Potential of olfactory neuroepithelial cells as a model to study schizophrenia: A focus on GPCRs (Review).

Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in Disrupted­in­Schizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G protein­coupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.

AI as an Epistemic Technology.

In this paper I argue that Artificial Intelligence and the many data science methods associated with it, such as machine learning and large language models, are first and foremost epistemic technologies. In order to establish this claim, I first argue that epistemic technologies can be conceptually and practically distinguished from other technologies in virtue of what they are designed for, what they do and how they do it. I then proceed to show that unlike other kinds of technology (including other epistemic technologies) AI can be uniquely positioned as an epistemic technology in that it is primarily designed, developed and deployed to be used in epistemic contexts such as inquiry, it is specifically designed, developed and deployed to manipulate epistemic content such as data, and it is designed, developed and deployed to do so particularly through epistemic operations such as prediction and analysis. As has been shown in recent work in the philosophy and ethics of AI (Alvarado, AI and Ethics, 2022a), understanding AI as an epistemic technology will also have significant implications for important debates regarding our relationship to AI technologies. This paper includes a brief overview of such implications, particularly those pertaining to explainability, opacity, trust and even epistemic harms related to AI technologies.

Should we replace radiologists with deep learning? Pigeons, error and trust in medical AI.

The sudden rise in the ability of machine learning methodology, such as deep neural networks, to identify and predict with great accuracy instances of malignant cell growth from radiological images has led prominent developers of this technology, such as Geoffrey Hinton, to hold the view that "[…] we should stop training radiologists." Similar views exist in other contexts regarding the replacement of humans with artificial intelligence (AI) technologies. The assumption in these kinds of views is that deep neural networks are better than human radiologists in that they are more accurate, less costly, and have more predictive power than their human counterparts. In this paper, I argue that these considerations, even if true, are simply inadequate as reasons for us to allocate the kind of trust suggested by Hinton and others to these sorts of artifacts. In particular, I show that if the same considerations were true of something other than an AI device, say a pigeon, we would not have sufficient reason to trust them in the same way as suggested of deep neural networks in a medical setting. If this is the case then these considerations are also insufficient to trust AI enough to replace radiologists. Furthermore, I argue that the reliability of AI methodologies such as deep neural networks-which are at the center of this argument-is something that has not yet been established, and doing so faces fundamental challenges. Because of these challenges, it is not possible to ascribe the level of reliability expected from the deployment of a medical device. So, not only are the reasons cited in favor of the deployment of AI technologies in medical settings not sufficient/adequate even if they are true, but knowing whether they are true or not faces non-trivial epistemic challenges. If this is so, then we have no good reasons to advocate replacing radiologists with AI methodologies such as deep neural networks.

Involvement of Melatonin in the Regulation of the Circadian System in Crayfish.

Melatonin (MEL) is an ancient molecule, broadly distributed in nature from unicellular to multicellular species. MEL is an indoleamine that acts on a wide variety of cellular targets regulating different physiological functions. This review is focused on the role played by this molecule in the regulation of the circadian rhythms in crayfish. In these species, information about internal and external time progression might be transmitted by the periodical release of MEL and other endocrine signals acting through the pacemaker. We describe documented and original evidence in support of this hypothesis that also suggests that the rhythmic release of MEL contributes to the reinforcement of the temporal organization of nocturnal or diurnal circadian oscillators. Finally, we discuss how MEL might coordinate functions that converge in the performance of complex behaviors, such as the agonistic responses to establish social dominance status in Procambarus clarkii and the burrowing behavior in the secondary digging crayfish P. acanthophorus.

Circadian rhythm in melatonin release as a mechanism to reinforce the temporal organization of the circadian system in crayfish.

Melatonin (MEL) is a conserved molecule with respect to its synthesis pathway and functions. In crayfish, MEL content in eyestalks (Ey) increases at night under the photoperiod, and this indoleamine synchronizes the circadian rhythm of electroretinogram amplitude, which is expressed by retinas and controlled by the cerebroid ganglion (CG). The aim of this study was to determine whether MEL content in eyestalks and CG or circulating MEL in hemolymph (He) follows a circadian rhythm under a free-running condition; in addition, it was tested whether MEL might directly influence the spontaneous electrical activity of the CG. Crayfish were maintained under constant darkness and temperature, a condition suitable for studying the intrinsic properties of circadian systems. MEL was quantified in samples obtained from He, Ey, and CG by means of an enzyme-linked immunosorbent assay, and the effect of exogenous MEL on CG spontaneous activity was evaluated by electrophysiological recording. Variation of MEL content in He, Ey, and CG followed a circadian rhythm that peaked at the same circadian time (CT). In addition, a single dose of MEL injected into the crayfish at different CTs reduced the level of spontaneous electrical activity in the CG. Results suggest that the circadian increase in MEL content directly affects the CG, reducing its spontaneous electrical activity, and that MEL might act as a periodical signal to reinforce the organization of the circadian system in crayfish.

Intrathecal gadodiamide for identifying subarachnoid and ventricular neurocysticercosis.

OBJECTIVE: Some neurocysticercosis cysts may remain hidden despite novel MRI sequences. This study evaluates the diagnostic value of gadodiamide (GDD)-contrasted MRI cisternography in selected cases of neurocysticercosis. METHODS: We included patients aged 18-65 years with a probable diagnosis of subarachnoid cysticercosis in whom previous neuroimaging studies failed to demonstrate the presence of cysts. One millilitre of GDD was administered intrathecally as a contrast agent with subsequent performance of MRI. RESULTS: Fourteen patients were included. Optimal contrast diffusion was achieved in nine patients, and partial diffusion was achieved in 4. Intracranial vesicles were identified in 10 patients, with the presence of more than 60 basal subarachnoid vesicles being revealed in all, with five cysts in the fourth ventricle in four patients and a floating cyst in the lateral ventricle in one. In one case, intrathecal GDD demonstrated spinal cysticercosis. No adverse events were reported after intrathecal GDD administration. CONCLUSIONS: Intrathecal GDD administration is useful for the diagnosis of subarachnoid and intraventricular neurocysticercosis and can be used to improve diagnostic accuracy in selected cases.

Pigment dispersing hormone modulates spontaneous electrical activity of the cerebroid ganglion and synchronizes electroretinogram circadian rhythm in crayfish Procambarus clarkii.

In crayfish, one very well-studied circadian rhythm is that of electroretinogram (ERG) amplitude. The cerebroid ganglion has been considered a plausible site for the circadian pacemaker of this rhythm and for the retinular photoreceptors, as the corresponding effectors. The pigment dispersing hormone (PDH) appears to synchronize ERG rhythm, but its characterization as a synchronizer cue remains incomplete. The main purposes of this work were a) to determine whether PDH acts on the cerebroid ganglion, and b) to complete its characterization as a non-photic synchronizer. Here we show that PDH increases the number of the spontaneous potentials of the cerebroid ganglion, reaching 149.92±6.42% of the activity recorded in the controls, and that daily application of PDH for 15 consecutive days adjusts the ERG circadian rhythm period to 24.0±0.2h and the end of the activity period of the rhythm coincides with the injection of the hormone. In this work, we hypothesized that in crayfish, PDH transmits the "day" signal to the ERG circadian system and acts upon both the presumptive circadian pacemaker and the corresponding effectors to reinforce the synchronization of the system.

Dopaminergic modulation of neurosecretory cells in the crayfish.

The main aims of this paper are (a) to locate possible dopaminergic neurons in the eyestalk with anti-tyrosine hydroxylase antibodies, (b) to search for the presence of dopamine (DA) in the nervous structures of the eyestalk, (c) to explore its release, and (d) to test the effect of DA on neurosecretory cells in the eyestalk. Experiments were performed in adult crayfishes Procambarus clarkii, in isolated optic peduncle. Immunocytochemistry was made with the antibody against its precursor synthesizing enzyme tyrosine-hydroxylase. The content and release studies of DA were made using high performance liquid chromatography (HPLC). Extracellular and intracellular recordings were conducted with conventional recording techniques. A large number (approximately 2000) of immunopositive somata of different sizes and shapes were identified in various regions of the eyestalk. The majority of somata are of the smallest size (5-25 microm diameter). DA content in the eyestalk was 5.6 +/- 0.1 pmol per structure; the greatest content is in the MT (over 60%). A basal level release of DA was observed. Incubation of eyestalks in solution containing a high K+ concentration increased the DA release (79%). Two effects of DA on the excitability of X-organ neurons were observed; an excitatory effect on neurons of approximately 25 microm somata diameter and another inhibitory effect in the group of approximately 35-microm somata diameter neurons. The excitation occurs with a depolarization and decrement of membrane conductance in the cell soma while the inhibition occurs with a hyperpolarization and increment of membrane conductance in soma. We concluded the following: (1) Dopamine is present in each optic ganglia of the crayfish eyestalk. (2) There is a basal release of DA from the isolated eyestalk. (3) DA release is enhanced threefold by eyestalk incubation in 40 mM [K+] solution. (4) DA selectively excites a population of neurons with low-speed conduction axons, and small somata in the X-organ-sinus gland system, while inhibiting another population characterized by higher axonal conduction speed and large somata. (5) These observations support a role for DA as a neurotransmitter or neuromodulator in the X-organ neurons of the crayfish eyestalk.

Ertapenem versus ceftriaxone and metronidazole as treatment for complicated intra-abdominal infections.

BACKGROUND: Prompt surgical intervention supplemented by appropriate antimicrobial therapy is usually required for successful treatment of complicated intra-abdominal infections. The objective of this study was to further evaluate the efficacy and safety of ertapenem relative to ceftriaxone/metronidazole as treatment for complicated intra-abdominal infections. METHODS: Adult patients with intra-abdominal infections requiring surgery were eligible for this open-label randomized trial comparing ertapenem 1 g daily with ceftriaxone 2 g daily plus metronidazole 30 mg/kg/day. The primary efficacy outcome was the clinical response rate in clinically and microbiologically evaluable participants at the test-of-cure (TOC) visit 2 weeks after discontinuation of therapy. All treated patients were included in the safety analysis. RESULTS: Participant demographics, disease characteristics, and duration of therapy in both treatment groups were generally similar. Escherichia coli was the most commonly isolated baseline pathogen, recovered in 52% of cases in each treatment group. Favorable clinical responses were achieved at TOC in 143 (96.6%) of 148 ertapenem recipients and in 146 (96.7%) of 151 ceftriaxone/metronidazole recipients. The frequencies of drug-related adverse events, most commonly nausea, diarrhea, vomiting, and elevated platelet count, were generally comparable in both treatment arms. Four ertapenem recipients (1.8%) and one ceftriaxone/metronidazole recipient (0.4%) experienced serious drug-related adverse events. CONCLUSIONS: In this study, ertapenem and ceftriaxone/metronidazole were comparably effective treatments for adult patients with complicated intra-abdominal infections.

[New Beta-lactam agent in the treatment of intra-abdominal sepsis: double blind and randomized stage III study of ertapenem versus piperacillin/tazobactam]. / Nuevo agents betalactámico en el manejo de la sepsis intra-abdominal: estudio de fase III, doble ciego y randomizado del ertapenem vs piperacilina/tazobactam.

The clinical and safety efficacy of a new wide spectrum beta-lactam agent for most pathogen intra-abdominal infection germs is evaluated herein. Its chemical name is Ertapenem (MK-0826). Its pharmacokinetic characteristics and the known antibacterial spectrum enable the potential use of one daily dose in the treatment of infections by aerobic and anaerobic bacteria. This is a sub-group of patients that have been treated within a multinational, prospective, randomized, controlled and double-blind study, to compare the safety and efficacy of ertapenem (100% vs 88%) with piperacillin/tazobactam in patients that have undergone surgery due to complicated intra-abdominal infection, from April 1998 to October 1999, pursuant to the IDSA/FDA standards. Twenty local patients were evaluated from a total of 623 patients in 17 countries. Acute perforated appendicitis was the most frequent pathology in both groups. The recovery ratio was slightly higher in the group, which was administered ertapenem, with no documented clinical failure. This study shows the efficacy of ertapenem in the treatment of intra-abdominal infections using a single 1-gr/day dose, equivalent to 3.375 gr of piperacillin/tazobactam every six hours. Tolerance and safety were similar in both groups. No side effects, or mortality cases were registered. The results of this study indicate that ertapenem might be the therapeutic option to discard the combination of antibiotics or the use of multiple doses in intra-abdominal infections.

Glioma del quiasma óptico en una paciente con neurofibromatosis tipo 1 morbilidad visual y cambios a largo plazo demostrados por TC y RM / Neurofibromatosis type 1 and chiasma glioma

Objetivo: reportar los hallazgos clínicos y radiológicos de una paciente de 27 años con neurofibromatosis tipo 1 y glioma del quiasma seguida durante 19 años, sin tratamiento, la progresión de la disminución de la agudeza visual y del campo, así como los cambios del tumor mediante neuroimagen. Material y método: revisión clínica de la paciente, del expediente y de su archivo radiológico. Se efectuaron resonancia magnética, tomografía, agudeza visual, campos visuales y visión al color. Resultados: los estudios de TC mostraron hiperintensidad del tumor en la fase simple que disminuyó con el tiempo y no hubo cambios en el tamaño del tumor durante los 19 años de seguimiento. La visión de cada ojo se deterioró dos líneas, el OD de 20/400 a cuenta dedos a 1 m y la del OI de 20/30 a 20/50. Sólo el ojo izquierdo que tenía el mejor campo visual mostró reducción, el ojo derecho mostró cambios mínimos. Conclusiones. muy lento deterioro de la visión y el campo ocurrieron en ambos ojos de esta paciente. Por neuroimagen no se comprobó crecimiento tumoral sólo hiperintensidad de la fase simple en TC. Esto apoya otras observaciones de la baja agresividad tumoral del glioma del quiasma que aparece en la infancia, sin involucro del hipotálamo y que pudo ser observado sin tratamiento durante 19 años.

Resonancia magnética en el síndrome de Vogt-Koyanagi-Harada (uveo-meningoencefalitis) / Magnetic resonance in the Not-Koyanagi-Harada syndrome (uveo-meningoencefalitis)

Propósito. Investigar posibles cambios en el síndrome VKH con los patrones de neuroimagen que pudiera identificarse y contribuir al diagnóstico, al determinar posibles alteraciones oculares y cerebrales en las diferentes fases del padecimiento. Método. Se estudiaron 11 pacientes, 5 con resonancia magnética en fase oftálmica aguda, 6 casos fase de convalecencia y 10 pacientes adultos sanos ocular y neurológicamente como grupo control para establecer parámetros comparativos en medidas de esclerótica, coriorretina y nervio óptico. Resultado. Los estudios de RM aportan información sobre el desprendimiento de retina, engrosamiento del tracto uveal en general, pero no permite diferenciar las señales precisas entre estas estructuras. La esclerótica en fase de convalecencia está más engrosada en OD 17 por ciento y OI 23 por ciento. La coriorretina engrosada en fase aguda OD 67 por ciento y OI 91 por ciento más en convalecencia más engrosada el 28 por ciento ambos ojos y los nervios ópticos menos gruesos en convalecencias el 13 por ciento OD y 16 por ciento en OI. Conclusión. Las medidas aportadas por la RM en mm del nervio óptico, esclerótica y coriorretina difieren de las anatómicas conocidas. La coriorretina se mostró engrosada tanto en fase aguda como de convalencencia y la esclerótica engrosada sólo en la convalecencia. El nervio óptico disminuido de grosor en fase de convalecencia, no se demostró alteración alguna en meninges ni estructuras vecinas excepto un caso

Colecistitis aguda: estudio comparativo de 3 alternativas médico - quirúrgicas / Acute cholecystitis: comparative study of three medical-surgical alternatives

Se estudian tres alternativas de tratamiento quirúrgico de la Colecistitis Aguda, el Grupo I de 40 pacientes estudiados en forma retrospectiva, recibieron tratamiento médico conservador y cirugía convencional diferida; el Grupo II de 40 pacientesestudiados en forma prospectiva y operados antes de las 72 horas de iniciado el cuadro vesicular agudo mediante técnica convencional y el Grupo III de 40 pacientes estudiados en forma prospectiva e intervenidos mediante técnica laparoscópica. Comparamos el tiempo operatorio, la caída de temperatura, el retiro de sondanasogástrica, el dolor postoperatorio, la tolerancia oral y el tiempo de hospitalización postoperatorio. Demostramos que hay una diferencia significativa en todos los parámetros antes mencionados sobre todo cuando comparamos la técnica convencional y la técnica laparoscópica, en favor de la última.

Three alternatives of surgical treatment tor acute cholescystitis were studied. The 40 patients integrating Group I were studied in a retrospective way and received conservative medical treatment and deterred conventional surgery. The 40 patients integrating Group II were studied in a prospective way and they were operated according to conventiónal technique 72 hours before the beginning of the acutevesicular condition. The 40 patients integrating Group III were studied in a prospective way and they were operated using laparoscopic technique.The operation time, fall of temperature, the removal of the nasogastric tube, thepostoperative pain, the oral tolerance and the postoperative hospitalization time were compared. We find out that there is a significant difference between all the aforementioned parameters and, particularly, between the conventional technique and the laparoscopic technique.

[ACUTE CHOLECYSTITIS: COMPARATIVE STUDEY OF THREE MEDICAL-SURGICAL ALTERNATIVES] / Colecistitis Aguda: Estudio Comparativo de 3 alternativas Médico - Quirúrgicas.

Three alternatives of surgical treatment for acute cholescystitis were studied. The 40 patients integrating Group I were studied in a retrospective way and received conservative medical treatment and deferred conventional surgery. The 40 patients integrating Group II were studied in a prospective way and they were operated according to conventional technique 72 hours before the beginning of the acute vesicular condition. The 40 patients integrating Group III were studied in a prospective way and they were operated using laparoscopic technique. The operation time, fall of temperature, the removal of the nasogastric tube, the postoperative pain, the oral tolerance and the postoperative hospitalization time were compared. We find out that there is a significant difference between all the aforementioned parameters and, particularly, between the conventional technique and the laparoscopic technique.

Patología tiroidea operada: 12 años de experiencia en el Hospital Cayetano Heredia / Thyroid pathology operated: 12 years of experience at the Hospital Cayetano Heredia

Se presenta las características clínicas, técnica operatoria, estudio histopatológico y evolución de 173 pacientes con patología tiroidea operada en el Hospital Nacional Cayetano Heredia entre 1976 y 1987. 52.6 por ciento presentaron bocio nodular, 63.5 por ciento presentaron nódulos fríos y 21.1 por ciento nódulos calientes. Las técnicas operatorias empleadas fueron: lobectomía total más istmectomía (65.8 por ciento), tiroidectomía subtotal bilateral (19 por ciento), lobectomía total más istmectomía más lobectomía parcial contralateral (8 por ciento) y tiroidectomía total (4 por ciento). La biopsia por congelación se realizó en 95 por ciento de los pacientes. Bocio coloide fue el resultaado histopatológico más frecuente (67.6 por ciento). La patología benigna se encontró en 84.6 por ciento y la maligna en 15.4 por ciento. Las complicaciones fueron: lesión unilateral del nervio recurrente (4 por ciento), hematomas sofocantes (2.3 por ciento) e hipoparatiroidismo transitorio (1.7 por ciento). La mortalidad fué de 0.5 por ciento