Surgical treatment of pancreaticojejunal stenosis after pancreaticoduodenectomy: case report.

Pancreaticoduodenectomy is established as the procedure of choice for malignant tumor pathologies of the head of the pancreas or ampulla, where the patient's life prognosis is low. Complications after pancreaticoduodenectomy (e.g. pancreatic fistulas, hemorrhages, or intra-abdominal collection) are well described in the literature and are generally acute. However, there is still a small risk for late complications (e.g. pancreatitis, pancreatic insufficiency), and due to its low incidence, there has not been a consensus on the treatment. We present the case of an 18-year-old female with recurrent bouts of acute pancreatitis as a late complication of a pancreaticoduodenectomy plus pancreatojejunal anastomosis due to a pseudopapillary tumor of the pancreas. The complication was managed though surgical revision consisting of dilation and stent placement in the stenosis. The patient had an adequate postoperative evolution without further complications. Despite the advances in the surgical field, pancreaticoduodenectomy represents a highly complex surgery with high morbidity and mortality rates. The late complications of this surgery are under continuous study due to its low incidence associated with low patient survival.

No evidence of association between inherited thrombophilia and increased risk of liver fibrosis.

BACKGROUND: Preliminary evidence suggests that inherited hypercoagulable disorders can lead to an increased risk of significant liver fibrosis. OBJECTIVE: We aimed to investigate the prevalence of significant fibrosis in patients with inherited thrombophilia, assessed by using liver stiffness (LS), and to compare this prevalence to that found in a large population-based cohort from the same region. METHODS: This was a single-center, cross-sectional study. A complete laboratory analysis for liver disease, LS by transient elastography and an abdominal ultrasound were performed in patients with inherited thrombophilia diagnosed between May 2013-February 2017. These patients were propensity score matched (ratio 1:4) with a population-based cohort from the same region (PREVHEP-ETHON study; NCT02749864; N = 5988). RESULTS: Of 241 patients with inherited thrombophilia, eight patients (3.3%) had significant fibrosis (LS ≥8 kPa). All of them had risk factors for liver disease and met diagnostic criteria for different liver diseases. After matching 221 patients with thrombophilia with 884 patients of the PREVHEP-ETHON cohort, the prevalence of significant fibrosis was similar between both cohorts (1.8% vs. 3.6%, p = 0.488). Multivariate analysis showed that age and liver disease risk factors, but not belonging to the thrombophilia cohort, were associated with the presence of significant fibrosis. The magnitude of the increased risk of significant fibrosis in patients with risk factors for liver disease was also similar in both cohorts. CONCLUSIONS: Our findings do not provide evidence supporting an association between inherited thrombophilia and an increased risk of significant liver fibrosis, independent of the presence of liver-related causes of fibrosis.

Microglial targeted therapy relieves cognitive impairment caused by Cntnap4 deficiency.

Contactin-associated protein-like 4 (Cntnap4) is critical for GABAergic transmission in the brain. Impaired Cntnap4 function is implicated in neurological disorders, such as autism; however, the role of Cntnap4 on memory processing is poorly understood. Here, we demonstrate that hippocampal Cntnap4 deficiency in female mice manifests as impaired cognitive function and synaptic plasticity. The underlying mechanisms may involve effects on the pro-inflammatory response resulting in dysfunctional GABAergic transmission and activated tryptophan metabolism. To efficiently and accurately inhibit the pro-inflammatory reaction, we established a biomimetic microglial nanoparticle strategy to deliver FDA-approved PLX3397 (termed MNPs@PLX). We show MNPs@PLX successfully penetrates the blood brain barrier and facilitates microglial-targeted delivery of PLX3397. Furthermore, MNPs@PLX attenuates cognitive decline, dysfunctional synaptic plasticity, and pro-inflammatory response in female heterozygous Cntnap4 knockout mice. Together, our findings show loss of Cntnap4 causes pro-inflammatory cognitive decline that is effectively prevented by supplementation with microglia-specific inhibitors; thus validating the targeting of microglial function as a therapeutic intervention in neurocognitive disorders.

Elevated asleep blood pressure and non-dipper 24h patterning best predict risk for heart failure that can be averted by bedtime hypertension chronotherapy: A review of the published literature.

Several prospective studies consistently report elevated asleep blood pressure (BP) and blunted sleep-time relative systolic BP (SBP) decline (non-dipping) are jointly the most significant prognostic markers of cardiovascular disease (CVD) risk, including heart failure (HF); therefore, they, rather than office BP measurements (OBPM) and ambulatory awake and 24 h BP means, seemingly are the most worthy therapeutic targets for prevention. Published studies of the 24 h BP pattern in HF are sparse in number and of limited sample size. They report high prevalence of the abnormal non-dipper/riser 24 h SBP patterning. Despite the established clinical relevance of the asleep BP, past as do present hypertension guidelines recommend the diagnosis of hypertension rely on OBPM and, when around-the-clock ambulatory BP monitoring (ABPM) is conducted to confirm the elevated OBPM, either on the derived 24 h or "daytime" BP means. Additionally, hypertension guidelines do not advise the time-of-day when BP-lowering medications should be ingested, in spite of known ingestion-time differences in their pharmacokinetics and pharmacodynamics. Between 1976 and 2020, 155 unique trials of ingestion-time differences in the effects of 37 different single and 14 dual-combination hypertension medications, collectively involving 23,972 patients, were published. The vast majority (83.9%) of them found the at-bedtime/evening in comparison to upon-waking/morning treatment schedule resulted in more greatly enhanced: (i) reduction of asleep BP mean without induced sleep-time hypotension; (ii) reduction of the prevalence of the higher CVD risk non-dipper/riser 24 h BP phenotypes; (iii) improvement of kidney function, reduction of cardiac pathology, and with lower incidence of adverse effects. Most notably, no single published randomized trial found significantly better BP-lowering, particularly during sleep, or medical benefits of the most popular upon-waking/morning hypertension treatment-time scheme. Additionally, prospective outcome trials have substantiated that the bedtime relative to the upon-waking, ingestion of BP-lowering medications not only significantly reduces risk of HF but also improves overall CVD event-free survival time.

Neuroendocrine tumor of the ampulla of Vater. Review of the literature.

Neuroendocrine tumors (NETs) or carcinoids represent a small percentage of gastrointestinal neoplasms (2%). The ileum (41.8%), rectum (27.4%) and stomach (8.7%) are the most common locations. We present an unusual case of NET due to its origin in the ampulla of Vater, as an extremely rare cause of biliary obstruction. A bibliographic review of the current recommendations of management and treatment for this case, different from other locations of the gastrointestinal tract is carried out. The curative treatment of choice for early-stage Vater ampulla NETs is Whipple surgery with lymphadenectomy due to Its high rate of lymphatic and metastatic dissemination, regardless of size and histological grade, although there are no updated official guidelines.

Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection.

Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.

An Unusual Cause of Right Heart Dysfunction and High Output Heart Failure in a Young Woman.

A 35-year-old female presented to our emergency department with clinical signs of acute heart failure. Clinical workup identified severe right heart (RH) dilation and dysfunction with a crossing membrane structure in the right atrium. Right heart catheterization confirmed high output heart failure (HOHF), pulmonary hypertension (PH), and left-to-right blood shunting followed by the documentation of multiple liver and pulmonary arteriovenous malformations (AVMs). Hereditary Hemorrhagic Telangiectasia (HHT) diagnosis was made according to clinical criteria and was established as the cause of HOHF because of chronic volume overload from systemic to pulmonary shunts. With this illustrative case, we aim to discuss the broad spectrum of clinical manifestations of HHT and the unusual phenotype of HOHF secondary to HHT. This case also highlights the broad diagnosis of atrial echocardiographic abnormalities and cardiac structural distortion secondary to high output that can be misleading at imaging evaluation.

Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that manifests sequential Aß and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer's disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive. METHODS: Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes. RESULTS: Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia. CONCLUSION: Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes.

Outcomes in Temporary ICUs Versus Conventional ICUs: An Observational Cohort of Mechanically Ventilated Patients With COVID-19-Induced Acute Respiratory Distress Syndrome.

Throughout the COVID-19 pandemic, thousands of temporary ICUs have been established worldwide. The outcomes and management of mechanically ventilated patients in these areas remain unknown. OBJECTIVES: To investigate mortality and management of mechanically ventilated patients in temporary ICUs. DESIGN SETTING AND PARTICIPANTS: Observational cohort study in a single-institution academic center. We included all adult patients with severe COVID-19 hospitalized in temporary and conventional ICUs for invasive mechanical ventilation due to acute respiratory distress syndrome from March 23, 2020, to April 5, 2021. MAIN OUTCOMES AND MEASURES: To determine if management in temporary ICUs increased 30-day in-hospital mortality compared with conventional ICUs. Ventilator-free days, ICU-free days (both at 28 d), hospital length of stay, and ICU readmission were also assessed. RESULTS: We included 776 patients (326 conventional and 450 temporary ICUs). Thirty-day in-hospital unadjusted mortality (28.8% conventional vs 36.0% temporary, log-rank test p = 0.023) was higher in temporary ICUs. After controlling for potential confounders, hospitalization in temporary ICUs was an independent risk factor associated with mortality (hazard ratio, 1.4; CI, 1.06-1.83; p = 0.016).There were no differences in ICU-free days at 28 days (6; IQR, 0-16 vs 2; IQR, 0-15; p = 0.5) or ventilator-free days at 28 days (8; IQR, 0-16 vs 5; IQR, 0-15; p = 0.6). We observed higher reintubation (18% vs 12%; p = 0.029) and readmission (5% vs 1.6%; p = 0.004) rates in conventional ICUs despite higher use of postextubation noninvasive mechanical ventilation (13% vs 8%; p = 0.025). Use of lung-protective ventilation (87% vs 85%; p = 0.5), prone positioning (76% vs 79%; p = 0.4), neuromuscular blockade (96% vs 98%; p = 0.4), and COVID-19 pharmacologic treatment was similar. CONCLUSIONS AND RELEVANCE: We observed a higher 30-day in-hospital mortality in temporary ICUs. Although both areas had high adherence to evidence-based management, hospitalization in temporary ICUs was an independent risk factor associated with mortality.

Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection.

Prevention of infection and propagation of SARS-CoV-2 is of high priority in the COVID-19 pandemic. Here, we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 Spike protein, thereby inhibiting viral entry, infectivity, and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and thus spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E-protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model, and thus provide a novel avenue for therapy.

Multicentre oncology clinical trials in primary health care in Cuba: evaluation of programme implementation in Villa Clara Province, 2010-2020.

BACKGROUND: The Center of Molecular Immunology of Cuba has developed a programme for the conducting of multicentre oncology clinical trials in primary healthcare centres since 2009. AIM: To evaluate the ability to conduct oncology clinical trials in primary health care. DESIGN & SETTING: A longitudinal, prospective, analytical study was developed between July 2010 and August 2020 in the Villa Clara province. METHOD: Structure, process, and outcome indicators were evaluated by the methods of a structured interview, direct observation, documentary observation, and databases analysis. The investigators' curricula vitae, the investigator site file, minutes of workshops, the monitoring reports, the clinical trial training records, and databases were employed as sources of information. The following criteria were considered adequate: when the indicator met the standard; and not adequate: when the indicator did not meet the standard. RESULTS: The six structure indicators reached adequate results and showed that the programme has allowed building of capacities to conduct clinical trials in primary care. The eight processes indicators and two outcome indicators were considered adequate too. Trials conducted in primary care showed better indicators of patient recruitment than secondary care. Both scenarios showed similar behaviour for the process indicators: retention, protocol compliance, and safety. Survival and satisfaction with health services were also comparable in both scenarios. CONCLUSION: The evaluation of the programme showed adequate indicators for conducting oncology clinical trials in primary care in Villa Clara and these were comparable to those determined in the secondary care.

Early work activities after sedation with propofol in digestive endoscopy. Reply.

We read with interest the letter by Dr. Cerezo-Ruiz and we agree in general with the commentaries and would like to add some information related to the use of propofol in deep sedation by our group.

Global carbon sequestration through continental chemical weathering in a climatic change context.

This study simulates carbon dioxide (CO2) sequestration in 300 major world river basins (about 70% of global surface area) through carbonates dissolution and silicate hydrolysis. For each river basin, the daily timescale impacts under the RCP 2.6 and RCP 8.5 climate scenarios were assessed relative to a historical baseline (1969-1999) using a cascade of models accounting for the hydrological evolution under climate change scenarios. Here we show that the global temporal evolution of the CO2 uptake presents a general increase in the annual amount of CO2 consumed from 0.247 ± 0.045 Pg C year-1 to 0.261 and 0.273 ± 0.054 Pg C year-1, respectively for RCP 2.6 and RCP 8.5. Despite showing a general increase in the global daily carbon sequestration, both climate scenarios show a decrease between June and August. Such projected changes have been mapped and evaluated against changes in hydrology, identifying hot spots and moments for the annual and seasonal periods.

Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior.

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose-response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.

Case report: Infrequent littoral cell angioma of the spleen.

INTRODUCTION AND IMPORTANCE: Littoral cell angioma is a rare solid spleen tumor with uncertain malignant potential. It is usually asymptomatic; therefore, its diagnosis is usually incidental. There are approximately 150 cases reported in the medical literature, but none of them in the Hispanic population. CASE PRESENTATION: We present a case of a 54-year-old woman who presented to our clinic with nonspecific abdominal pain. Imaging studies show a splenic mass with littoral cell angioma characteristics. The patient underwent an open splenectomy with subsequent histopathologic and immunohistochemical studies that confirmed the presence of a littoral cell angioma of a diameter of 8 × 4.5 × 3.5 cm. The patient was discharged after an uneventful postoperative recovery and was referred to the outpatient clinic for follow up. CLINICAL DISCUSSION: This case report highlights the close relationship between the littoral cell angioma, neoplasias, and autoimmune diseases. Even though LCA has a good prognosis, there is still the possibility of malignant transformation, especially when the spleen weighs 1500 g; our patient's sample pointed towards a benign pathology. LCA has a positive IHC for endothelial and histiocyte tissues. The IHC results of our patient were positive for CD34+ and CD68+, confirming the LCA diagnosis. CONCLUSION: Within red pulp spleen tumors, LCA should be highly considered as a differential diagnosis in all types of populations. In the case of a confirmed LCA, routine screening for neoplasias and autoimmune diseases should be performed.