Brain perfusion estimation by Tikhonov model-free deconvolution in a long axial field of view PET/CT scanner exploring five different PET tracers.

PURPOSE: New total-body PET scanners with a long axial field of view (LAFOV) allow for higher temporal resolution due to higher sensitivity, which facilitates perfusion estimation by model-free deconvolution. Fundamental tracer kinetic theory predicts that perfusion can be estimated for all tracers despite their different fates given sufficiently high temporal resolution of 1 s or better, bypassing the need for compartment modelling. The aim of this study was to investigate whether brain perfusion could be estimated using model-free Tikhonov generalized deconvolution for five different PET tracers, [15O]H2O, [11C]PIB, [18F]FE-PE2I, [18F]FDG and [18F]FET. To our knowledge, this is the first example of a general model-free approach to estimate cerebral blood flow (CBF) from PET data. METHODS: Twenty-five patients underwent dynamic LAFOV PET scanning (Siemens, Quadra). PET images were reconstructed with an isotropic voxel resolution of 1.65 mm3. Time framing was 40 × 1 s during bolus passage followed by increasing framing up to 60 min. AIF was obtained from the descending aorta. Both voxel- and region-based calculations of perfusion in the thalamus were performed using the Tikhonov method. The residue impulse response function was used to estimate the extraction fraction of tracer leakage across the blood-brain barrier. RESULTS: CBF ranged from 37 to 69 mL blood min-1 100 mL of tissue-1 in the thalamus. Voxelwise calculation of CBF resulted in CBF maps in the physiologically normal range. The extraction fractions of [15O]H2O, [18F]FE-PE2I, [11C]PIB, [18F]FDG and [18F]FET in the thalamus were 0.95, 0.78, 0.62, 0.19 and 0.03, respectively. CONCLUSION: The high temporal resolution and sensitivity associated with LAFOV PET scanners allow for noninvasive perfusion estimation of multiple tracers. The method provides an estimation of the residue impulse response function, from which the fate of the tracer can be studied, including the extraction fraction, influx constant, volume of distribution and transit time distribution, providing detailed physiological insight into normal and pathologic tissue.

Evolution of the human birth canal.

It seems puzzling why humans have evolved such a small and rigid birth canal that entails a relatively complex process of labor compared with the birth canal of our closest relatives, the great apes. This study reviewed insights into the evolution of the human birth canal from recent theoretical and empirical studies and discussed connections to obstetrics, gynecology, and orthopedics. Originating from the evolution of bipedality and the large human brain million years ago, the evolution of the human birth canal has been characterized by complex trade-off dynamics among multiple biological, environmental, and sociocultural factors. The long-held notion that a wider pelvis has not evolved because it would be disadvantageous for bipedal locomotion has not yet been empirically verified. However, recent clinical and biomechanical studies suggest that a larger birth canal would compromise pelvic floor stability and increase the risk of incontinence and pelvic organ prolapse. Several mammals have neonates that are equally large or even larger than human neonates compared to the size of the maternal birth canal. In these species, the pubic symphysis opens widely to allow successful delivery. Biomechanical and developmental constraints imposed by bipedality have hindered this evolutionary solution in humans and led to the comparatively rigid pelvic girdle in pregnant women. Mathematical models have shown why the evolutionary compromise to these antagonistic selective factors inevitably involves a certain rate of fetopelvic disproportion. In addition, these models predict that cesarean deliveries have disrupted the evolutionary equilibrium and led to new and ongoing evolutionary changes. Different forms of assisted birth have existed since the stone age and have become an integral part of human reproduction. Paradoxically, by buffering selection, they may also have hindered the evolution of a larger birth canal. Many of the biological, environmental, and sociocultural factors that have influenced the evolution of the human birth canal vary globally and are subject to ongoing transitions. These differences may have contributed to the global variation in the form of the birth canal and the difficulty of labor, and they likely continue to change human reproductive anatomy.

The variation in shape and thickness of the pelvic floor musculature in males and females: a geometric-morphometric analysis.

INTRODUCTION AND HYPOTHESIS: In women, the risk of pelvic floor prolapse is known to be associated with age and parity. Different studies suggested that it is also related to pelvic dimensions, e.g. biomechanical modelling showed that a larger pelvic canal results in higher values of displacement, stress and strain in the pelvic floor muscles, which can increase the risk of pelvic floor disorders. To better understand the multiple factors contributing to pelvic floor disorders, we assessed how age, body weight, body height, parity (in women), pelvic canal size and overall muscle development affected pelvic floor geometry. METHODS: A comprehensive geometric morphometric analysis of variation in pelvic floor muscle shape was conducted based on a dense set of 3D landmarks measured on CT scans in a cohort of 49 deceased men and 52 deceased women. The multivariate association between biological variables (parity, dimensions of the true pelvis, age, body weight, height) and pelvic floor muscle morphology was explored by reduced rank regression in both sexes. RESULTS: In women, advanced age, high body weight relative to body height and a large pelvic canal were associated with a deeper pelvic floor. Surprisingly, parity did not have any strong association with overall pelvic floor shape. In men, high body weight was associated with a deep pelvic floor. Age had little effect on male pelvic floor shape, except for the thickness of the ischiocavernosus muscle, which reduced with age. CONCLUSION: These results suggest that age, relative body weight and the size of the pelvic canal contribute to the risk of female pelvic floor disorders via their effect on pelvic floor shape, independently of birth-related factors such as injury and avulsion of pelvic floor muscles.

Pelvic inlet area is associated with birth mode.

INTRODUCTION: To determine whether a pelvis is wide enough for spontaneous delivery has long been the subject of obstetric research. A number of variables have been proposed as predictors, all with limited accuracy. In this study, we use a novel three-dimensional (3D) method to measure the female pelvis and assess which pelvic features influence birth mode. We compare the 3D pelvic morphology of women who delivered vaginally, women who had cesarean sections, and nulliparous women. The aim of this study is to identify differences in pelvic morphology between these groups. MATERIAL AND METHODS: This observational study included women aged 50 years and older who underwent a CT scan of the pelvis for any medical indication. We recorded biometric data including height, weight, and age, and obtained the obstetric history. The bony pelvis was extracted from the CT scans and reconstructed in three dimensions. By placing 274 landmarks on each surface model, the pelvises were measured in detail. The pelvic inlet was measured using 32 landmarks. The trial was registered at the German Clinical Trials Register DRKS (DRKS00017690). RESULTS: For this study, 206 women were screened. Exclusion criteria were foreign material in the bony pelvis, unknown birth mode, and exclusively preterm births. Women who had both a vaginal birth and a cesarean section were excluded from the group comparison. We compared the pelvises of 177 women between three groups divided by obstetric history: vaginal births only (n = 118), cesarean sections only (n = 21), and nulliparous women (n = 38). The inlet area was significantly smaller in the cesarean section group (mean = 126.3 cm2 ) compared with the vaginal birth group (mean = 134.9 cm2 , p = 0.002). The nulliparous women were used as a control group: there was no statistically significant difference in pelvic inlet area between the nulliparous and vaginal birth groups. CONCLUSIONS: By placing 274 landmarks on a pelvis reconstructed in 3D, a very precise measurement of the morphology of the pelvis is possible. We identified a significant difference in pelvic inlet area between women with vaginal delivery and those with cesarean section. A unique feature of this study is the method of measurement of the bony pelvis that goes beyond linear distance measurements as used in previous pelvimetric studies.

Seizure-related injuries in adults: A prospective case-controlled study on risk factors, seizure severity and quality of life.

OBJECTIVE: The current study was conducted to understand the occurrence of seizure-related injuries in people with epilepsy. The relationship between injuries and clinical variables, the perception of seizure severity and quality of life (QoL) and the practice of risky activities were also assessed. The characteristics of the injuries from the onset of epilepsy and in the previous year were assessed. METHODOLOGY: This is a prospective study to assess the occurrence of seizures-related injuries of 72 adult patients with epilepsy. Injury-related data were related to clinical variables and scores of the quality of life in epilepsy inventory (QOLIE-31) and the Seizure Severity Questionnaire (SSQ) with p < 0.05. RESULTS: The mean age of the people with epilepsy was 45.8 ± 15.2 years and the mean length of seizure disorder was 24.0 ± 18.7 years. Seizure-related injuries occurred since the onset of epilepsy in 55 (76.4%) cases and in the previous year in 17 (23.6%) cases. Throughout the lifespan, there was a greater occurrence of injuries in younger patients, with younger age at the onset of epilepsy, using various antiseizure medications and with higher SSQ scores (T test; 54.5 ± 27.7 vs 36.1 ± 23.4, p = 0.011). Injuries in the previous year were associated with a high occurrence of previous injuries, lower scores on the QOLIE-31 (56.7 ± 18.6 vs 66.6 ± 16.1; p = 0.048), higher frequency of seizures and the perception of greater severity of seizures. Seizure-related injuries during risky activities occurred in 11 (20%) cases, associated with a longer length of epilepsy disorder (34.9 ± 15.6 years vs 22.1 ± 17.4 years; p = 0.03) and the need for surgical procedures. CONCLUSION: The occurrence of seizure-related injuries suffered throughout the lifespan and recurrent injuries in the previous year were high. Injuries were significantly associated with epilepsy variables, the perception of greater severity of seizures and risky activities. Seizure-related injuries in the previous year have compromised QoL but not in individuals who suffered injuries throughout their lifespan.

The evolution of pelvic canal shape and rotational birth in humans.

BACKGROUND: The human foetus typically needs to rotate when passing through the tight birth canal because of the complex shape of the pelvis. In most women, the upper part, or inlet, of the birth canal has a round or mediolaterally oval shape, which is considered ideal for parturition, but it is unknown why the lower part of the birth canal has a pronounced anteroposteriorly oval shape. RESULTS: Here, we show that the shape of the lower birth canal affects the ability of the pelvic floor to resist the pressure exerted by the abdominal organs and the foetus. Based on a series of finite element analyses, we found that the highest deformation, stress, and strain occur in pelvic floors with a circular or mediolaterally oval shape, whereas an anteroposterior elongation increases pelvic floor stability. CONCLUSIONS: This suggests that the anteroposterior oval outlet shape is an evolutionary adaptation for pelvic floor support. For the pelvic inlet, by contrast, it has long been assumed that the mediolateral dimension is constrained by the efficiency of upright locomotion. But we argue that the mediolateral elongation has evolved because of the limits on the anteroposterior diameter imposed by upright posture. We show that an anteroposteriorly deeper inlet would require greater pelvic tilt and lumbar lordosis, which compromises spine health and the stability of upright posture. These different requirements of the pelvic inlet and outlet likely have led to the complex shape of the pelvic canal and to the evolution of rotational birth characteristic of humans.

Correlation of the human pubic symphysis surface with age-at-death: a novel quantitative method based on a bandpass filter.

Age-at-death estimation from skeletal remains typically utilizes the roughness of pubic symphysis articular surfaces. This study presents a new quantitative method adapting a tool from geometric morphometrics, bandpass filtering of partial warp bending energy to extract only age-related changes of the surfaces. The study sample consisted of 440 surface-scanned symphyseal pubic bones from men between 14 and 82 years of age, which were landmarked with 102 fixed and surface semilandmarks. From the original sample, 371 specimens within Procrustes distance of 0.05 of the side-specific average were selected. For this subsample, age was correlated with total bending energy (calculated as summed squared partial warps amplitudes) for a wide range of plausible bandpass filters. For our subsample's 188 right-side surfaces, the correlation between age and bandpass filtered versions of bending energy peaks relatively sharply at r = -0.648 for ages up through 49 years against the first seven partial warp amplitudes only. The finding for left symphyses is similar. The results demonstrate that below the age 50, the symphyseal surface form changes most systematically related to age may be best detected by a lowpass-filtered version of bending energy: signals at the largest geometric scales of roughness rather than its full spectrum. Combining this method with information from other skeletal features could further improve age-at-death estimation based on the symphyseal pubic surface.

Toward PET/MRI as one-stop shop for radiotherapy planning in cervical cancer patients.

BACKGROUND: Radiotherapy (RT) planning for cervical cancer patients entails the acquisition of both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Further, molecular imaging by Positron Emission Tomography (PET) could contribute to target volume delineation as well as treatment response monitoring. The objective of this study was to investigate the feasibility of a PET/MRI-only RT planning workflow of patients with cervical cancer. This includes attenuation correction (AC) of MRI hardware and dedicated positioning equipment as well as evaluating MRI-derived synthetic CT (sCT) of the pelvic region for positioning verification and dose calculation to enable a PET/MRI-only setup. MATERIAL AND METHODS: 16 patients underwent PET/MRI using a dedicated RT setup after the routine CT (or PET/CT), including eight pilot patients and eight cervical cancer patients who were subsequently referred for RT. Data from 18 patients with gynecological cancer were added for training a deep convolutional neural network to generate sCT from Dixon MRI. The mean absolute difference between the dose distributions calculated on sCT and a reference CT was measured in the RT target volume and organs at risk. PET AC by sCT and a reference CT were compared in the tumor volume. RESULTS: All patients completed the examination. sCT was inferred for each patient in less than 5 s. The dosimetric analysis of the sCT-based dose planning showed a mean absolute error (MAE) of 0.17 ± 0.12 Gy inside the planning target volumes (PTV). PET images reconstructed with sCT and CT had no significant difference in quantification for all patients. CONCLUSIONS: These results suggest that multiparametric PET/MRI can be successfully integrated as a one-stop-shop in the RT workflow of patients with cervical cancer.

Does multiparametric imaging with 18F-FDG-PET/MRI capture spatial variation in immunohistochemical cancer biomarkers in head and neck squamous cell carcinoma?

BACKGROUND: The purpose of this study is to test if functional multiparametric imaging with 18F-FDG-PET/MRI correlates spatially with immunohistochemical biomarker status within a lesion of head and neck squamous cell carcinoma (HNSCC), and also whether a biopsy with the highest FDG uptake was more likely to have the highest PD-L1 expression or the highest percentage of vital tumour cells (VTC) compared with a random biopsy. METHODS: Thirty-one patients with HNSCC were scanned on an integrated PET/MRI scanner with FDG prior to surgery in this prospective study. Imaging was quantified with SUV, ADC and Ktrans. A 3D-morphometric MRI scan of the specimen was used to co-register the patient and the specimen scans. All specimens were sectioned in consecutive slices, and slices from six different locations were selected randomly from each tumour. Core biopsies were performed to construct TMA blocks for IHC staining with the ten predefined biomarkers. The spatial correlation was assessed with a partial correlation analysis. RESULTS: Twenty-eight patients with a total of 33 lesions were eligible for further analysis. There were significant correlations between the three imaging biomarkers and some of the IHC biomarkers. Moreover, a biopsy taken from the most FDG-avid part of the tumour did not have a statistically significantly higher probability of higher PD-L1 expression or VTC, compared with a random biopsy. CONCLUSION: We found statistically significant correlations between functional imaging parameters and key molecular cancer markers.

Quality of life perception in patients with epilepsy for a period of 4 years.

The quality of life (QoL) perception over time in adult people with epilepsy (PWE) is important to define strategies of conduct. OBJECTIVE: The aim of this study was to assess the minimally important change (MIC) threshold of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) of PWE over a period of 4 years and its relationship with clinical epilepsy variables. METHODS: A total of 129 PWE (46 ±â€¯14.3 years) were included, and the clinical aspects of epilepsy and the QOLIE-31 were assessed in the initial and final assessment, with p < 0.05. RESULTS: The emotional well-being (-6.31) and social functioning (-5.36) showed clinically relevant effects between the assessments. Quality of life was compromised by increasing the number of antiepileptic drugs (AED) taken [total score (-8.53), social functioning (-14.70)] or by maintaining the use of polytherapy [social functioning (-12.89)]. Fewer seizures were associated with a better QoL [total score (7.99), social (17.88) and cognitive functioning (16.30)]. The reduction in seizures was not associated with a better QoL [total and social functioning score], and the increase in seizures did not change QoL perception (cognitive functioning). There was a reduction in the QoL perception in medication effects in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) (8.92) and with an increase in age in one year (-0.44). CONCLUSIONS: Quality of life was compromised in the emotional well-being and social functioning during the 4-year follow-up period. The increase in the number of AED taken and age and the TLE-HS compromised QoL changes in the frequency of seizures not associated with a significant improvement in QoL.

Home-based parent training for school-aged children with attention-deficit/hyperactivity disorder and behavior problems with remaining impairing disruptive behaviors after routine treatment: a randomized controlled trial.

The objective is to investigate the effectiveness of home-based behavioral parent training for school-aged children with attention-deficit/hyperactivity disorder (ADHD) and behavior problems with remaining impairing disruptive behaviors after routinely offered treatments in clinical practice. In a randomized controlled study including 73 referred children with ADHD and impairing disruptive symptoms after routine clinical pharmacotherapy and/or clinic-based parent training had been tried or, at least, offered, home-based behavioral parent training (n = 26) was compared to a waiting list (n = 23) and a care-as-usual home-based treatment (n = 24). It was unknown to families which of the home-based treatments that they received. Using mixed models for repeated measures, we examined the effectiveness on the primary outcome measure of children's severity of disruptive behaviors and on a number of secondary outcome measures [the degree to which parents experienced the disruptive behaviors as troublesome, ADHD symptoms, oppositional-defiant disorder (ODD) symptoms, and internalizing problems]. Compared to the waiting list, children receiving home-based parent training improved significantly more regarding severity of disruptive behaviors (ES = 0.75), ADHD symptoms (ES = 0.89), ODD symptoms (ES = 0.65), and internalizing problems (ES = 0.60). Compared to care-as-usual, home-based parent training was more effective in reducing disruptive behaviors (ES = 0.57), ADHD symptoms (ES = 0.89), and ODD symptoms (ES = 0.88). Significantly more reduction of children's internalizing problems was not found. In conclusion, children with ADHD and residual behavioral problems after routine treatment may benefit from home-based behavioral parent training.

Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma.

Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.

Breast cancer plus adjuvant chemotherapy- related cognitive impairment: a case study.

Breast cancer-related cognitive impairment (CRCI), a frequent concomitant of cancer diagnosis and management, has been difficult to measure objectively. This study longitudinally investigated cognitive function in an individual before and after breast cancer diagnosis and treatment. Comparison of test scores pre- and post- diagnosis/treatment revealed declines in multiple cognitive domains, including Performance IQ, processing speed, immediate auditory and visual memory, and delayed visual memory. Twelve years later, improvements were noted in domains of processing speed, memory and executive functioning. The results highlight the importance of heeding individuals' subjective reports of cognitive decline, and offer hope that such decrements may not be permanent.

Humans as inverted bats: A comparative approach to the obstetric conundrum.

OBJECTIVES: The narrow human birth canal evolved in response to multiple opposing selective forces on the pelvis. These factors cannot be sufficiently disentangled in humans because of the limited range of relevant variation. Here, we outline a comparative strategy to study the evolution of human childbirth and to test existing hypotheses in primates and other mammals. METHODS: We combined a literature review with comparative analyses of neonatal and female body and brain mass, using three existing datasets. We also present images of bony pelves of a diverse sample of taxa. RESULTS: Bats, certain non-human primates, seals, and most ungulates, including whales, have much larger relative neonatal masses than humans, and they all differ in their anatomical adaptations for childbirth. Bats, as a group, are particularly interesting in this context as they give birth to the relatively largest neonates, and their pelvis is highly dimorphic: Whereas males have a fused symphysis, a ligament bridges a large pubic gap in females. The resulting strong demands on the widened and vulnerable pelvic floor likely are relaxed by roosting head-down. CONCLUSIONS: Parturition has constituted a strong selective force in many non-human placentals. We illustrated how the demands on pelvic morphology resulting from locomotion, pelvic floor stability, childbirth, and perhaps also erectile function in males have been traded off differently in mammals, depending on their locomotion and environment. Exploiting the power of a comparative approach, we present new hypotheses and research directions for resolving the obstetric conundrum in humans.

Cliff-edge model of obstetric selection in humans.

The strikingly high incidence of obstructed labor due to the disproportion of fetal size and the mother's pelvic dimensions has puzzled evolutionary scientists for decades. Here we propose that these high rates are a direct consequence of the distinct characteristics of human obstetric selection. Neonatal size relative to the birth-relevant maternal dimensions is highly variable and positively associated with reproductive success until it reaches a critical value, beyond which natural delivery becomes impossible. As a consequence, the symmetric phenotype distribution cannot match the highly asymmetric, cliff-edged fitness distribution well: The optimal phenotype distribution that maximizes population mean fitness entails a fraction of individuals falling beyond the "fitness edge" (i.e., those with fetopelvic disproportion). Using a simple mathematical model, we show that weak directional selection for a large neonate, a narrow pelvic canal, or both is sufficient to account for the considerable incidence of fetopelvic disproportion. Based on this model, we predict that the regular use of Caesarean sections throughout the last decades has led to an evolutionary increase of fetopelvic disproportion rates by 10 to 20%.

Covariation between human pelvis shape, stature, and head size alleviates the obstetric dilemma.

Compared with other primates, childbirth is remarkably difficult in humans because the head of a human neonate is large relative to the birth-relevant dimensions of the maternal pelvis. It seems puzzling that females have not evolved wider pelvises despite the high maternal mortality and morbidity risk connected to childbirth. Despite this seeming lack of change in average pelvic morphology, we show that humans have evolved a complex link between pelvis shape, stature, and head circumference that was not recognized before. The identified covariance patterns contribute to ameliorate the "obstetric dilemma." Females with a large head, who are likely to give birth to neonates with a large head, possess birth canals that are shaped to better accommodate large-headed neonates. Short females with an increased risk of cephalopelvic mismatch possess a rounder inlet, which is beneficial for obstetrics. We suggest that these covariances have evolved by the strong correlational selection resulting from childbirth. Although males are not subject to obstetric selection, they also show part of these association patterns, indicating a genetic-developmental origin of integration.

Immunohistochemical and molecular imaging biomarker signature for the prediction of failure site after chemoradiation for head and neck squamous cell carcinoma.

OBJECTIVE: To identify a failure site-specific prognostic model by combining immunohistochemistry (IHC) and molecular imaging information to predict long-term failure type in squamous cell carcinoma of the head and neck. PATIENT AND METHODS: Tissue microarray blocks of 196 head and neck squamous cell carcinoma cases were stained for a panel of biomarkers using IHC. Gross tumor volume (GTV) from the PET/CT radiation treatment planning CT scan, maximal Standard Uptake Value (SUVmax) of fludeoxyglucose (FDG) and clinical information were included in the model building using Cox proportional hazards models, stratified for p16 status in oropharyngeal carcinomas. Separate models were built for time to locoregional failure and time to distant metastasis. RESULTS: Higher than median p53 expression on IHC tended toward a risk factor for locoregional failure but was protective for distant metastasis, χ2 for difference p = .003. The final model for locoregional failure included p53 (HR: 1.9; p: .055), concomitant cisplatin (HR: 0.41; p: .008), ß-tubulin-1 (HR: 1.8; p: .08), ß-tubulin-2 (HR: 0.49; p: .057) and SUVmax (HR: 2.1; p: .046). The final model for distant metastasis included p53 (HR: 0.23; p: .025), Bcl-2 (HR: 2.6; p: .08), SUVmax (HR: 3.5; p: .095) and GTV (HR: 1.7; p: .063). CONCLUSIONS: The models successfully distinguished between risk of locoregional failure and risk of distant metastasis, which is important information for clinical decision-making. High p53 expression has opposite prognostic effects for the two endpoints; increasing risk of locoregional failure, but decreasing the risk of metastatic failure, but external validation of this finding is needed.

Sarcopenic obesity: molecular clues to a better understanding of its pathogenesis?

An age-dependent decline in skeletal muscle mass, strength, and endurance during the aging process is a physiological development, but several factors may exacerbate this process, leading to the threatening state of sarcopenia, frailty, and eventually higher mortality rates. Obesity appears to be such a promoting factor and has been linked in several studies to sarcopenia. The reason for this causal association remains poorly understood. Notwithstanding the fact that a higher body mass might simply lead to diminished physical activity and therefore contribute to a decline in skeletal muscle, several molecular mechanisms have been hypothesized. There could be an obesity derived intracellular lipotoxicity (i.e., elevated intramuscular levels of lipids and their derivatives), which induces apoptosis by means of an elevated oxidative stress. Paracrine mechanisms and inflammatory cytokines, such as CRP and IL-6 could be confounders of the actual underlying pathological mechanism. Due to a cross-talk of the hypothalamo-pituitary axis with nutritional status, obese subjects are more in a catabolic state of metabolism, with a higher susceptibility to muscle wasting under energy restriction. Obesity induces insulin resistance in the skeletal muscle, which consequently leads to perturbed metabolism, and misrouted signaling in the muscle cells. In obesity, muscle progenitor cells could differentiate to an adipocyte-like phenotype as a result of paracrine signals from (adipo)cytokines leading to a reduced muscular renewal capacity. The present review outlines current knowledge concerning possible pathways, which might be involved in the molecular pathogenesis of sarcopenic obesity.