NCLs and ER: A stressful relationship.

The Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are a group of inherited neurodegenerative disorders with variable age of onset, characterized by the lysosomal accumulation of autofluorescent ceroid lipopigments. The endoplasmic reticulum (ER) is a critical organelle for normal cell function. Alteration of ER homeostasis leads to accumulation of misfolded protein in the ER and to activation of the unfolded protein response. ER stress and the UPR have recently been linked to the NCLs. In this review, we will discuss the evidence for UPR activation in the NCLs, and address its connection to disease pathogenesis. Further understanding of ER-stress response involvement in the NCLs may encourage development of novel therapeutical agents targeting these pathogenic pathways

Diffusion MRI Findings in Encephalopathy Induced by Immunosuppressive Therapy after Liver Transplantation

Neurological complications are common after liver transplantation, as they affect up to one-third of the transplanted patients and are associated with significant morbidity. The introduction of calcineurin inhibitors, cyclosporine A and tacrolimus, in immunosuppressive regimens significantly improved the outcome of solid-organ transplantation even though immunosuppression-associated neurotoxicity remains a significant complication, particularly occurring in about 25% of cases after liver transplantation. The immunosuppressant cyclosporine A and tacrolimus have been associated with the occurrence of major neurological complications, diffuse encephalopathy being the most common. The biochemical and pathogenetic basis of calcineurin inhibitors-induced neurotoxicity are still unclear although several mechanisms have been suggested. Early recognition of symptoms could help reduce neurotoxic event. The aim of the study was to evaluate cerebral changes through MRI, in particular with diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) maps, in two patients undergoing liver transplantation after immunosuppressive therapy. We describe two patients in which clinical pictures, presenting as a severe neurological condition, early after orthotopic liver transplantation during immunosuppression therapy, showed a different evolution in keeping with evidence of focal-multifocal lesions at DWI and ADC maps. At clinical onset, DWI showed hyperintensity of the temporo-parieto-occipital cortex with normal ADC values in the patient with following good clinical recovery and decreased values in the other one; in the latter case, MRI abnormalities were still present after ten days, until the patient's exitus. The changes in DWI with normal ADC may be linked to brain edema with a predominant vasogenic component and therefore reversible, while the reduction in ADC is due to cytotoxic edema and linked to more severe, nonreversible, clinical picture. Brain MRI and particularly DWI and ADC maps provide not only a good and early representation of neurological complications during immunosuppressant therapy but can also provide a useful prognostic tool on clinical outcome of the patient

Directed evolution to increase camptothecin sensitivity of human DNA topoisomerase I

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Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease

Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102–208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype–phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events

Structural Brain MR Imaging Changes Associated with Obsessive-Compulsive Disorder in Patients with Multiple Sclerosis

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Interleukin-6, interleukin-1β, and tumor necrosis factor α in menstrual effluents as biomarkers of chronic endometritis.

Objective: To assess the relationship between chronic endometritis (CE) and proin␣ammatory cytokine levels in menstrual ef␣uents and to develop a simple noninvasive test for screening CE. Design: Case-control study. Setting: Academic center. Patient(s): Sixty-four women referred to our center for infertility. Intervention(s): Of␣ce hysteroscopy; endometrial biopsy; collection of menstrual blood at subsequent cycle. Main Outcome Measure(s): Interleukin (IL) 6, IL-1b, and tumor necrosis factor (TNF) a concentrations in menstrual ef␣uents. Result(s): Thirty-sixoutof64infertilewomenhadhistologicallyprovenCE.Theremaining28womenwereincludedascontrols.IL-6, IL-1b, and TNF-a levels were markedly higher in menstrual ef␣uents of women with CE compared with control subjects. Receiver operating characteristic curve analysis revealed a good CE screening capacity for all of the cytokines. The combined evaluation of either IL-6/TNF-a or IL-6/IL-1b increased the diagnostic capacity of the test, which reached a 100% sensitivity and a negative predictive value of 100 when at least one cytokine was found to exceed its cutoff value; it also reached a 100% speci␣city and a positive predictive value of 100 in cases of positivity of both cytokines. Logistic regression analysis con␣rmed the IL-6/TNF-a– based model as a signi␣cant predictor of CE. Conclusion(s): Proin␣ammatorycytokinelevelsareincreasedinmenstrualef␣uentsofwomen with CE. A test dosing IL-6 and TNF-a seems to have a high screening capacity for CE. (Fertil Steril! 2014;101:242–7. !2014 by American Society for Reproductive Medicine.

Eradication of isolated para-aortic nodal recurrence in a patient with an advanced high grade sorous ovarian carcinoma: our experience and review of literature

Abstract: We report a case report regarding the eradication of isolated lymph-nodal para-aortic recurrence in the aortic region down the left renal vein (LRV) in a patient treated two years earlier in another hospital for a FIGO stage IC2 high-grade serous ovarian carcinoma with a video showing the para-aortic space after eradication of the metastatic tissue. A 66 year-old woman was admitted 24 months after the initial surgical procedure for an increased Ca 125 level and CT scan that revealed a 3 cm para-aortic infrarenal lymph-nodal recurrence that was confirmed by PET/CT scan. A secondary cytoreductive surgery (SCS) with a para-aortic lymph-nodal dissection of the tissue down the LRV and radical omentectomy were performed: during the cytoreduction, the right hemicolon was mobilized. The anterior surface of the inferior vena cava (IVC), aorta and LRV were exposed. The metastatic lymph nodes were detected in the para-ortic space down the proximal part of the LRV and eradicated; an en bloc infrarenal lymph-node dissection from the aortocaval region was performed. The operative time during the surgical procedure was 212 min with a blood loss of 120 mL. No intra- and postoperative complications, including ureteral or vascular injury or renal dysfunction, occurred. At histological examination, three dissected lymph nodes were positive for metastasis, and the patient was discharged five days after laparotomy without side effects and underwent chemotherapy 3 weeks later; after a follow-up of 42 months, no recurrence was detected. In conclusion, secondary debulking surgery can be considered a safe and effective therapeutic option for the management of recurrences, although long-term follow-ups are necessary to evaluate the overall oncologic outcomes of this procedure

Considerations for the optimal management of antibiotic therapy in elderly patients

Objectives: To maximise efficacy and minimise toxicity, special considerations are required for antibiotic prescription in elderly patients. This review aims to provide practical suggestions for the optimal management of antibiotic therapy in elderly patients. Methods: This was a narrative review. A literature search of published articles in the last 15 years on antibiotics and elderly patients was performed using the Cochrane Library and PubMed electronic databases. The three priority areas were identified: (i) pharmacokinetics/pharmacodynamics (PK/PD) for optimising dosage regimens and route of administration; (ii) antibiotic dosages in some special subpopulations; and (iii) treatment considerations relating to different antibiotic classes and their adverse events. Results: Clinicians should understand the altered PK/PD of drugs in this population owing to co-morbid conditions and normal physiological changes associated with ageing. The body of evidence justifies the need for individualised dose selection, especially in patients with impaired renal and liver function. Clinicians should be aware of the major drug–drug interactions commonly observed in the elderly as well as potential side effects. Conclusion: Antibiotic therapy in the elderly requires a comprehensive approach, including strategies to improve appropriate antibiotic prescribing, limit their use for uncomplicated infections and ensure the attainment of an optimal PK/PD target. To this purpose, further studies involving the elderly are needed to better understand the PK of antibiotics. Moreover, it is necessary to assess the role therapeutic drug monitoring in guiding antibiotic therapy in elderly patients in order to evaluate its impact on clinical outcome

Molecular markers and endometrial cancer

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