Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.	After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.
2.	The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).
3.	The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 
4.	This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 
5.	Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 
6.	Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.
7.	Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 
8.	Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. 
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The gut microbiota influences skeletal muscle mass and function in mice

The functional interactions between the gut microbiota and the host are important for host physiology, homeostasis, and sustained health. We compared the skeletal muscle of germ-free mice that lacked a gut microbiota to the skeletal muscle of pathogen-free mice that had a gut microbiota. Compared to pathogen-free mouse skeletal muscle, germ-free mouse skeletal muscle showed atrophy, decreased expression of insulin-like growth factor 1, and reduced transcription of genes associated with skeletal muscle growth and mitochondrial function. Nuclear magnetic resonance spectrometry analysis of skeletal muscle, liver, and serum from germ-free mice revealed multiple changes in the amounts of amino acids, including glycine and alanine, compared to pathogen-free mice. Germ-free mice also showed reduced serum choline, the precursor of acetylcholine, the key neurotransmitter that signals between muscle and nerve at neuromuscular junctions. Reduced expression of genes encoding Rapsyn and Lrp4, two proteins important for neuromuscular junction assembly and function, was also observed in skeletal muscle from germ-free mice compared to pathogen-free mice. Transplanting the gut microbiota from pathogen-free mice into germ-free mice resulted in an increase in skeletal muscle mass, a reduction in muscle atrophy markers, improved oxidative metabolic capacity of the muscle, and elevated expression of the neuromuscular junction assembly genes Rapsyn and Lrp4 Treating germ-free mice with short-chain fatty acids (microbial metabolites) partly reversed skeletal muscle impairments. Our results suggest a role for the gut microbiota in regulating skeletal muscle mass and function in mice

In situ macrophage phenotypic transition is affected by altered cellular composition prior to acute sterile muscle injury

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Clinical and radiologic features of extraskeletal myxoid chondrosarcoma including initial presentation, local recurrence, and metastases

Background: The aim of the study was to evaluate the clinical and imaging features of extraskeletal myxoid chondrosarcoma (EMC) including initial presentation, recurrence, and metastases. Patients and methods. In this institutional review board-approved retrospective study, imaging features of 13 patients with pathologically proven EMC seen from August 1995 to December 2011 were analyzed. The group included 3 women and 10 men and the mean age was 54 years (range 29–73 years). Imaging studies were evaluated by two radiologists in consensus. Location, size, and imaging features of primary tumors were recorded as well as the presence of recurrent disease and location of metastases. Results: Among 13 patients, 3 died during the timeframe of this study. Nine patients had primary tumor in the lower extremity, and average tumor size was 9.3 cm (range 3.3–18 cm). On MRI, primary tumors were hyperintense on T2, isointense to muscle on T1, and demonstrated peripheral/septal enhancement. Three patients had local recurrence and 12 had metastatic disease, with lung involvement being the most common. Tumor density on contrast enhanced CT ranged from 8.2 to 82.9 Hounsfield unit (HU). FDG-PET/CT imaging was performed in 3 patients. One patient had no FDG avid disease and 2 patients had metastatic disease with standard uptake values (SUV) of 2.8 and 7.4. The patient with intense FDG uptake demonstrated more solid appearing tumor burden and had the shortest survival. Conclusions: EMC is a rare tumor that often occurs in the lower extremities and frequently metastasizes to the lungs. Increased tumor density and increased FDG uptake may be related to more aggressive disease

Hematopoietic islands mimicking osteoblastic metastases within the axial skeleton

Background Hyperplasia of the hematopoietic bone marrow in the appendicular skeleton is common. In contrast, focal hematopoietic islands within the axial skeleton are a rare entity and can confuse with osteoblastic metastases. This study aimed to characterize typical MRI and CT findings of hematopoietic islands in distinction from osteoblastic metastases to help both radiologists and clinicians, on the one hand, not to overdiagnose this entity and, on the other hand, to decide on a reasonable work-up. Methods We retrospectively analyzed the imaging findings of 14 hematopoietic islands of the axial skeleton in ten patients (nine females, median age = 65.5 years [range, 49–74]) who received both MRI and CT at initial diagnosis between 2006 and 2020. CT-guided biopsy was performed in five cases to confirm the diagnosis, while the other five patients received long-term MRI follow-up (median follow-up = 28 months [range, 6–96 months]). Diffusion-weighted imaging was available in three, chemical shift imaging respectively 18 F- fluorodeoxyglucose PET/CT in two, and Technetium 99 m skeletal scintigraphy in one of the patients. Results All lesions were small (mean size = 1.72 cm 2 ) and showed moderate hypointense signals on T1- and T2-weighted MRI sequences. They appeared isointense to slightly hyperintense on STIR images and slightly enhanced after gadolinium administration. To differentiate this entity from osteoblastic metastases, CT provides important additional information, as hematopoietic islands do not show sclerosis. Conclusions Hematopoietic islands within the axial skeleton can occur and mimic osteoblastic metastases. However, the combination of MRI and CT allows for making the correct diagnosis in most cases

Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.	After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.
2.	The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).
3.	The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 
4.	This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 
5.	Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 
6.	Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.
7.	Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 
8.	Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. 
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Uner Tan Syndrome: History, Clinical Evaluations, Genetics, and the\ud Dynamics of Human Quadrupedalism

Abstract: This review includes for the first time a dynamical systems analysis of human quadrupedalism in Uner Tan syndrome, which is characterized by habitual quadrupedalism, impaired intelligence, and rudimentary speech. The first family was discovered in a small village near Iskenderun, and families were later found in Adana and two other small villages near Gaziantep and Canakkale. In all the affected individuals dynamic balance was impaired during upright walking,and they habitually preferred walking on all four extremities. MRI scans showed inferior cerebellovermian hypoplasia with slightly simplified cerebral gyri in three of the families, but appeared normal in the fourth. PET scans showed a decreased glucose metabolic activity in the cerebellum, vermis and, to a lesser extent the cerebral cortex, except for one patient,\ud whose MRI scan also appeared to be normal. All four families had consanguineous marriages in their pedigrees,\ud suggesting autosomal recessive transmission. The syndrome was genetically heterogeneous. Since the initial discoveries\ud more cases have been found, and these exhibit facultative quadrupedal locomotion, and in one case, late childhood onset. It has been suggested that the human quadrupedalism may, at least, be a phenotypic example of reverse evolution. From the viewpoint of dynamic systems theory, it was concluded there may not be a single factor that predetermines human quadrupedalism in Uner Tan syndrome, but that it may involve self-organization, brain plasticity, and rewiring, from the many decentralized and local interactions among neuronal, genetic, and environmental subsystems

Regulators of central and peripheral insulin sensitivity in humans

Insulin, secreted by pancreatic β-cells, has a preeminent role in regulating metabolism in virtually all tissues. Highly conserved through evolution, intracellular insulin signaling pathways are tightly regulated, but have been recently challenged by drastic changes in our lifestyles. The following impairment in insulin response, termed insulin resistance, is an important feature of type 2 diabetes, a condition that has reached the proportions of a worldwide epidemic. It is therefore important to gain a better understanding of how insulin resistance develops, what the interplay is between different tissues, and whether pharmacologically enhancing insulin sensitivity is possible. This thesis focuses on gathering novel information about how an inherited failure in insulin signaling (Study I), brain insulin signaling (Study II), and antidiabetic medicine dapagliflozin (Study III) can alter whole-body and tissue-specific insulin sensitivity. The studies were performed by using positron emission tomography (PET) scans with a glucose analogue tracer ([18F]-FDG) together with systemic (Studies I and III) and central hyperinsulinemia (Study II) to assess changes in tissue insulin-stimulated glucose uptake (GU). The results from Study I revealed that inherited impairment in skeletal muscle insulin sensitivity resulted in insulin resistance in all key metabolic organs even before the onset of T2D, while also establishing the role of [18F]-FDG-PET in determining the phenotype associated with a rare genetic variant. In Study II, it was demonstrated that brain insulin signaling induced by intranasal insulin does not have a significant effect on GU in peripheral tissues, but results in lower brain GU under mild systemic hyperinsulinemia. While dapagliflozin did not improve insulin sensitivity either (Study III), 8 weeks of treatment reduced liver fat content, as well as subcutaneous and visceral adipose tissue mass, in overweight T2D subjects. In conclusion, these studies elucidate how a genetic variant primarily impairing skeletal muscle insulin sensitivity, central response to hyperinsulinemia, and treatment with dapagliflozin can affect tissue-specific insulin sensitivity.Haiman β-solujen erittämällä insuliinilla on merkittävä rooli aineenvaihdunnan säätelijänä lähes kaikissa kudoksissa. Solunsisäinen insuliinisignalointi on kehittynyt evoluutiossa varhain ja on tiukasti säädeltyä, eikä ole vielä onnistunut vastaamaan erittäin nopeaan muutokseen elämäntyylissämme. Tästä seuraava kudosten heikentynyt kyky reagoida insuliiniin, eli insuliiniresistenssi, voi johtaa tyypin 2 diabeteksen puhkeamiseen. Sen vuoksi on tärkeää ymmärtää paremmin miten insuliiniresistenssi syntyy, miten eri kudokset vaikuttavat siihen, ja voidaanko tilannetta parantaa lääkkeellisesti. Tämän väitöskirjan tavoitteena on tutkia miten perinnöllinen vika erityisesti lihaksen insuliinisignaloinnissa (osatyö I), keskushermoston säätely (osatyö II) ja diabeteslääke dapagliflotsiini (osatyö III) voivat vaikuttaa kudosten insuliiniherkkyyteen. Tutkimuksissa käytettiin positroniemissiotomorafia (PET) –kuvauksia yhdessä glukoosimerkkiaineen ([18F]-FDG) kanssa. Insuliiniherkkyyden mittaamiseksi kuvausten aikana tutkittaville annettiin insuliinia verenkiertoon (osatyöt I ja III) tai nenäsumutteena (osatyö II). Osatyössä I todettiin ensisijaisesti lihaksen insuliiniherkkyyttä alentavan geenivariantin aiheuttavan insuliiniresistenssiä laajasti myös muissa kudoksissa. Lisäksi tutkimuksella vahvistettiin [18F]-FDG-PET:n roolia harvinaisten geenivarianttien vaikutusten tutkimisessa. Osatyössä II todettiin, ettei nenä-sumutteena annettu insuliini saanut aikaan merkittävää muutosta muiden kudosten glukoosiaineenvaihdunnassa, mutta aivojen glukoosinotto väheni merkittävästi sumutteen jälkeen. Myöskään dapagliflotsiini ei vaikuttanut merkitsevästi kudosten insuliiniherkkyyteen (osatyö III), mutta 8 viikon hoito vähensi maksan ja vartalon rasvan määrää ylipainoisilla tyypin 2 diabetesta sairastavilla tutkittavilla. Yhdessä nämä tutkimukset tuovat uutta tietoa siitä, miten lihaksen insuliini-resistenssiä aiheuttava geenivariantti, aivojen vaste korkeaan insuliiniannokseen, sekä hoito dapagliflotsiinilla voivat vaikuttaa kudosten insuliiniherkkyytee

Stem Cell Therapy in Pediatric Neurological Disabilities

Pediatric neurological disorders represent a major part of the disabilities worldwide. In over 10 decades of research to find a cure for these disorders, medical science has not been able to repair the underlying brain injury. This chapter focuses on recent advances in the application of stem cells as a therapeutic tool for some of the common neurodevelopmental disorders (cerebral palsy, autism, intellectual disability and muscular dystrophy). The mechanism of action of stem cells in each disorder has been explained. A review of clinical data has been described giving a clear understanding of current status of stem cell therapy in these disorders. Various factors influencing the outcome of stem cell therapy such as different types of cells, different routes of administration and dosage and frequency of transplantation have also been discussed. Our experience of treating these disorders is exhibited in the form of our published data. Use of novel monitoring tools such as MRI MSK and PET‐CT scan brain to track the changes occurring at cellular level after stem cell therapy are described. We also highlight the importance of a multidisciplinary approach of combining rehabilitation with stem cell therapy

Leigh syndrome followed by parkinsonism in an adult with homozygous c.626C > T mutation in MTFMT

Objective : To report the clinical, radiologic, biochemical, and molecular characteristics in a 46-year-old participant with adult-onset Leigh syndrome (LS), followed by parkinsonism. Methods : Case description with diagnostic workup included blood and CSF analysis, skeletal muscle investigations, blue native polyacrylamide gel electrophoresis, whole exome sequencing targeting nuclear genes involved in mitochondrial transcription and translation, cerebral MRI, 123I-FP-CIT brain single-photon emission computed tomography (SPECT), and C-11 raclopride positron emission tomography (PET). Results : The participant was found to have a defect in the oxidative phosphorylation caused by a c.626C>T mutation in the gene coding for mitochondrial methionyl-tRNA formyltransferase (MTFMT), which is a pathogenic mutation affecting intramitochondrial protein translation. The proband had a normal concentration of lactate in blood and no abnormal microscopic findings in skeletal muscle. Cerebral MRI showed bilateral lesions in the striatum, mesencephalon, pons, and medial thalamus. Lactate concentration in CSF was increased. FP-CIT SPECT and C-11 raclopride PET demonstrated a defect in the dopaminergic system. Conclusions : We report on a case with adult-onset LS related to a MTFMT mutation. Two years after the onset of symptoms of LS, the proband developed a parkinson-like disease. The c.626C>T mutation is the most common pathogenic mutation found in 22 patients reported earlier in the literature with a defect in MTFMT. The age of the previously reported cases varied between 14 months and 24 years. Our report expands the phenotypical spectrum of MTFMT-related neurologic disease and provides clinical evidence for involvement of MTFMT in extrapyramidal syndromes