bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishing cutting conditions for dry drilling of aluminium alloy stack materials
Authors: Assurin Siti Rozakiyah , Mativenga Paul , Cooke Kevin , Sun Hailin , Field Susan , Walker Mark , Chodynicki Jason , Sharples Colin , Jensen Boris , Mortensgaard Morten F
Published: January 2023

Aside from their remarkable lightness, high strength and corrosion resistance, aluminium alloys have dominated aircraft manufacturing for decades. The combination of aluminium alloys 2024 and 7150 is widely used in the fabrication of airframe structures. Numerous holes must be drilled through the materials in order for them to be connected. Due to structure size and use of mobile drilling machines, lubricant oil is released during the drilling operation and either becomes airborne or accumulates on the floor. The primary motivation for dry drilling development is to avoid this oil discharge. A significant disadvantage of the drilling process for aluminium alloys is the workpiece’s proclivity to stick to the cutting tool, especially when temperatures are high. This research investigated the selection of cutting conditions that enable dry drilling of stack aluminium panels. The selection of cutting parameters for experiment use was made based on the assessment of literature pertaining to drilling with carbide cutting tools. Apart from literature, the assessment of cutting parameters also took into consideration existing practices in Airbus UK. Results indicated that optimum cutting performance was achieved by drilling at higher feedrates and lower interaction time compared to existing fluid based processes. In addition, this paper outlines the aspects of energy and cutting forces in current cutting processes as well as focuses on determining optimum conditions that minimise energy input.
Study on molten pool dynamics and hump formation mechanism in laser wire feeding additive manufacturing
Authors: Peng Haiyong , Zheng Jie , Huang Wenhao , Long Jiangqi
Published: January 2023

The mechanism of the hump formation during the laser wire feeding process has been investigated in this paper. A numerical model was established to analyze the heat transfer and melt flow of molten pool during process with or without hump formation. And effects of laser power, traverse speed, and wire feeding speed on hump formation were also investigated through such a numerical model. The results showed that, under the condition with high wire feeding speed, the molten metal flowed rapidly to the tail of the molten pool due to the impact force of droplet and the metal vapor recoil pressure. Simultaneously, due to the high speed of laser movement, the thin channel of the trough solidified prematurely under the effect of surface tension, which isolated the heat transfer of the molten pool, and then formed periodic humps. By comparative analysis, the numerical simulation results were in good agreement with the experimental results.
Universal Constraints on Linguistic Event Categories: A Cross-Cultural Study of Child Homesign
Authors: Rissman Lilia , Horton Laura , Goldin-Meadow Susan
Published: January 2023

Languages carve up conceptual space in varying ways—for example, English uses the verb cut both for cutting with a knife and for cutting with scissors, but other languages use distinct verbs for these events. We asked whether, despite this variability, there are universal constraints on how languages categorize events involving tools (e.g., knife-cutting). We analyzed descriptions of tool events from two groups: (a) 43 hearing adult speakers of English, Spanish, and Chinese and (b) 10 deaf child homesigners ages 3 to 11 (each of whom has created a gestural language without input from a conventional language model) in five different countries (Guatemala, Nicaragua, United States, Taiwan, Turkey). We found alignment across these two groups—events that elicited tool-prominent language among the spoken-language users also elicited tool-prominent language among the homesigners. These results suggest ways of conceptualizing tool events that are so prominent as to constitute a universal constraint on how events are categorized in language.
A novel funnel control mechanism for hypersonic flight vehicles under input constraints
Authors: Li Xingge , Fan Zhengwei , Pang Xiaofei , Hu Jingwen
Published: January 2023

This article proposes a novel adaptive neural network funnel control scheme based on auxiliary system, which is used to solve the problem that the conventional funnel control strategies have difficulty in solving the control singularity problem caused by transiently increasing tracking errors under input constraints. To begin, the longitudinal motion model of hypersonic flight vehicle is split into a velocity subsystem and an altitude subsystem, with the velocity subsystem being controlled by a proportional integral funnel controller and the altitude subsystem being controlled by an adaptive neural network funnel controller. An adaptive neural network funnel controller is designed for altitude subsystem, which is turned into a pure feedback form. Next, the auxiliary system is used to compensate the control law and tracking error, the neural network is used to estimate the system uncertainty, and the funnel control is used to constrain the tracking error to meet the steady-state and dynamic requirements of hypersonic flight vehicle system. The stability analysis proves the stability of funnel controller. The robustness of our newly proposed method is demonstrated by the simulation results.
Kaempferol ameliorates palmitate-induced lipid accumulation in HepG2 cells through activation of the Nrf2 signaling pathway
Authors: Zhao Li , Yang Liping , Ahmad Khalidamir
Published: January 2023

Objectives

Kaempferol (KMF), has beneficial effects against hepatic lipid accumulation. In this study, we aimed to investigate molecular mechanism underlying the protective effect of KMF on lipid accumulation.

Methods

HepG2 cells were treated with different concentrations of KMF and 0.5 mM palmitate (PA) for 24  h. The mRNA and protein levels of genes involved in lipid metabolism were evaluated using real-time PCR and western blot. The expression of Nrf2 was silenced using siRNA.

Results

Data indicated that KMF (20 μM) reversed PA-induced increased triglyceride (TG) levels and total lipid content. These effects were accompanied by down-regulation of the mRNA and protein levels of lipogenic genes (FAS, ACC and SREBP1), and up-regulation of genes related to fatty acid oxidation (CPT-1, HADHα and PPARα). Kaempferol significantly decreased the levels of the oxidative stress markers (ROS and MDA) and enhanced the activities of antioxidant enzymes SOD and GPx in PA-challenged cells. Luciferase analysis showed that KMF increased the transactivation of Nrf2 in hepatocytes. The results also revealed that KMF-mediated activation of Nrf2 target genes was suppressed by Nrf2 siRNA. Furthermore, Nrf2 siRNA abolished the KMF-induced reduction in ROS and MDA levels in PA treated cells. In addition, the inhibitory effect of KMF on TG levels and the mRNA and protein levels of FAS, ACC and SREPB-1 were significantly abolished by Nrf2 inhibition. Nrf2 inhibition also suppressed the KMF-induced activation of genes involved in β oxidation (CPT-1 and PPAR-α).

Conclusion

The results suggest that KMF protects HepG2 cells from PA-induced lipid accumulation via activation of the Nrf2 signaling pathway.
The role of identity moderators and perceived degree of identity separation in librarian professional identity development
Authors: Pierson Cameron M.
Published: January 2023

This paper examines in-depth processes of librarian professional identity negotiations impacting practitioners’ perception of, affiliation with, and behaviour within the profession. It outlines three key themes which moderate librarian professional identity and introduces the Relational States of Librarian Professional Identity, outlining variations of individual affiliation with the profession. This paper also offers a theoretical framework of identity negotiations with theoretical propositions relating to librarian professional identity development. Forty semi-structed interviews were conducted with practicing public librarians throughout Aotearoa New Zealand. Interviews were analysed with an inductive approach. NVivo was used to code and query interview data. Findings demonstrate identity negotiations as grounded in perceptions of profession through meaning ascribed to the profession and its manifestations (professional associations, etc.), respectively; and perceptions of practice as related to organisational/institutional contexts. Six theoretical propositions are offered detailing the relationship of the three themes moderating librarian professional identity and the Relational States of Librarian Professional Identity to this identity and its negotiations.
Autism and disability sessions at state conferences for school librarians
Authors: Anderson Amelia , Layden Selena J.
Published: January 2023

With 1 in 44 children in the United States meeting the criteria for an autism diagnosis , it is likely that most, if not all, school librarians will have some contact with a student with autism spectrum disorder (ASD). One potential avenue for such education is through professional development opportunities such as state library conferences, in which school librarians share information with one another in forums such as breakout and poster sessions, while also attending keynote and sponsored presentations. To expand upon previous research related to training of school librarians in the area of ASD, this content analysis examines state library conference programs to determine if information is being shared through such conferences about autism and disability. Conferences from nine states, over a 5-year period, were analyzed for key terms related to autism and disability. Findings reveal few opportunities for school librarians to learn about autism and disability through sessions presented at state conferences, despite a previously established interest and need.
Applying Terror Management Theory to Explain International Faculty Responses to COVID-19 Control Measures
Authors: Kuzhabekova Aliya
Published: January 2023

The paper analyses an institutional approach and international faculty responses to implementation of social-distancing measures during COVID-19 on a residential campus of an international university in Kazakhstan. Terror-Management Theory is used to interpret the behavioral responses of the faculty. The theory predicts three types of international faculty responses to the conscious fear of death from COVID-19 – death avoidance, death acceptance, and death negation. These responses determine the extent of compliance with social distance-control measures. In addition three anxiety-buffering mechanisms proposed by the theory – commitment to particular worldviews, self-esteem enhancement and maintenance of social connections – serve as factors of variation in responses. Implications are drawn from the results about the relevance of the theory to the analysis of campus population responses to COVID-19-control measures on domestic and international campuses. Recommendations for university administrators at international universities are made about managing the three types of responses.
Preliminary evaluation of music-based emotion-regulation skills to augment CBT for adolescents with ADHD
Authors: Zemestani Mehdi , Azadbakht Matineh , Storch Eric A
Published: January 2023

Adjunctive strategies that effectively incorporate adolescents’ developmental needs may augment the therapeutic benefits of cognitive behavioral therapy (CBT) for adolescents with attention deficit hyperactivity disorder (ADHD). This preliminary study evaluated a combined CBT and music-based treatment designed to enhance emotion-regulation skills in adolescents with ADHD. Utilizing a single-case experimental design, eight adolescents with ADHD were assigned to a 3-week baseline assessment phase followed by 12 weekly individual sessions of treatment and a 2-month follow-up phase. The intervention was effective in reducing the core symptoms of ADHD, such that, participants showed an increase in adaptive emotion-regulation strategies (cognitive reappraisal) and decrease in maladaptive emotion-regulation strategies (expressive suppression). The intervention was also found to be highly acceptable to participants. The findings provide initial support for combining standard CBT with music-based treatment designed to enhance emotion-regulation skills, and add to the growing body of literature showing that adjunctive strategies can augment the therapeutic benefits of CBT for adolescents with ADHD.
An Integrative Review of Measures of Spirituality in Experimental Studies of Psilocybin in Serious Illness Populations
Authors: Baker Kayla M. , Ulrich Connie M. , Meghani Salimah H.
Published: January 2023

Background: Psilocybin-assisted therapies (PAT) are reemerging as a treatment for complex distress often prompting mystical experiences, enhanced meaning, and spiritual wellbeing. We sought to investigate how measures of spirituality are employed in experimental studies of PAT conducted with seriously ill adults. Methods: We included experimental studies of psilocybin conducted with seriously ill adults, which employed measures that contained spirituality and mysticism concepts within their domains or subdomains. Included studies were peer-reviewed and published in English language (up to December 2021). Results: Seven articles met our inclusion criteria. A total of 12 unique instruments were identified. The most frequently used instruments were the Mystical Experience Questionnaire (MEQ30), the Functional Assessment of Chronic Illness Therapy-Spirituality (FACIT-Sp-12), and the Demoralization Scale (DS-I/II) (used in four studies each), followed by the Persisting Effects Questionnaire (PEQ) (used in three studies). Overall, studies did not consistently define and contextualize spirituality domains and subdomains studied. Conclusions: Despite well-recognized significance of spirituality in PAT, there was considerable heterogeneity in number and types of spirituality measures employed across studies. There also seemed a lack of attention to defining and operationalizing spirituality and its domains and subdomains. This is notable as spirituality and overlapping concepts (eg mystical experiences) contributes substantially to this body of research and patients’ therapeutic outcomes. Towards developing more rigorous science of spirituality in PAT research, there is a critical need to evaluate and refine measures of spirituality to enhance their utility and replicability, limit participant burden, and better contextualize spirituality-related findings and outcomes.
Preclinical and Clinical Medical Student Attitudes Toward the Care of the Dying: Testing the 9-Item Version of the Frommelt Attitude Toward the Care of the Dying Scale
Authors: Loera Barbara , Molinengo Giorgia , Miniotti Marco , Leombruni Paolo
Published: January 2023

The demand for palliative care is increasing worldwide. Beyond the acquisition of technical knowledge, the development of adequate personal disposition toward the relationship with the dying is a key aspect of the future training of doctors. This study evaluates the psychometric properties of the 9-Item Version of the Frommelt Attitude Toward the Care of the Dying Scale (FATCOD-9IT) the authors recently developed and its capability to distinguish medical students with different attitudes toward the care of the dying and at different stages of medical training. The study included 595 medical students, 400 at the first and 195 at the fifth year. The Rasch rating scale model was specified to assess scale dimensionality, functioning and measurement invariance. Internal consistency, test-retest reliability and between-group difference sensitivity (first-vs fifth-year students) were evaluated using Cronbach’s alpha, Intraclass correlation coefficients, Paired sample t-test and Mann-Whitney U. Scale unidimensionality, rating scale functioning and measurement invariance were established. The scale demonstrated good internal consistency and test-retest reliability, and adequately discriminated between first- and fifth-year students. The study supports the validity and reliability of the FATCOD-9IT. Its effectiveness, simplicity of compilation and score calculation, and gratuitousness encourage its widespread use as fast assessment of the medical student attitudes toward the care of the dying.
Live to Work, Work to Live, and Work as a Necessary Evil: An Examination of the Structure and Stability of Work Ethic Profiles
Authors: Woehr David J. , Arciniega Luis M. , González Luis , Stanley Laura J.
Published: January 2023

The goal of the present study is twofold. First, we take a person-centered approach to individual differences in work ethic. Here, we focus on the identification and stability of profiles of work ethic dimensions across individuals from two relatively diverse samples. Second, we examine the extent to which work ethic profile membership influences which characteristics of an ideal coworker are viewed as most important. To assess our hypotheses, we used a diverse US-based sample of 2440 as well as a sample of 692 employees in sales-related positions in the financial sector in Mexico. Results from a series of latent profile analyses (LPAs) clearly support the idea that from the combination of scores on the seven dimensions of work ethic, clear and reliable profiles emerge and were generalizable across samples. The three profiles were identified as “Live to Work,” “Work to Live,” and “Work as a Necessary Evil.” Significant differences were found in 5 of 11 desired attributes of an ideal coworker between the employees in the three emerging profiles. Also, in line with our hypotheses, results show that employees belonging to the profile with the highest scores on the core dimensions of the work ethic construct reported that the top desired characteristic in an ideal peer is the hard worker attribute.
Free vibration analysis of cylindrical sandwich panel with electro-rheological core and FG-GPLRC facing sheets based on First order shear deformation theory referred by Qatu
Authors: Ghavidel Nima , Alibeigloo Akbar
Published: January 2023

In this study, free vibration and damping behavior of cylindrical sandwich panel with electro-rheological core and graphene platelets reinforced composite (GPLRC) facing sheets based on first-order shear deformation theory of thick cylindrical shells referred by Qatu (FSDTQ) is investigated. Effective material properties of graphene platelets reinforced composite are determined according to the Halpin–Tsai micromechanical model. The governing equations of motion with required boundary conditions are derived using Hamilton’s principle. Afterward, these equations are solved analytically using the Fourier series solution for simply-supported boundary conditions, and for the other edges boundary conditions, we used the generalized differential quadrature method. The exactness and correctness of the present formulation are validated by comparing the results with those of existing literature. Finally, the influences of various parameters such as the electric fields, geometrically parameters, boundary conditions, the volume fraction of GPL, and GPL distributions pattern on vibration behavior and modal loss factor is examined. According to the results, the influence of the GPL volume fraction and electric field on the frequencies and modal loss factor is significant. This achievement can help design intelligent controlling structures for various applications.
Identification of an elliptic void in a piezoelectric layer by two types of loads
Authors: Elmorabie Khaled M , Yahya Rania
Published: January 2023

This study investigates the effect of mechanical load and electric voltage on the scattering waves of a buried object in a piezoelectric layer, added to that, the study examines the detection of the buried object through its scattering surface waves. The procedure of the study includes two cases which include two steps each. During step 1 of case 1, the researchers applied a periodic mechanical load upon layer containing an elliptic void, where the size and location are predetermined. A system of coupled boundary integral equations utilizing the generalized Green’s identity and the reciprocal work theorem is formulated. The boundary element method supported by Green’s functions was employed to solve the formulated integral equations. Hence, the deformation and electric potential over the object’s contour are identified. Step 2 examined optimization problem to identify the object’s parameters, i.e., its size and location, by minimizing a structure of discrepancy functional. The quasi-Newton iterative method and the Genetic Algorithm (GA) are used for solving the inverse problem. Case 2 of the study examined the effect of electric voltage on the scattering waves of a buried object in the piezoelectric layer. The procedures of case 1 are administered to case 2 to compare the accuracy of detection results in both cases of the study. A series of practical examples are presented with random noisy data to compare the effect of such loads on the process of detection. The results indicate that using the mechanical load in detecting buried object is clearly accurate compared to voltage load detection.
Article Commentary: Translating Clinical Research into Practice: Practice-Based Research Networks—A Promising Solution
Authors: GeneI Myron , Dobs Adrian
Published: January 2023

Greater effort is needed to translate research discoveries into clinical practice and to ensure that proven treatments are routinely implemented by physicians. Practice-based research networks are an undervalued resource in the endeavor to bring research results to bear in patient care. These networks are groups of practicing health care providers who have organized to address research questions of primary importance to their patients. Existing practice-based research networks have addressed a wide range of issues, including improvement of preventive service delivery, reliability of diagnostic measures, practice variation, disease prevention, and systems of care coordination. Several deficiencies in the current system prevent practice-based research networks from reaching their full potential as mechanisms of translating clinical research into practice. For practice-based research networks to flourish, they need increased funding for practice-based research networks; information systems to facilitate research by practicing physicians; training programs for health care providers; and communication networks between providers, clinical researchers, professional societies, and academic health centers.
Article Commentary: Improving the US Health Care System: Action Plan to Enhance Efficiency, Reduce Errors, and Improve Quality
Authors: Tilson Hugh , Helms David , Dowdy David
Published: January 2023

The decisions made by stakeholders in the nation's health care system that affect the quality of care experienced by patients are too often made without the benefit of scientific evidence. A multidisciplinary set of investigators conducting health services research have traditionally filled this gap between research findings and clinical decision making, but several barriers are hindering this work. This article offers several recommendations—restructuring organizations, ensuring funding, developing infrastructure, strengthening the community of researchers, and forging new links among stakeholders—to promote high-quality information for health decision makers.
Cardiac Mitochondrial Calcium Loading Capacity is Severely Affected after Chronic Cholestasis in Wistar Rats
Authors: Oliveira Paulo J. , Rolo Anabela P. , Seiça Raquel , Santos Maria S. , Palmeira Carlos M. , Moreno António J. M.
Published: January 2023

Background

Cardiovascular changes correlated with some forms of hepatic disease are being reported in the literature. Objectives: The aim of this work was to characterize cardiac mitochondrial bioenergetics and calcium buffering capacity in Wistar rats injected with six weekly doses of α-naphthylisothio-cyanate (ANIT), a compound known to induce cholestasis in animal models.

Methods

Isolated heart mitochondria were obtained from both injected and control animals and bioenergetic parameters were measured, as well as the capacity to buffer externally added calcium and the mitochondrial content of reduced protein thiol groups. Blood biochemistry analyses were obtained at the initial and end points of treatment. The in vitro ANIT effect on isolated heart mitochondria was also studied.

Results and Discussion

Our results showed that the respiratory control ratio was the only parameter affected in injected animals ( p < .05, n = 5). Nevertheless, heart mitochondria from injected animals showed an inability to accumulate added calcium owing to an increased susceptibility to the calcium-dependent mitochondrial permeability transition ( p < .0001, n = 5). The effects were still present 1 week after ending ANIT administration, when serum markers for liver injury and hyperbilirubinemia were already abated (although in the presence of bile duct proliferation). To our knowledge, this is the first time that cardiac mitochondrial calcium homeostasis and mitochondrial respiratory ratio are seen affected during ANIT-induced cholestasis, prevailing even in the absence of hepatic damage serum markers.
Patient Education Strategies to Improve Pneumococcal Vaccination Rates: Randomized Trial
Authors: Thomas Donna M. , Ray Susan M. , Morton Felicia J. , Drew Jennifer S. , Offutt Gardiner , Whitney Cynthia G. , Jacobson Terry A.
Published: January 2023

Background

The pneumococcal vaccine is widely underused. Patient education is one mechanism not widely explored for increasing vaccination rates.

Objective

To evaluate the effects of a culturally appropriate patient education videotape on pneumococcal vaccination rates among the clinic population of an inner-city public hospital.

Methods

Randomized, controlled trial comparing (1) a videotape-brochure group who both viewed the videotape and received a low-literacy brochure, (2) a videotape only group, and (3) a control group.

Results

Of 2,962 charts reviewed, 558 patients were randomized. The study population was 94% black, 73% female, and elderly (mean age 63.0 years) and 64% had less than a high school education. Patients in the videotape-brochure group were 2.5 (1.8, 3.5 95% CI) times more likely to discuss the vaccine with their physician (p < .001) and 3.5 (1.9, 6.5 95% CI) times more likely to receive the vaccine ( p < .001) than the control group. The videotape-brochure group was 1.6 (1.2, 2.1 95% CI) times more likely to discuss the vaccine ( p < .001) and 2.3 (1.4, 3.8 95% CI) times more likely to receive the vaccine (p = .002) than the video only group. Patients in the video only group were 1.6 (1.1, 2.3 95% Cl) times more likely to discuss the vaccine with their physician than the control group (p = .041) but were not more likely to receive the vaccine.

Conclusion

A culturally appropriate videotape along with a low-literacy brochure significantly increased pneumococcal vaccination rates and physician-patient discussion about the vaccine. These significant outcomes were not observed with use of videotape alone and were likely attributable to the effect of the brochure. We recommend that patient education initiatives to increase vaccination rates not focus solely on audiovisual media.
Thyroid Hormone Action: Insight from Transgenic Mouse Models
Authors: Wondisford Fredric E.
Published: January 2023

Thyroid hormone receptors (TRs) are cellular homologues of the viral erythroblastic leukemia oncogene (v-erbA). TRs (c-crbA isoforms) are derived from two separate gene loci in mammals: a and p. Through a series of knockout experiments in mice in which one or several of the TR isoforms were deleted, it has been demonstrated that the TR-β isoforms control central regulation of thyroid-stimulating hormone. Of these isoforms, TR-β2 is the most important in mediating negative feedback control of the hypothalamic-pituitary-thyroid axis. Further analysis of TR knockout animals revealed, however, that they exhibited a much milder overall phenotype than hypothyroid animals, indicating that receptor loss was not equivalent to ligand loss in vivo. To understand this apparent paradox, we generated animals expressing a non-T3 binding receptor (Δ337T) from the TR-β allele. These mice displayed a complete hypothyroid phenotype, demonstrating that the unliganded TR mediates the effect of hypothyroidism. Because this mutant TR constitutively binds to nuclear coreprssors, it also suggests that this class of proteins is essential for mediating hypothyroidism in vivo.
Perinatal Asphyxia in the Guinea Pig Leads to Morphologic but not Neurologic, Cognitive, or Behavioral Changes
Authors: Hoeger Harald , Bubna-Littitz Herrmann , Engelmann Mario , Schwerdtner Ingrid , Schmid Diethard , Lahoda Robert , Seidl Rainer , Lubec Gert , Lubec Barbara
Published: January 2023

Background

In a recent publication, we described neurodegeneration along with neurotransmitter deficits and impaired differentiation in the guinea pig 3 months following severe perinatal asphyxia (PA). We were therefore interested in the clinical features in terms of neurology, cognitive functions, and behavior.

Methods

We tested the long-term effects of PA in an animal model, which in the rat are well documented and resemble the clinical situation. Examinations consisted of an observational battery for motor and reflex functions and the acoustic startle response setting. We tested cognitive functions in the multiple T-maze and evaluated behavior using the elevated plus maze and open field studies.

Results

No neurologic deficits were observed in the observational battery, including the acoustic startle response. Cognitive functions of memory and learning were not impaired in the multiple T-maze. In the open field and in the elevated plus maze, the system to test anxiety-related behavior, guinea pigs performed well.

Conclusion

Our findings of patent neurology, cognitive functions, and behavior do not reflect the prominent morphologic findings of neurodegeneration. This is in agreement with corresponding studies on PA in the rat at the identical time point. We learned from this study that both test systems, although representing the standard in neuroscience, are either not sensitive enough or central nervous system lesions are clinically fully compensated.
Molecular Mechanisms, Diagnosis, and Rational Approaches to Management of and Therapy for Charcot-Marie-Tooth Disease and Related Peripheral Neuropathies
Authors: Saifi Gulam Mustafa , Szigeti Kinga , Snipes G. Jackson , Garcia Carlos A. , Lupski James R.
Published: January 2023

During the last decade, 18 genes and 11 additional loci harboring candidate genes have been associated with Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies. Ten of these 18 genes have been identified in the last 2 years. This phenomenal pace of CMT gene discovery has fomented an unprecedented explosion of information regarding peripheral nerve biology and its pathologic manifestations in CMT. This review integrates molecular genetics with the clinical phenotypes and provides a flowchart for molecular-based diagnostics. In addition, we discuss rational approaches to molecular therapeutics, including novel biologic molecules (eg, small interfering ribonucleic acid [siRNA], antisense RNA, and ribozymes) that potentially could be used as drugs in the future. These may be applicable in attempts to normalize gene expression in cases of CMT type 1A, wherein a 1.5 Mb genomic duplication causes an increase in gene dosage that is associated with the majority of CMT cases. Aggresome formation by the PMP22 gene product, the disease-associated gene in the duplication cases, could thus be avoided. We also discuss alternative therapeutics, in light of other neurodegenerative disorders, to disrupt such aggresomes. Finally, we review rational therapeutic approaches, including the use of antioxidants such as vitamin E, coenzyme Q10, or lipoic acid to relax potential oxidative stress in peripheral nerves, for CMT management.
Antioxidant Potential and Transferrin, Ceruloplasmin, and Lipid Peroxidation Levels in Women with Preeclampsia
Authors: Aksoy Hulya , Taysi Seyithan , Altinkaynak Konca , Bakan Ebubekir , Bakan Nuri , Kumtepe Yakup
Published: January 2023

Background

The aim of this study was to evaluate lipid peroxidation and antioxidant function in patients with preeclampsia and in normotensive pregnant women and to assess an association with the severity of the disease.

Methods

Twenty-one patients with mild preeclampsia, 15 patients with severe preeclampsia, and 19 normotensive pregnant women were included in the study. Plasma antioxidant potential (AOP) status, ceruloplasmin (Cp) and transferrin (Trf) levels as antioxidants, and malondialdehyde (MDA) levels as an indicator of lipid peroxidation were measured.

Results

Whereas the AOP and Trf levels of the severe and mild preeclampsia groups were found to be reduced, the MDA and Cp levels were increased compared with those of the normotensive pregnant group. There were statistically significant negative correlations between AOP and MDA in all groups. No differences were observed between the groups with severe and mild preeclampsia with respect to these analytes.

Conclusion

Our findings suggest that lipid peroxidation may be an important factor in the pathogenesis of preeclampsia and that plasma antioxidants and oxidants are altered in preeclampsia. However, these findings may not be useful in distinguishing women with severe and mild preeclampsia.
Perinatal Asphyxia Exerts Lifelong Effects on Neuronal Responsiveness to Stress in Specific Brain Regions in the Rat
Authors: Salchner Peter , Engidawork Ephrem , Hoeger Harald , Lubec Barbara , Singewald Nicolas
Published: January 2023

Background

Perinatal asphyxia (PA) causes irreversible damage to the brain of newborns and can produce neurologic and behavioral changes later in life. To identify neuronal substrates underlying the effects of PA, we investigated whether and how neuronal responsiveness to an established stress challenge is affected.

Methods

We used Fos expression as a marker of neuronal activation and examined the pattern of Fos expression in response to acute swim stress in 24-month-old rats exposed to a 20-minute PA insult.

Results

Swim stress produced a similar pattern of Fos expression in control and asphyxiated rats in 34 brain areas. Asphyxiated rats displayed a higher number of stress-induced Fos-positive cells in the nucleus of the solitary tract, parabrachial nucleus, periaqueductal gray, paraventricular hypothalamic nucleus, nucleus accumbens, caudate-putamen, and prelimbic cortex. No differences in the Fos response to stress were observed in other regions, including the locus ceruleus, amygdala, hippocampus, or septum.

Conclusion

These data provide functional anatomic evidence that PA has lifelong effects on neuronal communication and leads to an abnormal, augmented neuronal responsiveness to stress in specific brain areas, particularly in the main telencephalic target regions of the mesencephalic dopamine projections, as well as in a functionally related set of brain regions associated with autonomic and neuroendocrine regulation.
Serum Metalloproteinase 9 Levels in Patients with Coronary Artery Disease: A Novel Marker of Inflammation
Authors: Ferroni Patrizia , Basili Stefania , Martini Francesca , Cardarello Cristiano M. , Ceci Fabrizio , Franco Manuela Di , Bertazzoni Giuliano , Gazzaniga Pier Paolo , Alessandri Cesare
Published: January 2023

Background

The finding that expression of metalloproteinases (MMPs) is induced in atherosclerotic plaques prone to rupture suggests the possibility that patients with atherosclerotic diseases would show enhanced blood levels of MMPs and that MMPs might represent a potential inflammatory risk factor for atherosclerosis. Therefore, the present study was aimed at verifying whether MMPs may represent sensitive markers of inflammation in patients with coronary artery disease.

Methods

MMP-2, MMP-9, interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen levels were measured in blood samples obtained from 66 cases with previous acute myocardial infarction and 66 control subjects similar for age, sex, and major atherosclerotic risk factors but without history or evidence of atherothrom-botic diseases.

Results

Biohumoral markers of inflammation and MMP-9 levels were significantly elevated in cases compared with controls (median values 40.6 versus 9.8 ng/mL; p < .0001), whereas MMP-2 levels did not differ between the two groups (median values 839 versus 873 ng/mL; p = .53). A direct correlation was found among MMP-9, CRP, IL-6, and fibrinogen levels. Conditional logistic regression analysis showed that MMP-9 is related to myocardial infarction (p = .006) even after adjusting for cardiovascular medications and CRP.

Conclusion

These findings suggest that measurement of serum MMP-9 levels may represent a novel marker of inflammation in patients with known coronary artery disease and might provide an index of plaque activity in this clinical setting.
Doris Duke Clinical Research Fellowship: Report of the Second Annual Meeting
Authors: Allen Alisha , Parikh Gunjan , McPhaul Michael J.
Published: January 2023

The second annual national meeting of the Doris Duke Charitable Foundation Clinical Research Fellowship for Medical Students program was held June 24 to 26, 2003, at Cold Spring Harbor Laboratory near Long Island Sound. This 3-day meeting offered an opportunity for 63 of the 2002 Doris Duke clinical research fellows, program directors, administrators, and invited physician-scientists to present and share their research with one another in an informal, inspiring setting at an institution with a history that mirrors the development of modern American medical research. Following a keynote lecture by Dr. Kenneth Davis, dean of the Mount Sinai School of Medicine, six physician-scientists representing different areas of clinical research presented their work. Oral and poster presentations by the Doris Duke fellows of their research were interspersed throughout the meeting and comprised its central focus. The fellows’ research spanned a broad spectrum of clinical research from studies translating basic research findings to those addressing clinical questions to epidemiologic and health outcomes studies. The meeting culminated in a forum entitled “‘Where Do We Go from Here?’ Residency Selection and Further Research Training in Pursuit of a Career as a Clinician-Scientist,” which was moderated by this year's clinical research fellow national program leader, Dr. Allyn L. Mark. The meeting celebrated the accomplishments of these talented medical students during their fellowship year and, it is hoped, instilled in them awareness that their continued efforts are important to the future progress of medicine.
Mitogen-Activated Protein Kinases in Endothelial Pathophysiology
Authors: Bogatcheva Natalia V. , Dudek Steven M. , Garcia Joe G. N. , Verin Alexander D.
Published: January 2023

Endothelial cells continuously respond to extracellular stimuli such as chemical signals produced by circulating blood elements or mechanical forces such as shear stress. Proinflammatory cytokines, mitogens, reactive oxygen species, and shear stress trigger signal molecules to initiate multiple intracellular pathways, which often converge at mitogen-activated protein (MAP) kinase activation. The MAP kinase superfamily represents a burgeoning area of clinical investigation for treatment of various inflammatory and oncologic diseases and plays an essential role in mediating response to infection, ischemia/reperfusion injury, and vessel healing and remodeling through regulation of such diverse phenomena as endothelial cell proliferation, migration, apoptosis, and endothelial barrier function. The downstream effects of MAP kinase activation include modulation of gene expression via up-regulation of various transcription factors. In addition to these sustained effects, MAP kinases coordinate more immediate responses that affect dynamic cytoskeletal rearrangements necessary for cell migration and regulation of barrier function. This review discusses the important regulatory roles of MAP kinases in the vital physiologic functions of endothelium, focusing mainly on the role of MAP kinases in the maintenance of endothelial barrier.
Comparison of Echocardiography Using Tissue Harmonics and Contrast Harmonics with Radionuclide Angiography for the Assessment of Left Ventricular Function
Authors: Almeda Francis Q. , Hendel Robert C. , Macioch James E. , Sandelski Joanne , Parrillo Joseph E , Meyer Peter M. , Johnson Mahala , Daniels Maria L. , Go Vanessa U. , Feinstein Steven B.
Published: January 2023

Background

Left ventricular ejection fraction (LVEF) is a significant predictor of morbidity and mortality; however, the optimal noninvasive modality for the quantitative determination of LVEF is not apparent.

Hypothesis

We verified the hypothesis that the various echocardiographic methods of assessing LVEF using the Method of Discs with contrast (Optison human albumin microspheres; Amersham Health, Princeton, NJ) and visual assessment of LVEF using tissue harmonics and contrast harmonics compare favorably with radionuclide angiography (RNA).

Methods

In a prospective analysis, 24 consecutive patients scheduled to undergo RNA had an echocardiogram using tissue harmonics and contrast harmonics on the same day. LVEF was assessed by RNA by an experienced, blinded reader using manual determination of the region of interest. LVEF was calculated using the Method of Discs (Simpson's Rule) by a blinded sonographer. LVEF was visually estimated by two blinded readers using echocardiography with tissue harmonics and contrast harmonics on separate occasions.

Results

By linear regression analysis, LVEF determination by echocardiography with contrast using the Method of Discs correlated well with RNA (r = .835, p < .0005). Using Bland-Altman analysis, the second echocardiogram reader had excellent agreement with RNA, whereas the first reader had a mean difference of 5.25% (CI 1.3–9.2; p = .012) with visual assessment using tissue harmonics and a mean difference of 4.67% (CI 0.4–8.8; p = .031) with visual assessment using contrast harmonics compared with RNA. Thus, a small difference in agreement between RNA and echocardiographic visual estimation was noted that appeared to be primarily reader dependent.

Conclusions

LVEF determination with echocardiography with contrast using the Method of Discs correlated well with RNA and provided agreement across a range of cardiac functions. Visual echocardiographic assessment of LVEF with both tissue harmonics and contrast harmonics correlated well with RNA, but contrast harmonics did not appear to offer an advantage over tissue harmonics alone.
Role of Oxidative Stress in the Etiology of Type 2 Diabetes and the Effect of Antioxidant Supplementation on Glycemic Control
Authors: Opara Emmanuel C.
Published: January 2023

Oxidative stress is a situation in which the amount of reactive oxygen species (ROS) exceeds the levels of neutralizing substances referred to as antioxidants. Numerous studies have shown that oxidative stress is associated with type 2 diabetes, and there is compelling biochemical evidence that suggests that ROS may even play a role, if only secondary, in the pathogenesis of type 2 diabetes. These observations have provided sufficient impetus for the use of antioxidant supplements as adjunct therapy for control of blood sugar in diabetic patients. However, there is currently no optimum regimen of antioxidant supplementation for diabetic patients. Studies are required to determine appropriate doses of relevant individual micronutrients that perhaps should be used in combination to diminish oxidative stress and improve glycemic control in individuals afflicted with type 2 diabetes.
Role for Oxidative Stress in the Regeneration of Islet Beta Cells?
Authors: Haskins Kathryn , Kench Jennifer , Powers Katherine , Bradley Brenda , Pugazhenthi Subbiah , Reusch Jane , McDuffie Mama
Published: January 2023

In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have found that there are increased markers of oxidative stress in islet beta cells in prediabetic animals when compared with control strains. Treatment of these mice with a superoxide dismutase (SOD) mimetic can markedly reduce the level of nitrotyrosine found in islets. In a diabetes-resistant NOD congenic mouse, the NOD.Lc7 mouse, we found increased beta cell proliferation and decreased apoptosis in islets. There are also lower levels of nitrotyrosine in islets of NOD.Lc7 mice than in NOD mice, suggesting that NOD.Lc7 islets are less susceptible to oxidative damage. We hypothesize that there may be a link between the ability of islet cells to regenerate and their resistance to oxidative stress.
Biologic Effects of Parathyroid Hormone Metabolites: Implications for Renal Bone Disease
Authors: Akhtar Irme , Gonzalez Esther A.
Published: January 2023

Renal bone disease or renal osteodystrophy is the term used to describe the spectrum of histologic abnormalities encountered in patients with chronic kidney disease (CKD). The patterns of bone histology encountered in the setting of CKD range from states of high bone turnover, such as osteitis fibrosa, the result of hyperparathyroidism, to states of abnormally low bone turnover, such as adynamic bone.1 The major factors involved in the pathogenesis of secondary hyperparathyroidism include phosphate retention as glomerular filtration rate decreases and low levels of calcitriol as renal mass is reduced. Both of these factors may lower serum calcium and therefore stimulate parathyroid hormone (PTH) secretion. In addition to these indirect effects, low levels of calcitriol and high serum phosphorus have been shown to have direct effects on the parathyroid gland to increase PTH secretion. The pathogenetic factors involved in the development of adynamic bone disease are less well understood, but it appears that oversuppression of PTH and the use of vitamin D compounds may play a role. Thus, in the management of renal osteodystrophy, it is important to be able to monitor and treat hyperparathyroidism effectively while at the same time avoiding oversuppression of PTH. In this regard, accurate measurements of circulating PTH levels are an essential guide in the management of renal bone disease.

It is well accepted that PTH is present in the circulation in the form of both the intact 84-amino acid peptide and a variety of truncated fragments.2–4 Although the role of the intact PTH molecule as a major regulator of mineral ion homeostasis is well established, the actions of PTH fragments have remained poorly understood. In this review, we discuss the generation of PTH metabolites and the evidence supporting their biologic activity and their potential role in renal bone disease.