Does SARS-Cov-2 invade the brain? Translational lessons from animal models.

The current coronavirus disease (COVID-19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS-CoV-2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS-CoV-2. One key finding that may unify these pathogens is that all require angiotensin-converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS-CoV-2 binds to cell membranes, binds angiotensin-converting enzyme 2 with a higher affinity compared with SARS-CoV. The expression of this receptor in neurons and endothelial cells hints that SARS-CoV-2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune-mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune-mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID-19.

Clinical predictors and microbiology of ventilator-associated pneumonia in the intensive care unit: a retrospective analysis in six Italian hospitals.

The purpose of this study was to assess the main clinical predictors and microbiological features of ventilator-associated pneumonia (VAP) in the Intensive Care Unit (ICU) environment. This work is a retrospective analysis over one year from September 2010 to September 2011. Patients' risk factors, causes of admission, comorbidities and respiratory specimens collected in six Italian ICUs were reviewed. Incidence and case fatality rate of VAP were evaluated. After stratification for VAP development, univariate and multivariate analyses were performed to assess the impact of patients' conditions on the onset of this infection. A total of 1,647 ICU patients (pts) were considered. Overall, 115 patients (6.9 %) experienced at least one episode of VAP. The incidence rate for VAP was 5.82/1,000 pts-days, with a case fatality rate of 44.3 %. Multivariate analysis showed that admission for neurological disorders (aIRR 4.12, CI 1.24-13.68, p = 0.02) and emergency referral to ICU from other hospitals (aIRR 2.11, CI 1.03-4.31, p = 0.04) were associated with higher risk of VAP, whereas a tendency to a higher risk of infection was detected for admission due to respiratory disease, cardiac disease, trauma and for having obesity or renal failure. A total of 372 microbiological isolates from respiratory specimens were collected in VAP patients. The most common species were Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, showing high resistance rates to carbapenems. Neurological disorders and emergency referral at the admission into the ICU are significantly associated with the onset of VAP. A high incidence of multi-drug resistant Gram- species was detected in the respiratory specimens.

Breakthrough pain in patients with multiple myeloma: a secondary analysis of IOPS MS study.

OBJECTIVE: The aim of this study was to characterize breakthrough pain (BTcP) in patients with multiple myeloma (MM). PATIENTS AND METHODS: This was a secondary analysis of a large multicenter study of patients with BTcP. Background pain intensity and opioid doses were recorded. The BTcP characteristics, including the number of BTcP episodes, intensity, onset, duration, predictability, and interference with daily activities were recorded. Opioids prescribed for BTcP, time to achieve a meaningful pain relief after taking a medication, adverse effects, and patients' satisfaction were assessed. RESULTS: Fifty-four patients with MM were examined. In comparison with other tumors, in patients with MM BTcP was more predictable (p=0.04), with the predominant trigger being the physical activity (p<0.001). Other BTcP characteristics, pattern of opioids used for background pain and BTcP, satisfaction and adverse effects did not differ. CONCLUSIONS: Patients with MM have their own peculiarities. Given the peculiar involvement of the skeleton, BTcP was highly predictable and triggered by movement.

The role of mesotherapy in the management of spinal pain. A randomized controlled study.

Background: Mesotherapy is a technique through which active ingredients are administered into the thickness of the skin in order to increase the local analgesic effect. Methods: 141 patients with spinal pain not responding to systemic therapy with NSAIDs were randomized to receive one or more intra-cutaneous drugs on a weekly basis. Results: All patients achieved a pain reduction of at least 50% compared to baseline, and all tolerated the therapy without having to resort to systemic drug dose increases. Conclusions: The data from our study show that the active ingredients infiltrated into the skin induce a mesodermal modulation between the infiltrated liquid and the cutaneous nervous and cellular structures from which the typical drug-saving effect of mesotherapy arises. Although further studies are needed to establish how to integrate mesotherapy in various clinical settings, it appears to be a useful technique available to the practicing physician. This research is also useful in guiding future clinical research.

Intradermal therapy (mesotherapy): the lower the better.

BACKGROUND: Intradermal therapy (mesotherapy) is a technique used to inject drugs into the surface layer of the skin. The intradermal micro deposit allows to modulate the kinetics of drugs, slowing down its absorption and prolonging the local mechanism of action. This technique is applied in the treatment of some forms of localized pain when a systemic drug-saving effect is useful, when it is necessary to synergize with other pharmacological or non-pharmacological thera-pies, when other therapies have failed or cannot be used. AIM: The purpose of our study was to evaluate the effect of a mixture with respect to its lower concentration. We also wanted to evaluate the number of sessions needed to reach the therapeutic goal (50% reduction in pain from baseline) in patients with acute or chronic neck pain. METHOD: We analyzed retrospectively data from 62 patients with cervicobrachial pain treated with intradermal drugs. Group A received a mixture of drugs; group B received half the dose of drugs. RESULTS: Patients who received a lower concentration of drugs achieved similar results to those who received a higher dose. The therapeutic goal was achieved on average with 3.5 + 1.7 sessions on a weekly basis (min 1; max 9). Subjects in group A required 4+1.7 treatments (min 1; max 9), while subjects in group B required 3+1.5 treatments (min 1; max 7). CONCLUSIONS: Our study confirms that even a lower dose of drugs can induce a clinically useful result. This study confirms that the useful effect of mesotherapy is only partly due to the pharmacological action. Further randomized prospective studies are needed to standardize the technique in the various pain syndromes, but it is recommended to follow the guidelines of the Italian Society of Mesotherapy to ensure patients receive appropriate treatment.

Should we be concerned when COVID-19-positive patients take opioids to control their pain? Insights from a pharmacological point of view.

OBJECTIVE: The purpose of this narrative review is to discuss the available information regarding the currently utilized COVID-19 therapies (and the evidence level supporting them) and opioids for chronic pain with a focus on warnings of potential interactions between these two therapeutic approaches. MATERIALS AND METHODS: Papers were retrieved from a PubMed search, using different combinations of keywords [e.g., pain treatment AND COVID-19 AND drug-drug interaction (DDI)], without limitations in terms of publication date and language. RESULTS: Remdesivir is an inhibitor of CYP3A4 and may increase the plasma concentration of CYP3A4 substrates (e.g., fentanyl). Dexamethasone is an inducer of CYP3A4 and glycoprotein P, thus coadministration with drugs metabolized by this isoform will lead to their increased clearance. Dexamethasone may cause hypokalemia, thus potentiating the risk of ventricular arrhythmias if it is given with opioids able to prolong the QT interval, such as oxycodone and methadone. Finally, the existing differences among opioids with regard to their impact on immune responses should also be taken into account with only tapentadol and hydromorphone appearing neutral on both cytokine production and immune parameters. CONCLUSIONS: Clinicians should keep in mind the frequent DDIs with drugs extensively metabolized by the CYP450 system and prefer opioids undergoing a limited hepatic metabolism. Identification and management of DDIs and dissemination of the related knowledge should be a major goal in the delivery of chronic care to ensure optimized patient outcomes and facilitate updating recommendations for COVID-19 therapy in frail populations, namely comorbid, poly-medicated patients or individuals suffering from substance use disorder.

Evidence based recommendations on mesotherapy: an update from the Italian society of Mesotherapy.

INTRODUCTION: Mesotherapy, also known as local intradermal therapy, widely used all over the world, is a technique used to inject substances into the surface layer of the skin. There are no international guidelines for the correct use of this technique and in many countries, it is still applied empirically without valid patient consent. The Italian society of mesotherapy has planned a study to assess the rationale and clinical applications based on current evidence. METHODS: An independent steering committee, based on the available scientific literature, has formulated a series of clinical questions. 21 experts responded by writing an evidence-based document. From this document 30 statements were obtained which were presented to 114 experts using the Delphi method. RESULTS: 28 statements reached a broad agreement on definition, technique, pharmacological rationale, indications and some crucial ethical aspect. CONCLUSIONS: Although further studies are needed to establish the clinical role of this technique in each field of application, our statements recommend the correct application according to the needs of the individual patient in full respect of ethics.

The combined use of VIGI@ct (bioMérieux) and fluorescent amplified length fragment polymorphisms in the investigation of potential outbreaks.

Even with good surveillance programmes, hospital-acquired infections (HAIs) are not always recognized and this may lead to an outbreak. In order to reduce this risk, we propose a model for prompt detection of HAIs, based on the use of a real-time epidemiological information system called VIGI@ct (bioMèrieux, Las Balmas, France) and on the rapid confirmation or exclusion of the genetic relationship among pathogens using fluorescent amplified length fragment polymorphism (f-AFLP) microbial fingerprinting. We present the results of one year's experience with the system, which identified a total of 306 suspicious HAIs. Of these, 281 (92%) were 'confirmed' by clinical evidence, 16 (5%) were considered to be simple colonization and the latter nine (3%) were archived as 'not answered' because of the absence of the physician's cooperation. There were seven suspected outbreaks; of these, f-AFLP analysis confirmed the clonal relationship among the isolates in four cases: outbreak 1 (four isolates of Pseudomonas aeruginosa), outbreak 2 (three Escherichia coli isolates), outbreak 6 (two Candida parapsilosis isolates) and outbreak 7 (30 ESbetaL-producing Klebsiella pneumoniae subsp. pneumoniae). Based on our results, we conclude that the combination of VIGI@ct and f-AFLP is useful in the rapid assessment of an outbreak due to Gram-positive or Gram-negative bacteria and yeasts.

Linezolid as rescue drug: a clinical case of soft tissue infection caused by a Staphylococcus aureus strain resistant in vivo to teicoplanin.

The authors report and discuss a patient admitted to intensive care unit (ICU) for acute respiratory failure due to upper airway obstruction caused by face and neck soft tissue infection. An oxacillin-resistant Staphyloccoccus aureus was isolated from necrotic skin lesions and from skin biopsy. The strain was susceptible in vitro to teicoplanin, but it showed resistance in vivo, despite appropriate dosage. After 6 days of full dose therapy, since the clinical course worsened, teicoplanin was interrupted and linezolid was started. In 48 hours signs of infection regressed, and the patient was discharged from the ICU after 10 days of linezolid treatment. Linezolid resulted as a rescue drug for a life-threatening infection.

Non-volatile memory devices with redox-active diruthenium molecular compound.

Reduction-oxidation (redox) active molecules hold potential for memory devices due to their many unique properties. We report the use of a novel diruthenium-based redox molecule incorporated into a non-volatile Flash-based memory device architecture. The memory capacitor device structure consists of a Pd/Al2O3/molecule/SiO2/Si structure. The bulky ruthenium redox molecule is attached to the surface by using a 'click' reaction and the monolayer structure is characterized by x-ray photoelectron spectroscopy to verify the Ru attachment and molecular density. The 'click' reaction is particularly advantageous for memory applications because of (1) ease of chemical design and synthesis, and (2) provides an additional spatial barrier between the oxide/silicon to the diruthenium molecule. Ultraviolet photoelectron spectroscopy data identified the energy of the electronic levels of the surface before and after surface modification. The molecular memory devices display an unsaturated charge storage window attributed to the intrinsic properties of the redox-active molecule. Our findings demonstrate the strengths and challenges with integrating molecular layers within solid-state devices, which will influence the future design of molecular memory devices.

Superoxide anion and hydroxyl radical release by collagen-induced platelet aggregation--role of arachidonic acid metabolism.

Previous study demonstrated that platelets undergoing anoxia-reoxygenation generate superoxide anion (O2-) and hydroxyl radical (OH ) which in turn contribute to activate arachidonic acid (AA) metabolism. However it has not been clarified if oxygen free radicals (OFRs) are also generated when platelets are aggregated by common agonists. We used two probes, i.e. lucigenin and salicylic acid (SA), to measure platelet release of O2- and OH(0), respectively. Among the agonists used, such as ADP, thrombin and collagen, the release of O2- and OH was observed mainly when platelets were stimulated with collagen. Such release was inhibited in platelets pre-treated by aspirin suggesting that AA metabolism was the main source of O2- and OH(0) formation. To further analyze this relationship, O2- and OH(0) formation was measured during AA-stimulated platelet aggregation (PA); we observed that O2- and OH(0) release were dependent upon AA concentration. Furthermore, we found that the incubation of platelets with AACOCF3, a potent inhibitor of cytosolic phospholipase A2, inhibited collagen-induced platelet O2- and OH(0) release. The incubation of platelets with salicylic acid or ascorbic acid, which blunt OH and O2- respectively, inhibited both collagen-induced platelet aggregation and AA-release. This study demonstrated that collagen-induced platelet aggregation is associated with O2- and OH formation, which is dependent upon AA release and metabolism.

Toxic shock syndrome due to group C streptococci. A case report.

BACKGROUND: Streptococcal toxic shock-like syndrome is a life-threatening illness which is on the increase. In early reports, only group A beta-hemolytic streptococcus was associated with the disease, but recent evidence indicates non-A streptococci groups are also involved. OBSERVATIONS: We describe the first reported case of streptococcal toxic shock-like syndrome caused by a group C strain in Italy. Prior to the disease, the patient, a 46-year-old man, had been in good health and had only a 3-day history of sore throat, low grade fever, vomiting, diarrhea, and myalgia before admission. Initially, diagnosis was based only on clinical evidence: shock, multiorgan failure, profound hypothermia, and no apparent signs of infection. Toxic cardiomyopathy was also present. RESULTS: Positive throat swab and blood culture confirmed a "definite case" following established criteria. Anamnesis showed a diagnosis of monoclonal gammopathy. Antibiotic treatment was begun immediately on admission of the patient, who was discharged 20 days later in good health. CONCLUSIONS: This case illustrates how an early diagnosis and prompt antibiotic therapy can determine a more favorable outcome.

Second-line gemcitabine in refractory stage IV non small-cell lung cancer: a phase II trial.

Two recent trials have suggested that docetaxel improves survival in the second-line treatment of non small-cell lung cancer (NSCLC) refractory to first-line platinum-based regimens. Given this, it is appropriate to continue to address the role of new agents in the second-line treatment of refractory NSCLC. Gemcitabine is a well-tolerated new agent that has been shown to have activity in NSCLC. Thirty-one previously treated patients with NSCLC were entered in this study. Eight patients had responsive disease (defined as response to first-line therapy lasting greater than or equal to 3 months) and 23 had refractory disease (defined as progressive disease on first-line therapy or progression less than 3 months from completing first-line therapy). Gemcitabine (1250 mg/m2) was infused over 30 minutes on days 1, 8, and 15 every 28 days. Quality of life (QOL) was assessed with each cycle using the Functional Assessment Cancer Therapy-Lung (FACT-L) questionnaire. Two patients (6.5%) had a partial response, and nine (29%) had disease stabilization. The most frequent grade 3/4 toxicity was myelosuppression, but this only occurred in 8% of doses delivered. Fifty-two percent of evaluable patients had stable or improved QOL over baseline, 10% had a decline in QOL, and the remainder completed only baseline questionnaires. Twenty-nine patients have died of progressive NSCLC; two patients remain alive. Overall, the 31 patients have a median survival of 5.1 months (95% confidence interval [CI]: 4.2-7.4 months) and 1-year survival rate of 16% (95% CI: 3%-29%). Gemcitabine was well tolerated in this patient population. An objective response rate of 6.5% was observed although a significant proportion of patients (29%) experienced stable disease, which may have impacted on their survival. QOL was improved or maintained in over half of the patients. Given these data, gemcitabine as a single agent is a therapeutic option for patients with refractory NSCLC.

Systemic and haemodynamic toxicity after isolated limb perfusion (ILP) with TNF-alpha.

The aim of this study was to evaluate the systemic and haemodynamic postoperative effects of ILP with medium-low dose of TNF alpha in patients diagnosed with primary or recurrent limb melanoma or sarcoma, and to compare the resulting toxicity with Systemic Inflammatory Response Syndrome (SIRS). A prospective study on 17 consecutive patients with primary or recurrent limb tumor (melanoma or sarcoma) subjected to ILP with escalating doses of TNF alpha (0.5-2.0mg) was carried out. Seventeen patients with primary or recurrent limb melanoma or sarcoma were subjected to ILP with escalating doses of TNF alpha. ILP was carried out with the standard techniques, blood being warmed at 42 degrees C for an hour. Serial serum TNF alpha determinations were performed before, during and after limb perfusion in nine patients. Systemic and pulmonary haemodynamics, by a radial and pulmonary artery catheter inserted before the induction of anesthesia, were monitored at 5 different times: before the induction of anesthesia (T0), and 6, 12, 24 and 48 hours after treatment (T1-4). Complete isolation of the limb was not always achieved, therefore leakage of TNF alpha occurred frequently during the perfusion in all patients with maximum systemic TNF alpha concentrations ranging from 431 to 111000 pg/ml. After perfusion only two patients showed detectable TNF alpha levels in peripheral blood which returned to baseline values within nine hours. These two patients had serious systemic toxicity: shock and respiratory failure secondary to pulmonary edema. Acute pulmonary edema was also observed in another patient. All three cases required supportive therapy provided by means of mechanical ventilation. In the remaining 14 patients a sepsis-like syndrome was observed. The most significant haemodynamic changes were due to the CO, which rose by 35%, and the SVR, which remained consistently low throughout. A reduction in Hb was observed in all patients (with an average decrease of 4 g/dl), while DO2 and VO2 levels rose, though not to statistically significant levels. Hypoxia occurred in all 14 patients. In three of the remaining 14 cases bilateral pulmonary leaks were noted, however the use of mechanical ventilation was not required. No perioperative death occurred and the aforementioned side effects were all reversible resulting in a patient's mean postoperative ICU permanence of 4 days (range 3 to 7 days). In conclusion, ILP with TNF alpha induces cardiovascular, respiratory and hematological toxicity with haemodynamic parameters being similar to those noted in SIRS probably due to leakage of TNF alpha in the systemic circulation during the perfusion. Nevertheless, this systemic toxicity was short-lived resulting in an acute reaction following a single application.

The integrated treatment of peritoneal carcinomatosis. A preliminary experience.

Some low-grade malignant tumors arising in the abdomen, lack of infiltrative attitude and "redistribute" on the peritoneum with no extraregional spreading. In this cases the complete tumor cytoreduction followed by intra- or postoperative regional chemotherapy has curative intent. Peritonectomy is the complete removal of all the parietal peritoneum and the visceral peritoneum involved by disease. After peritonectomy hyperthermic antiblastic perfusion is carried out throughout the abdomino-pelvic cavity for 60 minutes, at a temperature of 41.5 degrees C, with mitomycin C (3.3 mg/m2/Lt of perfusate) and cisplatin (25 mg/m2/Lt) (appendicular or colorectal primary), or cisplatin alone is (ovarian primary). Alternatively the immediate postoperative regional chemotherapy is performed with 5-fluorouracil (13.5 mg/Kg) and Lederfolin (125 mg/m2) (colic or appendicular tumor) or cisplatin (25 ng/m2) (ovarian tumor), each day for 5 days. Twenty patients affected by extensive peritoneal carcinomatosis (12 ovarian, 5 colonic, 1 appendicular, 1 mesothelial and 1 gastric primary) were submitted to peritonectomy with no residual macroscopic disease in all cases except three. Six patients were treated with intraoperative intra-abdominal hyperthermic antiblastic perfusion, while immediate postoperative intra-abdominal chemotherapy was given in 4 patients and systemic chemotherapy in other 5. Hospital mortality was 20%. At a mean follow-up of 11 months 14 patients are alive, 11 without disease and the median overall survival is 10.2 months. The curative potential of the combined therapeutic approach seems high in patients with peritoneal carcinomatosis from ovarian or colorectal primary not responding to systemic chemotherapy. Selection criteria of patients can strictly affect the surgical risk and the treatment has to be reserved for controlled clinical trials.

Complications with fully implantable venous access systems in oncologic patients.

AIMS: To evaluate the complications caused by long-term central venous catheterization in patients with malignant hemopathies or solid tumors. METHODS: Retrospective study from June 1988 to June 1993 in 211 consecutive patients who required 223 venous access devices for long-term use. A consistent analysis was possible only in 161 of these patients. RESULTS: Fourteen catheter systems were removed for complications. Infections were the most common complications, with an overall incidence rate of 9.6%, i.e. 0.033/100 catheter days/patient. A significant difference was noted between the two groups of patients: 10 cases (24%) in malignant hemopathies, 6 cases (4.8%) in solid tumors (P = 0.0002). The main mechanical complication was thrombosis, with an incidence rate of 3%. CONCLUSIONS: Given the cost-benefit ratio, our study indicates that fully implantable venous access systems in oncologic patients are extremely useful.

Decompressive craniectomy may cause diagnostic challenges to assess brain death by computed tomography angiography.

According to Italian legislation to diagnose brain death (BD) after the initial documentation of the clinical signs, repetition of clinical testing and confirmation of the loss of bioelectrical activity of the brain (EEG) is required. However, when EEG is unreliable it is necessary to demonstrate cerebral circulatory arrest (CCA). Accepted imaging techniques to demonstrate CCA include: cerebral angiography, cerebral scintigraphy, transcranial Doppler (TCD) and computed tomography angiography (CTA). This latter technique, due to its large availability, low invasivity and easy and fast acquisition is widely used over the country. Nevertheless its diagnostic reliability is affected by some limitations in patients with decompressive craniectomy. Here we report two cases of brain injury with clinical signs of BD and at the same time, opacification of intracranial arteries on CTA and a pattern consistent with flow arrest on the corresponding insonable arteries on TCD. The discrepancy between CTA and TCD results points out a methodology limitation that could be overcome by updating Italian legislation according to other European Countries legislation.