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Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated.Report the results of the first years (2017-2019) of the Mexican FH registry.There are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations.To date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033).The results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.

Two previous randomized controlled trials (RCTs) suggested that adjunctive aspirin is efficacious in treating schizophrenia. We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline; the primary outcome was PANSS-positive score. Dropout rates for aspirin/placebo were 12% in study 1 and 20% in study 2. Differences in outcome between aspirin and placebo were calculated with linear regression, adjusting for the baseline value of the outcome. No statistically significant between-group differences were found in primary or secondary outcomes in either study. Study 1: mean difference in PANSS at 16 weeks was −3.9 (95% CI: −8.4 to 0.5, P = .10, effect size (ES) = −0.25) and at 8 weeks was −3.5 (95% CI: −7.5 to 0.5, P = .11, ES = −0.22). Study 2: mean difference in PANSS at 16 weeks was 0.3 (95% CI: −4.1 to 4.7, P = .90, ES = 0.02) and in positive PANSS was 0.5 (95% CI: −1.0 to 2.1, P = .50, ES = 0.11). A meta-analysis of these data with the existing studies, excluding one with large baseline differences in total PANSS, found that the overall estimate of the effect of adjunctive aspirin on the PANSS total score comparing group means at the end of the study was −2.9 (95% CI: −6.6 to 0.7; P = .21), favoring aspirin. Our studies and meta-analysis failed to find a statistically significant improvement in the symptoms of schizophrenia from adjunctive aspirin therapy in comparison to placebo in schizophrenia. Trial registration: study 1: Clinicaltrials.gov: NCT01320982; study 2 (high CRP): EudraCT Number: 2014-000757-36.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Background and Purpose— The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population. Methods— Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ≈30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of ≥4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1. Results— A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention-to-treat analysis and in the per-protocol analysis. Conclusions— CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01949961.

Cardiovascular diseases are the number one cause of morbidity and mortality globally. Numerous pathophysiological modifications that develop are associated with the stenosis and occlusion of blood vessels and tissue damage due to inadequate nutrient supply. Despite a variety of therapies available today, the preferred treatment for the long-term revascularization is artery bypass surgery. The autologous vessels are considered the “gold” standard treatment for this category of patients; unfortunately, they are often unavailable due to comorbidities or unsuitable for use. Synthetic scaffolds are suitable in large-diameter arteries (>8.0 mm) and medium-diameter arteries (6.0–8.0 mm), but are of limited use in small-diameter vessels (

Background. Although amiodarone is a drug with many side effects, it is one of the most commonly used drugs in the treatment and prophylaxis of supraventricular and ventricular arrhythmias. Aim. The purpose of this pilot study was to evaluate plasma concentrations of amiodarone in patients with atrial fibrillation (AF) and to identify possible drug-drug interactions between amiodarone and concomitant medications. Method. A prospective observational study was conducted in 27 consecutive patients treated with amiodarone from May to July 2017 in a Clinical University Hospital. The patients included met our inclusion criteria. HPLC-UV was the device used to determine the plasma concentration of amiodarone. Results. Only 51.8% of the patients had amiodarone plasma concentration within therapeutic interval (500-2500 ng/ml). The drugs associated to amiodarone in the therapeutic plan were diuretics, beta blockers, statins, antiplatelets, fluoroquinolones, non-steroidal anti-inflammatory drugs. We observed a statistically significant difference between the plasmatic concentrations of amiodarone in patients treated with furosemide vs. patients concomitantly treated with other drugs. Interactions between other mentioned drugs and amiodarone were not registered. We can report an underuse of amiodarone for more than 50% of the patients. Also, we found a significant interaction between furosemide and amiodarone, most likely through the interaction with MDR. Conclusion. Furosemide may influence the pharmacokinetics of P-gp-interfering drugs. However, the relevance of these findings needs to be confirmed and further research is needed to characterize the interaction between amiodarone and furosemide.

Background Atrial fibrillation (AF) is one of the most common sustained cardiac arrhythmia. It is associated with significant morbidity, mortality and poor quality of life. This is the reason why it is very important to closely follow its treatment. Amiodarone is one of the most frequently used antiarrhythmic drugs in patients with AF both in prophylaxis and treatment. However, the treatment with this drug results in high healthcare resource use and costs due to its poor safety profile. Purpose The objective of this study was to assess the plasmatic concentration of amiodarone in patients with AF and also to identify possible factors that could influence it. The results were correlated with used doses, with concomitantly administered drugs, renal and liver function. Material and methods A prospective observational study was conducted in 27 consecutive patients treated with amiodarone from May to July 2017 in a Clinical University Hospital. The patients included met our inclusion criteria. HPLC-MS was the device used to determine the plasma concentration of amiodarone. Results The mean age of those 27 included patients was 65/6±11 years, 44.4% females. The used doses were 200 mg or 400 mg/day. In our patients, plasmatic concentration was given in a therapeutic interval (500–2,500 ng/ml) to 51.8%. In the patients with lower plasmatic concentrations of amiodarone, the drugs associated in the therapeutic plan belonged to: diuretics (furosemide), beta-blockers, statins, antiplatelets (clopidogrel), fluoroquinolones (ciprofloxacine) and non-steroidal anti-inflammatory drugs. It was observed that there was a statistically significant difference between the plasmatic concentrations of amiodarone in patients treated with furosemide vs patients treated concomitantly with other drugs. The interactions between other mentioned drugs and amiodarone were not registered. It was observed that an increase in transaminases or creatinine is correlated with an increase in amiodarone’s plasmatic concentration. Conclusion 48.2% of the patients with AF under chronic treatment with amiodarone had the plasmatic concentration of amiodarone out of the therapeutic range. We can report an underuse of amiodarone for these patients. It was found that there was a significant interaction between furosemide and amiodarone. In order to confirm this interaction, we need to continue the research on a larger sample. References and/or Acknowledgements Thanks to all the collaborators. No conflict of interest

Moerch-Rasmussen A, Nacu A, Waje-Andreassen U, Thomassen L,Naess H. Recurrent ischemic stroke is associated with the burden ofrisk factors.Acta Neurol Scand: DOI: 10.1111/ane.12457.© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.Aim – To determine the characteristics of acute ischemic strokepatients admitted to hospital with history of prior ischemic stroke(s).We hypothesized that there is an association between the number ofrisk factors and prior ischemic stroke irrespective of age. Methods –All patients with acute ischemic stroke admitted to HaukelandUniversity Hospital between 2006 and 2013 were registered in theNORSTROKE database. Variables included prior ischemic stroke(s)(based on self-report and patient records), risk factors, TOASTclassification, and CT and MRI findings. Comparison was madebetween patients with prior ischemic stroke and first-ever ischemicstroke. Multivariate analyses were performed. Results – In total, 2697patients were included and 461 (17.1%) had a history of priorischemic stroke(s). Logistic regression analyses showed that priorischemic stroke was associated with the number of risk factors,leukoaraiosis, hypertension, atrial fibrillation, and atherosclerosis.Conclusion – History of prior ischemic stroke in patients with acuteischemic stroke was associated with the burden of risk factors,atherosclerosis, and atrial fibrillation compared to first-ever ischemicstroke. This has important implications for secondary preventivetreatment.

Objectives Age dependency of acute ischaemic stroke aetiology and vascular risk factors have not been adequately evaluated in stroke patients in Norway. Aims of this study were to evaluate how stroke subtypes and vascular risk factors vary with age in a western Norway stroke population. Materials and methods Patients aged 15–100 years consecutively admitted to our neurovascular centre with acute ischaemic stroke between 2006 and 2012 were included. The study population was categorized as young (15–49 years), middle-aged (50–74 years) or elderly (≥75 years). Stroke aetiology was defined by TOAST criteria. Risk factors and history of cardiovascular disease were recorded. Results In total, 2484 patients with acute cerebral infarction were included: 1418 were males (57.3%). Mean age was 70.8 years (SD ± 14.9), 228 patients were young, 1126 middle-aged, and 1130 were elderly. The proportion of large-artery atherosclerosis and of small-vessel occlusion was highest among middle-aged patients. The proportion of cardioembolism was high at all ages, especially among the elderly. The proportion of stroke of other determined cause was highest among young patients. Some risk factors (diabetes mellitus, active smoking, angina pectoris, prior stroke and peripheral artery disease) decreased among the elderly. The proportions of several potential causes increased with age. Conclusion The proportion of stroke subtypes and vascular risk factors are age dependent. Age 50–74 years constitutes the period in life where cardiovascular risk factors become manifest and stroke subtypes change.

Background Contrast-enhanced sonothrombolysis (CEST) leads to a more rapid recanalization in acute ischemic stroke caused by intracranial large-vessel occlusion (LVO). Animal studies have shown that CEST also may be safe and efficient in treating the ischemic microcirculation in the absence of LVO. The exact mechanism behind this treatment effect is not known. We aimed to assess safety and efficacy of CEST in acute ischemic stroke patients included in the Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS) without LVO on admission CT angiography (CTA). Methods NOR-SASS was a randomized controlled trial of CEST in ischemic stroke patients treated with intravenous thrombolysis within 4.5 hours after stroke onset. Patients were randomized to either CEST or sham CEST. In this study, patients were excluded if they had partial or total occlusion on admission CTA, ultrasound-resistant bone window, had received CEST with incorrect insonation as compared to stroke location on Magnetic resonance imaging (MRI), or were stroke mimics. Results Of the 183 patients included in NOR-SASS, a total of 83 (45.4%) patients matched the inclusion criteria, of which 40 received CEST and 43 sham CEST. There were no patients with symptomatic intracranial hemorrhage (sICH) in the CEST group. Rates of asymptomatic ICH, microbleeds, and mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days were similar in both groups. Conclusion CEST is safe in ischemic stroke patients without intracranial LVO. There were no differences in clinical outcomes between the treatment groups.

Contrast-enhanced sonothrombolysis (CEST) seems to be a safe and promising treatment in acute ischemic stroke. It remains unknown if temporal bone features may influence the efficacy of CEST. We investigated the association between different temporal bone features on admission computed tomography (CT) scan and the outcome in acute ischemic stroke patients included in the randomized Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS). Patients diagnosed as stroke mimics and those with infratentorial stroke or with incorrect insonation were excluded. We retrospectively assessed temporal bone heterogeneity (presence of diploe), diploe ratio, thickness, and density on admission CT scans. National institute of Health Stroke Scale (NIHSS) at 24 h and modified Rankin Scale (mRS) at 3 months were correlated with CT findings both in CEST and sham CEST patients. A total of 99 patients were included of which 52 were assigned to CEST and 47 to sham CEST. Approximately 20% patients had a heterogeneous temporal bone in both the CEST and sham CEST group. All temporal bone CT features studied were associated with female sex. In the CEST group, temporal bone heterogeneity (p = 0.006) and higher temporal bone diploe ratio (p = 0.002) were associated with higher NIHSS at 24 h. There was no association between temporal bone features and mRS at 3 months. Approximately 20% of acute ischemic stroke patients have heterogeneous temporal bone and may be resistant to standard 2-MHz transcranial Doppler ultrasound treatment. Sonothrombolysis resistance may easily be predicted by admission CT for better selection.

Introduction: Sleep and mood disorders are frequently seen in elderly, with important consequences on morbidity and mortality. We analyzed sleep patterns in elderly with mood disorders.

Myasthenia gravis (MG) is an autoimmune disorder leading to skeletal muscle weakness and fatigability. MG subgroups are defined according to pathogenetic autoantibody (against acetylcholine receptor, muscle-specific tyrosine kinase or lipoprotein receptor-related protein 4), thymus pathology and clinical manifestations. MG patients have an increased risk for concordant autoimmune disease, in particular with early onset MG. Most common comorbidities are thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. Cardiomyositis and subclinical heart dysfunction have been described in patients with thymoma MG and late onset MG but represent no major threat. A thymic lymphoepithelioma implies an increased risk for another cancer. Autoimmune MG represents no distinct cancer risk factor, although lymphomas and a few other cancer types have been reported with slightly increased frequency. Severe MG-related muscle weakness means a risk for respiratory failure and respiratory tract infection. Drug MG treatment can lead to side-effects. Thymectomy is regarded as a safe procedure both short and long term. Non-MG-related comorbidity represents a diagnostic and therapeutic challenge, especially in elderly patients. Diagnostic accuracy and optimal follow-up is necessary to identify and treat all types of coexisting disease in MG.

Objectives Previous prospective studies on ischemic stroke patients have shown conflicting results concerning the association between cholesterol level and patient outcome. We aimed to investigate the relation between cholesterol level and prior ischemic stroke. We hypothesized that acute ischemic stroke patients with increased cholesterol on admission more frequently had experienced prior ischemic stroke. Methods All consecutive patients with acute ischemic stroke (the index stroke) admitted to the Stroke Unit, Department of Neurology, Haukeland University Hospital between February 2006 and October 2013 were prospectively registered in The Bergen NORSTROKE Registry. On admission, cholesterol, low-density lipoprotein, and high-density lipoprotein levels were measured and prior ischemic stroke, risk factors, and medication were registered. Patients with prior versus no prior ischemic stroke were compared regarding risk factors, cholesterol levels, and use of statins on admission for the index stroke. Only patients with available cholesterol values measured on admission were included in the analyses. Results Of the 2,514 included patients admitted with acute ischemic stroke, 429 (17%) patients had prior ischemic stroke. We found a U-curve relationship between the relative frequency of prior ischemic stroke and cholesterol level. Lower frequency of prior ischemic stroke was associated with high cholesterol level on admission up to 5.5 mmol/L. For cholesterol levels higher than this, the opposite was true. These associations included all patients and statin-naive patients. For patients using statin there was a declining relative frequency of prior ischemic stroke from low to high cholesterol levels. Conclusion Our hypothesis was falsified. The association between lower cholesterol levels and higher frequency of prior ischemic stroke in patients with cholesterol

Anatol Nacu,1 Robert Hoerr21Clinical Psychiatry Hospital, State University of Medicine and Pharmacy Nicolae TestemiÅ£anu, Chişinău, Republic of Moldova; 2Clinical Research Department, Dr Willmar Schwabe GmbH and Co. KG, Karlsruhe, GermanyBackground: In randomized controlled trials, Ginkgo biloba extract EGb 761® has proven to be effective in the treatment of dementia.Trial registration: Clinical-Trials.ru 390378.Patients and methods: In pre-specified descriptive analyses of data from a recently published trial, we examined the effects of EGb 761® on specific neuropsychiatric symptoms. In a 24-week, double-blind, multi-center trial, 410 outpatients with mild to moderate dementia and clinically significant neuropsychiatric symptoms were enrolled and randomized to receive 240 mg/day EGb 761® or placebo. The Neuropsychiatric Inventory composite score and the SKT short cognitive performance test were prospectively defined as co-primary outcomes; caregiver distress scores and single item scores were prospectively defined as secondary outcomes.Results: Post-baseline efficacy data were available for 402 patients included in the full analysis set. Neuropsychiatric Inventory composite and caregiver distress scores improved significantly more under EGb 761® treatment than under placebo (P

The repeated studies of the intervertebral disc degeneration pathogenesis shows that there is a high degree of the neovascularization in the terminal lamellas or the periphery of the herniated content. We studied 87 postoperative intervertebral discs obtained from the patients operated in the section of Vertebrology in Republican Clinical Hospital of Orthopedics and Traumatology in January 2008 - December 2009 and after the sampling of the corpse material (lumbar vertebral segments) of 28 cases with various somatic diseases, age and sex in the Municipal Clinical Hospital ”Holy Trinity”. The immunohistochemical staining of the lumbar spinal artery wall with CD34 and MCT shows that at different stages of the atherosclerosis development, in the atherosclerotic plaques the mast cells are found in their degranulation phase with the release of the proinflammatory enzymes that enhance the neovascularization process in the vascular wall. Histologically the moderate degenerative changes are better visualized: a high proliferation of fibroblasts, the tissue reorganization trend of the nucleus pulposus as well annulus fibrosus, mainly in the terminal blades where there is an abundance of capillaries with the neovascularization at this level. This explains the tendency to the disk tissue regeneration.

Introduction Bisphosphonates are important and effective drugs in oncology and osteoporosis therapy. They accumulate in the bone matrix becoming released and active by bone resorption. This leads to effective inhibition of tumor cells and bone degradation. A side effect of bisphosphonates similar to other drugs like denosumab is osteonecrosis of the jaws (ONJ). This problem mostly occurs after tooth extraction. We studied the cytoprotectant dexrazoxane known from anthracycline chemotherapy for cytoprotection in nitrogen-containing bisphosphonate treated cells and in the rabbit tibia model to evaluate a possible value in ONJ management. Materials & methods Human osteoblasts (HOB) P2 cells and Human ginigiva fibroblasts (HGF) P2 cells were treated with zoledronic acid (50μmol/L) and the cytoprotectant dexrazoxane (600μmol/L). Analysis included cell viability testing with MTT assay and morphology analysis using CellTracker™ Green CMFDA. A biomaterial carrier (Bio-Oss Collagen) was implanted in the rabbit tibia of 6 female chinchilla bastard rabbits on both sides with drill hole defects (d: 3.2mm). Implants were loaded with 25nmol zoledronic acid, with and without 300nmol dexrazoxane and unloaded in a control group. Analysis included histological examination of undecalcified samples with toloudine blue staining after 10days. Results In vitro experiments showed a significantly higher MTT activity in cells treated with zoledronic acid together with dexrazoxane compared to the same cells treated with the bisphosphonate alone in t -test (HOB: p =0.0003; HGF: p below 0.0001) and one-way ANOVA. Cell morphology changes were consistent with these results. In vivo results showed newly formed bone trabeculae directly growing towards the implanted hydroxylapatite particles and cortical bone interface resorption activities in the control and the experimental group only. Conclusion The study suggests a possible value of this patented technology for ONJ therapy and prevention with local or systemic application.

Missense mutations that reduce or abrogate myeloid cell expression of the F-BAR domain protein, proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), lead to autoinflammatory disease involving extramedullary hematopoiesis, skin and bone lesions. However, little is known about how PSTPIP2 regulates osteoclast development. Here we examined how PSTPIP2 deficiency causes osteopenia and bone lesions, using the mouse PSTPIP2 mutations, cmo, which fails to express PSTPIP2 and Lupo, in which PSTPIP2 is dysfunctional. In both models, serum levels of the pro-osteoclastogenic factor, MIP-1α, were elevated and CSF-1 receptor (CSF-1R)–dependent production of MIP-1α by macrophages was increased. Treatment of cmo mice with a dual specificity CSF-1R and c-Kit inhibitor, PLX3397, decreased circulating MIP-1α and ameliorated the extramedullary hematopoiesis, inflammation, and osteopenia, demonstrating that aberrant myelopoiesis drives disease. Purified osteoclast precursors from PSTPIP2-deficient mice exhibit increased osteoclastogenesis in vitro and were used to probe the structural requirements for PSTPIP2 suppression of osteoclast development. PSTPIP2 tyrosine phosphorylation and a functional F-BAR domain were essential for PSTPIP2 inhibition of TRAP expression and osteoclast precursor fusion, whereas interaction with PEST-type phosphatases was only required for suppression of TRAP expression. Thus, PSTPIP2 acts as a negative feedback regulator of CSF-1R signaling to suppress inflammation and osteoclastogenesis.

A multi-centre, double-blind, randomised, placebo-controlled, 24-week trial with 410 outpatients was conducted to demonstrate efficacy and safety of a 240 mg once-daily formulation of Ginkgo biloba extract EGb 761(®) in patients with mild to moderate dementia (Alzheimer's disease or vascular dementia) associated with neuropsychiatric symptoms. Patients scored 9 to 23 on the SKT cognitive battery, at least 6 on the Neuropsychiatric Inventory (NPI), with at least one of four key items rated at least 4. Primary outcomes were the changes from baseline to week 24 in the SKT and NPI total scores. The ADCS Clinical Global Impression of Change (ADCS-CGIC), Verbal Fluency Test, Activities of Daily Living International Scale (ADL-IS), DEMQOL-Proxy quality-of-life scale and 11-point box scales for tinnitus and dizziness were secondary outcome measures. Patients treated with EGb 761(®) (n = 200) improved by 2.2 ± 3.5 points (mean ± sd) on the SKT total score, whereas those receiving placebo (n = 202) changed only slightly by 0.3 ± 3.7 points. The NPI composite score improved by 4.6 ± 7.1 in the EGb 761(®)-treated group and by 2.1 ± 6.5 in the placebo group. Both drug-placebo comparisons were significant at p < 0.001. Patients treated with EGb 761(®) also showed a more favourable course in most of the secondary efficacy variables. In conclusion, treatment with EGb 761(®) at a once-daily dose of 240 mg was safe and resulted in a significant and clinically relevant improvement in cognition, psychopathology, functional measures and quality of life of patients and caregivers.

Objective: We studied the effect of pioglitazone on insulin levels, inflammation markers, high-density lipoprotein (HDL) composition and subclasses distribution, in young women with uncomplicated systemic lupus erythematosus (SLE). Methods: This double-blind trial included 30 premenopausal women (30 ±8 years old) with SLE, who were randomized to pioglitazone (30 mg/day) or placebo treatment for 3 months. Plasma and HDL lipids were determined by colorimetric enzymatic assays, insulin by radioimmunometric assay, inflammation by immunonephelometry and HDL size and subclasses distribution by a native 4–30% polyacrylamide gradient gel electrophoresis. Results: Compared with placebo, pioglitazone significantly increased HDL-cholesterol plasma levels (14.2%), reduced fasting insulin plasma levels (23.6%) and the homeostasis model assessment-insulin resistance (31.7%). C-reactive protein (70.9%) and serum amyloid A (34.9%) were also significantly reduced with the pioglitazone use, whereas the HDL particle size was increased (8.80 nm vs. 8.95 nm; p = 0.044) by changes in the distribution of HDL2b, HDL3b, and HDL3c subclasses. The change in HDL size correlated with a rise in free and cholesterol–ester content in the HDL particles. Conclusion: Pioglitazone significantly enhanced insulin sensitivity, reduced inflammation, and modified HDL characteristics, suggesting a potential beneficial effect of this drug in patients with SLE with a risk to develop cardiovascular disease. Trial registration: This trial is registered at ClinicalTrials.gov Protocol Registration System, with the number NCT01322308.

OBJECTIVE: This study aimed to evaluate high-density lipoprotein functionality and the cardiovascular risk factor profile in the overweight pediatric population. We hypothesized that overweight adolescents with low high-density lipoprotein cholesterol and elevated triglyceride plasma levels have metabolic abnormalities and dysfunctional high-density lipoprotein particles, similar to those reported in adults. PATIENTS AND METHODS: Overweight adolescents with (group 1 [n = 21]) and without (group 2 [n = 36]) atherogenic dyslipidemia (high-density lipoprotein cholesterol: ≤40 mg/dL and triglycerides: ≥150 mg/dL) and normal-weight normolipidemic subjects, as a reference (group 3 [n = 36]), were included. The cardiovascular risk factor profile (lipids, lipoproteins, high-sensitivity C-reactive protein, and insulin), high-density lipoprotein subclass distribution, composition, and cholesterol efflux capacity were studied. RESULTS: Group 1 adolescents showed abnormalities in high-density lipoprotein subclass distribution and high-density lipoprotein chemical composition, as well as a significantly lower capacity to promote cholesterol efflux (14.8 ± 2.8, 16.5 ± 3.8, 20.4 ± 3.5, for groups 1, 2 and 3, respectively). High-density lipoprotein2a (R2 = 0.212, β = 0.472, P < .0001) and the Tanner score (R2 = 0.054, β = −0.253, P = .02) were the independent predictors of cholesterol efflux. Group 1 also showed a higher degree of cardiovascular abnormalities (an adverse lipoprotein profile, greater insulin resistance and systemic inflammation; and lower low-density lipoprotein size) than group 2, even after BMI and Tanner score adjustment. CONCLUSIONS: This study suggests that atherogenic dyslipidemia identifies overweight adolescents with quantitative, qualitative, and functional high-density lipoprotein abnormalities. Atherogenic dyslipidemia seems to be a marker of an increased risk for developing cardiovascular disease and indicates that those adolescents should be a target of aggressive prevention programs and lipid management guidelines.

Little is known about qualitative abnormalities of high-density lipoproteins (HDL) in systemic lupus erythematosus (SLE). We studied distribution and composition of HDL subclasses in 30 premenopausal women with uncomplicated SLE, and 18 controls matched for age and sex. Plasma and HDL lipids were determined by colorimetric enzymatic assays, HDL size distribution by native gradient polyacrylamide gel electrophoresis (PAGE) and apolipoproteins in HDL by sodium dodecyl sulphate denaturing PAGE. Compared with controls, SLE patients had significantly lower proportions of HDL2b (−14.7%) and higher proportions of HDL3b (+8.8%) and HDL3c (+23.3%). Cholesteryl ester (−18%) and apolipoprotein AI (−9%) were lower, whereas triglycerides (+32%) and apolipoprotein E (+27%) were higher in SLE HDL ( P 2 = 0.327) and plasma total apo AI (R2 = 0.114) accounted independently to the variance in HDL size. This study shows that HDL distribution and composition are abnormal in non-complicated SLE patients. These HDL abnormalities have been reported to be associated to impaired atheroprotective properties of HDL and prevalence of coronary heart disease. Therefore, they may contribute to the premature atherosclerosis observed in young women with SLE.

The aim was to assess the frequency, risk factors and consequences of falls in elderly and the rate of reporting their occurrence to health professionals. Materials and methods: This is a cross-sectional study of 182 patients admitted to the National Institute of Geriatrics and Gerontology during December 2014–April 2015. Data was obtained from the medical records and by asking the patients to fill in a questionnaire. Results: 46.15% patients reported no fall during the previous year; 40.11% reported 1 fall; 17.34% were frequent fallers. We found a positive correlation between age and falls frequency (R=0.420. p=0.0001). There were significant associations between prevalent falls and: vestibular syndromes (p=0.001), postural hypotension (p=0.021), stroke (p=0.034) and foot deformities (p=0.048). The most important consequences were: pain (79.59%), limitations of the activities of daily life (46.94%), fear of falling (24.49%). Conclusions: Environmental hazards, vestibular syndromes, postural hypotension, vertigo, dizziness were the leading risk factor for falls in this study.

Dementia is one of the most disabling conditions associated with old age. With increasing life expectancy, prevalence of both dementia and diabetes is rising. The complex pathological relationship between diabetes mellitus (DM) and dementia has been studied, but is not yet fully understood. The main objective of this study was to investigate the relationship between metabolic parameters and the cognitive function in older diabetics. A total number of 360 diabetic subjects, age 65 years and over, and 300 older people controls were included. Clinical and biological parameters, together with the cognitive function, were assessed every 6 months over a 18-month period, for each study participant. By employing a multivariate linear regression analysis, several significant relationships have been identified: between Clock Drawing Test (CDT) scores and HbA1c (R 2 = 0.68); between CDT scores (R 2 = 0.51) and overall MMSE scores (R 2 = 0.43) on one hand, and DM duration in years, on the other hand; also between CDT scores and BMI (R 2 = 0.59). There was no significant association between fasting serum glucose (FSG), total serum cholesterol, LDL cholesterol or triglycerides levels and cognitive function scores (p > 0.05). The close detailed monitoring of the cognitive function and a rigorous metabolic control are important, especially in the very early stages of DM. Addressing factors such as weight control in older diabetic patients could contribute to better cognitive outcomes.

Myasthenia gravis (MG) is a rare autoimmune disease of skeletal muscle endplates. MG subgroup is relevant for comorbidity, but usually not accounted for. MG patients have an increased risk for complicating autoimmune diseases, most commonly autoimmune thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. In this review, we present concomitant autoimmune disorders associated with the different MG subgroups, and show how this influences treatment and prognosis. Concomitant MG should always be considered in patients with an autoimmune disorder and developing new neuromuscular weakness, fatigue or respiratory failure. When a second autoimmune disorder is suspected, MG should be included as a differential diagnosis. publishedVersion

Objectives Neurological worsening in acute ischaemic stroke patients is common with significant morbidity and mortality. Aims To determine the factors associated with early neurological worsening within the first 9 h after onset of acute ischaemic stroke. Materials & methods The National Institute of Health Stroke Scale (NIHSS) was used to assess stroke severity. Early neurological worsening was defined as NIHSS score increase ≥4 NIHSS points within 9 h of symptom onset compared to NIHSS score within 3 h of symptom onset. Patients with early neurological worsening were compared to patients with unchanged or improved NIHSS scores. Results Of the 2484 patients admitted with ischaemic stroke, 552 patients had NIHSS score within 3 h of symptom onset, and 44 (8.0%) experienced early neurological worsening. The median NIHSS on admission was 8.4 in both groups. Early neurological worsening was associated with low body temperature on admission (P = 0.01), proximal compared to distal MCA occlusion (P = 0.007) and with ipsilateral internal carotid artery stenosis >50% or occlusion (P = 0.04). Early neurological worsening was associated with higher NIHSS day 7 (P

Introduction

In 69 statin-treated male coronary patients with low-density lipoprotein cholesterol at goal levels (70 mg/dl), the investigators tested whether low high-density lipoprotein (HDL) cholesterol (40 mg/dl) and high triglyceride (150 mg/dl) are associated with dysfunctional HDL particles and abnormal insulin, adiponectin, C-reactive protein serum levels. Thirty-four patients with low HDL cholesterol and high triglyceride (dyslipidemia) and 35 patients with low-density lipoprotein cholesterol, HDL cholesterol, and triglyceride at target levels (normolipidemia) were studied. Twenty healthy men were also studied. High-sensitivity C-reactive protein was measured using immunonephelometry, insulin using a radioimmunometric assay, and total adiponectin by enzyme-linked immunosorbent assay. Cell cholesterol efflux to serum and total isolated HDL was assayed using rat hepatoma Fu5AH cells for scavenger receptor class B type 1-mediated efflux. Compared to the normolipidemia and healthy groups, and after adjustment for age and waist circumference, patients with dyslipidemia showed higher fasting insulin (14, 9.9, and 8.5 μU/ml, respectively), homeostasis model assessment of insulin resistance values (3.4, 2.3, and 1.8, respectively), lower adiponectin concentrations (5.1, 8.1, and 11 μg/ml, respectively), and reduced cholesterol efflux to serum (14%, 15%, and 19%, respectively) and to HDL fractions (4.4%, 4.6%, and 5.6%, respectively) (p0.05 for all variables). Multivariate analysis showed that adiponectin and apolipoprotein A1 accounted for 10.7% and 3.9%, respectively, of the variance in cholesterol efflux. In conclusion, the decreased cholesterol efflux and metabolic abnormalities found in the dyslipidemia group may contribute to the residual risk observed in the large statin trials and the higher morbidity and mortality in statin-treated coronary patients with low HDL cholesterol even when attaining low-density lipoprotein cholesterol70 mg/dl.

Pulmonary diseases associated with fibrosis, including scleroderma lung disease, are characterized by the accumulation of T cells in the lungs. These cells are thought to facilitate lung fibrosis, but the exact mechanisms of their profibrotic action are not clear. Several alphaV-containing integrins, including alphaVbeta3 and alphaVbeta5, have been shown to directly activate transforming growth factor beta (TGFbeta) and promote collagen accumulation. The aim of this study was to investigate whether pulmonary T cells express profibrotic integrins and regulate collagen accumulation.Expression of integrins was assessed by immunohistochemical analysis of lung tissue, by flow cytometry using bronchoalveolar lavage fluid from patients with systemic sclerosis (SSc), and in a CCL18 overexpression animal model of pulmonary T cell infiltration. Experiments in cell cultures were performed to determine whether integrin-expressing T cells are profibrotic in cocultures with pulmonary fibroblasts and, if so, through what possible mechanism.Lymphocytes and integrin-positive cells were present in the lungs, and pulmonary T cells expressed integrins alphaVbeta3 and alphaVbeta5 in patients with SSc and in the animal model. Systemic administration of neutralizing anti-integrin alphaV antibody or a genetic deficiency of integrin beta3 in the CCL18 overexpression model significantly attenuated CCL18-driven pulmonary lymphocytic infiltration and collagen accumulation. Jurkat T cells overexpressing integrin alphaVbeta3 or integrin alphaVbeta5 in cocultures with primary pulmonary fibroblasts stimulated collagen accumulation and Smad2 nuclear translocation. Neutralizing anti-TGFbeta antibody attenuated the profibrotic effect of integrin-expressing T cells.Pulmonary infiltrating T lymphocytes may express integrins alphaVbeta3 and alphaVbeta5 that are necessary for lymphocytic infiltration and T cell-associated TGFbeta activation and collagen accumulation.

We tested whether low high-density lipoprotein cholesterol (HDL-C) and/or high triglycerides are associated to abnormal HDL subclasses distribution and composition, and their relationships with fasting insulin and C-reactive protein (CRP). Four groups of adolescents were studied: group 1 (HDL-Cor =35 mg/dl+TGor =150 mg/dl; n=16); group 2 (isolated HDL-Cor =35 mg/dl; n=31); group 3 (isolated TGor =150 mg/dl; n=20); and group 4 (CT200 mg/dl, HDL-C35 mg/dl, LDL-C130 mg/dl, and TG150 mg/dl; n=39). Tanner score-adjusted proportions of large subspecies (HDL(2b), HDL(2a)) were lower, and small (HDL(3b), HDL(3c)) were higher in groups 1, 2 and 3 than in group 4. As a result, HDL particle size in the three dyslipidemic groups was smaller than in group 4 (p0.001). HDL CE, FC, PL, and apo AI percent contents were lower, whereas HDL TG percent content was higher in groups 1, 2 and 3 compared to group 4. CRP median values were also significantly higher in the three groups with dyslipidemia than in normolipidemic subjects (group 4). Fasting Insulin concentration and HOMA-IR were significantly higher in group 1 than in the other three groups. In stepwise multivariate analysis HDL subclass distribution and composition were independently associated only with HDL-C and waist circumference. As reported in adults, adolescents with low HDL-C and/or high TG have abnormalities in HDL subclasses distribution and lipid composition, which may render their HDL dysfunctional. In addition, these subjects have high CRP and insulin levels suggesting the presence of chronic low-grade inflammation.

Background: Alteplase is the only approved thrombolytic agent for acute ischaemic stroke. The overall benefit from alteplase is substantial, but some evidence indicates that alteplase also has negative effects on the ischaemic brain. Tenecteplase may be more effective and less harmfull than alteplase, but large randomised controlled phase 3 trials are lacking. The Norwegian Tenecteplase Stroke Trial (NOR-TEST) aims to compare efficacy and safety of tenecteplase vs. alteplase. Methods/Design: NOR-TEST is a multi-centre PROBE (prospective randomised, open-label, blinded endpoint) trial designed to establish superiority of tenecteplase 0.4 mg/kg (single bolus) as compared with alteplase 0.9 mg/kg (10% bolus + 90% infusion/60 minutes) for consecutively admitted patients with acute ischaemic stroke eligible for thrombolytic therapy, i.e. patients a) admitted

Christopher Elnan Kvistad,1 Andrej Khanevski,1 Aliona Nacu,1 Lars Thomassen,1 Ulrike Waje-Andreassen,1 Halvor Naess1,2 1Department of Neurology, Haukeland University Hospital, Bergen, Norway; 2Centre for Age-related Medicine, Stavanger University Hospital, Stavanger, NorwayBackground: Low body temperature is considered beneficial in ischemic stroke due to neuroprotective mechanisms, yet some studies suggest that higher temperatures may improve clot lysis and outcomes in stroke patients treated with tissue plasminogen activator (tPA). The effect of increased body temperature in stroke patients treated with tPA and with normal computed tomography angiography (CTA) on admission is unknown. We hypothesized a beneficial effect of higher body temperature in the absence of visible clots on CTA, possibly due to enhanced lysis of small, peripheral clots.Methods: Patients with ischemic stroke admitted to our Stroke Unit between February 2006 and April 2013 were prospectively registered in a database (Bergen NORSTROKE Registry). Ischemic stroke patients treated with tPA with normal CTA of the cerebral arteries were included. Outcomes were assessed by the modified Rankin Scale (mRS) after 1 week. An excellent outcome was defined as mRS=0, and a favorable outcome as mRS=0–1.Results: A total of 172 patients were included, of which 48 (27.9%) had an admission body temperature ≥37.0°C, and 124 (72.1%) had a body temperature

Background Dysfunction of the immune system has been documented in many types of cancers. The precise nature and molecular basis of immune dysfunction in the cancer state are not well defined. Methods and Findings To gain insights into the molecular mechanisms of immune dysfunction in cancer, gene expression profiles of pure sorted peripheral blood lymphocytes from 12 patients with melanoma were compared to 12 healthy controls. Of 25 significantly altered genes in T cells and B cells from melanoma patients, 17 are interferon (IFN)-stimulated genes. These microarray findings were further confirmed by quantitative PCR and functional responses to IFNs. The median percentage of lymphocytes that phosphorylate STAT1 in response to interferon-α was significantly reduced (Δ = 16.8%; 95% confidence interval, 0.98% to 33.35%) in melanoma patients (n = 9) compared to healthy controls (n = 9) in Phosflow analysis. The Phosflow results also identified two subgroups of patients with melanoma: IFN-responsive (33%) and low-IFN-response (66%). The defect in IFN signaling in the melanoma patient group as a whole was partially overcome at the level of expression of IFN-stimulated genes by prolonged stimulation with the high concentration of IFN-α that is achievable only in IFN therapy used in melanoma. The lowest responders to IFN-α in the Phosflow assay also showed the lowest gene expression in response to IFN-α. Finally, T cells from low-IFN-response patients exhibited functional abnormalities, including decreased expression of activation markers CD69, CD25, and CD71; TH1 cytokines interleukin-2, IFN-γ, and tumor necrosis factor α, and reduced survival following stimulation with anti-CD3/CD28 antibodies compared to controls. Conclusions Defects in interferon signaling represent novel, dominant mechanisms of immune dysfunction in cancer. These findings may be used to design therapies to counteract immune dysfunction in melanoma and to improve cancer immunotherapy., Prompted by altered expression patterns of interferon-responsive genes in T and B cells, Peter Lee and colleagues find that lymphocytes from melanoma patients have defects in interferon signaling., Editors' Summary Background. The immune system, in addition to fighting infections, provides one of the body's main defenses against cancer. During cancer development, normal cells acquire genetic changes that allow them to grow uncontrollably and to move around the body. Some of these changes alter the antigens (proteins recognized by the immune system) expressed on their surface. As a result, the immune system recognizes and eliminates the newly formed cancer cells. Tumors—large masses of cancer cells—occur when this immune surveillance fails. Some tumors, for example, hide from the immune system by altering the antigens they express. Others release factors that shut off the immune response. However, for many tumor types, it is not clear why immune surveillance fails during their development or why global immune suppression develops in most patients with advanced disease. Why Was This Study Done? Scientists want to understand the molecular basis of immune dysfunction in patients with cancer because if they knew what had gone wrong with the immune system, they might be able to repair it. Also, there is considerable interest in immunotherapy for cancer—for example, treatment with interferons (proteins made by certain immune system cells that activate other immune cells and also kill tumor cells) and the development of vaccines to stimulate antitumor immune responses. So far, immunotherapy has not been very successful, probably because of the underlying dysfunction of the immune system in patients with cancer. Understanding this dysfunction might lead to improvements in immunotherapy, so in this study the researchers have investigated the molecular mechanism responsible for immune dysfunction in patients with metastatic melanoma, a deadly form of skin cancer. What Did the Researchers Do and Find? The researchers purified lymphocytes (immune cells that are involved in antitumor responses) from the blood of patients with metastatic melanoma and healthy people and examined their patterns of gene expression using a technique called microarray expression profiling. CD8 T cells (which kill cells expressing foreign or altered antigens), CD4 T cells (which help other T and B lymphocytes do their jobs), and B cells (which make antibodies, proteins that recognize antigens and label cancer cells for destruction by the immune system) from patients with melanoma all expressed lower levels of 24 genes, and higher levels of one gene, than those from healthy individuals. 17 of these genes were interferon-stimulated genes, which encode proteins responsible for the effects of interferons. Therefore, the researchers checked the functional responses of patient and control lymphocytes to interferon. When interferon binds to lymphocytes, it triggers the addition of a phosphate group to the protein STAT1, which then induces changes in gene expression. STAT1 phosphorylation occurred in a lower percentage of patient lymphocytes than control lymphocytes in response to interferon-α (which is sometimes used to treat melanoma). The lymphocytes from one-third of the patients responded well to interferon-α, but those from the other patients showed little response. Furthermore, prolonged treatment with high concentrations of interferon-α partly overcame the defect in interferon signaling in patient lymphocytes. Finally, T cells from the patients failed to make the normal markers of immune cell activation or cytokines (proteins that mediate the killing of tumor cells) after exposure to activating stimuli and had reduced survival compared to control lymphocytes. What Do These Findings Mean? These results indicate that for patients with metastatic melanoma defects in interferon signaling are an important contributor to immune dysfunction. They also show that T cells from patients with melanoma (particularly those who respond poorly to interferon-α) have functional abnormalities that make them less likely to recognize and deal with melanoma cells. These results need confirming in many more patients, but they nevertheless represent an important step toward understanding the immune dysfunction associated with advanced melanoma and possibly other tumors. In addition, the identification of two subgroups of patients—interferon responders and poor interferon responders—may explain why only some patients with melanoma benefit from treatment with interferon-α. It might, therefore, be possible to pre-select those who would benefit from this treatment (which has some serious side effects) by examining patient lymphocytes for interferon responsiveness. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040176. US National Cancer Institute information (in English and Spanish) for patients on the immune system and its involvement in cancer, and for patients and professionals on melanoma American Cancer Society information for patients on immunotherapy Cancer Research Institute (New York) web-based book on cancer and the immune system MedlinePlus encyclopedia pages on melanoma (in English and Spanish) Cancer Research UK patient information on melanoma, including information on immunotherapy

A modification of the urine PABA tet published by Imondi et al. is described. Ninety minutes after oral administration of PABA peptide, PABA was determined in serum. The average concentration in healthy children was 0.42 +/- 0.055 mg per 100 ml. Up to that time we recovered in the urine 66.1 +/- 6.1% of the substance previously administered. In the children with cystic fibrosis of the pancreas (CF) serum PABA concentrations were less than 0.1 mg per 100 ml. The infants under 2 months old also had clearly low serum concentrations, on average 0.29 +/- 0.06 mg per 100 ml, whereas the PABA concentrations in the older babies lay within the range for the older children (0.40 +/- 0.07 mg%).