The differences in the anatomy of the thoracolumbar and sacral autonomic outflow are quantitative.

PURPOSE: We have re-evaluated the anatomical arguments that underlie the division of the spinal visceral outflow into sympathetic and parasympathetic divisions. METHODOLOGY: Using a systematic literature search, we mapped the location of catecholaminergic neurons throughout the mammalian peripheral nervous system. Subsequently, a narrative method was employed to characterize segment-dependent differences in the location of preganglionic cell bodies and the composition of white and gray rami communicantes. RESULTS AND CONCLUSION: One hundred seventy studies were included in the systematic review, providing information on 389 anatomical structures. Catecholaminergic nerve fibers are present in most spinal and all cranial nerves and ganglia, including those that are known for their parasympathetic function. Along the entire spinal autonomic outflow pathways, proximal and distal catecholaminergic cell bodies are common in the head, thoracic, and abdominal and pelvic region, which invalidates the "short-versus-long preganglionic neuron" argument. Contrary to the classically confined outflow levels T1-L2 and S2-S4, preganglionic neurons have been found in the resulting lumbar gap. Preganglionic cell bodies that are located in the intermediolateral zone of the thoracolumbar spinal cord gradually nest more ventrally within the ventral motor nuclei at the lumbar and sacral levels, and their fibers bypass the white ramus communicans and sympathetic trunk to emerge directly from the spinal roots. Bypassing the sympathetic trunk, therefore, is not exclusive for the sacral outflow. We conclude that the autonomic outflow displays a conserved architecture along the entire spinal axis, and that the perceived differences in the anatomy of the autonomic thoracolumbar and sacral outflow are quantitative.

Human Cardiac Development.

Many aspects of heart development are topographically complex and require three-dimensional (3D) reconstruction to understand the pertinent morphology. We have recently completed a comprehensive primer of human cardiac development that is based on firsthand segmentation of structures of interest in histological sections. We visualized the hearts of 12 human embryos between their first appearance at 3.5 weeks and the end of the embryonic period at 8 weeks. The models were presented as calibrated, interactive, 3D portable document format (PDF) files. We used them to describe the appearance and the subsequent remodeling of around 70 different structures incrementally for each of the reconstructed stages. In this chapter, we begin our account by describing the formation of the single heart tube, which occurs at the end of the fourth week subsequent to conception. We describe its looping in the fifth week, the formation of the cardiac compartments in the sixth week, and, finally, the septation of these compartments into the physically separated left- and right-sided circulations in the seventh and eighth weeks. The phases are successive, albeit partially overlapping. Thus, the basic cardiac layout is established between 26 and 32 days after fertilization and is described as Carnegie stages (CSs) 9 through 14, with development in the outlet component trailing that in the inlet parts. Septation at the venous pole is completed at CS17, equivalent to almost 6 weeks of development. During Carnegie stages 17 and 18, in the seventh week, the outflow tract and arterial pole undergo major remodeling, including incorporation of the proximal portion of the outflow tract into the ventricles and transfer of the spiraling course of the subaortic and subpulmonary channels to the intrapericardial arterial trunks. Remodeling of the interventricular foramen, with its eventual closure, is complete at CS20, which occurs at the end of the seventh week. We provide quantitative correlations between the age of human and mouse embryos as well as the Carnegie stages of development. We have also set our descriptions in the context of variations in the timing of developmental features.

Effect of a multi-domain intervention on the quality of life in older adults with major neurocognitive disorder: A pilot study.

PURPOSE: Major neurocognitive disorders (MND) have multiple negative consequences on patients' lives and on their caregivers' health. Occupational therapy and cognitive stimulation have failed to show any significant efficacy on quality of life (QoL), cognitive functioning and behavioural symptoms. Bretonneau Hospital's Day Care Unit offers personalized and structured multi-domain interventions to cognitively impaired older patients on a weekly basis, for a 3-month period. OBJECTIVES: Our objective was to determine whether a specific rehabilitation day care unit (RDCU) could influence the QoL of cognitively impaired community-dwelling elderly patients. We also aimed to better understand the characteristics of patients who had the most benefited from the RDCU. METHODS: Retrospective study based on a sample of outpatients participating in RDCU during three months. All patients underwent a cognitive (MMS), functional (IADl, ADL) and behavioral (NPI) assessment. We compared QoL using the QoL-Alzheimer's Disease (QoL-AD) scale before and after RDCU. RESULTS: Overall, we included 60 outpatients in our study (mean age 83.3±5.8; women=70%). We found a statistically significant improvement of QoL-AD scores after RDCU (31.8±4.9 to 32.9±5.2, P=0.008). Patients who benefitted the most from RDCU were older (P=0.01) and had lower baseline QoL (P=0.04). We did not find any other characteristics associated with QoL-AD score improvement in our population. CONCLUSION: RDCU showed positive effects on QoL in this uncontrolled pilot study of older adults with MND. These findings should be confirmed in a future randomized controlled trial to corroborate the potential benefits of RDCU on QoL in older cognitively impaired patients.

Ethical dilemma for healthcare professionals facing elderly dementia patients during the COVID-19 pandemic.

The management of elderly patients with dementia and COVID-19 infections without access to an intensive care unit gives rise to serious ethical conflicts. Therapeutic decisions have been made in psychogeriatric units, leaving a heavy moral burden on staff. They had to deal with the most difficult patients without the support of appropriate guidelines. The gap between established rules and hospital reality led to psychological distress and burnout. Managing uncertainty in medical decisions is a skill that doctors and staff learn through experience. However, with the COVID-19 pandemic, uncertainty about patient outcomes seems no longer acceptable. Geriatric triage has challenged professional conscience, emotions and values. The principle of distributive justice, which consists of giving each person in society what is rightfully his or hers, is not being respected during this pandemic. Charity has been reduced to patient survival. Staffs need to make decisions together, and it is important to allow all carers access to a space for reflection. In our unit, the involvement of nurses and care assistants in the decision-making process for patient care is crucial especially for refusal of care. Their view of the patient's condition is different from that of the doctors, as they provide daily care to the patient and stay in the wards for several hours with them. By including as many people as possible in the reflection, we could avoid moral or personal prejudices related to these difficult decisions. The current pandemic can give new meaning to team thinking, giving everyone a voice without hierarchical barriers. With these new waves of COVID-19, we need to rethink our therapeutic conduct for elderly patients with dementia to avoid ethical failure.

The development of the dorsal mesentery in human embryos and fetuses.

The vertebrate intestine has a continuous dorsal mesentery between pharynx and anus that facilitates intestinal mobility. Based on width and fate the dorsal mesentery can be subdivided into that of the caudal foregut, midgut, and hindgut. The dorsal mesentery of stomach and duodenum is wide and topographically complex due to strong and asymmetric growth of the stomach. The associated formation of the lesser sac partitions the dorsal mesentery into the right-sided "caval fold" that serves as conduit for the inferior caval vein and the left-sided mesogastrium. The thin dorsal mesentery of the midgut originates between the base of the superior and inferior mesenteric arteries, and follows the transient increase in intestinal growth that results in small-intestinal looping, intestinal herniation and, subsequently, return. The following fixation of a large portion of the abdominal dorsal mesentery to the dorsal peritoneal wall by adhesion and fusion is only seen in primates and is often incomplete. Adhesion and fusion of mesothelial surfaces in the lesser pelvis results in the formation of the "mesorectum". Whether Toldt's and Denonvilliers' "fasciae of fusion" identify the location of the original mesothelial surfaces or, alternatively, represent the effects of postnatal wear and tear due to intestinal motility and intra-abdominal pressure changes, remains to be shown. "Malrotations" are characterized by growth defects of the intestinal loops with an ischemic origin and a narrow mesenteric root due to insufficient adhesion and fusion.

Development of the sympathetic trunks in human embryos.

Although the development of the sympathetic trunks was first described >100 years ago, the topographic aspect of their development has received relatively little attention. We visualised the sympathetic trunks in human embryos of 4.5-10 weeks post-fertilisation, using Amira 3D-reconstruction and Cinema 4D-remodelling software. Scattered, intensely staining neural crest-derived ganglionic cells that soon formed longitudinal columns were first seen laterally to the dorsal aorta in the cervical and upper thoracic regions of Carnegie stage (CS)14 embryos. Nerve fibres extending from the communicating branches with the spinal cord reached the trunks at CS15-16 and became incorporated randomly between ganglionic cells. After CS18, ganglionic cells became organised as irregular agglomerates (ganglia) on a craniocaudally continuous cord of nerve fibres, with dorsally more ganglionic cells and ventrally more fibres. Accordingly, the trunks assumed a "pearls-on-a-string" appearance, but size and distribution of the pearls were markedly heterogeneous. The change in position of the sympathetic trunks from lateral (para-aortic) to dorsolateral (prevertebral or paravertebral) is a criterion to distinguish the "primary" and "secondary" sympathetic trunks. We investigated the position of the trunks at vertebral levels T2, T7, L1 and S1. During CS14, the trunks occupied a para-aortic position, which changed into a prevertebral position in the cervical and upper thoracic regions during CS15, and in the lower thoracic and lumbar regions during CS18 and CS20, respectively. The thoracic sympathetic trunks continued to move further dorsally and attained a paravertebral position at CS23. The sacral trunks retained their para-aortic and prevertebral position, and converged into a single column in front of the coccyx. Based on our present and earlier morphometric measurements and literature data, we argue that differential growth accounts for the regional differences in position of the sympathetic trunks.

Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling.

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1nih ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17ß-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo.

Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting l-arginine metabolism is intriguing, considering this amino acid is the substrate for antimicrobial NO production by macrophages. The importance of l-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor l-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in l-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the l-citrulline-generating (i.e., iNOS) and l-citrulline-using (i.e., Ass1) enzymes in key myeloid populations. Eliminating l-arginine synthesis from l-citrulline in myeloid cells via conditional deletion of either Ass1 or Asl resulted in increased Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis H37Rv burden in the lungs compared with controls. Our data illustrate the necessity of l-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.

Hippocampal subfields revealed through unfolding and unsupervised clustering of laminar and morphological features in 3D BigBrain.

The internal structure of the human hippocampus is challenging to map using histology or neuroimaging due to its complex archicortical folding. Here, we aimed to overcome this challenge using a unique combination of three methods. First, we leveraged a histological dataset with unprecedented 3D coverage, BigBrain. Second, we imposed a computational unfolding framework that respects the topological continuity of hippocampal subfields, which are traditionally defined by laminar composition. Third, we adapted neocortical parcellation techniques to map the hippocampus with respect to not only laminar but also morphological features. Unsupervised clustering of these features revealed subdivisions that closely resemble gold standard manual subfield segmentations. Critically, we also show that morphological features alone are sufficient to derive most hippocampal subfield boundaries. Moreover, some features showed differences within subfields along the hippocampal longitudinal axis. Our findings highlight new characteristics of internal hippocampal structure, and offer new avenues for its characterization with in-vivo neuroimaging.

Extrinsic innervation of the pelvic organs in the lesser pelvis of human embryos.

Realistic models to understand the developmental appearance of the pelvic nervous system in mammals are scarce. We visualized the development of the inferior hypogastric plexus and its preganglionic connections in human embryos at 4-8 weeks post-fertilization, using Amira 3D reconstruction and Cinema 4D-remodelling software. We defined the embryonic lesser pelvis as the pelvic area caudal to both umbilical arteries and containing the hindgut. Neural crest cells (NCCs) appeared dorsolateral to the median sacral artery near vertebra S1 at ~5 weeks and had extended to vertebra S5 1 day later. Once para-arterial, NCCs either formed sympathetic ganglia or continued to migrate ventrally to the pre-arterial region, where they formed large bilateral inferior hypogastric ganglionic cell clusters (IHGCs). Unlike more cranial pre-aortic plexuses, both IHGCs did not merge because the 'pelvic pouch', a temporary caudal extension of the peritoneal cavity, interposed. Although NCCs in the sacral area started to migrate later, they reached their pre-arterial position simultaneously with the NCCs in the thoracolumbar regions. Accordingly, the superior hypogastric nerve, a caudal extension of the lumbar splanchnic nerves along the superior rectal artery, contacted the IHGCs only 1 day later than the lumbar splanchnic nerves contacted the inferior mesenteric ganglion. The superior hypogastric nerve subsequently splits to become the superior hypogastric plexus. The IHGCs had two additional sources of preganglionic innervation, of which the pelvic splanchnic nerves arrived at ~6.5 weeks and the sacral splanchnic nerves only at ~8 weeks. After all preganglionic connections had formed, separate parts of the inferior hypogastric plexus formed at the bladder neck and distal hindgut.

Development of extrinsic innervation in the abdominal intestines of human embryos.

Compared to the intrinsic enteric nervous system (ENS), development of the extrinsic ENS is poorly documented, even though its presence is easily detectable with histological techniques. We visualised its development in human embryos and foetuses of 4-9.5 weeks post-fertilisation using Amira 3D-reconstruction and Cinema 4D-remodelling software. The extrinsic ENS originated from small, basophilic neural crest cells (NCCs) that migrated to the para-aortic region and then continued ventrally to the pre-aortic region, where they formed autonomic pre-aortic plexuses. From here, nerve fibres extended along the ventral abdominal arteries and finally connected to the intrinsic system. Schwann cell precursors (SCPs), a subgroup of NCCs that migrate on nerve fibres, showed region-specific differences in differentiation. SCPs developed into scattered chromaffin cells of the adrenal medulla dorsolateral to the coeliac artery (CA) and into more tightly packed chromaffin cells of the para-aortic bodies ventrolateral to the inferior mesenteric artery (IMA), with reciprocal topographic gradients between both fates. The extrinsic ENS first extended along the CA and then along the superior mesenteric artery (SMA) and IMA 5 days later. Apart from the branch to the caecum, extrinsic nerves did not extend along SMA branches in the herniated parts of the midgut until the gut loops had returned in the abdominal cavity, suggesting a permissive role of the intraperitoneal environment. Accordingly, extrinsic innervation had not yet reached the distal (colonic) loop of the midgut at 9.5 weeks development. Based on intrinsic ENS-dependent architectural remodelling of the gut layers, extrinsic innervation followed intrinsic innervation 3-4 Carnegie stages later.

Iatrogenesis and neurological manifestations in the elderly.

Older people are often exposed to polypharmacy in a multimorbidity context. Inappropriate polypharmacy is often harmful, increasing the risk of inappropriate prescriptions and therefore adverse drug events (ADEs). Five to 20% of all hospital admissions are related to ADE in older people, among which 40 to 70% could be prevented. However, identifying ADEs and drug-related admissions in the elderly is challenging because ADEs often present as common geriatric problems such as falls, delirium, which might be due to the aging process, underlying diseases, and/or medications. In the pharmacovigilance database of the World Health Organization, drug-related neurological manifestations are the third reported cause of ADEs in the elderly, and neurological drugs are the third leading class of medications involved in ADEs. We must therefore be particularly vigilant, both in our prescriptions but also in our diagnoses to avoid prescribing inappropriate treatments and detect ADEs. Even though multiple pharmacologic changes occur in the elderly (absorption, distribution, drug metabolism and excretion), most of medications are still often prescribed at the same daily dosage as in young adults. When prescribing any drug for old patients, we should remember that daily intake should be adapted to these specificities, keeping in mind the old well-known aphorism "start low, go slow". In this review, we describe the main drug-related neurological manifestations (drug-induced movement disorders, falls, seizures, delirium, hypoglycemia, stroke, hyponatremia, peripheral neuropathy and myopathy, and serotonin syndrome) and the main drugs associated with neurological manifestations (dopamine receptor blocking agents, antithrombotics, anticholinergics, beta-lactams, antidepressants, benzodiazepines, mood stabilizers).

[Innovative outpatient models]. / Innovative ambulante Modelle.

Innovative, multimodal, cross-professional and cross-sectoral approaches to outpatient care have been funded in Germany since 2004 when the integrated care (IV) according to § 140 ff Social Security Code V (SGB V) and selective contracts according to § 73 SGB V were introduced. As a result, almost 7000 IV contracts were established providing psychiatric care; however, most of them were short-term contracts and only 1-2% of the total number of patients were treated by means of IV contracts. Great attention has been paid to the multiprofessional care of patients in all service models. Here we present two service models that were permanently established: the network of the Psychiatry Initiative Berlin Brandenburg (PIBB), certified according to § 87b SGB V, and the project Neuropsychiatric and Psychotherapeutic Care (NPPV) North Rhine funded by the Innovation Fund. The care projects described show new opportunities by exploiting previously unused networking resources at various levels of care and by coordinating the necessary treatment steps. Furthermore, a better coordination of patients enables, among other things, the organization of group therapy. This form of treatment in particular offers the possibility of treating more patients by applying different treatment intensities and contents. Moreover, it intensifies the guideline-based treatment itself through an interactive, therapeutically desired exchange. In addition, the formation of medical networks, which are entitled to relevant financial support according to their statutory certification, is a special opportunity to use complex outpatient psychiatric treatment and thus to improve care.

Innervation of the human spleen: A complete hilum-embedding approach.

INTRODUCTION: The spleen is hypothesized to play a role in the autonomic nervous system (ANS)-mediated control of host defence, but the neuroanatomical evidence for this assumption rests on a sparse number of studies, which mutually disagree with respect to the existence of cholinergic or vagal innervation. METHODS: We conducted an immuno- and enzyme-histochemical study of the innervation of the human spleen using a complete hilum-embedding approach to ensure that only nerves that entered or left the spleen were studied, and that all splenic nerves were included in the sampled area. Furthermore, a complete embedded spleen was serially sectioned to prepare a 3D reconstruction of the hilar nerve plexus. RESULTS: All detected nerves entering the spleen arise from the nerve plexus that surrounds branches of the splenic artery and are catecholaminergic. Inside the spleen these nerves continue within the adventitia of the white pulpal central arteries and red pulpal arterioles. Staining for either choline acetyltransferase or acetylcholinesterase did not reveal any evidence for cholinergic innervation of the human spleen, irrespective of the type of fixation (regularly fixed, fresh-frozen post-fixed or fresh-frozen cryoslides). Furthermore, no positive VIP staining was observed (VIP is often co-expressed in postganglionic parasympathetic nerves). CONCLUSION: Our comprehensive approach did not produce any evidence for a direct cholinergic (or VIP-ergic) innervation of the spleen. This finding does not rule out (indirect) vagal innervation via postganglionic non-cholinergic periarterial fibres.

Efficacy of inpatient psychotherapy for major depressive disorder: a meta-analysis of controlled trials.

OBJECTIVE: This meta-analysis investigates the efficacy of inpatient psychotherapy in major depressive disorders compared to control conditions. METHODS: In total, 14 studies were entered into the meta-analysis with a total of 1.080 patients. Primary outcome was the standardized mean differences in self-rated depression outcomes. A priori planned subgroup analyses included the influence of different control conditions: (a) no psychiatric inpatient treatment (e.g., waitlist control), (b) treatment as usual (TAU; e.g., non-manualized clinical management), (c) TAU determined by study design (manualized/'placebo' control condition), as well as number of sessions and influence of self- vs. clinician ratings. RESULTS: The meta-analysis of 19 available comparisons resulted in a moderate pooled effect size showing a small and statistically significant benefit of the psychotherapeutic intervention over control conditions (g = 0.24, P < 0.001, I2  = 0%). This corresponds to a number needed to treat of 7.4. The effects of the interventions were stable over 12-month follow-up (g = 0.21, P < 0.01, I2  = 30%). Comparisons with waitlist or non-standardized control treatments tended to be associated with larger effect sizes than standardized control treatments. CONCLUSIONS: Despite some limitations (small number of studies), this meta-analysis provides evidence for a small but sustained effect of inpatient psychotherapy in patients with major depressive disorders.

Natural organic matter fractions and their removal in full-scale drinking water treatment under cold climate conditions in Nordic capitals.

Drinking water treatment plants (DWTPs) designed to remove natural organic matter (NOM) are challenged as concentrations of NOM in raw waters are increasing. Here, we assess seasonal differences in NOM quality and quantity, from raw waters to the distribution network, at three large DWTPs in Oslo, Stockholm and Helsinki. Samples, collected during stable stratification in both winter and summer and during the autumnal turnover, were analysed for NOM concentrations and composition. The NOM was characterized by common routine parameters, size and content (TFF, LC-OCD, fluorescence) and biodegradability. The NOM concentration decreased to 2.5 mg/L (55%), 4.0 mg/L (48%) and 5.7 mg/L (76%) at the respective DWTPs in Oslo, Stockholm and Helsinki. The NOM in raw waters were predominantly in the largest size fraction (>50 kDa), in particular from Oslo. High MW fractions >50 kDa and humics remained the largest fractions with minimum 30% and maximum 80% of the total NOM. The BDOC in treated water <0.3 mg/L and the conditions in the distribution network imply low probability for bacteria regrowth. The multi-step treatment consisting of coagulation/flocculation, sedimentation, rapid sand filtration, ozonation and biological activated carbon filtration (BAC) was most effective in removing NOM. Coagulation/flocculation followed by sedimentation and sand filtration were critical, especially for the removal of biopolymers and humics, and somewhat for building blocks. The sand filtration provided up to 25% additional removal of biopolymers and below 7% removal of other fractions. The ozonation and BAC was more effective and removed 11% of biopolymers, and about 35% of building blocks and LMW neutrals.

The development of the cloaca in the human embryo.

Subdivision of cloaca into urogenital and anorectal passages has remained controversial because of disagreements about the identity and role of the septum developing between both passages. This study aimed to clarify the development of the cloaca using a quantitative 3D morphological approach in human embryos of 4-10 post-fertilisation weeks. Embryos were visualised with Amira 3D-reconstruction and Cinema 4D-remodelling software. Distances between landmarks were computed with Amira3D software. Our main finding was a pronounced difference in growth between rapidly expanding central and ventral parts, and slowly or non-growing cranial and dorsal parts. The entrance of the Wolffian duct into the cloaca proved a stable landmark that remained linked to the position of vertebra S3. Suppressed growth in the cranial cloaca resulted in an apparent craniodorsal migration of the entrance of the Wolffian duct, while suppressed growth in the dorsal cloaca changed the entrance of the hindgut from cranial to dorsal on the cloaca. Transformation of this 'end-to-end' into an 'end-to-side' junction produced temporary 'lateral (Rathke's) folds'. The persistent difference in dorsoventral growth straightened the embryonic caudal body axis and concomitantly extended the frontally oriented 'urorectal (Tourneux's) septum' caudally between the ventral urogenital and dorsal anorectal parts of the cloaca. The dorsoventral growth difference also divided the cloacal membrane into a well-developed ventral urethral plate and a thin dorsal cloacal membrane proper, which ruptured at 6.5 weeks. The expansion of the pericloacal mesenchyme followed the dorsoventral growth difference and produced the genital tubercle. Dysregulation of dorsal cloacal development is probably an important cause of anorectal malformations: too little regressive development may result in anorectal agenesis, and too much regression in stenosis or atresia of the remaining part of the dorsal cloaca.

Hypoargininemia exacerbates airway hyperresponsiveness in a mouse model of asthma.

BACKGROUND: Asthma is a chronic respiratory condition, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. The hypothesis that the substantially increased expression of arginase 1 in activated macrophages limits the availability of L-arginine for nitric oxide synthesis, and thus increases AHR in lungs of mice with experimentally induced allergic asthma was recently refuted by several studies. In the present study, we tested the hypothesis that, instead, a low circulating concentration of arginine aggravates AHR in the same murine asthma model. Female FVB F/A2 tg/tg transgenic mice, which overexpress rat arginase 1 in their enterocytes, exhibit a ~ 50% decrease of their plasma L-arginine concentration. METHODS: Adult female F/A2 tg/tg mice and their wild-type littermates (F/A2 wt/wt ) were sensitized and challenged with ovalbumin (OVA/OVA). Lung function was assessed with the flexiVent™ system. Adaptive changes in the expression of arginine-metabolizing or -transporting enzymes, chemokines and cytokines, and lung histology were quantified with qPCR, ELISA, and immunohistochemistry, respectively. RESULTS: Reduction of circulating L-arginine concentration significantly increased AHR in OVA/OVA-treated mice and, to a lesser extent, even in PBS/OVA-treated mice. The pulmonary inflammatory response in OVA/OVA-treated F/A2 tg/tg and F/A2 wt/wt mice was comparable. OVA/OVA-treated F/A2 tg/tg mice differed from similarly treated female mice, in which arginase 1 expression in lung macrophages was eliminated, by a complete absence of an adaptive increase in the expression of arginine-metabolizing or -transporting enzymes. CONCLUSION: A reduction of the circulating L-arginine concentration rather than the macrophage-mediated increase of arginine catabolism worsens AHR.

[Autoimmune encephalitis with psychotic symptoms : Diagnostics, warning signs and practical approach]. / Autoimmunenzephalitis mit psychotischer Symptomatik : Diagnostik, Warnhinweise und praktisches Vorgehen.

Despite intensive research, a precise cause of schizophrenic and schizoaffective disorders has not yet been identified. Therefore, psychiatric diagnoses are still made based on clinical ICD-10/DSM­5 criteria and not on any objective markers; however, various causes or pathophysiological processes may ultimately lead to similar symptoms. An important task for the future of psychiatry is to identify disease subtypes with a distinct pathophysiology to develop more specific and causally acting therapies. A new diagnostic entity has become established in clinical neurology and psychiatry in recent years: autoimmune encephalitis with psychotic symptoms caused by specific antineuronal antibodies has been identified as a rare but potentially treatable cause of psychotic disorders; however, these inflammatory brain diseases are not reliably detected by routine psychiatric diagnostics. Therefore, this qualitative review is intended to provide structured support for clinical practice, which, guided by clinical warning signals, enables a rapid and reliable diagnosis as well as the initiation of immunotherapy. In the case of psychiatric symptoms, the additional onset of focal neurological signs, disturbances of consciousness and orientation, autonomic instability or epileptic seizures and electroencephalograph (EEG) abnormalities should always be followed by a more specific cerebrospinal fluid analysis with determination of antineuronal autoantibodies. Although the scientific evidence indicates that only a small subgroup of patients is affected, the swift and correct diagnosis is of high therapeutic and prognostic relevance for the affected individuals.