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The National Institute of Mental Health created the National Database for Autism Research (NDAR) to accelerate autism knowledge through data sharing and collaboration. However, our experience using NDAR reveals systematic challenges across several aspects of data submission, selection, management, and analysis that limit utility of this resource. We describe our NDAR experience in an ongoing project examining autism intervention outcomes among marginalized racial, ethnic, and gender groups. For this study, we planned to gather data from NDAR to conduct an individual participant data meta-analysis. Eighteen studies met inclusion criteria and reported data on participants at more than one point in time on the Vineland Adaptive Behavior Scales (Vineland) and the Autism Diagnostic Observation Schedule (ADOS). The difficulties with submitting, selecting, downloading, and managing data from NDAR posed limitations on data availability and analysis. Of the 3,850 unique participants in the selected studies, data at multiple time points were available for 312 participants on the Vineland and 278 on the ADOS. No participants had data on all assessment domains. To accelerate autism research via data sharing and collaboration with NDAR necessitates improving the processes for submitting, selecting, and managing data., Competing Interests: Declarations Competing Interests Dr. Scahill has served as a consultant to Roche, Janssen, Impel. He has received royalties from American Psychological Association, Guilford and Oxford University Press and licensing fees from Cogstate, Abbvie, Yamo. The remaining authors have no relevant financial or non-financial interests to disclose. Ethical Approval The Boston University Medical Campus Institutional Review Board approved this project as exempt. Consent to Participate Data for this commentary were drawn from the National Database for Autism Research (NDAR) data repository, available on National Institute of Mental Health National Data Archive. All participants were consented at the time of data collection in the original study before deposition in NDAR., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Loneliness represents a significant health risk and is associated with numerous mental and physical conditions. The aim of this paper was to describe the prevalence of loneliness in Bavaria before and during the COVID-19 pandemic with respect to socio-demographic attributes., Methods: Data sources were the German Ageing Survey (DEAS) and the Socio-Economic Panel (SOEP). Univariate statistical analyses were carried out for different socio-demographic attributes, such as age, gender, type of household, education, and financial resources., Results: According to the SOEP, the proportion of adults who are often or very often lonely increased from 2.3% in 2017 to 16.2% in 2021. In 2021, women had a higher prevalence of loneliness than men (21.0% vs. 11.3%), and younger adults had the highest prevalence of loneliness (18 to 25 years: 31.7%) compared to the other age groups., Discussion and Conclusions: During the COVID-19 pandemic, loneliness increased in almost every population subgroup in Bavaria. Further studies are needed to examine whether this development is temporary or represents a long-term effect even after the measures to prevent the spread of COVID-19 have been lifted., (© 2024. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

Newspaper reports provide a rich source of information on the unfolding of public debates, which can serve as basis for inquiry in political science. Such debates are often triggered by critical events, which attract public attention and incite the reactions of political actors: crisis sparks the debate. However, due to the challenges of reliable annotation and modeling, few large-scale datasets with high-quality annotation are available. This paper introduces DebateNet2.0 , which traces the political discourse on the 2015 European refugee crisis in the German quality newspaper taz . The core units of our annotation are political claims (requests for specific actions to be taken) and the actors who advance them (politicians, parties, etc.). Our contribution is twofold. First, we document and release DebateNet2.0 along with its companion R package, mardyR. Second, we outline and apply a Discourse Network Analysis (DNA) to DebateNet2.0 , comparing two crucial moments of the policy debate on the "refugee crisis": the migration flux through the Mediterranean in April/May and the one along the Balkan route in September/October. We guide the reader through the methods involved in constructing a discourse network from a newspaper, demonstrating that there is not one single discourse network for the German migration debate, but multiple ones, depending on the research question through the associated choices regarding political actors, policy fields and time spans., (© The Author(s) 2023.)

Over the past 10 years, identification of Autism Spectrum Disorder (ASD) risk has dramatically increased due to the wide-spread implementation of screening programs; yet, there is limited understanding about parent perceptions and experiences during the time period when risk is identified, but prior to receiving a formal diagnosis-a period that can last months to years given the long wait-lists for formal ASD evaluations. The current study aimed to examine parent perceptions of family impact (i.e., the impact their child's behaviors have on the family) between the time of risk-identification and formal diagnosis among 277 children identified as at-risk for ASD through screening positive in primary care. We aimed to compare family impact among those whose child met diagnostic criteria for ASD and those who did not. Parents of children who received a non-ASD diagnosis reported a higher baseline level of family impact (F[1, 274] = 5.82, p = .017); however, perceived difficult child behavior was a stronger predictor of family impact (t[6] = 13.11, p < .001) than later diagnostic group (t[6] = - 2.10, p = .037), and child functioning did not predict family impact (t[6] = -0.31, p = .76). These results suggest that in this population, perceived difficult child behavior is a stronger predictor of family impact than later diagnostic category and should be considered an important factor in family support., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Frogs of the families Mantellinae and Hyperoliidae possess male specific femoral or gular glands that are used during courtship. These glands release volatile compounds, e. g. the macrocyclic lactone gephyromantolide A (2,6,10-trimethyl-6-undecen-11-olide) in the case of Gephyromantis boulengeri (Mantellinae). During the analysis of the volatiles of Hyperolius cinnamomeoventris (Hyperoliidae) we detected an unknown compound A, which we called cinnamomeoventrolide, whose mass spectrum showed high similarity with the spectrum of gephyromantolide A. Nevertheless, slight spectral differences led to the proposal of a regioisomer of gephyromantolide A as a structure for A, 2,6,10-trimethyl-5-undecen-11-olide. A versatile synthesis of this compound was developed to allow access to all four stereoisomers from a single chiral starting material, the so-called (S)-Roche ester, using ring-closing metathesis as a key step. With these stereoisomers, the absolute configuration of the natural product was established to have the (2R,10S)-configuration by GC on a chiral phase. The configuration of natural gephyromantolide A is the opposite. Both frogs seem to use a similar biosynthetic pathway to access the target compounds, differing in the stereochemistry of the reduction steps, and requiring an additional isomerization in case of G. boulengeri. This unique regioisomeric differentiation of double bonds in semiochemicals has so far only been observed in insects. The compounds are likely to play a role in species-recognition of the frogs., (© 2022. The Author(s).)

Background: "Avoidable mortality" is used as an indicator in health reporting. The indicator aggregates selected causes of death. In Germany two versions exist, both of which are no longer up to date. A new version is proposed., Methods: The new version is based on preparatory work on the European level. The feasibility and plausibility of a common OECD Eurostat list are examined using official statistics data from Bavaria from 2016 to 2018. The analysis includes an examination of the variability over time and within the Bavarian administrative districts, as well as possible systematic errors through regional differences in coding behaviour or changes over time., Results: The OECD Eurostat list can be implemented at the regional level with only minor modifications. The age-standardized avoidable mortality in Bavaria in 2018 is almost 23 deaths per 10,000 inhabitants, with preventable deaths by far outweighing treatable deaths. For men, the death rate due to avoidable causes is 30 per 10,000 male inhabitants, which is almost twice as high as that for women (16 per 10,000 female inhabitants). The regional findings on avoidable mortality are consistent with findings on regional health from other studies., Discussion and Conclusion: The results do not indicate a threat to reliability due to random fluctuation or systematic methodological errors. The new version is recommended for application in health reporting., (© 2021. The Author(s).)

The COVID-19 pandemic, and associated social distancing mandates, has placed significant limitations on in-person health services, requiring creative solutions for supporting clinicians engaged in the diagnosis of autism spectrum disorder (ASD). This report describes the five virtual instruments available at the time of manuscript development for use by experienced clinicians making diagnostic determinations of ASD for toddlers across the 12- to 36-months age range. We focus on synchronous virtual assessments in which clinicians guide the child's caregiver through a range of assessment activities and observe spontaneous and elicited behaviors. Assessments are compared on dimensions of targeted behavioral domains, specific activities and presses employed, scoring approaches, and other key logistical considerations to guide instrument selection for use in varied clinical and research contexts., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Intracorporeal anastomosis (IA) may improve outcomes compared with extracorporeal anastomosis (EA) in minimally invasive right colectomy. This is a prospective series of robotic right hemicolectomies (RRC) with IA from one institution. 35 consecutive patients with verified or suspected right colon cancer undergoing RRC with IA, and historic control groups of 22 RRC and 40 laparoscopic right colectomies (LRC), both with EA. Primary outcome measure was length of stay (LOS). Secondary outcome measures were 30-day complication rates, readmissions, pain scores, analgesic consumption, and specimen quality. Median LOS did not differ significantly between the groups (RRC-IA, 4 days; LRC-EA, 4 days; RRC-EA, 5 days). In-hospital surgical complications Clavien-Dindo 3 + were seen in 1, 2, and 0 patients, respectively, and 3, 5, and 3 patients were readmitted to hospital within 30 days. Median pain score was 2 in all groups on postoperative day (POD) 2. Relatively more patients in the RRC-IA group received gabapentin on POD 2 (p = 0.006), but use of other analgetics did not differ between groups. Mean specimen lengths were 31, 25 and 27 cm, respectively (RRC-IA vs. LRC-EA, p = 0.003), but mesentery width, proportion of mesocolic excisions and number of lymph nodes did not differ between the groups. RRC-IA was not associated with shorter LOS, fewer complications or better specimen quality than recent controls undergoing either RRC-EA or LRC-EA., (© 2021. The Author(s).)

Oral health plays a subordinate role in the range of topics in health reporting. Possible reasons are the limited availability of oral health data as well as that health reporting has historically focused on major risk factors and common diseases. Given the fact that oral health is an important public health issue, particularly in the perspective of prevention and healthcare, it would be desirable to give more consideration to the issue in health reporting. Based on Internet research, this article attempts to take stock of the extent to which oral health is already being addressed in health reporting in Germany, what professional standards exist, and what data sources are available. On this basis, further development of health reporting is suggested.

In 2015 the "Act to Strengthen Health Promotion and Prevention" (German Prevention Act) was passed. This act stipulates reporting on its implementation and impact by means of a regular prevention report by the National Prevention Conference. It also furthers prevention reporting at the regional level in the federal states. There are varying approaches and concepts of prevention reporting.The first prevention report by the National Prevention Conference was published in 2019. In the federal states, prevention reporting develops in different ways and at different rates, mirroring the heterogeneous conditions and concepts at the local level. This includes a varied interpretation of the relation of health reporting to prevention reporting: some see prevention reporting as part of health reporting, others tend not to and focus on aspects like the reporting of prevention structures and interventions.Challenges for the future of prevention reporting include the development of indicators and identification of data sources, particularly regarding resources for health, structural aspects, and living conditions. Further tasks are the development of feasible approaches to survey and report prevention interventions as well as the attempt to report outcomes and effects within causal models instead of merely reporting inputs and outputs.In conclusion, the dynamic induced by the German Prevention Act serves as a stimulus to health reporting-with a view to its contents, methods and policy relevance. Research to accompany and support the development of prevention reporting would be highly desirable.

The purpose of this study was to adapt and validate a measure of HIV-related shame, the Shame Questionnaire (SQ), among Ugandan youth living with HIV. Culturally relevant, reliable and valid measurement is critical in the accurate assessment of HIV-related shame ( a painful internalized emotion encompassing feelings that the self is damaged and defective ) on psychosocial functioning, as well as the determination of the efficacy of interventions among youth living with HIV in sub-Saharan Africa. We utilized qualitative (i.e., cognitive interviews; N = 31) and quantitative (i.e., classical test theory and item response theory; N = 150) methods to establish, content, criterion and construct validity of the SQ. Cognitive interviews resulted in the revision in the wording of 2 out of 8 SQ items. Participants who endorsed having shame had statistically significant higher SQ scores than participants who did not endorse having shame ( p < 0.001), suggesting criterion validity. We found a statistically significant positive relationship between SQ scores and average trauma symptom scores among participants ( p < 0.001), also suggesting criterion validity. Finally, we found construct validity with discrimination parameters of the graded response IRT model all in the high range with a wide range of difficulty parameters across the 8 items of the SQ. Overall our results suggest that the SQ is a contextually relevant, valid and reliable assessment tool among Ugandan youth living with HIV. Findings provide support for the utilization of qualitative and quantitative methods in the adaptation of measures for cross-cultural use in order to maintain validity and contextual relevance., Competing Interests: Conflict of Interest The authors declare they have no conflict of interest.

Parents of children with autism spectrum disorders are generally known to experience elevated levels of stress and poorer psychological well-being. To provide treatments and resources that most effectively support parent mental health, it is critical to understand how parents' connections with various networks and systems impact their well-being. This study examined the relationship between the psychological well-being of mothers of adolescents with ASD (n = 20) and their systems of support from an ecological systems theoretical framework. Findings indicated that most connections across mothers' ecosystems were strong in nature. However, the presence of strong connections was not significantly related to psychological well-being. In contrast, stressful/weak connections were significantly related to elevated levels of depressive symptoms, perceived stress, and sense of burden.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

For the calculation of life expectancy on a regional level, data from the mortality statistics and population numbers are needed. The latter are derived from population censuses, which have to be undertaken every 10 years according to the EU regulation No. 763/2008. In Germany, the last census took place in 2011 (Census 2011). The current population numbers are calculated on the basis of the most recent population census (population update). Births, deaths, immigration and migration, in addition to other data, are taken into account in this calculation. However, with passing time since the last census, inaccuracies in population updates may increase, which can affect the value of life expectancy calculations.Based on the comparison of life expectancy rankings, the impact and extent of changing over from the 1987 to the more recent 2011 census for regional comparisons were examined in two parts of Germany, Bavaria and North Rhine-Westphalia. As expected, the results show that larger changes in the calculated life expectancy result from larger changes in population statistics. However, noteworthy changes in life expectancy rankings do not necessarily follow larger changes in the population numbers. Regional life expectancy rankings are potentially always influenced by inaccuracies in the underlying population statistics. This should be taken into account when interpreting such small-scale differences.

Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.

Xylosylation of core proteins takes place in the Golgi-apparatus as the transfer of xylose from UDP-xylose to specific serine residues in proteoglycan core proteins. This initial and rate-limiting step in glycosaminoglycan biosynthesis is catalyzed by human xylosyltransferase I (XT-I). XT-I is proteolytically cleaved from the Golgi surface and shed in its active form into the extracellular space. The secreted, circulating glycosyltransferase represents a serum biomarker for various diseases with an altered proteoglycan metabolism, whereas a physiological function of secreted XT-I is still unknown. To shed light on the secretion process of XT-I and on its biological function, the cleavage site was examined and the group of proteases involved in the cleavage was identified in this study. The peptide mass fingerprint from partly purified secreted XT-I revealed the cleavage site to be localized in the aminoterminal 231 amino acids. The addition of a cysteine protease inhibitor cocktail to cells recombinantly expressing XT-I led to a concentration-dependent shift of enzyme activity towards the cell lysates attended by consistent total intracellular and extracellular XT-I activities. In conclusion, our findings provide a first insight into the XT-I secretion process regulated by a cysteine protease and may contribute to understanding the biological and pathological role of this process.

Tobacco consumption is one of the most relevant behavior-based health risks. It has been estimated that there are 14,000-18,000 tobacco-related deaths each year in Bavaria, Germany. Thus, efficient tobacco prevention, which involves measures of behavior-oriented as well as of condition-oriented prevention at the Federal State level, is a priority objective of prevention politics in Bavaria. Measures of behavior-oriented prevention account for the fact that tobacco prevention affects private lifestyles, where statutory provisions may not be effectual. However, smoking bans have achieved the creation of smoke-free living spaces especially for children and adolescents. In the long term, it is essential to enhance evaluation of tobacco prevention, to pay more attention to sustainability of approved projects, and to ensure a smoke-free environment for children and adolescents. The Bavarian health program "Gesund.Leben.Bayern." is an important platform for this.

Ethical issues have always been part of the debate around work and its relation to people. In the context of workplace health management, however, ethical considerations have received little attention to date. This paper discusses some examples of the ethical questions arising in the pursuit of workplace health management, such as issues around the organization of work procedures, double loyalties, the significance of occupational screening examinations or how people in precarious working conditions are being dealt with. Subsequently, two ethical codes commonly used in the field of work and health in German-speaking countries are introduced. They originate from the field of occupational medicine, but have meanwhile been opened to other professions in the field of work and health. Finally, some perspectives for further discussion are put forward.

Introduction: Circulating tumor cells (CTCs) have recently been shown to be an independent predictor of progression-free and overall survival in patients undergoing treatment for metastatic breast cancer. This study evaluates the presence and significance of CTCs in patient undergoing surgical resection of clinically localized primary breast cancer., Methods: Patients undergoing surgery for clinically localized primary breast cancer were enrolled into a prospective study. Thirty milliliters of blood was drawn and studied using the CellSearch assay., Results: Forty-one patients were enrolled at a single tertiary referral center. Ten patients (24.4%) had detectable CTCs preoperatively (PreOp). Nine (30%) patients were found to have CTCs postoperatively (PostOp). Overall, 16 (39%) were found to have CTCs either PreOp or PostOp. Hormone-negative patients were significantly more likely to have CTCs than hormone-positive patients. No other pathologic factor was predictive of the presence of CTCs., Conclusion: CTCs are detectable and quantifiable in breast surgery patients. CTCs were more likely to be found in hormone receptor negative patients. Further study will allow correlation with other pathological variables and clinical outcome.

Skeletal growth and tissue remodelling processes are characterized by an elevated collagen and proteoglycan biosynthesis. The xylosyltransferases I and II are the rate-limiting step enzymes in proteoglycan biosynthesis and serum xylosyltransferase (XT) activity has been shown to be a biomarker for the actual proteoglycan biosynthesis rate. Here, XT, alkaline phosphatase (ALP), bone ALP (BALP) activities were measured in 133 juvenile Caucasians. Serum XT activities in juveniles were elevated and significantly correlated with ALP and BALP. In an osteoblast-like cell model using SAOS-2 cells mineralization and bone nodule formation were induced and XT-I, XT-II and ALP were monitored. Induction of mineralization in SAOS-2 cells resulted in a long-term increase of XT-I mRNA and enzyme activity, which could be paralleled with elevated ALP activity. In addition, HGH and IGF-I treatment of SAOS-2 cells led to an increased expression of XT-I and ALP. These results point to skeletal growth and tissue remodeling as a cause of the high XT activity in children.

The xylosyltransferases I and II (XT-I, XT-II, EC 2.4.2.26) catalyze the transfer of xylose from UDP-xylose to selected serine residues in the proteoglycan core protein, which is the initial and ratelimiting step in glycosaminoglycan biosynthesis. Both xylosyltransferases are Golgi-resident enzymes and transfer xylose to similar core proteins acceptors. XT-I and XT-II are differentially expressed in cell types and tissues, although the reason for the existence of two xylosyltransferase isoforms in all higher organisms remains elusive. Serum xylosyltransferase activity was found to be a biochemical marker for the assessment of disease activity in systemic sclerosis and for the diagnosis of fibrotic remodeling processes. Furthermore, sequence variations in the XT-I and XT-II coding genes were identified as risk factors for diabetic nephropathy, osteoarthritis or pseudoxanthoma elasticum. These findings point to the important role of the xylosyltransferases as disease modifiers in pathologies which are characterized by an altered proteoglycan metabolism. The present review discusses recent advances in mammalian xylosyltransferases and the impact of xylosyltransferases in proteoglycan-associated diseases.

Feeding larvae of Chrysomela lapponica (Coleoptera: Chrysomelidae) acquire characteristic O-glucosides from the leaves of their food plants. The glucosides are selectively channeled from the gut to the defensive gland. Subsequent enzymatic transformations generate a blend of different defensive compounds, e.g., salicylaldehyde and two series of 2-methylbutyl and isobutyryl esters. By using systematically modified and hydrolysis-resistant thioglucosides as structural mimics of the plant-derived glucosides, e.g., salicin and its o-, m-, and p-isomers 1, 2, and 3; o-, m-, and p-cresols 5, 6, 7; along with thioglucosides of 2-phenylethanol 9 and (3Z)-hexenol 10, we demonstrated that the larvae of C. lapponica are able to sequester a broad range of structurally different thioglucosides with comparable efficiency. This sharply contrasts with the sequestration habitus previously observed in Chrysomela populi and Phratora vitellinae, which secrete almost pure salicylaldehyde and posses a highly specific transport mechanism for salicin (Kuhn et al., Proc. Natl. Acad. Sci. USA 101:13808-13813, 2004). Also, neither C. lapponica nor C. populi sequester in their gland the thioglucoside of 8-hydroxygeraniol, the mimic of the glucoside specifically transported by larvae secreting iridoid monoterpenes (Phaedon cochleariae, Gastrophysa viridula). Accordingly, leaf beetle larvae possess selective membrane carriers in their gut and their defensive systems that match the orientation of the functional groups of glucosides from their food plants probably by embedding the substrate in a network of hydrogen bonds inside the membrane carriers. The synthesis and the spectroscopic properties of the test compounds along with a comparative evaluation of the transport capabilities of larvae of C. populi and C. lapponica are described.

Purpose: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug., Experimental Design: CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival., Results: Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks., Conclusions: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.

Objectives: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs., Study Design: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria., Results: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs., Conclusions: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

Objective: To examine the release of counterregulatory hormones and consecutive glimepiride serum concentrations during severe hypoglycaemia (SH) associated with glimepiride therapy., Methods: In nine type-2 diabetic patients [age 81+/-9 (65-93) years; diabetes duration 9+/-4 (3-15) years; initial blood glucose 33+/-16 (10-54) mg/dl (1.8+/-0.9 mmol/l); HbA1c 7.2+/-1.1 (5.6-8.7)%; creatinine clearance 49+/-33 (15-107) ml/min] who experienced SH associated with glimepiride therapy with neuroglucopenic presentation, insulin, C-peptide, glucagon, epinephrine, norepinephrine, cortisol, adenocorticotrophic hormone (ACTH), human growth hormone (HGH) and pancreatic polypeptide (PP) were determined in blood samples taken at 4-h intervals prior to and during treatment with glucose i.v. Serum from the same samples was screened for sulphonylurea-type oral antidiabetics. Glimepiride concentrations were determined by a validated atmospheric pressure chemical ionization liquid chromatographic-mass spectrometry (APCI-LC-MS) assay., Results: Once treatment had begun, normoglycaemia was maintained; most glimepiride levels were below the limit of detection (LOD <0.01 mg/l) and further sulphonylureas could be excluded. The secretion of glucagon and epinephrine as counterregulatory hormonal responses was unaffected. In addition, protracted marked increases of cortisol and norepinephrine levels were demonstrated. Protracted stimulation of insulin and C-peptide occurred in a period of up to 24 h after SH. No significant protracted responses were observed for ACTH, HGH or PP., Conclusion: In SH associated with glimepiride therapy, no correlation between glimepiride serum concentrations and the protracted stimulation of insulin and C-peptide was observed. The secretion of glucagon and epinephrine as counterregulatory hormonal responses was unaffected. Protracted increased release of cortisol might be a medium-term indicator of glimepiride-associated SH.

Dacarbazine (DTIC) is a chemotherapy drug which has antitumor activity at standard doses, exhibits a steep dose-response effect in vitro, and is associated with relatively few non-hematologic toxicities. These characteristics suggest a potential role for this drug in bone marrow transplant preparative regimens. To pursue this hypothesis, 16 patients with refractory solid tumors were enrolled in a phase I study of single agent DTIC to determine the dose of DTIC requiring bone marrow reinfusion and to define the dose-limiting toxicity and maximum tolerated dose when given with autologous bone marrow rescue. Pharmacokinetics were evaluated at the 4394 mg/m2 dose level. The marrow requiring dose was 2000 mg/m2 when given as a single intravenous (i.v.) infusion. The extramyeloid dose-limiting toxicity of DTIC was hypotension, with the maximum tolerated dose of DTIC being 3380 mg/m2 when given with bone marrow transplantation (BMT). Other toxicities were transient and tolerable. At 4394 mg/m2 of DTIC, plasma concentrations declined biexponentially with a terminal half-life of 3 hours. The mean clearance was 10.6 L/hr/m2 with a volume of distribution at steady state of 37.5 L/m2 and a mean maximum plasma concentration of 150 mcg/ml. One patient with melanoma developed a partial response of short duration after receiving 2600 mg/m2 of DTIC. Dacarbazine can be significantly dose escalated with an acceptable toxicity profile, when given with BMT. Future trials should focus on the addition of this drug to current BMT preparative regimens used for the treatment of patients with lymphoma.

For a comprehensive model of rheumatoid arthritis treatment, we designed an arthritis manual for continuous treatment of chronic illness. One goal of introducing the manual to the patients was the improvement of communication between patient and different doctors and therapists. The first part includes of a doctor's documentation sheet and a patient calendar (6 months each) for daily self-documentation of drug compliance. The second part is a daily pain-rating scale. The 3-year evaluation of 655 patient manuals for 286 patients was analyzed to estimate the compliance in using the manual. Overall, 87% of diagnoses, 83% of disease-modifying anti-rheumatic drugs (DMARDs), 87% of non-steroidal anti-rheumatic drugs (NSAIDs) had been documented in the manual. Data indicates that the general practitioner and the rheumatologist accepted the manual form. In addition, 85% of the documented patients used the DMARDs, 74% used the daily pain score, and 43% the daily physiotherapy. Subgroup data (n = 130 RA patients) suggest additional results: 1) there was no difference in sociodemographic data between the patient manual user group and the non-user group; 2) the user group consisted of patients with higher disease activity (ARA-criteria), higher pain score, and negative mood pattern. Furthermore, the user group was more active in daily physiotherapy, ergotherapy, and balneotherapy.