Is the transnasal access for esophagogastroduodenoscopy in routine use equal to the transoral route? A prospective, randomized trial.

BACKGROUND AND STUDY AIMS: Routine esophagogastroduodenoscopy (EGD) is increasingly performed without sedation. Transoral (TO) and transnasal (TN) EGD offer different patient comfort and complications. PATIENTS AND METHODS: For a controlled, randomized, clinical trial comparing TN-EGD with TO-EGD without sedation, patients were assigned to TN-EGD using a thin endoscope (group 1, 93 patients), or TO-EGD using a standard endoscope (group 2, 90 patients). Physician-rated procedural time and complications as well as patient-rated side effects and preferences were compared. In group 3, patients (118) who had previously undergone TO-EGD, now underwent TN-EGD. RESULTS: Between group 1 and 2 there was no significant difference for procedural time. Nausea (p = 0.047) and epistaxis (p < 0.001) were significantly more frequent for TN-EGD. Conversion rate from TN- to TO-EGD was low with 4.3 %. For TN-EGD, patients' tolerance was better (p < 0.001), gagging was less (p < 0.001). In case of a future EGD, patients who know both procedures (group 3), strongly vote for TN-EGD (80 %). All groups vote against sedation for future procedures (90 %/90 %/89 %). CONCLUSIONS: Epistaxis can be relevant after TN-EGD, but can mostly be managed conservatively. TN-EGD is superior to TO-EGD regarding subjective and objective gagging as well as procedural tolerance. Patients who experienced both access routes, prefer TN-EGD. TN-EGD without sedation should be aspired for patient comfort and is recommended for routine use.

[Evidence-based therapy guideline of the German Working Group on Obesity in Childhood and Adolescence]. / Evidenzbasierte Leitlinie der Arbeitsgemeinschaft Adipositas im Kindes- und Jugendalter zur Therapie der Adipositas im Kindes- und Jugendalter.

Obesity in childhood and adolescence has increased worldwide in recent years. A consensus guideline (S2) for treating obesity in childhood and adolescence in Germany was first published by the German Working Group on Obesity in Childhood and Adolescence (AGA) in 2000. The intention is to gradually replace this consensus-based (S2) guideline with an evidence-based (S3) guideline. Following a systematic literature search, 21 recommendations were predominantly approved with "strong consensus" (agreement >95%). Body weight and body fat mass can be significantly influenced by conventional behavior-based measures and also by the currently available drug therapies. However, the extent of the achieved weight reduction is small. Surgical measures (unproven, experimental therapy) to reduce body weight, in contrast, are very successful. In addition to the long version of this evidence-based guideline, an abbreviated version exists and a practice guideline is planned. This guideline should be further developed within the competence network on obesity of the German Federal Ministry of Education and Research. The guideline will be published in the scholarly journals of the professional associations concerned, will be available via the Internet, and will also be distributed through periodicals, congress events, and information at facilities.

[Treatment of extremely obese adolescents and young adults at the Insula Obesity Center in Bischofswiesen]. / Therapie der extremen juvenilen Adipositas im Adipositas-Zentrum Insula in Bischofswiesen.

The Insula Obesity Center has been treating extremely obese adolescents and young adults since 1992. Various programs ranging from 2-9 months' duration are offered. The mean BMI at admission has been increasing continuously and is presently 41.5 kg/m(2) with occasional extremes over 80 kg/m(2). Obesity comorbidities are common. A mean weight reduction of 1.3 kg/week is achieved during a mean duration of treatment of 4.7 months. Follow-up in residential support groups is offered for up to 2 years for selected patients with special challenges such as lack of family support.

Are overexpressed alternative survivin transcripts in human bladder cancer suitable targets for siRNA-mediated in vitro inhibition?

In order to reduce side effects of survivin-inhibiting anticancer therapies, we determined the expression of the survivin transcripts survivin-wild-type (survivin-wt), survivin-DeltaEx3 (DeltaEx3) and survivin-2B (2B) in cryo-preserved tumor and non-malignant bladder tissues (18 tumor and 22 non-malignant samples, including 17 autologous tissue pairs) by quantitative PCR. Furthermore, we investigated the biological effects following specific inhibition of the alternative transcripts DeltaEx3 and 2B in bladder cancer (BCa) cells. In BCa and non-malignant bladder tissues survivin-wt was the quantitatively dominant transcript followed by DeltaEx3 and 2B. The mean mRNA expression of DeltaEx3 (0.37 vs. 0.06 zmol/amol GAPDH, respectively) and 2B (0.13 vs. 0.01 zmol/amol GAPDH, respectively) was significantly higher in BCa compared to non-malignant bladder tissues, indicating their accessibility for an expression inhibition in BCa cells. Effective and long-lasting small interfering RNA-mediated inhibition of one alternative survivin transcript caused lower cell growth reduction effects (apoptosis induction, cell cycle arrest, colony formation) compared to simultaneous inhibition of multiple survivin transcripts including survivin-wt. Inhibition of one alternative survivin transcript increased the apoptosis rate by 11% vs. 33-46% when reducing several survivin transcripts. We observed no G2/M arrest or reduction of cell colony formation after inhibiting one alternative survivin transcript. Reduction of cell viability by the chemotherapeutics cisplatin, mitomycin C or gemcitabine was stronger in combination with inhibition of several survivin transcripts than in combination with the reduction of one alternative survivin splice variant. Furthermore, reducing one alternative transcript caused chemosensitization to only one chemotherapeutic agent in contrast to inhibition of several survivin transcripts. Therefore, the alternative survivin transcripts DeltaEx3 and 2B do not represent reasonable targets for anticancer, at least BCa, treatment.

[Working hours and job satisfaction among physicians in hospitals and general practice in Munich. Results of an anonymous questionnaire]. / Arbeitszeit und Arbeitszufriedenheit angestellter und beamteter Arzte in München. Ergebnisse einer anonymen Befragung.

PURPOSE: In autumn 2004 the local association of physicians (Arztlicher Kreis- und Bezirksverband München) performed a survey among employed physicians in Munich on working hours and working conditions. The aim of the study was to assess the extent to which the German law on working hours is actually implemented in employed physicians, and to obtain information about their work satisfaction. METHODS: A questionnaire was sent to all employed physicians in hospitals and medical practices. Participants were asked to give anonymous information and send it back per mail. RESULTS: In total, 2450 out of 5461 physicians took part in the survey. 45% reported that their working hours do not meet the German law on working hours of 1994. 44.4% stated that overtime is not fully recognized by their employers. 43.5% think the job would become more attractive if the law was implemented. 63.3% expect an income loss with the implementation. 53.7% are thinking about quitting their job. For 59.9% the burden of long working hours is an important reason for this. Women are more likely to be given a limited employment contract than men, and their overtime is more rarely recognized in full. CONCLUSION: Many employed physicians in Munich are dissatisfied with their job. The high burden of long working hours is a main reason for this.

CandidaDB: a genome database for Candida albicans pathogenomics.

CandidaDB is a database dedicated to the genome of the most prevalent systemic fungal pathogen of humans, Candida albicans. CandidaDB is based on an annotation of the Stanford Genome Technology Center C.albicans genome sequence data by the European Galar Fungail Consortium. CandidaDB Release 2.0 (June 2004) contains information pertaining to Assembly 19 of the genome of C.albicans strain SC5314. The current release contains 6244 annotated entries corresponding to 130 tRNA genes and 5917 protein-coding genes. For these, it provides tentative functional assignments along with numerous pre-run analyses that can assist the researcher in the evaluation of gene function for the purpose of specific or large-scale analysis. CandidaDB is based on GenoList, a generic relational data schema and a World Wide Web interface that has been adapted to the handling of eukaryotic genomes. The interface allows users to browse easily through genome data and retrieve information. CandidaDB also provides more elaborate tools, such as pattern searching, that are tightly connected to the overall browsing system. As the C.albicans genome is diploid and still incompletely assembled, CandidaDB provides tools to browse the genome by individual supercontigs and to examine information about allelic sequences obtained from complementary contigs. CandidaDB is accessible at http://genolist.pasteur.fr/CandidaDB.

[Ever more children and adolescents are overweight. How can the obesity epidemic be stopped?]. / Immer mehr Kinder und Jugendliche zu dick. Wie lässt sich die Adipositas-Epidemie stoppen?

In Germany, the number of overweight children and adolescents is increasing. The increase in the prevalence of obesity shows considerable regional differences. Related to recent German reference data with an expected prevalence of 3%, we find today in some regions a prevalence of 7% in 5- to 6-year-olds and 8% in 13- to 15-year-olds. While the reasons for this development are not fully clear, it may be assumed that the increase in physical inactivity, together with the ready availability of an abundance of high-energy foods are significant contributing factors. A large percentage of children and adolescents suffering from obesity also have considerable co-morbidity. It is to be expected that this will in the future considerably increase the financial burden on public health care and society as a whole. Effective prevention and therapeutic countermeasures are necessary to deal with this problem.

[Obesity in children and adolescents in Germany. Significant and persistent increase of prevalence. Appeal to treatment]. / Adipositas bei Kindern und Jugendlichen in Deutschland. Deutliche und anhaltende Zunahme der Prävalenz--Aufruf zum Handeln.

In Germany, the number of overweight children and adolescents is increasing. The increase in the prevalence of obesity shows considerable regional differences. Related to recent German reference data with an expected prevalence of 3%, we find today in some regions a prevalence of 7% in 5- to 6-year-olds and 8% in 13- to 15-year-olds. While the reasons for this development are not fully clear, it may be assumed that the increase in physical inactivity, together with the ready availability of an abundance of high-energy foods are significant contributing factors. A large percentage of children and adolescents suffering from obesity also have considerable co-morbidity. It is to be expected that this will in the future considerably increase the financial burden on public health care and society as a whole. Effective prevention and therapeutic countermeasures are necessary to deal with this problem.

Voltage-gated K+ channels in chemoreceptor sensory neurons of rat petrosal ganglion.

A subpopulation of sensory neurons in the petrosal ganglion transmits information between peripheral chemoreceptors (glomus cells) in the carotid body and relay neurons in the nucleus of the solitary tract. Expression of voltage-gated K+ channels in these neurons was characterized by immunohistochemical localization. Five members of the Kv1 family, Kv1.1, Kv1.2, Kv1.4, Kv1.5 and Kv1.6 and members of two other families, Kv2.1 and Kv4.3, were identified in over 90% of the chemoreceptor neurons. Although the presence of these channel proteins was consistent throughout the population, individual neurons showed considerable variation in K+ current profiles.

Thomsen-Friedenreich antigen presents as a prognostic factor in colorectal carcinoma: A clinicopathologic study of 264 patients.

BACKGROUND: Up to now, the expression of the tumor-associated Thomsen-Friedenreich (TF) antigen in colorectal carcinoma has not been thoroughly investigated with particular emphasis on its correlation with established clinicopathologic characteristics and classifications as well as its prognostic relevance. METHODS: Formalin fixed, paraffin embedded specimens from 264 patients with colorectal carcinoma were stained using an avidin-biotin complex-peroxidase assay. As primary monoclonal antibodies (MAbs), A78-G/A7, which binds to TFalpha and TFbeta antigen irrespective of its carrier, and BW835, which detects TFalpha on MUC1 repeat peptide, were applied. RESULTS: MAbs A78-G/A7 and BW835 labeled 64.8% and 58. 0%, respectively, of carcinomas. None of the binding patterns correlated with gender, tumor localization, or growth type. Only BW835 reactivity exhibited a significant correlation with increasing pTNM staging and histologic grading. Staining of the MAb A78-G/A7 was significantly stronger in carcinomas that contained a mucinous component. In univariate survival analysis, in addition to pTNM staging and histologic grading, reactivity with A78-G/A7 as well as BW835 were significantly correlated with lower survival probability. Multivariate analysis according to the Cox proportional hazards model revealed only pTNM staging, histologic grading, and A78-G/A7 staining to be independent prognostic factors. CONCLUSIONS: According to these results, TF disaccharide represents a cancer-associated antigen in colorectal carcinoma that exhibits qualities of a prognostic marker. As demonstrated by BW835 staining, it is obviously coexpressed with MUC1 peptide core in a great number of cases. These results suggest that TF, in addition to MUC1, might also serve as a useful target antigen in the treatment of patients with colorectal carcinoma.

Prognostic impact of p21/waf1/cip1 in colorectal cancer.

In addition to the tumor suppressor gene p53, Cyclin Dependent Kinases (CDK) are well known to influence the cell cycle in normal human tissues and various neoplasias as well. The purpose of our present study was to evaluate the expression of the CDK-inhibitor p21/waf1/cip1 in colorectal cancer with special emphasis on the prognostic impact. Between 1985 and 1991, 294 patients (median age, 65 years) underwent surgical operative therapy for colorectal cancer. Formalin-fixed and paraffin-embedded tumor specimens were investigated. For immunohistochemistry the Catalysed Reporter Deposition (CARD) technique was performed. The survival probability was calculated and possible prognostic risk factors were tested using multivariate analysis. The p21/ waf1/cip1 staining pattern was positive in 197 (67%) specimens and negative in 97 (33%) samples. No significant correlation could been calculated between p21/waf1/cip1 expression and other variables such as age, sex, WHO-Classification, localisation, grading, TNM-classification or UICC-stage. Patients with a positive staining reaction had a significantly better survival (p < 0.0052). Moreover, p21/waf1/cip1 was shown to be an independent prognostic parameter by multivariate analysis (p < 0.022). In contrast with these findings, the p53 tumor status had no impact on survival. P21/ waf1/cip1 appears to be an independent prognostic parameter in colorectal cancer and is associated with a favorable survival. This feature may be related to a cell cycle arrest in the G1 phase induced by p21/waf1/cip1, resulting in lower tumor cell proliferative activity.

Brain-derived neurotrophic factor acutely inhibits AMPA-mediated currents in developing sensory relay neurons.

Brain-derived neurotrophic factor (BDNF) is expressed by many primary sensory neurons that no longer require neurotrophins for survival, indicating that BDNF may be used as a signaling molecule by the afferents themselves. Because many primary afferents also express glutamate, we investigated the possibility that BDNF modulates glutamatergic AMPA responses of newborn second-order sensory relay neurons. Perforated-patch, voltage-clamp recordings were made from dissociated neurons of the brainstem nucleus tractus solitarius (nTS), a region that receives massive primary afferent input from BDNF-containing neurons in the nodose and petrosal cranial sensory ganglia. Electrophysiological analysis was combined in some experiments with anterograde labeling of primary afferent terminals to specifically analyze responses of identified second-order neurons. Our data demonstrate that BDNF strongly inhibits AMPA-mediated currents in a large subset of nTS cells. Specifically, AMPA responses were either completely abolished or markedly inhibited by BDNF in 73% of postnatal day (P0) cells and in 82% of identified P5 second-order sensory relay neurons. This effect of BDNF is mimicked by NT-4, but not NGF, and blocked by the Trk tyrosine kinase inhibitor K252a, consistent with a requirement for TrkB receptor activation. Moreover, analysis of TrkB expression in culture revealed a close correlation between the percentage of nTS neurons in which BDNF inhibits AMPA currents and the percentage of neurons that exhibit TrkB immunoreactivity. These data document a previously undefined mechanism of acute modulation of AMPA responses by BDNF and indicate that BDNF may regulate glutamatergic transmission at primary afferent synapses.

Opioid modulation of calcium current in cultured sensory neurons: mu-modulation of baroreceptor input.

We used the whole cell open-patch or perforated-patch technique to characterize mu-opioid modulation of Ca(2+) current (I(Ca)) in nodose sensory neurons and in a specific subpopulation of nodose cells, aortic baroreceptor neurons. The mu-opiate receptor agonist Tyr-D-Ala-Gly-MePhe-Gly-ol enkephalin (DAGO) inhibited I(Ca) in 95% of neonatal [postnatal day (P)1-P3] nodose neurons. To the contrary, only 64% of juvenile cells (P20-P35) and 61% of adult cells (P60-P110) responded to DAGO. DAGO-mediated inhibition of I(Ca) was naloxone sensitive, irreversible in the presence of guanosine 5'-O-(3-thiotriphosphate), absent with guanosine 5'-O-(2-thiodiphosphate), and eliminated with pertussis toxin; DAGO's inhibition of I(Ca) was G protein mediated. Incubation of neurons with omega-conotoxin GVIA eliminated the effect of DAGO in neonatal but not in juvenile cells. In the latter, DAGO reduced 37% of the current remaining in the presence of omega-conotoxin. In the subset of nodose neurons, aortic baroafferents, the effect of DAGO was concentration dependent, with an IC(50) of 1.82 x 10(-8) M. DAGO slowed activation of I(Ca), but activation curves constructed from tail currents were the same with and without DAGO (100 nM). In summary, mu-opiate modulation of I(Ca) in nodose neurons was demonstrated in three age groups, including specifically labeled baroafferents. The demonstration of a mechanism of action of mu-opioids on baroreceptor afferents provides a basis for the attenuation of the baroreflex that occurs at the level of the nucleus tractus solitarii.

Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes.

The protein sequence encoded by a creatine transporter cDNA cloned from a human heart library was identical to that cloned from a human kidney library (Nash et al., Receptors Channels 2, 165-174, 1994), except that at position 285 the former contained an Ala residue and the latter contained a Pro residue. Expression of this human heart cDNA clone in Xenopus laevis oocytes induced a Na+- and Cl--dependent creatine uptake activity that saturated with a Km of approximately 20 microM for creatine. The induced uptake was inhibited by beta-guanidinopropionic acid (IC50 approximately 44.4 microM), 2-amino-1-imidazolidineacetic acid (cyclocreatine; IC50 approximately 369.8 microM), gamma-guanidinobutyric acid (IC50 approximately 697.9 microM), gamma-aminobutyric acid (IC50 approximately 6.47 mM), and amiloride (IC50 approximately 2.46 mM). The inhibitors beta-guanidinopropionic acid, cyclocreatine, and gamma-guanidinobutyric acid also inhibited the uptake activity of the Ala285 to Pro285 (A285P) mutant as effectively as that of the wild type. In contrast, guanidinoethane sulfonic acid, a potent inhibitor of taurine transport, inhibited the uptake activity of the A285P mutant approx. two times more effectively than that of the wild type. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA), but not its inactive analog, 4alpha-phorbol 12, 13-didecanoate, inhibited the creatine uptake, and the inhibitory effect of PMA was both time and concentration dependent. The protein kinase A activator 8-bromo-cyclic AMP, however, had no effect on the creatine uptake. The rate of uptake increased hyperbolically with the increasing concentration of the external Cl- (equilibrium constant KCl- approximately 5 mM) and sigmoidally with the increasing concentration of the external Na+ (equilibrium constant KNa+ approximately 56 mM). Further analyses of the Na+ and Cl- concentration dependence data suggested that at least two Na+ and one Cl- were required to transport one creatine molecule via the creatine transporter.

Contribution of the hyperpolarization-activated current to the resting membrane potential of rat nodose sensory neurons.

1. The voltage- and time-dependent characteristics of the hyperpolarization-activated current (IH) and its contribution to the resting membrane potential of neonatal rat nodose sensory neurons were investigated using the whole-cell tight seal method of voltage and current clamp recording. 2. IH was found in all neonatal nodose neurons in vitro, contrary to previous reports where its presence was particular for A-type neurons. We used the presence of both tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium currents to distinguish C- from A-type neurons (TTX-S only). We obtained further support for the presence of IH in C-type neurons with experiments in which IH was demonstrated in a subset of neurons sensitive to capsaicin. 3. In both groups IH activated at potentials negative to -50 mV, developed slowly with time and was inhibited by 1-5 mM extracellular caesium. At -120 mV, IH activated with a fast time constant of 73 +/- 3 ms in A-type neurons and 163 +/- 37 ms in C-type neurons (P < 0.05). A second, slower time constant of 682 +/- 83 ms was observed in A-type neurons and 957 +/- 122 ms in C-type neurons. 4. A- and C-type neurons differed in the amplitude of IH. The mean magnitude of IH at -110 mV was -2338 +/- 258 pA in A-type neurons but only -241 +/- 40 pA (P < 0.001) in C-type neurons. This disparity persisted when currents were normalized for capacitance. The reversal potentials for IH were -39 +/- 4 mV for A-type neurons and -37 +/- 5 mV for C-type neurons (P > 0.05). 5. During current clamp recording IH caused time-dependent rectification in response to hyperpolarizing current injections from the resting membrane potential. CsCl abolished the rectification and hyperpolarized the resting potential of A-type neurons from -55 +/- 3 mV to -61 +/- 4 mV and C-type neurons from -62 +/- 2 mV to -71 +/- 3 mV. Taken together, the results in these studies indicate that IH contributes to the resting membrane potential in all nodose neurons.

Analysis of a Ca2+-activated K+ channel that mediates hyperpolarization via the thrombin receptor pathway.

Dami human leukemia cells express G protein-coupled thrombin receptors that operate through the phospholipase C pathway. When these receptors are activated by alpha-thrombin or by thrombin receptor-activating peptide, an elevation in cytosolic Ca2+ concentration develops that is accompanied by hyperpolarization of the plasma membrane. This transitory phase of hyperpolarization is primarily mediated by inwardly rectifying, Ca2+-activated K+ channels that have an inward conductance of approximately 24 pS. In cell-attached patches the channels open within seconds after superfusion of the cell with thrombin receptor-activating peptide. In inside-out patches, perfusion of submicromolar Ca2+ onto the cytosolic surface of the membrane is sufficient to activate the channels. In outside-out patches, channel opening can be blocked by nanomolar concentrations of charybdotoxin. The function of these intermediate-sized inwardly rectifying, Ca2+-activated K+ channels has not been established; however, by analogy with other cell systems, they may serve to regulate cell volume during cellular activation or to increase the electromotive drive that sustains Na+ and/or Ca2+ influx through ligand-gated cation channels.

Inwardly rectifying K+ channels in dispersed bovine parathyroid cells.

Excitation-secretion coupling in various endocrine cells is dependent on membrane voltage which is controlled by ion channels. In order to characterize and determine the functional significance of voltage-gated ion channels in the parathyroid cell, the patch clamp technique was used in cell-attached and whole cell configurations to study single channel and whole cell currents in dispersed bovine parathyroid cells. Whole cell voltage clamp recordings from dissociated bovine parathyroid cells were obtained in a physiologic solution containing (in mM): 140 NaCl, 5.4 KCI, 2 CaCl2, and 2 MgCl2. The pipette (intracellular) solution contained (in mM) 145 KAsp, 10(-5) CaCl2, and 2 MgCl2. Currents were recorded in response to 20-mV incremental changes in voltage of 300-ms duration every 3 s from -80 to +40 mV and from -40 to -140 mV. There was a small outward current recorded in response to 300-ms pulses of 20-mV increments from -80 to +40 mV. A large inward current was recorded following hyperpolarization of the parathyroid cell from -40 to -140 mV. The reversal potential for the current was -60 to -65 mV, suggesting that the majority of the current is carried by a channel that is K+ selective. Our results suggest that the whole cell currents of dispersed bovine parathyroid cells in physiologic extracellular solution include an in inwardly rectifying K+ current which is open at low intracellular calcium concentration. This inwardly rectifying K+ channel is likely to play a major role in maintaining negative membrane potential by opposing calcium-induced depolarization of the parathyroid cell and, as a result, may have an important role in regulation of PTH secretion.