A Neural Circuit for Gut-Induced Reward.

The gut is now recognized as a major regulator of motivational and emotional states. However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons recapitulates the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra. Cell-specific transneuronal tracing revealed asymmetric ascending pathways of vagal origin throughout the CNS. In particular, transneuronal labeling identified the glutamatergic neurons of the dorsolateral parabrachial region as the obligatory relay linking the right vagal sensory ganglion to dopamine cells in Substantia nigra. Consistently, optical activation of parabrachio-nigral projections replicated the rewarding effects of right vagus excitation. Our findings establish the vagal gut-to-brain axis as an integral component of the neuronal reward pathway. They also suggest novel vagal stimulation approaches to affective disorders.

Neuropod Cells: The Emerging Biology of Gut-Brain Sensory Transduction.

Guided by sight, scent, texture, and taste, animals ingest food. Once ingested, it is up to the gut to make sense of the food's nutritional value. Classic sensory systems rely on neuroepithelial circuits to convert stimuli into signals that guide behavior. However, sensation of the gut milieu was thought to be mediated only by the passive release of hormones until the discovery of synapses in enteroendocrine cells. These are gut sensory epithelial cells, and those that form synapses are referred to as neuropod cells. Neuropod cells provide the foundation for the gut to transduce sensory signals from the intestinal milieu to the brain through fast neurotransmission onto neurons, including those of the vagus nerve. These findings have sparked a new field of exploration in sensory neurobiology-that of gut-brain sensory transduction.

The neural basis of sugar preference.

When it comes to food, one tempting substance is sugar. Although sweetness is detected by the tongue, the desire to consume sugar arises from the gut. Even when sweet taste is impaired, animals can distinguish sugars from non-nutritive sweeteners guided by sensory cues arising from the gut epithelium. Here, we review the molecular receptors, cells, circuits and behavioural consequences associated with sugar sensing in the gut. Recent work demonstrates that some duodenal cells, termed neuropod cells, can detect glucose using sodium-glucose co-transporter 1 and release glutamate onto vagal afferent neurons. Based on these and other data, we propose a model in which specific populations of vagal neurons relay these sensory cues to distinct sets of neurons in the brain, including neurons in the caudal nucleus of the solitary tract, dopaminergic reward circuits in the basal ganglia and homeostatic feeding circuits in the hypothalamus, that alter current and future sugar consumption. This emerging model highlights the critical role of the gut in sensing the chemical properties of ingested nutrients to guide appetitive decisions.

Modulation of taste responsiveness by the satiation hormone peptide YY.

It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.

Neuroleptic malignant syndrome associated with atypical antipsychotics: A case report.

INTRODUCTION: Neuroleptic malignant syndrome (NMS) is uncommon, with an incidence of 0.01%-3.23%, and is associated with the use of drugs that intervene with dopamine, causing hyperthermia, muscular rigidity, confusion, autonomic instability and death. CASE REPORT: A 35-year-old man with a history of catatonia, refractory epilepsy and functional impairment, required frequent changes in his anticonvulsant and antipsychotic treatment, due to adverse effects. During 2019, in the month of July, clozapine was changed to amisulpride, in September he developed fever, muscle stiffness, stupor, diaphoresis and tachypnea over a two-week period; paraclinical tests showed elevated creatine phosphokinase (CPK) and leukocytosis, so NMS was considered. The antipsychotic was withdrawn and he was treated with bromocriptine and biperiden, with a good response. Ten days after discharge, he began treatment with olanzapine, which generated a similar episode to the one described in December, with subsequent management and resolution. DISCUSSION: The diagnosis is based on the use of drugs that alter dopamine levels, plus altered state of consciousness, fever, autonomic instability and paraclinical tests showing leukocytosis and elevated CPK. Differential diagnoses must be ruled out. Early diagnosis generally leads to total remission, although some patients will suffer complications, long-term sequelae or recurrences. The recurrence in this case derived from the early reintroduction of the neuroleptic after the first episode. Treatment should be individualised according to severity to avoid mortality. CONCLUSIONS: Atypical antipsychotics are rarely suspected of generating NMS. Moreover, the time to reintroduction after an episode must also be taken into account.

Multifunctional microelectronic fibers enable wireless modulation of gut and brain neural circuits.

Progress in understanding brain-viscera interoceptive signaling is hindered by a dearth of implantable devices suitable for probing both brain and peripheral organ neurophysiology during behavior. Here we describe multifunctional neural interfaces that combine the scalability and mechanical versatility of thermally drawn polymer-based fibers with the sophistication of microelectronic chips for organs as diverse as the brain and the gut. Our approach uses meters-long continuous fibers that can integrate light sources, electrodes, thermal sensors and microfluidic channels in a miniature footprint. Paired with custom-fabricated control modules, the fibers wirelessly deliver light for optogenetics and transfer data for physiological recording. We validate this technology by modulating the mesolimbic reward pathway in the mouse brain. We then apply the fibers in the anatomically challenging intestinal lumen and demonstrate wireless control of sensory epithelial cells that guide feeding behaviors. Finally, we show that optogenetic stimulation of vagal afferents from the intestinal lumen is sufficient to evoke a reward phenotype in untethered mice.

The preference for sugar over sweetener depends on a gut sensor cell.

Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.

Mycotic Pulmonary Aneurysm Managed With Covered Stent.

Mycotic aneurysms are vascular dilations caused by fungal or bacterial infections. The involvement of the pulmonary artery or its branches is extremely rare with only a few cases reported in the literature posing a diagnostic challenge. We present the case of a young adult patient with acute myeloid leukemia undergoing chemotherapy, who presented with febrile neutropenia, recurrent bacteremia due to Pseudomona Aeruginosa and Klebsiella Pneumonie and hemoptysis. The management was unconventional, opting for the placement of a covered endovascular stent, being the first successful case with this reported technique. Rapid detection of this pathology and individualization in the management of each patient is essential because of high risk of mortality due to sepsis and rupture of the aneurysm.

The nerve not taken.

Nutrients entering the gut influence our brains through uncharacterized circuits. In this issue of Cell Metabolism, Goldstein et al. (2021) show hypothalamic neurons responding, via distinct neural paths, to nutrients infused in different intestinal segments.

Neuroleptic Malignant Syndrome Associated with Atypical Antipsychotics: A Case Report. / Síndrome neuroléptico maligno asociado a antipsicóticos atípicos: a propósito de un caso.

INTRODUCTION: Neuroleptic malignant syndrome (NMS) is uncommon, with an incidence of 0.01% to 3.23%, and is associated with the use of drugs that intervene with dopamine, causing hyperthermia, muscular rigidity, confusion, autonomic instability and death. CASE REPORT: A 35-year-old man with a history of catatonia, refractory epilepsy and functional impairment, required frequent changes in his anticonvulsant and antipsychotic treatment, due to adverse effects. During 2019, in the month of July, clozapine was changed to amisulpride, in September he developed fever, muscle stiffness, stupor, diaphoresis and tachypnea over a two-week period; paraclinical tests showed elevated creatine phosphokinase (CPK) and leukocytosis, so NMS was considered. The antipsychotic was withdrawn and he was treated with bromocriptine and biperiden, with a good response. Ten days after discharge, he began treatment with olanzapine, which generated a similar episode to the one described in December, with subsequent management and resolution. DISCUSSION: The diagnosis is based on the use of drugs that alter dopamine levels, plus altered state of consciousness, fever, autonomic instability and paraclinical tests showing leukocytosis and elevated CPK. Differential diagnosis must be ruled out. Early diagnosis generally leads to total remission, although some patients will suffer complications, long-term sequelae or recurrences. The recurrence in this case derived from the early reintroduction of the neuroleptic after the first episode. Treatment should be individualised according to severity to avoid mortality. CONCLUSIONS: Atypical antipsychotics are rarely suspected of generating NMS. Moreover, the time to reintroduction after an episode must also be taken into account.

An intravital window to image the colon in real time.

Intravital microscopy is a powerful technique to observe dynamic processes with single-cell resolution in live animals. No intravital window has been developed for imaging the colon due to its anatomic location and motility, although the colon is a key organ where the majority of microbiota reside and common diseases such as inflammatory bowel disease, functional gastrointestinal disorders, and colon cancer occur. Here we describe an intravital murine colonic window with a stabilizing ferromagnetic scaffold for chronic imaging, minimizing motion artifacts while maximizing long-term survival by preventing colonic obstruction. Using this setup, we image fluorescently-labeled stem cells, bacteria, and immune cells in live animal colons. Furthermore, we image nerve activity via calcium imaging in real time to demonstrate that electrical sacral nerve stimulation can activate colonic enteric neurons. The simple implantable apparatus enables visualization of live processes in the colon, which will open the window to a broad range of studies.

You Are What You (First) Eat.

As far back as we can remember, we eat. In fact, we eat before we can remember. Our first meal is amniotic fluid. We swallow it during the first trimester of gestation, and with that, we expose our gut to a universe of molecules. These early molecules have a profound influence on gut and brain function. For example, the taste of the amniotic fluid changes based on the mother's diet. Indeed, recent findings suggest that food preferences begin in utero. Likewise, a baby's first exposure to bacteria, previously thought to be during birth, appears to be in utero as well. And just as postnatal food and microbiota are implicated in brain function and dysfunction, prenatal nutrients and microbes may have a long-lasting impact on the development of the gut-brain neural circuits processing food, especially considering their plasticity during this vulnerable period. Here, we use current literature to put forward concepts needed to understand how the gut first meets the brain, and how this encounter may help us remember food.

The now and then of gut-brain signaling.

Since their very beginnings, animals had gut sensory epithelial cells. In one of the first multicellular animals, Trichoplax - a literal wandering gut - food sensing and feeding was coordinated by specialized ventral sensor cells. In mammals, including humans, gut epithelial sensor cells (a.k.a enteroendocrine cells) have been recognized for an array of neuropeptides, like ghrelin and cholecystokinin, that modulate hunger or satiety. Indeed, since first described as "clear cells" by Rudfolf Heidenhain (1868), research efforts increasingly focused on their hormone neuropeptides leading to the alphabetical classification of one cell-one hormone (e.g. I-cell synthesizes only cholecystokinin). A recent explosion of molecular tools to study the biology of single cells is expanding the imagination of studies and unveiling intriguing aspects of gut sensory transduction. To mention a few: multimodal sensing, one cell expressing both ghrelin and cholecystokinin-the yin and yang of appetite-, and synapses with nerves. This brief account examines recent advances on gut sensory transduction to highlight how food and bacteria in the gut alter eating.

Tromboembolismo pulmonar asociado a COVID-19 en paciente con síndrome de May-Thurner / COVID-19-associated Pulmonary Thromboembolism in a Patient with May-Thurner Syndrome

Introducción: El síndrome de May-Thurner es una enfermedad cuya prevalencia real es desconocida. Suele ser asintomática y las manifestaciones clínicas aparecen en el contexto de las complicaciones asociadas a la enfermedad. La aproximación diagnóstica se realiza por medio de imágenes, donde se identifican alteraciones patognomónicas que permiten descartar diagnósticos diferenciales. Se ha demostrado que la COVID-19 genera un estado protrombótico, que en contexto del síndrome de May-Thurner puede derivar en complicaciones tromboembólicas. Objetivo: Comparar la clínica y la posible relación de la enfermedad tromboembólica venosa en el curso de la COVID-19 en pacientes con SMT. Caso clínico: Mujer de 24 años, secretaria de profesión y residente en Bucaramanga. Presentó un cuadro clínico de 20 días de evolución que inició con rinorrea hialina, tos ocasional y mialgias; cinco días después manifestó fiebre no cuantificada y tos con expectoración hemoptoica. Conclusiones: Dentro de la fisiopatología de la infección por SARS-CoV-2 se desarrollan mecanismos procoagulantes, lo cual incrementa el riesgo de eventos trombóticos en pacientes con o sin factores de riesgo(AU)

Introduction: May-Thurner syndrome is a disease whose actual prevalence is unknown. It is usually asymptomatic and clinical manifestations appear in the context of complications associated with the disease. The diagnostic approach is performed by imaging, where pathognomonic alterations are identified to rule out differential diagnoses. It has been demonstrated that COVID-19 generates a prothrombotic state, which particularly in patients with May-Thurner syndrome would lead to thromboembolic complications. Objective: To compare the clinical and possible relationship of venous thromboembolic disease in the course of COVID-19 in patients with May-Thurner syndrome. Clinical case: 24-year-old woman, secretary by profession and resident in Bucaramanga, Colombia. She presented a clinical picture of 20 days of evolution that began with hyaline rhinorrhea, occasional cough and myalgias; five days later she manifested unquantified fever and cough with hemoptotic expectoration. Conclusions: Within the pathophysiology of SARS-CoV-2 infection, procoagulant mechanisms develop, which increases the risk of thrombotic events in patients with or without risk factors(AU)

A gut-brain neural circuit for nutrient sensory transduction.

The brain is thought to sense gut stimuli only via the passive release of hormones. This is because no connection has been described between the vagus and the putative gut epithelial sensor cell-the enteroendocrine cell. However, these electrically excitable cells contain several features of epithelial transducers. Using a mouse model, we found that enteroendocrine cells synapse with vagal neurons to transduce gut luminal signals in milliseconds by using glutamate as a neurotransmitter. These synaptically connected enteroendocrine cells are referred to henceforth as neuropod cells. The neuroepithelial circuit they form connects the intestinal lumen to the brainstem in one synapse, opening a physical conduit for the brain to sense gut stimuli with the temporal precision and topographical resolution of a synapse.

Síndrome neuroléptico maligno asociado a antipsicóticos atípicos: a propósito de un caso

Introducción: El síndrome neuroléptico maligno (SNM) es infrecuente, con una incidencia del 0,01 al 3,23%, y tiene relación con el consumo de fármacos que interfieren con la dopamina; genera hipertermia, rigidez muscular, confusión, inestabilidad autonómica y la muerte. Caso clínico: Un varón de 35 arios, con antecedentes de catatonía, epilepsia refractaria y deterioro funcional, en tratamiento anticonvulsivo y antipsicótico, requirió cambio frecuente por efectos adversos de este. En julio de 2019 se cambió la clozapina por amisulprida; en septiembre se inicia un cuadro de 2 semanas de fiebre, rigidez muscular, estupor, diaforesis y taquipnea; los paraclínicos mostraron aumento de la creatininasa (CK) y leucocitosis, por lo que se consideró SNM. Se retiró el antipsicótico y se trató con bromocriptina y biperideno, que obtuvieron buena respuesta. A los 10 días del egreso, se inició tratamiento con olanzapina, que generó en diciembre un cuadro clínico similar al descrito, con posterior tratamiento y resolución. Discusión: El diagnóstico se basa en la toma de fármacos que alteren la dopamina, más alteración del estado de conciencia, fiebre e inestabilidad autonómica, junto con paraclínicos como leucocitosis y elevación de la CK. Se debe descartar diagnósticos diferenciales. El diagnóstico temprano generalmente lleva a la remisión total; algunos tendrán complicaciones, secuelas a largo plazo o recidivas. La recurrencia en este caso derivó de la reintroducción temprana del neuroléptico después del primer episodio. El tratamiento se debe individualizar según la gravedad para evitar la muerte. Conclusiones: Rara vez se sospecha que los antipsicóticos atípicos generen SNM; a su vez se debe tener en cuenta el tiempo a la reintroducción después de un episodio.

Introduction: Neuroleptic malignant syndrome (NMS) is uncommon, with an incidence of 0.01% to 3.23%, and is associated with the use of drugs that intervene with dopamine, causing hyperthermia, muscular rigidity, confusion, autonomic instability and death. Case report: A 35-year-old man with a history of catatonia, refractory epilepsy and functional impairment, required frequent changes in his anticonvulsant and antipsychotic treatment, due to adverse effects. During 2019, in the month of July, clozapine was changed to amisul-pride, in September he developed fever, muscle stiffness, stupor, diaphoresis and tachypnea over a two-week period; paraclinical tests showed elevated creatine phosphokinase (CPK) and leukocytosis, so NMS was considered. The antipsychotic was withdrawn and he was treated with bromocriptine and biperiden, with a good response. Ten days after discharge, he began treatment with olanzapine, which generated a similar episode to the one described in December, with subsequent management and resolution. Discussion: The diagnosis is based on the use of drugs that alter dopamine levels, plus altered state of consciousness, fever, autonomic instability and paraclinical tests showing leukocy-tosis and elevated CPK. Differential diagnosis must be ruled out. Early diagnosis generally leads to total remission, although some patients will suffer complications, long-term sequelae or recurrences. The recurrence in this case derived from the early reintroduction of the neuroleptic after the first episode. Treatment should be individualised according to severity to avoid mortality. Conclusions: Atypical antipsychotics are rarely suspected of generating NMS. Moreover, the time to reintroduction after an episode must also be taken into account.

Características de pacientes con exacerbación aguda grave de enfermedad pulmonar obstructiva crónica que requirieron ventilación mecánica invasiva en un hospital de Santander durante 2014-2020 / Characteristics of patients with severe acute exacerbation of chronic obstructive pulmonary disease who required invasive mechanical ventilation in a Santander hospital during 2014-2020

Introducción: la enfermedad pulmonar obstructiva crónica es una limitación del flujo de aire por anomalías alveolares. En una exacerbación aguda, la ventilación mecánica no invasiva es la primera línea en el manejo, sin embargo, existen ciertos factores de riesgo que hacen más probable el uso de ventilación mecánica invasiva en estos pacientes, que no están apropiadamente descritos en la literatura científica y que pueden guiar hacia una elección de soporte ventilatorio apropiado. Objetivo: describir los factores que se asociaron con mayor necesidad de ventilación mecánica no invasiva en una cohorte de pacientes hospitalizados con exacerbación aguda de la enfermedad pulmonar obstructiva crónica. Métodos: estudio observacional analítico de corte transversal, con muestreo no probabilístico que incluye todos los pacientes que consultaron a urgencias y fueron hospitalizados por exacerbación aguda de la enfermedad pulmonar obstructiva crónica en un hospital de tercer nivel de Santander, Colombia, durante el período 2014-2020. Resultados: fueron incluidos 81 pacientes, 36 requirieron ventilación mecánica no invasiva y 12 ventilación mecánica invasiva; 25 % de los pacientes con ventilación mecánica no invasiva fallaron a la terapia inicial y demandaron el uso de ventilación mecánica invasiva. Las comorbilidades más frecuentes fueron hipertensión arterial (70,3 %) y cardiopatía (49,38 %); 70 % había tenido exposición al tabaquismo como fumador directo. Conclusiones: el uso de ventilación mecánica invasiva estuvo relacionado de forma estadísticamente significativa en pacientes con perfil de disnea severa, acidosis por parámetros gasométricos, escalamiento antibiótico, uso de corticoides intravenosos, requerimiento de unidad de cuidado intensivo, infecciones asociadas al cuidado de la salud y estancia hospitalaria prolongada.

Introduction: Chronic obstructive pulmonary disease is airflow limitation due to alveolar abnormalities. In an acute exa- cerbation, non-invasive mechanical ventilation is the first line of management, however, there are certain risk factors that make the use of invasive mechanical ventilation more likely in these patients, which are not adequately described in the scientific literature and that can guide towards a choice of appropriate ventilatory support. Objective: To describe the factors that were associated with an increased need for invasive mechanical ventilation in a cohort of hospitalized patients with an acute exacerbation of chronic obstructive pulmonary disease. Methods: Cross-sectional analytical observational study, with non-probabilistic sampling including all patients who consulted the emergency room and were hospitalized for acute exacerbation of chronic obstructive pulmonary disease in a tertiary care hospital in Santander-Colombia during the period 2014-2020. Results: 81 patients were included, 36 required non-invasive mechanical ventilation and 12 invasive me- chanical ventilation. 25 % of the patients with non-invasive mechanical ventilation failed the initial therapy and demanded the use of invasive mechanical ventilation. The most frequent comorbidities were arterial hypertension (70.3 %) and heart disease (49.38 %). 70 % had been exposed to smoking as direct smokers. Conclusions: The use of invasive mechanical ven- tilation was associated in a statistically significant way in patients with a profile of: severe dyspnea, acidosis by gasometric parameters, antibiotic escalation, use of intravenous corticosteroids, intensive care unit requirement, infections associa- ted with health care and prolonged hospital stay.

The intestinal tuft cell nanostructure in 3D.

Once referred to as "peculiar," tuft cells are enigmatic epithelial cells. Here, we reasoned that future functional studies could be derived from a complete account of the tuft cell ultrastructure. We identified and documented the volumetric ultrastructure at nanometer resolution (4-5 nm/pixel) of specific intestinal tuft cells. The techniques used were Serial Block-Face (SBF) and Automated Tape-collecting Ultra-Microtome (ATUM) Scanning Electron Microscopy (SEM). Our results exposed a short (~15 µm) basal cytoplasmic process devoid of secretory vesicles. Volume rendering of serial sections unveiled several thin cytospinules (~1 µm). These cytospinules project from the tuft cell into the nuclei of neighboring epithelial cells. Volume rendering also revealed within the tuft cell an elegant network of interconnected tubules. The network forms a passage from the base of the microvilli to the rough endoplasmic reticulum. Based on their location and microanatomy, the tuft cells' cytospinules, and tubular network, might facilitate the exchange of molecular cargo with nuclei of neighboring cells, and the gut lumen.