Combat and Warfare in the Early Paleolithic and Medically Unexplained Musculo-Facial Pain in the 21st Century War Veterns and Active-Duty Military Personnel

In a series of recent articles, we suggest that family dentists, military dentists and psychiatrists with expertise in posttraumatic stress disorder (especially in the Veterans Health Administration) are likely to see an increased number of patients with symptomatic jaw-clenching and early stages of tooth- grinding (Bracha et al., 2005). Returning warfighters and other returnees from military deployment may be especially at risk for high rates of clenching- induced masticatory muscle disorders at early stages of incisor grinding. The literature we have recently reviewed strongly supports the conclusion that clenching and grinding may primarily be a manifestation of experiencing extreme fear or severe chronic distress (respectively). We have recently reviewed the clinical and paleoanthropological literature and have noted that ancestral warfare and ancestral combat, in the early Paleolithic Environment of Evolutionary Adaptedness (EEA) may be a neglected factor explaining the conservation of the archaic trait of bite-muscle strengthening. We have hypothesized that among ancestral warriors, jaw clenching may have rapidly strengthened the two primary muscles involved in biting, the masseter muscles and the much larger temporalis muscles. The strengthening of these muscles may have served the purpose of enabling a stronger, deeper, and therefore more lethal, defensive bite for early Paleolithic humans. The neuroevolutionary perspective presented here may be novel to many dentists. However, it may be useful in patient education and in preventing progression from jaw-clenching to chronic facial pain

Distribution and Movements of the Teshekpuk Caribou Herd 1990–2005: Prior to Oil and Gas Development

Four caribou (Rangifer tarandus grantii) herds calve on the North Slope of Alaska, three of which have been exposed to little or no resource development. We present 15 years of baseline data on the distribution and movements of 72 satellite-collared and 10 GPS-collared caribou from the Teshekpuk caribou herd (TCH) that have had little to no exposure to oil and gas activities. Fixed-kernel home range analyses of collared caribou revealed that calving grounds were concentrated (i.e., 50% kernel utilization distribution) along the northeastern, eastern, and southeastern shores of Teshekpuk Lake. During the postcalving period, 51% and 35% of caribou moved through two constricted zones to the east and west of Teshekpuk Lake, respectively, and accessed insect-relief habitat along the Beaufort Sea coast. During late summer and early fall, TCH caribou were concentrated to the southeast and southwest of Teshekpuk Lake. Although 65% of the Teshekpuk caribou wintered in two areas on the central coastal plain around the village of Atqasuk and south of Teshekpuk Lake, other TCH animals wintered in a great variety of places, including the Seward Peninsula, the eastern and southern Brooks Range, and the Arctic National Wildlife Refuge. We detected an apparent emigration rate of 6.9%. One male and five female TCH caribou joined the breeding populations of the Western Arctic and Central Arctic herds. TCH caribou traveled an average distance of 2348 ± 190 km annually. Movement rates were at a maximum in midsummer, lowest in winter, and intermediate during spring and fall migrations. Restrictions on oil and gas leasing and surface occupancy have been in place to protect calving, migratory corridors, and insect-relief habitat for the TCH, but these protections are likely to be removed. These data will provide a good baseline that can be used to compare predevelopment distribution and movement patterns of TCH caribou to distribution and movement patterns during and after petroleum development.Quatre hardes de caribous (Rangifer tarandus grantii) vêlent sur la côte nord de l’Alaska, dont trois de ces hardes ont été exposées à peu ou pas d’aménagement des ressources. Nous présentons des données de base échelonnées sur 15 ans relativement à la répartition et aux déplacements de 72 caribous dotés d’un collier émetteur par satellite et de 10 caribous munis d’un collier émetteur GPS de la harde de caribous de Teshekpuk (HCT), caribous qui ont été peu ou pas du tout frottés aux activités pétrolières et gazières. L’analyse du noyau fixe des domaines vitaux des caribous à collier a révélé que les lieux de vêlage étaient concentrés (c’est-à-dire 50 % de la répartition de l’utilisation du noyau) le long des côtes nord-est, est et sud-est du lac Teshekpuk. Après la période de vêlage, 51 pour cent et 35 pour cent des caribous se déplaçaient au sein de deux zones de constriction à l’est et à l’ouest du lac Teshekpuk, respectivement, et accédaient un habitat où se trouvait moins d’insectes sur la côte de la mer de Beaufort. Vers la fin de l’été et le début de l’automne, les caribous de la HCT étaient concentrés au sud-est et au sud-ouest du lac Teshekpuk. Bien que 65 pour cent des caribous de Teshekpuk passaient l’hiver dans deux régions de la plaine côtière centrale autour du village d’Atqasuk et au sud du lac Teshekpuk, les autres bêtes de la HCT passaient l’hiver dans divers endroits, dont la péninsule de Seward, les versants est et sud des montagnes de Brooks et la Réserve faunique nationale de l’Arctique. Nous avons détecté un taux d’émigration apparent de 6,9 pour cent. Un caribou mâle et cinq caribous femelles de la HCT ont rejoint les populations de reproduction des hardes de l’ouest et du centre de l’Arctique. En moyenne, le caribou de la HCT parcourait une distance de 2348 ± 190 km annuellement. Les taux de déplacement étaient à leur point le plus élevé au milieu de l’été, tandis qu’ils étaient à leur niveau le plus bas l’hiver et à un niveau intermédiaire pendant les migrations du printemps et de l’automne. Il existe des restrictions en matière de location et d’occupation en surface pour le pétrole et le gaz afin de protéger le vêlage, les corridors de migration et les habitats à faible taux d’insectes pour la HCT, mais il est vraisemblable que ces restrictions soient éliminées. Ces données fourniront une bonne base pour comparer la répartition et les déplacements du caribou de la HCT avant la mise en valeur des ressources à la répartition et aux déplacements du caribou de la HCT pendant et après la mise en valeur pétrolière

VISIBILITY OF MOOSE IN A TEMPERATE RAINFOREST

Aerial surveys are the principal methods used to estimate populations of moose (Alces alces gigas) in Alaska. Accounting for missed animals during aerial surveys is problematical, especially in forested habitats; incorporation of a visibility correction factor to account for the proportion of animals missed is known to improve accuracy of population estimates. Our purpose was to study factors affecting visibility of radio-collared moose during aerial surveys in a temperate rainforest on the Yakutat Foreland, Alaska, USA. Wildlife managers in the area typically assume they observe only 50% of moose during surveys regardless of widely varying conditions. We used logistic regression to examine factors that influenced visibility including vegetation, light conditions, snow cover, and sex, age, and group size of moose. We then used logistic regression to develop a simpler model that only contained variables easily measured during aerial surveys: forest cover, snow cover, light, open versus vegetated habitat, and group size. We used that model to estimate a visibility correction factor. The mean correction factor was 1.304, ranging from1.005-2.138, yielding a population estimate of 699 (90% CI = 671-724) moose from a survey count of 595 animals. Our correction factor was within the range reported for other populations of moose, and lower than the correction factor (2.0) currently used in this area. We conclude that application of site and time-specific visibility models is critical when estimating populations of large ungulates, especially in forested habitats

Health-seeking behaviors and self-care practices of Dominican women with lymphoedema of the leg: implications for lymphoedema management programs

BACKGROUND: In the Dominican Republic, a Latin American country with filariasis-endemic areas, more than 63,000 people have lymphatic filariasis and more than 400,000 people are at risk of future infection. In this paper, we explore the health beliefs, health-seeking behaviors and self-care practices of women with lymphoedema in filariasis-endemic areas to better understand the needs of women when developing lymphoedema morbidity control programs. METHODS: Qualitative data were collected through semi-structured interviews of 28 women, 3 focus group discussions with 28 women, field notes and photographs. RESULTS: Women described exhaustive and expensive attempts at seeking a cure for their lymphoedema. Family members were influential in providing women with initial care seeking referrals to indigenous healers credited with influence over physical, mental, spiritual and supernatural properties of illness. When indigenous treatments proved to be ineffectual, the women sought care from trained healthcare providers. Most healthcare providers incorrectly diagnosed the edema, failed to adequately treat and meet the needs of women and were viewed as expensive. Most women resorted to self-prescribing injectable, oral, or topical antibiotics along with oral analgesics as a standard practice of self-care. CONCLUSION: Healthcare providers must understand a woman's cultural perspectives of illness, her natural networks of support and referral, her behavioural practices of care-seeking and self-care and the financial burden of seeking care. In the culture of the Dominican Republic family members and traditional healthcare providers are influential advisors on initial health-seeking behaviors and self-care practices. For this reason family-oriented interventions, support groups for women and their families, community education and training on simple, low cost lymphoedema management techniques for indigenous healers are viable ways to influence the early detection, diagnosis and treatment of women with lymphoedema. The extensive use of injectable, oral and topical antibiotics by indigenous healers and women without medical supervision suggests a need for health education messages related to the risks of such practices

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. Conclusion Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

Monogenic variants in dystonia: an exome-wide sequencing study

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222;excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations

Spike-Timing Precision and Neuronal Synchrony Are Enhanced by an Interaction between Synaptic Inhibition and Membrane Oscillations in the Amygdala

The basolateral complex of the amygdala (BLA) is a critical component of the neural circuit regulating fear learning. During fear learning and recall, the amygdala and other brain regions, including the hippocampus and prefrontal cortex, exhibit phase-locked oscillations in the high delta/low theta frequency band (∼2–6 Hz) that have been shown to contribute to the learning process. Network oscillations are commonly generated by inhibitory synaptic input that coordinates action potentials in groups of neurons. In the rat BLA, principal neurons spontaneously receive synchronized, inhibitory input in the form of compound, rhythmic, inhibitory postsynaptic potentials (IPSPs), likely originating from burst-firing parvalbumin interneurons. Here we investigated the role of compound IPSPs in the rat and rhesus macaque BLA in regulating action potential synchrony and spike-timing precision. Furthermore, because principal neurons exhibit intrinsic oscillatory properties and resonance between 4 and 5 Hz, in the same frequency band observed during fear, we investigated whether compound IPSPs and intrinsic oscillations interact to promote rhythmic activity in the BLA at this frequency. Using whole-cell patch clamp in brain slices, we demonstrate that compound IPSPs, which occur spontaneously and are synchronized across principal neurons in both the rat and primate BLA, significantly improve spike-timing precision in BLA principal neurons for a window of ∼300 ms following each IPSP. We also show that compound IPSPs coordinate the firing of pairs of BLA principal neurons, and significantly improve spike synchrony for a window of ∼130 ms. Compound IPSPs enhance a 5 Hz calcium-dependent membrane potential oscillation (MPO) in these neurons, likely contributing to the improvement in spike-timing precision and synchronization of spiking. Activation of the cAMP-PKA signaling cascade enhanced the MPO, and inhibition of this cascade blocked the MPO. We discuss these results in the context of spike-timing dependent plasticity and modulation by neurotransmitters important for fear learning, such as dopamine

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways