Miracle-dz/UniFAR-FTUs huggingface dataset:
INTEGRATIVE MEDICINE SECTION Integrated Meditation and Exercise Therapy: A Randomized Controlled Pilot of a Combined Nonpharmacological Intervention Focused on Reducing Disability and Pain in Patients with Chronic Low Back Pain

Objective. This pilot trial examined the effects of a combined intervention of mindfulness meditation followed by aerobic walking exercise compared with a control condition in chronic low back pain patients. We hypothesized that meditation before exercise would reduce disability, pain, and anxiety by increasing mindfulness prior to physical activity compared with an audiobook control group. Participants. Thirty-eight adults completed either meditation and exercise treatment (MedExT) (n1⁄418) or an audiobook control condition (n1⁄420). Setting. Duquesne University Exercise Physiology Laboratory. Design. A pilot, assessor-blinded, randomized controlled trial. Methods. Over a 4week period, participants in the MedExT group performed 12–17 minutes of guided meditation followed by 30 minutes of moderate-intensity walking exercise 5 days per week. Measures of disability, pain, mindfulness, and anxiety were taken at baseline and postintervention. Pain perception measurements were taken daily. Results. Compared with the control group, we observed larger improvements in disability in the MedExT intervention, although the changes were modest and not statistically significant (mean between-group difference, –1.24; 95% confidence interval [CI], –3.1 to 0.6). For secondary outcome measures, MedExT increased mindfulness (within-group) from pre-intervention to postintervention (P1⁄40.0141). Additionally, mean ratings of low back pain intensity and unpleasantness significantly improved with time for the MedExT group compared with that of the control group, respectively (intensity P1⁄40.0008; unpleasantness P1⁄40.0022). Conclusion. Overall, 4 weeks of MedExT produced suggestive between-group trends for disability, significant between-group differences for measures of pain, and significant within-group increases in mindfulness.
Estimated third metatarsal bending stresses are highly susceptible to variations in bone geometry

Background: Third metatarsal stress fractures are relatively common during Royal Marines recruit training; however, their aetiology is poorly understood. Mathematical modelling of the third metatarsal may aid in understanding risk factors for stress fracture, particularly if the influence of footwear on peak bending stresses can be determined. This study built on previous models of metatarsal bending stress by integrating individual metatarsal geometry and gait data. Methods: Data from five males with size 11 (UK) feet were acquired. MRI images were digitised to determine cross-sectional bone parameters. Gait variables included vertical ground reaction forces, plantar pressure and foot orientation. The magnitude and location of peak bending stresses were calculated for barefoot running, before standard issue combat boots and trainers were compared. Findings: Estimated peak compressive, tensile and torsional stresses were greater in combat assault boots than in trainers (p < 0.05) with medium effect sizes but wide confidence intervals. However, differences in bone geometry between individuals had a much greater influence on estimated peak stresses. Interpretation: Results suggest that bone geometry has a greater influence on third metatarsal stress fracture risk than footwear. Future bone stress simulations should account for bone geometry. Further development of the model in a variety of participants should proceed to verify these suggestions.
Genetic and environmental factors in Parkinson’s converge on immune function and inflammation

Idiopathic Parkinson’s disease (iPD) is a movement disorder characterized by degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and non-motor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors which activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable future development of immunomodulatory approaches to prevent or delay onset of iPD. Author Roles Elizabeth M. Kline – writing of the first draft, manuscript preparation Madelyn C. Houser – writing of the first draft, review and critique Mary K. Herrick – writing of the first draft, review and critique Philip Seibler – writing of the first draft, review and critique Christine Klein – review and critique Andrew West – review and critique Malú G. Tansey – review and critique Conflicts of Interests MGT is a current member of advisory boards for the W. Garfield Weston Foundation advisory board, the World Parkinson Coalition, the Quebec Parkinson’s Network, the Michael J. Fox Foundation for Parkinson’s Research, the Alzheimer’s Association Medical and Scientific Advisory Board, and has active collaborations/consults with/for INmune Bio, Denali, Merck, Biogen/Ionis, Lundbeck, Longevity Bio, Cerebral Therapeutics, and Prevail Therapeutics. ABW is a current member of the Michael J. Fox Foundation for Parkinson’s Research Executive Scientific Advisory Board and consults for EscapeBio Inc. and Neuro23 Inc. CK is a medical advisor to Centogene for genetic testing reports in the fields of movement disorders and dementia, excluding Parkinson’s disease. HHS Public Access Author manuscript Mov Disord. Author manuscript; available in PMC 2022 January 01. Published in final edited form as: Mov Disord. 2021 January ; 36(1): 25–36. doi:10.1002/mds.28411. A uhor M anscript
KINETICS OF ACTIVATION OF ACETYLCHOLINE

We studied, using the patch-clamp technique, the kinetics of single acetylcholine (ACh)-activated channels in a mouse muscle cell line. In the presence of high ACh concentrations we estimated the rate of channel isomerization into the open state (/3) from the dwell time between openings. Also, we obtained estimates for ,B under low agonist concentrations by assuming a linear sequential model of channel activation and applying burst analysis. If the linear model is correct, then the two estimates of /3 should agree since ,B should be independent of ACh concentration. However, the estimates of /3 obtained under low ACh concentrations were slower than those obtained independently under high ACh concentrations. The discrepancy in the estimates of /3 suggests that the linear model is inadequate, but the discrepancy can be explained if open channels can close through two separate pathways. Two alternative kinetic models that can account for our data are discussed.
Practice of Epidemiology Flexible Modeling of the Association Between Cumulative Exposure to Low-Dose Ionizing Radiation FromCardiac Procedures andRisk of Cancer in AdultsWith Congenital Heart Disease

Adults with congenital heart disease are increasingly being exposed to low-dose ionizing radiation (LDIR) from cardiac procedures. In a recent study, Cohen et al. (Circulation. 2018;137(13):1334–1345) reported an association between increased LDIR exposure and cancer incidence but did not explore temporal relationships. Yet, the impact of past exposures probably accumulates over years, and its strength may depend on the amount of time elapsed since exposure. Furthermore, LDIR procedures performed shortly before a cancer diagnosis may have been ordered because of early symptoms of cancer, raising concerns about reversal causality bias. To address these challenges, we combined flexible modeling of cumulative exposures with competing-risks methodology to estimate separate associations of time-varying LDIR exposure with cancer incidence and all-cause mortality. Among 24,833 patients from the Quebec Congenital Heart Disease Database, 602 had incident cancer and 500 died during a follow-up period of up to 15 years (1995–2010). Initial results suggested a strong association of cancer incidence with very recent LDIR exposures, likely reflecting reverse causality bias. When exposure was lagged by 2 years, an increased cumulative LDIR dose from the previous 2–6 years was associated with increased cancer incidence, with a stronger association for women. These results illustrate the importance of accurate modeling of temporal relationships between time-varying exposures and health outcomes.
Consequences of ethanol exposure on cued and contextual fear conditioning and extinction in adulthood differ depending on timing of exposure

Some evidence suggests that adolescents are more sensitive than adults to ethanol-induced cognitive deficits and that these effects may be long-lasting. The purpose of Exp 1 was to determine if early-mid adolescent [Postnatal day (P) 28-48] intermittent ethanol exposure would affect later learning and memory in a Pavlovian fear conditioning paradigm differently than comparable exposures in adulthood (P70-90). In Exp 2 animals were exposed to ethanol during mid-late adolescence (P35-55) to assess whether age of initiation within the adolescent period would influence learning and memory differentially. Male Sprague-Dawley rats were given 4 g/kg i.g. ethanol (25%) or water every 48 hours for a total of 11 exposures. After a 22 day non-ethanol period, animals were fear conditioned to a context (relatively hippocampal-dependent task) or tone (amygdala-dependent task), followed by retention tests and extinction (mPFC-dependent) of this conditioning. Despite similar acquisition, a deficit in context fear retention was evident in animals exposed to ethanol in early adolescence, an effect not observed after a comparable ethanol exposure in mid-late adolescence or adulthood. In contrast, animals that were exposed to ethanol in mid-late adolescence or adulthood showed enhanced resistance to context extinction. Together these findings suggest that repeated ethanol imparts long-lasting consequences on learning and memory, with outcomes that differ depending on age of exposure. These results may reflect differential influence of ethanol on the brain as it changes throughout ontogeny and may have implications for alcohol use not only throughout the developmental period of adolescence, but also in adulthood.
U V . R FREEMAN , CO , MC Biochemical and Electrophoretic Studies of a-Galactosidase in Normal Man , in Patients with Fabry ' s Disease , and in Equidae

Fabry's disease is a glycolipid storage disorder characterized by the accumulation of ceramide trihexoside and by deficiency of a-galactosidase [1-3]. Pedigrees of patients with Fabry's disease clearly show X-linkage of the disorder [3]. X-linkage is further supported by the demonstration that clones of fibroblasts of heterozygotes display a bimodal population with respect to a-galactosidase activity [4]. It has been suggested that normal plasma infusions may result in enzyme production in patients with this disease [5, 6], which suggests that a disorder of regulation of enzyme production could be involved. The sex-linked nature of the enzyme deficiency could be explained on the basis of either the existence of an X-linked regulator gene or X-linkage of the structural locus for a-galactosidase. If the residual a-galactosidase activity in the cells of patients with Fabry's disease were abnormal, this would prove that the disorder is due to a structural gene mutation. On the other hand, if no abnormal protein could be found, a regulatory mutation would be a possibility. Localization of the structural gene for a-galactosidase to an autosome would indicate that the basic abnormality in the disorder was of a regulatory nature, since the gene for deficiency is sex-linked. For these reasons, we have investigated some of the biochemical characteristics of x-galactosidase in normal leukocytes and fibroblasts and in leukocytes and/or fibroblasts from three patients with Fabry's disease. We have also developed electrophoretic techniques which permit the detection of a-galactosidase activity on starch gels and have attempted to obtain information regarding linkage of a-galactosidase using both human subjects and interspecific hybrids of Equidae. These studies reveal that at least two isozymes of oa-galactosidase are present in normal cells, and that one of these isozymes, which we have designated a-galactosidase A, is absent from the cells of patients with Fabry's disease. Although we have not been able to obtain any information regarding the location of the structural gene for a-galactosidase in man, this enzyme was found to be autosomally linked in Equidae.
ORIGINALARTICLES Homeopathictreatmentofheadaches: Asystematicreviewoftheliterature

Objective: To systematically review published prospective trials relating to the homeopathic treatment of tension type, cervicogenic, and migraine headache. Data Sources: Pre-MEDLINE, MEDLINE, MANTIS, Cochrane Database of Systematic Reviews, and AMED were searched from the initial indexing year of each database through May 2002. Studies were further identified through a manual search of obtained article references. Study Selection: English and non-English randomized clinical trials and prospective observational trials were included if there were at least ten subjects in the homeopathic portion of the trial and, for randomized clinical trials, if there was a placebo group. Treatment in these studies included single dose and individualized homeopathic prescription. Case studies, homeopathic provings, unpublished material, non-peer reviewed papers, and studies that combined multiple homeopathic remedies, introduced other complementary and alternative medicine therapies and/or introduced additional medical therapy for patients in the homeopathic treatment groups were excluded. Data Extraction: Qualitative data were extracted from each paper and entered into an evidence table. Data Synthesis: A critical evaluation list of 20 methodological items and their operational definitions was used, resulting in a validity score determined for each paper. Results: Six papers met criteria for inclusion. Three out of the six papers studied migraine headache, two studied cervicogenic and tension type headache, and one included all types of headaches. Four studies were randomized clinical trials, and two were prospective observational studies. Validity scores ranged from 25.0% to 63.4%. Homeopathy was superior to placebo in one randomized clinical trial and equal to placebo in three randomized trials. In no study was homeopathy less effective than placebo in treating headache, or harmful. Two prospective observational studies demonstrated improvement in patients receiving homeopathic care. Conclusion: There is insufficient evidence to support or refute the use of homeopathy for managing tension type, cervicogenic, or migraine headache. The studies reviewed possessed several flaws in design. Given these findings, further research is warranted to better investigate the effectiveness of homeopathic treatment of headaches. (J Chiropr Med 2004;3:45–52)
Progress and pitfalls in defining the influence of HAART on HPV- associated cervical disease

The results of the study reported by Minkoff, et al in this issue of the Journal [1] provide important new information to the continued debate on whether immune deficiency is responsible for the increase in human papillomavirus (HPV) infections, cervical squamous intraepithelial lesions (SILs), and cervical cancers among HIV-infected women [2,3]. Evidence that the increase in two other AIDS-defining malignancies, Kaposi’s sarcoma (KS) and nonHodgkin lymphoma (NHL), is due to immune deficiency is clear. The standardized incidence rate of these cancers is orders of magnitude higher among individuals with HIV/AIDS, and increased risk has been well documented with more advanced immune deficiency manifest as lower CD4 cell counts. Importantly, the rates of KS and NHL declined substantially in the HAART era, suggesting that restoration of human herpesvirus 8 (HHV-8) and Epstein Barr Virus (EBV) immunologic control was sufficient to reduce the risk of these virally-associated malignancies [4,5]. The influence of immune deficiency on the risk of HPV and associated neoplasia has been less clear. The standardized incidence rate comparing persons with HIV/ AIDS to the general population shows a more modest difference compared to KS and NHL [3,4]. It can be argued that the moderately elevated rates of cervical cancer among HIV-infected individuals reflect simply a common shared behavior (e.g., increasing number of lifetime sexual partners). However, invasive cervical cancer rates are higher among renal transplant patients who would presumably be unlikely to report higher rates of sexual exposure to viral infection compared to the general population [6]. In addition, natural history studies have shown convincing evidence of an independent association between CD4 cell count and HIV load with an increase in HPV squamous intraepithelial lesions (SIL) incidence and persistence [7]. Based on these data, it would have been predicted that HPV and SIL prevalence and incidence would decline in the HAART era; unfortunately the results of early studies that evaluated this have been inconsistent [8–13]. Several factors are likely to have influenced the validity of these prior studies of HAART on HPV and SIL natural history. Predominant is the inherent non-comparability of women in whom HAART is initiated compared to those who are not placed on treatment. Because women that initiate HAART are more likely to have advanced HIV disease, with lower CD4 cell counts and higher HIV loads, than women in whom HAART is not initiated, true effects of treatment could be substantially attenuated. Furthermore, adherence to, and effectiveness of, treatment were often not ascertained, which could further attenuate the ability to observe true treatment effects.
OP-NDTJ200051 1263..1281

Background. The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. The degree to which secretory solute clearance corresponds with the glomerular filtration rate (GFR) and potential metabolic implications of net secretory clearance are largely unknown. Methods. We evaluated 1240 participants with chronic kidney disease (CKD) from the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used targeted massspectrometry to quantify candidate secretory solutes in paired 24-h urine and plasma samples. CRIC study personnel measured GFR using I-iothalamate clearance (iGFR). We used correlation and linear regression to determine cross-sectional associations of secretory clearances with iGFR and common metabolic complications of CKD. Results. Correlations between iGFR and secretory solute clearances ranged from q 1⁄4þ0. 30 for hippurate to q1⁄4þ0. 58 for kynurenic acid. Lower net clearances of most secretory solutes were associated with higher serum concentrations of parathyroid hormone (PTH), triglycerides and uric acid. Each 50% lower kynurenic acid clearance was associated with a 21% VC The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 1271 O R IG IN A L A R T IC LE higher serum PTH concentration [95% confidence interval (CI) 15–26%] and a 10% higher serum triglyceride concentration (95% CI 5–16%) after adjustment for iGFR, albuminuria and other potential confounders. Secretory solute clearances were not associated with statistically or clinically meaningful differences in serum calcium, phosphate, hemoglobin or bicarbonate concentrations. Conclusions. Tubular secretory clearances are modestly correlated with measured GFR among adult patients with CKD. Lower net secretory clearances are associated with selected metabolic complications independent of GFR and albuminuria, suggesting potential clinical and biological relevance.
An MRI study: Mutant G2019S-LRRK2 induces abnormalities in arteriolar cerebral blood volume in mouse brains

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine (DA) neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20–47% of genetic forms of PD in Caucasian population. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. Objectives: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space-occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. Method: Anatomic and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild type (WT)-LRRK2, and 5 female and 7 male G2019SLRRK2 mice of 9-month age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex and prefrontal cortex. Results: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in olfactory and prefrontal cortex in both male and female groups, whereas WTLRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female) and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. Conclusions: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.
Discovery of inhibitors that overcome the G1202R ALK Resistance Mutation

The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of ‘second generation’ ALK inhibitors, including alectinib and ceritinib that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JHVIII-157-02 is capable of penetrating the CNS of mice following oral dosing. Corresponding Author, Nathanael_Gray@dfci.harvard. edu. Phone: 1-617-582-8590 or Pasi_Janne@dfci.harvard. edu. Phone: 1-617-632-6036. ASSOCIATED CONTENT Ba/F3 cellular IC50 curves for crizotinib, ceritinib, alectinib and compound 6. Cellular IC50 curves for patient derived NSCLC cells and neuroblastoma cells for compound 6. Cellular IC50’s with standard deviations for crizotinib, ceritinib, alectinib and compound 6. Full Ambit profiling for Compound 6 and 32. This material is available free of charge via the internet at http://pubs.acs. org HHS Public Access Author manuscript J Med Chem. Author manuscript; available in PMC 2016 December 10. Published in final edited form as: J Med Chem. 2015 December 10; 58(23): 9296–9308. doi:10.1021/acs.jmedchem. 5b01136. A uhor M anscript