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Following SARS‐CoV‐2 infection, some patients develop lingering neurologic symptoms of post‐acute sequelae of COVID‐19 (PASC) that commonly include fatigue and "brain fog." PASC symptoms are also linked with reduced growth hormone (GH) secretion, but GH treatment has not been tested to relieve symptoms. We enrolled 13 adults with neurologic PASC symptoms and peak stimulated GH secretion less than 10 ng/mL (glucagon stimulation) in a pilot study to receive 9 months of daily GH injections and an additional 3 months of off‐treatment assessment. We compared peak stimulated GH secretion at baseline and 12 months and assessed measures of cognition, metabolism, body composition, and physical performance over the first 6 months of treatment. Patient‐reported outcomes of fatigue, quality of life, sleep, and mood were recorded at baseline and compared with timepoints at 6, 9, and 12 months. GH treatment was associated with significantly improved scores for Brief Fatigue Inventory, Multidimensional Fatigue Symptom Inventory, Quality of Life Assessment of Growth Hormone Deficiency in Adults, Profile of Mood States, and Beck Depression Inventory‐II, with no significant change in Pittsburgh Sleep Quality Index. Six months of adjunct GH treatment was not associated with significant changes in cognition, body composition, resting energy expenditure, or physical performance. Peak stimulated GH secretion was not altered at 12 months following 9 months of GH treatment. GH treatment significantly improved neurologic symptoms in PASC patients but cognition, sleep, and physical performance were not significantly altered. [ABSTRACT FROM AUTHOR]

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. Methods: The Fatigue and Altered Cognition Scale (FACs) digital questionnaire was used to assess self-reported fatigue and cognitive impairment. Adults aged 18–70 were digitally recruited for the online anonymous study. Eligible participants provided online consent, demographic data, information about lifetime TBI history, and completed the 20 item FACs questionnaire. Results: A total of 519 qualifying participants completed the online digital study which included 204 participants with a history of TBI of varied cause and severity and 315 with no history of TBI. FACs Total Score was significantly higher in the TBI group (57.7 ± 22.2) compared to non-TBI (39.5 ± 23.9; p<0.0001) indicating more fatigue and cognitive impairment. When stratified by TBI severity, FACs score was significantly higher for all severity including mild (53.9 ± 21.9, p<0.0001), moderate (54.8 ± 24.4, p<0.0001), and severe (59.7 ± 20.9, p<0.0001) TBI. Correlation analysis indicated that more severe TBI was associated with greater symptom severity (p<0.0001, r = 0.3165). Ancillary analysis also suggested that FACs scores may be elevated in participants with prior COVID-19 infection but no history of TBI. Conclusions: Adults with a history of even mild TBI report significantly greater fatigue and cognitive impairment than those with no history of TBI, and symptoms are more profound with greater TBI severity. [ABSTRACT FROM AUTHOR]

Background. We performed a meta-analysis of randomized clinical trials to determine the risks of adverse events associated with testosterone replacement in older men. Methods. The MEDLINE database was searched from 1966 to April 2004, using testosterone as the indexing term; limits included human, male, >45 years old, and randomized controlled trial. Of the 417 studies thus identified, 19 met the inclusion criteria: testosterone replacement for at least 90 days, men [greater than or equal to] 45 years old with low or low-normal testosterone level, randomized controlled trial, and medically stable men. Odds ratios (ORs) were pooled using a random effects model, assuming heterogeneous results across studies, and were weighted for sample size. Results. In the 19 studies that met eligibility criteria, 651 men were treated with testosterone and 433 with placebo. The combined rate of all prostate events was significantly greater in testosterone-treated men than in placebo-treated men (OR 1.78, 95% confidence interval [CI], 1.07-2.95). Rates of prostate cancer, prostate-specific antigen (PSA) >4 ng/ml, and prostate biopsies were numerically higher in the testosterone group than in the placebo group, although differences between the groups were not individually statistically significant. Testosterone-treated men were nearly four times as likely to have hematocrit >50% as placebo-treated men (OR = 3.69, 95% CI, 1.82-7.51). The frequency of cardiovascular events, sleep apnea or death was not significantly different between the two groups. Conclusions. Testosterone replacement in older men was associated with a significantly higher risk of detection of prostate events and of hematocrit >50% than was placebo; hematocrit increase was the most frequent adverse event associated with testosterone replacement. These data reaffirm the need to monitor hematocrit, PSA, and digital examination of the prostate during testosterone replacement in older men.

Protein kinase C[iota] enhances the transcriptional activity of the porcine P-450 side-chain cleavage insulin-like response element. Am J Physiol Endocrinol Metab 286: E975-E979, 2004. First published January 28, 2004; 10.1152/ajpendo. 00520.2003.--IGF-I enhances steroidogenesis in granulosa cells by stimulating the expression of the rate-limiting steroidogenic enzyme, cytochrome P-450 side-chain cleavage (P-[450.sub.scc]). This effect is mediated through an IGF response element (IGFRE) that binds polypyrimidine tract-binding protein (PTB)-associated splicing factor (PSF) and Sp1. Sp1 is essential for activation of the IGFRE, and PSF functions as a repressor. We investigated mechanisms of modulation of the IGFRE by the atypical protein kinase C (PKC)[iota] in a porcine stable granulosa cell line, JC-410. PKC[iota] was found in nuclear extracts, and levels were increased by IGF-I after 24 and 48 h of treatment. Immunoprecipitation experiments demonstrated that PSF and PKC[iota] associated with each other in nuclear extracts from JC-410 cells. Transient transfection with expression plasmids of kinase-active and kinase-deficient PKC[iota] isoforms enhanced transcriptional activity of the IGFRE regardless of kinase catalytic activity. Depletion of PKC[iota] protein by small interfering RNA suppressed basal IGFRE activity but did not prevent IGF-I stimulation of the IGFRE. We conclude that PKC[iota] enhances transcriptional activity of the porcine P-[450.sub.scc]. IGFRE independently of kinase activity by a mechanism involving protein-protein interaction with PSF. protein kinase C iota; polypyrimidine tract-binding protein-associated splicing factor; insulin-like growth factor I

An insulin-like growth factor I (IGF-I) response element (IGFRE) in the porcine P-450 cholesterol side-chain cleavage gene (P450scc) binds two transcription factors, Sp1 and polypyrimidine tract-binding protein-associated splicing factor (PSF). In this study, we investigated expression of these transcription factors in mouse Y1 adrenal cells, a cell line that does not increase P450scc expression in response to IGF-I. Western blot analysis showed a greater expression of PSF in Y1 cells when compared with a mouse fibroblast cell line (NWTb3) in which IGF-I stimulates the P450scc IGFRE. The two cell lines expressed Sp1 equally, and IGF-I did not increase expression of either transcription factor. Chromatin immunoprecipitation analysis with Y1 chromatin confirmed that PSF and Sp1 bound to the IGFRE. When increasing amounts of Sp1 were expressed in Y1 cells, the IGFRE became responsive to IGF-I. Moreover, a mutant oligonucleotide IGFRE reporter construct that lacks PSF binding was responsive to IGF-I. In conclusion, Y1 adrenal cells are a physiological example of PSF repression of growth factor-stimulated (IGF-I) gene expression (P450scc). The dynamic nature of this repression is consistent with PSF functioning as a regulator of growth factor-stimulated gene expression in mammalian cells. polypyrimidine tract-binding protein-associated splicing factor; P-450 cholesterol side-chain cleavage; insulin-like growth factor I; Y1 adrenal cells; Sp1

An insulin-like growth factor (IGF) I response element (IGFRE) in the porcine P-450 cholesterol side-chain cleavage gene (P450scc) regulates transcription through the binding of two proteins, Sp1 and polypyrimidine tract-binding protein-associated splicing factor (PSF). PSF is a component of spliceosomes and contains RNA-binding domains. In this study, we localized the N[H.sub.2]-terminal amino acid residues necessary for binding of PSF to the IGFRE. Three COOH-terminal truncated proteins (aa 304, 214, and 134) of PSF were designed to empirically partition the N[H.sub.2]-terminal region while excluding the RNA-binding domains. Southwestern analysis showed that only the largest expressed truncated protein, P3, strongly bound the porcine P450scc IGFRE. Truncated PSF protein expression in Y1 adrenal cells showed that P3 repressed transcriptional activity of the IGFRE similar to full-length PSF, whereas P2 (minimal binding to the IGFRE) had no effect. In conclusion, the N[H.sub.2]-terminal region of PSF contains the amino acid residues necessary for binding to the porcine P450scc IGFRE and repressing the transcriptional activity of the element. polypyrimidine tract-binding protein; P-450 cholesterol side-chain cleavage; steroidogenesis; insulin-like growth factor-I; Sp1; transcription

We investigated the effects of 6 mo of near-physiological testosterone administration to older men on skeletal muscle function and muscle protein metabolism. Twelve older men ([greater than or equal to] 60 yr) with serum total testosterone concentrations aging; muscle strength; lean body mass; insulin-like growth factor I

Marcell, Taylor J., S. Mitchell Harman, Randall J. Urban, Daniel D. Metz, Buel D. Rodgers, and Marc R. Blackman. Comparison of GH, IGF-I, and testosterone with mRNA of receptors and myostatin in skeletal muscle in older men. Am J Physiol Endocrinoi Metab 281: E1159-E1164, 2001.--Growth hormone (GH), insulin-like growth factor I (IGF-I), and testosterone (T) are important mediators of muscle protein synthesis, and thus muscle mass, all of which decline with age. We hypothesized that circulating hormones would be related to the transcriptional levels of their respective receptors and that this expression would be negatively related to expression of the myostatin gene. We therefore determined content of mRNA transcripts (by RT-PCR) for GH receptor (GHR), IGF-I, androgen receptor (AR), and myostatin in skeletal muscle biopsy samples from 27 healthy men >65 yr of age. There were no significant relationships between age, lean body mass, or percent body fat and transcript levels of GHR, IGF-I, AR, or myostatin. Moreover, there were no significant correlations of serum GH, IGF-I, or T with their corresponding target mRNA levels (GHR, intramuscular IGF-I, or AR) in skeletal muscle. However, GHR was negatively correlated (r = -0.60, P = 0.001) with myostatin mRNA levels. The lack of apparent relationships of muscle transcripts with their respective ligands in healthy older adults suggests that age-related deficits in both GH and T may lead to an increase in myostatin expression and a dis-association in autocrine IGF-I effects on muscle protein synthesis, both of which could contribute to age-related sarcopenia. androgens; reverse transcription-polymerase chain reaction; gene expression; elderly; protein metabolism Received 8 September 2000; accepted in final form 20 July 2001