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The great physical resemblance between epileptic and dissociative seizures and a diagnosis of epilepsy that had been made years ago and usually had been treated unsuccessfully makes it difficult for both physician and patient to communicate the diagnosis of dissociative seizures. A direct referral to psychotherapy treatment is rarely accepted by patients. Intermediate steps, which are based on cooperation between neurologists and psychotherapists, are necessary. The approach that we use to communicate diagnosis and motivation for psychotherapeutic treatment includes eight steps: 1. Welcome and introduction; 2. Jointly watching a video of documented seizures; 3. The message that the seizures are not of epileptic origin, 4. Development of an alternative disease concept; 5. Motivation for a conversation with a representative from psychosomatics; 6. Responding to the fear of "going crazy"; 7. If necessary, briefly touching on the subject of sexual violence; 8. More recommendations and conclusion of the conversation. The manual was discussed and practiced with the attending neurologist in two sessions and is now being regularly used by two neurologists with concomitant supervision.

Die Wirkung von Hydrochlorothiazid auf die Plasma-Renin-Aktivitat (PRA) und die Aldosteron-Exkretionsrate (AER) wird bei 10 Normalpersonen untersucht. Gleichzeitig werden Bestimmungen der Serum- und Urinelektrolyte, des Hamatokrits und der Flussigkeitsbilanz durchgefuhrt. In derjenigen Gruppe, die wahrend 7 Tagen taglich 50 mg Hydrochlorothiazid (Esidrex®) erhielt, steigen die PRA am 2. und 4. Tag und die AER am 3. Tag nach Beginn der Diuretikagabe signifikant an, wahrend am 6. bzw. am 7. Tag ein Abfall beider Parameter zur Norm einsetzt. Wesentliche Anderungen der Serumelektrolyte und des Hamatokrits werden nicht registriert. Die Stimulation des Renin-Angiotensin-Aldosteron-Systems (RAAS) kann mit einer erhohten Natriurese und Diurese korreliert werden. Die Kaliurese steigt ebenfalls deutlich an, so das der Na/K-Quotient im Urin unter 1 abfallt. In derjenigen Gruppe, die wahrend 6 Wochen taglich 50 mg Hydrochlorothiazid erhielt, werden nach 2, 4 und 6 Wochen der Diuretikaverabreichung keine signifikanten Veranderungen der PRA, AER, Serumelektrolyte und des Hamatokrits festgestellt. Es entwickelt sich demnach unter langerdauernden Saluretikagaben kein sekundarer Hyperaldosteronismus. Die Wirkung sowohl einer Natriumrestriktion als auch einer saluretikainduzierten Natriumexkretion auf das RAAS wird besprochen. Schlieslich werden die Moglichkeiten diskutiert, die einen Ruckgang der Stimulation des RAAS trotz andauernder Diuretikagaben bewirken konnen.

Bei 2 Patientinnen mit idiopathischen Odemen wurden Bestimmungen der Plasmareninaktivitat (PRA) und der Aldosteronexkretionsrate (AER) durchgefuhrt. Die PRA-Basiswerte lagen bei beiden Patientinnen im Normbereich, wahrend nach Stimulation durch Salzentzug und Orthostase ein starker Anstieg der PRA erfolgte, wie man ihn vor allem bei der renovascularen und bei der malignen Hypertonie beobachten kann. Die AER waren ebenfalls normal und wurden nur nach Gaben von Saluretica deutlich erhoht. Die Befunde werden im Hinblick auf die pathophysiologischen Storungen erortert, die dieser besonderen Odemerkrankung zugrundeliegen. Weiterhin werden die Faktoren diskutiert, die neben dem Renin-Angiotensin-Aldosteron-System fur die Atiologie oder die Pathogenese der idiopathischen Odeme als verantwortlich betrachtet werden.

Durch Gabe von 3 mg d-Aldosteron taglich i.m. unter gleichzeitiger Natriumbelastung konnte bei einem Patienten mit Kraniopharyngeom und Panhypopituitarismus sowie bei einer Patientin mit Cushing-Symptomatik bei einem lokal malignen chromophoben Hypophysenadenom nach Hypophysencoagulation zuerst eine positive Natriumbilanz und nach einigen Tagen das typische renale Escape-Phanomen hervorgerufen werden. Die menschliche Hypophyse scheint demnach nicht entscheidend am Zustandekommen des Escape-Phanomens beteiligt zu sein. Die Theorien, die heute zur Erklarung des Escape-Phanomens herangezogen werden konnen, werden diskutiert.

Incubated capsular adrenal glands (»zona glomerulosa«) of potassiumdeficient rats converted 57% less tritiated deoxycorticosterone to 11β-hydroxycorticosteroids and 45 % less tritiated cortexolone to cortisol than the capsular adrenals of potassium-replete rats. A similarly decreased conversion of cortexolone to cortisol was observed when capsular adrenal mitochondria were incubated. Potassium deficiency resulted in only a slight decrease in the rate of 11β-hydroxylation by decapsulated adrenals (»zona fasciculata-reticularis«). These findings indicate that the 11β-hydroxylase activity of the zona glomerulosa of the rat adrenal cortex is dependent on the potassium intake but to a lesser extent than 18-hydroxylase activity. We had previously observed that potassium deficiency induced a decreased production of aldosterone, an unchanged corticosterone output and an increased deoxycorticosterone output by capsular adrenals incubated with stimulating agents. The same alterations in endogenous corticosteroid production could be induced in vitro by the addition of a selective inhibitor of 18-hydroxylation (Su 8000) to the incubation medium. On the other hand, metopirone, i.e. an inhibitor of both 11β- and 18-hydroxylation, diminished corticosterone as well as aldosterone output by capsular adrenals. These results suggest that an increased deoxycorticosterone output by capsular adrenals may be due not only to a decrease in 11β-hydroxylase activity but may also be indirectly related to a decreased conversion of corticosterone to 18-hydroxycorticosterone and aldosterone.

Die Wirkung von Angiotensin II (A II) auf den Katecholaminhaushalt wurde an 6 narkotisierten Hunden gepruft. Dabei wurden subpressorische (5 ng/kg/min) und stark pressorische (1000 ng/kg/min) Angiotensin-Dosen, denen jeweils Infusionen von 0,9%igen NaCl-Losungen vorausgingen, in die Arteria carotis interna infundiert.

Different species of microorganisms including yeasts, filamentous fungi and bacteria have been used in the past 25 years for the controlled production of foreign proteins of scientific, pharmacological or industrial interest. A major obstacle for protein production processes and a limit to overall success has been the abundance of misfolded polypeptides, which fail to reach their native conformation. The presence of misfolded or folding-reluctant protein species causes considerable stress in host cells. The characterization of such adverse conditions and the elicited cell responses have permitted to better understand the physiology and molecular biology of conformational stress. Therefore, microbial cell factories for recombinant protein production are depicted here as a source of knowledge that has considerably helped to picture the extremely rich landscape of in vivo protein folding, and the main cellular players of this complex process are described for the most important cell factories used for biotechnological purposes.

Contains fulltext : 218867.pdf (Publisher’s version ) (Closed access) AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m(2) ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

Background MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods Ovarian cancer patients recurring or progressing 6–12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intention-to-treat. Results Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P = 0.001) and objective response rate (51.6% versus 19.4%, P = 0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand–foot skin reaction, rash/desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion MITO-8 QoL analysis shows that deterioration of some functioning and symptom scales is lower with PBC, with improvement of emotional functioning and pain, despite worsening of toxicity-related items. ClinicalTrials.gov NCT00657878.

Purpose Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy. Patients and Methods Nine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators. Results Maintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%). Conclusion Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).

Purpose To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission. Patients and Methods Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response. Results Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti–anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response. Conclusion Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.

Background In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer. Methods In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10 mg or placebo once-daily, plus paclitaxel 175 mg/m2 iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability. Results A total of 120 patients were randomized (zibotentan: n = 59; placebo: n = 61). Addition of zibotentan 10 mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR = 1.46, [80% CI: 1.10–1.94]; P = 0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: − 16%; paclitaxel: − 14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43–48% of patients). Conclusions Zibotentan 10 mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.

Microorganisms encounter diverse stress conditions in their native habitats but also during fermentation processes, which have an impact on industrial process performance. These environmental stresses and the physiological reactions they trigger, including changes in the protein folding/secretion machinery, are highly interrelated. Thus, the investigation of environmental factors, which influence protein expression and secretion is still of great importance. Among all the possible stresses, temperature appears particularly important for bioreactor cultivation of recombinant hosts, as reductions of growth temperature have been reported to increase recombinant protein production in various host organisms. Therefore, the impact of temperature on the secretion of proteins with therapeutic interest, exemplified by a model antibody Fab fragment, was analyzed in five different microbial protein production hosts growing under steady-state conditions in carbon-limited chemostat cultivations. Secretory expression of the heterodimeric antibody Fab fragment was successful in all five microbial host systems, namely Saccharomyces cerevisiae, Pichia pastoris, Trichoderma reesei, Escherichia coli and Pseudoalteromonas haloplanktis. In this comparative analysis we show that a reduction of cultivation temperature during growth at constant growth rate had a positive effect on Fab 3H6 production in three of four analyzed microorganisms, indicating common physiological responses, which favor recombinant protein production in prokaryotic as well as eukaryotic microbes. © 2010 American Institute of Chemical Engineers.