Disease Assessments in Patients with Glioblastoma.

PURPOSE OF REVIEW: The neuro-oncology team faces a unique challenge when assessing treatment response in patients diagnosed with glioblastoma. Magnetic resonance imaging (MRI) remains the standard imaging modality for measuring therapeutic response in both clinical practice and clinical trials. However, even for the neuroradiologist, MRI interpretations are not straightforward because of tumor heterogeneity, as evidenced by varying degrees of enhancement, infiltrating tumor patterns, cellular densities, and vasogenic edema. The situation is even more perplexing following therapy since treatment-related changes can mimic viable tumor. Additionally, antiangiogenic therapies can dramatically decrease contrast enhancement giving the false impression of decreasing tumor burden. Over the past few decades, several approaches have emerged to augment and improve visual interpretation of glioblastoma response to therapeutics. Herein, we summarize the state of the art for evaluating the response of glioblastoma to standard therapies and investigational agents as well as challenges and future directions for assessing treatment response in neuro-oncology. RECENT FINDINGS: Monitoring glioblastoma responses to standard therapy and novel agents has been fraught with many challenges and limitations over the past decade. Excitingly, new promising methods are emerging to help address these challenges. Recently, the Response Assessment in Neuro-Oncology (RANO) working group proposed an updated response criteria (RANO 2.0) for the evaluation of all grades of glial tumors regardless of IDH status or therapies being evaluated. In addition, advanced neuroimaging techniques, such as histogram analysis, parametric response maps, morphometric segmentation, radio pharmacodynamics approaches, and the integrating of amino acid radiotracers in the tumor evaluation algorithm may help resolve equivocal lesion interpretations without operative intervention. Moreover, the introduction of other techniques, such as liquid biopsy and artificial intelligence could complement conventional visual assessment of glioblastoma response to therapies. Neuro-oncology has evolved over the past decade and has achieved significant milestones, including the establishment of new standards of care, emerging therapeutic options, and novel clinical, translational, and basic research. More recently, the integration of histopathology with molecular features for tumor classification has marked an important paradigm shift in brain tumor diagnosis. In a similar manner, treatment response monitoring in neuro-oncology has made considerable progress. While most techniques are still in their inception, there is an emerging body of evidence for clinical application. Further research will be critically important for the development of impactful breakthroughs in this area of the field.

The landscape of brain tumor mimics in neuro-oncology practice.

BACKGROUND AND OBJECTIVE: Differentiating neoplastic and non-neoplastic brain lesions is essential to make management recommendations and convey prognosis, but the distinction between brain tumors and their mimics in practice may prove challenging. The aim of this study is to provide the incidence of brain tumor mimics in the neuro-oncology setting and describe this patient subset. METHODS: Retrospective study of adult patients referred to the Division of Neuro-oncology for a presumed diagnosis of brain tumor from January 1, 2005 through December 31, 2017, who later satisfied the diagnosis of a non-neoplastic entity based on neuroimaging, clinical course, and/or histopathology evaluation. We classified tumor mimic entities according to clinical, radiologic, and laboratory characteristics that correlated with the diagnosis. RESULTS: The incidence of brain tumor mimics was 3.4% (132/3897). The etiologies of the non-neoplastic entities were vascular (35%), inflammatory non-demyelinating (26%), demyelinating (15%), cysts (10%), infectious (9%), and miscellaneous (5%). In our study, 38% of patients underwent biopsy to determine diagnosis, but in 26%, the biopsy was inconclusive. DISCUSSION: Brain tumor mimics represent a small but important subset of the neuro-oncology referrals. Vascular, inflammatory, and demyelinating etiologies represent two-thirds of cases. Recognizing the clinical, radiologic and laboratory characteristics of such entities may improve resource utilization and prevent unnecessary as well as potentially harmful diagnostic and therapeutic interventions.

Neurologic and Medical Management of Brain Tumors.

Patients with brain tumor encounter a wide spectrum of tumor and treatment-related complications during their disease course. Tumors may serve as seizure substrates, are associated with a hypercoagulable state that results in thromboembolic complications, and may influence mood and cognition. Antitumor and supportive therapies may also have deleterious effects. Herein, we discuss major aspects of supportive care for patients with brain tumors, with attention to benefit and complications derived from the management of seizures, brain edema, venous thromboembolism, fatigue, mood alterations, and cognitive dysfunction.

Regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor: a case report.

Intramedullary spinal cord metastasis is an increasingly common diagnosis in patients with cancer largely owing to new imaging techniques and the increase lifespan of patients with malignant tumors. The diagnosis confers significant morbidity and a poor prognosis. Mainstay palliative treatment options include corticosteroids, fractionated radiotherapy and surgery in select cases. In the modern era of immunotherapy for the treatment of several tumor types, the efficacy of these agents against parenchymal CNS tumors remains unanswered. Here, we report a case of regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor.

Association between metabolic syndrome and 10-year risk of developing cardiovascular disease in a Nigerian population.

BACKGROUND: Prevalence of metabolic syndrome (MetS) and consequential cardiovascular disease (CVD) events are on the increase in Nigeria. The study aimed to identify the prevalence of 10-year CVD risk in a Nigerian population and assess its relationship with different indices of MetS. METHOD: A cross-sectional study was carried out on apparently healthy persons aged 18 years of age or older. Ten-year risk was calculated using the ATPIII/Framingham criteria. Subjects with risk score <10% were considered as having low risk, 10-20% moderate risk and >20% at high risk of developing CVD in 10 years. MetS was defined based on the Joint Scientific Statement on Harmonizing the MetS. RESULT: Of the 211 subjects, mean age was 51.3±17.3 years. Average risk of developing CVD in the next 10 years was 3.7±5.3%. Prevalence of low, moderate and high risk of developing CVD among study participants was 86.3% (95% CI 82.0-91.3%), 11.8% (95% CI 6.9-16.1%) and 1.9% (95% CI 0.0-3.8%), respectively. Prevalence of MetS was 26.7% (95% CI 21.0-33.3%). There was poor agreement between MetS and the CVD risk scores (kappa=0.209, p=0.001) CONCLUSIONS: The results showed that complementary use of MetS and CVD risk score is imperative, as there is indication of risk in individuals without MetS. Also a large proportion of the study population requires lifestyle intervention. These findings provide the evidence necessary to tailor public health interventions in this population, especially towards younger age groups.

Maximum accuracy obesity indices for screening metabolic syndrome in Nigeria: A consolidated analysis of four cross-sectional studies.

BACKGROUND: In sub-Saharan Africa, there is no precise use of metabolic syndrome (MetS) definitions and risk factors screening indices in many clinical and public health services. Methods proposed and used in Western populations are adopted without validation within the local settings. The aim of the study is to assess obesity indices and cut-off values that maximise screening of MetS and risk factors in the Nigerian population. METHOD: A consolidated analysis of 2809 samples from four population-based cross-sectional study of apparently healthy persons≥18 years was carried out. Optimal waist circumference (WC) and waist-to-height ratio (WHtR) cut points for diagnosing MetS and risk factors were determined using Optimal Data Analysis (ODA) model. The stability of the predictions of the models was also assessed. RESULTS: Overall mean values of BMI, WC and WHtR were 24.8±6.0kgm(-2), 84.0±11.3cm and 0.52±0.1 respectively. Optimal WC cut-off for discriminating MetS and diabetes was 83cm in females and 85cm in males, and 82cm in females and 89cm in males, respectively. WC was stable in discriminating diabetes than did WHtR and BMI, while WHtR showed better stability in predicting MetS than WC and BMI. CONCLUSION: The study shows that the optimal WC that maximises classification accuracy of MetS differs from that currently used for sub-Saharan ethnicity. The proposed global WHtR of 0.50 may misclassify MetS, diabetes and hypertension. Finally, the WC is a better predictor of diabetes, while WHtR is a better predictor of MetS in this sample population.

Association of physical activity with metabolic syndrome in a predominantly rural Nigerian population.

AIMS: Physical activity is an essential determinant of health. However, there is dearth of evidence regarding prevalence of physical activity in developing countries, especially its association with metabolic syndrome risk factors. This study assessed the association of physical activity with metabolic syndrome in a Nigerian population. MATERIALS AND METHODS: A cross-sectional study was carried out on apparently healthy persons who are ≥ 18 years old. The World Health Organisation (WHO) Global Physical Activity Questionnaire (GPAQ) was used to collect five domains of physical activity. Participants were classified as physically active or inactive based on meeting the cut-off value of 600 MET-min/week. Metabolic syndrome was diagnosed using the Joint Scientific Statement on Harmonizing the Metabolic Syndrome criteria. RESULTS: Overall prevalence of physically active individuals was 50.1% (CI: 45.6-54.7%). Physical inactivity is significantly more in females (p<0.01) and among participants >40 years old (p<0.0001). Whereas individuals with metabolic syndrome appeared more likely to be physically active (OR=1.48, CI: 0.71-3.09); physical inactivity showed to exist more among participants who were living in urban area (OR=6.61, CI: 3.40-12.85, p<0.001). Participants with prediabetes (OR=1.69, CI: 0.62-4.61) and diabetes (OR=1.91, CI: 0.65-5.63) were more likely to be physically inactive as compared to other metabolic syndrome risk factors. CONCLUSION: The high prevalence of physical inactivity in this study population is a clear indication that concerted efforts to improve physical activity may be required. However, it seems that metabolic syndrome is not improved by being physically active. This suggests that interventions directed at physical activity alone may not produce optimal efficacy in this study population.

Prevalence and Risk Factors of Microalbuminuria among Type 2 Diabetes Mellitus: A Hospital-Based Study from; Warri; Nigeria

"Aims: The aim of this study was to determine the prevalence of microalbuminuria (MA) in patients with type 2 diabetes mellitus (T2DM) and to identify the associated risk factors. Settings and Design: The study was a prospective; descriptive; cross-sectional study carried out in the medical outpatient department of the Central Hospital; Warri from March to August 2014 after approval by the hospital's health and ethics committee. Materials and Methods: Two hundred T2DM aged 45-80 years were randomly selected for the study after obtaining their informed consent. Three-morning urine samples collected at 1-month interval were tested for MA using the ""MICRAL test"" strip. A fasting blood sample was also drawn after 10-12 h overnight fasting for plasma glucose; hemoglobin A1c (HbA1c); lipid profile; and serum creatinine investigations. MA was diagnosed if the urinary albumin excretion ratio was between 30 and 300 mg/24 h from two separate urine samples. Statistical Analysis Used: Data was analyzed using Statistical Package for Social Sciences version 16. Differences at P 0.05 were considered significant. Results: The prevalence of MA was 58. The mean age; duration of T2DM; systolic blood pressure; fasting blood glucose; HbA1c level; serum creatinine of type 2 diabetes with MA were significantly higher when compared to T2DM patients without MA while the mean diastolic blood pressure body mass index and age did not differ significantly between the two groups. Conclusions: The overall prevalence of the MA among type 2 diabetes visiting a medical outpatient clinic in Central Hospital; Warri were high and similar to that reported in other studies."

Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort.

BACKGROUND: The importance of fatigue in chronic disease has been increasingly recognized; however, little is known about fatigue in inflammatory bowel disease (IBD). The aim of the present study was to investigate the prevalence and severity of fatigue and the impact on health-related quality of life (HRQoL) in patients included in a population-based IBD cohort in the Netherlands. METHODS: IBD patients, diagnosed between January 1st, 1991, and January 1st, 2003, were followed up for a median of 7.1 years. They completed a questionnaire, which included a disease activity score, the Multidimensional Fatigue Inventory (MFI-20), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Short Form health survey (SF-36). Hemoglobin levels were recorded. RESULTS: Data were available in 304 Crohn's disease (CD), 368 ulcerative colitis (UC), and 35 indeterminate colitis (IC) patients. During quiescent disease, the prevalence of fatigue was nearly 40%. MFI-20 and HRQoL scores were significantly worse in IBD patients having active disease. In a multivariate analysis, disease activity was positively related with the level of fatigue in both CD and UC. In UC, anemia influenced the general fatigue score independently of disease activity. Disease activity as well as fatigue were independently associated with an impaired IBDQ. CONCLUSIONS: In IBD, even in remission, fatigue is an important feature. Both in CD and in UC, fatigue determined HRQoL independently of disease activity or anemia. This implies that in IBD patients physicians need to be aware of fatigue in order to better understand its impact and to improve the HRQoL.

Affective symptoms as predictors of Alzheimer's disease in subjects with mild cognitive impairment: a 10-year follow-up study.

BACKGROUND: Affective symptoms are common in subjects with mild cognitive impairment (MCI), but there is disagreement whether these symptoms are predictive for Alzheimer's disease (AD). We investigated the predictive accuracy of affective symptoms for AD during a follow-up study in subjects with MCI, and whether the predictive accuracy was modified by age, the presence of amnestic MCI or the length of follow-up. METHOD: Newly referred subjects (n=263) with MCI older than 55 years were selected from a memory clinic and followed up after 2, 5 and 10 years. Predictors investigated were: symptoms of depression, anxiety, apathy and sleeping problems. RESULTS: Affective symptoms were present in 50-70% of the subjects. The average follow-up period was 5.4 years and 79 subjects (29%) developed AD. Sleeping problems were associated with a decreased risk for AD [odds ratio (OR) 0.35, p<0.001]. Symptoms of depression (OR 0.61, p=0.059) and anxiety (OR 0.58, p=0.051) showed a trend in the same direction. The OR of apathy for AD was 0.67 (p=0.14). Depression was associated with a decreased risk for AD only in subjects without amnestic MCI, but not in subjects with amnestic MCI. Moreover, anxiety was related to the risk for AD differently between subjects diagnosed with AD at the 5-year follow-up (OR 0.23) and subjects diagnosed with AD at the 10-year follow-up (OR 1.7). CONCLUSIONS: Affective symptoms are associated with a decreased risk for AD. The risk may be dependent on MCI subtype or length of follow-up, but it does not depend on age.

Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons.

The basis for selective death of specific neuronal populations in neurodegenerative diseases remains unclear. Parkinson's disease (PD) is a synucleinopathy characterized by a preferential loss of dopaminergic neurons in the substantia nigra (SN), whereas neurons of the ventral tegmental area (VTA) are spared. Using intracellular patch electrochemistry to directly measure cytosolic dopamine (DA(cyt)) in cultured midbrain neurons, we confirm that elevated DA(cyt) and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DA(cyt) provide neuroprotection. L-DOPA increased DA(cyt) in SN neurons to levels 2- to 3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DA(cyt) was not altered by alpha-synuclein deletion, although dopaminergic neurons lacking alpha-synuclein were resistant to L-DOPA-induced cell death. Thus, an interaction between Ca2+, DA(cyt), and alpha-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.

The contribution of six polymorphisms to cardiovascular risk in a Dutch high-risk primary care population: the HIPPOCRATES project.

This study was designed to examine the contribution of six polymorphisms to the occurrence of cardiovascular disease (CVD) in a Dutch primary care population with a high prevalence of cardiovascular risk factors. In this cross-sectional case-control study, 232 patients with CVD and 571 event-free controls were studied. Patients were genotyped for the AGTR1 (A1166C), AGT (M235T), ACE (4656rpt), NOS3 (E298D), GNB3 (C825T) and ADD1 (G460W) polymorphisms. Univariate and multivariate odds ratios (ORs) were calculated to assess the relationship between genotypes and CVD. Receiver operating characteristic (ROC) analysis was used to quantify the contribution of the polymorphisms to the prediction of CVD. No differences in either genotype or allele frequencies were found between CVD cases and controls. Multivariate analyses, corrected for multiple testing according to Bonferroni, showed significant protective associations for the T-allele of AGT (OR=0.55 (0.34-0.84)) and for the T-allele of ADD1 (OR=0.52 (0.31-0.82)). ROC analysis showed only a very small improvement of CVD risk prediction by adding the six polymorphisms to a model with traditional risk factors. Our data suggest that a major attribution of the six polymorphisms to the cardiovascular risk prediction in a primary care population such as HIPPOCRATES is unlikely.

Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease.

OBJECTIVES: Disease course in inflammatory bowel disease (IBD) is variable and difficult to predict. To optimize prognosis, it is of interest to identify phenotypic characteristics at disease onset and other prognostic factors that predict disease course. The aim of this study was to evaluate such factors in a population-based IBD group. METHODS: IBD patients diagnosed between 1 January 1991 and 1 January 2003 were included. A follow-up questionnaire was developed and medical records were reviewed. Patients were classified according to phenotype at diagnosis and risk factors were registered. Disease severity, cumulative medication use, and "surgical" and "nonsurgical" recurrence rates were calculated as outcome parameters. RESULTS: In total, 476 Crohn's disease (CD), 630 ulcerative colitis (UC), and 81 indeterminate colitis (IC) patients were diagnosed. In CD (mean follow-up 7.6 years), 50% had undergone resective surgery. In UC (mean follow-up 7 years), colectomy rate was 8.3%. First year cumulative recurrence rates per 100 patient-years for CD, UC, and IC were 53, 44, and 42%, respectively. In CD, small bowel localization and stricturing disease were negative prognostic factors for surgery, as was young age. Overall recurrence rate was increased by young age and current smoking. In UC, extensive colitis increased surgical risk. In UC, older age at diagnosis initially increased recurrence risk but was subsequently protective. CONCLUSIONS: This population-based IBD study showed high recurrence rates in the first year. In CD, small bowel localization, stricturing disease, and young age were predictive for disease recurrence. In UC, extensive colitis and older age at diagnosis were negative prognostic predictors.

Long-term follow-up after cancer rehabilitation using high-intensity resistance training: persistent improvement of physical performance and quality of life.

The short-term beneficial effects of physical rehabilitation programmes after cancer treatment have been described. However, little is known regarding the long-term effects. The purpose of this study was to investigate the long-term effects of high-intensity resistance training compared with traditional recovery. A total of 68 cancer survivors who completed an 18-week resistance training programme were followed for 1 year. During the 1-year follow-up, 19 patients dropped out (14 due to recurrence of cancer). The remaining 49 patients of the intervention group were compared with a group of 22 patients treated with chemotherapy in the same period but not participating in any rehabilitation programme. Outcome measures were muscle strength, cardiopulmonary function, fatigue, and health-related quality of life. One year after completion of the rehabilitation programme, the outcome measures in the intervention group were still at the same level as immediately after rehabilitation. Muscle strength at 1 year was significantly higher in patients who completed the resistance training programme than in the comparison group. High-intensity resistance training has persistent effects on muscle strength, cardiopulmonary function, quality of life, and fatigue. Rehabilitation programmes for patients treated with chemotherapy with a curative intention should include high-intensity resistance training in their programme.

Biomarker reproducibility in exhaled breath condensate collected with different condensers.

Optimal collection and analysis of exhaled breath condensate (EBC) are prerequisites for standardisation and reproducibility of assessments. The present study aimed to assess reproducibility of EBC volume, hydrogen peroxide (H(2)O(2)), 8-isoprostane and cytokine measurements using different condensers, including a newly developed glass condenser. At four points in time, 30 healthy subjects performed sequential EBC collections randomly using the following four condensers: glass, silicone, EcoScreen (Erich Jaeger GmbH, Hoechberg, Germany) and an optimised glass condenser. In small EBC samples, H(2)O(2) was measured by spectrophotometer, 8-isoprostane by enzyme immunoassay, and cytokines by multiplexed xMAP technology (Luminex Corporation, Austin, TX, USA). The optimised glass condenser yielded significantly more EBC volume (median 2,025 microL, interquartile range 1,600-2,525). The reproducibility of EBC volume, yielded by the new glass condenser, was comparable with EcoScreen (19-20 coefficients of variation (CV)%), but was significantly better compared with silicone and glass (29-37 CV%). The new condenser was associated with significantly more detections of H(2)O(2), 8-isoprostane, interleukin-2, -4, -5 and -13, and tumour necrosis factor-alpha. Isoprostane concentrations were significantly higher using the new condenser, whereas H(2)O(2) and cytokine concentrations were not. Reproducibility of biomarkers was equally variable for all condenser types. In conclusion, significantly more exhaled breath condensate volume and biomarker detections were found using the optimised glass condenser, including higher 8-isoprostane levels. However, biomarker reproducibility in exhaled breath condensate in healthy adults was not influenced by the type of condenser.

Feasibility and acceptability of a computerised system with automated reminders for prescribing behaviour in primary care.

OBJECTIVE: To evaluate the feasibility and acceptability of a computer reminder system (CRS) to improve prescribing behaviour in general practice and to explore the strengths and weaknesses of a reminder system. One group of GPs received reminders on cholesterol lowering drugs, the other group on antibiotics, asthma and COPD drugs. METHODS: Process evaluation of the computer reminder system being used by 53 GPs in 20 practices, by means of an analysis of the research database of the CRS. In addition, a questionnaire and semi-structured face-to-face interview were conducted with all GP practices, two project leaders, and one technical consultant. RESULTS: The strategy was largely carried out as planned, although the development period for the CRS had to be extended. Nine percent of the GPs dropped out. We found a significant learning curve without extinguishing effect (p=0.03) for the antibiotics reminders. The questionnaire showed that, in general, GPs were satisfied with the user-friendliness and the content of the different types of reminders, but less satisfied with certain specific technical performance issues of the system. The GPs reported mixed feelings towards the CRS in the interviews. They were generally positive about the guidelines themselves, but negative regarding to the organisational context and the method of implementing the CRS. GPs stated that they sometimes manipulated the system to bypass reminders. Interviews with the project leaders and technical consultant revealed barriers to cooperation and miscommunication between the different parties, and technical problems with multiple updates of the GP information system and the operating system. CONCLUSIONS: This process evaluation demonstrated that the implementation of the CRS was mainly carried out as planned, but the subjective experience of working with the CRS was not only positive. Participating GPs had mixed feelings, and quite a number of barriers need to be addressed to facilitate large-scale implementation of the CRS. Costs cannot be neglected, so it is important to analyse the balance between costs and effects.

The effect of computer reminders on GPs' prescribing behaviour: a cluster-randomised trial.

OBJECTIVE: It is difficult to control drug-prescribing behaviour in general practice, despite the development and distribution of guidelines. The purpose of this study was to assess the effect on drug-prescribing behaviour of implementing prescribing guidelines by means of a reactive computer reminder system (CRS). DESIGN: Cluster-randomised controlled trial with an incomplete block design in the south of the Netherlands: 25 GPs (7 GP practices) received reminders about antibiotics and asthma/COPD prescriptions, 28 GPs (7 GP practices) received reminders about cholesterol prescriptions. Prescription guidelines were integrated into the computerised GP information system. MEASUREMENTS: Both performance indicators and prescription volumes were calculated as the main outcome measures. Next to individual volume measure, sum scores were constructed on the volume measures per drug group (antibiotics, asthma/COPD and cholesterol). RESULTS: Variation between GPs turned out to be larger and more skewed than expected. No differences between groups were found for indicators and volumes related to recommendations advocating certain drugs. Although there was a tendency towards clinically relevant results for prescription volumes that were supposed to drop, the difference in sum score between the groups was not significant. For antibiotic prescriptions that were supposed to drop, the sum score for the intervention group was 28.2 (95% CI: 20.8-44.5) prescriptions per 1000 patients per GP, while this was 39.7 (95% CI: 29.7-64.1) for the control group (p 0.2). For prescriptions asthma/COPD that were supposed to drop, the sum score for the intervention group was 1.1 (95% CI: 0.6-2.6) prescriptions per 1000 patients per GP, while this was 2.2 (95% CI: 1.4-4.3) for the control group (p 0.1). On three specific recommendations (on quinolones for cystitis, corticosteroids for CPOD, and antibiotics for acute sore throat) significant differences were found. CONCLUSIONS: This study turned out to be underpowered due to high inter doctor variation in prescribing behaviour. Nevertheless, computerised reminders sometimes have a favourable effect on restricting certain drugs that are not or no longer indicated in general practice.

A glial cell line-derived neurotrophic factor (GDNF):tetanus toxin fragment C protein conjugate improves delivery of GDNF to spinal cord motor neurons in mice.

Glial cell line-derived neurotrophic factor (GDNF) has shown robust neuroprotective and neuroreparative activities in various animal models of Parkinson's Disease or amyotrophic lateral sclerosis (ALS). The successful use of GDNF as a therapeutic in humans, however, appears to have been hindered by its poor bioavailability to target neurons in the central nervous system (CNS). To improve delivery of exogenous GDNF protein to CNS motor neurons, we employed chemical conjugation techniques to link recombinant human GDNF to the neuronal binding fragment of tetanus toxin (tetanus toxin fragment C, or TTC). The predominant species present in the purified conjugate sample, GDNF:TTC, had a molecular weight of approximately 80 kDa as determined by non-reducing SDS-PAGE. Like GDNF, addition of GDNF:TTC to culture media of neuroblastoma cells expressing GFRalpha-1/c-RET produced a dose-dependent increase in cellular phospho-c-RET levels. Treatment of cultured midbrain dopaminergic neurons with either GDNF or the conjugate similarly promoted both DA neuron survival and neurite outgrowth. However, in contrast to mice treated with GDNF by intramuscular injection, mice receiving GDNF:TTC revealed intense GDNF immunostaining associated with spinal cord motor neurons in fixed tissue sections. That GDNF:TTC provided neuroprotection of axotomized motor neurons in neonatal rats further revealed that the conjugate retained its GDNF activity in vivo. These results indicate that TTC can serve as a non-viral vehicle to substantially improve the delivery of functionally active growth factors to motor neurons in the mammalian CNS.

Breath condenser coatings affect measurement of biomarkers in exhaled breath condensate.

Exhaled breath condensate collection is not yet standardised and biomarker measurements are often close to lower detection limits. In the current study, it was hypothesised that adhesive properties of different condenser coatings interfere with measurements of eicosanoids and proteins in breath condensate. In vitro, condensate was derived from a collection model using two test solutions (8-isoprostane and albumin) and five condenser coatings (silicone, glass, aluminium, polypropylene and Teflon). In vivo, condensate was collected using these five coatings and the EcoScreen condenser to measure 8-isoprostane, and three coatings (silicone, glass, EcoScreen) to measure albumin. In vitro, silicone and glass coatings had significantly higher albumin recovery compared with the other coatings. A similar trend was observed for 8-isoprostane recovery. In vivo, median (interquartile range) 8-isoprostane concentrations were significantly higher using silicone (9.2 (18.8) pg.mL(-1)) or glass (3.0 (4.5) pg.mL(-1)) coating, compared with aluminium (0.5 (2.4) pg.mL(-1)), polypropylene (0.5 (0.5) pg.mL(-1)), Teflon (0.5 (0.0) pg.mL(-1)), and EcoScreen (0.5 (2.0) pg.mL(-1)). Albumin in vivo was mainly detectable using glass coating. In conclusion, a condenser with silicone or glass coating is more efficient for measurement of 8-isoprostane or albumin in exhaled breath condensate, than EcoScreen, aluminium, polypropylene or Teflon. Guidelines for exhaled breath condensate standardisation should include the most valid condenser coating to measure a specific biomarker.

Prognostic factors and clinical outcome in acute lower respiratory tract infections: a prospective study in general practice.

BACKGROUND: Unrealistic expectations about illness duration are likely to result in reconsultations and associated unnecessary antibiotic prescriptions. An evidence-based account of clinical outcomes in patients with lower respiratory tract infection (LRTI) may help avoid unnecessary antibiotic prescriptions and reconsultations. OBJECTIVES: We aimed to identify clinical factors that may predict a prolonged clinical course or poor outcome for patients with LRTI and to provide an evidence-based account of duration of an LRTI and the impact of the illness on daily activities in patients consulting in general practice. METHODS: A prospective cohort study of 247 adult patients with a clinical diagnosis of LRTI presenting to 25 GPs in The Netherlands was carried out. Multivariable Cox regression analysis was used to identify baseline clinical and infection parameters that predicted the time taken for symptoms to resolve. A Kaplan-Meier curve was used to analyse time-to-symptom resolution. Clinical cure was recorded by the GPs at 28 days after the initial consultation and by the patients at 27 days. RESULTS: Co-morbidity of asthma was a statistically significant predictor of delayed symptom resolution, whereas the presence of fever, perspiring and the prescription of an antibiotic weakly predicted enhanced symptom resolution. The GPs considered 89% of the patients clinically cured at 28 days, but 43% of these nevertheless reported ongoing symptoms. Patient-reported cure was much lower (51%), and usual daily activities were limited in 73% of the patients at baseline, and 19% at final follow-up. CONCLUSIONS: The course of LRTI was generally uncomplicated, but the morbidity of this illness was considerable with a longer duration than generally reported, especially for patients with co-existent asthma. These results underline once again the importance of providing GPs with an evidence-based account of outcomes to share with patients in order to set realistic expectations and of enhancing their communication skills within the consultation.