Do German university medical centres promote robust and transparent research? A cross-sectional study of institutional policies.

BACKGROUND: In light of replication and translational failures, biomedical research practices have recently come under scrutiny. Experts have pointed out that the current incentive structures at research institutions do not sufficiently incentivise researchers to invest in robustness and transparency and instead incentivise them to optimize their fitness in the struggle for publications and grants. This cross-sectional study aimed to describe whether and how relevant policies of university medical centres in Germany support the robust and transparent conduct of research and how prevalent traditional metrics are. METHODS: For 38 German university medical centres, we searched for institutional policies for academic degrees and academic appointments as well as websites for their core facilities and research in general between December 2020 and February 2021. We screened the documents for mentions of indicators of robust and transparent research (study registration; reporting of results; sharing of research data, code and protocols; open access; and measures to increase robustness) and for mentions of more traditional metrics of career progression (number of publications; number and value of awarded grants; impact factors; and authorship order). RESULTS: While open access was mentioned in 16% of PhD regulations, other indicators of robust and transparent research were mentioned in less than 10% of institutional policies for academic degrees and academic appointments. These indicators were more frequently mentioned on the core facility and general research websites. Institutional policies for academic degrees and academic appointments had frequent mentions of traditional metrics. CONCLUSIONS: References to robust and transparent research practices are, with a few exceptions, generally uncommon in institutional policies at German university medical centres, while traditional criteria for academic promotion and tenure still prevail.

Parent-reported family impact in children and young adults with acquired brain injury in the outpatient rehabilitation setting.

Purpose: To increase knowledge/awareness on family impact (FI) after acquired brain injury (ABI) in rehabilitation settings, it is essential to investigate the associations between patient-functioning and impact on families. This has been explored in hospital-based cohorts, but not in rehabilitation settings.Methods: A cross-sectional, multi-center study among parents of children/young adults (aged 5-24 years) with ABI referred to rehabilitation was performed. Patient/injury/family-characteristics were noted, and parents completed the PedsQL™Family-Impact-Module and PedsQL™generic-core-4.0 to assess FI and health-related quality of life (HRQoL). Univariate- and multivariable-regression analyses were performed to investigate associations between HRQoL/patient/injury/family-related factors and FI.Results: 246 families participated; patients' median age was 14 year (IQR 11-16), 65 had non-traumatic-brain-injury (nTBI) (26%), 127 were female. FI was found to be considerable (median FIM-score 71.9, IQR:60-85). Especially referral to rehabilitation >6 months after onset, diminished patients' mental/emotional health and HRQoL (child/family factors), and premorbid problems were associated with higher FI.Conclusions: In this rehabilitation cohort, pediatric ABI caused considerably higher FI than in hospital-based studies with referral to rehabilitation >6 months, diminished child/family factors and presence of premorbid problems increasing FI. Assessing and monitoring FI and its associated factors enables professionals to individualize treatment, psychoeducation, support and follow-up.

Multi-column ultra-high performance liquid chromatography screening with chaotropic agents and computer-assisted separation modeling enables process development of new drug substances.

Modern process research and development can often be hampered by the tedious method development required to chromatographically resolve mixtures of chemical species with very similar physical properties. Herein, we describe a simple approach for the development and implementation of an efficient ultra-high performance liquid chromatography (UHPLC) assay that is extensively applied to the separation and analysis of multicomponent reaction mixtures of closely related pharmaceutical intermediates and impurities. Methods are optimized using multi-column and multi-solvent UHPLC screening in conjunction with chromatography simulation software (ACD Labs/LC Simulator). This approach is implemented to enable the separation, identification, mapping and control of impurities formed within the process chemistry optimization of the dimeric catalyst used in the synthesis of new drug substances. The final method utilized a sub-2 µm C18 stationary phase (2.1 mm I.D. × 50 mm length, 1.7 µm particle size ACQUITY UPLC BEH C18) with a non-conventional chaotropic mobile phase buffer (35 mM potassium hexafluorophosphate in 0.1% phosphoric acid/acetonitrile) in order to achieve baseline separation of all reaction components. The chromatographic simulation and modeling strategy served to generate 3D resolution maps with robust separation conditions that match the outcome of subsequent experimental data (overall ΔtR < 0.35%). Our multi-column UHPLC screening with computer-assisted chromatographic modeling is a great addition to the toolbox of synthetic chemists and can be a powerful tool for streamlining process chemistry optimization in organic chemistry laboratories across both academic and industrial sectors.

Longitudinal alterations in nutrient intake and food pattern in patients with non-small cell lung cancer during anti-neoplastic treatment: a cohort study.

BACKGROUND: Unintentional weight loss is frequently observed in cancer patients. Nutritional therapy is essential, and dietary counselling is the first step. The present study aimed to explore the nutrient intake and food patterns in weight-stable and weight-losing patients with non-small cell lung cancer (NSCLC) during anti-neoplastic treatment. METHODS: Patients with NSCLC (n = 62) were observed during first-line systemic anti-neoplastic treatment. Body weight and dietary intake were assessed on the first and second cycle, and after completing three cycles of treatment. Longitudinal changes were analysed in three groups: weight stable, weight losers and mixed weight. RESULTS: Nutrient intake did not change during treatment in weight stable, although weight losers significantly increased the relative protein intake. Weight stable maintained the food pattern during treatment apart from a decreased consumption of oral nutritional support (ONS). At baseline, weight losers were characterised by pretreatment weight loss, high consumption of ONS, as well as low consumption of grains and animal products. During treatment, weight losers increased the consumption of protein, fatty foods and ONS but decreased the consumption of sweets and alcohol. CONCLUSIONS: Large heterogeneity in nutrient and food intake was observed in NSCLC patients during anti-neoplastic treatment. Weight losers and weight stable had a similar nutrient intake although protein intake increased in weight losers. Grains and animal products were lower and ONS higher in weight losers compared to weight stable during treatment. Weight losers further increased the consumption of ONS and fatty foods, while the consumption of sweets and alcohol decreased during treatment.

Individualised dietary counselling for nutritionally at-risk older patients following discharge from acute hospital to home: a systematic review and meta-analysis.

BACKGROUND: Many older patients are undernourished after hospitalisation. Undernutrition impacts negatively on physical function and the ability of older patients to perform activities of daily living at home after discharge from acute hospital. The present study aimed to evaluate the evidence for an effect of individualised dietary counselling following discharge from acute hospital to home on physical function, and, second, on readmissions, mortality, nutritional status, nutritional intake and quality of life (QoL), in nutritionally at-risk older patients. METHODS: A systematic review of randomised controlled trials was conducted. The overall quality of the evidence was assessed according to Grading of Recommendations Assessment, Development and Evaluation system (GRADE) criteria. RESULTS: Four randomised controlled trials (n = 729) were included. Overall, the evidence was of moderate quality. Dietitians provided counselling in all studies. Meta-analyses showed a significant increase in energy intake [mean difference (MD) = 1.10 MJ day(-1), 95% confidence interval (CI) = 0.66-1.54, P < 0.001], protein intake (MD = 10.13 g day(-1), 95% CI = 5.14-15.13, P < 0.001) and body weight (BW) (MD = 1.01 kg, 95% CI = 0.08-1.95, P = 0.03). Meta-analyses revealed no significant effect on physical function assessed using hand grip strength, and similarly on mortality. Narrative summation of effects on physical function using other instruments revealed inconsistent effects. Meta-analyses were not conducted on QoL and readmissions as a result of a lack of data. CONCLUSIONS: Individualised dietary counselling by dietitians following discharge from acute hospital to home improved BW, as well as energy and protein intake, in older nutritionally at-risk patients, although without clearly improving physical function. The effect of this strategy on physical function and other relevant clinical outcomes warrants further investigation.

Effect of meal portion size choice on plate waste generation among patients with different nutritional status. An investigation using Dietary Intake Monitoring System (DIMS).

BACKGROUND: The trolley meal system allows hospital patients to select food items and portion sizes directly from the food trolley. The nutritional status of the patient may be compromised if portions selected do not meet recommended intakes for energy, protein and micronutrients. The aim of this study was to investigate: (1) the portion size served, consumed and plate waste generated, (2) the extent to which the size of meal portions served contributes to daily recommended intakes for energy and protein, (3) the predictive effect of the served portion sizes on plate waste in patients screened for nutritional risk by NRS-2002, and (4) to establish the applicability of the dietary intake monitoring system (DIMS) as a technique to monitor plate waste. METHODS: A prospective observational cohort study was conducted in two hospital wards over five weekdays. The DIMS was used to collect paired before- and after-meal consumption photos and measure the weight of plate content. RESULTS: The proportion of energy and protein consumed by both groups at each meal session could contribute up to 15% of the total daily recommended intake. Linear mixed model identified a positive relationship between meal portion size and plate waste (P = 0.002) and increased food waste in patients at nutritional risk during supper (P = 0.001). CONCLUSION: Meal portion size was associated with the level of plate waste produced. Being at nutritional risk further increased the extent of waste, regardless of the portion size served at supper. The use of DIMS as an innovative technique might be a promising way to monitor plate waste for optimizing meal portion size servings and minimizing food waste.

How practice contributes to trolley food waste. A qualitative study among staff involved in serving meals to hospital patients.

This study investigated the generation of trolley food waste at the ward level in a hospital in order to provide recommendations for how practice could be changed to reduce food waste. Three separate focus group discussions were held with four nurses, four dietitians and four service assistants engaged in food service. Furthermore, single qualitative interviews were conducted with a nurse, a dietitian and two service assistants. Observations of procedures around trolley food serving were carried out during lunch and supper for a total of 10 weekdays in two different wards. All unserved food items discarded as waste were weighed after each service. Analysis of interview and observation data revealed five key themes. The findings indicate that trolley food waste generation is a practice embedded within the limitations related to the procedures of meal ordering. This includes portion size choices and delivery, communication, tools for menu information, portioning and monitoring of food waste, as well as the use of unserved food. Considering positive changes to these can be a way forward to develop strategies to reduce trolley food waste at the ward level.

Positive effect of protein-supplemented hospital food on protein intake in patients at nutritional risk: a randomised controlled trial.

BACKGROUND: New evidence indicates that increased dietary protein ingestion promotes health and recovery from illness, and also maintains functionality in older adults. The present study aimed to investigate whether a novel food service concept with protein-supplementation would increase protein and energy intake in hospitalised patients at nutritional risk. METHODS: A single-blinded randomised controlled trial was conducted. Eighty-four participants at nutritional risk, recruited from the departments of Oncology, Orthopaedics and Urology, were included. The intervention group (IG) received the protein-supplemented food service concept. The control group (CG) received the standard hospital menu. Primary outcome comprised the number of patients achieving ≥75% of energy and protein requirements. Secondary outcomes comprised mean energy and protein intake, body weight, handgrip strength and length of hospital stay. RESULTS: In IG, 76% versus 70% CG patients reached ≥75% of their energy requirements (P = 0.57); 66% IG versus 30% CG patients reached ≥75% of their protein requirements (P = 0.001). The risk ratio for achieving ≥75% of protein requirements: 2.2 (95% confidence interval = 1.3-3.7); number needed to treat = 3 (95% confidence interval = 2-6). IG had a higher mean intake of energy and protein when adjusted for body weight (CG: 82 kJ kg(-1) versus IG: 103 kJ kg(-1) , P = 0.013; CG: 0.7 g protein kg(-1) versus 0.9 g protein kg(-1) , P = 0.003). Body weight, handgrip strength and length of hospital stay did not differ between groups. CONCLUSIONS: The novel food service concept had a significant positive impact on overall protein intake and on weight-adjusted energy intake in hospitalised patients at nutritional risk.

Substance P alterations in skin and brain of chronically stressed atopic-like mice.

BACKGROUND: Stress is known to worsen the symptoms of atopic eczema (AE). Substance P is likely to play an important role in the development and pathogenesis of AE. OBJECTIVE: To examine a possible connection between chronic mild stress and changes in the expression of substance P and its receptor (R) neurokinin (NK) 1 in the skin and stress-related brain regions in NC/Nga atopic-like mice. METHODS: The mice were divided into three groups (eight animals per group): SE (stressed eczematous), NSE (non-stressed eczematous) and SC (stressed control). Ears and brains of the mice were investigated using immunohistochemistry and RT-PCR. RESULTS: In the skin, there was a decrease in the number of substance P immunoreactive nerve fibres in SE compared with SC group. RT-PCR showed a strong tendency to an increase in mRNA for NK1R in the skin of SE compared with NSE mice. There was an increase in the number of mast cells and the degree of their degranulation in the SE compared with both other groups. A decrease in substance P immunoreactivity in medial hippocampus was found in SE compared with NSE animals. In prefrontal cortex and central amygdala, there were no significant differences in substance P immunoreactivity between the three groups. CONCLUSION: Exposure to chronic mild stress in NC/Nga atopic-like mice may result in altered expression patterns of substance P in the skin and hippocampus.

A longitudinal follow-up study of parent-reported family impact and quality of life in young patients with traumatic and non-traumatic brain injury.

PURPOSE: Brain injuries (traumatic-/nontraumatic, TBI/nTBI) in young patients may lead to problems e.g., decreased health-related quality of life (HRQoL), and causes family impact. Knowledge regarding the family impact and the relationship with patients' HRQoL over time is scarce. This follow-up study describes family impact/HRQoL and their mutual relationship in young patients (5-24 years) after TBI/nTBI. MATERIALS AND METHODS: Parents of patients that were referred to outpatient rehabilitation completed the PedsQL™Family-Impact-Module questionnaire to assess the family impact and the parent-reported PedsQL™Generic-core-set-4.0 to assess patients' HRQoL (lower scores: more family impact/worse HRQoL). Questionnaires were completed at the time of referral to rehabilitation (baseline) and one/two years later (T1/T2). Linear-mixed models were used to examine family impact/HRQoL change scores, and repeated-measure correlations (r) to determine longitudinal relationships. RESULTS: Two-hundred-forty-six parents participated at baseline, 72 (at T2), median patient's age at baseline was 14 years (IQR:11-16), and 181 (74%) had TBI. Mean (SD) PedsQL™Family-Impact-Module score at baseline was 71.7 (SD:16.4) and PedsQL™Generic-core-set-4.0: 61.4 (SD:17.0). Over time, PedsQL™Family-Impact-Module scores remained stable, while PedsQL™Generic-core-set-4.0 scores improved significantly(p < 0.05). A moderately strong longitudinal correlation was found between family impact&HRQoL (r = 0.51). CONCLUSIONS: Family impact does not tend to decrease over time but remained a considerable problem, although patients' HRQoL improved. Next to focusing on patients' HRQoL, it remains important to consider family impact and offer family support throughout rehabilitation.IMPLICATIONS FOR REHABILITATIONThis longitudinal study found that in young patients with traumatic brain injury (TBI) or non-traumatic brain injury (nTBI) referred for rehabilitation there is a considerable impact on the family until two years after referral, whereas the patients' health-related quality of life (HRQoL) improved significantly.Improvements in patients' quality of life status may not automatically lead to a decrease of family impact.Rehabilitation clinicians should monitor the impact on the family over time and provide long-term family support with special attention to parental worrying when needed.Clinicians should be aware that, despite significant differences between the clinical characteristics of patients with TBI and nTBI, the courses of family impact are very similar.

Towards a paradigm shift in pediatric rehabilitation: accelerating the uptake of evidence on participation into routine clinical practice.

PURPOSE: Evidence for the importance of focusing on participation to promote health and wellbeing in childhood-onset disability exists, but practice is slow to change. This paper provides a knowledge translation roadmap to accelerate uptake of participation evidence into day-to-day practice. MATERIALS AND METHODS: A structured roadmap to guide knowledge translation initiatives for implementing participation-based practices in co-creation with service users was developed based on elements from: the Five-factorframework for predicting implementation outcomes, the Cultural Cone framework, and the Knowledge-to-Action model. RESULTS: Guiding principles paired with examples of multi-component knowledge implementation strategies to facilitate readiness for change by stakeholders at the micro (e.g., client/family, service providers), meso (e.g., administrators within organisations such as rehabilitation centres, hospitals, schools) and macro (e.g., local and governmental policy, regulatory bodies) levels are introduced. Solution-based strategies are provided to facilitate "readiness to change" for each stakeholder group. The strategies are examples for successful implementation of evidence-based interventions/approaches that can be contextualized across settings. CONCLUSIONS: The knowledge translation roadmap can assist children and families, service providers, administrators, and policymakers to bridge existing knowledge-to-practice gaps surrounding participation. Partnering and collaborating through a "family-clinician-manager-community leader-policymaker" synergy is key for achieving strategic practice change focussed on participation.Implications for RehabilitationSound evidence surrounding the topic of participation, including effective assessments and interventions, is available and ready for use.Shifting towards participation-focused practices for children and youth with disabilities requires a systemic multi-level KT approach.Our Participation-KT roadmap, comprised of a framework and a list of principles and strategies for implementation, can be used to guide all stakeholders to foster a shift in practice.Forming partnerships and working collaboratively with all stakeholders is key for successful implementation.

Development and validation of ion-pairing HPLC-CAD chromatography for measurement of Islatravir's phosphorylated intermediates.

Biocatalytic processes have become more prevalent in the pharmaceutical industry, leading to analytical challenges not faced when characterizing more traditional synthetic routes. A novel one-pot biocatalytic process has been established for Islatravir, an HIV reverse transcriptase translocation inhibitor for the treatment and prevention of HIV-1. As a one-pot reaction, the Islatravir chemistry contains multiple intermediates that are not isolated. Additionally, these unisolated intermediates have no chromophores, making traditional LC-UV techniques ineffective for characterization. A hydrophilic interaction chromatography (HILIC) method with a charged aerosol detector (CAD) was initially developed, however numerous inorganic species present in the one-pot reaction were retained; this led to co-elution of compounds and poor peak shapes. An innovative ion-pairing LC method was developed in order to resolve inorganic species, intermediates, and the API, for use during in-process control of the Islatravir biocatalytic reaction. Aided by a volatile ion-pairing reagent compatible with the CAD, this method successfully retains and resolves the highly polar intermediates of interest and Islatravir API. This novel method was successfully validated and has allowed the Islatravir biocatalytic process to be fully characterized from the early intermediates through the final API within the one-pot reaction without the need for isolations. This novel ion-pairing HPLC-CAD technique lays the groundwork for method development on current and future biocatalytic-produced drug substances.

Expression of tachykinins and their receptors in plaque psoriasis with pruritus.

UNLABELLED: BACKGROUND Various mediators of pruritus have been suggested that might be responsible for the mechanism of pruritus in psoriasis. OBJECTIVES: To study the expression levels of members of the tachykinin family, substance P and neurokinin (NK) A and their receptors, NK-1 and NK-2, in psoriasis and to correlate their expression with the intensity of pruritus. A possible correlation with chronic stress and depression was also evaluated. METHODS: Biopsies were obtained from 28 patients with chronic plaque psoriasis; the majority had pruritus. The samples were taken from lesional and nonlesional areas on the back and also from 10 healthy controls, for immunohistochemistry staining, and from lesional skin for radioimmunoassay. Prior to biopsy, the clinical severity of the psoriasis of each patient was assessed by the Psoriasis Area and Severity Index (PASI) and the intensity of pruritus was measured by using a visual analogue scale (VAS). Levels of depression and stress were measured using Beck's Depression Inventory (BDI) and the salivary cortisol test, respectively. RESULTS: Substance P-, NKA- and NK-2 receptor-immunoreactive nerves, and non-neuronal inflammatory cells positive for substance P and NKA and their respective receptors, NK-1 and NK-2, were numerous in psoriasis compared with healthy controls. The numbers of substance P-positive nerves and NK-2 receptor-positive cells in lesional skin were significantly correlated to pruritus intensity. The cortisol ratio was inversely correlated with the number of NK-1 receptor-immunoreactive inflammatory cells in lesional and nonlesional psoriasis skin. There was also a positive correlation between the BDI score and the number of substance P-positive cells in nonlesional skin and with NK-1 receptor-positive cells in lesional and nonlesional skin. CONCLUSIONS: Tachykinins may play a role in psoriasis per se, in addition to pruritus in this disease. Targeting the combined NK-1 and NK-2 receptors might be a possible treatment.

Absence of colon as the predominant risk factor for liver fibrosis in adults requiring home parenteral nutrition.

BACKGROUND: Liver fibrosis is a well-known complication of long-term use of parenteral nutrition in patients with intestinal failure associated to the nutrient composition in parenteral nutrition. This study investigates the prevalence of significant liver fibrosis and identifies risk factors for liver fibrosis. METHODS: This was a retrospective study of 35 parenteral nutrition-dependent patients with intestinal failure and 54 patients with intestinal insufficiency and oral nutrition only with a valid liver stiffness measurement obtained with transient elastography from November 2016 to August 2018. Clinical and demographic parameters including age, fat mass index and fat-free mass index, intact colon or colectomy, and nutritional management were analyzed for their association with liver stiffness. RESULTS: A prevalence for liver fibrosis (liver stiffness >7.0 kPa) was established at 37.1% in parenteral nutrition-dependent patients and at 22.2% in patients on oral nutrition. Several factors were significantly and independently associated with liver fibrosis including lipids in home parenteral nutrition (OR 10.66, p = 0.010) and colectomies (OR 3.24, p = 0.036). CONCLUSION: More than a third of patients receiving home parenteral nutrition have liver fibrosis. Several risk factors were demonstrated such as the amount of lipids and performed colectomies despite current international guidelines for lipids are followed. Our findings emphasize suggest a new perspective to prevent significant hepatic complications: colectomies.

Adenosine selectively inhibits labeling of chromosomal RNA, especially hnRNA, probably by acting at or near the site of chain initiation.

The effects of adenosine on labeling of nucleolar preribosomal RNA, chromosomal plus nuclear sap hnRNA, and 4-5S RNA in explanted salivary gland cells of chironomus tentans has been studied. Of chromosomal transcripts it is the labeling of polymerase II-promoted RNA that is interrupted preferentially, but 4-5S RNA is influenced as well. The labeling of hnRNA and 4-5S RNA is diminished by 70-90 percent and 45-60 percent, repectively, while the incorporation into the nucleolar preribosomal RNA remains essentially unchanged. Labeled adenosine is transported efficiently across the plasma membrane and becomes phosphorylated to AMP, ADP, and ATP, of which ATP predominates at noninhibitory concentrations. The rate of the formation of [(3)H]AMP is, however, enhanced in response to the increase in external adenosine doses, whereas that of [(3)H]ATP increases only slowly or remains essentially unaltered. A rise in exogenous [(3)H] adenosine concentration to 200 muM yields a [(3)H]ATP/[(3)H]AMP ratio that is about one order of magnitude lower than that at 20 muM of the nucleoside. In parallel with this, there is a gradual repression of the labeling of chromosomal RNA. A similar treatment with guanosine produces only minor reduction in GTP/GMP quotient and does not influence significantly the labeling of any sizable RNA fraction. Thus the experimental data strongly indicate that the purine ribonucleoside adenosine, but not guanosine, gives rise to a markedly diminished triphosphate/monophosphate quotient simultaneously with a selective suppression of the labeling of chromosomal RNA, especially hnRNA, when applied in overdoses. The sequence of hnRNA events during inhibition by adenosine resembles the effect of the purine nucleoside analogue 5,6-dichloro-1-beta-D- ribofuranosylbenzimidazole, indicating that the site of inhibitory action is at or close to the initiation of transcription.

Phosphorylation of some chromosomal nonhistone proteins in active genes is blocked by the transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB).

The distribution of rapidly phosphorylated chromosomal proteins between chromosome I, chromosome II + III, chromosome IV, and nuclear sap including the matrix was investigated in salivary gland cells of Chironomus tentans. Chromosome IV, which carries most active nonribosomal genes in the cell, was found to be enriched in four rapidly phosphorylated nonhistone polypeptides (Mr = 25,000, 30,000, 33,000, and 42,000) in parallel with the transcriptional activity rather than with the DNA content of the chromosome. Also the histones H2A and H4 are rapidly phosphorylated but the phosphorylation is proportional to the DNA content of each chromosome sample. The 32P-labeled Mr = 42,000 polypeptide immunologically cross-reacted with an antibody elicited against the transcription stimulatory factor S-II isolated from Ehrlich ascites tumor cells (Sekimizu, K., D. Mizuno, and S. Natori, 1979, Exp. Cell Res., 124:63-72). In addition, indirect immunofluorescence studies on chromosome IV with antisera against the stimulatory factor II revealed a selective staining of the active gene loci. The incorporation of 32P into three chromosome IV nonhistone polypeptides, especially into the Mr = 42,000 polypeptide, was lowered by 70-85% shortly after administration of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), a likely inhibitor of heterogeneous nuclear RNA transcription at initiation level. The possibility of a causal relationship between inhibited phosphorylation of chromosomal proteins and blocked transcription of heterogeneous nuclear RNA genes by DRB is discussed.

Insulin-like growth factor-1 receptor acts as a growth regulator in synovial sarcoma.

Synovial sarcomas account for 5-10% of all soft tissue sarcomas and the majority of synovial sarcomas display characteristic t(X;18) translocations that result in enhanced transcription of the insulin-like growth factor-2 (IGF-2) gene. IGF-2 is an essential fetal mitogen involved in the pathogenesis of different tumours, leading to cellular proliferation and inhibition of apoptosis. Here we asked whether activation of IGF signalling is of functional importance in synovial sarcomas. We screened human synovial sarcomas for expression of IGF-2 and the phosphorylated IGF-1 receptor (IGF-1R), which mainly mediates the proliferative and anti-apoptotic effects of IGF-2. Since both the phosphatidylinositol 3'-kinase (PI3K)-AKT pathway and the MAPK signalling cascade are known to be involved in the transmission of IGF-1R signals, expression of phosphorylated (p)-AKT and p-p44/42 MAPK was additionally assessed. All tumours expressed IGF-2 and 78% showed an activated IGF-1R. All tumours were found to express p-AKT and 92% showed expression of activated p44/42 MAPK. To analyse the functional and potential therapeutic relevance of IGF-1R signalling, synovial sarcoma cell lines were treated with the IGF-1R inhibitor NVP-AEW541. Growth was impaired by the IGF-1R antagonist, which was consistently accompanied by a dose-dependent reduction of phosphorylation of AKT and p44/42 MAPK. Functionally, inhibition of the receptor led to increased apoptosis and diminished mitotic activity. Concurrent exposure of selected cells to NVP-AEW541 and conventional chemotherapeutic agents resulted in positive interactions. Finally, synovial sarcoma cell migration was found to be dependent on signals transmitted by the IGF-1R. In summary, our data show that the IGF-1R might represent a promising therapeutic target in synovial sarcomas.

Insufficient intake of energy and protein is related to physical functional capacity among COPD patients referred to municipality based pulmonary rehabilitation.

BACKGROUND: Malnutrition is frequent in COPD. Malnourished patients participating in pulmonary rehabilitation (PR) may benefit less and even worsen prognosis. The aim of this study was to investigate energy and protein intake in outpatients with COPD referred to municipality based PR and to investigate the relation to functional capacity. METHODS: COPD patients referred to PR at five Danish municipals were assessed for energy and protein intake by self-reported intake record and 24-hour recall by a dietician. Nutritional status was assessed by BMI, weight loss, and eating validation scheme, functional status by 30-seconds chair stand (30s-CST), and 6-minutes walking test (6MWT), and severity of disease by FEV1 and mMRC. RESULTS: We included 79 patients (41% male and 73% above 65 + y). Ninety-six% had a FEV1 below 80%, 59% had a mMRC-score of 3 + and 14% had a BMI below 20 kg/m2. Fifty-one % and 41% of the patients had insufficient intake of protein and energy, respectively, defined as an average intake below the 75% of the recommended. Kruskal Wallis test showed a significant positive association between protein intake and 30s-CST (p = 0.012) and 6MWT (p = 0.024) but no association with energy intake. CONCLUSIONS: Among patients with COPD referred for PR, there is a high prevalence of insufficient intake of energy and protein. This causes concern, as the physical training, which is the main component of PR, is likely to be futile unless the patients obtain a sufficient intake of energy and protein during the pulmonary; rehabilitation program.

Generic gas chromatography flame ionization detection method using hydrogen as the carrier gas for the analysis of solvents in pharmaceuticals.

Within the pharmaceutical industry, the determination of residual solvents by Gas Chromatography Flame Ionization Detection (GC-FID) is a highly utilized analytical test that often employs helium (He) as the carrier gas. However, many do not realize that helium is a non-renewable resource that will eventually become progressively more difficult to source. In recent years, analytical chemists are increasingly adopting hydrogen (H2) in place of helium for routine GC analysis. In this study, a simple and efficient generic/universal GC-FID method using H2 as the carrier gas has been developed with the capability of baseline resolution of over 30 of the most commonly used solvents in development and manufacturing with a method run time of less than eight minutes. The use of this method for the separation and analysis of solvents within a pharmaceutical manufacturing process is demonstrated with additional method validation data presented using five different diluents as a means to increase flexibility for the chromatographer. Furthermore, it is the recommendation of the authors that the current compendia for residual solvent analysis be updated to allow for hydrogen as a carrier gas. The similarity between He and H2 observed within this study supports the use of hydrogen as a suitable replacement for helium, and an update of the EU and USP compendia for residual solvent analysis should be made to reflect this.

Protein and energy intake improved by in-between meals: An intervention study in hospitalized patients.

BACKGROUND/AIM: Disease related malnutrition is a major problem in hospitals. Malnutrition in hospitalized patients is caused by many factors. Among these factors are decreased appetite and early satiety, and reaching nutritional requirements in nutritional risk patients is a challenge when using ordinary energy and protein dense food. The aim of this study was to examine if total protein and energy intake in medical and surgical patients at nutritional risk could be improved by protein fortified and energy rich in-between meals. METHODS: An assortment of fortified in-between meals including 10 g of protein was developed based on patient preferences and served in the Departments of Lung Medicine and Abdominal Surgery for a period of three months. Nutrition intake was recorded before and after intervention. RESULTS: Food intake records were collected from a total of 92 patients, (46 before and 46 after intervention). The total amount of protein intake per in-between meal was increased from 2,6 g to 10,3 g. Total daily protein intake increased from 49% to 88% (p < 0.00) and total energy intake from 74% to 109% (p < 0.00) of requirements. CONCLUSION: Protein and energy intake for surgical and medical patients at in-between meals as well as total daily intake increased significantly. Recommended average level for individually measured requirements was reached.