Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis.

PURPOSE: The present review aims to emphasize that malignant gliomas are characterized by the diffuse invasion of distant brain tissue by a myriad of single migrating cells that exhibit decreased levels of apoptosis (programmed cell death type I), thus a resistance to cytotoxic insult. METHODS: The present review surveys the molecular mechanisms of migration in malignant gliomas and potential issues arising from treatments, in addition to relationships between glioma cell migration and resistance to apoptosis in terms of the molecular signaling pathways. RESULTS: Clinical and experimental data demonstrate that glioma cell migration is a complex combination of multiple molecular processes, including the alteration of tumor cell adhesion to a modified extracellular matrix, the secretion of proteases by the cells, and modifications to the actin cytoskeleton. Intracellular signaling pathways involved in the acquisition of resistance to apoptosis by migrating glioma cells concern PI3K, Akt, mTOR, NF-kappaB, and autophagy (programmed cell death type II). CONCLUSION: A number of signaling pathways can be constitutively activated in migrating glioma cells, thus rendering these cells resistant to cytotoxic insults. However, these pathways are not all constitutively activated at the same time in any one glioma. Particular inhibitors should therefore only be chosen if the target is present in the tumor tissue, but this is only possible if individual patients are submitted to the molecular profiling of their tumors before undergoing any treatment to combat their migratory glioma cells. Specific antimigratory compounds should be added to conventional radio- and/or chemotherapy.     

mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior.

The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.     

The challenge of pain assessment in children with cognitive disabilities: Features and clinical applicability of different observational tools

Children with cognitive disabilities are at greater risk of experiencing pain. It has been shown that this paediatric population often receive inadequate pain management. Pain may be very difficult to assess, especially in a defined subgroup with non‐communicating intellectual disability or severe cognitive disability. Accordingly, several observational pain assessment tools have been proposed to overcome this issue. Due to the absence of an ideal measurement tool, accurate pain assessment requires, after a case‐by‐case analysis, selecting the more appropriate tool or a variety of combined instruments. The aim of this work is to provide a comprehensive review of the pain assessment tools commonly used in cognitively impaired children. Critical discussion on features and clinical applicability may suggest how to overcome this difficult challenge. Furthermore, this review will help further research aiming to design new instruments and to improve already‐in‐use tools.     

Characterization of Vaccine Breakthrough Cases during Measles Outbreaks in Milan and Surrounding Areas,Italy, 2017–2021

Despite the existence of an effective live-attenuated vaccine, measles can appear in vaccinated individuals. We investigated breakthrough measles cases identified during our surveillance activities within the measles/rubella surveillance network (MoRoNet) in Milan and surrounding areas (Northern Italy). Between 2017 and 2021, we confirmed measles virus (genotypes B3 or D8) infections in 653 patients and 51 of these (7.8%) were vaccinees. Among vaccinated individuals whose serum was available, a secondary failure was evidenced in 69.4% (25/36) of cases while 11 patients (30.6%) were non-responders. Non-responders were more frequently hospitalized and had significantly lower Ct values in both respiratory and urine samples. Median age and time since the last immunization were similar in the two groups. Importantly, we identified onward transmissions from vaccine failure cases. Vaccinees were involved in 20 outbreaks, in 10 of them they were able to transmit the virus, and in 8 of them, they were the index case. Comparing viral hemagglutinin sequences from vaccinated and non-vaccinated subjects did not show a specific mutation pattern. These results suggest that vaccination failure was likely due to the poor immune response of single individuals and highlights the importance of identifying breakthrough cases and characterizing their clinical and virologic profiles.     

Using the Smith-Watson-Topper Parameter and Its Modifications to Calculate the Fatigue Life of Metals: The State-of-the-Art

The Smith-Watson-Topper parameter (SWT) in its original form was designed to estimate the fatigue life of metal materials in a uniaxial load state (tension–compression) in the range up to fatigue crack initiation, with non-zero mean values. This parameter is based on the analysis of both stress and strain. Therefore, the stress–strain criterion is the focus, rather than the energy criterion. This paper presents the original SWT model and its numerous modifications. The first part presents different versions of this parameter defined by the normal parameters. Then, it presents versions defined through the tangent parameter and the most promising parameter defined through the tangent and normal parameters. It was noted that the final form of the equivalent value is defined either by stress or by an energy parameter. Therefore, the possible characteristics from which the fatigue life can be determined are also presented.     

Clinical Effects of the Immunization Protocol Using Loxosceles Venom in Naïve Horses

Bites of brown spiders (Loxosceles spp.) are responsible for dermonecrotic lesions and potentially systemic envenoming that can lead to death. The only effective therapy is the use of the antivenom, usually produced in horses. However, little is known about the consequences of the systematic use of the Loxosceles venom and adjuvants and of the bleedings on antivenom-producing horses. Thus, the aim of this study was to evaluate the clinical changes in horses in their first immunization protocol for Loxosceles antivenom production. Eleven healthy horses, never immunized, were evaluated in three different periods: T0 (before immunization); T1 (after their first venom immunization); and T2 (after their first bleeding). Horses were clinically evaluated, sampled for blood, and underwent electrocardiographic (ECG) recordings. Several suppurated subcutaneous abscesses occurred due to the use of Freund’s adjuvants and thrombophlebitis due to systematic venipunctures for the bleeding procedures. ECG showed arrhythmias in few horses in T2, such as an increase in T and R waves. In summary, the immunization protocol impacted on horses’ health, especially after bleeding for antivenom procurement.     

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI)

ABSTRACT: BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2--3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS: Term newborns (gestational age >= 36 weeks and birth weight >= 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns. Trial registration Current Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25.     

The role of choroidal hypoperfusion associated with photodynamic therapy in neovascular age-related macular degeneration and the consequences for combination strategies

The clinical benefits of verteporfin therapy have been documented in a wide variety of patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), and there is encouraging evidence of improved outcomes when this angioocclusive modality is combined with antiangiogenic agents. Although the clinical benefits of verteporfin mono- and combination therapy are well established, there has been concern that treatment with verteporfin results in hypoperfusion in the treated area and that concomitant use of antiangiogenic agents could prolong this effect. However, despite well-documented occurrences of hypoperfusion on fluorescein and indocyanine green angiography, there is little evidence of associations with functional impairment or other adverse effects. It has also been suggested that hypoperfusion might actually help to reduce recanalization of CNV and permit neuronal recovery by decreasing exposure to oxygen and oxidative radicals. The reduced need for frequent retreatments clearly has a major appeal due to the lower costs associated with fewer interventions and reduced burden of clinical monitoring and diagnostic reevaluations. Ongoing evaluation in randomized clinical trials will provide further clarification on the effect of verteporfin plus ranibizumab compared with ranibizumab monotherapy in terms of visual acuity, anatomical outcomes, treatment frequency, and health economics. The results of these large-scale clinical trials will provide a strong basis for determining the benefits and risks of combination therapy.