Reconstructing the Neanderthal Eustachian Tube: New Insights on Disease Susceptibility,Fitness Cost,and Extinction

Neanderthals are among the best studied and yet most enigmatic fossil human groups with aspects of their anatomy and functional morphology remaining poorly understood. We present the first anatomical reconstruction of the Neanderthal cartilaginous Eustachian tube (CET), a vital component of the upper respiratory tract and nexus for the middle ear and postnasal airway. The Eustachian (auditory, pharyngotympanic) tube, comprised of a bony and cartilaginous (CET) portion, is integral to normal physiological functions such as middle ear aeration and pressure equilibration. Findings indicate that Neanderthal tubal morphology may have predisposed them to high rates of middle ear disease (otitis media [OM]). In living humans, mechanical CET dysfunction underlies OM in infants and young children, with sequelae including hearing loss, meningitis, and pneumonia. Despite proven linkage of CET malfunction with OM, the role of CET morphology in Neanderthal health and disease remains unstudied. We reconstructed Neanderthal CET morphology, comparing their crania to a modern human growth series. Methods included geometric morphometrics and univariate measures among Procrustes-fitted coordinates. Results showed Neanderthal adults exhibiting primitively tall and narrow nasopharynges with infant-like horizontal CET and choanal orientation. As horizontal CET orientation is associated with increased OM incidence in infants and children until around age six, its appearance in Neanderthal adults strongly indicates persistence of high OM susceptibility at this time. This could have compromised fitness and disease load relative to sympatric modern humans, affecting Neanderthals' ability to compete within their ecological niche, and potentially contributing to their rapid extinction. Anat Rec, 302:2109–2125, 2019. © 2019 American Association for Anatomy     

Cetacean Skull Telescoping Brings Evolution of Cranial Sutures into Focus

Many modifications to the mammalian bauplan associated with the obligate aquatic lives of cetaceans—fusiform bodies, flukes, flippers, and blowholes—are evident at a glance. But among the most strikingly unusual and divergent features of modern cetacean anatomy are the arrangements of their cranial bones: (1) bones that are situated at opposite ends of the skull in other mammals are positioned close together, their proximity resulting from (2) these bones extensively overlapping the bones that ordinarily would separate them. The term “telescoping” is commonly used to describe the odd anatomy of modern cetacean skulls, yet its usage and the particular skull features to which it refers vary widely. Placing the term in historical and biological context, this review offers an explicit definition of telescoping that includes the two criteria enumerated above. Defining telescoping in this way draws attention to many specific biological questions that are raised by the unusual anatomy of cetacean skulls; highlights the central role of sutures as the locus for changes in the sizes, shapes, mechanical properties, and connectivity of cranial bones; and emphasizes the importance of sutures in skull development and evolution. The unusual arrangements of cranial bones and sutures referred to as telescoping are not easily explained by what is known about cranial development in more conventional mammals. Discovering the evolutionary-developmental processes that produce the extensive overlap characteristic of cetacean telescoping will give insights into both cetacean evolution and the “rules” that more generally govern mammalian skull function, development, and evolution. Anat Rec, 302:1055–1073, 2019. © 2019 Wiley Periodicals, Inc.     

Mitochondrial Deformation During the Cardiac Mechanical Cycle

Cardiomyocytes both cause and experience continual cyclic deformation. The exact effects of this deformation on the properties of intracellular organelles are not well characterized, although they are likely to be relevant for cardiomyocyte responses to active and passive changes in their mechanical environment. In the present study we provide three-dimensional ultrastructural evidence for mechanically induced mitochondrial deformation in rabbit ventricular cardiomyocytes over a range of sarcomere lengths representing myocardial tissue stretch, an unloaded “slack” state, and contracture. We also show structural indications for interaction of mitochondria with one another, as well as with other intracellular elements such as microtubules, sarcoplasmic reticulum and T-tubules. The data presented here help to contextualize recent reports on the mechanosensitivity and cell-wide connectivity of the mitochondrial network and provide a structural framework that may aide interpretation of mechanically-regulated molecular signaling in cardiac cells. Anat Rec, 302:146–152, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.     

Severe Herpes Zoster Requiring Intravenous Antiviral Treatment in Allogeneic Hematopoietic Cell Transplantation Recipients on Standard Acyclovir Prophylaxis

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. The incidence, timing, and risk factors for severe herpes zoster (HZ) are not well described in the era of acyclovir (ACV) prophylaxis. We performed a retrospective cohort study of all patients who underwent first allogeneic HCT between October 2006 and December 2015 at our institution. Patients were followed until December 2017 for the development of severe HZ, defined as necessitating administration of i.v. antiviral medication. Out of 2163 patients who underwent allogeneic HCT, 22 (1.0%) developed severe HZ at a rate of 1 per 228 person-years, including dermatomal/multidermatomal disease (n = 5), disseminated skin disease (n = 5), HZ ophthalmicus (n = 4), meningitis/encephalitis (n = 4), pneumonia (n = 2), viremia (n = 1), and erythema multiforme (n = 1). Severe HZ infection occurred in a bimodal distribution during the early peri-HCT period and at 12 to 24 months post-HCT (median, 12.7 months). Twelve patients (54.5%) were compliant with ACV prophylaxis at the time of HZ diagnosis. Eleven patients (50%) died during the study period, only 2 of whom (9.1%) with active VZV infection. Mortality was higher in patients on immunosuppressive therapy (62.5% versus 16.7%; P = .045) and with concurrent graft-versus-host disease (75.0% versus 35.7%; P= .044). These data suggest that severe HZ remains an important consideration despite ACV prophylaxis.     

Risk Factors for Transplant-Associated Thrombotic Microangiopathy after Autologous Hematopoietic Cell Transplant in High-Risk Neuroblastoma

High-risk neuroblastoma has a poor prognosis, and research studies have shown that increasing the intensity of therapy improves outcomes. Autologous hematopoietic cell transplant (aHCT) as consolidation therapy confers a significant survival advantage but is accompanied by significant morbidity. Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication caused by endothelial injury that often leads to hemolytic anemia, microthrombotic platelet consumption, and renal injury. Here we investigated the incidence, potential risk factors, and sequelae of TA-TMA in patients with high-risk neuroblastoma. We conducted a retrospective chart review of all patients (n = 141) with neuroblastoma in our institutions who underwent aHCT from 2000 to 2017. Ten patients (7%) developed TA-TMA. The patients in the TA-TMA group were similar to the rest of the subjects in demographics, disease burden, prior therapies, renal function, and timing of transplant. The type of conditioning regimen was the only statistically significant pretransplant variable (P < .001). Six of 15 patients (40%) intended to receive tandem transplants (cyclophosphamide/thiotepa and then carboplatin/etoposide/melphalan (CEM)), 4 of 68 patients (6%) who received conditioning with single CEM, and none of the 56 patients who received busulfan/melphalan were diagnosed with TA-TMA. Patients with TA-TMA were more likely to require intensive care unit transfer, have a longer length of stay in the hospital, and experience a delay or change in their subsequent therapy. In our cohort overall, patients with a delay in therapy after transplant appeared to have a worse overall survival, although the difference was not statistically significant. Because of this high incidence and significant morbidity, we have implemented standardized screening for TA-TMA during and after transplant. We anticipate that screening will lead to earlier intervention and decreased severity of disease.