Immunopathology in ocular toxoplasmosis: facts and clues

Although parasite-mediated host cell lysis is deemed to be an important cause of tissue destruction in ocular toxoplasmosis (OT), the severity of the disease is probably correlated with hypersensitivity and inflammation. Notwithstanding, the mechanisms that regulate the inflammatory process in recurrent OT are poorly understood. Recent evidence has identified interleukin (IL) 17 as a marker for disease severity. The ocular and cerebral presence of this cytokine is generally associated with the induction of autoimmune responses in the brain and the eye. Indeed, there are indications that autoimmunity may contribute to clinical variability in the activity of OT. IL-23, which induces the proliferation of IL-17-producing cells and IL-27, which is a counterplayer to IL-17, may regulate T(H)-1-cell-mediated responses in OT. The importance of these cytokines in experimental models of uveitis and encephalitis has been recently reported. CD25(+) regulatory T-cells may control the local inflammatory response and protect the host against collateral inflammatory tissue damage. The responses of these cells to OT may be suitably tailored to cope with either an acquired or a congenital aetiology. Knowledge relating to immunoreactivity in OT has grown impressively during the past few years. Its characteristic and variable features have been identified and the potential relevance of autoimmunity has been assessed. In light of this knowledge, potential future treatment options have been considered.

Treating ocular toxoplasmosis: current evidence

The current treatment of ocular toxoplasmosis is controversial. The mainstay of treatment has been pyrimethamine and sulphonamides with or without systemic corticosteroids, but the actual evidence that antibiotics have a beneficial effect in recurrent toxoplasmic retinochoroiditis is unsupported by randomised placebo controlled trials. Thus far there have only been three studies looking at the efficacy of antibiotic treatment, all of which were methodologically weak and two of which were perfomed more than 30 years ago. All studies reported adverse effects from treatment. There is an urgent need for further randomised, double blind, placebo controlled studies for lesions in all parts of the retina and to test the efficacy of adjunctive corticosteroid treatment.

Ocular toxoplasmosis: the influence of patient age

The influence of patient age on various features of ocular toxoplasmosis has been a subject of study for many years. The age at which Toxoplasma gondii infection occurs in different populations is related to socioeconomic factors and studies suggest that ocular toxoplasmosis is a more severe disease at the extremes of age. The prevalence of ocular involvement is markedly different between individuals with congenital and those with post-natally acquired infections. Even among those with post-natally acquired infections, age influences the risk and timing of ocular involvement. The severity of toxoplasmic retinochoroiditis (in terms of lesion size, location and associated inflammation) is also affected by patient age at the time of initial infection or recurrence. The risk of recurrent toxoplasmic retinochoroiditis is influenced by age at the time of initial infection and age at most recent episode of active disease. Understanding of relationships between ocular toxoplasmosis and patient age is incomplete; evidence has often been indirect and in some cases conflicting. The influence of patient age on ocular toxoplasmosis should be studied in a systematic manner to provide a better understanding of disease mechanisms and to provide clinical information that can used to establish better strategies for disease treatment and prevention.

A genome-wide significant linkage for severe depression on chromosome 3: the depression network study.

Objective: The purpose of this study was to find loci for major depression via linkage analysis of a large sibling pair sample. Method: The authors conducted a genome-wide linkage analysis of 839 families consisting of 971 affected sibling pairs with severe recurrent major depression, comprising waves I and II of the Depression Network Study cohort. In addition to examining affected status, linkage analyses in the full data set were performed using diagnoses restricted by impairment severity, and association mapping of hits in a large case-control data set was attempted. Results: The authors identified genome-wide significant linkage to chromosome 3p25-26 when the diagnoses were restricted by severity, which was a maximum LOD score of 4.0 centered at the linkage marker D3S1515. The linkage signal identified was genome-wide significant after correction for the multiple phenotypes tested, although subsequent association mapping of the region in a genome-wide association study of a U.K. depression sample did not provide significant results. Conclusions: The authors report a genome-wide significant locus for depression that implicates genes that are highly plausible for involvement in the etiology of recurrent depression. Despite the fact that association mapping in the region was negative, the linkage finding was replicated by another group who found genome-wide-significant linkage for depression in the same region. This suggests that 3p25-26 is a new locus for severe recurrent depression. This represents the first report of a genome-wide significant locus for depression that also has an independent genome-wide significant replication.

Duodenal duplication cyst and pancreas divisum causing acute pancreatitis in an adult male acute pancreatitis in an adult male

Duodenal duplication cysts are rare congenital abnormalities which are more commonly diagnosed in infancy and childhood. However, in rare cases, these lesions can remain asymptomatic until adulthood. The combination of duplication cyst and pancreas divisum is extremely rare and both conditions have been linked with acute recurrent pancreatitis. We present the case of a 37 years-old patient who presented with repeated episodes of acute pancreatitis. By means of magnetic resonance imaging and endoscopic ultrasonography we discovered a duplication cyst whose cavity received drainage from the dorsal pancreas. After opening the cyst cavity to the duodenal lumen with a needle knife the patient presented no further episodes in the clinical follow-up. Comparable literature findings and therapeutic options for these abnormalities are discussed with regard to the presented case.

5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer

This work aimed to develop a new therapeutic approach to increase the efficacy of 5-fluorouracil (5-FU) in the treatment of advanced or recurrent colon cancer. 5-FU-loaded biodegradable poly(ε-caprolactone) nanoparticles (PCL NPs) were combined with the cytotoxic suicide gene E (combined therapy). The SW480 human cancer cell line was used to assay the combined therapeutic strategy. This cell line was established from a primary adenocarcinoma of the colon and is characterized by an intrinsically high resistance to apoptosis that correlates with its resistance to 5-FU. 5-FU was absorbed into the matrix of the PCL NPs during synthesis using the interfacial polymer disposition method. The antitumor activity of gene E from the phage ϕX174 was tested by generating a stable clone (SW480/12/E). In addition, the localization of E protein and its activity in mitochondria were analyzed. We found that the incorporation of 5-FU into PCL NPs (which show no cytotoxicity alone), significantly improved the drug's anticancer activity, reducing the proliferation rate of colon cancer cells by up to 40-fold when compared with the nonincorporated drug alone. Furthermore, E gene expression sensitized colon cancer cells to the cytotoxic action of the 5-FU-based nanomedicine. Our findings demonstrate that despite the inherent resistance of SW480 to apoptosis, E gene activity is mediated by an apoptotic phenomenon that includes modulation of caspase-9 and caspase-3 expression and intense mitochondrial damage. Finally, a strongly synergistic antiproliferative effect was observed in colon cancer cells when E gene expression was combined with the activity of the 5-FU-loaded PCL NPs, thereby indicating the potential therapeutic value of the combined therapy.

Dietoterapia en paciente con linfangiectasia intestinal primaria y ascitis quilosa de repetición.

OBJECTIVES Primary intestinal lymphangiectasia is a lymphatic system's disorder, where lymphatic drainage is blockaged. Clinically it produces malabsorption, protein-losing enteropathy, hypogammaglobulin in blood, and several degrees of malnutrition. Its treatment is not easy and includes dietetic-therapy and drugs. MATERIAL AND METHOD A 35-year-old-woman case report is exposed. She has recurrent chylosa ascites, requiring several admissions and evacuatory paracentesis. After food-fat was replaced by medium-chain triacyl-glicerol-enriched diet, a clinical, analytical and anthropometric improvement was demonstrated. CONCLUSIONS The major way of treatment in intestinal lymphangiectasia in this case is the employement of specific-diet and adaptaded-basic-food. It's difficult and high collaboration of the patient is required, being necessary medical revisions during the whole life, due to the not well known evolution of this long-standing disease.

Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene.

Glucokinase is essential for glucose-stimulated insulin release from the pancreatic beta-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported.

Hippocampal sparing whole brain radiotherapy and simultaneously integrated boost with helical tomotherapy in patients with brain metastases

Materials/Methods: Four patients who underwent whole-brain radiotherapy (WBRT) and simultaneous integrated boost (SIB) between August 2010 and February 2011 were included to this study. Their age were 60, 61, 65, and 70 years. Primary diagnosis was infiltrative ductal breast cancer in two patients, sigmoid adenocarcinoma in one, and transitional bladder cancer in the other patient. All patients underwent cranial surgery but not all of the metastases were operated in 2 patients. All but one (five metastases) patient presented with single brain metastasis. In 2 of the 4 patients, hippocampus was spared contralaterally due to vicinity of the lesions to unilateral hippocampus. Planning irradiation dose was 30 Gy in 10 fractions for WBRT and 40 Gy in 10 fractions for SIB over two weeks in three patients. In one patient, WBRT and boost doses were 36Gy and 50.4 Gy in 18 fractions. Our maximum dose constraints for hippocampus and eyes were 10 and 20 Gy, respectively. All organs were contoured manually. Hippocampi were contoured according to published guidelines, and 5-mm margin expansion was used for hippocampal avoidance volume. All plans utilized a field width of 2.5 cm. Modulation factors ranged between 2 and 3.5. A pitch of 0,287 was used for all patients. All plans were evaluated according to conformity index (CI), homogeneity index (HI), target coverage (TC), and mean normalized total dose (NTDmean). An alpha/beta ratio of 2 was assumed for the hippocampus.Results: Median planning target volume (PTV) for metastases was 17.47 cc.Median hippocampal avoidance volume was 14.73 cc (range, 9.25-16.18 cc). Median average hippocampaldose was 11.84 Gy (range, 10.14-21.01 Gy). PTVs were fully covered with more than 95% of the prescribed dose for all patients. With a median follow-up time of 6 months (range, 3-9 months), all patients were alive without recurrent intracranial disease. To date, no neurocognitive decline reported in any of the patients.Conclusions: Preclinical evidence suggests that hippocampal sparing during cranial irradiation may mitigate neurocognitive decline. Using HT, we significantly reduced the mean dose to the hippocampus without jeopardizing coverage of metastases and whole brain.

Sex differences in patients receiving anticoagulant therapy for venous thromboembolism.

In patients with venous thromboembolism (VTE), the outcome during the course of anticoagulant therapy may differ according to the patient's sex. We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the rate of VTE recurrences, major bleeding, and mortality due to these events according to sex.As of August 2013, 47,499 patients were enrolled in RIETE, of whom 24,280 (51%) were women. Women were older, more likely presented with pulmonary embolism (PE), and were more likely to have recent immobilization but less likely to have cancer than men. During the course of anticoagulation (mean duration: 253 d), 659 patients developed recurrent deep vein thrombosis (DVT), 576 recurrent PE, 1368 bled, and 4506 died. Compared with men, women had a lower rate of DVT recurrences (hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.67-0.91), a similar rate of PE recurrences (HR: 0.98; 95% CI: 0.83-1.15), a higher rate of major bleeding (HR: 1.21; 95% CI: 1.09-1.35), and higher mortality due to PE (HR: 1.24; 95% CI: 1.04-1.47). On multivariable analysis, any influence of sex on the risk for recurrent DVT (HR: 0.88; 95% CI: 0.75-1.03), major bleeding (HR: 1.10; 95% CI: 0.98-1.24), or fatal PE (HR: 1.01; 95% CI: 0.84-1.22) was no longer statistically significant.In conclusion, women had fewer DVT recurrences and more bleeds than men during the course of anticoagulation. These differences were not due to sex, but very likely to other patient characteristics more common in female patients and differences in treatment choice.

Human pregnane X receptor is expressed in breast carcinomas, potential heterodimers formation between hPXR and RXR-alpha.

BACKGROUND The human pregnane X receptor (hPXR) is an orphan nuclear receptor that induces transcription of response elements present in steroid-inducible cytochrome P-450 gene promoters. This activation requires the participation of retinoid X receptors (RXRs), needed partners of hPXR to form heterodimers. We have investigated the expression of hPXR and RXRs in normal, premalignant, and malignant breast tissues, in order to determine whether their expression profile in localized infiltrative breast cancer is associated with an increased risk of recurrent disease. METHODS Breast samples from 99 patients including benign breast diseases, in situ and infiltrative carcinomas were processed for immunohistochemistry and Western-blot analysis. RESULTS Cancer cells from patients that developed recurrent disease showed a high cytoplasmic location of both hPXR isoforms. Only the infiltrative carcinomas that relapsed before 48 months showed nuclear location of hPXR isoform 2. This location was associated with the nuclear immunoexpression of RXR-alpha. CONCLUSION Breast cancer cells can express both variants 1 and 2 of hPXR. Infiltrative carcinomas that recurred showed a nuclear location of both hPXR and RXR-alpha; therefore, the overexpression and the subcellular location changes of hPXR could be considered as a potential new prognostic indicator.

Ocular toxoplasmosis: evaluation of lacrimal - specific secretory IgA levels in both patients with active and inactive phases of the disease

Ocular toxoplasmosis can result in recurrent uveitis. Studies have shown that a correlation between active ocular toxoplasmosis and the presence of anti-Toxoplasma gondii secretory IgA (SIgA) in tears. This study compares anti-T. gondii SIgA levels in patients' tears during the acute and inactive phases of toxoplasmic uveitis. Twenty-nine positive tear specific SIgA for T. gondii patients with acute toxoplasmic uveitis were selected and were followed-up for at least two years, when the anti-T. gondii SIgA tears levels were determined. Specific SIgA for T. gondii was negative in 22 patients (75.86%) and positive in seven patients (24.13%) of whom six (85.7%) were followed over three years. Average SIgA levels during the acute phase are 1.54 and decrease significantly to 0.72 (p = 0.0001) during the inactive phase of disease. Because anti-T. gondii SIgA in the tear is negative in 75.86% of patients after the acute phase of infection, T. gondii SIgA levels may be used as a complementary diagnostic marker for active ocular toxoplasmosis.

Chronology of extraintestinal manifestations relative to IBD diagnosis in the Swiss IBD Cohort

Background and Aims: Due to a p aucity of s uch data we aimed to a ssess the type and f requency o f extraintestinal manifestations ( EIM) in I BD p atients and to e valuate their chronologic behavior. Methods: A nalysis of d ata from t he Swiss Inflammatory Bowel Disease Cohort (SIBDCS) which c ollects data since 2 005 on a large sample o f IBD patients f rom hospitals and private practices across Switzerland. Results: A t total o f 1,143 patients were a nalyzed ( 572 (50%) female, mean age 42.1 ± 14.4 years), 629 with Crohn's disease (CD), 501 with ulcerative colitis (UC), and 13 with indeterminate colitis ( IC). Of t hese, 3 74 (32.7%) presented o ne to five E IM (65% w ith CD, 3 3% w ith UC, 2% w ith IC). O f those patients suffering from EIM, 4 1.7% p resented two, 1 2.4% t hree, 5 .3% four, and 3.2% f ive E IM d uring lifetime. T he initial EIM presented with the following frequencies: p eripheral a rthritis (PA) 6 3.4%, ankylosing spondylitis (AS) 8 .1%, primary sclerosing cholangitis (PSC) 6%, uveitis 5.7%, oral a phthosis 5.7%, erythema nodosum (EN) 5 %, other 3 .6%, pyoderma gangrenosum 1.8%, psoriasis 0.7%. In only 7.1% of cases, the EIM m anifested before IBD diagnosis was made (median time 28 months b efore IBD diagnosis, I QR 7 -60 months), in 9 2.9% EIM m anifested a fter e stablished IBD d iagnosis (median 72 months, IQR 9-147 months). Conclusions: EIM are a frequent problem in IBD patients. The vast m ajority of E IM m anifest a fter I BD d iagnosis has b een established. P eripheral a rthritis, a nkylosing spondylitis, a nd PSC represent the most frequent first manifestations of an EIM.

Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study.

PURPOSE: To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma. PATIENTS AND METHODS: This multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m(2) followed by topotecan at 0.75mg/m(2) intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently. RESULTS: Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8-34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11-40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63-90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1-12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia. CONCLUSION: Temozolomide-Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile.

Atypical Vascular Involvement in a Case of Behçet's Disease.

Introduction. Behçet's disease (BD) is a form of vasculitis of unknown etiology which is rare in our environment. It is characterized by a variety of clinical manifestations and usually affects young adults. Recurrent oral and genital ulcers are a characteristic and extremely frequent symptom, but mortality is linked with more significant symptoms such as aortic pseudoaneurysm, pulmonary pseudoaneurysm, and cerebral venous thrombosis. Patient and Method. We present a case of a young male with atypical BD and severe polyvascular involvement (previous cerebral venous thrombosis and current peripheral venous thrombosis, acute ischemia, and peripheral arterial pseudoaneurysm) who required urgent surgical intervention due to a symptomatic external iliac pseudoaneurysm. Result. The pseudoaneurysm was successfully treated, we performed an iliofemoral bypass, and we treated it with steroids and immunosuppressive therapy. Conclusions. These rare clinical manifestations highlight the importance of considering BD in young patients, even in usual cases of vascular intervention, whether arterial or venous in nature.