What is the association between the microbiome and cognition? An umbrella review protocol.

Introduction: Cognitive impairment is reported in a variety of clinical conditions including Alzheimer's disease, Parkinson's and 'long-COVID'. Interestingly, many of these clinical conditions are also associated with microbial dysbiosis. This comanifestation of cognitive and microbiome findings in seemingly unrelated maladies suggests that they could share a common mechanism and potentially presents a treatment target.

The altered TBI fecal microbiome is stable and functionally distinct.

Introduction: Patients who suffer a traumatic brain injury (TBI) often experience chronic and sometimes debilitating sequelae. Recent reports have illustrated both acute and long-term dysbiosis of the gastrointestinal microbiome with significant alterations in composition and predicted functional consequences.

Methods: Working with participants from past research, metagenomic stability of the TBI- associated fecal microbiome (FMB) was evaluated by custom qPCR array comparing a fecal sample from 2015 to one collected in 2020.

Prevalence of fatigue and cognitive impairment after traumatic brain injury.

Background: Following traumatic brain injury (TBI) some patients develop lingering comorbid symptoms of fatigue and cognitive impairment. The mild cognitive impairment self-reported by patients is often not detected with neurocognitive tests making it difficult to determine how common and severe these symptoms are in individuals with a history of TBI. This study was conducted to determine the relative prevalence of fatigue and cognitive impairment in individuals with a history of TBI.

Traumatic brain injury, abnormal growth hormone secretion, and gut dysbiosis.

The gut microbiome has been implicated in a variety of neuropathologies with recent data suggesting direct effects of the microbiome on host metabolism, hormonal regulation, and pathophysiology. Studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. However, no study to date has examined the specific role of GH on the fecal microbiome (FMB) or the changes in this relationship following a traumatic brain injury (TBI).

Is there a role for growth hormone replacement in adults to control acute and post-acute COVID-19?

The SARS-CoV-2 pandemic created a multitude of medical crossroads requiring real time adaptations of best practice covering preventative and interventional aspects of care. Among the many discoveries borne from efforts to address the myriad clinical presentations across multiple organ systems was a common impact on tissues with cells that express the ACE-2 receptor. The vast majority of acute infections began and often ended in the respiratory tract, but more recent evaluations have confirmed significant extrapulmonary manifestations including symptom clusters that extend beyond the acute phase of infection collectively referred to as "post-acute sequelae SARS-CoV-2 infection" (PASC) or more commonly as "long (-haul) COVID".

Low growth hormone secretion associated with post-acute sequelae SARS-CoV-2 infection (PASC) neurologic symptoms: A case-control pilot study.

Objective: To determine if patients that develop lingering neurologic symptoms of fatigue and "brain fog" after initial recovery from coronavirus disease 2019 (COVID-19) have persistent low growth hormone (GH) secretion as seen in other conditions with similar symptom etiology.

Design: In this case-control observational pilot study, patients reporting lingering neurologic post-acute sequelae of SARS-CoV-2 (PASC, n = 10) symptoms at least 6 months after initial infection were compared to patients that recovered from COVID-19 without lingering symptoms (non-PASC, n = 13). We compared basic blood chemistry and select metabolites, lipids, hormones, inflammatory markers, and vitamins between groups.

Impact of Adjunct Testosterone on Cancer-Related Fatigue: An Ancillary Analysis from a Controlled Randomized Trial.

Many cancer patients undergoing treatment experience cancer-related fatigue (CRF). Inflammatory markers are correlated with CRF but are not routinely targeted for treatment. We previously demonstrated in an NIH-funded placebo-controlled, double-blind, randomized clinical trial (NCT00878995, closed to follow-up) that seven weekly injections of 100 mg adjunct testosterone preserved lean body mass in cancer patients undergoing standard-of-care treatment in a hospital setting.

Cancer and Associated Therapies Impact the Skeletal Muscle Proteome.

Both cancer and cancer associated therapies (CAT; including chemotherapy or concurrent chemoradiation) disrupt cellular metabolism throughout the body, including the regulation of skeletal muscle mass and function. Adjunct testosterone therapy during standard of care chemotherapy and chemoradiation modulates CAT-induced dysregulation of skeletal muscle metabolism and protects lean body mass during CAT. However, the extent to which the skeletal muscle proteome is altered under these therapeutic conditions is unknown.

Classroom Management Strategies for Hyflex Instruction: Setting Students Up for Success in the Hybrid Environment.

The COVID-19 pandemic changed the way that schools provide instruction to learners and these changes may last for an extended period of time. One current trend is the use of hyflex instruction, which involves teachers providing instruction to students simultaneously in the classroom and online. This form of instruction provides unique challenges for teachers, including establishing expectations and managing classroom behaviors.

Exercise and Testosterone Countermeasures to Mitigate Metabolic Changes during Bed Rest.

Background/objectives: Exercise is a front-line countermeasure used to maintain astronaut health during long-duration spaceflight; however, reductions in metabolic health still occur. Accordingly, we evaluated serial changes in metabolic parameters in a spaceflight analog and evaluated the efficacy of exercise with or without the addition of low-dose testosterone treatment on mitigating adverse metabolic changes.

Subjects/methods: Healthy young (<55 years) men were randomly assigned to one of three groups during 70-days of strict, diet controlled, 6° head-down bed rest: Control (CON, n=9), exercise plus testosterone countermeasure (TEX, n=8), or exercise countermeasure plus placebo (PEX, n=9).

Altered Fecal Microbiome Years after Traumatic Brain Injury.

Patients with chronic traumatic brain injury (TBI) requiring long-term, permanent care suffer a myriad of clinical symptoms (i.e., impaired cognition, fatigue, and other conditions) that persist for years beyond the acute brain injury.

Growth Hormone Alters Brain Morphometry, Connectivity, and Behavior in Subjects with Fatigue after Mild Traumatic Brain Injury.

Pituitary dysfunction with reduced growth hormone (GH) secretion is common in patients following traumatic brain injury (TBI), and these patients often develop chronic symptoms including fatigue and altered cognition. We examined 18 subjects with a history of mild TBI, fatigue, and insufficient GH secretion. Subjects received GH replacement in a year-long, double-blind, placebo-controlled, crossover study, and were assessed for changes in physical performance, body composition, resting energy expenditure, fatigue, sleep, mood, and neuropsychological status.

Proteomic investigation of human skeletal muscle before and after 70 days of head down bed rest with or without exercise and testosterone countermeasures.

Introduction: Long-term head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-term space flight. Agents such as testosterone, in addition to regular exercise, are effective countermeasures for reducing loss of skeletal muscle mass and function.

Objective: We investigated the skeletal muscle proteome of healthy men in response to long term HDBR alone (CON) and to HDBR with exercise (PEX) or exercise plus testosterone (TEX) countermeasures.

Efficacy of Testosterone plus NASA Exercise Countermeasures during Head-Down Bed Rest.

Introduction: Prolonged confinement to head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-duration space flight. Exercise countermeasures by themselves have not completely prevented the deleterious losses in muscle mass or function in HDBR or space flight.

Purpose: The objective was to investigate the safety and efficacy of intermittent, low-dose testosterone treatment in conjunction with NASA exercise (SPRINT) countermeasures during 70 d of 6° HDBR.

A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women.

Background: Cancer cachexia negatively impacts cancer-related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment.

Methods: A randomized, double-blind, placebo-controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation.

Hypoaminoacidemia Characterizes Chronic Traumatic Brain Injury.

Individuals with a history of traumatic brain injury (TBI) are at increased risk for a number of disorders, including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. However, mediators of the long-term morbidity are uncertain. We conducted a multi-site, prospective trial in chronic TBI patients (∼18 years post-TBI) living in long-term 24-h care environments and local controls without a history of head injury.

Sildenafil increases muscle protein synthesis and reduces muscle fatigue.

Reductions in skeletal muscle function occur during the course of healthy aging as well as with bed rest or diverse diseases such as cancer, muscular dystrophy, and heart failure. However, there are no accepted pharmacologic therapies to improve impaired skeletal muscle function. Nitric oxide may influence skeletal muscle function through effects on excitation-contraction coupling, myofibrillar function, perfusion, and metabolism.

Isotopic decay of urinary or plasma 3-methylhistidine as a potential biomarker of pathologic skeletal muscle loss.

Background: Skeletal muscle loss accompanying aging or cancer is associated with reduced physical function and predicts morbidity and mortality. 3-Methylhistidine (3MH) has been proposed as a biomarker of myofibrillar proteolysis, which may contribute to skeletal muscle loss.

Methods: We hypothesized that the terminal portion of the isotope decay curve following an oral dose of isotopically labeled 3MH can be measured non-invasively from timed spot urine samples.

Cancer cachexia and anabolic interventions: a case report.

Background: Standard-of-care (SOC) cancer treatments are primarily aimed at reducing size and progression of a tumor. There is a need for successful supplemental anabolic therapies to combat cancer cachexia in addition to these SOC treatment modalities. Anabolic interventions, including testosterone and amino acid supplements, may be beneficial in reducing and/or reversing muscle wasting in these patient populations.

Muscle protein metabolism responds similarly to exogenous amino acids in healthy younger and older adults during NO-induced hyperemia.

The combination of increasing blood flow and amino acid (AA) availability provides an anabolic stimulus to the skeletal muscle of healthy young adults by optimizing both AA delivery and utilization. However, aging is associated with a blunted response to anabolic stimuli and may involve impairments in endothelial function. We investigated whether age-related differences exist in the muscle protein anabolic response to AAs between younger (30 ± 2 yr) and older (67 ± 2 yr) adults when macrovascular and microvascular leg blood flow were similarly increased with the nitric oxide (NO) donor, sodium nitroprusside (SNP).

Transmembrane helix 7 in the Na+/dicarboxylate cotransporter 1 is an outer helix that contains residues critical for function.

Citric acid cycle intermediates, including succinate and citrate, are absorbed across the apical membrane by the NaDC1 Na+/dicarboxylate cotransporter located in the kidney and small intestine. The secondary structure model of NaDC1 contains 11 transmembrane helices (TM). TM7 was shown previously to contain determinants of citrate affinity, and Arg-349 at the extracellular end of the helix is required for transport.

Inhibitor binding in the human renal low- and high-affinity Na+/glucose cotransporters.

The kidney contains two Na(+)/glucose cotransporters, called SGLT2 and SGLT1, arranged in series along the length of the proximal tubule. The low-affinity transporter, SGLT2, is responsible for the reabsorption of most of the glucose in the kidney. There is recent interest in SGLT2 as a target for the treatment of type II diabetes using selective inhibitors based on the structure of the phenylglucoside, phlorizin (phloretin-2'-beta-glucoside).

Inhibition of the Na+/dicarboxylate cotransporter by anthranilic acid derivatives.

The Na(+)/dicarboxylate cotransporter NaDC1 absorbs citric acid cycle intermediates from the lumen of the small intestine and kidney proximal tubule. No effective inhibitor has been identified yet, although previous studies showed that the nonsteroidal anti-inflammatory drug, flufenamate, inhibits the human (h) NaDC1 with an IC(50) value of 2 mM. In the present study, we have tested compounds related in structure to flufenamate, all anthranilic acid derivatives, as potential inhibitors of hNaDC1.

A novel processive mechanism for DNA synthesis revealed by structure, modeling and mutagenesis of the accessory subunit of human mitochondrial DNA polymerase.

Mitochondrial DNA polymerase (pol gamma) is the sole DNA polymerase responsible for replication and repair of animal mitochondrial DNA. Here, we address the molecular mechanism by which the human holoenzyme achieves high processivity in nucleotide polymerization. We have determined the crystal structure of human pol gamma-beta, the accessory subunit that binds with high affinity to the catalytic core, pol gamma-alpha, to stimulate its activity and enhance holoenzyme processivity.