Side effects of the calcineurin inhibitor, such as new-onset diabetes after kidney transplantation.

New-onset diabetes after transplantation (NODAT) is one of the frequent complications following kidney transplantation. Patients were randomized to receive cyclosporine A- or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following three groups based on the results: normal, impaired fasting glucose/impaired glucose tolerance (IFG/IGT), or NODAT. NODAT developed in 14% of patients receiving cyclosporine A-based immunosuppression and in 26% of patients taking tacrolimus (p = 0.0002). Albumin levels were similar, but uric acid level (p = 0.002) and the age of the recipient (p = 0.003) were significantly different comparing the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection (ACR) and interstitial fibrosis/tubular atrophy (IF/TA) were significantly different in the NODAT group. The pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.

Early histopathological changes in new-onset diabetes after kidney transplantation.

BACKGROUND: New-onset diabetes after transplantation (NODAT) is one of the most common complications after kidney transplantation. METHODS: Patients were randomly assigned to receive cyclosporine A-based or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following 3 groups, on the basis of the results: normal, impaired fasting glucose/impaired glucose tolerance, or NODAT. NODAT developed in 14% of patients receiving cyclosporine A-based immunosuppression and in 26% of patients taking tacrolimus (P = .0002). RESULTS: Albumin levels were similar, but uric acid level (P = .002) and the age of the recipient (P = .003) were significantly different between the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection and interstitial fibrosis/tubular atrophy were significantly different in the NODAT group. Changes in the Banff score provided significant difference regarding tubulitis and interstitial inflammation (P = .05). CONCLUSIONS: The pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.

Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes.

There are substantial advances in understanding disordered gastrointestinal autonomic dysfunction in diabetes. It occurs frequently. The underlying pathogenesis is complex involving defects in multiple interacting cell types of the myenteric plexus as well. These defects may be irreversible or reversible. Gastrointestinal symptoms represent a major and generally underestimated source of morbidity for escalating health care costs in diabetes. Acute changes in glycaemia are both determinants and consequences of altered gastrointestinal motility. 35-90% of diabetic men have moderate-to-severe erectile dysfunction (ED). ED shares common risk factors with CVD. Diagnosis is based on medical/sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to patient's complaints and risk factors. Treatment is based on PDE5-inhibitors (PDE5-I). Other explorations may be useful in patients who do not respond to PDE5-I. Patients at high cardiovascular risk should be stabilized by their cardiologists before sexual activity is considered or ED treatment is recommended. Estimates on bladder dysfunction prevalence are 43-87% of type 1 and 25% of type 2 diabetic patients, respectively. Common symptoms include dysuria, frequency, urgency, nocturia and incomplete bladder emptying. Diagnosis should use validated questionnaire for lower urinary tract symptoms. The type of bladder dysfunction is readily characterized with complete urodynamic testing. Sudomotor dysfunction is a cause of dry skin and is associated with foot ulcerations. Sudomotor function can be assessed by thermoregulatory sweat testing, quantitative sudomotor axon reflex test, sympathetic skin response, quantitative direct/indirect axon reflex testing and the indicator plaster.

Microarray profiling reveals that placental transcriptomes of early-onset HELLP syndrome and preeclampsia are similar.

BACKGROUND: The involvement of the placenta in the pathogenesis of preeclampsia and HELLP syndrome is well established, and placental lesions are also similar in these two syndromes. Here we aimed to examine the placental transcriptome and to identify candidate biomarkers in early-onset preeclampsia and HELLP syndrome. METHODS: Placental specimens were obtained at C-sections from women with early-onset preeclampsia and HELLP syndrome, and from controls who delivered preterm or at term. After histopathological examination, fresh-frozen placental specimens were used for microarray profiling and validation by qRT-PCR. Differential expression was analysed using log-linear models while adjusting for gestational age. Gene ontology and pathway analyses were used to interpret gene expression changes. Tissue microarrays were constructed from paraffin-embedded placental specimens and immunostained. RESULTS: Placental gene expression was gestational age-dependent among preterm and term controls. Out of the 350 differentially expressed genes in preeclampsia and 554 genes in HELLP syndrome, 224 genes (including LEP, CGB, LHB, INHA, SIGLEC6, PAPPA2, TREM1, and FLT1) changed in the same direction (elevated or reduced) in both syndromes. Many of these encode proteins that have been implicated as biomarkers for preeclampsia. Enrichment analyses revealed similar biological processes, cellular compartments and biological pathways enriched in early-onset preeclampsia and HELLP syndrome; however, some processes and pathways (e.g., cytokine-cytokine receptor interaction) were over-represented only in HELLP syndrome. CONCLUSION: High-throughput transcriptional and tissue microarray expression profiling revealed that placental transcriptomes of early-onset preeclampsia and HELLP syndrome largely overlap, underlying a potential common cause and pathophysiologic processes in these syndromes. However, gene expression changes may also suggest a more severe placental pathology and pronounced inflammatory response in HELLP syndrome than in preeclampsia.

Coronary flow reserve, insulin resistance and blood pressure response to standing in patients with normoglycaemia: is there a relationship?

AIMS: To establish the relationships between coronary flow reserve, cardiovascular autonomic function, and insulin resistance characterized by the homeostasis model assessment insulin resistance score in patients with normal carbohydrate metabolism according to the World Health Organization (WHO) and American Diabetes Association (ADA) criteria, and with morphologically normal epicardial coronary arteries. METHODS: Twenty-five patients [12 women and 13 men, mean (sd) age: 53 +/- 11 years] with normal coronary angiography were enrolled into the study. Coronary flow reserve was measured during stress transoesophageal echocardiography. Autonomic dysfunction was assessed by means of five standard cardiovascular reflex tests. The fasting serum glucose and insulin levels were determined and the homeostasis assessment model insulin resistance score was calculated. RESULTS: In patients with normal carbohydrate metabolism, negative correlations were observed between the coronary flow reserve and both the serum insulin level (r = -0.445, P = 0.026) and the homeostasis assessment model insulin resistance score (r = -0.449, P = 0.024). The systolic blood pressure response to standing also correlated with the coronary flow reserve (r = -0.519, P = 0.011). The heart rate response to deep breathing, the Valsalva ratio, the 30/15 ratio and the sustained handgrip test results were not correlated with the coronary flow reserve. CONCLUSIONS: Our data suggest the possible role of insulin resistance and early sympathetic nerve dysfunction in the development of decreased coronary flow reserve in patients without diabetes mellitus or impaired glucose tolerance.

Regional differences in the manifestation of gastrointestinal motor disorders in type 1 diabetic patients with autonomic neuropathy.

OBJECTIVE: The aim of this work was to establish the prevalence and severity of different gastrointestinal symptoms and their relationships to esophageal, gastric and recto-anal motor disturbances by manometry in patients with Type 1 diabetes mellitus and autonomic neuropathy. PATIENTS AND METHODS: Sixteen patients (mean age: 53.4 +/- 14.9 years) with long standing type 1 diabetes mellitus (mean diabetes duration: 22.1 +/- 14.7 years) and autonomic neuropathy (mean Ewing score: 5.73 +/- 2.34) were investigated. The gastrointestinal symptom scores were established by using the Talley dyspepsia questionnaire. The motor function of the digestive tract was tested in the esophagus, in the stomach, and in the ano-rectum by perfusion manometry. RESULTS: Manometric evaluation of the esophagus did not reveal significant abnormalities in the region of the upper sphincter in patients with diabetes mellitus. In contrast, diabetic patients had decreased peristaltic wave amplitude, prolonged duration, decreased wave propagation velocity, and increased number of simultaneous contractions in the esophageal body, and decreased lower esophageal sphincter pressures with prolonged relaxation compared to the age- and sex-matched controls. Symptom analysis showed correlations between reflux symptoms and LES relaxation times, and between dysphagia scores and esophageal body peristaltic wave duration, propagation velocity and the rate of simultaneous contractions. In the gastric antrum, frequent, and often severe, fasting motility disorders were observed, which had no correlation with dyspeptic symptoms. In the ano-rectal region the diabetic patients had a lower squeezing-resting pressure difference, and impaired fecal expulsive function. Motility disorders were simultaneously present at multiple parts of the gastrointestinal tract in 13/16 cases. CONCLUSIONS: In patients with type 1 diabetes mellitus and autonomic neuropathy gastrointestinal motility disorders were observed frequently, and in most of the cases simultaneously. While esophageal and ano-rectal symptoms correlated better with the manometric abnormalities, the lack of correlation between the impaired fasting gastric motility and dyspeptic symptoms shows that, on the basis of the clinical symptom analysis, the prevalence of such motor disorders could be underestimated. The early recognition of gastrointestinal motility disorders may be important for the better long-term management of patients with type 1 diabetes mellitus.

Autonomic nervous system dysfunction involving the gastrointestinal and the urinary tracts in primary Sjögren's syndrome.

OBJECTIVE: Antibodies reacting with the m3 subtype muscarinic acetylcholine receptor appear to be an important pathogenic factor in primary Sjögren's syndrome (pSS). As this receptor subtype is functionally important in the gastrointestinal and urinary tracts, and very little is known about the autonomic nervous system function in these organs in pSS patients, the occurrence and clinical significance of an autonomic nervous system dysfunction involving the gastrointestinal and urinary tracts were investigated. METHODS: Data on clinical symptoms attributable to an autonomic dysfunction were collected from 51 pSS patients. Gastric emptying scintigraphy and urodynamic studies were performed on 30 and 16 patients, respectively, and the results were correlated with patient characteristics and with the presence of autonomic nervous system symptoms. RESULTS: Gastric emptying was abnormally slow in 21 of the 30 examined patients (70%). Urodynamic findings, compatible with a decreased detrusor muscle tone or contractility were found in 9 of the 16 patients tested (56%). Various symptoms of an autonomic nervous system dysfunction were reported by 2-16% of the patients. CONCLUSION: Signs of an autonomic nervous system dysfunction involving the gastrointestinal and the urinary systems can be observed in the majority of pSS patients. This high occurrence is rarely associated with clinically significant symptoms. The authors presume a role of autoantibodies reacting with the m3 muscarinic acetylcholine receptor in the elicitation of the autonomic dysfunction.

Impaired accommodation of proximal stomach in patients with alcoholic liver cirrhosis.

BACKGROUND: Impaired gastric emptying has previously been detected by ultrasonography in cirrhotic patients, and the role of the type of meal has also been discussed. While these earlier studies dealt with the distal part of the stomach, the aim of our study was to examine the effects of three different types of meal on the proximal stomach in cirrhotic patients. METHODS: The proximal stomach was examined by ultrasonography in 15 healthy volunteers and in 21 alcoholic cirrhotic patients. The subjects received a liquid meal with a low calorie content and two different semisolid test meals with a low calorie content or high calorie and fat contents. The proximal gastric size was assessed by ultrasonography in a sagittal area and a frontal diameter. On the basis of assessment of the autonomic nervous function, the cirrhotic patients were divided into two groups: autonomic neuropathy positive and autonomic neuropathy negative. RESULTS: The postcibal gastric size immediately after ingestion of the liquid test meal was significantly lower in the cirrhotic patients than in the healthy controls. In the healthy volunteers, the measures of the proximal gastric size were significantly higher than in either group of cirrhotic patients at to, and at 10, 20 or 30 min after ingestion of a semisolid test meal with low calorie and fat contents. The proximal gastric sizes in the three groups of investigated subjects did not differ when the meal with high fat and calorie contents was tested. When the liquid meal was administered, the proximal gastric size was significantly lower in the cirrhotic patients with autonomic neuropathy. A significant intragroup difference was not observed when the semisolid meals were tested. CONCLUSIONS: This study reveals an impairment of the proximal stomach in alcoholic cirrhotic patients. The low calorie liquid meal distinguishes between the two groups of cirrhotic patients and healthy controls.

Brainstem auditory-evoked potential examinations in diabetic patients.

Brainstem auditory-evoked potential (BAEP) examinations were performed in 15 patients with long-standing type-1 diabetes mellitus (DM). Cardiovascular reflex tests were applied for assessment of autonomic neuropathy. The aim of our investigation was to compare the BAEP results of this patient group with controls and to look for a possible correlation between the alteration of the auditory brainstem function and the cardiovascular autonomic neuropathy. Analysis of the latencies (waves I, II, III and V) and the inter-peak latencies (waves I-III and I-V) of BAEPs revealed a significant difference between diabetics and healthy controls. The amplitudes of waves I, III and V were definitely lower in comparison with those of healthy controls. A positive correlation was observed between the overall autonomic score and the latencies (waves III and V) and inter-peak latencies (waves I-III and I-V). These data support the hypothesis that long-standing DM and diabetic neuropathy might be related as a cause of certain dysfunctions of the central auditory pathways.

Adenocarcinoma of the colon developing on the basis of Crohn's disease in childhood.

Colorectal carcinoma rarely affects children and has a dismal prognosis with 5-year survival rates as low as 2.5%-7% despite apparently radical surgery. Here we report the case of an adenocarcinoma of the sigmoid colon in a 15-year-old girl preceded by uncertain abdominal complaints of 5 years' duration. Pathological work-up revealed a tumour with lymph node metastases (pT3NI). Immunohistochemical evidence of p53 overexpression by the tumour cells raised the suspicion of an underlying Li-Fraumeni syndrome. In addition, there were aphthoid ulceration, fissuration of the non-tumorous mucosa, along with a mixed transmural infiltrate composed of macrophages, eosinophils, and non-typical giant cells, which were compatible with simultaneous Crohn's disease. Anamnestic data concerning the occurrence of idiopathic inflammatory bowel disease or colorectal carcinoma in the patient's relatives were non-contributory. The present results suggest a possible relationship between Crohn's disease and colon cancer due to the defective p53 gene product.

Gallbladder hypomotility in diabetic polyneuropathy.

This study was performed to evaluate the gallbladder motility in long-standing diabetes mellitus. The gallbladder function of diabetic patients was measured by means of quantitative hepatobiliary scintigraphy, and the severity of the associated autonomic and sensory polyneuropathy was determined. The presence of a marked gallbladder hypomotility was established, and a positive correlation was observed between the severity of the autonomic disturbance and the contractile disorder. This study underlines the important role of the neuropathy in the development of gallbladder hypomotility accompanying long-term diabetes mellitus.

[Gallbladder hypomotility in diabetic polyneuropathy]. / Epehólyag-hypomotilitas diabeteses polyneuropathiában.

A study was made of the pathogenic role of gallbladder hypomotility, which is presumably responsible for the high incidence of gallstone disease in long-standing diabetes mellitus. The gallbladder motility of diabetic patients (n = 10) was measured by means of quantitative hepatobiliary scintigraphy, and the severity of concomitant autonomic and sensory polyneuropathy was determined. The presence of marked gallbladder hypomotility was proven, and a positive correlation was observed between the severity of autonomic neuropathy and the contractile disorder. In this group of diabetic patients, a hypaesthetic sensory polyneuropathy too was recognized, the degree of which exhibited a positive correlation with the autonomic neuropathy score. This study underlines the important role of the autonomic neural dysfunction in the development of gallbladder hypomotility accompanying long-term diabetes mellitus.

[Erythrocyte-induced "torsade de pointes" ventricular tachycardia]. / Erythromycin által elöidézett "torsades de pointes" kamrai tachycardia.

A case of erythromycin-induced acquired long QT syndrome and "torsades de pointes" ventricular tachycardia is reported. The peculiar ventricular tachyarrhythmia was evoked by orally administered erythromycin (1.5 g/die) in the presence of diuretic (clopamide)-induced hypokalaemia. The pause-dependent "torsades de pointes" was preceded by prolonged QTU interval (560 ms), "particular bigeminy" and "short-long-short" RR interval sequence. The recurrent ventricular tachycardia causing syncopal attacks was abolished by the discontinuation of erythromycin treatment, K+/Mg(2+)-supplementation and oral mexiletine therapy. It is emphasized that the macrolide antibiotic/prokinetic erythromycin, applied in therapeutic dosages, blocks the rapidly activating delayed rectifier potassium current (IKr), and as such, prolongs ventricular repolarization and may be "torsadogenic".

[Increase of the QT interval dispersion in diabetes mellitus]. / A QT-szakasz-diszperzió növekedése cukorbetegségben.

The QT dispersion, measured as the interlead variability of QT interval (QTd = QTmax-QTmin), reflects the spatial inhomogeneity of ventricular repolarization times. The authors studied QTd and heart rate-corrected QTd (QTc-d) in 81 patients with diabetes mellitus (IDDM: 39, NIDDM: 42) using Bazett's formula; 20 non-diabetic subjects acted as controls (means +/- SD). QTd (43 +/- 17 ms) and QT c-d (52 +/- 20 ms) were increased (p < 0.05) as compared to the control values (QTd = 32 +/- 17 and, QTc-d = 35 +/- 17 ms, respectively). A significant difference was also observed in QTc-d if the two diabetic groups were compared to the control separately (p < 0.05). Moreover, comparison of the diabetic groups (IDDM vs NIDDM) revealed that type I diabetes mellitus is accompanied by a more pronounced spatial dispersion of ventricular reporlarization (QTd = 49 +/- 16, and QTc-d = 59 +/- 19 ms) as compared to NIDDM (QTd = 38 +/- 16, QTc-d = 46 +/- 20 ms [p < 0.01]). The hypothesis that increased QTd/QTc-d is truly a predictive marker of sudden arrhythmic cardiac death in patients with diabetes mellitus needs further clinical investigation.

Elevated levels of plasma vasoactive intestinal peptide in human acute myocardial infarction.

The plasma levels of vasoactive intestinal peptide in peripheral vein were measured in human acute myocardial infarction. The plasma vasoactive intestinal peptide level was increased within 1 h after the onset of the symptoms of acute myocardial infarction (Group 1, n = 9), compared with normal values (6.3 +/- 0.7 vs. 2.8 +/- 0.9 pg/ml, P < 0.05). Two or more hours after the onset of acute myocardial infarction there was no subsequent increase in peripheral plasma vasoactive intestinal peptide levels (n = 26). Ten days after the onset of acute myocardial infarction, the elevated plasma vasoactive intestinal peptide levels in Group 1 had normalized (3.5 +/- 0.5 pg/ml).

[Amiodarone-induced pulmonary fibrosis]. / Amiodaron által elöidézett tüdöfibrosis.

The most feared side-effect of long-term amiodarone therapy is progressive alveolitis/pneumonitis leading to pulmonary fibrosis. The case history of a patient is presented who received amiodarone unnecessarily in a high dose (600 mg/day) for 4 years: drug-induced dermatopathy, hypothyroidism and lung fibrosis developed. After cessation of amiodarone treatment the pulmonary complication did not disappear therefore glucocorticoid therapy was introduced. New-onset improductive cough, dyspnea, fever and/or enhanced erythrocyte sedimentation rate may suggest the presence of amiodarone pulmonary toxicity and may form the basis of indication of high-resolution computed tomography (HRCT). Amiodarone-induced pulmonary involvement can be shown by HRCT early, before the appearance of any considerable abnormality of chest radiography.

Efficacy of nizatidine, clarithromycin and bismuth subcitrate therapy for Helicobacter pylori eradication in duodenal ulcer patients--a preliminary report.

The triple combination of nizatidine, clarithromycin, and bismuth subcitrate resulted in an ulcer healing rate of 98% and an H. pylori eradication rate of 90%. Corresponding 'intention-to-treat' figures were 92% and 84%, respectively. These results suggest that further studies, shorter in duration, using lower dosages, and possibly testing other combinations with a double-blind methodology, are required.

[Diagnosis of Verner-Morrison syndrome (VDHA) and its treatment with sandostatin an streptozocitin]. / Verner-Morrison (WDHA) szindróma diagnózisa és kezelése Sandostatin és streptozotocin adagolással.

A case report is presented of a man with Verner-Morrison syndrome of extreme severity, caused by an unresectable pancreatic VIPoma. The pathological role of vasoactive intestinal polypeptide (VIP) is discussed in the pathogenesis of Watery Diarrhoea, Hypokalaemia, Achlorhydria (WDHA) syndrome. The authors describe the typical symptoms of the syndrome and provide a diagnostic and therapeutic strategy. Plasma level of VIP was determined by the authors' own VIP RIA method. Administration of a long acting somatostatin analogue, octreotide (Sandostatin, Sandoz) at a dose of 100 micrograms daily, decreased the plasma level of VIP from about 55 to 38 fmol/ml, which was associated with complete regression of the diarrhoea. Due to the 'escape phenomenon' the dose of Sandostatin was gradually increased and finally completed with streptozotocin (Zanosar, Upjohn) administration, which was repeated every 8 weeks. The combination of Sandostatin and streptozotocin resulted in complete regression of diarrhoea and substantial diminution of the tumour mass. The patient displayed a weight gain and returned to normal life.