Author Correction: Features of fragile people with SARS-CoV-2 infection in isolation in a COVID-19 hotel in Rome, Italy.

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (7): 2631-2638-DOI: 10.26355/eurrev_202204_28501-PMID: 35442479, published online on 15 April 2022. After publication, at the request of the Italian Ministry of Health, the authors asked to insert the following statement in the Acknowledgments section: "This research was funded by the Italian Ministry of Health (RC 2022)". There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/28501.

Features of fragile people with SARS-CoV-2 infection in isolation in a COVID-19 hotel in Rome, Italy.

OBJECTIVE: Temporary COVID-19 hotels have been established in Italy to assist the homeless people that test positive for SARS-CoV-2 and require isolation. This observational study aimed to investigate the characteristics of the subjects who were isolated at the Casa tra Noi COVID-19 hotel in Rome between October 2020 and May 2021 and to estimate the duration of SARS-CoV-2 positivity according to their main socio-demographic, behavioural and clinical features. SUBJECTS AND METHODS: Socio-demographic data, clinical history, and anamnestic data of guests were collected by the clinicians reviewing the medical documentation and face-to-face interviewing. Nasopharyngeal swabs were performed every 7 days and the presence of SARS-CoV-2 was assessed by RT-PCR. Median duration of SARS-CoV-2 positivity according to socio-demographic, behavioral factors and clinical condition was calculated. RESULTS: The 196 guests (161 males, 82.1%) had a median age of 41 years (IQR: 30-53), and were mostly African (87, 44.4%). Only asymptomatic/paucisymptomatic infections were observed. Almost half of the individuals (84, 42.9%) were affected by at least one co-morbidity, the frequency of which was higher among women (57.1% vs. 39.8%, p=0.06). The date of the negative SARS-CoV-2 molecular test was known for 144 guests (73.5%). Among these, the median duration of positivity was 21 days (IQR: 14-26) and did not significantly vary with age, country of origin, smoking status, alcohol or drug abuse. Among the co-morbidities, only infectious diseases significantly modified the duration of positivity, which increased from 21 to 34 days (p=0.013). CONCLUSIONS: Hotel guests were frequently affected by physical/mental co-morbidities. Duration of SARS-CoV-2 positivity was significantly prolonged only in individuals affected by an infectious disease.

Notch Signaling Activation as a Hallmark for Triple-Negative Breast Cancer Subtype.

Triple-negative breast cancer (TNBC) is a subgroup of 15%-20% of diagnosed breast cancer patients. It is generally considered to be the most difficult breast cancer subtype to deal with, due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), which usually direct targeted therapies. In this scenario, the current treatments of TNBC-affected patients rely on tumor excision and conventional chemotherapy. As a result, the prognosis is overall poor. Thus, the identification and characterization of targets for novel therapies are urgently required. The Notch signaling pathway has emerged to act in the pathogenesis and tumor progression of TNBCs. Firstly, Notch receptors are associated with the regulation of tumor-initiating cells (TICs) behavior, as well as with the aetiology of TNBCs. Secondly, there is a strong evidence that Notch pathway is a relevant player in mammary cancer stem cells maintenance and expansion. Finally, Notch receptors expression and activation strongly correlate with the aggressive clinicopathological and biological phenotypes of breast cancer (e.g., invasiveness and chemoresistance), which are relevant characteristics of TNBC subtype. The purpose of this up-to-date review is to provide a detailed overview of the specific role of all four Notch receptors (Notch1, Notch2, Notch3, and Notch4) in TNBCs, thus identifying the Notch signaling pathway deregulation/activation as a pathognomonic feature of this breast cancer subtype. Furthermore, this review will also discuss recent information associated with different therapeutic options related to the four Notch receptors, which may be useful to evaluate prognostic or predictive indicators as well as to develop new therapies aimed at improving the clinical outcome of TNBC patients.

A Novel Cooling Device for Targeted Brain Temperature Control and Therapeutic Hypothermia: Feasibility Study in an Animal Model.

BACKGROUND: Therapeutic hypothermia (i.e., temperature management) is an effective option for improving survival and neurological outcome after cardiac arrest and is potentially useful for the care of the critically ill neurological patient. We analyzed the feasibility of a device to control the temperature of the brain by controlling the temperature of the blood flowing through the neck. METHODS: A lumped parameter dynamic model, with one-dimensional heat transfer, was used to predict cooling effects and to test experimental hypotheses. The cooling system consisted of a flexible collar and was tested on 4 adult sheep, in which brain and body temperatures were invasively monitored for the duration of the experiment. RESULTS: Model-based simulations predicted a lowering of the temperature of the brain and the body following the onset of cooling, with a rate of 0.4 °C/h for the brain and 0.2 °C/h for the body. The experimental findings showed comparable cooling rates in the two body compartments, with temperature reductions of 0.6 (0.2) °C/h for the brain and 0.6 (0.2) °C/h for the body. For a 70 kg adult human subject, we predict a temperature reduction of 0.64 °C/h for the brain and 0.43 °C/h for the body. CONCLUSIONS: This work demonstrates the feasibility of using a non-invasive method to induce brain hypothermia using a portable collar. This device demonstrated an optimal safety profile and represents a potentially useful method for the administration of mild hypothermia and temperature control (i.e., treatment of hyperpyrexia) in cardiac arrest and critically ill neurologic patients.

Plasminogen activator inhibitor-1, factor V, factor II and methylenetetrahydrofolate reductase polymorphisms in women with recurrent miscarriage.

The present study investigated the association between genetic polymorphisms of selected thrombophilic factors with recurrent miscarriage (RM). The genetic polymorphisms for plasminogen activator inhibitor-1 4G/5G (PAI-1), Factor V Leiden (FVL), Factor II G20210A (FII) and methylenetetrahydrofolate reductase MTHFR C677T were determined in 186 RM women and 129 healthy women. In RM women, the frequency of heterozygosity for PAI-1 5G/4G (31%) was significantly higher than in controls (5G/4G: 22%) whereas no difference was found in the case of homozygosity 4G/4G and 5G/5G. The frequencies of genotype G/A for FVL and FII were significantly higher in RM women (FVL, 10%; FII, 8%) than in controls (FVL, 3%; FII, 2%). No difference was found in the case of MTHFR C677T. The polymorphisms of FVL and FII should be screened in RM women, whereas PAI-1 seems to be weakly associated with RM. The role of MTHFR C677T polymorphisms without hyperhomocysteinemia appears negligible.

Critical illness in energy metabolism genetic disorder: rhabdomyolysis, acute kidney injury, respiratory arrest / Enfermedad crítica por trastorno genético en el metabolismo de la energía: rabdomiolisis, lesión renal aguda, paro respiratorio

In very long-chain acylCoA dehydrogenase deficiency (VLCAD), the activity of this enzyme is either reduced or absent with the inability to use long-chain fatty acids as energy substrates. A 25-year old male with VLCAD was admitted to the Emergency Department of Policlinico Teaching Hospital (Modena, Italy) for generalized weakness and oliguria, after a period of physical and mental stress and inadequate compliance to a long-chain fatty acid free diet. Laboratory tests were compatible with acute kidney injury. Seventy-two hours after admission, the subject had an episode of chest pain with elevated markers of myocardial necrosis. The rapid deterioration of muscular strength and the subsequent worsening respiratory failure necessitated ventilator support within the local Medical Intensive Care Unit. There, the patient showed a prompt normalization of respiratory parameters and a steady improvement of renal function. An inadequate compliance to lifestyle and dietary restriction in VLCAD may trigger severe and potentially lethal crisis. The in-hospital management of these patients calls for early intensive care admission as their conditions may deteriorate without warning.

En el caso de deficiencia de acylCoA deshidrogenasa de cadena muy larga (VLCAD), o bien se reduce la actividad de esta enzima, o la misma se halla ausente con la consiguiente incapacidad para utilizar los ácidos grasos de cadena larga como sustratos de energía. Un hombre de 25 años fue ingresado con VLCAD fue admitido en el Departamento de emergencia del Hospital Policlínico Docente Hospital de Modena, en Italia, a causa de presentar debilidad generalizada y oliguria, después de un período de estrés físico y mental, y por no cumplir adecuadamente con una dieta libre de ácidos grasos de cadena larga. Las pruebas de laboratorio eran compatibles con una lesión renal aguda. Setenta y dos horas después de su ingreso, el sujeto tuvo un episodio de dolor en el pecho con marcadores elevados de necrosis miocárdica. El rápido deterioro de la fuerza muscular, y el posterior empeoramiento de la insuficiencia respiratoria requirieron el apoyo de un ventilador en la Unidad de Cuidados Médicos Intensivos. Una vez allí, el paciente mostró una pronta normalización de los parámetros respiratorios, y una constante mejoría de la función renal. Un inadecuado cumplimiento con las restricciones dietéticas y el estilo de vida en los casos de VLCAD, pueden desatar una crisis grave y potencialmente fatal. El tratamiento intrahospitalario de estos pacientes requiere un ingreso temprano en cuidados intensivos, ya que sus condiciones pueden deteriorarse sin previo aviso.

Clinical severity of ischemic stroke and neural damage biomarkers in the acute setting: the STROke MArkers (STROMA) study.

BACKGROUND: Stroke is a leading cause of long-term morbidity and mortality affecting several hundred-thousand people annually in the Western Countries. Various panels of biomarkers of neural damage have been developed and validated. The primary objective of this investigation was to measure the correlation between the clinical severity of stroke and the serum/plasma concentrations of neural damage biomarkers. METHODS: A prospective investigation was conducted on a panel of biomarkers composed of S100ß, matrix metalloproteinase-9 (MMP-9), N-terminal pro-B-type natriuretic peptide (NT pro-BNP) and D-dimer at admission and after 24 hours, in a cohort patients with a confirmed diagnosis of stroke in an emergency setting (STROke-MArkers STROMA). RESULTS: A total of 58 consecutive patients were enrolled, no participant was excluded; according to clinical severity measured by National Institute of Health Stroke Scale (NIHSS) there were 29 minor strokes, 24 moderate, 3 moderate-severe, 2 severe. The Spearman's rank correlation test was used to assess the relationship between the baseline NIHSS value and the concentrations of the four biomarkers: all the studied biomarkers showed a statistically significant correlation with baseline NIHSS at 24 hours. A multivariate ordinal regression model was used to analyze the correlation of markers with stroke severity, stratified, according to NIHSS score: MMP-9 and S100ß showed a statistically significant correlation after 24 hours. CONCLUSION: MMP-9, S100ß, NT pro-BNP and D-dimer showed a good correlation with the clinical severity of stroke which may become an additional resource in the acute patient evaluation and potentially follow-up.

Critical illness in energy metabolism genetic disorder: rhabdomyolysis, acute kidney injury, respiratory arrest.

In very long-chain acylCoA dehydrogenase deficiency (VLCAD), the activity of this enzyme is either reduced or absent with the inability to use long-chain fatty acids as energy substrates. A 25-year old male with VLCAD was admitted to the Emergency Department of Policlinico Teaching Hospital (Modena, Italy)for generalized weakness and oliguria, after a period of physical and mental stress and inadequate compliance to a long-chain fatty acid free diet. Laboratory tests were compatible with acute kidney injury. Seventy-two hours after admission, the subject had an episode of chest pain with elevated markers of myocardial necrosis. The rapid deterioration of muscular strength and the subsequent worsening respiratory failure necessitated ventilator support within the local Medical Intensive Care Unit. There, the patient showed a prompt normalization of respiratory parameters and a steady improvement of renal function. An inadequate compliance to lifestyle and dietary restriction in VLCAD may trigger severe and potentially lethal crisis. The in-hospital management of these patients calls for early intensive care admission as their conditions may deteriorate without warning.

Plasma renin concentration as a predictor of outcome in a medical intensive care setting: a retrospective pilot study.

BACKGROUND: Renin and aldosterone are involved in an organ perfusion pathway that may be an estimate of disease severity. The primary objective was to explore the relationship between outcome and aldosterone and renin levels at medical intensive care unit (MICU) admissions in comparison to SAPS II scores. METHODS: This retrospective study was conducted on patients admitted to the adult MICU during 12 months. Exclusion: subjects with creatinine >176 mmol/l, chronic arrhythmia and ACE-inhibitor therapy. Admission aldosterone and renin plasma levels were measured and SAPS II scores were calculated. RESULTS: Eighty-two patients were included. Only the plasma renin median concentration difference between survivors and non-survivors was significant (P=0.0168). The area under the ROC curve for mortality and plasma renin concentration was similar to that of SAPS II. The correlation between mortality and renin >84 pg/mL showed an odds ratio of 5.78±3.45, P=0.003. CONCLUSION: Renin was correlated to outcome in critically ill medical patients.

Prolonged neurological burden in severe lithium intoxication.

A 53-year-old woman was brought to the Emergency Department for a persistent state of stupor, tremors, fever and oliguria. The patient had been under treatment for depression. The electrocardiogram showed a wider QRS complex; laboratory tests were as follows: urea 110 mg/dL, creatinine 3 mg/dL, sodium 135 mEq/L, potassium 4.5 mEq/L, and lithium 8.0 mEq/L. Renal replacement was initiated to normalize plasma lithium levels; both stupor and speech impairment persisted for several days after dialysis. Complete recovery was achieved several days afterwards.

Human platelets bind and degrade 2-arachidonoylglycerol, which activates these cells through a cannabinoid receptor.

The endocannabinoid 2-arachidonoylglycerol (2-Delta(4)Ach-Gro) activates human platelets in platelet-rich plasma at physiological concentrations. The activation was inhibited by selective antagonists of CB(1) and CB(2) cannabinoid receptors, but not by acetylsalicylic acid. Human platelets can metabolize 2-Delta(4)Ach-Gro by internalization through a high affinity transporter (K(m) = 300 +/- 30 nM, V(max) = 10 +/- 1 pmol.min(-1).mg protein(-1)), followed by hydrolysis by a fatty acid amide hydrolase (K(m) = 8 +/- 1 microM, V(max) = 400 +/- 50 pmol.min(-1).mg protein(-1)). The anandamide transport inhibitor AM404, and anandamide itself, were ineffective on 2-Delta(4)Ach-Gro uptake by platelets, whereas anandamide competitively inhibited 2-Delta(4)Ach-Gro hydrolysis (inhibition constant = 10 +/- 1 microM). Platelet activation by 2-Delta(4)Ach-Gro was paralleled by an increase of intracellular calcium and inositol-1,4,5-trisphosphate, and by a decrease of cyclic AMP. Moreover, treatment of preloaded platelet-rich plasma with 2-Delta(4)Ach-Gro induced an approximately threefold increase in [(3)H]2-Delta(4)Ach-Gro release, according to a CB receptor-dependent mechanism. On the other hand, ADP and collagen counteracted the activation of platelets by 2-Delta(4)Ach-Gro, whereas 5-hydroxytryptamine (serotonin) enhanced and extended its effects. Remarkably, ADP and collagen also reduced [(3)H]2-Delta(4)Ach-Gro release from 2-Delta(4)Ach-Gro-activated platelets, whereas 5-hydroxytryptamine further increased it. These findings suggest a so far unnoticed interplay between the peripheral endocannabinoid system and physiological platelet agonists.

Clustering of endothelial markers of vascular damage in human salt-sensitive hypertension: influence of dietary sodium load and depletion.

The contributing role of vascular endothelium in the development of hypertension-related vascular damage is well accepted. Salt-sensitive hypertension is characterized by a cluster of renal, hormonal, and metabolic derangements that might favor the development of cardiovascular and renal damage. To evaluate endothelial involvement in salt-sensitive essential hypertension, plasma levels of several markers of endothelial damage such as endothelin-1 (ET-1), von Willebrand factor (vWf), and soluble (S-) adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and 24-hour urinary albumin excretion (UAE) were measured in 39 nondiabetic, nonobese, never-treated essential hypertensive patients after intermediate (120 mmol/d), high (220 mmol/d), and low (20 mmol/d) NaCl diets. Patients were classified as salt sensitive (n=18) or salt resistant (n=21) according to their blood pressure responses to changes in dietary NaCl intake. Salt-sensitive hypertensives showed higher plasma ET-1 (P<0.05), vWf (P<0.005), and S-E-selectin levels (P<0.04) and increased UAE (P<0.05) than salt-resistant hypertensives. By contrast, circulating S-ICAM-1 and S-VCAM-1 concentrations were not significantly higher in salt-sensitive (596. 56+/-177.05 ng/mL and 541.06+/-157.84 ng/mL, respectively) than salt-resistant patients (516.86+/-147.99 ng/mL and 449.48+/-158.91 ng/mL, respectively). During the intermediate NaCl diet, plasma ET-1 responses to oral glucose load were greater in salt-sensitive (P<0. 05) than in salt-resistant patients. A marked (P<0.05) hyperinsulinemic response to oral glucose load was evident in salt-sensitive but not salt-resistant patients after each diet. This study shows increased plasma levels of the endothelium-derived substances E-selectin, vWf, and ET-1 in salt-sensitive hypertensives. Our findings support the hypothesis that salt sensitivity is correlated with an increased risk for developing hypertension-related cardiovascular damage.

N-Arylalkyl pseudopeptide inhibitors of farnesyltransferase.

Inhibitors of Ras protein farnesyltransferase are described which are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Reduction of the carbonyl groups linking the first three residues of the tetrapeptide leads to active inhibitors which are chemically unstable. Stability can be restored by alkylating the central amine of the tetrapeptide. Studies of the SAR of these alkylated pseudopeptides with concomitant modification of the side chain of the third residue led to 2(S)-(2(S)-¿[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)- methylpentyl]naphthalen-1-ylmethylamino¿acetylamino)-4 -methylsulfany lbutyric acid (11), a subnanomolar inhibitor. The methyl ester (10) of this compound exhibited submicromolar activity in the processing assay and selectively inhibited anchorage-independent growth of Rat1 cells transformed by v-ras at 2.5-5 microM.

Clozapine metabolism rate as a possible index of drug-induced granulocytopenia.

A possible relationship between haematological adverse reactions and clozapine (CLZ) metabolism rate was studied. Sixteen chronic schizophrenic outpatients (mean age 34.62 years +/- 7.56 SD) were treated with CLZ, 75-600 mg/daily for 9 weeks. CLZ and norclozapine (NCLZ) plasma levels were determined weekly, contemporarily with blood cell counts. CLZ plasma levels ranged from 25 to 1270 ng/ml (mean 266.27 ng/ml +/- 197.44 SD), while NCLZ plasma levels ranged from 25 to 1280 ng/ml (mean 169.0 ng/ml +/- 127.94 SD). NCLZ/CLZ ratio ranged from 0.13 to 1.72 (mean 0.72 +/- 0.28 SD). Leukocyte count ranged from 5.2 to 18.8 10(9)/l (mean 9.37 10(9)/l +/- 2.94 SD) and neutrophil count ranged from 1.8 to 13.4 10(9)/l (mean 5.73 +/- 2.57 SD). No correlation was found between CLZ dosage and NCLZ plasma levels. Both CLZ and NCLZ plasma levels correlated positively with neutrophil count (CLZ: P = 0.001, r = 0.26; NCLZ: P = 0.01, r = 0.20). The correlation between NCLZ/CLZ plasma level ratio and neutrophil count was significantly negative (P = 0.002, r = 0.25). These preliminary data suggest that the NCLZ/CLZ ratio, as an index of CLZ metabolism, might be a possible risk factor associated with CLZ treatment.