Neuroprotective Effects of Cerebral Ischemic Preconditioning in a Rat Middle Cerebral Artery Occlusion Model: The Role of the Notch Signaling Pathway

Cerebral ischemia-reperfusion (I/R) injury is a major problem worldwide. The Notch signaling pathway plays an important role in neural progenitor cell differentiation and in the inflammatory response after central nervous system injury. This study evaluated whether the neuroprotective effect of cerebral ischemic preconditioning (cIPC) is mediated by the preactivation of the Notch signaling pathway. A rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and glucose deprivation/reoxygenation (OGD/R) cell model were constructed to detect the neuroprotective effects of cIPC. In in vivo experiments, cIPC reduces the neurological functional deficit, cerebral infarction, and cellular apoptosis in the hippocampus induced by middle cerebral artery occlusion/reperfusion (MCAO/R), thus indicating that cIPC can improve neurologic function. Moreover, cIPC can reveal the expression peak of Jagged1, Notch1, NICD, and Hes1 protein, thereby indicating that cIPC can preactivate Notch signaling. However, cIPC-induced improvements in neurologic function are compromised by the γ-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-1-alanyl)-S-phenylglycine t-butyl ester (DAPT). In in vitro experiments, OGD preconditioning (OGDPC) can clearly upregulate Notch1 expression in the OGD/R-treated neuron and neural stem cell. Notch1 pre-overexpression can decrease neuron death and apoptosis under OGD/R treatment. Notch1 pre-overexpression can decrease the percentage of G1 stage cells and increase the percentage of S stage cells in OGD/R-treated neural stem cell. Furthermore, Notch1 pre-knockdown has the opposite effect on cell survival, apoptosis, and cycle in both OGD/R-treated neuron and neural stem cell. In conclusion, our results demonstrate that the neuroprotective effects of cIPC in a rat MCAO/R model are mediated by the preactivation of the Notch signaling pathway.

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Effectiveness and Safety of Acupotomy for Lumbar Disc Herniation: A Randomized, Assessor-Blinded, Controlled Pilot Study

Objective. Patients with lumbar disc herniation (LDH) suffer from pain, physical disabilities, and low quality of life. This study was designed to evaluate the effectiveness and safety of acupotomy in patients with LDH. Method. Fifty participants with LDH were recruited to this randomized, assessor-blinded, controlled study and randomly assigned to the acupotomy (n = 25) or manual acupuncture (n = 25) group. The acupotomy group received acupotomy four times in 2 weeks, while the manual acupuncture group received manual acupuncture six times in 2 weeks. The follow-up visit was planned in the 4th week (i.e., 2 weeks after the final intervention). The primary outcome was the change in the Visual Analogue Scale (VAS) at follow-up. The changes in the Oswestry Disability Index (ODI), Modified-Modified Schober Test (MMST), and EuroQol Five Dimensions (EQ-5D) questionnaire were also evaluated. An intention-to-treat analysis was applied and adverse events were recorded. Results. The acupotomy group showed significant changes in VAS, ODI, and EQ-5D after intervention. VAS and ODI in the 4th week were lower in the acupotomy than in the manual acupuncture group. The acupotomy group showed consistent changes in VAS and ODI in the 1st, 2nd, and 4th week. No serious adverse event was reported in the acupotomy group. Conclusion. This study suggests greater therapeutic effects of acupotomy on relieving pain and improving the functional disability associated with LDH than those observed with manual acupuncture.

https://ift.tt/2LZgj0f

Histiocytic cell neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016

Abstract

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAF^V600E mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.

https://ift.tt/2OKIXAH

Male Fertility After Inguinal Hernia Mesh Repair: A National Register Study

Objective: To determine whether patients who receive an inguinal hernia repair father the same number of children as the background population. Background: Although the effect of inguinal hernia repair on male fertility has previously been investigated through indirect measures, no previous studies have evaluated the final measure of male fertility, which is the number of children fathered by patients. Methods: Prospectively collected data on 32,621 male patients between the ages of 18 and 55 years who received 1 or more inguinal hernia repairs during the years 1998 to 2012 were found in 5 comprehensive Danish linked registers. Patients were matched with 97,805 controls, and the number of fathered children was recorded as the primary outcome. Results: Patients who were operated unilaterally fathered more children than controls (156 vs 147 children per 1000 individuals, P = 0.02), whereas patients who were operated bilaterally fathered the same number of children as controls. Unilateral Lichtenstein operation resulted in an increase in number of children fathered by patients (161 vs 151 children per 1000 patients, P = 0.009). No difference in the number of children fathered was found for any year following operation. Meanwhile, time between operation and first child was longer among controls than patients (log-rank P = 0.003). The youngest (18–30 years of age) bilaterally operated patients fathered the same number of children as controls. Conclusions: Patients who underwent inguinal hernia repair using Lichtenstein technique or laparoscopic approach did not father fewer children than expected. Thus, inguinal hernia repair using Lichtenstein or laparoscopic approach did not impair male fertility.

https://ift.tt/2u927Yg

Tamoxifen withdrawal in women with progressive metastatic breast cancer: a case series of six patients

Abstract

Estrogen receptor (ER)-positive metastatic breast cancers after a period of response to tamoxifen develop resistance, and the disease progresses clinically. Domination of partial agonistic activity of tamoxifen over its antagonist activity has been implicated as one of the mechanisms for acquired tamoxifen resistance. Six patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who were treated with tamoxifen withdrawal were retrospectively reviewed. Three patients were premenopausal and three were postmenopausal at the beginning of this treatment. Three patients had stage IV disease and three had recurrent breast cancers with median disease-free intervals of 153 months. The treatment lines of tamoxifen therapy were first-line in two, second-line in two, and third-line in one patient. One patient had relapsed during adjuvant tamoxifen therapy. The median duration of tamoxifen therapy was 16 months. The metastatic disease sites at the time of tamoxifen withdrawal were lymph nodes in six, bone in three, chest wall in one, lung in two, pleura in one, and liver in one patient. The median duration of tamoxifen withdrawal was 6.5 months (range 5–> 23 months). Five of six patients had clinical benefits with tamoxifen withdrawal: partial response in one, long stable disease (SD) in four, and SD in one patient. Five patients were treated with aromatase inhibitors after tamoxifen withdrawal. Two patients had metastatic lymph nodes examined by multi-gene panel testing, and both of their tumors had the AKT1 E17K somatic mutation. One patient also had a BRCA1 germline mutation. Tamoxifen withdrawal at the time of tumor progression while on treatment might be an important treatment option, especially for women with highly endocrine-responsive disease.

https://ift.tt/2LY1JXk

Comparison of levetiracetam with phenytoin for the prevention of intravenous busulfan-induced seizures in hematopoietic cell transplantation recipients

Abstract

Purpose

Busulfan is used as a conditioning regimen for hematopoietic stem cell transplantation and is known to cause seizures as a side effect. As various anticonvulsant drugs have been reported, we conducted a retrospective investigation regarding the preventive effects and adverse events associated with different anticonvulsants administered alongside intravenous busulfan (ivBu) in our institution.

Methods

We targeted 104 patients who received ivBu at our institution from May 1, 2010 to April 30, 2017. We investigated the seizure prevention rate and adverse events rate under anticonvulsant prophylaxis.

Results

There were 70 cases (67.3%) of phenytoin administration and 34 cases (32.7%) of levetiracetam administration for anticonvulsant therapy. The seizure prevention rate was 98.6% for phenytoin and 100% for levetiracetam; seizures occurred in one out of 104 patients. There were no significant differences in the seizure prevention rate depending on the type of anticonvulsant. Further, there were no differences in adverse events.

Conclusions

Anticonvulsant prophylaxis is considered necessary for safe conditioning with ivBu. Adverse events associated with the use of levetiracetam are within an acceptable range. Further, levetiracetam is considered useful as a preventive drug against seizures during ivBu administration because it is easy to administer and has ideal pharmacokinetics for supportive care.

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Should patients with NAFLD/NASH be surveyed for HCC?

Background Patients with nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatocellular carcinoma (HCC), but the magnitude of the association still needs to be determined in order to define the need for a specific surveillance strategy. Methods We based our assessment on a previously published review by White et al (1992-2011) and on a systematic review (2012-2017). Results The new search identified 328 abstracts. Combining both eras (1992-2011 and 2012-2017), 25 studies were included in the analysis. Four were prospective, 2 described a retrospective analysis of a prospective database, and the others were retrospective. All studies were published after 2004, but the inclusion period of half of them ended before the year 2000. Studies showed variation in the definition of NAFLD, in the incidence of fibrosis/cirrhosis, in the presence of comorbidities (potentially affecting HCC incidence), and in the type and duration of screening. Considering only studies strictly including patients with or without cirrhosis, the reported incidence of HCC in NAFLD patients with cirrhosis was between 6.7 and 15% at 5-10 years, while the incidence in NAFLD patients without cirrhosis was 2.7% at 10 years and 23 per 100 000 person-years. Conclusions HCC screening in NAFLD patients with cirrhosis is mandatory. However, the currently observed low (and insufficiently documented) incidence of HCC in NAFLD-patients without cirrhosis does not justify a systematic surveillance. Research efforts should focus on developing a score, which could aid the clinician in identifying NAFLD patients without cirrhosis who are at higher risk of developing HCC. Corresponding authors: María Reig, BCLC group. Liver Unit. IMDiM. CIBEREHD. IDIBAPS. Hospital Clínic. c/ Villarroel, 170. Escala 11, 4ª planta. 08036. Barcelona. Spain. Phone: +34 932279803; Fax: +34 932275792. Email: mreig1@clinic.ub.es; Christian Toso, Geneva University Hospitals, Department of Surgery, Rue Gabrielle-Perret-Gentil, 1211 Geneva, Switzerland, Phone: +41 223723311, Fax : +41 223727755. E-mail : christian.toso@hcuge.ch Authorship: María Reig and Christian Toso, participated in the research design, and all authors participated in the writing of the paper, performance of the research, and/or participated in data analysis. Disclosure: The authors declare no conflict of interest. Funding: CT was supported by the Swiss National Science Foundation (PP00P3_165837). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2AKDeYH