Potential role of peste des petits ruminants virus in small ruminant abortions.

The aim of the present study was to investigate the frequency, genetic variability, and phylogeny of the peste des petits ruminants virus (PPRV) in ovine and caprine fetuses. During 2014 and 2017, a total of 1054 embryos/fetuses were collected in Turkey. A real-time RT-PCR assay was used for the detection of the PPRV RNA. Genetic characterization and phylogenetic analysis of the PPRV field isolates were conducted by sequencing fusion (F) protein and nucleoprotein (N) gene segments. Samples were also collected from ewes (n = 83) and nanny goats (n = 3) that had aborted and whose embryos/fetuses were found to be PPRV positive. PPRV positive embryos/fetuses were also tested for the presence of Listeria monocytogenes, Campylobacter spp., Coxiella burnetii, Chlamydophila abortus, Brucella spp., akabane virus, aino virus, bluetongue virus, border disease virus, bovine viral diarrhea virus, Cache Valley virus, and Schmallenberg virus. PPRV RNA was detected in 123 (11.7 %) of the 1054 embryos/fetuses, 78 of the 83 (94 %) ewes and 3 (100 %) nanny goats. Border disease virus RNA and Chlamydophila abortus DNA were detected in 7 and 12 PPRV positive sheep fetuses, respectively, while other bacterial and viral agents were not detected. Phylogenetically, the field isolates in this study belong to lineage IV, and compared to other strains of lineage IV considered in this study, they showed 1 and 5 new amino acid substitutions in the F and N gene sequences, respectively. The results of the study suggest that PPRV plays an important role in abortion. Therefore, PPRV needs to be taken into consideration in sheep and goats abortions.

Regulation of the hippocampal translatome by Apoer2-ICD release.

BACKGROUND: ApoE4, the most significant genetic risk factor for late-onset Alzheimer's disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-ß toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described. Alternative splicing of the Apoer2 intracellular domain (Apoer2-ICD) regulates Apoer2 signaling. Splicing of juxtamembraneous exon 16 alters the γ-secretase mediated release of the Apoer2-ICD as well as synapse number and LTP, and inclusion of exon 19 ameliorates behavioral deficits in an AD mouse model. The Apoer2-ICD has also been shown to alter transcription of synaptic genes. However, the role of Apoer2-ICD release upon transcriptional regulation and its role in AD pathogenesis is unknown. METHODS: To assess in vivo mRNA-primed ribosomes specifically in hippocampi transduced with Apoer2-ICD splice variants, we crossed wild-type, cKO, and Apoer2 cleavage-resistant mice to a Cre-inducible translating ribosome affinity purification (TRAP) model. This allowed us to perform RNA-Seq on ribosome-loaded mRNA harvested specifically from hippocampal cells transduced with Apoer2-ICDs. RESULTS: Across all conditions, we observed ~4,700 altered translating transcripts, several of which comprise key synaptic components such as extracellular matrix and focal adhesions with concomitant perturbation of critical signaling cascades, energy metabolism, translation, and apoptosis. We further demonstrated the ability of the Apoer2-ICD to rescue many of these altered transcripts, underscoring the importance of Apoer2 splicing in synaptic homeostasis. A variety of these altered genes have been implicated in AD, demonstrating how dysregulated Apoer2 splicing may contribute to neurodegeneration. CONCLUSIONS: Our findings demonstrate how alternative splicing of the APOE and Reelin receptor Apoer2 and release of the Apoer2-ICD regulates numerous translating transcripts in mouse hippocampi in vivo. These transcripts comprise a wide range of functions, and alterations in these transcripts suggest a mechanistic basis for the synaptic deficits seen in Apoer2 mutant mice and AD patients. Our findings, together with the recently reported AD-protective effects of a Reelin gain-of-function mutation in the presence of an early-onset AD mutation in Presenilin-1, implicate the Reelin/Apoer2 pathway as a target for AD therapeutics.

A foundation model for generalizable disease detection from retinal images.

Medical artificial intelligence (AI) offers great potential for recognizing signs of health conditions in retinal images and expediting the diagnosis of eye diseases and systemic disorders1. However, the development of AI models requires substantial annotation and models are usually task-specific with limited generalizability to different clinical applications2. Here, we present RETFound, a foundation model for retinal images that learns generalizable representations from unlabelled retinal images and provides a basis for label-efficient model adaptation in several applications. Specifically, RETFound is trained on 1.6 million unlabelled retinal images by means of self-supervised learning and then adapted to disease detection tasks with explicit labels. We show that adapted RETFound consistently outperforms several comparison models in the diagnosis and prognosis of sight-threatening eye diseases, as well as incident prediction of complex systemic disorders such as heart failure and myocardial infarction with fewer labelled data. RETFound provides a generalizable solution to improve model performance and alleviate the annotation workload of experts to enable broad clinical AI applications from retinal imaging.

IgG4 Positivity in Chronic Tonsillitis: A New Component of IgG4-Related Disease?

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) and chronic tonsillitis are both chronic fibroinflammatory diseases in which tissue atrophy is sometimes observed. In this study, the authors aimed to investigate the pathologic IgG4 positivity in tonsillectomy specimens and hypothesized to name it as a new clinical component of IgG4-RD if there is significant IgG4 positivity in chronic tonsillitis. METHODS: A total of 73 patients who underwent tonsillectomy for chronic tonsillitis were included in this study. Of these, 31 patients had atrophic form chronic tonsillitis. Pathologic examinations and specific IgG4 immunohistochemical staining were performed by the same experienced pathologist in terms of IgG4-RD. RESULTS: Sixty-three percent (n=46) of the cases were male, 37% (n=27) were female, their ages ranged from 3 to 51, and the mean age was 19.11±14.82. It was determined that 23.3% (n=17) of the cases participating in the study were IgG4-positive. When the pathologic grades of the cases were examined; it was observed that 13.7% (n=10) were Grade I, 65.8% (n=48) were Grade II, and 20.5% (n=15) were Grade III. A statistically significant difference was found between the pathology degrees of the cases according to the IgG4 groups ( P =0.001; P <0.01). CONCLUSION: The authors concluded that as the histopathologic grades of chronic lymphoplasmacytic inflammation in tonsils specimen increase, IgG4 positivity rates also increase. Therefore, this clinical entity may be a new IgG4-related disease state in cases with chronic tonsillitis. LEVEL OF EVIDENCE: Level II.

Apoer2-ICD-dependent regulation of hippocampal ribosome mRNA loading.

Background ApoE4, the most significant genetic risk factor for late-onset Alzheimer's disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-ß toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described. Alternative splicing of the Apoer2 intracellular domain (Apoer2-ICD) regulates Apoer2 signaling. Splicing of juxtamembraneous exon 16 alters the g-secretase mediated release of the Apoer2-ICD as well as synapse number and LTP, and inclusion of exon 19 ameliorates behavioral deficits in an AD mouse model. The Apoer2-ICD has also been shown to alter transcription of synaptic genes. However, the role of Apoer2 splicing for transcriptional regulation and its role in AD pathogenesis is unknown. Methods To assess in vivo mRNA-primed ribosomes specifically in hippocampi transduced with Apoer2-ICD splice variants, we crossed wild-type, cKO, and Apoer2 cleavage-resistant mice to a Cre-inducible translating ribosome affinity purification (TRAP) model. This allowed us to perform RNA-Seq on ribosome-loaded mRNA harvested specifically from hippocampal cells transduced with Apoer2-ICDs. Results Across all conditions, we observed ~ 4,700 altered ribosome-associated transcripts, several of which comprise key synaptic components such as extracellular matrix and focal adhesions with concomitant perturbation of critical signaling cascades, energy metabolism, translation, and apoptosis. We further demonstrated the ability of the Apoer2-ICD to rescue many of these altered transcripts, underscoring the importance of Apoer2 splicing in synaptic homeostasis. A variety of these altered genes have been implicated in AD, demonstrating how dysregulated Apoer2 splicing may contribute to neurodegeneration. Conclusions Our findings demonstrate how alternative splicing of the APOE and Reelin receptor Apoer2 and release of the Apoer2-ICD regulates numerous ribosome-associated transcripts in mouse hippocampi in vivo . These transcripts comprise a wide range of functions, and alterations in these transcripts suggest a mechanistic basis for the synaptic deficits seen in Apoer2 mutant mice and AD patients. Our findings, together with the recently reported AD-protective effects of a Reelin gain-of-function mutation in the presence of an early-onset AD mutation in Presenilin-1, implicate the Reelin/Apoer2 pathway as a target for AD therapeutics.

BRCA 1/BRCA 2 Pathogenic/Likely Pathogenic Variant Patients with Breast, Ovarian, and Other Cancers.

The demographic and clinical characteristics of patients who have BRCA 1/BRCA 2 pathogenic/likely pathogenic variants may differ from their relatives who had BRCA-related cancer. In this study, we aimed to demonstrate the clinical and demographic findings of patients who had BRCA-related cancer and to assess the differences comparing their relatives who had BRCA-related cancer with breast, genital tract, prostate, and pancreas cancers as well. The results of sequencing analysis of 200 cancer patients (190 women, 10 men) who have been directed to genetic counseling with an indication of BRCA1/BRCA2 testing from different regions across 9 medical oncology centers were retrospectively analyzed. A total of 200 consecutive cancer patients who harbored the BRCA1/BRCA2 pathogenic/likely pathogenic variant (130 (65%) patients harbored BRCA 1 pathogenic/likely pathogenic variant, and 70 harbored BRCA 2 pathogenic/likely pathogenic variant) were included. Of these, 64.0% had breast cancer (43.8% of them had the triple-negative disease, and about 2.3% had only the HER-2 mutant), 31.5% had genital cancers (92.1% of them had ovarian cancer, 3.2% had endometrium, and 1.6% had peritoneum cancer as the primary site and mostly serous adenocarcinoma was the most common histopathology and 14.3% of the patients had endometrioid adenocarcinoma), 3.5% had prostate (median time from metastasis to castration-resistant status was 28 months) and 1.0% had pancreas cancer. Newly diagnosed cancer (breast and ovary) patients who had BRCA 1/BRCA 2 pathogenic/ likely pathogenic variant were younger than their previous cancer diagnosed (breast, ovary, and pancreas) parents who harbored BRCA pathogenic/likely pathogenic variant. We suggest that the genetic screening of BRCA 1/ BRCA 2 pathogenic/likely pathogenic variant is needed as a routine screening for those with a personal or family history of breast, ovarian, tubal, or peritoneal cancer. In addition, once BRCA 1 or BRCA 2 germline pathogenic variant has been identified in a family, testing of at-risk next-generation relatives earlier can identify those family members who also have the familial pathogenic variant, and thus need increased surveillance.

Impact of COVID-19 on interest in pediatric neurosurgery related symptoms, diseases, and treatments.

BACKGROUND: More and more often, patients use online resources to increase their knowledge/confidence in conventional medicine. Thus, the evaluation of the internet search trends may offer an insight into patients' perception of the healthcare system during the pandemic, especially for medical specialties with invasive interventions such as pediatric neurosurgery. METHODS: A total of 140 keywords representing a wide range of pediatric neurosurgery related symptoms/signs, diseases, and treatments were defined. Google Trends tool was queried for the predefined keywords within the United States from January 01, 2016, to November 17, 2020. Two periods in 2020, March 15 to July 4 and July 5 to October 31, were compared with similar periods over the preceding four years (2016-2019). We performed analyses in three sections: symptoms/signs, diseases, and treatments. RESULTS: Public interest has shifted from regular pediatric neurosurgery related symptoms/signs, diseases, and treatments to the ones related with neurological aspects of COVID-19 both in initial and short-term stages of the pandemic. CONCLUSIONS: Google Trends highlights that the link between neurosurgeon/pediatric patients/caregivers needs to be further empowered by growing educational efforts.

Lumbar intervertebral disc degeneration, end-plates and paraspinal muscle changes in children and adolescents with low-back pain.

The prevalence of low-back pain (LBP) in adolescents ranges from 7 to 72%. We aimed to define the radiologic characteristics of the lumbar spine in children and adolescents with LBP with/without leg pain. Two hundred and fourteen children and adolescents, who were born between 2001 and 2009 and had lumbar spine MRI for LBP with/without leg pain, were evaluated in terms of intervertebral disc degeneration (IVDD), end-plates and paraspinal muscle changes on lumbar spine MRIs. Severe IVDD was detected at all lumbar levels except for L2-L3. Modic changes were present in 4.2% of the patients. Modic changes were more common in patients with severe IVDD than in those with mild-to-moderate IVDD. Severe IVDD was significantly associated with Modic changes at the corresponding L1-L2 and L3-L4 disc levels. Girls had significantly more fatty infiltration in the paraspinal muscles when compared to boys. The risk of having severe IVDD concomitant with Modic changes was high [odds ratio (OR), 8.6]. The OR was 20.7 for predicting the presence of severe IVDD at any level if Modic changes presented particularly at the L3-L4 level. The ORs of Modic changes presented at any lumbar level at the background of fat-infiltrated multifidus at L3-L4 and L4-L5 levels were 8.3 and 9.1, respectively. Fatty infiltration in the paraspinal muscles and IVDD were closely associated with Modic changes in children and adolescents with LBP. Lumbar IVDD in children and adolescents could be the result of a mechanical pathology.

Correction of Areolar Protuberance During Augmentation Mammoplasty in Transfemale Patients.

Augmentation mammoplasty refers to "top surgery" for transfemale patients. Before this surgery, due to the hormonal treatment being taken, it may be encountered that there would be a glandular tissue of breast that seems to be similar to the simple tuberous breast disease, which is one of the diseases in female breast development. The presence of areolar protuberance in transfemale would of course undermine the cosmetic gain after augmentation mammoplasty operation. This situation, which can be difficult to diagnose before surgery especially in transfemale patients, will manifest itself clearly after the end of augmentation mammoplasty. As a precaution, resection of a part of glandular tissue equal to the protruding height of the areola from the posterior wall of the gland is an effective method both in terms of its simple applicability and not to use of an extra skin incision while performing augmentation mammoplasty.

NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load.

Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer's disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis, and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of EEs caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4-induced endolysosomal trafficking defect and reduces plaque load.

Reelin Regulates Neuronal Excitability through Striatal-Enriched Protein Tyrosine Phosphatase (STEP61) and Calcium Permeable AMPARs in an NMDAR-Dependent Manner.

Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles. Aß oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP61). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aß toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aß-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP61, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca2+-permeable GluA2-lacking AMPA receptors along with higher STEP61 levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.SIGNIFICANCE STATEMENT Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-ß has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration.

Concomittant occurence of well-differentiated thyroid carcinoma metastasis and chronic lymphocytic leukemia in the same lymph node along with internal jugular vein thrombus: a case report.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common adult leukemia. The coexistence of CLL and papillary thyroid carcinoma (PTC) is extremely rare. PTC sometimes shows microscopic vascular invasion but rarely cause a tumor thrombus in the internal jugular vein (IJV). It is also rare to find both differentiated and poorly differentiated types of thyroid cancer in the same metastatic location. We report a case of 63-year-old Turkish man with history of CLL who had CLL/SLL involvement and PTC metastasis in the same lymph node. Additionally, there was macroscopic metastasis to the IJV with poorly differentiated areas in the removed tumor thrombus. Patient was treated with total thyroidectomy, left radical neck dissection, resection of the left IJV segment that contained the tumor thrombus and radioactive iodine (RAI) therapy. Furthermore, metastatic lesions were found in the brain, lung and bone. Radiotherapy and chemotherapy were performed. However, our patient died approximately 12 months after thyroidectomy. To our knowledge, our present report is the first description with its current features.

Is there a unique symptom in lower urinary tract dysfunction in children?

OBJECTIVES: Lower urinary tract symptoms (LUTS), particularly urgency, incontinence and intermittency are common in children and it is suggested that the specific symptoms may be used for definite diagnosis for LUT dysfunction (LUTD). This study was performed to investigate the relationship between each LUTD and its associated symptoms, using uroflowmetry/electromyography (UF/EMG) as a diagnostic tool. METHODS: Each patient was categorized into one of four LUT conditions which were overactive bladder (OAB), dysfunctional voiding (DV), underactive bladder and primary bladder neck dysfunction (PBND), according to UF/EMG results. Patients' complaints and findings were documented by using voiding dysfunction symptom score, bladder diary, urine analysis and ultrasonography. In addition, a detailed history of bowel habits (including use of Rome III criteria) was obtained. RESULTS: There were 189 children of which 106 were female. The OAB was the largest group including 91 patients, followed by the DV group which had 61 patients. The symptoms specific to any LUTD group were constipation and hesitancy (P < .05). Hesitancy was present in 89.4% with PBND and constipation was present in 78.6% of patients with DV. None of other symptoms were able to differentiate any LUTD group from the other. CONCLUSIONS: While certain symptoms are often presumed by clinicians to imply specific diagnoses, the main outcome of this study is that there is a generally weak correlation between the specificity of symptoms and LUTD. Symptoms-based approach may lead to misdiagnosis in LUTD. Thus, it may be essential to focus on the underlying pathologies and UF/EMG test may help this.

Genetic characterization of White Fulani cattle in Nigeria: A comparative study.

OBJECTIVE: The objective of the present study was to evaluate heterozygosis in cattle population, and to characterize White Fulani breed by identifying DNA markers considering microsatellites. MATERIALS AND METHODS: A total of 41 cattle were randomly selected and used for sample (wool) collection for the characterization and identification of phenotypic traits of cattle in Nigeria. The DNA samples from the samples were prepared. Twelve microsatellite primers were used for the microsatellite analysis in the genomic DNA of cattle. The reinforced products were analyzed to determine polymorphic alleles and their frequencies. RESULTS: White Fulani is characterized by a high degree of genetic diversity. The microsatellites have multiple alleles and may show heterozygosity frequencies of at least 70%. White Fulani cows and their F1 descendants form a common cluster, to which the bulls of the Kuru and Red Boro breeds are adjacent. There is a clear differentiation of purebred populations of Tajik zebu-like cattle (Q = 98.7%) and a significant proportion of white Fulani (Q = 81.8%) from Nigeria. The microsatellite analysis of zebu of Nigeria allowed identifying a total of 80 alleles. In the KURU and PAX-KR-BOR rocks, 17 and 19 alleles were identified, respectively. In F1, 51 alleles were detected. CONCLUSION: White Fulani cattle are characterized by a high degree of genetic diversities. This makes it a highly informative source in genetic analysis. The results can be applied in dealing with the conservation and sustainable applications of genetic resources in the Nigerian cattle population.

Human Lung Microbiome on the Way to Cancer.

Recent research on cancer-associated microbial communities led to the accumulation of data on the interplay between bacteria, immune and tumor cells, the pathways of bacterial induction of carcinogenesis, and its meaningfulness for medicine. Microbial communities that have any kind of impact on tumor progression and microorganisms associated with tumors have been defined as oncobiome. Over the last decades, a number of studies were dedicated to Helicobacter pylori and its role in the progression of stomach tumors, so this correlation can be regarded as proven. Involvement of bacteria in the induction of lung cancer has been largely ignored for a long time, though some correlations between this type of cancer and lung microbiome were established. Despite the fact that in the present the microbial impact on lung cancer progression has many confirmations, the underlying mechanisms are poorly understood. Microorganisms can contribute to tumor initiation and progression through production of bacteriotoxins and other proinflammatory factors. The purpose of this review is to organize the available data on lung cancer microbiome and its role in malignant tumor progression.

NGP 555, a γ-secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses.

INTRODUCTION: Currently, there is no cure for Alzheimer's disease (AD), and it is widely accepted that AD is a complex disease with multiple approaches necessary to prevent and treat the disease. METHODS: Using amyloid biomarkers in human cerebrospinal fluid, pharmacokinetic, safety, and metabolism studies, we investigate the properties of NGP 555, γ-secretase modulator, for the first time in human clinical trials. RESULTS: Our preclinical and clinical studies combined show beneficial effects with NGP 555 on synaptic response and amyloid cerebrospinal fluid biomarkers while avoiding negative side effects. Importantly, pharmacokinetic and pharmacodynamic parameters combined with safety outcomes indicate that NGP 555 penetrates the blood-brain barrier and increases the ratio of amyloid-ß peptide Aß37 and Aß38 compared with that of Aß42, establishing a proof of target engagement in humans in a 14 day, once-daily oral dosing trial. DISCUSSION: In humans, NGP 555 has demonstrated a beneficial shift in the production of Aß37 and Aß38 versus Aß42 biomarker levels in the cerebrospinal fluid while maintaining an adequate safety profile. The overall clinical goal is to achieve an optimal balance of efficacy for altering amyloid-ß peptide (Aß) biomarkers while maintaining a safe profile so that NGP 555 can be given early in AD to prevent production of Aß42 and accumulation of amyloid plaques, in an effort to prevent aggregation of tau and destruction of neurons and synapses resulting in cognitive decline.

Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer's disease.

ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer's disease (AD). Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification. We found that pharmacological and genetic inhibition of NHE6, the primary proton leak channel in the early endosome, in rodents completely reverses the ApoE4-induced recycling block of the ApoE receptor Apoer2/Lrp8 and the AMPA- and NMDA-type glutamate receptors that are regulated by, and co-endocytosed in a complex with, Apoer2. Moreover, NHE6 inhibition restores the Reelin-mediated modulation of excitatory synapses that is impaired by ApoE4. Our findings suggest a novel potential approach for the prevention of late-onset AD.

Factors Associated With the Development of and Revision for Proximal Junctional Kyphosis in 440 Consecutive Adult Spinal Deformity Patients.

MINI: Proximal junctional kyphosis (PJK) is a common, yet incompletely understood, complication of surgery for adult spinal deformity. We analyzed 440 consecutive adult spinal deformity patients for trends in development of PJK and need for revision surgery. pelvic tilt and thoracic kyphosis were predictive for developing PJK, while radiographic evidence of proximal junctional failure was predictive for proceeding to revision. STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: The aim of this study was to examine which radiographic parameters and surgical strategies are most closely associated with proximal junctional kyphosis (PJK) after adult spinal deformity (ASD) surgery, the need for revision surgery for PJK, and whether these differ based on the upper instrumented vertebra (UIV). SUMMARY OF BACKGROUND DATA: Multiple parameters are considered when planning correction of ASD. Determining which of these factors contribute to the development of and need for revision surgery for PJK presents a challenging problem. METHODS: Consecutive patients undergoing long fusion to the pelvis with age >18 years, minimum 6-month follow-up, and adequate radiographs for analysis in a single institution between 2003 and 2011 were included. Along with chart review, measurement of proximal junctional angle (PJA), sagittal balance, and pelvic parameters was performed on preoperative, postoperative, and latest follow-up radiographs. Postoperative radiographs were also examined for signs of PJF. RESULTS: A total of 440 patients with a mean follow-up of 34 months met inclusion criteria, 159 of whom developed PJK (36%), with 65 requiring revision surgery (41%). Higher preoperative pelvic tilt (PT) (P = 0.018) and postoperative thoracic kyphosis (TK) (P ≤ 0.001) were predictive for development of PJK, whereas hooks at UIV were protective (odds ratio [OR] 0.049). In patients who developed PJK, revision was more frequent in younger patients (P = 0.005) with greater postoperative sagittal vertical axis and PJA (P = 0.029, P = 0.018). PJF with spondylolisthesis, fracture, or instrumentation failure at the UIV had the highest ORs for proceeding to a revision (5.1, 1.6, and 2.2, respectively). CONCLUSION: TK and PT are important indicators of overall rigidity and reference the ability of the spine to compensate for sagittal plane deformity. Special attention should be paid to these characteristics and to the choice of proximal instrumentation when attempting to prevent PJK. Prevention of radiographically evident PJF may hold the key to reducing the need for revision surgery. LEVEL OF EVIDENCE: 3.

Double nasoseptal flap technique for endonasal pituitary surgery.

Endoscopic endonasal approach has been successfully used for the management of pituitary tumors; however, the loss of septal mucosa especially around sphenoethmoidal recess and posterior nasal septum might be a disadvantage of this technique. The aim of this study is to describe a variation of the endonasal approach, "double nasoseptal flap" technique in endoscopic transsphenoidal pituitary surgery, and to evaluate its outcomes. The technique depends on fully harvested bigger nasoseptal flap on one side and smaller on the other. Thirty patients were included. Functional results were assessed by preoperative and postoperative first month visual analogue scale (VAS), and morphology was evaluated by achieving intact septum from the sphenoid ostium to the columella. Sphenoid sinusitis, the presence of synechia and crusting in the sphenoethmoidal recess was also assessed. Mean VAS was 71 and 67 mm preoperatively and postoperatively, respectively (p > 0.01). There were no septal perforations, synechia, and sphenoid sinusitis postoperatively. Three patients had (10 %) crusts on sphenoethmoidal recess on first month postoperatively. Double nasoseptal flap technique has advantages, such as wider exposure during surgery; prepared flaps could be used if needed, better morphological and functional outcomes postoperatively. The technique is safe without any perforations and minimal crusting.