Control of Immune Response to Allogeneic Embryonic Stem Cells by CD3 Antibody-Mediated Operational Tolerance Induction.

Implantation of embryonic stem cells (ESCs) and their differentiated derivatives into allogeneic hosts triggers an immune response that represents a hurdle to clinical application. We established in autoimmunity and in transplantation that CD3 antibody therapy induces a state of immune tolerance. Promising results have been obtained with CD3 antibodies in the clinic. In this study, we tested whether this strategy can prolong the survival of undifferentiated ESCs and their differentiated derivatives in histoincompatible hosts. Recipients of either mouse ESC-derived embryoid bodies (EBs) or cardiac progenitors received a single short tolerogenic regimen of CD3 antibody. In immunocompetent mice, allogeneic EBs and cardiac progenitors were rejected within 20-25 days. Recipients treated with CD3 antibody showed long-term survival of implanted cardiac progenitors or EBs. In due course, EBs became teratomas, the growth of which was self-limited. Regulatory CD4(+)FoxP3(+) T cells and signaling through the PD1/PDL1 pathway played key roles in the CD3 antibody therapeutic effect. Gene profiling emphasized the importance of TGF-ß and the inhibitory T cell coreceptor Tim3 to the observed effect. These results demonstrate that CD3 antibody administered alone promotes prolonged survival of allogeneic ESC derivatives and thus could prove useful for enhancing cell engraftment in the absence of chronic immunosuppression.

[Changes associated with aging in angular kinematic parameters during a controlled speed walk]. / Cambios asociados al envejecimiento normal en los parámetros angulares de la marcha a una velocidad controlada.

BACKGROUND: During normal aging, a reduction in walking speed and changes in stability are observed. AIM: To characterize and compare gait kinematic parameters of young (YA) and older adults (OA) at a controlled speed. MATERIAL AND METHODS: Gait angular kinematic parameters were analyzed in OA aged over 60 years and YA aged between 20 and 30 years. For data capture, six VICON Bonita cameras were used. Recording were made at a gait speed of 1.2 m/s. Kinematic data were normalized to 100% of the gait cycle using the Polygon 4.1 software. Time windows representing the phases of gait were created for analysis. RESULTS: At the hip-pelvis level, OA reduce their pelvic obliquity motion and increase hip abduction. At the knee level OA reduce movements in the frontal plane during the plantar support and half swing phases. At the ankle level OA reduce their maximum ranges of plantar flexion, during the toe-off and final swing phases. CONCLUSIONS: At a controlled speed, kinematic changes observed in OA allow an increase in body support base to maintain gait stability.

Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism.

Loss-of-function mutations in the α3 isoform of the Na(+)/K(+) ATPase (sodium pump) are responsible for rapid-onset dystonia parkinsonism (DYT12). Recently, a pharmacological model of DYT12 was generated implicating both the cerebellum and basal ganglia in the disorder. Notably, partially blocking sodium pumps in the cerebellum was necessary and sufficient for induction of dystonia. Thus, a key question that remains is how partially blocking sodium pumps in the cerebellum induces dystonia. In vivo recordings from dystonic mice revealed abnormal high-frequency bursting activity in neurons of the deep cerebellar nuclei (DCN), which comprise the bulk of cerebellar output. In the same mice, Purkinje cells, which provide strong inhibitory drive to DCN cells, also fired in a similarly erratic manner. In vitro studies demonstrated that Purkinje cells are highly sensitive to sodium pump dysfunction that alters the intrinsic pacemaking of these neurons, resulting in erratic burst firing similar to that identified in vivo. This abnormal firing abates when sodium pump function is restored and dystonia caused by partial block of sodium pumps can be similarly alleviated. These findings suggest that persistent high-frequency burst firing of cerebellar neurons caused by sodium pump dysfunction underlies dystonia in this model of DYT12.

Immune-mediated hepatitis: Basic concepts and treatment.

Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized advanced cancer management. Nevertheless, the generalized use of these medications has led to an increase in the incidence of adverse immune-mediated events and the liver is one of the most frequently affected organs. Liver involvement associated with the administration of immunotherapy is known as immune-mediated hepatitis (IMH), whose incidence and clinical characteristics have been described by different authors. It often presents as mild elevations of amino transferase levels, seen in routine blood tests, that spontaneously return to normal, but it can also manifest as severe transaminitis, possibly leading to the permanent discontinuation of treatment. The aim of the following review was to describe the most up-to-date concepts regarding the epidemiology, diagnosis, risk factors, and progression of IMH, as well as its incidence in different types of common cancers, including hepatocellular carcinoma. Treatment recommendations according to the most current guidelines are also provided.

Position paper on perioperative management and surgical risk in the patient with cirrhosis.

INTRODUCTION: Management of the patient with cirrhosis of the liver that requires surgical treatment has been relatively unexplored. In Mexico, there is currently no formal stance or expert recommendations to guide clinical decision-making in this context. AIMS: The present position paper reviews the existing evidence on risks, prognoses, precautions, special care, and specific management or procedures for patients with cirrhosis that require surgical interventions or invasive procedures. Our aim is to provide recommendations by an expert panel, based on the best published evidence, and consequently ensure timely, quality, efficient, and low-risk care for this specific group of patients. RESULTS: Twenty-seven recommendations were developed that address preoperative considerations, intraoperative settings, and postoperative follow-up and care. CONCLUSIONS: The assessment and care of patients with cirrhosis that require major surgical or invasive procedures should be overseen by a multidisciplinary team that includes the anesthesiologist, hepatologist, gastroenterologist, and clinical nutritionist. With respect to decompensated patients, a nephrology specialist may be required, given that kidney function is also a parameter involved in the prognosis of these patients.

Beyond conventional physical examination in hepatology: POCUS.

Point-of-care ultrasound (POCUS) refers to the use of ultrasound imaging through pocket-sized sonographic devices at the patient's bedside, to make a diagnosis or direct a procedure and immediately answer a clinical question. Its goal is to broaden the physical examination, not to replace conventional ultrasound studies. POCUS has evolved as a complement to physical examination and has been adopted by different medical specialties, including hepatology. A narrative synthesis of the evidence on the applications of POCUS in hepatology was carried out, describing its usefulness in the diagnosis of cirrhosis of the liver, metabolic dysfunction-associated steatotic liver disease (MASLD), decompensated cirrhosis, and portal hypertension. The review also encompasses more recent applications in the hemodynamic evaluation of the critically ill patient with cirrhosis of the liver, patients with other liver diseases, as well as in the ultrasound guidance of procedures. POCUS could make up part of the daily clinical practice of gastroenterologists and hepatologists, simplifying the initial evaluation of patients and optimizing clinical management. Its accessibility, ease of use, and low adverse event profile make POCUS a useful tool for the properly trained physician in the adequate clinical setting. The aim of this review was to describe the available evidence on the usefulness of POCUS in the daily clinical practice of gastroenterologists and hepatologists.

Evaluation and management of emergencies in the patient with cirrhosis.

The approach to and management of critically ill patients is one of the most versatile themes in emergency medicine. Patients with cirrhosis of the liver have characteristics that are inherent to their disease that can condition modification in acute emergency treatment. Pathophysiologic changes that occur in cirrhosis merit the implementation of an analysis as to whether the overall management of a critically ill patient can generally be applied to patients with cirrhosis of the liver or if they should be treated in a special manner. Through a review of the medical literature, the available information was examined, and the evidence found on the special management required by those patients was narratively synthesized, selecting the most representative decompensations within chronic disease that require emergency treatment.

The effect of lameness on the resting behavior and metabolic status of dairy cattle during the transition period in a freestall-housed dairy herd.

The objective of this observational study was to examine the effect of lameness on the resting behavior of dairy cattle through the transition period in a mattress-bedded commercial freestall facility, and explore the relationships between lameness, behavior, and metabolic indicators of disease. A convenience sample was used, comprised of 40 multiparous and 17 primiparous Holstein cows that were recruited as they entered the close-up pen and tracked through the maternity, hospital, and fresh pens. At recruitment, 87.5% of multiparous cows and 23.5% of primiparous cows showed evidence of abnormal gait. Lying time decreased from 16 d before calving from a least squares means ± standard error of 13.5 ± 0.6 h/d to a nadir of 10.6 ± 0.38 h/d on the day of calving. After a period of increased rest after calving, lying time stabilized by d 6 to between 9.8 and 10.8h/d. This change was accompanied by an increase in the number of lying bouts per day from least squares means (95% confidence limits) of 11.2 (10.0 to 12.4) bouts per day to a peak of 17.7 (16.5 to 18.8) bouts per day on the day before calving, and a decrease in the duration of each lying bout. Resting behavior was influenced by calving month, temperature humidity index, body condition, parity, and lameness. Moderate and severely lame cows had significantly longer lying times throughout the transition period before and after calving, but most notable was a dramatic increase in the number of lying bouts observed 3 d before and after calving. In the straw-bedded, loose-housed maternity pen, moderate and severely lame cows had 20.3 (19.1 to 21.5) bouts per day, compared with 15.6 (14.3 to 16.8) bouts per day for nonlame cows. We hypothesized that this alteration in behavior may be associated with hypersensitivity to pain due to lameness. A total of 26.3% of cows tested above a threshold of 1,400 µM ß-hydroxybutyrate. Moderate and severely lame cows had a least squares means (95% confidence limits) ß-hydroxybutyrate concentration of 1,165 (1,037 to 1,291) µM that was significantly greater than 697 (560 to 834) µM for slightly lame cows and 687 (551 to 824) µM for nonlame cows. In summary, lameness significantly altered the resting behavior of cows during the transition period and was associated with elevated risk for ketosis in the study herd.

Activating an anterior nucleus gigantocellularis subpopulation triggers emergence from pharmacologically-induced coma in rodents.

Multiple areas within the reticular activating system (RAS) can hasten awakening from sleep or light planes of anesthesia. However, stimulation in individual sites has shown limited recovery from deep global suppression of brain activity, such as coma. Here we identify a subset of RAS neurons within the anterior portion of nucleus gigantocellularis (aNGC) capable of producing a high degree of awakening represented by a broad high frequency cortical reactivation associated with organized movements and behavioral reactivity to the environment from two different models of deep pharmacologically-induced coma (PIC): isoflurane (1.25%-1.5%) and induced hypoglycemic coma. Activating aNGC neurons triggered awakening by recruiting cholinergic, noradrenergic, and glutamatergic arousal pathways. In summary, we identify an evolutionarily conserved population of RAS neurons, which broadly restore cerebral cortical activation and motor behavior in rodents through the coordinated activation of multiple arousal-promoting circuits.

Extrahepatic complications of non-alcoholic fatty liver disease: Its impact beyond the liver. / Complicaciones extrahepáticas de la enfermedad por hígado graso no alcohólico: impacto más allá del hígado.

Non-alcoholic fatty liver disease (NAFLD) is currently one of the main causes of chronic liver disease in Western countries, with a 25% prevalence reported in the general population worldwide. Visceral adiposity and liver fat promote a state of systemic inflammation, predisposing individuals with NAFLD to the extrahepatic pathologies of cardiovascular disease (the most common cause of death in patients with NAFLD), diabetes mellitus, chronic kidney disease, hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, and an increased risk for presenting with gastrointestinal and extraintestinal neoplasias. Different mechanisms between NAFLD and its association with extrahepatic diseases have been reported, and lipotoxicity is the main cause of inflammatory pathway activation that results in extrahepatic tissue damage.

Regulation of connexin hemichannels by monovalent cations.

Opening of connexin hemichannels in the plasma membrane is highly regulated. Generally, depolarization and reduced extracellular Ca2+ promote hemichannel opening. Here we show that hemichannels formed of Cx50, a principal lens connexin, exhibit a novel form of regulation characterized by extraordinary sensitivity to extracellular monovalent cations. Replacement of extracellular Na+ with K+, while maintaining extracellular Ca2+ constant, resulted in >10-fold potentiation of Cx50 hemichannel currents, which reversed upon returning to Na+. External Cs+, Rb+, NH4+, but not Li+, choline, or TEA, exhibited a similar effect. The magnitude of potentiation of Cx50 hemichannel currents depended on the concentration of extracellular Ca2+, progressively decreasing as external Ca2+ was reduced. The primary effect of K+ appears to be a reduction in the ability of Ca2+, as well as other divalent cations, to close Cx50 hemichannels. Cx46 hemichannels exhibited a modest increase upon substituting Na+ with K+. Analyses of reciprocal chimeric hemichannels that swap NH2- and COOH-terminal halves of Cx46 and Cx50 demonstrate that the difference in regulation by monovalent ions in these connexins resides in the NH2-terminal half. Connexin hemichannels have been implicated in physiological roles, e.g., release of ATP and NAD+ and in pathological roles, e.g., cell death through loss or entry of ions and signaling molecules. Our results demonstrate a new, robust means of regulating hemichannels through a combination of extracellular monovalent and divalent cations, principally Na+, K+, and Ca2+.

Gq/11-induced and spontaneous waves of coordinated network activation in developing frontal cortex.

Repeated episodes of spontaneous large-scale neuronal bursting and calcium influx in the developing brain can potentially affect such fundamental processes as circuit formation and gene expression. Between postnatal day 3 (P3) and P7, the immature cortex can express one such form of activation whereby a wave of neuronal activity propagates through cortical networks, generating massive calcium influx. We previously showed that this activity could be triggered by brief stimulation of muscarinic receptors. Here, we show, by monitoring large cortical areas at low magnification, that although all areas respond to muscarinic agonists to some extent, only some areas are likely to generate the coordinated wave-like activation. The waves can be triggered repeatedly in frontal areas where, as we also show, waves occur spontaneously at a low frequency. In parietal and occipital areas, no such waves are seen. This selectivity may be related in part to differences in the cortical distribution of dopaminergic signaling, because we find that activation of dopamine receptors enables the response. Because M1 muscarinic receptors are typically coupled with G-alpha(q)/11, we investigated whether other receptors known to couple with this G-protein (group I glutamate metabotropic receptors, neurotensin type 1) could similarly elicit wave-like activation in responsive cortical areas. Our results suggest that multiple neurotransmitter systems can enable this form of activation in the frontal cortex. The findings suggest that a poorly recognized, developmentally regulated form of strong network activation found predominantly in the frontal cortex could potentially exert a profound influence on brain development.

Generalized CNS arousal: An elementary force within the vertebrate nervous system.

Why do animals and humans do anything at all? Arousal is the most powerful and essential function of the brain, a continuous function that accounts for the ability of animals and humans to respond to stimuli in the environment by producing muscular responses. Following decades of psychological, neurophysiological and molecular investigations, generalized CNS arousal can now be analyzed using approaches usually applied to physical systems. The concept of "criticality" is a state that illustrates an advantage for arousal systems poised near a phase transition. This property provides speed and sensitivity and facilitates the transition of the system into different brain states, especially as the brain crosses a phase transition from less aroused to more aroused states. In summary, concepts derived from applied mathematics of physical systems will now find their application in this area of neuroscience, the neurobiology of CNS arousal.

Use of EC criteria for determining health and environmental hazards for classification of chemicals for environmental risk

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[Preocclusive stenosis of the extracranial vertebral artery. Treatment by percutaneous transluminal angioplasty and insertion of endoprosthesis]. / Estenosis preoclusiva de la arteria vertebral extracraneal. Tratamiento mediante angioplastia transluminal percutánea y colocación de endoprótesis.

INTRODUCTION: Atherosclerotic occlusive disease of the extracranial portion of the vertebral artery is relatively frequent and is usually related to vertebrobasilar ischemia. Due to the lack of a noninvasive diagnostic technique, at present it is often not diagnosed. Surgical treatment is difficult and risky. Percutaneous transluminal angioplasty (PTA) is only partly useful due to a high rate of restenosis. The recent development of stenting has led to an evident improvement of PTA results, reducing restenosis and offering an effective treatment with low morbidity and mortality. CLINICAL CASE: Sixty year old male patient, smoker and moderate drinker, who is hospitalized due to repeated ischemic strokes (cerebellar stroke in the left posterior and interior inferior cerebellar arteries, and cerebral stroke at occipito-parietal and ipsilateral capsulo-thalamic levels) in spite of antithrombotic treatment. Angiography showed: a) occlusion of the left vertebral artery; b) preocclusive stenosis of the right vertebral artery in the ostium; c) fetal origin of the right posterior cerebral artery, and d) left hypoplasic posterior communicating artery. PTA and stent placement at the right vertebral artery is performed with an excellent angiographic result, a partial recovery of neurological symptomatology and absence of new episodes of cerebral ischemia during a three-month follow-up. CONCLUSION: Percutaneous transluminal angioplasty and stent placement is an effective low morbidity-mortality treatment in occlusive atherosclerosis of the vertebral artery, although further randomized multicenter studies are required in order to validate this conclusion.

[Pheochromocytoma and paraganglioma]. / Feocromocitoma y paraganglioma.

Pheochromocytoma and paraganglioma are neoplasias of the chromaffin cells that manifest themselves in some 40-60% of cases by symptoms of episodic freeing of catecholamines. They are the cause of stable and malign HTA in some 0.1-1% of cases and must be discounted in a study of the same. They most frequently affect males and their incidence increases with age. The symptomatic episodes are basically characterised by high blood pressure, migraines, sweating and palpitations, although they can have other multiple manifestations and even take a silent form in upto 40-50% of cases. They are frequently associated (10%) with multiple endocrine neoplasias and other neuroectodermic syndromes. For their diagnosis it is essential to measure the catecholamines and their metabolites, both plasmatic and urinary, and to locate the tumour by means of image tests, especially magnetic resonance. In the handling of these tumours it must be born in mind that the carrying out of physical maneuvers on the tumour and the employment of drugs that free catecholamines can induce hypertensive crises. The treatment chosen is always surgical, curative in cases of benign pheochromocytoma or producing a reduction of the tumourous mass and associated symptoms in cases of malign pheochromocytoma (10%); in this latter case treatment is complemented with chemotherapy or drugs that control the tumourous symptoms. Untreated pheochromocytoma can be a mortal disease, hence the importance of its detection and early treatment.

[Lipidic changes in subclinical hypothyroidism. Evolution according to whether or not corrections are made of TSH levels]. / Modificaciones lipídicas en el hipotiroidismo subclínico. Evolución según se corrijan o no los nivels de TSH.

INTRODUCTION: The repercussion of subclinical hypothyroidism and its treatment on the levels of circulating lipids has received scarce definition. With the aim of obtaining our own data for evaluating the need of treatment in this pathology, we designed a study protocol in two phases. MATERIAL AND METHODS: In the first phase we determined the plasma values of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides, Apo A-I, Apo B-100 and Lp(a) in two groups of patients: a control group formed by 123 healthy women from a Pamplona Health Area and a second group formed by 29 women affected by subclinical hypothyroidism who were attending our surgeries. In the second phase we included 42 women with subclinical hypothyroidism, on whom we carried out a comparative longitudinal study for three months, dividing them into two groups. One that was formed by 30 women, who were treated until their levels of TSH were normalised, and another in which the women were left in subclinical hypothyroidism. In both groups we have evaluated the lipidic profile and Apo A-I, Apo B100 and Lp (a). RESULTS: 1st phase: The total cholesterol and the LD-cholesterol were significantly higher in the group with SH than in the control group. There were no differences in the HDL-cholesterol nor in the triglycerides. 2nd phase: Group 1: The figures of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and Lp (a) were not modified on normalisation of the levels of TSH. The Apo A-I increased significantly and the Apo B-100 showed a tendency to diminish although without significant differences. Group 2: None of the parameters changed significantly as they remained in subclinical hypothyroidism. On comparing the final parameters between groups 1 and 2 (after 3 months), only the Apo A-I and the Lp (a) increased significantly on correction of SH. CONCLUSIONS: Subclinical hypothyroidism is accompanied by a modification of the lipidic profile of an atherogenic character although its treatment, according to our data, does not achieve significant variations.