Behavioral outputs and overlapping circuits between conditional fear and active avoidance.

Aversive learning can produce a wide variety of defensive behavioral responses depending on the circumstances, ranging from reactive responses like freezing to proactive avoidance responses. While most of this initial learning is behaviorally supported by an expectancy of an aversive outcome and neurally supported by activity within the basolateral amygdala, activity in other brain regions become necessary for the execution of defensive strategies that emerge in other aversive learning paradigms such as active avoidance. Here, we review the neural circuits that support both reactive and proactive defensive behaviors that are motivated by aversive learning, and identify commonalities between the neural substrates of these distinct (and often exclusive) behavioral strategies.

Argentine Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis in Postmenopausal Women and Men Aged 50 Years and Older.

OBJECTIVE: The aim of this study was to provide an evidence-based framework to guide health care professionals treating patients under glucocorticoid (GC) therapy and develop guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (GIO) in postmenopausal women and men aged ≥50 years. METHODS: An expert panel on bone diseases designed a series of clinically meaningful questions following the PICO (Population, Intervention, Comparator, and Outcome) structure. Using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, we made a systematic literature review, extracted and summarized the effect estimates, and graded the quality of the evidence. The expert panel voted each PICO question and made recommendations after reaching an agreement of at least 70%. RESULTS: Seventeen recommendations (9 strong and 8 conditional) and 8 general principles were developed for postmenopausal women and men aged ≥50 years under GC treatment. Bone mineral density (BMD), occurrence of fragility fractures, probability of fracture at 10 years by Fracture Risk Assessment Tool, and other screening factors for low BMD are recommended for patient evaluation and stratification according to fragility fracture risk. The treatment of patients under GC therapy should include counseling on lifestyle habits and strict control of comorbidities. The goal of GIO treatment is the nonoccurrence of new fragility fractures as well as to increase or maintain BMD in certain clinical situations. This was considered for the therapeutic approach in different clinical scenarios. CONCLUSIONS: This GIO guideline provides evidence-based guidance for health care providers treating patients.

Single cell cloning of free-living amoebae with isolated square agar.

An alternative amoeba cloning technique is described. The amoebic cells were scraped from the agar and inoculated in a new agar medium separated in isolated squares, preventing a cell from invading the space of another cell, increasing the reliability of cloning, and providing an efficient quality control of technique.

Genotype distribution of Acanthamoeba in keratitis: a systematic review.

Acanthamoeba spp. are among the most worldwide prevalent protozoa. It is the causative agent of a disease known as Acanthamoeba keratitis, a painful and severe sight-threatening corneal infection that can lead to blindness. In recent years, the prevalence of Acanthamoeba keratitis has rapidly increased, growing its importance to human health. This systematic review aims to assess the distribution of Acanthamoeba sp. genotypes causing keratitis around the world, considering the sample collected type and the used identification method. Most of the cases were found in Asia and Europe. Not surprisingly, the T4 genotype was the most prevalent worldwide, followed by T3, T15, T11, and T5. Furthermore, the T4 genotype contains a higher number of species. Given the differences in pathology, susceptibility to treatment, and clinical outcome between distinct genotypes, it is essential to genotype isolates from Acanthamoeba keratitis cases to help to establish a better correlation between in vitro and in vivo activities, resulting in better drug therapies and successful treatment in cases of this important ocular infection.

Prolonged social lockdown during COVID-19 pandemic and hip fracture epidemiology.

PURPOSE: To analyse the impact of prolonged mandatory lockdown due to COVID-19 on hip fracture epidemiology. METHODS: Retrospective case-control study of 160 hip fractures operated upon between December 2019 and May 2020. Based on the date of declaration of national lockdown, the cohort was separated into two groups: 'pre-COVID time' (PCT), including 86 patients, and 'COVID time' (CT), consisting of 74 patients. All CT patients tested negative for SARS-CoV-2. Patients were stratified based on demographic characteristics. Outcome measures were 30-day complications, readmissions and mortality. A logistic regression model was run to evaluate factors associated with mortality. RESULTS: Age, female/male ratio, body mass index and American Society of Anaesthesia score were similar between both groups (p > 0.05). CT patients had a higher percentage of Charlson ≥ 5 and Rockwood Frailty Index ≥ 5 scores (p < 0.05) as well as lower UCLA and Instrumental Activities of Daily Living scores (p < 0.05). This translated into a higher hemiarthroplasty/total hip arthroplasty ratio during CT (p = 0.04). Thromboembolic disease was higher during CT (p = 0.02). Readmissions (all negative for SARS-CoV-2) were similar between both groups (p = 0.34). Eight (10.8%) casualties were detected in the CT group, whereas no deaths were seen in the control group. Logistic regression showed that frailer (p = 0.006, OR 10.46, 95%CI 8.95-16.1), less active (p = 0.018, OR 2.45, 95%CI 1.45-2.72) and those with a thromboembolic event (p = 0.005, OR 30, 95%CI 11-42) had a higher risk of mortality. CONCLUSION: Despite testing negative for SARS-CoV-2, CT patients were less active and frailer than PCT patients, depicting an epidemiological shift that was associated with higher mortality rate.

Responses of prefrontal multisensory neurons to mismatching faces and vocalizations.

Social communication relies on the integration of auditory and visual information, which are present in faces and vocalizations. Evidence suggests that the integration of information from multiple sources enhances perception compared with the processing of a unimodal stimulus. Our previous studies demonstrated that single neurons in the ventrolateral prefrontal cortex (VLPFC) of the rhesus monkey (Macaca mulatta) respond to and integrate conspecific vocalizations and their accompanying facial gestures. We were therefore interested in how VLPFC neurons respond differentially to matching (congruent) and mismatching (incongruent) faces and vocalizations. We recorded VLPFC neurons during the presentation of movies with congruent or incongruent species-specific facial gestures and vocalizations as well as their unimodal components. Recordings showed that while many VLPFC units are multisensory and respond to faces, vocalizations, or their combination, a subset of neurons showed a significant change in neuronal activity in response to incongruent versus congruent vocalization movies. Among these neurons, we typically observed incongruent suppression during the early stimulus period and incongruent enhancement during the late stimulus period. Incongruent-responsive VLPFC neurons were both bimodal and nonlinear multisensory, fostering their ability to respond to changes in either modality of a face-vocalization stimulus. These results demonstrate that ventral prefrontal neurons respond to changes in either modality of an audiovisual stimulus, which is important in identity processing and for the integration of multisensory communication information.

Long-range GABAergic neurons in the prefrontal cortex modulate behavior.

Cortical glutamatergic projections are extensively studied in behavioral neuroscience, whereas cortical GABAergic projections to downstream structures have been overlooked. A recent study by Lee and colleagues (Lee AT, Vogt D, Rubenstein JL, Sohal VS. J Neurosci 34: 11519-11525, 2014) used optogenetic and electrophysiological techniques to characterize a behavioral role for long-projecting GABAergic neurons in the medial prefrontal cortex. In this Neuro Forum, we discuss the potential implications of this study in several learning and memory models.

Hypercalcemia secondary to granulomatous disease caused by the injection of methacrylate: a case series.

Association of dysregulated calcium homeostasis and granulomatous disease is well established. There exist reports in the literature of granulomatous reactions produced by silicones associated with hypercalcemia. In this case series we report four young women that underwent methacrylate injections in gluteus, thighs and calves that developed granulomas with posterior appearance of hypercalcemia. This complication presented as subacute around 6 months after the procedure. The four patients have as common elements the presence of moderate to severe renal insufficiency, suppressed PTH and elevated calcitriol levels for the degree of renal function. In the image studies, two patients presented in the nuclear magnetic resonance of the gluteus hypodense nodular images compatible with granulomas. Two patients had a positron emission tomography performed showing increased metabolic activity in the muscles of the gluteal region compatible with granulomas. Two patients had a partial surgical resection of the gluteal lesions with the finding of methacrylate associated to foreign body granulomas. In these patients hypercalcemia was treated with oral or local injections of corticoids, intravenous bisphosphonates or ketoconazole with good response. Although the prevalence of this complication with methacrylate injection is not common, hypercalcemia secondary to granulomas should be considered in the differential diagnosis of patients with hypercalcemia when there is a history of this procedure, and especially if they have a reduction in their renal function.

Active avoidance recruits the anterior cingulate cortex regardless of social context in male and female rats.

Actively avoiding danger is necessary for survival. Most research has focused on the behavioral and neurobiological processes when individuals avoid danger alone, under solitary conditions. Therefore, little is known about how social context affects active avoidance. Using a modified version of the platform-mediated avoidance task in rats, we investigated whether the presence of a social partner attenuates conditioned freezing and enhances avoidance learning compared to avoidance learned under solitary conditions. Rats spent a similar percentage of time avoiding during the tone under both conditions; however, rats trained under social conditions exhibited greater freezing during the tone as well as lower rates of darting and food seeking compared to solitary rats. Under solitary conditions, we observed higher levels of avoidance in females compared to males, which was not present in rats trained under social conditions. To gain greater mechanistic insight, we optogenetically inactivated glutamatergic projection neurons in the anterior cingulate cortex (ACC) following avoidance training. Photoinactivation of ACC neurons reduced expression of avoidance under social conditions both in the presence and absence of the partner. Under solitary conditions, photoinactivation of ACC delayed avoidance in males but blocked avoidance in females. Our findings suggest that avoidance is mediated by the ACC, regardless of social context, and may be dysfunctional in those suffering from trauma-related disorders. Furthermore, sex differences in prefrontal circuits mediating active avoidance warrant further investigation, given that females experience a higher risk of developing anxiety disorders.

[Calciphylaxis, risk factors, treatment and outcomes. Retrospective study of 39 patients]. / Calcifilaxis, factores de riesgo, tratamiento y evolución. Estudio retrospectivo de 39 pacientes.

INTRODUCTION: Calciphylaxis is a serious vascular disorder characterized by calcification of tunica media, intimal hyperplasia, thrombosis, and skin necrosis. It was described in patients with renal failure (UC), although it can occur in its absence (NUC). Its risk factors are under study and its diagnosis can be complex. Over a decade ago, its mortality was estimated at 60-80%. Recent studies indicate that it has decreased (40%). METHODS: A retrospective study was carried out in the period between January 1, 2011 and December 31, 2019. The past medical record, clinical characteristics, laboratory and histopathological findings, and evolution of all patients with calciphylaxis evaluated at the Hospital Italiano de Buenos Aires were reviewed. RESULTS: Thirty-nine patients were included. Sixtyone percent were men and 39% were NUC cases. Eightytwo percent had arterial hypertension, 66% obesity and 46% diabetes. Of those, 49% received coumarin anticoagulants. All patients with NUC and 75% with UC presented ulcers with necrosis, located more frequently on the legs. In 72% of the cases the histological diagnosis was made with one biopsy. In all the treatment was multimodal and mortality at one year was 42%. CONCLUSION: We observed a high proportion of patients with NUC, in relation to what is reported in the literature, and that half received vitamin K antagonists. The histological diagnosis was made with one biopsy in most of the cases, as the surgical technique for taking the sample, the Von Kossa staining and the evaluation by an expert pathologist were the key of it.

Introducción: La calcifilaxis es un trastorno vascular grave caracterizado por depósito de calcio en túnica media arteriolar, trombosis y necrosis cutánea. Se describió en pacientes con insuficiencia renal (CU), aunque puede producirse en su ausencia (CNU). Sus factores de riesgo están en estudio y su diagnóstico puede ser complejo. Su mortalidad se estimaba en 60-80%, aunque trabajos recientes indican que ha disminuido (40%). Métodos: Estudio retrospectivo entre el 1/1/2011 y el 31/12/2019. Se revisaron los antecedentes, las características clínicas, los hallazgos de laboratorio e histopatológicos, y la evolución de todos los pacientes con diagnóstico de calcifilaxis evaluados en el Hospital Italiano de Buenos Aires. Resultados: Se incluyeron 39 pacientes. El 61.5% (24) eran hombres y 38.5% (15) fueron casos de CNU. De éstos, 82% presentaba hipertensión arterial, 66% obesidad y 46% diabetes. El 49% recibía anticoagulantes dicumarínicos. Todos los pacientes con CNU y 75% con CU presentaron úlceras de fondo necrótico, localizadas con mayor frecuencia en las piernas. En 72% de los casos el diagnóstico histológico se efectuó con una toma de biopsia. En todos, el tratamiento fue multimodal y la mortalidad al año fue de 42%. Conclusión: Observamos una elevada proporción de pacientes con CNU, en relación con lo comunicado en la literatura, y la mitad recibía anticoagulantes dicumarínicos. El diagnóstico histológico se efectuó por biopsia en la mayor parte de los casos, para lo cual la toma quirúrgica de la muestra, la tinción con Von Kossa y la evaluación por un patólogo experto fueron claves.

[Guidelines for the diagnosis, prevention and treatment of osteoporosis, 2012]. / Guías 2012 para el diagnóstico, la prevención y el tratamiento de la osteoporosis.

Osteoporosis is a constantly growing disease which affects over 200 million people worldwide. The present recommendations are guidelines for its diagnosis, prevention and treatment, but they do not constitute standards for clinical decisions in individual patients. The physician must adapt them to individual patients and special situations, incorporating personal factors that transcend the limits of these guidelines and are dependent on the knowledge and art of the physician. These guidelines should be reviewed and updated periodically as new, better and more effective diagnostic and therapeutic tools become available.

A Novel Insular/Orbital-Prelimbic Circuit That Prevents Persistent Avoidance in a Rodent Model of Compulsive Behavior.

BACKGROUND: A common symptom of obsessive-compulsive disorder is the persistent avoidance of cues incorrectly associated with negative outcomes. This maladaptation becomes increasingly evident as subjects fail to respond to extinction-based treatments such as exposure-with-response prevention therapy. While previous studies have highlighted the role of the insular-orbital cortex in fine-tuning avoidance-based decisions, little is known about the projections from this area that might modulate compulsive-like avoidance. METHODS: Here, we used anatomical tract-tracing, single-unit recording, and optogenetics to characterize the projections from the insular-orbital cortex. To model exposure-with-response prevention and persistent avoidance in rats, we used the platform-mediated avoidance task followed by extinction-with-response prevention training. RESULTS: Using tract-tracing and unit recording, we found that projections from the agranular insular/lateral orbital (AI/LO) cortex to the prefrontal cortex predominantly target the rostral portion of the prelimbic (rPL) cortex and excite rPL neurons. Photoinhibiting this projection induced persistent avoidance after extinction-with-response prevention training, an effect that was still present 1 week later. Consistent with this, photoexcitation of this projection prevented persistent avoidance in overtrained rats. This projection to rPL appears to be key for AI/LO's effects, considering that there was no effect of photoinhibiting AI/LO projections to the ventral striatum or basolateral amygdala. CONCLUSIONS: Our findings suggest that projections from the AI/LO to the rPL decreases the likelihood of avoidance behavior following extinction. In humans, this connectivity may share some homology of projections from lateral prefrontal cortices (i.e., ventrolateral prefrontal cortex, orbitofrontal cortex, and insula) to other prefrontal areas and the anterior cingulate cortex, suggesting that reduced activity in these pathways may contribute to obsessive-compulsive disorder.

Threshold based on bone mineral density for therapeutic decision-making in postmenopausal women and men over 50 years old under glucocorticoid therapy.

INTRODUCTION AND AIM: T-score bone mineral density (BMD) thresholds may influence guidance for treatment in patients under glucocorticoid (GC) therapy. Different BMD thresholds have been described but there is no international consensus. The aim of this study was to find a threshold to help in treatment decision-making in the population under GC therapy. METHODS: A working group representing three scientific societies from Argentina was convened. The first team was formed by specialists with expertise in glucocorticoid-induced osteoporosis (GIO) who voted according to summary of evidence. The second team was constituted by a methodology group who coordinated and supervised each stage. We conducted two systematic reviews to synthesize the evidence. The first included trials of drugs used in GIO to analyze the BMD cut-off used as inclusion criteria. In the second, we analyzed the evidence regarding the densitometric thresholds to discriminate between fractured and non-fractured patients under GC treatment. RESULTS: In the first review, 31 articles were included for qualitative synthesis and more than 90% of the trials included patients regardless of their densitometric T-score or range of osteopenia. In the second review, 4 articles were included and more than 80% of the T-scores were in the range -1.6 to -2.0. The summary of findings was analyzed and put to a vote. CONCLUSIONS: With more than 80% agreement of the voting expert panel, a T-score≤-1.7 was considered the most appropriate for treatment in postmenopausal women and men over 50 years of age under GC therapy. This study could help in treatment decision-making in patients under GC therapy without fractures but other fracture risk factors should certainly be considered.

Representation of Expression and Identity by Ventral Prefrontal Neurons.

Evidence has suggested that the ventrolateral prefrontal cortex (VLPFC) processes social stimuli, including faces and vocalizations, which are essential for communication. Features embedded within audiovisual stimuli, including emotional expression and caller identity, provide abundant information about an individual's intention, emotional state, motivation, and social status, which are important to encode in a social exchange. However, it is unknown to what extent the VLPFC encodes such features. To investigate the role of VLPFC during social communication, we recorded single-unit activity while rhesus macaques (Macaca mulatta) performed a nonmatch-to-sample task using species-specific face-vocalization stimuli that differed in emotional expression or caller identity. 75% of recorded cells were task-related and of these >70% were responsive during the nonmatch period. A larger proportion of nonmatch cells encoded the stimulus rather than the context of the trial type. A subset of responsive neurons were most commonly modulated by the identity of the nonmatch stimulus and less by the emotional expression, or both features within the face-vocalization stimuli presented during the nonmatch period. Neurons encoding identity were found in VLPFC across a broader region than expression related cells which were confined to only the anterolateral portion of the recording chamber in VLPFC. These findings suggest that, within a working memory paradigm, VLPFC processes features of face and vocal stimuli, such as emotional expression and identity, in addition to task and contextual information. Thus, stimulus and contextual information may be integrated by VLPFC during social communication.

Alliance for the development of the Argentinian Hip Fracture Registry.

Age expectancy has significantly increased over the last 50 years, as well as some age-related health conditions such as hip fractures. The development of hip fracture registries has shown enhanced patient outcomes through quality improvement strategies. The development of the Argentinian Hip Fracture Registry is going in the same direction. INTRODUCTION: Age expectancy has increased worldwide in the last 50 years, with the population over 64 growing from 4.9 to 9.1%. As fractures are an important problem in this age group, specific approaches such as hip fracture registries (HFR) are needed. Our aim is to communicate the Argentinian HFR (AHFR) development resulting from an alliance between Fundación Trauma, Fundación Navarro Viola, and the Argentinian Network of Hip Fracture in the elderly. METHODS: Between October 2020 and May 2021, an iterative consensus process involving 5 specialty-focused meetings and 8 general meetings with more than 20 specialists was conducted. This process comprised inclusion criteria definitions, dataset proposals, website deployment with data protection and user validation, the definition of hospital-adjusted registry levels, implementation planning, and sustainability strategies. RESULTS: By June 2021, we were able to (1) outline data fields, including epidemiological, clinical, and functional dimensions for the pre-admission, hospitalization, discharge, and follow-up stages; (2) define three levels: basic (53 fields), intermediate (85), and advanced (99); (3) identify 21 benchmarking indicators; and (4) make a correlation scheme among fracture classifications. Simultaneously, we launched a fundraising campaign to implement the AHFR in 30 centers, having completed 18. CONCLUSION: AHFR development was based on four pillars: (1) representativeness and support, (2) solid definitions from onset, (3) committed teams, and (4) stable funding. This tool may contribute to the design of evidence-based health policies to improve patient outcomes, and we hope this experience will help other LMICs to develop their own tailored-to-their-needs registries.

Know safety, no fear.

Every day we are bombarded by stimuli that must be assessed for their potential for harm or benefit. Once a stimulus is learned to predict harm, it can elicit fear responses. Such learning can last a lifetime but is not always beneficial for an organism. For an organism to thrive in its environment, it must know when to engage in defensive, avoidance behaviors and when to engage in non-defensive, approach behaviors. Fear should be suppressed in situations that are not dangerous: when a novel, innocuous stimulus resembles a feared stimulus, when a feared stimulus no longer predicts harm, or when there is an option to avoid harm. A cardinal feature of anxiety disorders is the inability to suppress fear adaptively. In PTSD, for instance, learned fear is expressed inappropriately in safe situations and is resistant to extinction. In this review, we discuss mechanisms of suppressing fear responses during stimulus discrimination, fear extinction, and active avoidance, focusing on the well-studied tripartite circuit consisting of the amygdala, medial prefrontal cortex and hippocampus.

Divergent projections of the prelimbic cortex bidirectionally regulate active avoidance.

The prefrontal cortex (PFC) integrates incoming information to guide our actions. When motivation for food-seeking competes with avoidance of danger, the PFC likely plays a role in selecting the optimal choice. In platform-mediated active avoidance, rats avoid a tone-signaled footshock by stepping onto a nearby platform, delaying access to sucrose pellets. This avoidance requires prelimbic (PL) PFC, basolateral amygdala (BLA), and ventral striatum (VS). We previously showed that inhibitory tone responses of PL neurons correlate with avoidability of shock (Diehl et al., 2018). Here, we optogenetically modulated PL terminals in VS and BLA to identify PL outputs regulating avoidance. Photoactivating PL-VS projections reduced avoidance, whereas photoactivating PL-BLA projections increased avoidance. Moreover, photosilencing PL-BLA or BLA-VS projections reduced avoidance, suggesting that VS receives opposing inputs from PL and BLA. Bidirectional modulation of avoidance by PL projections to VS and BLA enables the animal to make appropriate decisions when faced with competing drives.

Hypercalcemia as an Early Finding of Opportunistic Fungal Pneumonia in Renal Transplantation: A Case Series Report.

BACKGROUND: Pneumonia caused by opportunistic fungi is a serious complication in immunocompromised patients. Hypercalcemia has been described in renal transplantation associated with Pneumocystis jirovecii (PJP) or Histoplasma capsulatum (HCP) pneumonia. METHODS: We describe 5 patients who underwent kidney transplant between 2014 and 2019 and developed hypercalcemia before the diagnosis of pulmonary fungal infection: 4 patients with PJP and 1 with HCP. We assessed calcium metabolism and kidney function by total and ionized calcium, phosphorus, intact parathormone (iPTH), 25-OH vitamin D, 1,25(OH)2 vitamin D, and serum creatinine levels. RESULTS: Mean albumin-corrected calcium and ionized calcium were 12.56 mg/dL (range, 10.8-13.8 mg/dL) and 1.57 mmol/L (range, 1.43-1.69 mmol/L). Patients were normocalcemic, at 10.12 mg/dL (range, 9.6-10.5 mg/dL), before diagnosis and resolved hypercalcemia after antifungal treatment, at 8.86 mg/dL (range, 8.0-9.5 mg/dL). All patients had low or normal iPTH values, at 29.1 pg/mL (range, <3-44 pg/mL), with higher PTH levels 3 months before diagnosis and after treatment, at 147.3 pg/mL (range, 28.1-479 pg/mL) and 117.5 pg/mL (range, 18.2-245 pg/mL), respectively. The mean value for 25-OH vitamin D was 30.8 ng/mL (range, 14.6-62.8 ng/mL). This supports a PTH-independent mechanism, and we postulated an extrarenal production of 1,25(OH)2 vitamin D. CONCLUSION: In kidney transplant patients, hypercalcemia independent of PTH and refractory to treatment should alert for the possibility of opportunistic fungal pneumonia.

The study of active avoidance: A platform for discussion.

Traditional active avoidance tasks have advanced the field of aversive learning and memory for decades and are useful for studying simple avoidance responses in isolation; however, these tasks have limited clinical relevance because they do not model several key features of clinical avoidance. In contrast, platform-mediated avoidance (PMA) more closely resembles clinical avoidance because the response i) is associated with an unambiguous safe location, ii) is not associated with an artificial termination of the warning signal, and iii) is associated with a decision-based appetitive cost. Recent findings on the neuronal circuits of PMA have confirmed that amygdala-striatal circuits are essential for avoidance. In PMA, however, the prelimbic cortex facilitates the avoidance response early during the warning signal, perhaps through disinhibition of the striatum. Future studies on avoidance should account for additional factors such as sex differences and social interactions that will advance our understanding of maladaptive avoidance contributing to neuropsychiatric disorders.