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Global estimates indicate that over 600 million individuals worldwide consume the areca (betel) nut in some form. Nonetheless, its consumption is associated with a myriad of oral and systemic ailments, such as precancerous oral lesions, oropharyngeal cancers, liver toxicity and hepatic carcinoma, cardiovascular distress, and addiction. Users commonly chew slivers of areca nut in a complex consumable preparation called betel quid (BQ). Consequently, the user is exposed to a wide array of chemicals with diverse pharmacokinetic behavior in the body. However, a comprehensive understanding of the metabolic pathways significant to BQ chemicals is lacking. Henceforth, we performed a literature search to identify prominent BQ constituents and examine each chemical's interplay with drug disposition proteins. In total, we uncovered over 20 major chemicals (e.g., arecoline, nicotine, menthol, quercetin, tannic acid) present in the BQ mixture that were substrates, inhibitors, and/or inducers of various phase I (e.g., CYP, FMO, hydrolases) and phase II (e.g., GST, UGT, SULT) drug metabolizing enzymes, along with several transporters (e.g., P-gp, BCRP, MRP). Altogether, over 80 potential interactivities were found. Utilizing this new information, we generated theoretical predictions of drug interactions precipitated by BQ consumption. Data suggests that BQ consumers are at risk for drug interactions (and possible adverse effects) when co-ingesting other substances (multiple therapeutic classes) with overlapping elimination mechanisms. Until now, prediction about interactions is not widely known among BQ consumers and their clinicians. Further research is necessary based on our speculations to elucidate the biological ramifications of specific BQ-induced interactions and to take measures that improve the health of BQ consumers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction/background: Osteoporosis is a common disorder and is associated with an increased risk of bone fracture. Falls are a proximate cause of a high proportion of medical costs and mortality. Improving balance can reduce the risk of falls and improve health outcomes, especially for the at-risk population of people with osteoporosis and osteopenia. The FrameWorks TM exercise program is a formal, standardized, informational and interventional 10-month exercise program. The purpose of this study was to quantitatively assess the improvement in standing balance, functional reach, and overall confidence in balance after participating in the 10-month program., Methodology: This study is a prospectively designed study with a pre and post study measurement of balance metrics. Sixty-two female participants, 45 years of age or older and at increased risk for fragility fractures, completed the 10-month program as well the pre and post program testing. Confidence was measured with the Activities-specific Balance Confidence Scale, a self-reported survey. Balance was measured digitally by means of testing with a NeuroCom® Basic Balance Master® system. Measurements were made of the Limits of Stability (LOS) Test and Modified Clinical Test of Sensory Interaction on Balance (mCTSIB). Balance was clinically assessed with the Functional Reach Test (FRT)., Results: Participation in the 10 months FrameWorksTM program resulted in improvement in quantitative measures of balance (Composite Sway Velocity, -12%, p < 0.001; End point excursion, 17.1%, p < 0.000001). A clinical measure of balance, the Functional Reach Test, improved, (2.9 cm, p < 0.0001). Participation also resulted in improvement in balance confidence (9.4 %, p < 0.00001). A height increase was observed (0.6 cm, p < 0.000001)., Conclusions: The 10-month FrameWorks TM program improves balance and confidence in women at risk for fragility fractures. By improving balance and confidence, people are less likely to fall and therefore sustain fewer fractures and associated injuries., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Although research has investigated financial planning for retirement, less is known about how adults plan their retirement activities. Even less is known about couples' congruence and incongruence in retirement activities planning. The authors examined husband and wife reports of retirement plans across a 5-year period that involved a U.S. economic recession., Method: Using data from 335 midlife couples who participated in the Flourishing Families project, retirement plans were grouped into five categories-family, leisure, volunteer, work, and uncertain. We estimated probit dyadic structural equation models to explore longitudinal predictors of retirement plans., Results: Results indicated mean differences in retirement plans between husbands and wives, and also across time that might have been influenced by surrounding economics. Wife poor health, number of children, both spouses working, and financial assets were linked with the likelihood of reporting certainty in retirement plans. Greater retirement uncertainty was predicted by lower marital quality, higher financial adjustments, lower education, and ethnic diversity., Conclusion: Husband and wife reports of retirement plans are not always congruent, and plans in retirement can be affected by large scale changes in the U.S. economy., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: To examine the characteristics of primary stabbing headache (PSH) in typically developing children and adolescents., Method: In this prospective non-interventional hospital-based study, we examined 42 eligible individuals (24 females, 18 males; 26 white; mean age 12y 1mo, range 6y-16y 1mo) with spontaneous transient stabs. A headache focused history and/or a headache diary was obtained from each patient. All patients had normal neurological examination. Diagnosis of primary headache was based on the International Classification of Headache Disorders, Third Edition (ICHD-3) beta version., Results: Duration of stabs ranged from a few seconds to up to 10 minutes. Stabs were located in a variety of sites on the cranium but mostly in the extra-trigeminal regions (n=28). Intensity of stabs varied from moderate (n=4) to severe (n=38). The frequency of the stabs ranged from daily to monthly. There were up to 50 stabs per headache attack. Stabs among our patients occurred independently from those caused by other primary headache types. Accompanying symptoms during stabs were reported by eight patients. Family history of primary headaches was identified (n=17). Familial transmission of PSH was recognized among two patients. All patients had normal brain magnetic resonance imaging., Interpretation: The presentation and nature of PSH in children and adolescents varies widely. PSH in children may be a different entity to that in adults, and there is a need for further research to support changes in the ICHD-3 criteria for PSH in children and adolescents., What This Paper Adds: Presentation of childhood primary stabbing headache (PSH) varies widely. Duration of PSH could last from a few seconds up to 10 minutes., (© 2019 Mac Keith Press.)

Chronic pain is one of the most burdensome health issues facing the planet (as costly as diabetes and cancer combined), and in desperate need for new diagnostic targets leading to better therapies. The bioactive lipid sphingosine 1-phosphate (S1P) and its receptors have recently been shown to modulate nociceptive signaling at the level of peripheral nociceptors and central neurons. However, the exact role of S1P generating enzymes, in particular sphingosine kinase 2 (Sphk2), in nociception remains unknown. We found that both sphingosine kinases, Sphk1 and Sphk2, were expressed in spinal cord (SC) with higher levels of Sphk2 mRNA compared to Sphk1. All three Sphk2 mRNA-isoforms were present with the Sphk2.1 mRNA showing the highest relative expression. Mice deficient in Sphk2 (Sphk2(-/-)) showed in contrast to mice deficient in Sphk1 (Sphk1(-/-)) substantially lower spinal S1P levels compared to wild-type C57BL/6 mice. In the formalin model of acute peripheral inflammatory pain, Sphk2(-/-) mice showed facilitation of nociceptive transmission during the late response, whereas responses to early acute pain, and the number of c-Fos immunoreactive dorsal horn neurons were not different between Sphk2(-/-) and wild-type mice. Chronic peripheral inflammation (CPI) caused a bilateral increase in mechanical sensitivity in Sphk2(-/-) mice. Additionally, CPI increased the relative mRNA expression of P2X4 receptor, brain-derived neurotrophic factor and inducible nitric oxide synthase in the ipsilateral SC of wild-type but not Sphk2(-/-) mice. Similarly, Sphk2(-/-) mice showed in contrast to wild-type no CPI-dependent increase in areas of the dorsal horn immunoreactive for the microglia marker Iba-1 and the astrocyte marker Glial fibrillary acidic protein (GFAP). Our results suggest that the tightly regulated cell signaling enzyme Sphk2 may be a key component for facilitation of nociceptive circuits in the CNS leading to central sensitization and pain memory formation.

Context/objective: Herbal preparations derived from various species and parts of Echinacea (Asteraceae) have been advocated for various medical applications, as a result of the many antimicrobial and immunomodulatory activities attributed to them., Materials and Methods: In order to investigate their effects on parasites, four preparations of Echinacea, with distinct chemical compositions, were evaluated for growth inhibition of three species of trypanosomatids: Leishmania donovani, Leishmania major, and Trypanosoma brucei. In addition one Echinacea preparation was tested for anti-inflammatory activity in cell culture models designed to measure pro-inflammatory cytokines induced by L. donovani., Results and Discussion: All Echinacea preparations inhibited growth of the organisms, though with different relative potencies, and in some cases morphological changes were observed. However, there was no obvious correlation with the composition of the marker compounds, alkylamides, caffeic acid derivatives, and polysaccharides. L. donovani stimulated the production of the pro-inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial cells and in human skin fibroblasts, but in both cases the standardized ethanol extract of E. purpurea (L.) Moench (Echinaforce) abolished the stimulation, indicating anti-inflammatory activity of this extract., Conclusions: Thus various Echinacea extracts can inhibit the proliferation of these parasites and at least one can reverse the pro-inflammatory activity of Leishmania donovani.

Neuropathologic examination of transgenic (Tg) mice which express different prion protein (PrP) constructs is essential because spongiform (vacuolar) degeneration of neurons, the distribution of PrPSc and whether PrP amyloid plaques form are the phenotypes of prion diseases. In Tg models of experimental scrapie, it was found that all of the parameters that define prion isolates ('strains') can be manipulated by changing the structure of PrP. In those studies, further evidence that PrPSc causes scrapie neuropathology and determines scrapie incubation time was obtained. In addition, the distribution of PrPSc in the brain was unique for each prion isolate. The implications of these findings are first, that prion isolates target different neuron populations for synthesis of nascent pathogenic PrPSc and, secondly, that prion isolate diversity is determined by neurons. In Tg mice which express mutated PrP mimicking human prion protein gene mutations linked to familial prion diseases, the neuropathological changes have been faithfully reproduced. A new age-related, neuromuscular disorder has also been identified in uninfected Tg mice which overexpress wild-type PrPc. All of the findings with different PrP constructs plus the absence of scrapie pathology in PrP null mice are the strongest argument that the prion protein is the main etiologic and pathogenic factor of prion disorders.

Prion diseases of humans and animals are known to be caused by infection with prions containing PrPSc or mutation of the prion protein (PrP) gene. During transgenetic studies, we discovered that uninoculated older mice harboring high copy numbers of wild-type (wt) PrP transgenes derived from Syrian hamsters (SHa), sheep (She), and PrP-B mice developed truncal ataxia, hindlimb paralysis, and tremors. These transgenic (Tg) mice exhibited a profound necrotizing myopathy involving skeletal muscle, a demyelinating polyneuropathy, and focal vacuolation of the central nervous system. Development of disease was dependent on transgene dosage. For example, half of all Tg(SHaPrP+/+)7 mice homozygous for the SHaPrP transgene array developed disease by approximately 460 days of age, while no hemizygous Tg(SHaPrP+/o)7 mice became ill before 650 days. The novel neurologic syndrome found in older Tg(wtPrP) mice implies that overexpression of wtPrPC is pathogenic and widens the spectrum of prion diseases.