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The opportunity to examine the defleshed skeleton of an individual diagnosed in life (Hamann-Todd collection, individual 2036) afforded a unique opportunity to demonstrate the bone damage characteristic of at least one form of juvenile rheumatoid arthritis (JRA). Characteristics helpful for recognition of JRA in archaeological material include peripheral articular marginal and subchondral erosions, axial (e.g., zygapophyseal or sacroiliac) joint erosions, fusion of axial (cervical zygapophyseal) and/or peripheral joints, premature epiphyseal closure and/or ballooned epiphyses, growth retardation with underdeveloped (short and overtubulated) long bones, short mandibular rami with underdeveloped condyles and concomitant micrognathia, and demineralization (osteopenia). Distinguishing between JRA and juvenile spondyloarthropathy, however, is not always possible, as illustrated by this case. KEY WORDS growth retardation; bone erosion; pseudoarthrosis; pathology

The present study investigates in detail a lesion on the cranial vault, known as button osteoma (BtO). The frequency of BtO is similar in modern (37.6%) and archaeological (41.1%) populations, in blacks and whites and in males and females. The frequency of BtO rises from infancy to early adulthood, and remain constant thereafter. The majority of skulls with button osteoma (64.1%) had only one button osteoma, 20.4% had two and 15.4% had multiple button osteomas. Microscopically, BtO is composed of well-organized dense lamellated bone, poorly vascularized with very few osteocytes. It forms a dome-shape roof to an underlying diploizied area. As this structural pattern differs from that of exostosis or osteoma, and considering its unique nature (hamartoma), and demographic characteristics, we suggest a new name for this disorder: Cupa Ectocranialis Eburneurn (CEE). Its possible etiology will be discussed.

An upright, habitual striding form of bipedalism distinguishes modern humans from all other extant terrestrial mammals. A comparative analysis of Homo sapiens, Pan troglodytes, and Gorilla gorilla distal tibiae indicates that humans have adaptively altered the architecture of cortical and cancellous bone within the metaphysis (Kunos, 1997). Given that the muscular mechanisms responsible for load attenuation are severely compromised in erect bipeds, the unique architecture of human tibial metaphyses may be related to impact attenuation especially during heel strike. Human and African ape cortical and cancellous bone demonstrate no significant difference in mineralization or mineral ash density. Under compression, the elastic moduli of human and African ape bone within the tibia do not differ significantly. Similarly, there are no differences in apparent density or porosity of cortical and cancellous bone. Structural differences in the human tibial metaphysis allow structural dampening of applied compressive loads. In African apes, peak strain amplitude coincides with peak force amplitude. In humans, peak strain amplitude occurs later than the registration of peak force. A phase lag between peak force and peak strain indicates load attenuation. Given the anatomical specializations of the modern human metaphysis, the unusual structural distribution of cortical and cancellous bone likely serves as an additional mechanism by which humans, and our hominid ancestors, insulate themselves from peak locomotor loads engendered during single limb support. Kunos, CA. 1997. Distal Metaphysis of the Tibia: Implications for the Evolution of Bipedality. Amer J Phys Anthrop Suppl 24: 147-148.

Influenza viruses cause severe illnesses and death, mainly in the aged population. Protection afforded by licensed vaccines through subtype-specific neutralizing antibodies is incomplete, especially when the vaccine antigens fail to closely match those of the circulating viral strains. Efforts are underway to generate a so-called universal influenza vaccine expressing conserved viral sequences that induce broad protection to multiple strains of influenza virus through the induction of CD8+ T cells. Here we assess the effect of a potent antiviral CD8+ T cell response on influenza virus infection of young and aged mice. Our results show that CD8+ T cell-inducing vaccines can provide some protection to young mice, but they exacerbate influenza virus-associated disease in aged mice, causing extensive lung pathology and death. [ABSTRACT FROM AUTHOR]

Influenza viruses cause severe illnesses and death, mainly in the aged population. Protection afforded by licensed vaccines through subtype-specific neutralizing antibodies is incomplete, especially when the vaccine antigens fail to closely match those of the circulating viral strains. Efforts are underway to generate a so-called universal influenza vaccine expressing conserved viral sequences that induce broad protection to multiple strains of influenza virus through the induction of CD8¿ T cells. Here we assess the effect of a potent antiviral CD8¿ T cell response on influenza virus infection of young and aged mice. Our results show that CD8¿ T cell-inducing vaccines can provide some protection to young mice, but they exacerbate influenza virus-associated disease in aged mice, causing extensive lung pathology and death. [ABSTRACT FROM AUTHOR]

Background: Experiential learning activities on care for people with disabilities (PWD) would help nursing students develop the knowledge, skills, and attitudes (KSAs) needed to provide quality care for PWD., Purpose: The purpose of this study was to evaluate the perceived changes in nursing students' KSAs related to the care for PWD following participation in health assessment and prevention (HAP) experiential learning activities., Methods: This was a quasi-experimental, pre- and posttest educational intervention study. Nursing students (n = 160) attended multiple experiential learning activities as a required part of their HAP coursework and completed a pre and posttest survey to assess changes in their KSAs., Results: Participation in experiential learning activities on care for PWD was associated with significant increases in perceived knowledge, skills and positive attitudes toward PWD., Conclusions: Experiential learning activities aligned with core competencies for health care providers caring for PWDs have the potential to change nursing care and address health inequities for this population., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The accidental human pathogen Legionella pneumophila (Lp) is the etiological agent for a severe atypical pneumonia known as Legionnaires' disease. In human infections and animal models of disease alveolar macrophages are the primary cellular niche that supports bacterial replication within a unique intracellular membrane-bound organelle. The Dot/Icm apparatus-a type IV secretion system that translocates ~300 bacterial proteins within the cytosol of the infected cell-is a central virulence factor required for intracellular growth. Mutant strains lacking functional Dot/Icm apparatus are transported to and degraded within the lysosomes of infected macrophages. The early foundational work from Dr. Horwitz's group unequivocally established that Legionella does not replicate extracellularly during infection-a phenomenon well supported by experimental evidence for four decades. Our data challenges this paradigm by demonstrating that macrophages and monocytes provide the necessary nutrients and support robust Legionella extracellular replication. We show that the previously reported lack of Lp extracellular replication is not a bacteria intrinsic feature but rather a result of robust restriction by serum-derived nutritional immunity factors. Specifically, the host iron-sequestering protein Transferrin is identified here as a critical suppressor of Lp extracellular replication in an iron-dependent manner. In iron-overload conditions or in the absence of Transferrin, Lp bypasses growth restriction by IFNγ-primed macrophages though extracellular replication. It is well established that certain risk factors associated with development of Legionnaires' disease, such as smoking, produce a chronic pulmonary environment of iron-overload. Our work indicates that iron-overload could be an important determinant of severe infection by allowing Lp to overcome nutritional immunity and replicate extracellularly, which in turn would circumvent intracellular cell intrinsic host defenses. Thus, we provide evidence for nutritional immunity as a key underappreciated host defense mechanism in Legionella pathogenesis., (© 2024. The Author(s).)

Abstract: Simulation-enhanced interprofessional education is widely viewed as an effective teaching pedagogy to foster effective communication and teamwork for healthcare students. Pharmacists and registered nurses must learn to work collaboratively during their educational programs in order to be prepared for the complexities of modern healthcare. This study evaluated prelicensure pharmacy and prelicensure nursing students' perceptions of professional collaboration before and after caring for a standardized patient exhibiting opioid dependence secondary to inappropriate use of an opioid analgesic. Statistically significant gains in communication, collaboration, roles and responsibilities, patient-centered care, conflict management, and team functioning were measured for both pharmacy and nursing students after the interprofessional simulation. This study adds to the existing evidence that suggests simulation-enhanced interprofessional education is an effective teaching strategy; however, this study demonstrates its usefulness for students learning about safer opioid analgesic practices., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2024 International Nurses Society on Addictions.)

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague Dawley rats were provided 90 min or 12 h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12 h access to methamphetamine and those that had 90 min or 12 h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal monoamine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).

Synchronous activities among neurons in the brain generate emergent network oscillations such as the hippocampal Sharp-wave ripples (SPWRs) that facilitate information processing during memory formation. However, how neurons and circuits are functionally organized to generate oscillations remains unresolved. Biophysical models of neuronal networks can shed light on how thousands of neurons interact in intricate circuits to generate such emergent SPWR network events. Here we developed a large-scale biophysically realistic neural network model of CA1 hippocampus with functionally organized circuit modules containing distinct types of neurons. Model simulations reproduced synaptic, cellular and network aspects of physiological SPWRs. The model provided insights into the role of neuronal types and their microcircuit motifs in generating SPWRs in the CA1 region. The model also suggests experimentally testable predictions including the role of specific neuron types in the genesis of hippocampal SPWRs.

Learning in the mammalian lateral amygdala (LA) during auditory fear conditioning (tone - foot shock pairing), one form of associative learning, requires N-methyl-D-aspartate (NMDA) receptor-dependent plasticity. Despite this fact being known for more than two decades, the biophysical details related to signal flow and the involvement of the coincidence detector, NMDAR, in this learning, remain unclear. Here we use a 4000-neuron computational model of the LA (containing two types of pyramidal cells, types A and C, and two types of interneurons, fast spiking FSI and low-threshold spiking LTS) to reverse engineer changes in information flow in the amygdala that underpin such learning; with a specific focus on the role of the coincidence detector NMDAR. The model also included a Ca 2s based learning rule for synaptic plasticity. The physiologically constrained model provides insights into the underlying mechanisms that implement habituation to the tone, including the role of NMDARs in generating network activity which engenders synaptic plasticity in specific afferent synapses. Specifically, model runs revealed that NMDARs in tone-FSI synapses were more important during the spontaneous state, although LTS cells also played a role. Training trails with tone only also suggested long term depression in tone-PN as well as tone-FSI synapses, providing possible hypothesis related to underlying mechanisms that might implement the phenomenon of habituation.

Background: Despite recommendations to include disability content in nursing education, nursing students have little exposure to disability education, which would help to develop necessary knowledge, skills, and attitudes in learning to care for patients with disabilities., Purpose: This study evaluated learners' perceptions of the effectiveness of a tabletop simulation in meeting their learning needs related to nursing care for children with disabilities and their families., Methods: The research design was a descriptive educational intervention study. Nursing students (n = 234) enrolled in the pediatric nursing course attended the simulation as a required part of their coursework., Results: The majority of the students found the tabletop simulation with disability content to be an effective educational intervention., Conclusions: The results obtained from this study indicated that the tabletop simulation was an effective educational strategy for nursing students' learning to provide care for children with disabilities and their families., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Host membranes are inherently critical for niche homeostasis of vacuolar pathogens. Thus, intracellular bacteria frequently encode the capacity to regulate host lipogenesis as well as to modulate the lipid composition of host membranes. One membrane component that is often subverted by vacuolar bacteria is cholesterol - an abundant lipid that mammalian cells produce de novo at the endoplasmic reticulum (ER) or acquire exogenously from serum-derived lipoprotein carriers. Legionella pneumophila is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires' disease. From within a unique ER-derived vacuole L. pneumophila promotes host lipogenesis and experimental evidence indicates that cholesterol production might be one facet of this response. Here we investigated the link between cellular cholesterol and L. pneumophila intracellular replication and discovered that disruption of cholesterol biosynthesis or cholesterol trafficking lowered bacterial replication in infected cells. These growth defects were rescued by addition of exogenous cholesterol. Conversely, bacterial growth within cholesterol-leaden macrophages was enhanced. Importantly, the growth benefit of cholesterol was observed strictly in cellular infections and L. pneumophila growth kinetics in axenic cultures did not change in the presence of cholesterol. Microscopy analyses indicate that cholesterol regulates a step in L. pneumophila intracellular lifecycle that occurs after bacteria begin to replicate within an established intracellular niche. Collectively, we provide experimental evidence that cellular cholesterol promotes L. pneumophila replication within a membrane bound organelle in infected macrophages., Competing Interests: Conflict of Interest: The authors declare that no competing interests exist., (Copyright: © 2022 Ondari et al.)

Background: Fomepizole is the preferred antidote for treatment of methanol and ethylene glycol poisoning, acting by inhibiting the formation of the toxic metabolites. Although very effective, the price is high and the availability is limited. Its availability is further challenged in situations with mass poisonings. Therefore, a 50% reduced maintenance dose for fomepizole during continuous renal replacement therapy (CRRT) was suggested in 2016, based on pharmacokinetic data only. Our aim was to study whether this new dosing for fomepizole during CRRT gave plasma concentrations above the required 10 µmol/L. Secondly, we wanted to study the elimination kinetics of fomepizole during CRRT, which has never been studied before., Methods: Prospective observational study of adult patients treated with fomepizole and CRRT. We collected samples from arterial line (pre-filter) = plasma concentration, post-filter and dialysate for fomepizole measurements. Fomepizole was measured using high-pressure liquid chromatography with a reverse phase column., Results: Ten patients were included in the study. Seven were treated with continuous veno-venous hemodialysis (CVVHD) and three with continuous veno-venous hemodiafiltration (CVVHDF). Ninety-eight percent of the plasma samples were above the minimum plasma concentration of 10 µmol/L. Fomepizole was removed during CRRT with a median saturation/sieving coefficient of 0.85 and dialysis clearance of 28 mL/min., Conclusion: Fomepizole was eliminated during CCRT. The new dosing recommendations for fomepizole and CRRT appeared safe, by maintaining the plasma concentration above the minimum value of 10 µmol/L. Based on these data, the fomepizole maintenance dose during CRRT could be reduced to half as compared to intermittent hemodialysis.

Context: Diethylene glycol (DEG) is an organic compound found in household products but also as a counterfeit solvent in medicines. DEG poisonings are characterized by acute kidney injury (AKI) and by neurological sequelae such as decreased reflexes or face and limb weakness. Previous studies in male rats have demonstrated that neurotoxic effects develop only with the establishment of AKI, but the dose sensitivity of females to DEG toxicity is unknown., Objectives: Assessing whether subacute administration of DEG in female rats would delineate any sex-differences in neuropathy or in kidney injury., Methods: Female Wistar-Han rats were orally administered doses of 4 - 6 g/kg DEG every 12 h and monitored for 7 days. Urine was collected every 12 h and endpoint blood and cerebrospinal fluid (CSF) were collected for renal plasma parameters and total protein estimation, respectively. Motor function tests were conducted before and after treatment. Kidney and brain tissue were analyzed for metabolite content., Results: Of 12 animals treated with DEG, 3 developed AKI as confirmed by increased BUN and creatinine concentrations. Renal and brain DGA contents were increased in animals that developed AKI compared to animals without AKI. Total CSF protein content in animals with AKI was markedly elevated compared to control and to treated animals without AKI. Decreases in forelimb grip strength and in locomotor and rearing activity were observed in animals with AKI compared to control and to animals without AKI., Discussion: Repeated dosing with DEG in a female model produced nephrotoxic effects at a dose similar to that in males. The decrease in motor function and increase in CSF protein were only present in females that developed AKI. However, kidney and neurologic effects were assessed only at the end of the treatments, thus limiting determination of which effect occurs first. Limb function and coordination were measured globally and more sensitive tests such as nerve conduction studies might offer a detailed neurotoxicity assessment of the effects of DEG., Conclusions: These studies show that DEG toxicity does not appear to be sex-specific and that, in males and females, neurological symptoms are present only when DGA accumulation and kidney injury also occur.

Studying endocasts has long allowed anthropologists to examine changes in the external topography and the overall size of the brain throughout the evolutionary history of hominins. The nearly complete calvaria of Manot 1 presents an opportunity to gain insights into the external brain morphology, vascular system, and dimensions of the brain of this late Middle Paleolithic hominin. Detailed size and shape analyses of the Manot 1 endocast indicate a modern Homo sapiens anatomy, despite the presence of some primitive features of the calvaria. Traits considered to be derived endocranial features for H. sapiens are present in Manot 1, including an elongated parietal sagittal chord with an elevated superior part of the hemisphere, a widened posterior part of the frontal lobes, a considerable development of the parietal reliefs such as the supramarginal lobules, and a slight posterior projection of the occipital lobes. These findings, together with data presented in previous studies, rule out the possibility of a direct Neanderthal ancestry for the Manot 1 hominin and instead confirm its affiliation with H. sapiens. The Manot 1 calvaria is more similar to that of later Upper Paleolithic H. sapiens than it is to the earlier Levantine populations of Skhul and Qafzeh. The late Middle Paleolithic date of Manot 1 provides an opportunity to analyze the recent developments in human cerebral morphology and organization., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The transition from the Middle Paleolithic to the Upper Paleolithic in the Levant represents a major event in human prehistory with regards to the dispersal of modern human populations. Unfortunately, the scarcity of human remains from this period has hampered our ability to study the anatomy of Upper Paleolithic populations. This study describes and examines pedal bones recovered from the Early Upper Paleolithic period at Manot Cave, Israel, from 2014 to 2017. The Manot Cave foot bones include a partial, left foot skeleton comprising a talus, a calcaneus, a cuboid, a first metatarsal, a second metatarsal, a fifth metatarsal, and a hallucal sesamoid. All these remains were found in the same archaeological unit of the cave and belong to a young adult. Shape and size comparisons with Neanderthals, Anatomically Modern Human and modern human foot bones indicate a modern human morphology. In some characteristics, however, the Manot Cave foot bones display a Neanderthal-like pattern. Notably, the Manot Cave foot is remarkable in its overall gracility. A healed traumatic injury in the second metatarsal (Lisfranc's fracture) is most likely due to a remote impact to the dorsum of the foot. This injury, its subsequent debility, and the individual's apparent recovery suggest that the members of the Manot Cave community had a supportive environment, one with mutual responsibilities among the members., (Copyright © 2019. Published by Elsevier Ltd.)

This study presents the dental remains discovered at Manot Cave (MC), Western Galilee, Israel. The cave contains evidence for human occupation during the Early Upper Paleolithic period (46-33 ka) mainly of Early Ahmarian (∼46-42 ka) and Levantine Aurignacian (∼38-34 ka) cultural levels. Six teeth (three deciduous and three permanent) were found at the site, of which four could be thoroughly analyzed. The morphology of the teeth was qualitatively described and analyzed using traditional and geometric morphometric methods. A large comparative sample was used in order to assess the morphological affiliation of the Manot specimens with other Homo groups. The results provided equivocal signals: the upper first premolar (MC-9 P 3 ) is probably modern human; the upper deciduous second molar (MC-10 dm 2 ) and the upper second permanent molar (MC-8 M 2 ) might be modern humans; the lower second deciduous molar (MC-7 dm 2 ) might be Neanderthal. Owing to the small sample size and the almost total lack of distinctive characteristics, our outcome could not supply conclusive evidence to address the question of whether Manot Aurignacian population came from Europe or descended from the local Ahmarian population., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Context: Diethylene glycol (DEG) is an organic compound found in household products but also as an adulterant in medicines by acting as a counterfeit solvent. DEG poisonings have been characterized predominately by acute kidney injury (AKI), but also by delayed neurological sequelae such as decreased reflexes or face and limb weakness., Objectives: Characterizing the neurological symptoms of DEG poisoning in a subacute animal model would create a clearer picture of overall toxicity and possibly make mechanistic connections between kidney injury and neuropathy., Methods: Male Wistar-Han rats were orally administered doses of 4 - 6 g/kg DEG every 12 or 24 h and monitored for 7 days. Urine was collected every 12 h and endpoint blood and cerebrospinal fluid (CSF) were collected for a renal plasma panel and total protein estimation, respectively. Motor function tests were conducted before and after treatment. Kidney and brain tissue was harvested for metabolic analysis., Results: Of the 43 animals treated with DEG, 11 developed AKI as confirmed by increased BUN and creatinine levels. Renal and brain DGA accumulation was markedly increased in animals that developed AKI compared to animals without AKI. The total protein content in CSF in animals with kidney injury was markedly elevated compared to control and to treated animals without AKI. Significant decreases in forelimb grip strength and decreases in locomotor and rearing activity were observed in animals with AKI compared to control and to animals without AKI., Discussion: Repeated dosing with DEG in an animal model produced nephrotoxic effects like those in studies with acute DEG administration. The decrease in motor function and increase in CSF protein were only present in animals that developed AKI., Conclusions: These studies show development of neurotoxicity in this DEG animal model and suggest that neurological symptoms are observed only when DGA accumulation and kidney injury also occur.