new route for tizanidine administration: a pharmacokinetics and light microscope autoradiography study

Spasticity could represent a complication of several central nervous system (CNS) disorders. Multiple sclerosis and painful paroxysmal syndromes (e.g. trigeminal neuralgia) are pathologies in which anti-spastic drugs are used to a greater extent . Baclofen, tizanidine (TIZ), benzodiazepines, dantrolene, and, more recently, gabapentin are the pharmacological agents more widely used. Baclofen, TIZ, benzodiazepines, gabapentin, clonidine but not dantrolene are active on CNS. The alpha2 adrenoceptor agonist TIZ is one of the most eff ective and largely used anti-spastic drugs. Oral treatment is the only route of anti-spastics administration, although it may cause problems of bioavailability and/or compliance in spastic patients with impaired deglutition. This study was designed to assess the possibility of develop a new route of administration of TIZ and to identify its targets in the spinal cord. New Zealand rabbits were treated with oral (OR , n=6), intramuscular (IM, n=6) or intranasal (IN, n=6) TIZ (3.2 mg/kg/day). Plasma concentration was measured by HPLC on samples collected at 0, 30, 60, 90, 120 and 480 min after treatment. Curves of average concentrations of TIZ vs. time were constructed. In plasma, TIZ reached a peak between 45-65 min after administration. Cmax was in the range of 268.33–1213.64 ng/ml for IM treatment, of 73.95–135.92 ng/ml for IN treatment and of 16.86–857.25 ng/ml for OR treatment. After pharmacokinetic studies, diff erent spinal cord tracts were removed and used for radioligand binding assay and autoradiography. Using [3H]-RX821002 ([3H]-RX) (0.1-14nM), the Kd and Bmax for every spinal cord segment were calculated. The non-specifi c binding was obtained with 100μM of (-)-epinephrine. [3H]-RX sites were accumulated in the superfi cial laminae of dorsal horn. Dense [3H]-RX binding in control was seen over the superfi cial dorsal horn (laminae I-II) and centrally located lamina X. The ventral horn showed moderate levels of binding. [3H]-RX was displaced after TIZ treatment using diff erent administration routes. The heaviest accumulation of silver grains (lowest displacement of TIZ) occurred after OR administration of the compound, the lowest after IM administration. These results suggest that both IM and IN administration of TIZ may represent routes of administration of the drug alternative to the OR one. Considering predictable adverse eff ects of IM treatment, the IN administration could represent the elective route to administrate this kind of drugs

OPTIMAL PITCH MAP GENERATION FOR SCANNING PITCH DESIGN IN SELECTIVE SAMPLING

The reverse engineering process represents one of the best known methodologies for creating three-dimensional (3D) virtual models starting from physical ones. Even if in the last few years its usage has significantly increased, the remarkable involvement of the operator has until now represented a significant constraint for its growth. Having regard to the fact that this process, and in particular its first step (that is the acquisition phase), strongly depends on the operator's ability and expertise, this paper aims at proposing a strategy for automatically supporting an "optimal" acquisition phase. Moreover, the acquisition phase represents the only moment in which there is a direct contact between the virtual model and the physical model. For this reason, designing an "optimal" acquisition phase will provide as output an efficient set of morphological data, which will turn out to be extremely useful for the following reverse engineering passages (pre-processing, segmentation, fitting, …). This scenario drives the researcher to use a selectivesampling plan, whose grid dimensions are correlated with the complexity of the local surface region analyzed, instead of a constant one. As a consequence, this work proposes a complete operative strategy which, starting from a first raw preliminary acquisition, will provide a new selectivesampling plan during the acquisition phase, in order to allow a deeper and more efficient new scansion. The proposed solution does not require the creation of any intermediate model and relies exclusively on the analysis of the metrological performances of the 3D scanner device and of the morphological behaviour of the surface acquired

Artificial Intelligence Models in the Diagnosis of Adult-Onset Dementia Disorders: A Review

Background: The progressive aging of populations, primarily in the industrialized western world, is accompanied by the increased incidence of several non-transmittable diseases, including neurodegenerative diseases and adult-onset dementia disorders. To stimulate adequate interventions, including treatment and preventive measures, an early, accurate diagnosis is necessary. Conventional magnetic resonance imaging (MRI) represents a technique quite common for the diagnosis of neurological disorders. Increasing evidence indicates that the association of artificial intelligence (AI) approaches with MRI is particularly useful for improving the diagnostic accuracy of different dementia types. Objectives: In this work, we have systematically reviewed the characteristics of AI algorithms in the early detection of adult-onset dementia disorders, and also discussed its performance metrics. Methods: A document search was conducted with three databases, namely PubMed (Medline), Web of Science, and Scopus. The search was limited to the articles published after 2006 and in English only. The screening of the articles was performed using quality criteria based on the Newcastle-Ottawa Scale (NOS) rating. Only papers with an NOS score ≥ 7 were considered for further review. Results: The document search produced a count of 1876 articles and, because of duplication, 1195 papers were not considered. Multiple screenings were performed to assess quality criteria, which yielded 29 studies. All the selected articles were further grouped based on different attributes, including study type, type of AI model used in the identification of dementia, performance metrics, and data type. Conclusions: The most common adult-onset dementia disorders occurring were Alzheimer's disease and vascular dementia. AI techniques associated with MRI resulted in increased diagnostic accuracy ranging from 73.3% to 99%. These findings suggest that AI should be associated with conventional MRI techniques to obtain a precise and early diagnosis of dementia disorders occurring in old age

Bounding Helly numbers via Betti numbers

We show that very weak topological assumptions are enough to ensure the existence of a Helly-type theorem. More precisely, we show that for any non-negative integers $b$ and $d$ there exists an integer $h(b,d)$ such that the following holds. If $\mathcal F$ is a finite family of subsets of $\mathbb R^d$ such that $\tilde\beta_i\left(\bigcap\mathcal G\right) \le b$ for any $\mathcal G \subsetneq \mathcal F$ and every $0 \le i \le \lceil d/2 \rceil-1$ then $\mathcal F$ has Helly number at most $h(b,d)$. Here $\tilde\beta_i$ denotes the reduced $\mathbb Z_2$-Betti numbers (with singular homology). These topological conditions are sharp: not controlling any of these $\lceil d/2 \rceil$ first Betti numbers allow for families with unbounded Helly number. Our proofs combine homological non-embeddability results with a Ramsey-based approach to build, given an arbitrary simplicial complex $K$, some well-behaved chain map $C_*(K) \to C_*(\mathbb R^d)$.Comment: 29 pages, 8 figure

Morphology of cardiac and renal microvasculature in spontaneously hypertensive rat. Activity of thioctic acid

Accumulation of intimal vascular smooth muscle cells is a trait of atherosclerosis. Endothelial cells lining vascular luminal surface represent an important site of signalling and development of damage induced by reactive oxygen species (ROS) during ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules provides site-specific interventions leading to endothelial damage. Excessive ROS production causes pathological activation of endothelium including exposure of cell adhesion molecules. The intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin (Ig) superfamily which is present on the surface of several other cell types, including endothelial cells. Adhesion molecules [e.g., ICAM-1, vascular cell adhesion molecule 1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1)] if in contact with an activated endothelium could represent attractive targets for delivery of drugs and imaging probes to vascular pathological sites. The present study was designed to investigate, with immunochemical and immunohistochemical techniques, the effect of treatment with thioctic acid enantiomers on heart and kidney endothelium in spontaneously hypertensive rats (SHR) used as a model of hypertensive end organ damage. Normotensive Wistar-Kyoto rats were used as a reference group. Arterial hypertension was accompanied by an increased oxidative stress status in the kidney and heart. ICAM, VCAM and PECAM expression was significantly greater in the renal endothelium of SHR. In the heart VCAM expression was higher than ICAM and PECAM and increased in SHR. (+/-)-Thioctic acid and (+)-thioctic acid treatment prevented adhesion molecules expression in renal and cardiac vascular endothelium. Based on these data, it is possible to conclude that endothelial molecules investigated can be used for studying vascular injury on target organs of hypertension. The effects observed after treatment with thioctic acid could open new perspectives for countering heart and kidney microvascular injury, quite common in several diseases affecting these organs

Managing the Socially Marginalized: Attitudes Towards Welfare, Punishment and Race

Welfare and incarceration policies have converged to form a system of governance over socially marginalized groups, particularly racial minorities. In both of these policy areas, rehabilitative and social support objectives have been replaced with a more punitive and restrictive system. The authors examine the convergence in individual-level attitudes concerning welfare and criminal punishment, using national survey data. The authors\u27 analysis indicates a statistically significant relationship between punitive attitudes toward welfare and punishment. Furthermore, accounting for the respondents\u27 racial attitudes explains the bivariate relationship between welfare and punishment. Thus, racial attitudes seemingly link support for punitive approaches to opposition to welfare expenditures. The authors discuss the implications of this study for welfare and crime control policies by way of the conclusion

Patient, primary care provider, and stakeholder perspectives on mammography screening frequency: lessons learned from a qualitative study

Background U.S. professional organizations have provided conflicting recommendations on annual vs. biennial mammography screening. Potential harms of more frequent screening include increased anxiety and costs of false positive results, including unnecessary breast biopsies and overdiagnosis. Objective To characterize current practices and beliefs surrounding mammography screening frequency and perspectives on using risk-based screening to inform screening intervals. Design Semi-structured interviews informed by the Consolidated Framework for Implementation Research (CFIR). Participants Patients, primary care providers (PCPs), third-party stakeholders (breast radiologists, radiology administrators, patient advocates). Main measures Qualitative data, with a codebook developed based upon prespecified implementation science constructs. Key results We interviewed 25 patients, 11 PCPs, and eight key stakeholders, including three radiologists, two radiology administrators, and three patient advocates. Most patients reported having annual mammograms, however, half believed having mammograms every two years was acceptable. Some women were worried early breast cancer would be missed if undergoing biennial screening. PCPs were equally split between recommending annual and biennial mammograms. Although PCPs were interested in using breast cancer risk models to inform screening decisions, concerns raised include time burden and lack of familiarity with breast cancer risk assessment tools. All breast radiologists believed patients should receive annual mammograms, while patient advocates and radiology administrators were split between annual vs. biennial. Radiologists were worried about missing breast cancer diagnoses when mammograms are not performed yearly. Patient advocates and radiology administrators were more open to biennial mammograms and utilizing risk-based screening. Conclusions Uncertainty remains across stakeholder groups regarding appropriate mammogram screening intervals. Radiologists recommend annual mammography, whereas patients and PCPs were evenly split between annual vs. biennial screening, although both favored annual screening among higher-risk women. Breast cancer risk assessment tools may help facilitate decisions about screening intervals, but face barriers to widespread implementation in the primary care setting. These results will inform future implementation strategies to adopt risk-stratified breast cancer screening