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Titanium dioxide (TiO(2)) nanoparticles are extensively used today in sunscreens and coatings as protective compounds for human skin and material surfaces from UV radiation. In this paper, such particles are investigated by electron paramagnetic resonance spectroscopy as sources of free radicals under UV irradiation. The surface density of a placebo with embedded particles corresponds to the recommendations of dermatologists (2 mg cm(-2)). It is revealed that if applied onto glass, small particles 25 nm in diameter produce an increased amount of free radicals compared to the larger ones of 400 nm diam and the placebo itself. However, if applied onto porcine skin in vitro, there is no statistically distinct difference in the amount of radicals generated by the two kinds of particles on skin and by the skin itself. This proves that although particles as part of sunscreens produce free radicals, the effect is negligible in comparison to the production of radicals by skin in vitro.

Background: Symptoms of gastroesophageal reflux are widely prevalent. There is a continuum between subjects with mild reflux symptoms and those severely affected by gastroesophageal reflux disease (GERD). Both groups may at times access over-the-counter (OTC) therapies. For the purpose of this review, relevant papers, including national and international guidelines were reviewed and recommendations made for appropriate use of OTC proton pump inhibitor (PPI) therapy., Results: PPIs are the gold standard for treatment of reflux symptoms. OTC therapy with histamine(2) receptor antagonists (H2RAs) also plays a role. For the majority affected by reflux symptoms, effective symptom control is the most important outcome, as only a subgroup requires investigations or interventions. However, patients with alarm features (i.e. troublesome dysphagia, weight loss, predominant upper abdominal pain) are not recommended for OTC therapy and need prompt medical referral. Frequent relapses or failure to adequately respond to OTC therapy are additional triggers for medical assessment., Conclusions: OTC treatment of typical reflux symptoms (acid regurgitation, heartburn) with antacids and H2RAs is now accepted as safe and results in short-term relief of symptoms. There is no evidence of additional risk with OTC PPIs compared to these existing OTC therapies and PPIs are significantly more efficacious., (2009 S. Karger AG, Basel.)

Objective: Tricyclic antidepressants (TCAs) are well established in the treatment of patients with irritable bowel syndrome (IBS). The effects are believed to be linked to serotoninergic antinociceptive properties, but data on the antinociceptive effects of various TCAs with variable serotoninergic and non-serotoninergic properties have not been investigated. The aim of this study was to compare the antinociceptive effects of different TCAs., Material and Methods: Colorectal distension (CRD) using a barostat device was carried out in rats and the visceromotor response (VMR) to CRD was quantified by abdominal wall electromyography. Prior to CRD, saline (control), amitriptyline (AM), desipramine (DES), reserpine (RES) or a combination of TCAs and RES (AM + RES or DES + RES) was applied intraperitoneally. Serum 5-HT levels were determined using high-performance liquid chromatography (HPLC). RES was used to antagonize the serotoninergic actions of TCAs in order to discriminate between these effects and others., Results: Both TCAs decreased the VMR compared to placebo. After RES application without TCAs, the VMR was increased compared to controls (6403 microV+/-1772 microV). Co-administration of AM and RES resulted in a modest decrease in VMR (5774 microV+/-1953 microV), while in rats treated with RES and DES the VMR again was significantly lower (3446 microV (+/-1347 microV; p <0.05)). 5-HT levels were higher in TCA pretreated rats than those in controls and significantly lower 5-HT levels were found in all rats pretreated with RES., Conclusions: AM and DES have antinociceptive properties while RES is pro-nociceptive. The antinociceptive effects of DES are not abolished by RES pretreatment, while AM only attenuates the pro-nociceptive effects of RES. The non-serotoninergic properties of TCAs substantially contribute to the differences in the antinococeptive effects of various TCAs.

In lung fibroblasts, proliferation is inhibited by activation of EP(2) prostanoid receptors which are known to couple to adenylyl cyclase. Beside the classic target of cAMP, protein kinase A (PKA), alternative cAMP effectors have been identified, among them Epac (exchange protein activated by cAMP). The present study aimed to illuminate transduction pathways mediating the anti-proliferative effects of EP(2) receptors in lung fibroblasts. Proliferative activity of human lung fibroblasts was determined by measuring [(3)H]-thymidine incorporation. The selective EP(2) receptor agonist butaprost inhibited [(3)H]-thymidine incorporation by 75%, an effect mimicked by forskolin, the phosphodiesterase inhibitor IBMX, the stable cAMP analogues dibutyryl-cAMP and bromo-cAMP, as well as by the Epac selective cAMP analogues 8-pCPT-2'-O-Me-cAMP and Sp-8-pCPT-2'-O-Me-cAMPS, whereas the PKA selective agonist 6-Bnz-cAMP was inactive. The PKA inhibitor Rp-8-Br-cAMPS inhibited butaprost-induced phosphorylation of CREB (cAMP response element-binding protein), but did not affect butaprost-induced inhibition of [(3)H]-thymidine incorporation. Partial knockdown of Epac1 by specific siRNA transfection resulted in a marked attenuation of the inhibitory potency of butaprost, whereas transfection of Epac2 siRNA or non-silencing siRNA did not affect the effectiveness of butaprost to inhibit [(3)H]-thymidine incorporation. In conclusion, Epac1 rather than the classic cAMP effector PKA is a crucial element in the signal transduction pathway mediating anti-proliferative effects of EP(2) receptor activation.

Clinical observations indicate that in chronic obstructive pulmonary disease patients, the long-acting muscarinic antagonist tiotropium delays decline in airway function, suggesting that cholinergic mechanisms contribute to long-term structural changes. Human lung fibroblasts express muscarinic receptors and the present study aimed to explore their role in controlling collagen synthesis. MRC-5, HEL-299 and primary human lung fibroblasts (phLFb) were cultured. Incorporation of [(3)H]-proline into cellular proteins was determined as measure of collagen synthesis. In MRC-5 cells, the muscarinic agonist carbachol enhanced [(3)H]-proline incorporation in a concentration-dependent manner (effective concentration of 50%: 220 nM, increase at 10 microM by 40-55%, in a different series of experiments). Likewise, 10 microM oxotremorine caused an increase of approximately 65%. For comparison, transforming growth factor-beta1 (5 ng x mL(-1)) caused an increase of approximately 80%. Effects of carbachol on total [(3)H]-proline incorporation and collagenase-sensitive [(3)H]-proline fraction were similar. The effect of 10 microM carbachol was inhibited by tiotropium (inhibitory concentration of 50%: 110 pM), prevented by pertussis toxin and the mitogen-activated protein kinase inhibitor, PD 98059. Muscarinic agonists also enhanced [(3)H]-proline incorporation in a tiotropium-sensitive manner in HEL-299 cells and phLFb. In human lung fibroblasts, muscarinic receptors exert stimulatory effects on collagen synthesis. Prolonged blockade of muscarinic-induced collagen synthesis may contribute to reported beneficial long-term effects of anticholinergics in chronic obstructive pulmonary disease.

Fibrotic alterations are part of the airway re-modelling processes observed in asthma and chronic obstructive pulmonary disease. There is increasing evidence that in addition to acute bronchodilatory effects, classical anti-obstructive drugs such as muscarinic antagonists and beta-adrenoceptor agonists may also modulate long-term re-modelling processes. The present review aims to summarise muscarinic and beta-adrenergic effects on pulmonary fibroblasts. Recent experimental evidence demonstrated muscarinic stimulatory effects on pulmonary fibroblasts, and long-term blockade of these pro-fibrotic effects may contribute to the beneficial effects of muscarinic antagonists, as observed particularly for the long-acting muscarinic antagonist tiotropium. On the other hand, beta-adrenoceptor agonists, via activation of adenylyl cyclase, can also exert various inhibitory effects on pulmonary fibroblasts, and these anti-fibrotic effects are mimicked by other agents that cause an increase in intracellular cyclic adenosine monophosphate (cAMP), such as phosphodiesterase inhibitors or EP2 prostanoid receptor agonists. In addition, the role of the extracellular signal-regulated kinase-mitogen-activated protein kinase pathway, protein kinase A and exchange protein activated by cAMP (Epac) and potential interactions between these cellular signalling pathways are discussed.

Long-term memory of haptic, visual, and cross-modality information was investigated. In Experiment 1, subjects briefly explored 40 commonplace objects visually or haptically and then received a recognition test with categorically similar foils in the same or the alternative modality both immediately and after 1 week. Recognition was best for visual input and test, with haptic memory still apparent after a week's delay. Recognition was poorest in the cross-modality conditions, with performance on the haptic-visual and visual-haptic cross-modal conditions being nearly identical. Visual and haptic information decayed at similar rates across a week delay. In Experiment 2, subjects simultaneously viewed and handled the same objects, and transfer was tested in a successive cue-modality paradigm. Performance with the visual modality again exceeded that with the haptic modality. Furthermore, initial errors on the haptic test were often corrected when followed by the visual presentation, both immediately and after 1 week. However, visual test errors were corrected by haptic cuing on the immediate test only. These results are discussed in terms of shared information between the haptic and visual modalities, and the ease of transfer between these modalities immediately and after a substantial delay.

Background: Health-related quality of life (HRQOL) is a marker of disease severity. Data on the relative impairment of HRQOL in chronic liver disease (CLD) and functional gastrointestinal disorders are lacking and no studies have assessed the link between impairment of HRQOL and psychosocial factors yet., Aim: To assess predictors for, and the impairment of, HRQOL in CLD and FD., Methods: In 181 functional dyspepsia (FD) patients, 204 CLD patients and 337 healthy blood donors, HRQOL was assessed with the Short Form-36 (mental and physical component), and anxiety and depression utilizing the Hospital Anxiety and Depression Scale., Results: Compared with HC, HRQOL is significantly lower in FD and CLD (P-value for all <0.001). The mental but not physical component of HRQOL was significantly more impaired in FD compared with CLD (P < 0.05). After adjusting for confounders, impairment of mental (P < 0.001) and physical (P = 0.005) component of HRQOL was associated with the severity of CLD and FD. In FD, the multivariate analysis revealed depression and severity of symptoms as the most important predictors of HRQOL (R2 = 21.9 and 7.1). In CLD, the mental component of HRQOL was associated with depression and anxiety (R(2) = 9.9 and 9.7)., Conclusions: In tertiary care, HRQOL is more severely impaired in FD compared with CLD. Co-morbid psychiatric conditions significantly contribute to the impairment of HRQOL.

Previous research has reported that when compared to heterosexual women, lesbians may use alcohol and illicit substances to a greater degree and may experience greater psychiatric symptomatology. This study sought to describe any differences in clinical diagnoses, familial histories, and substance usage between lesbian and heterosexual women in a psychiatric outpatient clinic. A chart review was conducted and a sample of 455 heterosexuals and 75 lesbians was obtained. Data, where available, included demographic information, clinical diagnoses, time in treatment, sexual orientation, past and present substance use, and familial substance abuse and psychiatric history. Lesbians were found to have greater past illicit substance use but less current use. No significant differences were found for alcohol use. Similarly, no significant differences in clinical diagnoses were found. Significant differences were found among families. Family members of lesbians had greater substance use and psychiatric histories. These findings both support and dispute some previous research and suggest areas for future researchers to explore.

Endothelin (ET) stimulates potent ETA/ETB receptors important in the pathogenesis of pulmonary arterial hypertension (PAH) and fibrosis. Though therapy with ET-receptor antagonists is well established uncertainty exists whether selective ETA or dual ETA/ETB-receptor antagonism is superior in PAH. The objective of this study was to further elucidate the pro-inflammatory effects of ET-1 on ETB receptors in cultured human monocytes (10(5)/20 h) compared with non-specific stimulation with LPS in vitro and to define the antagonizing effects of bosentan, a dual ETA/ETB-receptor antagonist, on inflammatory mediator production. We further hypothesized that ETB-receptor antagonism reduces the requirement of PGE2 to control inflammatory mediator production. Activation of the monocyte ETB subtype by ET (1 ng/ml) concentration-dependently stimulated TNF-alpha (744%) >PGE2 (570%) > IL-1 beta (112%) and had no effect on 5-lipoxygenase metabolism. Compared with ET a different profile of IL-1 beta >TNF-alpha >PGE2 was induced by LPS. ETB-receptor antagonism attenuated ET- and LPS-responses in monocytes, in particular of TNF-alpha and PGE2 to a similar extend (40%) that were only demonstrable following LPS at therapeutic plasma concentrations of bosentan and had no effect on IL-1 beta. Inhibition of ETB receptors in LPS-stimulated monocytes by bosentan was responded with suppression of PGE2 and increased production of leukotrienes indicating strong effects in the cyclooxygenase pathway that is known to control cellular ET transcription. These data suggest an important signaling pathway between ET-induced cytokine production following ETB-receptor activation with no further control of ET transcription by PGE2 required following ETB receptor antagonism. Therefore, in states of inflammation increased ETB-receptor expression and activation mediated by elevated ET concentrations may be an underestimated mechanism, which warrants the application of combined ETA/ETB-receptor antagonists.

Background: The mechanisms of interindividual variations in visceral pain sensitivity remain poorly understood. We characterized the neuroendocrine responses to rectal distensions in healthy individuals with high vs. low rectal pain sensitivity., Methods: Rectal sensory and pain thresholds were determined, and a series of random painful distensions was carried out. Eighteen subjects were stratified into groups with a low rectal pain threshold ("High Sensitivity" group) vs. a high rectal pain threshold ("Low Sensitivity" group) by median split, and were compared with regard to adrenocorticotropic hormone (ACTH) and cortisol, cardiovascular, and emotional responses., Results: Distensions led to an anticipatory stress response, reflected by elevated baseline anxiety, and increased baseline ACTH and cortisol in both groups. In response to distensions, the "Low Sensitivity" group showed significantly greater ACTH and cortisol concentrations analysis of variance (ANOVA time x group for ACTH: p<.05; for cortisol: p<.01), and elevated diastolic blood pressures (BP) (ANOVA group: p<.01) when compared to the "High Sensitivity" group., Conclusions: Painful rectal distensions are associated with a pronounced anticipatory stress response, reflected by elevated anxiety and elevated stress hormones. Individuals with high rectal pain sensitivity differ from those with low pain sensitivity in distension-induced hormonal and blood pressure responses, suggesting that neuroendocrine responses may be relevant to the pathophysiology of visceral hyperalgesia.

Aim: In a prospective randomized, controlled trial, to compare the long-term outcome of intensive medical therapy (with or without cognitive-behavioural or muscle relaxation therapy) vs. standard medical therapy in patients with refractory functional dyspepsia (FD), referred to a tertiary referral medical center., Methods: A total of 100 consecutive FD patients were allocated to a standardized symptom-oriented 4 month therapy (SMT, n = 24), intensive medical therapy (IMT, medical therapy with testing-for and targeting-of abnormalities of motor-and-sensory function, n = 28) or IMT plus psychological interventions (either progressive-muscle relaxation (IMT-MR, n = 20) or cognitive-behavioural therapy (IMT-CBT, n = 28). The symptom intensity (SI) and health-related quality-of-life (HRQoL) after 12 months were prespecified primary outcome parameters., Results: After 12 months, significantly greater improvement of SI occurred in patients with IMT-all (with or without psychological interventions) compared with SMT (P < 0.025 vs. IMT-all). IMT, IMT-MR and IMT-CBT alone also resulted in significantly better improvement of the primary outcome parameters (P all < 0.025 vs. SMT). HRQoL significantly improved in all groups with intensive medical therapy but not standard medical therapy. Differences between intensive medical therapy-all and standard medical therapy were not significant. Concomitant anxiety and depression was improved significantly by IMT-CBT (vs. SMT) but not other treatments., Conclusions: In FD patients with refractory symptoms, intensified medical management involving function testing and psychological intervention yields superior long-term-outcomes. Additional CBT may be effective for the control of concomitant anxiety and depression.

Objective: Psychological stress has been implicated in the pathophysiology of both inflammatory and functional gastrointestinal (GI) diseases. The goal of this study was to address neuroendocrine modulation of cytokine production by peripheral blood cells in GI diseases., Methods: We analyzed the in vitro effects of the beta-adrenergic agonist terbutaline and the glucocorticoid agonist dexamethasone on TNF-alpha and IL-10 production by LPS-stimulated monocytes in whole cell blood cultures in patients with inflammatory bowel diseases in remission (N=10), diarrhoea-predominant irritable bowel syndrome (IBS, N=12), patients with a recent gastroenteritis (post-infectious group, N=10), and healthy controls (N=15)., Results: In response to terbutaline, there was a significant increase in IL-10 production (concentration effect: p<0.05), which was diminished in IBD (group effect: p<0.01), comparable in IBS and controls, but enhanced in the post-infectious group (group x concentration effect: p<0.05). In contrast, terbutaline resulted in a concentration-dependent suppression of TNF-alpha production, which was comparable in all groups. Dexamethasone suppressed TNF-alpha production in a dose-dependent manner in all groups, but this effect was significantly more pronounced in post-infectious subjects (group effect: p<0.05)., Conclusions: In IBD, disturbed adrenergic regulation of IL-10 could be part of the mechanism(s) underlying the modulation of disease activity by psychological stress. Diarrhoea-predominant IBS was not associated with altered adrenergic or glucocorticoid regulation of cytokine production by peripheral blood cells, whereas a recent history of gastroenteritis was associated with disturbed neuroendocrine modulation of cytokine production, which may play role in the pathophysiology of post-infectious IBS.

Airway remodeling is a structural alteration associated with chronic inflammatory and obstructive airway diseases, wherein fibroblasts are crucially involved. The present study investigates whether lung fibroblast proliferation is influenced by muscarinic mechanisms. For this purpose, expression of muscarinic receptors in MRC-5 human lung fibroblasts was characterized by semiquantitative RT-PCR, and the effects of muscarinic agonists and antagonists on ((3)H)-thymidine incorporation as a measure of proliferative activity were studied under different culture conditions. MRC-5 fibroblasts express mRNA encoding different subtypes of muscarinic receptors (M(2) > M(3) > M(4), traces for M(5) and no M(1)). Expression of M(2) and M(3) receptors was confirmed at the protein level by immunoblot analysis. Under different culture conditions, carbachol (up to 10 microM) or oxotremorine (10 microM) stimulated ((3)H)-thymidine incorporation, with maximum increases between about 40 and 100%. The stimulatory effect of 10 microM carbachol was prevented by pretreatment with pertussis toxin and antagonized in a concentration-dependent manner by the muscarinic receptor antagonists tiotropium, AQ-RA 741, AF-DX 384, 4-diphenylacetoxy-N-methylpiperidine methoiodide, himbacine, p-fluorohexahydrosiladifenidol, and pirenzepine, with concentrations producing 50% inhibition of 14 pM, 24, 64, 127, 187, 452 nM, and 1.5 microM, respectively. Primary human lung fibroblasts were also found to express mRNA for muscarinic receptors (M(2) > M(1) > M(3), traces for M(4) and no M(5)), and showed a pertussis toxin-sensitive proliferative response to muscarinic receptor stimulation. In conclusion, proliferation of human lung fibroblasts can be stimulated by activation of muscarinic receptors with a pharmacologic profile correlating best to M(2) receptors.

Background: In Germany the physician staffed emergency systems have announced an increase in rescue missions over the years. The aim of this study is to analyse the development of the spectrum of patients in an emergency system over the last 20 years in order to highlight the significant changes., Methods: In a retrospective study we analyzed the prehospital chart views from 2004, 1992 and 1984 with respect to patients' demography, type of rescue mission, degree of internal disease or injury (NACA), state of consciousness (GCS), as well as prehospital interventions performed by prehospital emergency physician., Results: In 2004 (3,825), the absolute number of missions was 2 and 4 times higher than 1992 (2,114) and 1984 (957), resp. In all of these investigated time periods non-trauma missions (74%; 2,812 vs. 66%; 1,390 vs. 51%; 485) were leading, followed by trauma missions (18%; 690 vs. 22%; 464 vs. 39%; 375), aborted missions (3%; 126 vs. 7%; 154 vs. 6%; 56), and dead on arrival (5%; 197 vs. 5%; 106 vs. 4%; 41). Although, the percentage of patients with NACA IV-VI (39% vs. 50%) or patients with GCS < or =8 (18% vs. 34%) was lower in 2004, the absolute number of patients in each category was higher than in 1984 (NACA IV-VI: 1,434 vs. 448, p<0.01; GCS: 672 vs. 303, p<0.01)., Conclusions: The results of this study demonstrate, that the percentage of trauma, severely ill/injured or unconscious patients is lower than in previous years. However, the higher absolute numbers of patients demonstrate that the emergency physician now encounters more critically ill/injured, unconscious and trauma patients. It does not seem necessary to question the qualifications for an emergency physician, which have previously been considered essential for the management of acute life-threatening situations.

Objectives: Augmented neuroendocrine stress responses and altered immune functions may play a role in the manifestation of functional gastrointestinal (GI) disorders. We tested the hypothesis that IBS patients would demonstrate enhanced psychological and endocrine responses, as well as altered stress-induced redistribution of circulating leukocytes and lymphocytes, in response to an acute psychosocial stressor when compared with healthy controls., Methods: Responses to public speaking stress were analyzed in N = 17 IBS patients without concurrent psychiatric conditions and N = 12 healthy controls. At baseline, immediately following public speaking, and after a recovery period, state anxiety, acute GI symptoms, cardiovascular responses, serum cortisol and plasma adrenocorticotropic hormone (ACTH) were measured, and numbers of circulating leukocytes and lymphocyte subpopulations were analyzed by flow cytometry., Results: Public speaking led to significant cardiovascular activation, a significant increase in ACTH, and a redistribution of circulating leukocytes and lymphocyte subpopulations, including significant increases in natural killer cells and cytotoxic/suppressor T cells. IBS patients demonstrated significantly greater state anxiety both at baseline and following public speaking. However, cardiovascular and endocrine responses, as well as the redistribution of circulating leukocytes and lymphocyte subpopulations after public speaking stress, did not differ for IBS patients compared with controls., Conclusions: In IBS patients without psychiatric comorbidity, the endocrine response as well as the circulation pattern of leukocyte subpopulations to acute psychosocial stress do not differ from healthy controls in spite of enhanced emotional responses. Future studies should discern the role of psychopathology in psychological and biological stress responses in IBS.

Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation. All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls. Mean serum IgG trough levels increased in the pre-IVIG children from 7.8 to 9.2 g/L (non-inferiority: p < 0.001) and in the adults from 8.6 to 8.9 g/L (non-inferiority: p < 0.001). Totally 114 respiratory tract infections occurred, 90% of them mild. One serious bacterial infection (pneumonia) was reported for one adult. The annualized rate of serious infections was 0.04 episodes/patient. In total 2297 infusions were given and 28 (1%) systemic adverse reactions occurred, none of them severe. Local tissue reactions declined over time, this being particularly distinct after 8 to 10 weeks. In conclusion, the SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections.

The lifelong IgG replacement therapy for patients with primary immunedeficiencies (PIDD) may be provided by intravenous (IVIG) or by subcutaneous IgG (SCIG) infusions. We investigated the impact of weekly SCIG self-infusions at home on the health-related quality of life, treatment satisfaction, and preferences in patients treated with IVIG at the hospital/doctor's office (Group A) or at home (Group B) before the study started. Forty-four adult North American PIDD patients were included in the study, 28 patients in Group A and 16 in Group B. Patients in Group A reported significantly less limitations with their work/daily activities, a significantly improved vitality, and better general health. Treatment satisfaction was significantly improved in Group A. The preference for the subcutaneous route and for home therapy was respectively 81% and 90% in Group A. In Group B, 69% preferred the subcutaneous route and 92% home therapy.

Background: The aim of this study was to evaluate the frequency and the assessment of the different conservative modalities of treatment in Peyronie's disease. A representative survey among 3187 German urologists was performed using a standardized questionnaire comprising currently used concepts of therapy, their efficacy, and their tolerability., Material and Methods: A total of 636 urologists participated in the study. Altogether they had treated 6019 patients with Peyronie's disease in 2003. The majority of urologists treated between 3 and 15 patients per year. The most frequent treatment modality was the administration of potassium paraaminobenzoate, followed by vitamin E and extracorporeal shock wave therapy. Other oral drugs and intralesional drug administrations were used considerably less frequently., Results: The most commonly used treatment modalities were assessed for the best results in terms of efficacy and tolerability. However, this outcome is contradictory to the few controlled studies regarding the efficacy of the different drugs., Conclusions: The large number of patients treated demonstrates the importance of conservative therapy for Peyronie's disease. Therefore, it is unfortunate that no conservative treatment modality is currently available that cures the symptoms of this disorder in all patients affected.

Background: Treatment satisfaction of patients with primary immunodeficiency diseases receiving hospital-based intravenous (IVIG) or home-based subcutaneous (SCIG) immunoglobulin infusions requires investigation., Objective: Evaluation of the properties and suitability of the Life Quality Index (LQI), as an instrument to assess treatment satisfaction., Methods: Patients received weekly SCIG and completed the LQI, two global treatment satisfaction questions and the CHQ-PF50 (children) or the SF-36 (adults) at baseline and 10 months. The LQI was psychometrically evaluated., Results: The LQI comprised four scales: treatment interference (I), therapy related problems (II), therapy setting (III), treatment costs (IV). Convergent/discriminant validity for scales I, II, III was acceptable, for scale IV moderate. CHQ-PF50 scales behavior, bodily pain, global behavior, global health, mental health, parental impact-emotion significantly correlated with LQI scale II, the family activity scale with LQI scales I, III. SF-36 scale bodily pain significantly correlated with scale III. Internal consistency was good for scales I, II, III, but poor for scale IV. Score values significantly increased for scales I, III, IV in patients switching from IVIG to SCIG., Conclusions: Three valid LQI scales were determined. Cost-related questions should be removed due to low reliability. Patients-perceived therapy effectiveness and patient-physician/nurse interaction should be included in the instrument.

Heartburn is a common physiological event often associated with an underlying occurrence of gastroesophageal reflux disease (GERD). Studies show that GERD is a highly prevalent and chronic condition that significantly impacts on the patient's quality of life (QoL) and, in the long term, increases the risk for developing esophageal adenocarcinoma, more commonly referred to as Barrett's esophagus. Data indicate that symptom severity is a poor predictor of either the presence of erosive mucosal lesions or the development of complications. Given that lifestyle modifications are often insufficient for long-term treatment of GERD, drugs that inhibit gastric acid production--such as the proton pump inhibitors (PPIs)--are now the most effective strategy. Although generally well tolerated, the potential of PPIs for interactions with other drugs needs to be considered. This review discusses the symptoms and risk factors associated with GERD, possible links to Helicobacter pylori infection, and effective treatment strategies within a primary care setting.

Background: A large number of children and adults with primary antibody deficiencies need lifelong IgG replacement therapy. It is mostly unknown what effect the choice of replacement therapy has on the patients' health-related quality of life (HRQOL) and treatment satisfaction (TS)., Objective: To investigate whether a switch from hospital-based intravenous IgG (IVIG) to home-based subcutaneous IgG (SCIG) therapy would improve the HRQOL and TS., Methods: Fifteen children (<14 years; hospital-based IVIG therapy at enrollment) and 32 adults (> or =14 years; 22 on hospital-based IVIG and 10 on home-based SCIG therapy at enrollment) were included. Questionnaires were completed at baseline and at 6 and 10 months: the Child Health Questionnaire-Parental Form 50 (children) or Short Form 36 (adults), the Life Quality Index, and questions regarding therapy preferences., Results: The SCIG home therapy was reported to give better health (P=.001) and improved school/social functioning (P=.02) for the children, reduced emotional distress (P=.02) and limitations on personal time for the parents (P=.004), and fewer limitations on family activities (P=.002). Adults switching therapy reported improved vitality (P=.04), mental health ( P=.05), and social functioning ( P=.01). Adults already on SCIG home therapy at enrollment retained high HRQOL and TS scores. The SCIG home therapy improved TS because it led to greater independence and better therapy convenience ( P <.05). The patients preferred the SCIG administration route and having the treatment at home., Conclusions: Home-based SCIG therapy improves several important aspects of HRQOL and provides the patients with primary antibody deficiencies and their families with greater independence and better control of the therapy situation and daily life. SCIG home therapy is an appreciated therapeutic alternative for adults and children in need of lifelong IgG replacement therapy.

Background: Our aim was to assess the relationship between gastric motor and sensory function and symptom patterns in community subjects and patients with functional dyspepsia (FD) or irritable bowel syndrome (IBS)., Methods: We recruited 291 asymptomatic blood donors, 151 symptomatic blood donors (recurrent abdominal pain or discomfort), and 40 patients with FD or IBS. Abdominal symptoms were assessed using the bowel disease questionnaire (BDQ) and, in addition, the most bothersome symptom complex identified (dysmotility-type, ulcer-type dyspepsia, or IBS). Gastric emptying time (GET (t(1/2), min)) was measured by (13)C-octanoic breath test and a nutrient challenge performed. Twenty randomly selected asymptomatic blood donors, 48 symptomatic blood donors (30 FD, 18 IBS), and 40 patients (23 FD, 17 IBS) had additional function testing., Results: GET (t(1/2)) was significantly (p<0.05) longer in blood donors with FD symptoms (99 (6) min) and FD patients (110 (12) min) compared with asymptomatic controls (76.7 (7) min), but was not significant in IBS blood donors or patients. Overall, 25 of 48 blood donors with symptoms and 18 of 40 patients had slow gastric emptying. GET was most delayed in subjects with predominantly dysmotility-type symptoms (167 (36) min v controls; p<0.01). Symptom intensities after a nutrient challenge were significantly higher in FD patients and symptomatic blood donors compared with asymptomatic controls; 14 of 48 blood donors with symptoms and 16 of 40 patients had a symptom response to the nutrient challenge exceeding the response (mean (2SD)) of healthy asymptomatic controls., Conclusion: Gastric emptying and the global symptom response to a standardised nutrient challenge are abnormal in population based (non-health care seeking) subjects with dyspepsia.

The role of psychological factors or symptom pattern for the response to treatment in patients with unexplained (functional) dyspepsia is unknown. We hypothesized that patients with reflux- and ulcer-like symptoms would be more likely to respond to acid-lowering therapy, while psychological disturbances would be associated with a less favorable response to treatment. Seventy-eight patients with a diagnosis of functional dyspepsia were recruited and 75 completed the trial. Patients were treated for 4 weeks in a double-blind, placebo-controlled crossover trial starting in random order with either active drug (ranitidine, 150 mg b.d.) or placebo. Every 7 days, medication was switched from active drug to placebo, or vice versa. At entry, patient characteristics were assessed utilizing a semistructured standardized interview and standardized questionnaires, and weekly intensity of symptoms was assessed utilizing a visual analogue scale. Patients with a greater reduction of the symptom score during active treatment and an overall reduction of the global symptom score by more than 50% at the end of the study period were categorized as responders. Logistic regression analysis was utilized to assess the influence of symptom type and presence of psychological disturbances on the treatment response. During treatment the symptom score decreased significantly, from 32.1 +/- 1.44 (SD) to 21.3 +/- 1.9 at the end of the trial (P < 0.001). Twenty of 75 were responders. High scores for somatization (OR, 3.6; 95% Cl, 1.2-11.4), anxiety (OR, 3.3; 95% Cl, 0.9-11.8), and reflux-like symptoms (OR, 5.3; 95% Cl, 1.7-16.7) were associated with response to treatment, while dysmotility-like symptoms were associated with an unfavorable response (OR, 0.3; 95% Cl, 0.1-0.9). Symptom pattern and psychological disturbances are independent predictors of treatment response. Patients with reflux-like symptoms and greater psychological disturbances are more likely to respond to an acid-lowering compound.

Background & Aims: In patients with functional dyspepsia, altered alpha-adrenoreceptor function and depression are prevalent, features that are linked to a G-protein beta 3 (GNB3) subunit gene polymorphism (C825T). We aimed to assess the association of specific G-protein beta 3 subunit genotypes with functional dyspepsia., Methods: In study A, abdominal symptoms were assessed in 67 patients with unexplained, upper abdominal symptoms and 259 consecutive blood donors with and without abdominal symptoms. In study B, a further 56 patients with functional dyspepsia and 112 age- and sex-matched healthy controls from a blood donor population study were evaluated. Genomic DNA was isolated from buccal swabs and genotyping of the C825T polymorphisms was performed by polymerase chain reaction and restriction analysis., Results: In the blood donors with no abdominal symptoms in study A (controls, n = 161), genotype distribution was 17 TT, 77 TC, and 67 CC. In blood donors and patients with unexplained abdominal symptoms, genotype distribution was 22 TT, 54 TC, and 89 CC (P = 0.007 vs. controls). In study B, the genotype distribution in functional dyspepsia patients was 4 TT, 18 CT, and 34 CC compared with 4 TT, 62 CT, and 46 CC in the controls (P < 0.02). Combining studies A and B, the odds ratio (OR) adjusted for age and sex for upper abdominal symptoms associated with the CC genotype was 2.2 (95% confidence interval [CI]: 1.4-3.3), compared with subjects with TC and TT genotype carrying an allele., Conclusions: Homozygous GNB3 825C carrier status is associated with unexplained predominantly upper abdominal symptoms.

Background: This study aimed to assess the efficacy of artichoke leaf extract (ALE) in the treatment of patients with functional dyspepsia (FD)., Methods: In a double-blind, randomized controlled trial (RCT), 247 patients with functional dyspepsia were recruited and treated with either a commercial ALE preparation (2 x 320 mg plant extract t.d.s.) or a placebo. The primary efficacy variable was the sum score of the patient's weekly rating of the overall change in dyspeptic symptoms (four-point scale). Secondary variables were the scores of each dyspeptic symptom and the quality of life (QOL) as assessed by the Nepean Dyspepsia Index (NDI)., Results: Two hundred and forty-seven patients were enrolled, and data from 244 patients (129 active treatment, 115 placebo) were suitable for inclusion in the statistical analysis (intention-to-treat). The overall symptom improvement over the 6 weeks of treatment was significantly greater with ALE than with the placebo (8.3 +/- 4.6, vs. 6.7 +/- 4.8, P < 0.01). Similarly, patients treated with ALE showed significantly greater improvement in the global quality-of-life scores (NDI) compared with the placebo-treated patients (- 41.1 +/- 47.6 vs. - 24.8 +/- 35.6, P < 0.01)., Conclusion: The ALE preparation tested was significantly better than the placebo in alleviating symptoms and improving the disease-specific quality of life in patients with functional dyspepsia.

This paper reviews the current knowledge of the etiological pathogenesis of Peyronie's disease. De la Peyronie himself supposed a connection with venereal diseases. Herein, infectious, traumatic, autoimmune and genetic causes are discussed. An important hypothesis is that the recurrent microtraumatisation of the tunica albuginea during sexual intercourse leads to small lesions that activate processes of wound healing and development of fibrotic plaque. According to recent data, an association with the antigens of the HLA-system could be ruled out. Transforming growth factor beta (TGF-beta) seems to have an important impact due to its increased expression in the plaque. Furthermore it is possible to induce a condition similar to Peyronie's disease by intratunical injection of cytomodulin - a substance with TGF-beta-like activity - in an animal model. As in other fibrotic diseases, an imbalance between nitric oxide (NO) and reactive oxygen species (ROS) seems to be of importance. The most important new insights were gained from cell-culture models in which increased expression of basic fibroblast growth factor (bFGF), as well as a change in cell cycle regulation (p53) and cytogenetic instability were observed.

Metformin (1,1-dimethylbiguanide; MET) is used in the treatment of type 2 diabetes mellitus. MET's antihyperglycemic action depends at least in part on its inhibitory effect on hepatic gluconeogenesis. As to gluconeogenesis from amino acids (e.g. L-alanine), this is associated with an inhibition of L-alanine uptake into hepatocytes. Since this uptake is mediated by an electrogenic transport mechanism, the aim of the present study was to investigate whether MET has an influence on the liver cell membrane potential which might explain its inhibitory effect on L-alanine uptake. The experiments were performed in vivo in anesthetized rats and in vitro using superfused mouse liver slices with the conventional microelectrode technique. In vivo, MET (160 mg/kg intraperitoneally (i.p.)) significantly depolarized (dV) the liver cell membrane by 6 mV. MET (1 mmol/l) also depolarized the liver cell membrane in vitro (e.g. 15 min after start of superfusion: dV=8 mV). MET's effect was at least partly reversible. Glucagon (10(-7) mol/l), which hyperpolarized the liver cell membrane, abolished MET's effect. Further, the MET-induced depolarization was completely absent during superfusion with low Cl(-) ([Cl(-)]=27 mmol/l) medium, and significantly attenuated by the Cl(-) channel blocker NPPB (25 micromol/l). While MET's effect was only somewhat attenuated by blockade of the Na(+)/K(+)/2Cl(-) cotransporter or by superfusion with (HCO(-)(3)-free) HEPES buffer, the carboanhydrase blocker acetazolamide (1 mmol/l) or blockade of the HCO(-)(3)/Cl(-) exchanger by DIDS (100 micromol/l), which, however, also blocks Cl(-) channels, abolished its effect. The depolarization of the liver cell membrane by MET was unaffected by a blockade of K(+) channels with Ba(2+), a blockade of the Na(+)/K(+) pump or superfusion with low Na(+) medium ([Na(+)]=26 mmol/l). According to these results, the MET-induced depolarization of the liver cell membrane could be due to an activation of the Cl(-)/HCO(-)(3) exchanger and thus depend on intracellular HCO(-)(3) formation. This activation could then lead to a disturbance of the equilibrium between intra- and extracellular Cl(-) and therefore to an enhanced Cl(-) efflux via Cl(-) channels. It is plausible that the depolarizing effect induced by MET is associated with its inhibitory effect on gluconeogenesis by inhibiting uptake of L-alanine and other amino acids into hepatocytes.

Urdamycin A, the principal product of Streptomyces fradiae Tu2717, is an angucycline-type antibiotic and anticancer agent containing C-glycosidically linked D-olivose. To extend knowledge of the biosynthesis of urdamycin A the authors have cloned further parts of the urdamycin biosynthetic gene cluster. Three new ORFs (urdK, urdJ and urdO) were identified on a 3.35 kb fragment, and seven new ORFs (urdL, urdM, urdJ2, urdZl, urdGT2, urdG and urdH) on an 8.05 kb fragment. The deduced products of these genes show similarities to transporters (urdJ and urdJ2), regulatory genes (urdK), reductases (urdO), cyclases (urdL) and deoxysugar biosynthetic genes (urdG, urdH and urdZ1). The product of urdM shows striking sequence similarity to oxygenases (N-terminal sequence) as well as reductases (C-terminal sequence), and the deduced amino acid sequence of urdGT2 resembles those of glycosyltransferases. To determine the function of urdM and urdGT2, targeted gene inactivation experiments were performed. The resulting urdM deletion mutant strains accumulated predominantly rabelomycin, indicating that UrdM is involved in oxygenation at position 12b of urdamycin A. A mutant in which urdGT2 had been deleted produced urdamycin I, urdamycin J and urdamycin K instead of urdamycin A. Urdamycins I, J and K are tetracyclic angucyclinones lacking a C-C connected deoxysugar moiety. Therefore UrdGT2 must catalyse the earliest glycosyltransfer step in the urdamycin biosynthetic pathway, the C-glycosyltransfer of one NDP-D-olivose.

Unrecognized and untreated depression occurs frequently in Alzheimer's disease (AD) patients, adding to the agony already experienced by patient and caregiver. The authors screened AD patients living with a family caregiver for depression. Twelve patients with confirmed depression were treated in an open-label study with antidepressant medication, with dosage adjustment by a psychiatrist at Weeks 2, 4, 8, and 16. Data collection occurred at baseline, Week 4, and Week 16. Depression decreased significantly (p < .01). Contrary to expectations, patient functional capacity declined (p = .045). Cognition remained unchanged (p > .05). Caregiver burden, caregiver depressive symptomatology, and quality of life of patient and caregiver remained unchanged (p > .05). The authors conclude that depression in AD can be detected if a collateral source, such as the caregiver, is available. The depression can and should be treated. More research is needed to determine the impact on patient functioning, caregiver burden, caregiver depressive symptomatology, and quality of life of patient and caregiver.

In a nine-year period, 46 patients with early gastric cancer were diagnosed and operated at a county hospital. Fiberscopy of the stomach raised the percentage of early gastric cancer from 1% in a five year pre-endoscopic period to 11.9% with endoscopy. On an average, subjects with early gastric cancer were 8 years younger than all cases with gastric carcinoma, those with the diffuse type according to Laurén significantly younger than those with the intestinal type, too. Postoperative mortality amounted to 6.5%; five more patients of 43 surviving the operation have died in the meanwhile. Besides synchronous and metachronous cancer in the resected stomach and other organs, late distant metastasis must be considered, too, in the follow-up of patients operated from early cancer of the stomach. These complications may endanger the five-years survival rate of 89% observed in the first series of our patients.