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Editor's note. This appeared at Secular Pro-Life and is reposted with permission. The way I see it, there are three keys to fetal pain: 1. The IASP's revised definition of [...]

The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(−/−) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(−/−) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(−/−) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(−/−) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(−/−) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.

Members of the Shank protein family are master scaffolds of the postsynaptic architecture and mutations within the SHANK genes are causally associated with autism spectrum disorders (ASDs). We generated a Shank2-Shank3 double knockout mouse that is showing severe autism related core symptoms, as well as a broad spectrum of comorbidities. We exploited this animal model to identify cortical brain areas linked to specific autistic traits by locally deleting Shank2 and Shank3 simultaneously. Our screening of 10 cortical subregions revealed that a Shank2/3 deletion within the retrosplenial area severely impairs social memory, a core symptom of ASD. Notably, DREADD-mediated neuronal activation could rescue the social impairment triggered by Shank2/3 depletion. Data indicate that the retrosplenial area has to be added to the list of defined brain regions that contribute to the spectrum of behavioural alterations seen in ASDs.

Background: Dominant-activating mutations in the RET protooncogene, a receptor tyrosine kinase, have been identified as a cause of medullary thyroid carcinoma. Such oncogenic RET mutations induce its ligand-independent constitutive trans-autophosphorylation. We investigated the role of endogenous oncogenic RET autophosphorylation in maintaining the neoplastic phenotype in medullary thyroid carcinoma cells and orthotopic medullary thyroid carcinomas in RET transgenic mice. Methods: We constructed adenoviral vectors expressing a dominant-negative truncated form of RET, termed RE[T.sup.[DELTA]TK], and analyzed its effect on cell viability, apoptosis, and proliferation of TT medullary thyroid carcinoma cells. We investigated the effect of RE[T.sup.[DELTA]TK] on downsteam signaling by assessing alterations in phosphorylation or in gene expression. The effect of RE[T.sup.[DELTA]TK] in primary medullary thyroid carcinomas in transgenic mice was assessed by monitoring tumor growth. All statistical tests were two-sided. Results: Cell viability was reduced. Phosphorylation of Akt and extracellular signal-regulated kinase (ERK), components of downstream signal transduction pathways, was abolished, and cell cycle progression was reduced. Expression of cell cycle regulator cyclin D1 was decreased, and expression of cell cyle regulators [p21.sup.CIP1/WAF1] and [p27.sup.KIP1] was increased. Apoptosis was stimulated and concurrently the expression of BCL-2 was decreased. All in vitro experiments compared TT cells expressing RE[T.sup.[DELTA]TK] with untreated control cells or control vector-treated cells. Furthermore, 2 weeks after injecting adenovirus-carrying RE[T.sup.[DELTA]TK] into thyroid glands of transgenic mice with orthotopic medullary thyroid carcinoma, tumors were statistically significantly smaller than their initial size in mice treated with RE[T.sup.[DELTA]TK] (43.6%, 95% confidence interval [CI] = 30.7% to 56.5% ; P = .010; two-sided unpaired Student's t test), whereas tumors in mice treated with a control vector were larger than their initial size (139.8%, 95% CI = 120.3% to 159.3%; P

This study aimed to determine the relative contribution of genetic and environmental factors in the phenotypic variation of the palate in the primary dentition stage.

German lime and cement producer Marker Kalkwerk GmbH has developed a new lime quarry to feed its existing plant. The new reserves are aimed at meeting demand of around 600,000 t/y for the lime plant and some 1 million t/y for the cement facility. Development of the new quarry required meeting local and national planning regulations. The plants began production at the start of 1996 and some 100,000 t/y of limestone was crushed during the last quarter of the year.

Dynamic horizontal instability is considered to be the main reason for poor outcome after treatment for acromioclavicular (AC) joint instability. In this study, we describe a simple technique to quantify this pathology via sonography. Thirty‐six shoulders from 18 patients with ac joint instabilities were examined using modified Alexander views and a standardized sonographic examination. On the Alexander views, overlap of acromion and clavicle (OLAC), glenoid center to posterior clavicle distance (GCPC), and lateral extension (LE) were measured. Afterwards, the results were analyzed and compared with sonography. Posterior translation of the clavicle and the difference of translation between healthy and injured shoulder were evaluated. The mean age of the patients was 39 ± 14 years (range 19–61 years). We included 4 (22%) Rockwood type 3, 1 (6%) Rockwood type 4, and 13 (72%) Rockwood type 5 lesions. Four (22%) patients were female and 14 (78%) male patients. Posterior clavicle translation of the injured shoulder correlated strongly between OLAC and sonography (r= −0.514, P= .029), and the difference of translation between healthy and injured shoulder correlated very strongly between LE and sonography (r= 0.737, P< .001). The sonographic measurement technique for horizontal instability presented in this work could help detect horizontal instabilities. While the observation of dynamic horizontal displacement is a strength of this technique, measurements are hindered in cases of high coracoclavicular distances. Level III—retrospective cohort study. Access the CME test hereand search by article title.

We examined the effect of the pattern of body-fat distribution on the modification of atherogenic risk factors in obese adolescent girls during weight reduction. During the 6-wk program, which included a mixed diet of 4321 kJ/d and intensive physical exercise, the girls lost 8.5 [+ or -] 2.4 kg and their waist-to-hip ratio (WHR) decreased from 0.86 [+ or -] 0.05 to 0.81 [+ or -] 0.05 (P < 0.01). Significant reductions were observed for total cholesterol, LDL cholesterol, uric acid, fasting insulin, and systolic and diastolic blood pressure. Girls with abdominal obesity (WHR > 0.88) had greater reductions in serum cholesterol, LDL cholesterol, and uric acid than did girls with gluteal-femoral obesity (WHR < 0.81). In a multivariate-regression analysis these differences could be partly explained by the greater weight loss of the girls with abdominal obesity. These results suggest that during weight reduction girls with abdominal obesity exhibit more beneficial changes in the atherogenic-risk-factor profile than do girls with gluteal-femoral obesity, partly because of a greater weight loss.

Older patients with severe physical trauma are at high risk of developing neuropsychiatric syndromes with global impairment of cognition, attention, and consciousness. We employed a thoracic trauma (TxT) mouse model and thoroughly analyzed age-dependent spatial and temporal posttraumatic alterations in the central nervous system. Up to 5 days after trauma, we observed a transient 50% decrease in the number of excitatory synapses specifically in hippocampal pyramidal neurons accompanied by alterations in attention and motor activity and disruption of contextual memory consolidation. In parallel, hippocampal corticotropin-releasing hormone (CRH) expression was highly upregulated, and brain-derived neurotrophic factor (BDNF) levels were significantly reduced. In vitro experiments revealed that CRH application induced neuronal autophagy with rapid lysosomal degradation of BDNF via the NF-κB pathway. The subsequent synaptic loss was rescued by BDNF as well as by specific NF-κB and CRH receptor 1 (CRHR1) antagonists. In vivo, the chronic application of a CRHR1 antagonist after TxT resulted in reversal of the observed histological, molecular, and behavioral alterations. The data suggest that neuropsychiatric syndromes (i.e., delirium) after peripheral trauma might be at least in part due to the activation of the hippocampal CRH/NF-κB/BDNF pathway, which results in a dramatic loss of synaptic contacts. The successful rescue by stress hormone receptor antagonists should encourage clinical trials focusing on trauma-induced delirium and/or other posttraumatic syndromes.

Hintergrund: Instabilitäten des Akromioklavikular- (AC-)Gelenks sind nach wie vor eine große Herausforderung. Wachsende Aufmerksamkeit richtet sich auf die dynamische horizontale AC-Gelenkinstabilität. Die Detektierung derselben ist anspruchsvoll und bedient sich einer Mehrzahl von Messmethoden. Zunehmend stehen auch spezielle Techniken zur additiven Stabilisierung des AC-Kapsel-Band-Apparats zur Verfügung. Ziel: Ziel der nun vorliegenden Arbeit ist es, eine Zusammenfassung des derzeitigen Wissensstands über die horizontale Instabilität des AC-Gelenks zu geben.

Fetal pain has long been a contentious issue, in large part because fetal pain is often cited as a reason to restrict access to termination of pregnancy or abortion. We have divergent views regarding the morality of abortion, but have come together to address the evidence for fetal pain. Most reports on the possibility of fetal pain have focused on developmental neuroscience. Reports often suggest that the cortex and intact thalamocortical tracts are necessary for pain experience. Given that the cortex only becomes functional and the tracts only develop after 24 weeks, many reports rule out fetal pain until the final trimester. Here, more recent evidence calling into question the necessity of the cortex for pain and demonstrating functional thalamic connectivity into the subplate is used to argue that the neuroscience cannot definitively rule out fetal pain before 24 weeks. We consider the possibility that the mere experience of pain, without the capacity for self reflection, is morally significant. We believe that fetal pain does not have to be equivalent to a mature adult human experience to matter morally, and so fetal pain might be considered as part of a humane approach to abortion.