The Late Cretaceous eutherian Zalambdalestes reveals unique axis and complex evolution of the mammalian neck.

The typical mammalian neck consisting of seven cervical vertebrae (C1-C7) was established by the Late Permian in the cynodont forerunners of modern mammals. This structure is precisely adapted to facilitate movements of the head during feeding, locomotion, predator evasion, and social interactions. Eutheria, the clade including crown placentals, has a fossil record extending back more than 125 million years revealing significant morphological diversification in the Mesozoic. Yet very little is known concerning the early evolution of eutherian cervical morphology and its functional adaptations. A specimen of Zalambdalestes lechei from the Late Cretaceous of Mongolia boasts exceptional preservation of an almost complete series of cervical vertebrae (C2-C7) revealing a highly modified axis (C2). The significance of this cervical morphology is explored utilizing an integrated approach combining comparative anatomical examination across mammals, muscle reconstruction, geometric morphometrics and virtual range of motion analysis. We compared the shape of the axis in Zalambdalestes to a dataset of 88 mammalian species (monotremes, marsupials, and placentals) using three-dimensional landmark analysis. The results indicate that the unique axis morphology of Zalambdalestes has no close analog among living mammals. Virtual range of motion analysis of the neck strongly implies Zalambdalestes was capable of exerting very forceful head movements and had a high degree of ventral flexion for an animal its size. These findings reveal unexpected complexity in the early evolution of the eutherian cervical morphology and suggest a feeding behavior similar to insectivores specialized in vermivory and defensive behaviors in Zalambdalestes akin to modern spiniferous mammals.

Feasibility and Performance of Continuous Glucose Monitoring to Guide Computerized Insulin Infusion Therapy in Cardiovascular Intensive Care Unit.

BACKGROUND: We evaluated the feasibility of real-time continuous glucose monitoring (CGM) for titrating continuous intravenous insulin infusion (CII) to manage hyperglycemia in postoperative individuals in the cardiovascular intensive care unit and assessed their accuracy, nursing acceptance, and postoperative individual satisfaction. METHODS: Dexcom G6 CGM devices were applied to 59 postsurgical patients with hyperglycemia receiving CII. A hybrid approach combining CGM with periodic point-of-care blood glucose (POC-BG) tests with two phases (initial-ongoing) of validation was used to determine CGM accuracy. Mean and median absolute relative differences and Clarke Error Grid were plotted to evaluate the CGM accuracy. Surveys of nurses and patients on the use of CGMs experience were conducted and results were analyzed. RESULTS: In this cohort (mean age 64, 32% female, 32% with diabetes) with 864 paired POC-BG and CGM values analyzed, mean and median absolute relative difference between POC-BG and CGM values were 13.2% and 9.8%, respectively. 99.7% of paired CGM and POC-BG were in Zones A and B of the Clarke Error Grid. Responses from nurses reported CGMs being very or quite convenient (n = 28; 93%) and it was favored over POC-BG testing (n = 28; 93%). Majority of patients (n = 42; 93%) reported their care process using CGM as being good or very good. CONCLUSION: This pilot study demonstrates the feasibility, accuracy, and nursing convenience of adopting CGM via a hybrid approach for insulin titration in postoperative settings. These findings provide robust rationale for larger confirmatory studies to evaluate the benefit of CGM in postoperative care to improve workflow, enhance health outcomes, and cost-effectiveness.

The functional significance of aberrant cervical counts in sloths: insights from automated exhaustive analysis of cervical range of motion.

Besides manatees, the suspensory extant 'tree sloths' are the only mammals that deviate from a cervical count (CC) of seven vertebrae. They do so in opposite directions in the two living genera (increased versus decreased CC). Aberrant CCs seemingly reflect neck mobility in both genera, suggesting adaptive significance for their head position during suspensory locomotion and especially increased ability for neck torsion in three-toed sloths. We test two hypotheses in a comparative evolutionary framework by assessing three-dimensional intervertebral range of motion (ROM) based on exhaustive automated detection of bone collisions and joint disarticulation while accounting for interacting rotations of roll, yaw and pitch. First, we hypothesize that the increase of CC also increases overall neck mobility compared with mammals with a regular CC, and vice versa. Second, we hypothesize that the anatomy of the intervertebral articulations determines mobility of the neck. The assessment revealed that CC plays only a secondary role in defining ROM since summed torsion (roll) capacity was primarily determined by vertebral anatomy. Our results thus suggest limited neck rotational adaptive significance of the CC aberration in sloths. Further, the study demonstrates the suitability of our automated approach for the comparative assessment of osteological ROM in vertebral series.

Is it inappropriate to ask for your age? Evaluating parameter impact on tree dating in a challenging clade (Macroscelidea).

Sengis (order Macroscelidea) are small mammals endemic to Africa. The taxonomy and phylogeny of sengis has been difficult to resolve due to a lack of clear morphological apomorphies. Molecular phylogenies have already significantly revised sengi systematics, but until now no molecular phylogeny has included all 20 extant species. In addition, the age of origin of the sengi crown clade and the divergence age of its two extant families remain unclear. Two recently published studies based on different datasets and age-calibration parameters (DNA type, outgroup selection, fossil calibration points) proposed highly different divergent age estimates and evolutionary scenarios. We obtained nuclear and mitochondrial DNA from mainly museum specimens using target enrichment of single-stranded DNA libraries to generate the first phylogeny of all extant macroscelidean species. We then explored the effects of different parameters (type of DNA, ratio of ingroup to outgroup sampling, number and type of fossil calibration points) and their resulting impacts on age estimates for the origin and initial diversification of Macroscelidea. We show that, even after correcting for substitution saturation, both using mitochondrial DNA in conjunction with nuclear DNA or alone results in much older ages and different branch lengths than when using nuclear DNA alone. We further show that the former effect can be attributed to insufficient amounts of nuclear data. If multiple calibration points are included, the age of the sengi crown group fossil prior has minimal impact on the estimated time frame of sengi evolution. In contrast, the inclusion or exclusion of outgroup fossil priors has a major effect on the resulting node ages. We also find that a reduced sampling of ingroup species does not significantly affect overall age estimates and that terminal specific substitution rates can serve as a means to evaluate the biological likeliness of the produced temporal estimates. Our study demonstrates how commonly varied parameters in temporal calibration of phylogenies affect age estimates. Dated phylogenies should therefore always be seen in the context of the dataset which was used to produce them.

Enhanced Submentoplasty as an Adjunct to Orthognathic Surgery for the Improvement of the Neck-Throat Point.

Orthognathic surgery has been used to enhance the function of the maxillomandibular complex with numerous positive effects on facial esthetics, as it can profoundly alter the skeletal architecture of the face. Numerous adjunctive surgical techniques are used to enhance the overall cosmetic results of orthognathic surgery to include the following: genioplasty, midface augmentation, rhinoplasty, fillers, and liposuction. Mandibular advancement, submental liposuction and genioplasty are all techniques that help to define the neck throat point (NTP), minimize submental sagging, and enhance throat length (TL) in order to establish a more harmonious facial profile. However, these procedures may still be insufficient to define the NTP in the low hyoid, retrognathic patient. This report presents the case of an adult male, with a non-existent NTP and retrognathia, who underwent corrective orthognathic surgery with the novel enhanced submentoplasty and a suture assisted resuspension of the platysma in order to establish the NTP, increase TL, minimize submental sagging, and enhance mandibular border definition.

[Interest of ambulatory management of patients with chronic heart failure by protocolized follow-up and therapeutic education: results of the USICAR experiment]. / Intérêt de la prise en charge ambulatoire des patients insuffisants cardiaques chroniques par suivi protocolisé et éducation thérapeutique : résultats de l'expérimentation USICAR.

OBJECTIVE: The objective of this study is to determine whether the implementation of regular and structured follow-up of patients with chronic heart failure (CHF), combined with therapeutic education, led to better management of these patients. PATIENTS AND METHOD: This was a monocentric, retrospective study on a cohort of patients with a proven CHF, followed in the Mulhouse region (France), between January 2016 and December 2017, by the Unit for Monitoring Heart Failure Patients (USICAR). These patients benefited from a regular protocolized follow-up and a therapeutic education program for a period of 2 years. The main criterion of this study was: the number of days of hospitalization for HF per year and per patient. The secondary endpoints were: the number of days of hospitalization for cardiac causes other than HF and the number of hospital stays for HF per patient. These criteria were collected over the one-year period before inclusion, at one-year-follow-up, and at two-years-follow-up. RESULTS: 159 patients with a mean age of 72.9 years were included in this study. They all had a CHF, mainly stage I-II NYHA (88.7%), of predominantly ischemic origin (50.9%), with altered left ventricular ejection fraction in 69.2% of cases. The primary endpoint averaged 8.33 days (6.84-10.13) in the year prior to inclusion, 2.6 days (1.51-4.47) in the first year of follow-up, and 2.82 days (1.30-6.11) (p <0.01 for both comparisons). The mean number of days of hospitalization for other cardiac causes other than HF to patient numbers was: 1.73 days (1.16-2.6), 1.81 days (1.04-3.16), and 1.32 days (0.57-3.08) (p = ns). The percentage of hospitalization for HF for each patient was: 69.5% (60.2-77.4) before inclusion, 16.2% (10-25.2) during the first year of follow-up and 19.3% (11-31.8) during the second (p < 0.001 for both comparisons). CONCLUSION: This study demonstrates the value of a protocolized follow-up associated with a therapeutic education program to improve the management of ambulatory CHF patients, particularly for moderate CHF.

Improving Hospital Glucometrics, Workflow, and Outcomes with a Computerized Intravenous Insulin Dose Calculator Built into the Electronic Health Record.

OBJECTIVE: To adjust for dynamic insulin requirements in critically ill patients, intravenous (IV) insulin infusions allow for titration of the dose according to a prespecified algorithm. Despite the adaptability of IV insulin protocols, human involvement in dose calculation allows for error. We integrated a previously validated IV insulin calculator into our electronic health record (Epic) and instituted it in the cardiovascular intensive care unit (CVICU). We aim to describe the design of the calculator, the implementation process, and evaluate the calculator's impact. METHOD: Employing an aggressive training program and user acceptance testing prior to significant elbow support at the time of institution, we successfully integrated the insulin calculator in our CVICU. We evaluated the glucometrics before and after implementation as well as nursing satisfaction following calculator implementation. RESULTS: Overall, our implementation led to increased frequency of blood sugar at various glycemic targets, a trend toward less hypoglycemia or hyperglycemia. For severe hypoglycemia, our preintervention cohort had 0.02% of blood sugars less than 40 mg/dL but no blood sugars less than 40 mg/dL were identified in our patient's postintervention. For the CVICU target blood glucose of 70-180 mg/dL, 87.97% blood sugars at baseline met goal compared to 91.39% at one month, 91.24% at three months, and 90.87% at six months postintervention. CONCLUSION: By utilizing an aggressive education campaign championing superusers and making adjustments to the calculator based on early problems that were encountered, we were able to improve glycemic control and limit glucose variability at our institution.

Insulin Bolus Calculator: Lessons Learned from Institutional Experience.

Insulin bolus calculators have proven effective in improving glycemia and patient safety. Insulin calculators are increasingly being implemented for inpatient hospital care. Multidisciplinary teams are often involved in the design and review of the efficacy and utilization for these calculators. At times, unintended consequences and benefits of utilization are found on review. Integration of our insulin calculator into our electronic health record system was a multidisciplinary effort. During implementation, several obstacles to effective care were identified and are discussed in the following manuscript. We describe the barriers to utilization and potential pitfalls in clinical integration. We further describe benefits in patient education, time of insulin administration versus meal delivery, variations in insulin bolus for ketone correction, variation in care, and maximum bolus administration. Sharing lessons learned from experiences using electronic insulin calculator order sets will further our goals of improved patient care in the hospital setting.

Benefit of Ambulatory Management of Patients with Chronic Heart Failure by Protocolized Follow-Up Therapeutic Education and Remote Monitoring Solution: An Original Study in 159 Patients.

This study sought to determine whether the implementation of regular and structured follow-up of patients with chronic heart failure (CHF), combined with therapeutic education and remote monitoring solution, leads to better management. This was a single-center retrospective study conducted in a cohort of patients with proven CHF who were followed up in the Mulhouse region (France) between January 2016 and December 2017 by the Unité de Suivi des Patients Insuffisants Cardiaques (USICAR) unit. These patients received regular protocolized follow-up, a therapeutic education program, and several used a telemedicine platform for a two-year period. The primary endpoint was the number of days hospitalized for heart failure (HF) per patient per year. The main secondary endpoints included the number of days hospitalized for a heart condition other than HF and the number of hospital stays for HF per patient. These endpoints were collected during the year preceding enrollment, at one year of follow-up, and at two years of follow-up. The remote monitoring solution was evaluated on the same criterion. Overall, 159 patients with a mean age of 72.9 years were included in this study. They all had CHF, mainly NYHA Class I-II (88.7%), predominantly of ischemic origin (50.9%), and with altered left ventricular ejection fraction in 69.2% of cases. The mean number of days hospitalized for HF per patient per year was 8.33 (6.84-10.13) in the year preceding enrollment, 2.6 (1.51-4.47) at one year of follow-up, and 2.82 at two years of follow-up (1.30-6.11) (p < 0.01 for both comparisons). The mean number of days hospitalized for a heart condition other than HF was 1.73 (1.16-2.6), 1.81 (1.04-3.16), and 1.32 (0.57-3.08), respectively (p = ns). The percentage of hospitalization for HF for each patient was 69.5% (60.2-77.4), 16.2% (10-25.2), and 19.3% (11-31.8), respectively (p < 0.001 for both comparisons). In the group telemedicine, the mean number of days hospitalized for HF per patient per year was 8.33 during the year preceding enrollment, 2.3 during the first year of follow-up, and 1.7 during the second. This difference was significant (p < 0.001). The "number of days hospitalized for a heart condition other than HF" was significantly reduced in the group of patient's beneficiating from the remote monitoring solution. This study demonstrates the value of a protocolized follow-up associated with a therapeutic optimization, therapeutic education program, and the use of a remote monitoring solution to improve the management of ambulatory patients with CHF, particularly of moderate severity.

Femoral morphology of sciuromorph rodents in light of scaling and locomotor ecology.

Sciuromorph rodents are a monophyletic group comprising about 300 species with a body mass range spanning three orders of magnitude and various locomotor behaviors that we categorized into arboreal, fossorial and aerial. The purpose of this study was to investigate how the interplay of locomotor ecology and body mass affects the morphology of the sciuromorph locomotor apparatus. The most proximal skeletal element of the hind limb, i.e. the femur, was selected, because it was shown to reflect a functional signal in various mammalian taxa. We analyzed univariate traits (effective femoral length, various robustness variables and the in-levers of the muscles attaching to the greater, third and lesser trochanters) as well as femoral shape, representing a multivariate trait. An ordinary least-squares regression including 177 species was used to test for a significant interaction effect between body mass and locomotor ecology on the variables. Specifically, it tested whether the scaling patterns of the fossorial and aerial groups differ when compared with the arboreal, because the latter was identified as the ancestral sciuromorph condition via stochastic character mapping. We expected aerial species to display the highest trait values for a given body mass as well as the steepest slopes, followed by the arboreal and fossorial species along this order. An Ornstein-Uhlenbeck regression fitted to a phylogenetically pruned dataset of 140 species revealed the phylogenetic inertia to be very low in the univariate traits, hence justifying the utilization of standard regressions. These variables generally scaled close to isometry, suggesting that scaling adjustments might not have played a major role for most of the femoral features. Nevertheless, the low phylogenetic inertia indicates that the observed scaling patterns needed to be maintained during sciuromorph evolution. Significant interaction effects were discovered in the femoral length, the centroid size of the condyles, and the in-levers of the greater and third trochanters. Additionally, adjustments in various femoral traits reflect the acquisitions of fossorial and aerial behaviors from arboreal ancestors. Using sciuromorphs as a focal clade, our findings exemplify the importance of statistically accounting for potential interaction effects of different environmental factors in studies relating morphology to ecology.

Reverse-engineering the locomotion of a stem amniote.

Reconstructing the locomotion of extinct vertebrates offers insights into their palaeobiology and helps to conceptualize major transitions in vertebrate evolution1-4. However, estimating the locomotor behaviour of a fossil species remains a challenge because of the limited information preserved and the lack of a direct correspondence between form and function5,6. The evolution of advanced locomotion on land-that is, locomotion that is more erect, balanced and mechanically power-saving than is assumed of anamniote early tetrapods-has previously been linked to the terrestrialization and diversification of amniote lineages7. To our knowledge, no reconstructions of the locomotor characteristics of stem amniotes based on multiple quantitative methods have previously been attempted: previous methods have relied on anatomical features alone, ambiguous locomotor information preserved in ichnofossils or unspecific modelling of locomotor dynamics. Here we quantitatively examine plausible gaits of the stem amniote Orobates pabsti, a species that is known from a complete body fossil preserved in association with trackways8. We reconstruct likely gaits that match the footprints, and investigate whether Orobates exhibited locomotor characteristics that have previously been linked to the diversification of crown amniotes. Our integrative methodology uses constraints derived from biomechanically relevant metrics, which also apply to extant tetrapods. The framework uses in vivo assessment of locomotor mechanics in four extant species to guide an anatomically informed kinematic simulation of Orobates, as well as dynamic simulations and robotics to filter the parameter space for plausible gaits. The approach was validated using two extant species that have different morphologies, gaits and footprints. Our metrics indicate that Orobates exhibited more advanced locomotion than has previously been assumed for earlier tetrapods7,9, which suggests that advanced terrestrial locomotion preceded the diversification of crown amniotes. We provide an accompanying website for the exploration of the filters that constrain our simulations, which will allow revision of our approach using new data, assumptions or methods.

Homeotic transformations reflect departure from the mammalian 'rule of seven' cervical vertebrae in sloths: inferences on the Hox code and morphological modularity of the mammalian neck.

BACKGROUND: Sloths are one of only two exceptions to the mammalian 'rule of seven' vertebrae in the neck. As a striking case of breaking the evolutionary constraint, the explanation for the exceptional number of cervical vertebrae in sloths is still under debate. Two diverging hypotheses, both ultimately linked to the low metabolic rate of sloths, have been proposed: hypothesis 1 involves morphological transformation of vertebrae due to changes in the Hox gene expression pattern and hypothesis 2 assumes that the Hox gene expression pattern is not altered and the identity of the vertebrae is not changed. Direct evidence supporting either hypothesis would involve knowledge of the vertebral Hox code in sloths, but the realization of such studies is extremely limited. Here, on the basis of the previously established correlation between anterior Hox gene expression and the quantifiable vertebral shape, we present the morphological regionalization of the neck in three different species of sloths with aberrant cervical count providing indirect insight into the vertebral Hox code. RESULTS: Shape differences within the cervical vertebral column suggest a mouse-like Hox code in the neck of sloths. We infer an anterior shift of HoxC-6 expression in association with the first thoracic vertebra in short-necked sloths with decreased cervical count, and a posterior shift of HoxC-5 and HoxC-6 expression in long-necked sloths with increased cervical count. CONCLUSION: Although only future developmental analyses in non-model organisms, such as sloths, will yield direct evidence for the evolutionary mechanism responsible for the aberrant number of cervical vertebrae, our observations lend support to hypothesis 1 indicating that the number of modules is retained but their boundaries are displaced. Our approach based on quantified morphological differences also provides a reliable basis for further research including fossil taxa such as extinct 'ground sloths' in order to trace the pattern and the underlying genetic mechanisms in the evolution of the vertebral column in mammals.

Trabecular architecture in the sciuromorph femoral head: allometry and functional adaptation.

BACKGROUND: Sciuromorpha (squirrels and close relatives) are diverse in terms of body size and locomotor behavior. Individual species are specialized to perform climbing, gliding or digging behavior, the latter being the result of multiple independent evolutionary acquisitions. Each lifestyle involves characteristic loading patterns acting on the bones of sciuromorphs. Trabecular bone, as part of the bone inner structure, adapts to such loading patterns. This network of thin bony struts is subject to bone modeling, and therefore reflects habitual loading throughout lifetime. The present study investigates the effect of body size and lifestyle on trabecular structure in Sciuromorpha. METHODS: Based upon high-resolution computed tomography scans, the femoral head 3D inner microstructure of 69 sciuromorph species was analyzed. Species were assigned to one of the following lifestyle categories: arboreal, aerial, fossorial and semifossorial. A cubic volume of interest was selected in the center of each femoral head and analyzed by extraction of various parameters that characterize trabecular architecture (degree of anisotropy, bone volume fraction, connectivity density, trabecular thickness, trabecular separation, bone surface density and main trabecular orientation). Our analysis included evaluation of the allometric signals and lifestyle-related adaptation in the trabecular parameters. RESULTS: We show that bone surface density, bone volume fraction, and connectivity density are subject to positive allometry, and degree of anisotropy, trabecular thickness, and trabecular separation to negative allometry. The parameters connectivity density, bone surface density, trabecular thickness, and trabecular separation show functional signals which are related to locomotor behavior. Aerial species are distinguished from fossorial ones by a higher trabecular thickness, lower connectivity density and lower bone surface density. Arboreal species are distinguished from semifossorial ones by a higher trabecular separation. CONCLUSION: This study on sciuromorph trabeculae supplements the few non-primate studies on lifestyle-related functional adaptation of trabecular bone. We show that the architecture of the femoral head trabeculae in Sciuromorpha correlates with body mass and locomotor habits. Our findings provide a new basis for experimental research focused on functional significance of bone inner microstructure.

Trabecular architecture in the forelimb epiphyses of extant xenarthrans (Mammalia).

BACKGROUND: Bone structure has a crucial role in the functional adaptations that allow vertebrates to conduct their diverse lifestyles. Much has been documented regarding the diaphyseal structure of long bones of tetrapods. However, the architecture of trabecular bone, which is for instance found within the epiphyses of long bones, and which has been shown experimentally to be extremely plastic, has received little attention in the context of lifestyle adaptations (virtually only in primates). We therefore investigated the forelimb epiphyses of extant xenarthrans, the placental mammals including the sloths, anteaters, and armadillos. They are characterised by several lifestyles and degrees of fossoriality involving distinct uses of their forelimb. We used micro computed tomography data to acquire 3D trabecular parameters at regions of interest (ROIs) for all extant genera of xenarthrans (with replicates). Traditional, spherical, and phylogenetically informed statistics (including the consideration of size effects) were used to characterise the functional signal of these parameters. RESULTS: Several trabecular parameters yielded functional distinctions. The main direction of the trabeculae distinguished lifestyle categories for one ROI (the radial trochlea). Among the other trabecular parameters, it is the degree of anisotropy (i.e., a preferential alignment of the trabeculae) that yielded the clearest functional signal. For all ROIs, the armadillos, which represent the fully terrestrial and fossorial category, were found as characterised by a greater degree of anisotropy (i.e., more aligned trabeculae). Furthermore, the trabeculae of the humeral head of the most fossorial armadillos were also found to be more anisotropic than in the less fossorial species. CONCLUSIONS: Most parameters were marked by an important intraspecific variability and by a size effect, which could, at least partly, be masking the functional signal. But for some parameters, the degree of anisotropy in particular, a clear functional distinction was recovered. Along with data on primates, our findings suggest that a trabecular architecture characterised by a greater degree of anisotropy is to be expected in species in which the relevant epiphyses withstand a restricted range of load directions. Trabecular architecture therefore is a promising research avenue for the reconstruction of lifestyles in extinct or cryptic species.

Musculoskeletal networks reveal topological disparity in mammalian neck evolution.

BACKGROUND: The increase in locomotor and metabolic performance during mammalian evolution was accompanied by the limitation of the number of cervical vertebrae to only seven. In turn, nuchal muscles underwent a reorganization while forelimb muscles expanded into the neck region. As variation in the cervical spine is low, the variation in the arrangement of the neck muscles and their attachment sites (i.e., the variability of the neck's musculoskeletal organization) is thus proposed to be an important source of neck disparity across mammals. Anatomical network analysis provides a novel framework to study the organization of the anatomical arrangement, or connectivity pattern, of the bones and muscles that constitute the mammalian neck in an evolutionary context. RESULTS: Neck organization in mammals is characterized by a combination of conserved and highly variable network properties. We uncovered a conserved regionalization of the musculoskeletal organization of the neck into upper, mid and lower cervical modules. In contrast, there is a varying degree of complexity or specialization and of the integration of the pectoral elements. The musculoskeletal organization of the monotreme neck is distinctively different from that of therian mammals. CONCLUSIONS: Our findings reveal that the limited number of vertebrae in the mammalian neck does not result in a low musculoskeletal disparity when examined in an evolutionary context. However, this disparity evolved late in mammalian history in parallel with the radiation of certain lineages (e.g., cetartiodactyls, xenarthrans). Disparity is further facilitated by the enhanced incorporation of forelimb muscles into the neck and their variability in attachment sites.

Differential scaling patterns of vertebrae and the evolution of neck length in mammals.

Almost all mammals have seven vertebrae in their cervical spines. This consistency represents one of the most prominent examples of morphological stasis in vertebrae evolution. Hence, the requirements associated with evolutionary modifications of neck length have to be met with a fixed number of vertebrae. It has not been clear whether body size influences the overall length of the cervical spine and its inner organization (i.e., if the mammalian neck is subject to allometry). Here, we provide the first large-scale analysis of the scaling patterns of the cervical spine and its constituting cervical vertebrae. Our findings reveal that the opposite allometric scaling of C1 and C2-C7 accommodate the increase of neck bending moment with body size. The internal organization of the neck skeleton exhibits surprisingly uniformity in the vast majority of mammals. Deviations from this general pattern only occur under extreme loading regimes associated with particular functional and allometric demands. Our results indicate that the main source of variation in the mammalian neck stems from the disparity of overall cervical spine length. The mammalian neck reveals how evolutionary disparity manifests itself in a structure that is otherwise highly restricted by meristic constraints.

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats.

BACKGROUND: Nutritional ketosis induced by the ketogenic diet (KD) has therapeutic applications for many disease states. We hypothesized that oral administration of exogenous ketone supplements could produce sustained nutritional ketosis (>0.5 mM) without carbohydrate restriction. METHODS: We tested the effects of 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague-Dawley rats. The supplements included: 1,3-butanediol (BD), a sodium/potassium ß-hydroxybutyrate (ßHB) mineral salt (BMS), medium chain triglyceride oil (MCT), BMS + MCT 1:1 mixture, and 1,3 butanediol acetoacetate diester (KE). Rats received a daily 5-10 g/kg dose of their respective ketone supplement via intragastric gavage during treatment. Weekly whole blood samples were taken for analysis of glucose and ßHB at baseline and, 0.5, 1, 4, 8, and 12 h post-gavage, or until ßHB returned to baseline. At 28 days, triglycerides, total cholesterol and high-density lipoprotein (HDL) were measured. RESULTS: Exogenous ketone supplementation caused a rapid and sustained elevation of ßHB, reduction of glucose, and little change to lipid biomarkers compared to control animals. CONCLUSIONS: This study demonstrates the efficacy and tolerability of oral exogenous ketone supplementation in inducing nutritional ketosis independent of dietary restriction.

Different calorie restriction treatments have similar anti-seizure efficacy.

PURPOSE: Previous studies showed that a single oral administration of a synthetic ketone ester (1,3-butanediol acetoacetate diester, BD-AcAc2) could elevate blood ketones with promising acute anti-epileptic effects. The aim of the present work was to evaluate the tolerability of a prolonged administration of BD-AcAc2 and the anti-epileptic efficacy of such treatment. METHODS: The threshold for seizure induction with progressive intravenous infusion of pentylenetrazole (PTZ) was evaluated in anesthetized Wistar rats after a ten-day oral administration of BD-AcAc2 (gavage). The effects of this treatment were compared to those of: (1) a ten-day water gavage administration, (2) a ten-day ketogenic diet, (3) a standard rodent chow diet. RESULTS: Compared to the standard diet, all other treatments produced a calorie restriction and an elevation of the seizure threshold. CONCLUSION: These results indicate that supplementation with an oral synthetic ketone can have anti-seizure effects, but the formulation has to be further ameliorated to be more palatable; further studies are also needed to better understand the role played by ketone bodies alone in vivo, without any calorie restriction.

Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure.

The ketogenic diet is known to have an anti-epileptic effect; in fact it is currently used to treat drug resistant epilepsies. The efficacy of this diet is thought to be correlated to the elevation of blood ketone bodies. Because of problems with compliance to this diet, there is an interest in evaluating alternative pharmacological treatments that can have anti-seizure effects by elevating ketone bodies. In the present experiment, an orally administered synthetic ketone ester (R,S - 1,3-butanediol acetoacetate diester, or BD-AcAc2) was evaluated for its anti-seizure efficacy in a rat model. The threshold for seizure induction with progressive intravenous infusion of pentylenetrazole (PTZ) was evaluated in anesthetized Wistar rats two hours after a single 1 ml intragastric administration of BD-AcAc2 (i.e. 4 g/kg b.w., treated group) or water (control group). After correction for the dose of anesthetic, the results showed that the administration of BD-AcAc2 induced an elevation of the PTZ threshold (140 ± 11 mg/kg for the treated group, 122 ± 6 mg/kg for the control group), along with an increased level of blood ß-hydroxybutyrate (2.7 ± 0.3mM for the treated group, 1.4 ± 0.1mM for the control group). This result suggests that ketone esters may pave the road towards the establishment of a "ketogenic diet in a pill".

The effect of a hypoglycemia treatment protocol on glycemic variability in critically ill patients.

INTRODUCTION: Hypoglycemia and glucose variability are independently associated with increased mortality in septic, surgical, and mixed intensive care unit (ICU) patients. Treatment of hypoglycemia with dextrose 50% can overcorrect blood glucose levels and increase glucose variability. The purpose of this study is to evaluate the effect of a hypoglycemia treatment protocol focused on minimizing glucose variability in critically ill patients. METHODS: This retrospective analysis was conducted at a 772-bed community teaching hospital in Detroit, Michigan. A standardized nursing-driven hypoglycemia treatment protocol specific to critically ill patients was implemented. Glucose variability, amount of dextrose administered, subsequent glucose monitoring, hypoglycemia recurrence, and mortality were compared between pre- and postprotocol groups. RESULTS: The coefficient of variability of blood glucose in the postprotocol group (n = 53) was decreased compared with the preprotocol group (n = 52), 40.9% versus 49.3%, respectively (P = .048). Dextrose usage was significantly reduced between groups (21.2 g preprotocol vs 11.5 g postprotocol; P < .001). The time to first blood glucose check was 36 minutes after protocol implementation compared to 61 minutes before the protocol (P = .003). Finally, the incidence of continued hypoglycemia following dextrose administration and ICU mortality was similar between groups. CONCLUSIONS: Implementation of the hypoglycemia treatment protocol described led to a reduction in glucose variability, while still providing a safe and effective way to manage hypoglycemia in critically ill patients.