Effects of transcranial magnetic stimulation on cocaine addiction: A systematic review of randomized controlled trials.

OBJECTIVE: While pharmacological strategies appear to be ineffective in treating long-term addiction, repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising new tool for the attenuation of craving among multiple substance dependent populations. METHOD: A systematic review of randomized controlled trials (RCTs) was conducted on the efficacy and tolerability of rTMS in treating cocaine use disorder (CUD). Relevant papers published in English through November 30th 2022 were identified, searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. RESULTS: Eight studies matched inclusion criteria. The best findings were reported by the RCTs conducted at high-frequency (≥5 Hz) multiple sessions of rTMS delivered over the left dorsolateral prefrontal cortex (DLPFC): a significant decrease in self-reported cue-induced cocaine craving and lower cocaine craving scores and a considerable amelioration in the tendency to act rashly under extreme negative emotions (impulsivity) were found in the active group compared to controls. CONCLUSION: Although still scant and heterogeneous, the strongest evidence so far on the use of rTMS on individuals with CUD support the high frequency stimulation over the left DLPFC as a well tolerated treatment of cocaine craving and impulsivity.

Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?

Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.

Uterine PEComa with aggressive behavior: A review with an additional case of spontaneous vaginal expulsion.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor originating from perivascular epitheloid cells showing melanocytic and smooth muscle differentiation. The uterus represents the second most common site of origin. A 49 years woman presented to our Hospital for a vaginal spontaneous expulsion of a mass suggestive for malignant mesenchymal tumor. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy and the histopathological report was compliant with a PEComa with aggressive behavior. Medical Literature databases about PEComa were searched. The current literature identified near 90 cases of uterine PEComas and they are categorized as uncertain malignant potential or with aggressive behavior. Primary surgical excision represents the gold-standard treatment. Recently targeted therapy with mTOR inhibitors has been introduced with an important beneficial. In this paper we review the Literature about the uPEComa with aggressive behavior reporting the first case of spontaneous vaginal expulsion.

Oligodendroglioma Cells Lack Glutamine Synthetase and Are Auxotrophic for Glutamine, but Do not Depend on Glutamine Anaplerosis for Growth.

In cells derived from several types of cancer, a transcriptional program drives high consumption of glutamine (Gln), which is used for anaplerosis, leading to a metabolic addiction for the amino acid. Low or absent expression of Glutamine Synthetase (GS), the only enzyme that catalyzes de novo Gln synthesis, has been considered a marker of Gln-addicted cancers. In this study, two human cell lines derived from brain tumors with oligodendroglioma features, HOG and Hs683, have been shown to be GS-negative. Viability of both lines depends from extracellular Gln with EC50 of 0.175 ± 0.056 mM (Hs683) and 0.086 ± 0.043 mM (HOG), thus suggesting that small amounts of extracellular Gln are sufficient for OD cell growth. Gln starvation does not significantly affect the cell content of anaplerotic substrates, which, consistently, are not able to rescue cell growth, but causes hindrance of the Wnt/ß-catenin pathway and protein synthesis attenuation, which is mitigated by transient GS expression. Gln transport inhibitors cause partial depletion of intracellular Gln and cell growth inhibition, but do not lower cell viability. Therefore, GS-negative human oligodendroglioma cells are Gln-auxotrophic but do not use the amino acid for anaplerosis and, hence, are not Gln addicted, exhibiting only limited Gln requirements for survival and growth.

Reduction of Myocardial Ischemia-Reperfusion Injury by Inhibiting Interleukin-1 Alpha.

BACKGROUND: Interleukin-1α (IL-1α) released by dying cells is an alarmin that activates the innate immunity. We hypothesized that after myocardial ischemia-reperfusion (I/R) injury, IL-1α amplifies the myocardial damage by activating the inflammasome and caspase-1. METHODS: Adult male CD1 mice were used. The left anterior descending coronary artery was ligated for 30 minutes, after 24 hours of reperfusion. An IL-1α blocking antibody (15 µg/kg intraperitoneally) or matching vehicle was given after reperfusion. A subgroup of mice underwent sham surgery. We assessed the effects of IL-1α blockade on caspase-1 activity, infarct size, cardiac troponin I serum levels, and left ventricular fractional shortening, 24 hours after I/R. RESULTS: I/R led to inflammasome formation, and IL-1α blockade significantly reduced inflammasome formation, reflected by a >50% reduction in caspase-1 activity versus vehicle (P = 0.03). IL-1α blockade also reduced the infarct size (-52% infarct expressed as percentage of area at risk, and -79% for cardiac troponin I serum levels, P < 0.001 vs. vehicle) and preserved the left ventricular fractional shortening (31 ± 3% vs. 25 ± 2%, P < 0.001 vs. vehicle). CONCLUSION: IL-1α blockade after I/R reduces the inflammasome activation, decreases the infarct size, and preserves the left ventricular function. IL-1α blockade may therefore represent a novel therapeutic strategy to reduce I/R injury.

[Neurological diseases and suicide: from neurobiology to hopelessness]. / Maladies neurologiques et suicide: de la neurobiologie au manque d'espoir.

Neurologic diseases expose at a high risk of suicidal behaviors and they constitute a privileged domain for exploring the heterogeneity of underlying mechanisms. They are in fact characterized by strictly biological injuries that may be involved in cerebral systems considered at the basis of neurobiological vulnerability for suicide. At the same time, they oblige a numberof existential topics to emerge, as the hopelessness in respect of several particularly severe conditions without an etiologic treatment. A clinical approach reserving an unconditional listening can prevent a suicidal attempt. Furthermore, it can illustrate the role of the liaison's psychiatrist, who tries to transform a hopelessness situation into a patient's personal questioning and try to be present when therapeutic action is not longer possible.

HOW FUNGI INTERACT WITH NEMATODE TO ACTIVATE THE PLANT DEFENCE RESPONSE TO TOMATO PLANTS.

Management of plant parasitic nematodes with nematode predators, parasites or antagonists is an eco-friendly approach that may avoid the problems arisen by the use of toxic chemicals. Fungi belonging to Trichoderma spp. are well known in literature for their role in control of plant parasitic nematodes. Root-knot nematodes (RKNs), Meloidogyne spp., are obligate parasites that cause the formation of familiar galls on the roots of many cultivated plants. The interaction between the M. incognita motile second stage juveniles (J2s) and the isolate ITEM 908 of Trichoderma harzianum was examined in its effect on the nematode infestation level of susceptible tomato plants. To gain insight into the mechanisms by which ITEM 908 interacts with nematode-infected tomato plants, the expression patterns of the genes PR1 (marker of Salycilic Acid-depending resistance signalling pathway) and JERF3 (marker of the Jasmonic Acid/Ethylene-depending resistance signalling pathway) were detected over time in: i) untreated roots; ii) roots pre-treated with the fungus; iii) roots inoculated with the nematode; iv) pre-treated and inoculated roots. Infestation parameters were checked in untreated plants and plants treated with the fungus to test the effect of the fungus on nematode infestation level and to compare this effect with the expression of the genes PR1 and JERF3, involved in induced resistance.

[Alzheimer disease: from pathogenetic issues to clinical perspectives]. / Maladie d'Alzheimer: de la pathogénie aux perspectives cliniques.

The aim of this article is a critical review of the main pathogenetic issues debated in Alzheimer disease, with a focus on the clinical perspectives that could derive from. The pertinence of the amyloid cascade hypothesis as a unique and causal explanation of cognitive deterioration is challenged in the light of recent therapeutic failures of clinical trials and increasing role of tau protein in clinical expression. The detection of very early and possibly preclinical stages of the disease emerges as a necessary condition for the efficacy of future amyloid or tau-oriented curative strategies. In this respect, the possibility of finding individual vulnerability markers--in the group of patients with "mild cognitive impairment" or even in cognitively intact subjects--represents a major challenge of the clinical research in this field.

Review: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates.

Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology and pathogenesis of CTE and Alzheimer's disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia.

Evidence for the involvement of 5-HT2A receptors in mild mesenteric ischemia/reperfusion dysfunctions in mice.

In this study, the involvement of 5-HT2A receptors on mesenteric ischemia-reperfusion injury was examined in mice. Intestinal ischemia produced by 45 min occlusion of superior mesenteric artery was followed by 24h reperfusion (I/R). The 5-HT2A selective antagonist, ketanserin (0.5 mgkg(-1)) or the 5-HT2A agonist DOI (0.25 mgkg(-1)) was intravenously administered before ischemia and 8h after the beginning of reperfusion. The effects were compared with those obtained in sham operated animals (S). Ketanserin prevented the upper gastrointestinal transit delay induced by I/R (P<0.01), protected intestine from leukocyte recruitment as indicated by jejunal myeloperoxidase activity (P<0.05) and reverted Evans Blue extravasation elicited by I/R in lung, colon and jejunum (P<0.05). On the other hand, 5-HT2A activation by DOI mimicked the effects of I/R in S mice prolonging small intestine transit (P<0.05) and enhancing neutrophil accumulation in jejunal tissues (P<0.05). Furthermore, the reduction of ADP-induced platelet aggregation in plasma of I/R mice was prevented by ketanserin treatment. All together, these findings support the critical involvement of 5-HT2A receptor subtype in mediating the damage induced by mesenteric I/R in mice.

The selective inhibition of inducible nitric oxide synthase prevents intestinal ischemia-reperfusion injury in mice.

Nitric oxide (NO) involvement in intestinal ischemia-reperfusion (I/R) injury has been widely suggested but its protective or detrimental role remains still question of debate. Here, we examine the impact of supplementation or inhibition of NO availability on intestinal dysmotility and inflammation caused by mesenteric I/R in mice. Ischemia 45min and reperfusion 24h were performed by superior mesenteric artery occlusion in female Swiss mice. Saline-treated sham-operated (S) or normal mice without surgery (N) served as controls. Drugs were subcutaneously injected 0, 4, 8, and 18 h after ischemia. Upper gastrointestinal transit (GIT, estimated through black marker gavage), intestinal myeloperoxidase activity (MPO), intestinal malondialdehyde levels (MDA), Evans blue extravasation (EB), intestinal histological damage, and mean arterial pressure (MAP) were considered. In I/R mice, GIT was significantly delayed compared to S and N groups; MPO activity and EB extravasation enhanced, whereas MDA levels did not change. Compared to N and S groups, in I/R mice selective iNOS inhibitor P-BIT significantly prevented motor, MPO and EB changes; putative iNOS inhibitor aminoguanidine significantly counteracted GIT delay but not neutrophil recruitment and the increase in vascular permeability; NOS inhibitor l-NAME and NO precursor l-arginine were scarcely or no effective. Furthermore, in S mice aminoguanidine caused a significant increase of MPO activity reverted by H(1) histamine receptor antagonist pre-treatment. Unlike P-BIT, aminoguanidine and l-NAME injection increased MAP. These findings confirm a detrimental role for iNOS-derived NO overproduction during reperfusion. Aminoguanidine-associated neutrophil recruitment suggests that this drug could act through mechanisms additional to iNOS inhibition involving both eNOS blockade, as indicated by its hemodynamic effects, and indirect activation of H(1) histamine receptors.

Radiotherapy and chemotherapy of brain metastases.

The authors have reviewed the results, the indications and the controversies regarding radiotherapy and chemotherapy of patients with newly diagnosed and recurrent brain metastases. Whole-brain radiotherapy, radiosurgery, hypofractionated stereotactic radiotherapy, brachytherapy and chemotherapy are the available options. New radiosensitizers and cytotoxic or cytostatic agents are being investigated. Adjuvant whole brain radiotherapy, either after surgery or radiosurgery, and prophylactic cranial irradiation in small-cell lung cancer are discussed, taking into account local control, survival, and risk of late neurotoxicity. Increasingly, the different treatments are tailored to the different prognostic subgroups, as defined by Radiation Therapy Oncology Group RPA Classes.

A carbon balance method for paper and wood products.

The approach used to track the flow of carbon sequestered in the forest through harvest, processing into products, and final disposition of products is described. The methodology is broadly flexible and applicable to forest-based carbon balance assessments. A carbon balance is computed across all forestland ownerships for the production facility of interest. The balance considers forest uptake, harvest, combustion of fuels, emissions from process steps and losses from product use, disposition and recycling. The method also allows for sensitivity and marginal assessments of a variety of real and hypothetical situations using variable assumptions. Example results for a vertically integrated pulp and paper mill are presented. Results suggest that integrated forest products facilities drawing their raw material from sustainably managed forests can achieve a net positive carbon balance over the product cycle. The amount of net carbon sequestration attributable to such facilities depends upon a number of factors. The most critical of these include net forest growth, the method for allocating the growth in forest carbon among all of those harvesting from the drain area of a given facility, and the use and disposal patterns for the paper or wood products manufactured.

Factors related to the length of in-hospital stay of geriatric patients.

The aim of this study was to evaluate factors predicting length of stay in hospital of geriatric patients. Study participants were 402 patients (183 males and 219 females) consecutively admitted to four geriatric wards located in Chieti, Perugia, Pescara and Prato, Italy. Information on potential predictors of length of stay was collected; in particular, we assessed the presence and severity of specific chronic medical conditions, level of physical function, cognitive status, and depressive symptoms. Moreover, information on family and social support was obtained. In general, participants were old, often cognitively impaired and physically disabled. Average length of stay ranged from 9.4 +/- 3.3 days (Perugia) to 14.1 +/- 7.2 days (Chieti), and was statistically different across centers (p < 0.001). None of the specific medical diagnoses was associated with different length of stay. However, higher comorbidity score (p < 0.001), living alone (p < 0.01), lower MMSE score (p = 0.03), and poor functional status (p = 0.05) were all associated with longer length of stay. When these variables were included in a multivariate model predicting length of stay, differences between centers were no longer statistically significant. Findings of this study show that specific medical diagnoses are not adequate instruments to estimate length of stay in geriatric units. Other assessment systems based on extension of the social network, comorbidity, and the cognitive as well as the functional level need to be developed.

Characteristics of geriatric patients related to early and late readmissions to hospital.

The aim of the study was to evaluate which characteristics of geriatric patients account for readmission to hospital, 6 months after discharge. All patients (203 females, 176 males) consecutively admitted over a two-month period to four acute geriatric care units, located in the cities of Chieti, Perugia, Pescara and Prato, participated in the study. Data that could potentially explain early and late readmissions were collected for each patient. Prevalence of diseases and comorbidity were assessed with the Cumulative Illness Rating Scale (CIRS); physical function by self-report (ADL, IADL) and objective (Stand and Walking Speed) measures; cognitive level by MMSE; and depressive symptoms by the Geriatric Depression Scale (GDS). Information on family and social support were also obtained. After discharge, data on hospital readmissions were collected for six months. For each readmitted patient (cases), medical records were reviewed, and supplementary information was obtained from families and general practitioners. Readmissions were classified as "early" (within the first three months), "late" (within the third and sixth month), and "multiple" (2 or more readmissions irrespective of the period). Patients not readmitted (alive at home) were considered as controls. Systematic differences between centers and between periods of readmissions were evaluated using one-way analyses of variance, and Pearson's chi 2 test. Factors related to early, late, and multiple readmission were identified in multivariate logistic regression models. On univariate analysis, patients readmitted over the first three-month period were sicker than controls (CIRS classes 3-4: 52.1% vs 34.1%), had more social problems or behavioral symptoms, and were more functionally impaired (ADL dependencies 3.3 +/- 0.4 vs 2.1 +/- 0.2). Patients who were readmitted between the third and the sixth month after discharge had a significantly higher CIRS total score (p = 0.006). Patients with multiple readmissions had more severe diseases, and more social problems. On multivariate analysis, early readmission was associated with unsatisfactory social conditions, living alone, severity of diseases and cognitive impairment, while late readmission was associated with comorbidity only. Multiple readmissions were related only to social factors, and to hospital admission before the baseline evaluation. The findings of this study suggest that interventions aimed at improving unfavorable social conditions may reduce the rate of rehospitalization in geriatric patients.

[Minimal celiosurgery in endometriosis]. / Celiochirurgia minima dell'endometriosi.

After a brief consideration of the recent therapeutic approaches to endometriosis, the Authors suggest their laparoscopic method which includes drainage by aspiration of the endometrioma using a wide biopsy, followed by careful lavage of the cystic cavity and abdomen and partial thermocoagulation of the same capsule and any visible residual implants. The patients were admitted for infertility in 47% of cases, chorionic pelvic pain in 16% of cases and pelvic mass in 10%. By using this procedure symptomatic relief was seen in 72% of cases and a pregnancy rate of 81% obtained with encouraging results even in moderate and severe endometriosis.