Influence of cholecalciferol (Vitamin D3) on the course of experimental systemic lupus erythematosus in F1 (NZBxW) mice

The course of systemic lupus erythematosus (SLE), an autoimmune disease, is markedly affected by hormones such as estrogen and prolactin. It is well known that heavy exposure to sunlight has deleterious effects on SLE, triggering episodes of the disease. Classical explanations for this occurrence suggest that UV radiation damages DNA, which becomes immunogenic, or induces exposure of the Ro antigen in keratinocytes. In recent years, it has been shown that vitamin D3 has important effects on the immune system. Thus, we proposed an alternative hypothesis, suggesting that UV radiation, by promoting vitamin D3 synthesis, could be a factor aggravating the course of SLE after exposure to sunlight. To test this hypothesis, we injected F1(NZBxW) mice, which are prone to developing SLE, with vitamin D3, and we demonstrated a worsening of the histopathological findings in the kidney. (C) 2000 Wiley-Liss, Inc.

Neurocysticercosis: The enigmatic disease

Neurocysticercosis (NCC) is an infection of the central nervous system (CNS) caused by the metacestode larval form of the parasite Taenia sp. Many factors can contribute to the endemic nature of cysticercosis. The inflammatory process that occurs in the tissue surrounding the parasite and/or distal from it can result from several associated mechanisms and may be disproportionate with the number of cysts. This discrepancy may lead to difficulty with the proper diagnosis in people from low endemic regions or regions that lack laboratory resources. In the CNS, the cysticerci have two basic forms, isolated cysts (Cysticercus cellulosae = CC) and racemose cysts (Cysticercus racemosus = CR), and may be meningeal, parenchymal, or ventricular or have a mixed location. The clinical manifestations are based on two fundamental syndromes that may occur in isolation or be associated: epilepsy and intracranial hypertension. They may be asymptomatic, symptomatic or fatal; have an acute, sub-acute or chronic picture; or may be in remission or exacerbated. The cerebrospinal fluid (CSF) may be normal, even in patients with viable cysticerci, until the patients begin to exhibit the classical syndrome of NCC in the CSF, or show changes in one or more routine analysed parameters. Computed tomography (CT) and magnetic resonance imaging (MRI) have allowed non-invasive diagnoses, but can lead to false negatives. Treatment is a highly controversial issue and is characterised by individualised therapy sessions. Two drugs are commonly used, praziquantel (PZQ) and albendazole (ABZ). The choice of anti-inflammatory drugs includes steroids and dextrochlorpheniramine (DCP). Hydrocephalus is a common secondary effect of NCC. Surgical cases of hydrocephalus must be submitted to ventricle-peritoneal shunt (VPS) immediately before cysticidal treatment, and surgical extirpation of the cyst may lead to an absence of the surrounding inflammatory process. The progression of NCC may be simple or complicated, have remission with or without treatment and may exhibit symptoms that can disappear for long periods of time or persist until death. Unknown, neglected and controversial aspects of NCC, such as the impaired fourth ventricle syndrome, the presence of chronic brain oedema and psychic complaints, in addition to the lack of detectable glucose in the CSF and re-infection are discussed. © 2011 Bentham Science Publishers.

Time-course of neuroendocrine changes and its correlation with hypertension induced by ethanol consumption

Ethanol (ETOH) consumption has been associated with endocrine and autonomic changes, including the development of hypertension. However, the sequence of pathophysiological events underlying the emergence of this effect is poorly understood. Aims: This study aimed to establish a time-course correlation between neuroendocrine and cardiovascular changes contributing to the development of hypertension following ETOH consumption. Methods: Male adult Wistar rats were subjected to the intake of increasing ETOH concentrations in their drinking water (first week: 5%, second week: 10%, third and fourth weeks: 20% v/v). Results: ETOH consumption decreased plasma and urinary volumes, as well as body weight and fluid intake. Furthermore, plasma osmolality, plasma sodium and urinary osmolality were elevated in the ETOH-treated rats. ETOH intake also induced a progressive increase in the mean arterial pressure (MAP), without affecting heart rate. Initially, this increasein MAP was correlated with increased plasma concentrations of adrenaline and noradrenaline. After the second week of ETOH treatment, plasma catecholamines returned to basal levels, and incremental increases were observed in plasma concentrations of vasopressin (AVP) and angiotensin II (ANG II). Conversely, plasma oxytocin, atrial natriuretic peptide, prolactin and the hypothalamus-pituitary-adrenal axis components were not significantly altered by ETOH. Conclusions: Taken together, these results suggest that increased sympathetic activity may contribute to the early increase in MAP observed inETOHtreated rats. However, the maintenance of this effect may be predominantly regulated by the long-term increase in the secretion of other circulating factors, such as AVP and ANG II, the secretion of both hormones being stimulated by the ETOH-induced dehydration. © The Author 2013. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Symptom dimensions, clinical course and comorbidity in men and women with obsessive-compulsive disorder

The study aimed to compare male and female patients with obsessive-compulsive disorder (OCD) across symptom dimensions, clinical course and comorbidity. A cross-sectional study was undertaken with 858 adult OCD patients (DSM-IV) from the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. Patients were evaluated using structured interviews, including the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) and the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). The sample was composed of 504 women (58.7%) and 354 men (41.3%) with a mean age of 35.4 years-old (range: 18-77). Men were younger, more frequently single and presented more tics, social phobia and alcohol use disorders. Among men, symptom interference occurred earlier and symptoms of the sexual/religious dimension were more common and more severe. Conversely, women were more likely to present symptoms of the aggressive, contamination/cleaning and hoarding dimension and comorbidity with specific phobias, anorexia nervosa, bulimia, trichotillomania, skin picking and compulsive buying. In the logistic regression, female gender remained independently associated with the aggressive and contamination/cleaning dimensions. In both genders the aggressive dimension remained associated with comorbid post-traumatic stress disorder, the sexual/religious dimension with major depression and the hoarding dimension with tic disorders. Gender seems to be relevant in the determination of OCD clinical presentation and course and should be considered an important aspect when defining more homogeneous OCD subgroups. © 2012 Elsevier B.V.

Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease: Concept and standards of the EARLYSTIM-study

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for advanced Parkinson's disease (PD) with disabling motor complications. However, stimulation may be beneficial at an earlier stage of PD when motor fluctuations and dyskinesia are only mild and psychosocial competence is still maintained. The EARLYSTIM trial was conducted in patients with recent onset of levodopa-induced motor complications (<3 years) whose social and occupational functioning remained preserved. This is called 'early' here. The study was a randomized, multicenter, bi-national pivotal trial with a 2 year observation period. Quality of life was the main outcome measure, and a video-based motor score was a blinded secondary outcome of the study. Motor, neuropsychological, psychiatric and psychosocial aspects were captured by established scales and questionnaires. The patient group randomized here is the earliest in the disease course and the youngest recruited in controlled DBS trials so far. The methodological innovation for DBS-studies of this study lies in novel procedures developed and used for monitoring best medical treatment, neurosurgical consistency, best management of stimulation programming, blinded video assessment of motor disability, and prevention of suicidal behaviors.

Treatment of fibrostenotic and fistulizing Crohn's disease

The majority of Crohn's disease patients will develop a complicated disease course over time which is characterized by the occurrence of stricturing and penetrating disease. Penetrating disease comprises internal fistulas (e.g. enteroenteric) and perianal disease. A complicated disease course may be associated with considerable morbidity and professional and personal disabilities. Treatment options for fibrostenotic Crohn's disease comprise endoscopic balloon dilation, stricturoplasties and surgical resection. Treatment of symptomatic perianal fistulizing disease is based on antibiotics, immunomodulators and anti-TNF drugs. Surgical measures include fistula drainage by means of setons, temporary ileostomy or a proctectomy. The presence of internal fistulas often necessitates surgical measures. A close collaboration between the gastroenterologist and the surgeon is mandatory to solve these interdisciplinary challenges.

A disease model for wheezing disorders in preschool children based on clinicians' perceptions

BACKGROUND: Wheezing disorders in childhood vary widely in clinical presentation and disease course. During the last years, several ways to classify wheezing children into different disease phenotypes have been proposed and are increasingly used for clinical guidance, but validation of these hypothetical entities is difficult. METHODOLOGY/PRINCIPAL FINDINGS: The aim of this study was to develop a testable disease model which reflects the full spectrum of wheezing illness in preschool children. We performed a qualitative study among a panel of 7 experienced clinicians from 4 European countries working in primary, secondary and tertiary paediatric care. In a series of questionnaire surveys and structured discussions, we found a general consensus that preschool wheezing disorders consist of several phenotypes, with a great heterogeneity of specific disease concepts between clinicians. Initially, 24 disease entities were described among the 7 physicians. In structured discussions, these could be narrowed down to three entities which were linked to proposed mechanisms: a) allergic wheeze, b) non-allergic wheeze due to structural airway narrowing and c) non-allergic wheeze due to increased immune response to viral infections. This disease model will serve to create an artificial dataset that allows the validation of data-driven multidimensional methods, such as cluster analysis, which have been proposed for identification of wheezing phenotypes in children. CONCLUSIONS/SIGNIFICANCE: While there appears to be wide agreement among clinicians that wheezing disorders consist of several diseases, there is less agreement regarding their number and nature. A great diversity of disease concepts exist but a unified phenotype classification reflecting underlying disease mechanisms is lacking. We propose a disease model which may help guide future research so that proposed mechanisms are measured at the right time and their role in disease heterogeneity can be studied.

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12 Years of Follow-up

BACKGROUND Trials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization. OBJECTIVE Based on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences. DESIGN, SETTING, AND PARTICIPANTS EORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0-4 N0-2 M0 PCa patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Time to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival. RESULTS AND LIMITATIONS After a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3-5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05-1.39; p [noninferiority]=0.72, p [difference] = 0.0085). CONCLUSIONS This study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.

Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study

BackgroundNiemann-Pick disease type C (NP-C) is a rare autosomal recessive disorder of lysosomal cholesterol transport. The objective of this retrospective cohort study was to critically analyze the onset and time course of symptoms, and the clinical diagnostic work-up in the Swiss NP-C cohort.MethodsClinical, biochemical and genetic data were assessed for 14 patients derived from 9 families diagnosed with NP-C between 1994 and 2013. We retrospectively evaluated diagnostic delays and period prevalence rates for neurological, psychiatric and visceral symptoms associated with NP-C disease. The NP-C suspicion index was calculated for the time of neurological disease onset and the time of diagnosis.ResultsThe shortest median diagnostic delay was noted for vertical supranuclear gaze palsy (2y). Ataxia, dysarthria, dysphagia, spasticity, cataplexy, seizures and cognitive decline displayed similar median diagnostic delays (4¿5y). The longest median diagnostic delay was associated with hepatosplenomegaly (15y). Highest period prevalence rates were noted for ataxia, dysarthria, vertical supranuclear gaze palsy and cognitive decline. The NP-C suspicion index revealed a median score of 81 points in nine patients at the time of neurological disease onset which is highly suspicious for NP-C disease. At the time of diagnosis, the score increased to 206 points.ConclusionA neurologic-psychiatric disease pattern represents the most characteristic clinical manifestation of NP-C and occurs early in the disease course. Visceral manifestation such as isolated hepatosplenomegaly often fails recognition and thus highlights the importance of a work-up for lysosomal storage disorders. The NP-C suspicion index emphasizes the importance of a multisystem evaluation, but seems to be weak in monosymptomatic and infantile NP-C patients.

Disease evolution and outcomes in familial AML with germline CEBPA mutations

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

[Smoking and digestive tract: a complex relationship. Part 1: Inflammatory bowel disease and cigarette smoking]

Little is known about the effects of smoking on inflammatory bowel diseases (IBD). However the co-occurrence of smoking and IBD often happens in ambulatory care. Smokers have a doubled risk of developing a Crohn's disease with a more active disease course. After quitting, a decrease in risk can be observed after only one year. An inverse relationship is found between smoking and ulcerative colitis. Smoking seems protective for the development of the disease and its course is less active among smokers. Smoking cessation transitorily increases the risk of developing ulcerative colitis. Nevertheless, continuing smoking cannot be justified among those patients given the risks of long-term extra-digestive effects. It is thus important to counsel all smokers with an IBD to quit smoking.

Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma

BACKGROUND. The authors compared gemcitabine and carboplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) or mitomycin, vinblastine, and cisplatin (MVP) in patients with advanced nonsmall cell lung carcinoma (NSCLC). The primary objective was survival. Secondary objectives were time to disease progression, response rates, evaluation of toxicity, disease-related symptoms, World Health Organization performance status (PS), and quality of life (QoL). METHODS. Three hundred seventy-two chemotherapy-naïve patients with International Staging System Stage III/IV NSCLC who were ineligible for curative radiotherapy or surgery were randomized to receive either 4 cycles of gemcitabine (1000 mg/m2 on Days 1, 8, and 15) plus carboplatin (area under the serum concentration-time curve, 5; given on Day 1) every 4 weeks (the GC arm) or MIC/MVP every 3 weeks (the MIC/MVP arm). RESULTS. There was no significant difference in median survival (248 days in the MIC/MVP arm vs. 236 days in the GC arm) or time to progression (225 days in the MIC/MVP arm vs. 218 days in the GC arm) between the 2 treatment arms. The 2-year survival rate was 11.8% in the MIC/MVP arm and 6.9% in the GC arm. The 1-year survival rate was 32.5% in the MIC/MVP arm and 33.2% in the GC arm. In the MIC/MVP arm, 33% of patients responded (4 complete responses [CRs] and 57 partial responses [PRs]) whereas in the GC arm, 30% of patients responded (3 CRs and 54 PRs). Nonhematologic toxicity was comparable for patients with Grade 3-4 symptoms, except there was more alopecia among patients in the MIC/MVP arm. GC appeared to produce more hematologic toxicity and necessitated more transfusions. There was no difference in performance status, disease-related symptoms, of QoL between patients in the two treatment arms. Fewer inpatient stays for complications were required with GC. CONCLUSIONS. The results of the current study failed to demonstrate any difference in efficacy between the newer regimen of GC and the older regimens of MIC and MVP. © 2003 American Cancer Society.

Advances in the systemic therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. This Review summarizes the evidence supporting the clinical activity of chemotherapy, discusses the use of end points for its assessment and examines the influence of clinical and biochemical prognostic factors on the natural history of malignant pleural mesothelioma. Early-phase clinical trials of second-line and novel agents are emerging from an increased understanding of mesothelioma cell biology. Coupled with high-quality translational research, such developments have real potential to improve the outlook of patients at a time of increasing incidence.

The role of the molecular footprint of EGFR in tailoring treatment decisions in NSCLC

The majority of patients with non-small-cell lung cancer (NSCLC) present with advanced disease, with targeted therapies providing some improvement in clinical outcomes. The epidermal growth factor receptor (EGFR) tyrosine kinase (TK) plays an important role in the pathogenesis of NSCLC. Tyrosine kinase inhibitors (TKIs), which target the EGFR TK domain, have proven to be an effective treatment strategy; however, patient responses to treatment vary considerably. Therefore, the identification of patients most likely to respond to treatment is essential to optimise the benefit of TKIs. Tumour-associated activating mutations in EGFR can identify patients with NSCLC who are likely to have a good response to TKIs. Nonetheless, the majority of patients relapse within a year of starting treatment. Studies of tumours at relapse have demonstrated expression of a T790M mutation in exon 20 of the EGFR TK domain in approximately 50% of cases. Although conferring resistance to reversible TKIs, these patients may remain sensitive to new-generation irreversible/panerb inhibitors. A number of techniques have been employed for genotypic assessment of tumourassociated DNA to identify EGFR mutations, each of which has advantages and disadvantages. This review presents an overview of the current methodologies used to identify such molecular markers. Recent developments in technology may make the monitoring of changes in patients' tumour genotypes easier in clinical practice, which may enable patients' treatment regimens to be tailored during the course of their disease, potentially leading to improved patient outcomes.

Galectin-1 : a link between tumor hypoxia and tumor immune privilege

Purpose: To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression. Methods: We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CDS (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes. Results: SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O 2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CDS staining (P = .01). Expression of galectin-1 and CDS were significant predictors for overall survival on multivariate analysis. Conclusion: Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege. © 2005 by American Society of Clinical Oncology.