001), 1,25-dihydroxy-vitamin D (P = 0.048) and osteocalcin (P = 0.045), whereas levels of parathyroid hormone were decreased (P = 0.007). Bone mineral density did not change over time. CONCLUSION: Disturbances of calcium and bone metabolism are common after gastrectomy. Calcium and vitamin D supplementation normalized levels of markers of calcium metabolism and might have prevented age-related bone mass loss, although it did not increase bone mineral density after 1 year.

The aetiology of sporadic adult-onset ataxia.

The nosology and aetiology of sporadic adult-onset ataxia are poorly understood. The aim of the present study was to answer the following questions: (i) How many sporadic ataxia patients have a genetic cause? (ii) How many sporadic ataxia patients suffer from multiple system atrophy (MSA)? (iii) Is there a specific association between sporadic ataxia and serum anti-glutamic acid decarboxylase (GAD) or antigliadin antibodies? and (iv) What are the clinical features of patients with unexplained sporadic ataxia? The study was performed in 112 patients who met the following inclusion criteria: (i) progressive ataxia; (ii) onset after 20 years; (iii) informative and negative family history (no similar disorders in first- and second-degree relatives; parents older than 50 years); and (iv) no established symptomatic cause. Thirty-two patients (29%) met the clinical criteria of possible (7%) or probable (22%) MSA. The Friedreich's ataxia mutation was found in five patients (4%), the spinocerebellar ataxia (SCA) 2 mutation in one (1%), the SCA3 mutation in two (2%) and the SCA6 mutation in seven (6%). The disease remained unexplained in 65 patients (58%). We did not detect anti-GAD antibodies in any of our patients. Antigliadin antibodies were present in 14 patients, 10 patients with unexplained ataxia (15%) and 4 patients with an established diagnosis (9%). Patients with unexplained sporadic ataxia had a median disease onset of 56.0 years. Decreased vibration sense (62%), decreased or absent ankle reflexes (40%), increased ankle reflexes (39%), dysphagia (38%) and extensor plantar responses and/or spasticity (34%) were the most frequent extracerebellar symptoms. Compared with MSA, disease progression was significantly slower.

Sporadic cerebellar ataxia associated with gluten sensitivity.

A total of 104 patients with sporadic cerebellar ataxia were tested for antigliadin and antiendomysium antibodies. Twelve individuals (11.5%) with gluten sensitivity underwent duodenal biopsy and extensive clinical, electrophysiological, neuropsychological, radiological and laboratory investigations including human leucocyte antigen (HLA) typing. Two patients showed typical changes of gluten-sensitive enteropathy with crypt hyperplasia and mucosal flattening. In five patients, the intraepithelial lymphocyte count was elevated. Sporadic ataxia with gluten sensitivity was found to be tightly linked to the HLA DQB1*0201 haplotype (70%). Neurological symptoms were not related to hypovitaminosis or inflammatory CSF changes. The clinical syndrome was dominated by progressive cerebellar ataxia with ataxia of stance and gait (100%), dysarthria (100%) and limb ataxia (97%). Oculomotor abnormalities were gaze-evoked nystagmus (66.7%), spontaneous nystagmus (33.3%), saccade slowing (25%) and upward gaze palsy (16.7%). Extracerebellar features also included deep sensory loss (58.3%), bladder dysfunction (33.3%) and reduced ankle reflexes (33.3%). In accordance with clinical findings, electrophysiological investigations revealed prominent axonal neuropathy with reduced amplitudes (50%) and abnormal evoked potentials (58.3%). On neuropsychological testing, patients presented with moderate verbal memory and executive dysfunction. All patients had evidence of cerebellar atrophy on MRI. We conclude that sporadic ataxia may be associated with positive antibodies against gliadin. Nevertheless, mucosal pathology does not represent an obligatory condition of ataxia with gluten sensitivity. The fact that the disease is strongly associated with the same HLA haplotypes found in coeliac disease not only demonstrates coeliac disease and ataxia with gluten sensitivity to be part of the same disease entity but supports the hypothesis of an immunological pathogenesis of cerebellar degeneration.

Multicentre evaluation of a new point-of-care test for the quantitative determination of D-dimer.

Imprecision studies, interference testing and multicentre method comparisons using patient samples were carried out with of a new point-of-care test for D-dimer (CARDIAC D-Dimer). The CV of the within-series and the day-to-day imprecision with blood samples and control materials were between 7% and 13%. Compared with Tina-quant D-Dimer, CARDIAC D-Dimer showed a good correlation and accuracy (n=353; r=0.91; y=1.06x-0.03), compared with STA LIATEST D-Dimer some poorer accuracy (n=304; r=0.91; y=1.12x-0.03). No interference was detected for different hematocrit values (16% to 51%) and in investigations with hemoglobin (up to 0.13 mmol/l), biotin (up to 30 microg/l), bilirubin (up to 340 micromol/l), intralipid (up to 31.1 mmol/l) and rheumatic factor (up to 79 IU/ml). Overdosing or underdosing by 10 microl did not affect the test result. The diagnostic sensitivity of CARDIAC D-Dimer for the detection of acute venous thromboembolic diseases was 100% in our study. With CARDIAC D-Dimer reliable quantitative D-dimer results can be easily obtained. Because of the good analytical and clinical agreement with Tina-quant D-Dimer, it should be suitable for ruling out venous thromboembolic diseases.

Serial transplants of DMBA-induced mammary tumors in Fischer rats as a model system for human breast cancer. VI. The role of different forms of tumor-associated stress for the regulation of pineal melatonin secretion.

Previous studies on human breast cancer patients showed a decline in circulating melatonin levels corresponding to primary tumor growth and an increase when relapse occurred. The aim of the current investigation was to study in an experimental model possible mechanisms involved. Inbred female F344 Fischer rats were used for serial passages derived from a chemically induced mammary adenocarcinoma. Animals with slow-growing carcinosarcomas at passage 2 showed a significant elevation of nocturnal urinary melatonin (23. 00-07.00 h; +50%, p < 0.05) and a nominal increase in plasma melatonin (+41%; 02.00-03.00 h). By contrast, these parameters were significantly depressed in animals with fast-growing sarcomas (urinary melatonin: -22%, p < 0.025; plasma melatonin: -56%, p < 0. 01). At passage 2 nocturnal pineal N-acetylserotonin (02.00-03.00 h) was significantly enhanced (+62%, p < 0.05) probably due to an increased activity of serotonin-N-acetyltransferase (SNAT, +45%), the rate-limiting step of pineal melatonin biosynthesis converting serotonin to N-acetylserotonin. The activation of SNAT may be due to a stimulation of the sympathetic nervous system (urinary noradrenaline; NA: +243%, p < 0.005) when the cellular immune system responded towards tumor growth (urinary biopterin, +214%, p < 0.005). At passage 12 SNAT and N-acetylserotonin were unaffected but a depletion of plasma tryptophan (-34%, p < 0.0001), the precursor amino acid of melatonin, was found. The marginal decline in pineal serotonin (-18%, p < 0.05) disputes that the drastic depletion in circulating melatonin (-56%, p < 0.01) can be exclusively explained by a reduced availability of tryptophan. Therefore, the involvement of an additional mechanism has to be postulated, such as a degradation of melatonin via indoleamine 2,3-dioxygenase, an extrahepatic enzyme which has been detected in tumor tissue and is related to tryptophan 2,3-dioxygenase (TDO). TDO occurs only in the liver, is highly specific for L-tryptophan and is induced by glucocorticoids which would account for the observed depletion of plasma tryptophan resulting from a tumor-associated activation of the hypothalamo-pituitary-adrenal axis (urinary corticosterone +208%, p < 0.01). These findings present first explanations for the previously observed modulation of melatonin levels in cancer patients but also illustrate the high degree of complexity of mechanisms involved in the interactions between tumor growth and the immunoneuroendocrine system.

Comparative long-term experience with immunoadsorption and dextran sulfate cellulose adsorption for extracorporeal elimination of low-density lipoproteins.

Two low-density lipoprotein (LDL) apheresis methods allowing a specific extracorporeal removal of atherogenic lipoproteins from plasma were compared concerning their efficacy and safety in the long-term therapy of severe familial hypercholesterolemia. Five patients were treated with immunoadsorption (IMA) at weekly intervals over 3 years each, and three patients received weekly therapy with dextran sulfate cellulose adsorption (DSA) for up to 2 years. The mean plasma volume processed per session to decrease total cholesterol to a target level of 100-150 mg/dl at the end of LDL apheresis was significantly lower in DSA than in IMA: 143% vs. 180% of the individual plasma volume. Both LDL apheresis procedures achieved a mean acute reduction of plasma LDL cholesterol by more than 70%. The average interval concentrations of plasma LDL cholesterol obtained without concomitant lipid-lowering medication were 151 +/- 26 mg/dl compared to 351 +/- 65 mg/dl at baseline in the IMA-treated patients and 139 +/- 18 mg/dl compared to 359 +/- 48 mg/dl at baseline in the DSA-treated patients. Two patients from the DSA group died after 2 years of study participation due to a stroke and a sudden cardiac death several days after the last plasma therapy. Treatment-related side effects were infrequent. Long-term therapy with IMA and DSA was associated with symptomatic improvement of coronary artery disease and mobilization of tissue cholesterol deposits. Analysis of coronary angiograms after 3 years of weekly LDL apheresis with IMA revealed in five patients nearly identical atherosclerotic lesions without definite regression or progression.

Preservation studies using acinar cell cultures of the pancreas: stimulation of amylase/lipase release before and after hypoxic stress.

In clinical pancreas transplantation, postischemic (i. e. postpreservation) transplant pancreatitis is a major problem in some cases but also an interesting model of pancreatitis. In this study, the effect of simulated organ preservation of isolated acinar cells was evaluated as regards enzyme release (basic and cerulein-stimulated), using common preservation solutions as the incubation media. Primary pancreas acinar cell cultures were isolated from the pancreas of male Wistar rats using the modified method of Amsterdam and Jamieson. After resting the cells in culture flasks for 1 week, monolayer cultures were obtained. The basic enzyme release of amylase and lipase was measured as well as the effect of stimulation with cerulein (10(-8) M) and the effect of replacing the medium (without changing the consistence or temperature of the medium). In a second step, the cultures were incubated under conditions of cold hypoxia for 6 h (4 degrees C, P O2 < 0.1 mm Hg) using Krebs-Henseleit solution (KH), Euro-Collins solution (EC), HTK solution of Bretschneider (HTK) or University of Wisconsin solution (UW) as the incubation solution. After 6 h, the media were changed to warm normoxic KH, and a second stimulation test with cerulein was performed. The native microstructure of the cultures was observed as well. Enzyme release was elevated by a factor of 5 by stimulating the acinar cells with cerulein as well as by changing the medium in the experiments prior to the hypoxic incubation. After hypoxic incubation and change to KH, the morphology of the cultures was excellent, while the basic enzyme release was on a very low level, no matter which preservation solution was used during cold hypoxia. Stimulation with cerulein caused only minimal elevation of enzyme release during an observation period of 60 min. These observations show that cold storage in preservation solution provides maintenance of the cell morphology and sufficient down-regulation of enzyme release of pancreatic acinar cells. Thus, acinar cells alone do not seem to be the pacemaker of pancreatitis after organ preservation. The presented experimental model will be the subject of extended evaluation in the future.

Application of a new LDL apheresis system using two dextran sulfate cellulose columns in combination with an automatic column-regenerating unit and a blood cell separator.

Extracorporeal procedures for selective removal of low-density lipoproteins have become a promising new approach for treatment of severe familial hypercholesterolemia. We tested efficacy and safety of a new LDL apheresis system by using two dextran sulfate cellulose adsorbents (Liposorber LA 15TM from Kanegafuchi) under the control of an automatic column-regenerating unit for continuous alternate adsorption and desorption. Plasma was taken from a continuous-flow blood cell separator (model IBM/Cobe 2997) allowing an extracorporeal circuit from one cubital vein to another. A 57-year-old male with drug-resistant heterozygous familial hypercholesterolemia accompanied by moderate hypertriglyceridemia and severe coronary artery disease has been treated every 2 weeks for 3 months so far. Treatment of 4-5 liters of plasma resulted in a mean decrease of total cholesterol from 355 to 111 mg/dl (9.20 to 2.88 mmol/l), of LDL cholesterol from 272 to 49 mg/dl (7.05 to 1.53 mmol/l), and of apolipoprotein B from 175 to 44 mg/dl. HDL cholesterol, apolipoprotein A-I, and other plasma proteins did not substantially change apart from hemodilution. No side effects were seen. This new technique of LDL apheresis represents a very effective and safe method for treatment of drug-resistant familial hypercholesterolemia without or with concomitant hypertriglyceridemia.

Influence of breakfasts with different nutrient contents on glucose, C peptide, insulin, glucagon, triglycerides, and GIP in non-insulin-dependent diabetics.

To examine the influence of coingestion of fat and protein in a mixed meal on carbohydrate metabolism, subjects with non-insulin-dependent diabetes mellitus (NIDDM) received three different breakfasts varying in the amount of fat and protein (group 1) or only in the amount of fat (group 2). Compared with the changes after a standard breakfast, insulin increased after the protein-rich meal and decreased after the fat-rich meal in group 1. Glucose and gastric inhibitory polypeptide (GIP) remained constant. In contrast, only GIP showed a significant increase after a high-fat meal in group 2. Thus, in NIDDM subjects, glucose and insulin responses to different mixed meals do not appear to be exclusively mediated by GIP. Protein was confirmed as a potent stimulator of insulin secretion. Other factors, such as an altered beta-cell response in diabetics to GIP or other incretions, must be considered to explain the reported results.