[Transgastric-, transhepatic endosonography-guided biliary drainage (EUCD) in a patient with locally advanced cholangiocarcinoma]. / Endosonografisch gesteuerte transgastrisch-, transhepatische Cholangiodrainage (EUCD) bei einer Patientin mit lokal fortgeschrittenem Gallengangskarzinom.

We report on a 63-year-old female patient with locally advanced cholangiocarcinoma of the extrahepatic biliary tract. She was admitted with progressive obstructive jaundice, initiating cholangitis and distinctive itching. The biliodigestive anastomosis was secondarily barred by tumour infiltration and not accessible via an endoscopic route. Because the patient asked expressively for internal drainage, we successfully performed an endosonography-guided transgastric, transhepatic internal biliary drainage (EUCD). The jaundice and itching were regredient and the patient was discharged in a stable condition.

The -174G>C IL-6 gene promoter polymorphism and diabetic microvascular complications.

This study examined a possible association of the G>C polymorphism at nucleotide -174 in the promoter region of the interleukin-6 (IL-6) gene (rs1800795) with the prevalence of diabetic complications in 235 patients with type 1 and 498 patients with type 2 diabetes. Genotyping was performed using polymerase chain reaction (PCR) and subsequent cleavage by Nla III restriction endonuclease. Analyzing all diabetic patients together demonstrated that 301 patients (41.1%) carried the GG genotype, 114 (15.6%) the CC genotype, and 318 (43.3%) were heterozygous for the GC genotype. However, there was no correlation of any of the genotypes with the prevalence of diabetic nephropathy or diabetic neuropathy, but subjects with the CC genotype had a significantly higher prevalence of diabetic retinopathy compared to patients with the GC and GG genotype (p=0.016). This association was mainly lost when a logistic regression model was adjusted for diabetes duration (p=0.07). Consistently, a weak but not significant association of the polymorphism with diabetic retinopathy was observed when type 1 and type 2 diabetic patients were analyzed separately (patients with type 1 diabetes: p=0.12; patients with type 2 diabetes: p=0.09). Analogically, no association of the polymorphism was found for diabetic nephropathy or diabetic neuropathy in these groups. In conclusion these data suggest no major influence of the -174G>C variant in the promoter region of the IL-6 gene on the development of microvascular complications in patients with diabetes.

A M55V polymorphism in the SUMO4 gene is associated with a reduced prevalence of diabetic retinopathy in patients with Type 1 diabetes.

AIMS: We studied the association between a functionally relevant M55V polymorphism in the SUMO4 gene with microvascular diabetic complications in patients with type 1 diabetes. METHODS: 223 patients with type 1 diabetes were studied using polymerase chain reaction and subsequent cleavage by restriction endonucleases for the M55V SUMO4 gene variant. RESULTS: No effect of the polymorphism on diabetic neuropathy or diabetic nephropathy was found, but heterozygous or homozygous patients for the M55V polymorphism in the SUMO4 gene had a markedly reduced prevalence of diabetic retinopathy (odds ratio 0.37, 95%-confidence interval (CI) [0.32;0.43]; p=0.004). Furthermore, a multiple logistic regression model showed an age and diabetes duration independent effect of the M55V polymorphisms on the prevalence of diabetic retinopathy (p=0.03), but not of diabetic neuropathy or nephropathy. CONCLUSIONS: Our data indicate that the M55V polymorphism in the SUMO4 gene is associated with a reduced risk of diabetic retinopathy in type 1 diabetes. Thus, the results of our study suggest that posttranslational modification of proteins via SUMO4 could contribute to the development of certain diabetic complications.

Revolutionary advances in organic foods.

'Organic' is a labelling term that denotes products produced under the authority of the Organic Foods Production Act. Before a product can be labelled 'organic', a government-approved certifier inspects the farm where the food is grown to make sure the farmer is following all the rules necessary to meet the US Department of Agriculture (USDA) organic standards. Companies that handle or process organic food before it gets to your local supermarket or restaurant must be certified, too. Along with the national organic standards, the USDA developed strict labelling rules to help consumers know the exact content of the food they buy. It is important to emphasise that the USDA has not made any health claims for organic foods. It is indeed fortunate that the US Department of Health and Human Services, Centers for Disease Control and Prevention, USDA and the Environmental Protection Agency are now expanding their research to explore the scientific basis for the health benefits of organic foods.

Improved vascular function upon pioglitazone treatment in type 2 diabetes is not associated with changes in mononuclear NF-kappaB binding activity.

Thiazolidinediones such as pioglitazone have been shown to exert anti-inflammatory effects independent of their insulin sensitizing effects by reducing activation of the proinflammatory transcription factor NF-kappaB in animal models of experimental diabetes. Furthermore, short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries of patients with type 2 diabetes. Since inflammation is supposed to impair flow-mediated vasodilatation, we studied the effects of an 8-week pioglitazone intervention on endothelial function and mononuclear NF-kappaB activation in patients with type 2 diabetes. Twenty patients were included in a randomized, double-blind, placebo-controlled study receiving 30 mg pioglitazone or placebo, respectively. Flow-mediated endothelium dependent vasodilatation (FMD) of the brachial artery, NF-kappaB binding activity in peripheral blood mononuclear cells [pBMC, determined by electrophoretic mobility shift assay (EMSA)] and interleukin-6 (IL-6)-transcription rates (determined by real-time PCR) were measured at study entry and after eight weeks of intervention. Pioglitazone treatment resulted in a significant improvement of FMD (4.3%+/-3.3; p=0.003), while no effect was seen under placebo medication (2.0%+/-2.7; p=0.71). The correction of FMD was neither paralleled by a pioglitazone-dependent reduction in mononuclear NF-kappaB binding activity (DeltaNF-kappaB activity: pioglitazone: 9.2%+/-6.7, p=0.24; placebo: 5.7%+/-19.6; p=0.82) nor in NF-kappaB dependent gene transcription as determined for IL-6 (DeltaIL-6 pioglitazone: +1.8%+/-12.0, p=0.93; placebo: -0.2%+/-9.7; p=0.92). These data demonstrate for the first time that pioglitazone treatment improves endothelial dysfunction in patients with type 2 diabetes without affecting NF-kappaB binding activity and NF-kappaB dependent proinflammatory gene expression in pBMC.

Long-term treatment of central Cushing's syndrome with rosiglitazone.

CONTEXT: Central Cushing's syndrome is not always curable by surgery or radiation of the pituitary. Medical treatment is often not possible or effective. Some studies revealed beneficial effects of the PPARgamma (Peroxisome-Proliferator-Activator- Receptor-gamma)-agonist rosiglitazone (RG) in in vitro studies, animal models and short term clinical studies. OBJECTIVE: of this study was to observe the long-term effects of RG-treatment on cortisol- and ACTH -secretion, clinical outcomes and morphological changes of the pituitary in patients with persistent ACTH-overproduction despite previous operation and radiation. DESIGN, SETTING AND PATIENTS: 14 patients with persistent central ACTH -production were included and monitored over a period up to 12 months. RG was administered daily and increased to a maximum dosage of 24 mg daily, according to the response of ACTH and cortisol secretion. ACTH and cortisol were measured at least every 4 weeks during RG treatment. RESULTS: Patients were treated between 4 and 12 months with RG (mean 6.8 months). Compared to baseline, ACTH- and cortisol levels dropped significantly (p<0.01) after 12, 16, 20, 24 and 28 weeks but thereafter rose again during the study period, despite continuous RG- treatment and dose increase up to the maximum dosage. This was paralleled by reocurrence of clinical symptoms. MRI-scans were performed in 6 patients because of persisting visible adenoma, but showed no morphological changes. CONCLUSION: RG seems not to be a long-term treatment option for patients with persistent central ACTH-evcess. Though, in order to reduce perioperative complications, short term treatment of patients could be an alternative.

No association of the 94T/G polymorphism in the adiponectin gene with diabetic complications.

AIM: This study examined a possible association of the T/G polymorphism at nucleotide 94 in the adiponectin gene with the prevalence of diabetic complications. METHODS: The study was performed in 696 patients with type 1 diabetes and type 2 diabetes. Genotyping was performed by means of polymerase chain reaction and subsequent cleavage by using SmaI restriction endonuclease. RESULTS: The 94G/G genotype was significantly more prevalent in patients with type 2 diabetes (2.2%) than in type 1 diabetics (0.0%) (p = 0.02), whereas no differences were found for frequencies of the 94T/T and the 94G/T genotypes, respectively. In patients with type 1 diabetes, 45 of 239 patients were heterozygous for the 94T/G polymorphism (carrier rate (CR): 18.8%; allele frequency (AF): 0.094). In type 2 diabetics, 71 of 457 patients were heterozygous and 10 patients were homozygous for the 94G/G genotype (CR: 17.7%; AF: 0.10). No association with diabetic nephropathy, diabetic neuropathy or diabetic retinopathy was found for either genotype in patients with type 1 and type 2 diabetes. CONCLUSIONS: The 94T/G polymorphism in the adiponectin gene is not associated with diabetic complications. The significance of a higher prevalence of the G allele in type 2, compared to type 1 diabetes remains to be clarified.

Variants in the human beta 1-, beta 2-, and beta 3-adrenergic receptor genes are not associated with morbid obesity in children and adolescents.

AIM: beta-adrenergic receptors (beta-ARs) are of key importance for the regulation of lipolysis and thermogenesis by catecholamines. Genetic defects in expression or function of beta(1)- beta(2)- and/or beta(3)-AR could affect energy homeostasis and predispose an individual towards the development of obesity. We therefore investigated the possible association of polymorphisms in the beta-adrenergic receptor genes with early onset obesity. METHODS: Frequencies of the following variants were assessed in extremely obese children and healthy underweight controls: Gly/Ser in codon 49 and Arg/Gly in codon 389 of the beta(1)-AR, Arg/Gly in codon 16 and Gln/Glu in codon 27 of the beta(2)-AR, Trp/Arg in codon 64 of the beta(3)-AR. RESULTS: The Ser49 allele in the beta(1)-AR gene was found at a frequency of 0.131 in obese and 0.136 in lean subjects (p = 0.835), while the Gly389 allele in the beta(1)-AR had a frequency of 0.319 in obese and 0.328 in lean subjects (p = 0.802). Gly16 in the beta(2)-AR was found with a frequency of 0.590 in obese and 0.611 in lean subjects (p = 0.591) and the Glu27 allele in the beta(2)-AR had a frequency of 0.380 in obese and 0.420 in lean subjects (p = 0.298). CONCLUSION: We did not detect significant differences for allele and carrier frequencies of individual polymorphisms. Together with previously obtained data on genotype distribution of a beta(3)-AR variant in the same study group, no significant differences were found between obese and lean subjects for the distribution of individuals with variants in none, one, two or all three beta-ARs. Our data make it unlikely that polymorphisms in beta-ARs are involved in the pathogenesis of early onset obesity.

[Molecular principles of obesity]. / Molekulare Grundlagen der Adipositas.

BACKGROUND: The deposition of excess amounts of energy in adipose tissue is enhanced by high-fat diets and lack of physical activity. Furthermore, the existence of a specific genetic predisposition towards the development of obesity becomes evident by marked interindividual differences in the response to caloric oversupply. GENETIC DEFECTS AND HORMONES: In recent years, numerous genes and genetic defects with importance for human obesity were identified, especially through studies in animal models. The adipocyte-derived hormone leptin and its hypothalamic receptor play a premier role, as they interact with a network of proteins and neuropeptides within the regulation of food intake and energy expenditure. CONCLUSION: The search for the key molecular mechanisms in the pathogenesis of obesity will not only improve our understanding of energy metabolism, but may ultimately also lead to the development of new treatment strategies for obese patients.

Identification of a deletion variant in the gene encoding the human alpha(2A)-adrenergic receptor.

OBJECTIVE: The alpha(2)-adrenergic receptors are involved in the effects of catecholamines on energy metabolism. Of three known subtypes with differential expression, alpha(2A)-adrenergic receptors are also localized in adipose tissue where they counteract the lipolytic activity of beta-adrenergic receptors. This study was undertaken to assess whether variants in the alpha(2A)-adrenergic receptor gene are associated with body weight. DESIGN AND METHODS: Single strand conformation polymorphism (SSCP) screening and subsequent sequencing were applied to determine genetic variants in DNA samples from individuals with obesity, those of normal weight and those underweight. RESULTS: Analysis of the coding region resulted in the identification of an 18 bp deletion, with no other mutation found. Of 429 genotyped subjects, 7 carried the deletion, with no significant differences between lean and obese subjects. A previously identified polymorphism in the promoter of the alpha(2A)-adrenergic receptor gene also did not show an association with any of the tested body weight categories. CONCLUSION: Our data suggest that variants in the alpha(2A)-adrenergic receptor gene are unlikely to contribute to the predisposition for the lean or obese state.

[Etiology of overweight and obesity]. / Pathogenese von Ubergewicht und Adipositas.

Obesity results from a predominance of caloric intake over energy expenditure. Twin, adoption and family studies have demonstrated that, together with environmental conditions, various genetic factors play an important role in the pathogenesis of obesity. In recent years, it was possible to identify several defects in single genes responsible for obesity in rodents, some of which may also be involved in human obesity. Besides leptin as the most notable example, numerous other proteins and neuropeptides have been identified in recent years that participate in a complex network to regulate food intake and energy expenditure. The ongoing search for the important obesity genes should not only result in a better understanding of energy metabolism, but may also help in the development of new strategies for the treatment of obese patients.

Analysis of the uncoupling protein-1 (UCP1) gene in obese and lean subjects: identification of four amino acid variants.

Uncoupling protein-1 (UCP1) is uniquely expressed in brown adipose tissue (BAT) and of major importance for the tissues thermogenic capacity. This study was undertaken to detect variants in the UCP1 gene by single strand conformational polymorphism (SSCP) analysis and subsequent sequencing, and determine their potential association with obesity. Four variants predicting for amino acid substitutions were detected, of which Arg40Trp (exon 1) and Lys257Arg (exon 5) were rare mutations. In contrast, the allele frequency of a polymorphism in exon 2 predicting for an Ala64Thr substitution was 8.2% in a cohort of 293 obese children and adolescents compared to 4.1% in 134 lean individuals, while the allele frequency of a Met229Leu variant (exon 5) was not markedly different between the obese (10.4%) and lean (12.0%) study groups. Although one of the identified polymorphisms tends to have a higher frequency in obese than in lean subjects, variants of the UCP1 gene do not seem to contribute significantly to the development of early-onset obesity in the German population.

Screening for variability in the ciliary neurotrophic factor (CNTF) gene: no evidence for association with human obesity.

Systemic administration of the neurocytokine ciliary neurotrophic factor (CNTF) normalizes the obese phenotype of ob/ob and db/db mice. CNTF exerts its multiple effects through a receptor complex whose sequence, localization in hypothalamic nuclei and mode of signal transduction share remarkable similarities with the leptin receptor. In the human CNTF gene, a mutation in the first intron creates a new splice acceptor site, with the resulting mRNA coding for an aberrant protein (Takahashi et al., 1994). Given the potential of CNTF to influence energy homeostasis, this study was undertaken to determine whether variability in the CNTF gene is associated with human obesity. The previously described mutation was found in 30.3% of obese children and adolescents, 7 of which were homozygous (allele frequency 0.163). 29.5% of lean subjects carried the mutation, none of which were homozygous (allele frequency 0.148; corrected p = 1 compared to obese). No further mutations were detected by single strand conformational polymorphism (SSCP) analysis. In conclusion, variants in the CNTF gene are unlikely to be associated with the development of early-onset obesity.

Reduced incidence of ovarian hyperstimulation syndrome by prophylactic infusion of hydroxyaethyl starch solution in an in-vitro fertilization programme.

Prophylactic infusion of human serum albumin can reduce or mitigate severe ovarian hyperstimulation syndrome (OHSS) in patients at high risk. Recently, concern has been expressed in the lay press regarding the potential viral transmissions with blood constituents. Hence, we looked for a safe non-biological substitute with comparable physical properties in order to cope with this concern. One hundred patients of our in-vitro fertilization (IVF) programme with oestradiol serum concentrations > or = 11010 pmol/l on the day of human chorionic gonadotrophin injection and/or > or = 20 oocytes retrieved and/or previous severe OHSS were infused with 1000 ml 6% hydroxyaethyl starch solution at the time of oocyte collection and 500 ml 48 h later. A total of 82 IVF patients at risk without prophylactic infusions during the preceding years served as controls. Both groups were identical according to patient's age, body mass index, androgen concentrations, peak oestradiol concentrations, number of retrieved oocytes, fertilization and pregnancy rates. There were seven cases of severe OHSS in untreated patients and two cases in the treatment group (P = 0.08). In moderate OHSS a significant difference became obvious with only ten cases in the treatment group and 32 cases in the control group (P < 0.00001). Hydroxyaethyl starch solution seems to be an effective and economic alternative in reducing severe and moderate OHSS during IVF treatment.

Late effects of polio: critical review of the literature on neuromuscular function.

Many individuals who have had poliomyelitis are now complaining of several new problems attributed to their former illness including muscle atrophy; fatigue; progressive weakness; and muscle, back, and joint pain. This paper critically examines the literature regarding the neuromuscular effects of poliomyelitis. Weakness resulting from poliomyelitis was due to destruction of anterior horn cells. After the illness, muscle strength was partially recovered as a result of several physiologic adaptive mechanisms including terminal sprouting and reinnervation, myofiber hypertrophy, and, possibly, myofiber type transformation. Several pathophysiologic and functional etiologies have been proposed for late neuromuscular deterioration, but none has been proven. In fact, to date, there is no objective evidence documenting progressive loss of strength in polio survivors. Studies attempting to differentiate polio survivors with and without symptoms of deterioration have resulted in conflicting results; however, it appears reasonable to conclude that symptomatic postpolio subjects had a more severe illness with greater loss of neuromuscular function. Exercise may be helpful for many postpolio patients, but the prescription must be tailored to the individual to avoid problems of overuse or excessive fatigue.

Cold injuries.

Until recently, military personnel have had the greatest risk for cold injuries. During the past two decades, however, destitute persons without adequate clothing or shelter, and sports enthusiasts participating in snowmobiling, mountain climbing, and skiing have been responsible for the increased incidence of cold exposure seen in a large civilian population. Consequently, cold injury remains a crippling problem. Although research is opening new avenues of accurate diagnosis and expeditious treatment, the standard against which these methods must be measured continues to be a rational treatment plan that often prevents the sequelae of cold injuries.

Recurrent skin infections: a diagnostic enigma.

Our 25 years of experience with treating patients with recurrent skin infections has resulted in a rational plan that usually solves this diagnostic enigma. Our evaluation consists of a comprehensive examination of the infected tissue, as well as a search for systemic factors and diseases that interfere with host defenses and/or the biology of wound repair. Patient assessment begins with a detailed history, a search for foreign bodies in the wound, as well as histologic and microbiologic examinations of the infected tissue. Clinical recognition and laboratory evaluation for metabolic and endocrinologic dysfunction, a deficiency of the immune system, protein-calorie malnutrition, or a specific defect in collagen synthesis are other integral components of our diagnostic plan for patients with recurrent skin infections.