Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer's disease pathology progression.

A recent large genome-wide association study has identified EGFR (encoding the epidermal growth factor EGFR) as a new genetic risk factor for late-onset AD. SHIP2, encoded by INPPL1, is taking part in the signalling and interactome of several growth factor receptors, such as the EGFR. While INPPL1 has been identified as one of the most significant genes whose RNA expression correlates with cognitive decline, the potential alteration of SHIP2 expression and localization during the progression of AD remains largely unknown. Here we report that gene expression of both EGFR and INPPL1 was upregulated in AD brains. SHIP2 immunoreactivity was predominantly detected in plaque-associated astrocytes and dystrophic neurites and its increase was correlated with amyloid load in the brain of human AD and of 5xFAD transgenic mouse model of AD. While mRNA of INPPL1 was increased in AD, SHIP2 protein undergoes a significant solubility change being depleted from the soluble fraction of AD brain homogenates and co-enriched with EGFR in the insoluble fraction. Using FRET-based flow cytometry biosensor assay for tau-tau interaction, overexpression of SHIP2 significantly increased the FRET signal while siRNA-mediated downexpression of SHIP2 significantly decreased FRET signal. Genetic association analyses suggest that some variants in INPPL1 locus are associated with the level of CSF pTau. Our data support the hypothesis that SHIP2 is an intermediate key player of EGFR and AD pathology linking amyloid and tau pathologies in human AD.

Predictive and Prognostic Value of Plasma Zonulin for Gestational Diabetes Mellitus in Women at 24-28 Weeks of Gestation.

OBJECTIVE: We aimed to examine the predictive and prognostic value of plasma zonulin for gestational diabetes mellitus (GDM) in women at 24-28 weeks of gestation. METHODS: This retrospective study was carried out with pregnant women with GDM (n=98) and normal glucose tolerance (control group) (n=132). GDM was diagnosed according to American Diabetes Association (ADA) criteria with a one-step 75-g OGTT at 24-28 gestational weeks. Their serum zonulin levels measured during one-step 75-g OGTT and perinatal outcomes were compared, and the cut-off value of plasma zonulin for the prediction of GDM was calculated with receiver operating characteristic curve analysis. RESULTS: Plasma zonulin level was significantly higher in women with GDM compared to controls (28.8±24.9 and 7.3±11.3 ng/mL, respectively). According to logistic regression analysis, plasma zonulin levels and GDM were statistically significant. The plasma zonulin cut-off value was>45.2 ng/mL. The rate of cesarean section, the rate of meconium in the amniotic fluid, and the need for admission to the neonatal intensive care unit significantly differed between women with GDM and controls. CONCLUSION: In pregnant women with GDM, plasma zonulin increases, and with the cut-off level of>45.2 ng/mL, it can predict GDM with values of sensitivity and specificity levels significantly higher in pregnant women with GDM, suggesting that it can be used as a tool for its screening and early diagnosis.

Picalm reduction exacerbates tau pathology in a murine tauopathy model.

Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer's disease (AD) after APOE and BIN1. PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubule-associated protein tau (MAPT) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau-MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPicalm+/- by crossing Tg30 tau transgenic mice with Picalm-haploinsufficient mice to test whether Picalm reduction may modulate tau pathology. While Picalm haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPicalm+/- mice developed markedly more severe motor deficits than Tg30 by the age of 9 months. Tg30xPicalm+/- had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that Picalm haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and tau-mediated neurodegeneration, supporting a role for changes in Picalm expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.

Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model.

Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampal neurogenesis we analyzed adult neurogenesis in the hippocampal dentate gyrus in wild-type mice, Tg30 mice expressing a FTDP-17 mutant tau and the same Tg30 mice deficient for mouse tau (Tg30/tauKO). The volume of the granular layer, the number of granule cells and of neuronal precursors expressing the immature markers DCX or 3R-tau were analyzed in the dentate gyrus (DG) using unbiased stereological methods. The co-localization of neurogenic markers with the human mutant tau was also analyzed. We observed a significant reduction of the volume of the granular layer and of granule cells number in mutant tau Tg30 mice, but not in Tg30/tauKO mice. The number of neuronal precursors expressing the immature markers DCX or 3R-tau (the latter only expressed in wild-type and Tg30 mice) and the number of cells expressing the proliferation marker Ki-67 in the neurogenic subgranular zone of the DG was reduced in Tg30 but not in Tg30/tauKO mice. The density of phosphotau positive cells in the DG and the level of soluble human phosphotau was lower in Tg30/tauKO compared to Tg30 mice. The human mutant tau was expressed in mature granule cells in Tg30 and Tg30/tauKO mice but was not expressed in Sox2 positive neural stem cells and in DCX positive neuronal precursors/immature newborn neurons. These results demonstrate an impairment of adult hippocampal neurogenesis in a FTDP-17 mutant tau mice resulting from a decrease of proliferation affecting the pool of neuronal precursors. The mutant tau was not expressed in precursors cells in these mutant tau mice, suggesting that this neurogenic defect is cell non-autonomous. Interestingly, expression of endogenous wild-type tau in mature granule cells was necessary to observe this toxic effect of human mutant tau, since this impaired adult neurogenesis was rescued by lowering tau expression in Tg30/tauKO mice. These observations suggest that development of tau pathology in granule cells of the dentate gyrus is responsible for reduction of adult hippocampal neurogenesis also in human tauopathies by impairing proliferation of neuronal precursors, and that reduction of tau expression might be an approach to rescue this impairment.

Amyloid-ß pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo.

Neuropathological analysis in Alzheimer's disease (AD) and experimental evidence in transgenic models overexpressing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutant tau suggest that amyloid-ß pathology enhances the development of tau pathology. In this work, we analyzed this interaction independently of the overexpression of an FTDP-17 mutant tau, by analyzing tau pathology in wild-type (WT), 5xFAD, APP-/- and tau-/- mice after stereotaxic injection in the somatosensory cortex of short-length native human AD-PHF. Gallyas and phosphotau-positive tau inclusions developed in WT, 5xFAD, and APP-/- but not in tau-/- mice. Ultrastructural analysis demonstrated their intracellular localization and that they were composed of straight filaments. These seeded tau inclusions were composed only of endogenous murine tau exhibiting a tau antigenic profile similar to tau aggregates in AD. Insoluble tau level was higher and ipsilateral anteroposterior and contralateral cortical spreading of tau inclusions was more important in AD-PHF-injected 5xFAD mice than in WT mice. The formation of large plaque-associated dystrophic neurites positive for oligomeric and phosphotau was observed in 5xFAD mice injected with AD-PHF but never in control-injected or in non-injected 5xFAD mice. An increased level of the p25 activator of CDK5 kinase was found in AD-PHF-injected 5xFAD mice. These data demonstrate in vivo that the presence of Aß pathology enhances experimentally induced tau seeding of endogenous, wild-type tau expressed at physiological level, and demonstrate the fibrillar nature of heterotopically seeded endogenous tau. These observations further support the hypothesis that Aß enhances tau pathology development in AD through increased pathological tau spreading.

Structural analysis and biological functionalities of iron(III)- and manganese(III)-thiosemicarbazone complexes: in vitro anti-proliferative activity on human cancer cells, DNA binding and cleavage studies.

One iron(III) and two manganese(III) complexes based on thiosemicarbazone were synthesized and characterized using analytical and spectroscopic data. The crystallographic analysis showed the square pyramid structures of the complexes. Electronic spectra analysis was performed to determine the nature of the interaction between the complexes and calf thymus DNA (CT-DNA). DNA cleavage activities of the complexes were examined by gel electrophoresis (pBR322 DNA). The cytotoxicity of the complexes was determined against human cervical carcinoma (HeLa) and human colorectal adenocarcinoma (HT-29) cell lines by MTT assay. The results indicated that complex Fe1 is bound to CT-DNA via the intercalation mode, while complexes Mn1 and Mn2 are bound to CT-DNA via groove binding and/or electrostatic interactions rather than the intercalation mode. In addition, they showed good binding activity, which followed the order of Fe1 > Mn2 > Mn1. Complexes were found to promote the cleavage of DNA from supercoiled form (SC, Form I) to nicked circular form (NC, Form II) without concurrent formation of Form III, revealing the single-strand DNA cleavage. No significant cleavage was found in the presence of Mn1 and Mn2; however, it was observed at 2000 and 3000 µM concentrations of Fe1. The ability of Fe1 to cleave DNA was greater than that of other complexes and these results are in conformity with their DNA-binding affinities. Cytotoxicity determination tests revealed that the complex Fe1 on HeLa and HT-29 cells exhibited a higher anti-proliferative effect than Mn1 and Mn2 (Fe1 > Mn2 > Mn1). These studies suggested that the complex Fe1 could be a good candidate as a chemotherapeutic drug targeting DNA.

Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology.

Abeta deposits and tau pathology were investigated in 24 French patients that died from iatrogenic Creutzfeldt-Jakob disease after exposure to cadaver-derived human growth hormone (c-hGH) in the 1980s. Abeta deposits were found only in one case that had experienced one of the longest incubation periods. Three cases had also intracellular tau accumulation. The analysis of 24 batches of c-hGH, produced between 1974 and 1988, demonstrated for the first time the presence of Abeta and tau contaminants in c-hGH (in 17 and 6 batches, respectively). The incubation of prion disease was shorter in the French patients than the incubation times reported in two previously published British series. We interpreted the low incidence of Abeta in this French series as a consequence of the shorter incubation period observed in France, as compared to that observed in the United Kingdom. This concept suggested that a mean incubation period for the development of detectable Abeta deposits would be longer than 18 years after the first exposure. Moreover, we hypothesized that tau pathology might also be transmissible in humans.

Low serum vitamin D level is associated with intrahepatic cholestasis of pregnancy.

AIM: Intrahepatic cholestasis of pregnancy (ICP) is a unique hepatic disorder of pregnancy and is related to adverse maternal and perinatal outcomes. The pathogenesis of the disease is not clear and appears to be multifactorial. There is increasing evidence that vitamin D (Vit D) plays a role in hepatobiliary homeostasis and in various liver diseases. We aimed to investigate the association between serum Vit D level and ICP. METHODS: A total of 40 pregnant women with ICP and 40 healthy pregnant women were included in this controlled cross-sectional study. Their demographic characteristics, including age, body mass index (BMI), gestational week, gravidity and parity, and laboratory parameters, including 25(OH) Vit D3 levels, liver function tests, fasting and postprandial bile acid concentrations, were recorded. Gestational age at delivery, birth weight (BW), neonatal intensive care unit (NICU) admission, meconium staining of amniotic fluid and appearance pulse grimace activity respiration (APGAR) score at 5 min were obtained from medical records for assessment of perinatal outcomes. RESULTS: There was no significant difference between groups in terms of demographic characteristics. The mean serum 25(OH) Vit D3 level was significantly lower in pregnant women with ICP compared to control pregnant women (8.6 ± 4.9, 11.3 ± 6.1; P =0.033), and it was significantly lower in severe disease than mild disease (6.9 ± 2.1, 10.3 ± 6.2, respectively; P =0.029). We also found that lower serum 25(OH) Vit D3 levels were significantly and inversely correlated with fasting and postprandial bile acid levels. However, in subgroup analyses in ICP pregnant women, there was no difference in mean 25(OH) Vit D3 levels for women with or without perinatal complications. CONCLUSION: Our study suggests that low levels of 25(OH) Vit D3 were associated with ICP disease and its severity. However, further larger studies are needed to evaluate the effect of Vit D in the pathogenesis and outcome of the disease.

High-Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo.

In Alzheimer disease, the development of tau pathology follows neuroanatomically connected pathways, suggesting that abnormal tau species might recruit normal tau by passage from cell to cell. Herein, we analyzed the effect of stereotaxic brain injection of human Alzheimer high-molecular-weight paired helical filaments (PHFs) in the dentate gyrus of wild-type and mutant tau THY-Tau22 mice. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus and a tau pathology characterized by Gallyas and tau-positive grain-like inclusions into granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria. Gallyas-positive neuropil threads and oligodendroglial coiled bodies were also observed. These tau inclusions were composed only of mouse tau, and were immunoreactive with antibodies to 4R tau, phosphotau, misfolded tau, ubiquitin, and p62. Although local hyperphosphorylation of tau was increased in the dentate gyrus in THY-Tau22 mice, the development of neurofibrillary tangles made of mutant human tau was not accelerated in the hippocampus, indicating that wild-type human PHFs were inefficient in seeding tau aggregates made of G272V/P301S mutant human tau. Our results indicate thus that injection of human wild-type Alzheimer PHF seeded aggregation of wild-type murine tau into an argyrophilic 4R tau pathology, and constitutes an interesting model independent of expression of a mutant tau protein.

Influence of Behçet's disease on first and second trimester serum screening markers.

AIM: Behçet's disease (BD) is a rare and multisystemic vasculitis disease. In this study, we investigated whether BD had any effect on the biochemical components of first and second trimester aneuploidy screening tests. METHODS: A case-control retrospective study was conducted with 32 pregnant women with BD and 60 healthy pregnant women as controls. All pregnant womens' first trimester maternal serum pregnancy-associated plasma protein-A, free ß-human chorionic gonadotropin and second trimester serum alpha-fetoprotein, unconjugated estriol and total human chorionic gonadotropin levels were examined from medical records. First and second serum screening markers were compared between pregnancies with BD and without. RESULTS: There was no difference in age, body mass index and obstetric history between the groups. No significant difference was observed between the groups in terms of first and second trimester serum screening test results in the absence of aneuploidy or neural tube defect. Gestational age at birth, birth weight and neonatal intensive care admission rate were also similar between the groups. CONCLUSION: Both first and second serum screening tests for Down syndrome may be recommended to pregnant women with BD without the need to readjust these markers. Pregnancy with BD was not associated with adverse perinatal outcome with respect to gestational age at birth or birth weight.

A Survey of the Opinion and Experience of UK Dentists: Part 2: Risk Assessment Strategies and the Management of Iatrogenic Trigeminal Nerve Injuries Related to Dental Implant Surgery.

BACKGROUND: Dental implant-related iatrogenic injuries are proportionally increasing with dental implant surgery. This study assessed the experience of implant-related trigeminal nerve (TG) injuries among UK dentists. Risk management strategies and management of implant-related inferior alveolar nerve (IAN), mental nerve (MN), and lingual nerve injuries were investigated. METHODS: A survey was distributed among 405 dentists attending an Association of Dental Implantology (ADI) congress, of which 187 completed the survey. RESULTS: Most dentists (76% of 134 responses) allowed a 2 to 4 mm safety zone radiologically above the IAN when placing implants, and over half of the responders (56%) used implants that were 10 mm in length. The most frequent precautionary measure used by 73 (80%) responders was antibiotic coverage routinely to reduce the risk of infection when placing grafts in the posterior mandible. Other precautionary measures included unilateral staging of implant placement (57%), and 43% always identified the MN when placing implants. Nineteen dentists used steroids (eg, dexamethasone) routinely preoperatively and postoperatively. Twenty-six dentists used basic cone-beam CT (CBCT) minimally invasive techniques, and drill stops during implant placement were used by 14 responders. Although it is not highly recommended, steroids were used to manage the neuropathic pain and discomfort experienced by patients with IAN injuries in 40% of cases. CONCLUSION: Further training of dentists undertaking implant surgery is required so that they acquire up-to-date and evidence-based knowledge and skills in the prevention, diagnosis, and management of dental implant-related TG injuries. This training should also involve the justification and interpretation of CBCTs.

A Survey of the Opinion and Experience of UK Dentists Part 3: An Evidence-Based Protocol of Surgical Risk Management Strategies in the Mandible.

BACKGROUND: Implant surgery in the mandible can cause serious complications that can be life threatening. The incidence and cause of iatrogenic trigeminal nerve injury (TNI) related to dental implant surgery was investigated in a survey of the opinion and experience of the UK dentists and reported by the authors in part 1 of this series of articles. Part 2 reported on the risk assessment and management of implant-related inferior alveolar nerve (IAN), mental nerve (MN), and lingual nerve (LN) injuries. This article evaluates the significance of these findings and recommends an evidence-based protocol of risk management strategies to reduce the risk of TNI related to dental implant surgery. METHODS: A survey was distributed among 405 dentists attending an Association of Dental Implantology (ADI) congress, of which 187 completed the survey. RESULTS: In this study, the strategies to manage the risk of TNI included unilateral staging of implant placement (57%) and identification the MN when placing implants (43%). Twelve percent used drill stops when operating in the mandible. Nineteen dentists used steroids (eg, dexamethasone) routinely preoperatively and postoperatively. Twenty-six dentists used basic cone beam computed tomography minimally invasive techniques, and 70% encountered a large anterior loop of the IAN. Most dentists (76%) allowed a 2- to 4-mm safety zone radiologically above the IAN when placing implants, and over half of the responders (56%) used implants that were 10 mm in length. CONCLUSION: Given the elective nature of implant surgery, TNI should be fully avoidable. The evidence suggest that TNI can be minimized with meticulous attention to accurate assessment and surgical planning as well as carrying out the surgery with a high degree of precision. In part 3 of their series of articles, the authors presented an evidence-based protocol that comprises preoperative, intraoperative, and postoperative risk management strategies for dental implant surgical procedures in the mandible.

Impact of body mass index, waist circumference and Pfannenstiel sitetissue thickness, and elastosonography on operative parameters

Background/aim: This study aimed to evaluate the impact of body fat distribution measured by body mass index (BMI), waist circumference (WC) and Pfannenstiel incision site tissue thickness, and elastosonography on bleeding and operation time during cesarean delivery.Materials and methods: A prospective study was made of 52 healthy, term pregnant women with prior cesarean deliveries. The impact of BMI, WC, incision site thickness, and elastosonography on preoperative and postoperative differences in hemoglobin (Hb) and hematocrit (Htc) levels and operation times was evaluated.Results: A moderate negative relationship was found between Htc levels and WC. Htc levels were found to decrease by 0.148 units for each 1-cm increase in WC. Skin-to-fascia time was found to increase by 0.697 s with each 1-unit increase in BMI, whereas fascia-to-uterus time was found to increase by 1.117 s with each 1-cm increase in Pfannenstiel site tissue thickness. None of the elastosonographies or differences in Hb levels were found to be significant for any parameter.Conclusion: Each of the evaluated parameters was found to have an impact on different factors: WC on Htc levels, BMI on skin-to-fascia time, and Pfannenstiel tissue thickness on fascia-to-uterus time.

Elevated red blood cell distribution width is associated with intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy is the most common pregnancy specific liver disease and related with adverse maternal and perinatal outcome. Red blood cell distribution width, an anisocytosis marker in a complete blood count, has been used as an inflammation marker in various diseases. However the association of red blood cell distribution width with intrahepatic cholestasis of pregnancy is unknown. We aimed to evaluate the relationship between red blood cell distribution width and intrahepatic cholestasis of pregnancy. MATERIAL AND METHODS: Ninety pregnant women with intrahepatic cholestasis of pregnancy and ninety healthy pregnant women were included in the study. Their clinical and laboratory characteristics including red blood cell distribution width, liver function tests, fasting and postprandial bile acid concentrations were analyzed. RESULTS: Serum red blood cell distribution width cell levels were significantly higher in pregnants with intrahepatic cholestasis of pregnancy than healthy pregnants. We also demonstrated that red blood cell distribution Width levels were higher in severe disease than mild disease and was significantly correlated with fasting and postprandial bile acid concentration in intrahepatic cholestasis of pregnancy group. CONCLUSIONS: Our study showed that red blood cell distribution width, an easy and inexpensive marker; were associated with intrahepatic cholestasis of pregnancy and can be used as a diagnostic and prognostic marker in intrahepatic cholestasis of pregnancy.

Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease.

Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.

Motor deficit in a tauopathy model is induced by disturbances of axonal transport leading to dying-back degeneration and denervation of neuromuscular junctions.

Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases.

A Survey of the Opinion and Experience of UK Dentists: Part 1: The Incidence and Cause of Iatrogenic Trigeminal Nerve Injuries Related to Dental Implant Surgery.

BACKGROUND: Dental implant-related iatrogenic trigeminal nerve (TG) injuries are proportionally increasing with dental implant surgery. This study, which is presented in greater detail over a series of articles, assessed the experience of implant-related TG nerve injuries among UK dentists. Incidence and cause of inferior alveolar nerve (IAN), mental nerve (MN), and lingual nerve (LN) injuries, together with preoperative assessment and the consent process, are presented in this article. METHODS: A survey was distributed among 405 dentists attending an Association of Dental Implantology congress in the United Kingdom, of which 187 completed the survey. RESULTS: Most responding dentists were full-time general practitioners. Implant dentistry training was predominately through industry-organized courses. Eighty dentists encountered implant-related IAN injuries, whereas 8 encountered LN injuries. Inaccurate radiological identification of the IAN/MN and their anatomical variations (48%) were seen to be the most frequent cause of TG injuries. Disclosure of the relative risk and benefits of alternative implant treatment strategies as part of the informed consent process was not deemed to be essential by 47 (25%) of the participants. CONCLUSION: Inadequate radiological assessment was the most common cause of TG nerve injury. The use of small field of view cone beam computer tomography (CBCT) is therefore recommended when placing implants in the posterior mandible. Implant surgeons should acquire evidence-based skills in the prevention, diagnosis, and management of TG nerve injury as well as specific training on justification and interpretation of CBCT scans.

Effects of melatonin on the serum levels of pro-inflammatory cytokines and tissue injury after renal ischemia reperfusion in rats.

We investigated the changes in the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6, the pro-inflammatory cytokines, and the possible effect of melatonin on the modulation of these inflammatory molecules after renal ischemia reperfusion (IR). The study was carried out in the laboratory of Department of Pharmacology. Forty-six male Wistar albino rats were divided into five groups as control (n=6), positive control (n=4), sham (n=12), renal IR (n=12), and renal IR melatonin (n=12). After 1 h renal pedicle occlusion, the blood samples were taken for the measurement of cytokine levels at second hour of the reperfusion. The rats were sacrificed after 24 h of reperfusion for histopathological evaluation. Melatonin or vehicle was administrated to IR rats. Lipopolysaccharide (LPS) was administered to the positive control group and the blood was taken at fourth hour. Serum TNF-α levels increased significantly in renal IR and LPS groups. Serum IL-6 levels were not different from control except the LPS group. There was no significant correlation between the serum TNF-α levels and the histopathological score after renal IR. Melatonin treatment reversed the increase of serum TNF-α levels and histopathological injury in renal tissue after renal IR. Melatonin may have a protective effect by reducing the serum level of TNF-α in renal IR.

Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice.

Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Aß pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in a new transgenic mouse model combining APP, PS1 and tau mutations (5xFAD×Tg30 mice) by comparison with littermates expressing only a FTD mutant tau (Tg30 mice). These 5xFAD×Tg30 mice showed a more severe deficient motor phenotype than Tg30 mice and developed with age a dramatically accelerated NFT load in the brain compared to Tg30 mice. Insoluble tau in 5xFAD×Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and truncation changes mimicking more closely the post-translational changes characteristic of PHF-tau in Alzheimer's disease. Endogenous wild-type mouse tau was recruited at much higher levels in insoluble tau in 5xFAD×Tg30 than in Tg30 mice. Extracellular amyloid load, Aß40 and Aß42, ß-CTFs and ß-CTF phosphorylation levels were lower in 5xFAD×Tg30 mice than in 5xFAD mice. Despite this reduction of Aß, a significant hippocampal neuronal loss was observed in 5xFAD×Tg30 but not in 5xFAD mice indicating its closer association with increased tau pathology. This 5xFAD×Tg30 model thus mimics more faithfully tau pathology and neuronal loss observed in AD and suggests that additional post-translational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in the presence of Aß pathology.

The effect of intrahepatic cholestasis of pregnancy and ursodeoxycholic acid treatment on Doppler parameters of fetal and maternal circulation.

OBJECTIVES: We aimed to evaluate feto-maternal blood flow parameters using Doppler ultrasonography (USG) in pregnant women with intrahepatic cholestasis of pregnancy (ICP) and the effect of ursodeoxycholic acid (UDCA) treatment on these parameters. MATERIAL AND METHODS: This prospective cohort study was performed at Dr. Sami Ulus Women's and Children's Health Teaching and Research Hospital, in Turkey between September 2022 and February 2023. Sixty pregnant women, 30 with ICP disease and 30 healthy women were included in the study. Obstetric Doppler parameters were measured by USG at diagnosis and after 48 hours of UDCA treatment for the ICP group. RESULTS: The obstetric Doppler parameters did not significantly differ in the ICP group and the healthy control group. The Doppler findings were similar after UDCA treatment in the ICP group. Gestational week at delivery and birth weight were lower in the ICP group in our study. CONCLUSIONS: We demonstrated that pregnant women with ICP had similar obstetric Doppler parameters when compared with healthy pregnant women and that the UDCA agent used for treatment of ICP disease did not affect these parameters.