Epidemiology of invasive fungal infections and rationale for antifungal therapy in patients with haematological malignancies.

Invasive fungal infections (IFIs) in patients with haematological malignancies are difficult to diagnose and outcome is often fatal. Over the 7-month study period, 117 cases with haematological malignancies receiving systemic antifungal treatment were included. Data regarding antifungal agents, dosage and reason for administration were recorded. Fungal infections in study patients were classified as possible, probable or proven according to recent European Organization for Research and Treatment of Cancer criteria. During the study period, 690 cases with haematological malignancies were admitted. A total of 117 cases received systemic antifungal therapy. Twenty-four of 117 patients (21%) had possible, six (5.1%) had probable and four (3.4%) had proven IFI. Seven of 10 probable and proven infections were caused by Candida spp., 2 by Aspergillus spp. and 1 by a fungus belonging to Zygomycetes. Fifty-two of 117 patients (44%) received antifungal prophylaxis, 81 of 117 (69%) received empirical (31/117; 26%) or pre-emptive (50/117; 43%) antifungal therapy and four of 117 patients (3.4%) directed antifungal therapy. Mostly, systemic antifungal therapy was administered empirically or pre-emptively. Twenty-nine per cent of cases receiving systemic antifungal treatment met the international consensus criteria of mostly possible IFI, whereas 71% did not. Proven invasive fungal infections were rare.

Somatostatin receptor scintigraphy in patients with cat-scratch disease.

AIM: Somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immune diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. PATIENTS, METHODS: Twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. RESULTS: Eleven of 12 patients showed IgG antibodies against B. henselae. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. CONCLUSION: Somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD.

STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells.

The glucose analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific beta-cell cytotoxic effect, but the mechanism by which systemic injection of STZ causes beta-cell destruction is not well understood. In the current study, we have used insulinoma (RIN) and AtT-20ins cell lines engineered for overexpression of GLUT2 or GLUT1 to investigate the role of glucose transporter isoforms in mediating STZ cytotoxicity. The in vivo effects of STZ were evaluated by implantation of RIN cells expressing or lacking GLUT2 into athymic nude rats. The drug had a potent cytotoxic effect on RIN cells expressing GLUT2, but had no effect on cells lacking GLUT2 expression, as indicated by histological analysis and measurement of the blood glucose levels of treated animals. The preferential cytotoxic effect of STZ on GLUT2-expressing cell lines was confirmed by in vitro analysis of GLUT2-expressing and untransfected RIN cells, as well as GLUT2- and GLUT1-overexpressing AtT-20ins cells. Consistent with these data, only GLUT2-expressing RIN or AtT-20ins cells transported STZ efficiently. We conclude that expression of GLUT2 is required for efficient killing of neuroendocrine cells by STZ, and this effect is related to specific recognition of the drug as a transported substrate by GLUT2 but not GLUT1.

Evaluation of HbA1c determination methods in patients with hemoglobinopathies.

OBJECTIVE: To evaluate commercially available determination methods for HbA1c in patients with hemoglobin variants. RESEARCH DESIGN AND METHODS: HbA1c values were determined with various commercially available methods, including ion-exchange high-performance liquid chromatography (HPLC), boronate affinity assay, and immunoagglutination in patients with the hemoglobin mutations Hb Graz, Hb Sherwood Forest, Hb O Padova, Hb D, and Hb S. RESULTS: The effect of hemoglobinopathies on glycohemoglobin measurements was highly method dependent. The HPLC methods for HbA1c determination lacked the resolution necessary to differentiate hemoglobin variants. They demonstrated additional peaks in the chromatograms and HbA1c results either too low or too high compared with the nondiabetic reference range. With all immunoassays, Hb Graz demonstrated falsely low values. The other hemoglobinopathies in our study caused falsely low and/or high HbA1c results in immunoagglutination methods. The boronate affinity method showed values in an acceptable range for all hemoglobin variants. CONCLUSIONS: Because of the local occurrence of Hb variants and the ethnic origin of a given population, every individual laboratory must establish and validate its own assay method. In managing diabetic patients, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential because hemoglobin variants could cause mismanagement of diabetes resulting from false HbA1c determinations.

Evaluation of a structured outpatient group education program for intensive insulin therapy.

OBJECTIVE: To determine the efficacy and safety of a structured diabetes teaching and treatment program (DTTP) in patients with insulin-dependent diabetes mellitus (IDDM) in an outpatient setting. RESEARCH DESIGN AND METHODS: All patients with IDDM who completed a structured 5-day outpatient DTTP were reevaluated after a mean follow-up of 3 years. A standardized interview was used to assess frequency of severe hypoglycemia, type of insulin treatment, self-monitoring, and other diabetes-related parameters. HbA1c was measured by high-performance liquid chromatography. RESULTS: Of 205 patients, 4 (2%) died during the observation period. HbA1c in the 201 surviving patients decreased significantly from 8.7 +/- 2.0 to 7.5 +/- 1.2% at follow-up (P < 0.001); frequency of severe hypoglycemia decreased from a mean of 0.46 to 0.13 per patient per year (P < 0.001). Hospital admission due to acute metabolic disturbances decreased from 4.5 +/- 11.1 to 1.4 +/- 6.7 days/patient-year (P < 0.001). At follow-up, intensive insulin therapy was carried out by 98% of the patients, and 80% of the patients reported three or more measurements of blood glucose per day. Diabetes-related knowledge had a positive (P < 0.01) and body mass index a negative (P < 0.02) influence on improving HbA1c assessed by multiple regression analysis. Severe hypoglycemia after DTTP was associated with a history of severe hypoglycemia before DTTP (P < 0.001) and the existence of overt diabetic nephropathy (P < 0.05). CONCLUSIONS: A structured outpatient DTTP as used in this study is able to improve overall metabolic control and decrease the frequency of severe hypoglycemia in patients with IDDM.

Patatin-like phospholipase 3 (rs738409) gene polymorphism is associated with increased liver enzymes in obese adolescents and metabolic syndrome in all ages.

BACKGROUND: Obesity is associated with non-alcoholic fatty liver disease (NAFLD), and the patatin-like phospholipase 3 (PNPLA3) rs738409 (Ile148Met, C>G) gene polymorphism is one of the most important genetic determinants of NAFLD. Carriers have been reported to better respond to lifestyle modification. AIM: To investigate the effect of rs738409 on overweight/obese adolescents and adults with and without metabolic syndrome (MetS). METHODS: Two hundred and eighty-eight overweight/obese and 209 normal weight participants of the STYJOBS/EDECTA cohort (NCT00482924) were analysed for PNPLA3 genotypes. RESULTS: Compared to overweight/obese without MetS, in overweight/obese study participants with MetS, the presence of the G allele (148Met) was significantly higher (CC: 5.0% vs. 9.2%, Spearman's correlation, 0.12; P = 0.038). Persons with CG (heterozygote for the risk allele) and with GG (homozygote for the risk allele) genotypes showed significantly higher ALT levels than those with CC genotypes. Even young individuals aged below 20 years had significantly increased ALT levels if they were homozygote with the G allele. CONCLUSIONS: The PNPLA3 rs738409 polymorphism is associated already in youths with increased ALT, and is more frequent in obese with MetS of all ages. Hence, overweight/obese rs738409 carriers should be identified early in life and treated with a rigorous life style intervention.

Evidence of accelerated gastric emptying in longstanding diabetic patients after ingestion of a semisolid meal.

UNLABELLED: This study investigated the prevalence of accelerated gastric emptying in 40 consecutive nonselected patients with longstanding insulin-dependent diabetes mellitus (range 11-54 yr; mean 27 yr). METHODS: The gastric emptying of a semisolid meal labeled with 99mTc was continuously recorded with a dual-head gamma camera for 90 min in patients who were supine. RESULTS: Eleven patients demonstrated delayed gastric emptying, but three male diabetics showed accelerated gastric emptying with retention values that were different from controls already after 10 min of recording (89% +/- 3% versus 96% +/- 4%; p < 0.02). During the 90-min segment, accelerated gastric emptying reduced initial gastric contents to 11% +/- 8% (p < 0.001) as compared to 50% +/- 10% in control subjects and 78% +/- 6% (p < 0.001) in patients with delayed gastric emptyings. Accelerated gastric emptying was characterized by an almost equal initial meal distribution in proximal and distal compartments of stomach, both emptying approximately 90% of their contents within 90 min. Normal and delayed gastric emptying was characterized by a 60%-40% initial ratio of meal distribution between gastric compartments. During normal emptying, both compartments reduced contents with approximately 50%, but delayed gastric emptying was caused by only a 15% reduction of proximal contents accompanied by a 34% reduction in distal contents. CONCLUSION: Recording in the supine position to abolish gravitational influences demonstrated accelerated gastric emptying of a firm semisolid meal with a prevalence of 8%. However, delayed gastric emptying was shown as the predominant gastric manifestation of longstanding insulin-dependent diabetes mellitus with a prevalence of 28%.

Smooth muscle cell migration promoting activity of plasma predicts restenosis in patients with peripheral arterial occlusive disease undergoing angioplasty.

BACKGROUND: Efficacy of percutaneous transluminal angioplasty (PTA) is limited by restenosis occurring in a large proportion of patients. Smooth muscle cell (SMC) migration is a major pathomechanism of restenosis. We studied SMC migration inducing activity of plasma from patients with peripheral arterial occlusive disease (PAOD) undergoing PTA. METHODS AND RESULTS: SMC migration was determined in a two-dimensional assay system after addition of 1/25 plasma dilutions. Mean increase in migration area was 65.5 +/- 33.8% in normal controls and 67.7 +/- 53.2% in patients with PAOD. 6 hours after PTA, plasmatic migration inducing activity was largely unchanged. In 19/30 patients with restenosis (6 months after PTA) migration promoting activity (82.7 +/- 60.0) was significantly higher than in 11/30 patients with patent vessels (41.8 +/- 21.0; p = 0.03). No correlation of clinical risk factors with outcome was observed. A weak correlation was found between plasmatic migration promoting activity and levels of epidermal growth factor and transforming growth factor-beta. CONCLUSION: The capacity of human plasma to stimulate SMC migration in tissue culture can be used to assess the risk for restenosis after PTA in patients with PAOD.

Hemoglobin Sherwood Forest detected by high performance liquid chromatography for hemoglobin A1c.

Hb Sherwood Forest has been so far identified in only one patient in 1977. This study describes the second detection of this hemoglobin variant by routine high performance liquid chromatography (HPLC) in a diabetic patient and her healthy grand niece. In both, glycosylated hemoglobin (HbA1c) values were excessively elevated (52%), as determined by HPLC with a cation exchange column. The latex agglutination test showed values of HbA1c in the expected normal range. Citrate agar electrophoresis revealed a hemoglobin variant with a mobility similar to HbF. Amino acid analysis and DNA sequence analysis revealed an Arg-->Thr exchange at codon 104 of the beta-chain. This sequence has been described as Hb Sherwood Forest in 1977. The hemoglobin variant is clinically silent and might be confused with excessively high HbA1c in routine measurement of glycosylated hemoglobin.

Silent haemoglobin variants and determination of HbA(1c) with the HPLC Bio-Rad Variant II.

AIMS: To evaluate the determination of HbA(1c) with an automated high performance liquid chromatography (HPLC) method in patients with clinically silent haemoglobin variants. METHODS: HbA(1c) values were determined with the ion exchange HPL Bio-Rad Variant II using the high resolution beta thalassaemia programme in patients with silent haemoglobin variants, namely: Hb Graz, Hb Sherwood Forest, Hb O Padova, and Hb D. RESULTS: All of these haemoglobin variants caused additional peaks in the chromatograms. No clinically useful HbA(1c) results were produced for patients with Hb Graz and Hb Sherwood Forest, the results for the patient with Hb D were too low, but the results for patients with Hb O Padova were acceptable. CONCLUSIONS: The development of this automated HPLC method modification with high resolution mode aids the identification of interference caused by the described clinically silent haemoglobin variants in HbA(1c) determination.

Haemoglobin O Padova and falsely low haemoglobin A1c in a patient with type I diabetes.

Glycated haemoglobin (HbA1c) measured by high performance liquid chromatography (HPLC) in a 20 year old female with insulin dependent diabetes mellitus was consistently within the normal range although her daily blood glucose values were > 11.1 mmol/l. HbA1c measured by immunoagglutination and fructosamine was elevated and correlated with the patient's blood glucose values. The HPLC chromatogram showed an additional peak at HbA0. Electrophoresis of haemoglobin on citrate agar gel revealed an abnormal haemoglobin anodal of HbS. Cellulose acetate electrophoresis and isoelectric focusing demonstrated an additional haemoglobin migrating close to HbA2. Amino acid analysis and DNA sequencing revealed an alpha 30 (B11) Glu-->Lys replacement, that is, haemoglobin O Padova. Investigations of two family members without diabetes revealed the same rare haemoglobin variant. This case showed that this silent haemoglobin mutation caused an additional peak and falsely low HbA1c values when measured by HPLC, the gold standard for this evaluation.

Predicting the risk of restenosis after angioplasty in patients with peripheral arterial disease.

Restenosis is a serious therapeutic problem after percutaneous transluminal angioplasty (PTA). Strategies for the prevention of late restenosis include the use of antiaggregatory and anticoagulant drugs, aggressive lipid-lowering, intravascular radiation and others. As some of these therapeutic options are not without side effects it is important to identify patients with an increased risk to develop restenosis. Major clinically recognizable risk factors for restenosis are advanced disease stage and female gender. Elevated plasma levels of fibrinogen, Lp(a), CRP, and migration-inducing activity appear to indicate an unfavorable clinical outcome, and so does post-interventional increase of vWF and PAI-1 antigen. For peripheral arterial disease, only one study has addressed the influence of homocysteine levels upon the restenosis rate after PTA. Although homocysteine levels were elevated in >50% of patients at entry, they were not associated with a higher restenosis rate. Currently the available data allow a rough approximation of a patient's individual risk.

Oxidative stress during peripheral angioplasty. Implication for late restenosis?

BACKGROUND: Percutaneous transluminal angioplasty (PTA) is routine treatment for patients with peripheral arterial disease (PAD). The procedure induces local generation of reactive oxygen species (ROS), such as H2O2. Since these have been shown to stimulate vascular smooth muscle cell growth (VSMCG), we investigated peroxide levels in patients with PAD during PTA and related these results to late clinical outcome. METHODS: Thirty patients (17 male, 13 female, 20 Fontain stage II, 10 Fontaine stage IV, median age 68 years) undergoing PTA of a 2-6 cm stenosis of the femoral or popliteal artery were included. The procedure was performed successfully in all patients. At follow-up six months thereafter restenosis was evaluated by duplex sonography. Total peroxide concentrations were determined in plasma drawn before, 6, 24 and 48 hours after the procedure by the Operoxide activityO assay, which is based on the reaction of horseradish peroxidase with plasma peroxides, using tetramethylbenzidine as the chromogenic substrate. RESULTS: The median peroxide level before angioplasty was 280 mmol/L (range 47-549). Levels were higher in patients with advanced disease, in smokers and in patients with diabetes. In response to angioplasty, peroxide levels increased within 48 hours (p<0.001). Six months after the procedure, restenosis was observed in 10/30 (33 percent) of patients. Clinical outcome was not dependent upon baseline or postinterventional peroxide levels. CONCLUSIONS: Elevated peroxide levels are seen in patients with advanced arteriosclerotic disease and in those with diabetes, but are not predictive for late restenosis.

[Development of insulinoma cells as therapy in insulin-dependent diabetes mellitus]. / Die Entwicklung von Insulinomzellen als Therapie bei insulinabhängigem Diabetes mellitus.

In healthy persons insulin secreting beta-cells of the pancreas regulate blood glucose levels within a narrow physiological range. Since the detection of insulin in 1922 by Banting and Best, subcutaneous insulin replacement has remained the sole treatment modality for insulin-dependent diabetes mellitus (IDDM). However, even trained patients undergoing intensive insulin therapy fail to achieve normal function of the pancreatic beta-cells. One approach to solve this problem is pancreas and islet cell transplantation. Because of technical problems, limited number of transplantable organs and toxicity of immunosuppressive therapy, both are still in an experimental state. An alternative approach is the development of genetically modified insulin secreting cell lines for replacement of islet cells. So far, experiments support the expectation to develop genetically manipulated cell lines who imitate the function of islet beta-cells and are protected from the immune response. The ultimate goal is the development of an engineered human beta-cell line and, after animal experiments, to use it for treatment of patients with IDDM.

[Management of diabetes in Austria 5 years after the St. Vincent Declaration]. / Diabetesbetreuung in Osterreich 5 Jahre nach der St. Vincent-Erklärung.

In 1989 representatives of all European governments agreed on the "St. Vincent Declaration". In this statement of intent and recommendations all governments, including that of Austria, pledged to implement policies on preventive measures geared to reduce morbidity and mortality of all diabetic patients in Europe. Structured patient education has been shown to improve the overall quality of care in Type 1 diabetic patients. Reduction of acute metabolic disturbances after participation in the patient education programme reduces hospitalizations and allows significant savings in health care costs, which can help to make safe and effective therapy available to all patients with Type 1 diabetes without additional costs. A teaching and treatment programme for Type 2 diabetics by general practitioners has proven to be effective, feasible and inexpensive. Nationwide implementation of such an evaluated patient education programme shifts diabetes care to "primary health care" level, and increases long-term quality of diabetes care without generating new expenses. Patient education is considered not only the basis for successful management of diabetes, but also, as laid down in the St. Vincent Declaration, a basic human right of all patients, which still needs to be put into practice.

Primary epiploic appendagitis and fructose malabsorption.

Primary epiploic appendagitis (PEA) is a rare cause of abdominal acute or subacute complaints. Diagnosis of PEA is made when computed tomography (CT) reveals a characteristic lesion. We report on contrast-enhanced CT images of a patient with PEA and regression of inflammation and the reduction in size of the inflamed appendage over the time period of 4 months. Patients with PEA usually recover without medication or surgical treatment within a few weeks. However, due to continuing bloating and irregular bowel movements we investigated carbohydrate malabsorption and diagnosed a fructose malabsorption. Bloating and irregular bowel movements in this patient with PEA were correlated to carbohydrate malabsorption and were treated successfully with a diet free of culprit carbohydrates.