Use of a Continuous Glucose Monitoring System in High-Risk Hospitalized Noncritically Ill Patients With Diabetes After Cardiac Surgery and During Their Transition of Care From the Intensive Care Unit During COVID-19: A Pilot Study.

OBJECTIVE: Continuous glucose monitoring (CGM) has demonstrated benefits in managing inpatient diabetes. We initiated this single-arm pilot feasibility study during the COVID-19 pandemic in 11 patients with diabetes to determine the feasibility and accuracy of real-time CGM in patients who underwent cardiac surgery and whose care was being transitioned from the intensive care unit. METHODS: A Clarke error grid analysis was used to compare CGM and point-of-care measurements. The mean absolute relative difference (MARD) of the paired measurements was calculated to assess the accuracy of CGM for glucose measurements during the first 24 hours on CGM, the remaining time on CGM, and for different chronic kidney disease (CKD) strata. RESULTS: Overall MARD between point-of-care and CGM measurements was 14.80%. MARD for patients without CKD IV and V with an estimated glomerular filtration rate (eGFR) of ≥20 mL/min/1.73 m2 was 12.13%. Overall, 97% of the CGM values were within the no-risk zone of the Clarke error grid analysis. For the first 24 hours, a sensitivity analysis of the overall MARD for all patients and those with an eGFR of ≥20 mL/min/1.73 m2 was 15.42% ± 14.44% and 12.80% ± 7.85%, respectively. Beyond the first 24 hours, overall MARD for all patients and those with an eGFR of ≥20 mL/min/1.73 m2 was 14.54% ± 13.21% and 11.86% ± 7.64%, respectively. CONCLUSION: CGM has shown great promise in optimizing inpatient diabetes management in the noncritical care setting and after the transition of care from the intensive care unit with high clinical reliability and accuracy. More studies are needed to further assess CGM in patients with advanced CKD.

Differential pulsatile secretagogue control of GH secretion in healthy men.

Pulsatile growth hormone (GH) secretion putatively reflects integrated regulation by GH-releasing hormone (GHRH), somatostatin (SST), and GH-releasing peptide (GHRP). GHRH and SST secretion is itself pulsatile. However, how GHRH and SST pulses act along with GHRP to jointly determine pulsatile GH secretion is unclear. Moreover, how testosterone (T) modulates such interactions is unknown. These queries were assessed in a prospectively randomized, placebo-controlled double-blind cohort comprising 26 healthy older men randomized to testosterone (T) vs. placebo supplementation. Pulses of GHRH, SST, or saline were infused intravenously at 90-min intervals for 13 h, along with either continuous saline or ghrelin analog (GHRP-2). The train of pulses was followed by a triple stimulus (combined l-arginine, GHRH, and GHRP-2) to estimate near-maximal GH secretion over a final 3 h. Testosterone vs. placebo supplementation doubled pulsatile GH secretion during GHRH pulses combined with continuous saline (GHRH/saline) (P < 0.01). Pulsatile GH secretion correlated positively with T concentrations (270-1,170 ng/dl) in the 26 men during saline pulses/saline (P = 0.015, R(2) = 0.24), GHRH pulses/saline (P = 0.020, R(2) = 0.22), and combined GHRH pulses/GHRP-2 (P = 0.016, R(2) = 0.25) infusions. Basal nonpulsatile GH secretion correlated with T during saline pulses/GHRP-2 drive (P = 0.020, R(2) = 0.16). By regression analysis, pulsatile GH secretion varied negatively with body mass index (BMI) during saline/GHRP-2 infusion (P = 0.001, R(2) = 0.36), as well as after the triple stimulus preceded by GHRH/GHRP-2 (P = 0.013, R(2) = 0.23). Mean (10-h) GH concentrations under GHRP-2 were predicted jointly by estradiol (positively) and BMI (negatively) (P < 0.001, R(2) = 0.520). These data indicate that estradiol, T, and BMI control pulsatile secretagogue-specific GH-regulatory mechanisms in older men.

Manifestations of thyroid disease post COVID-19 illness: Report of Hashimoto thyroiditis, Graves' disease, and subacute thyroiditis.

OBJECTIVE: We present three cases of thyroid dysfunction such as Hashimoto thyroiditis, Graves' disease and subacute thyroiditis which developed few weeks after resolution of acute phase of COVID -19 infection in patients with no prior thyroid disease. METHODS: We discuss clinical presentation, diagnostic evaluation and subsequent management and follow-up in three patients. RESULTS: All three patients tested positive for COVID-19 infection prior to diagnosis. Patient 1. A 38-year-old female developed hypothyroidism 6 weeks after COVID-19 infection, confirmed by TSH 136 mIU/L (range 0.34-5.6), free T4 level 0.2 ng/dL (range 0.93-1.7). Patient 2. A 33-year-old female developed Graves' disease 8 weeks after COVID-19 infection, with a TSH <0.01 mIU/L (range 0.4-4.5), Free T4 2.1 ng/dl (range 0.8-1.8), total T3 216 ng/dl (range 76-181), elevated TSI 309 (normal <140). A 24-h thyroid uptake was calculated at 47.1% (normal values between 8% and 35). Patient responded favorably to methimazole 10 mg in few weeks. Patient 3. A 41-year old healthy female developed thyroiditis at 6 weeks after COVID-19 infection, with a TSH 0.01 mIU/L and free T4 1.9 ng/dL accompanied by low 24-h thyroid uptake, calculated at 0.09%. Three weeks later, she developed hypothyroidism, with a TSH 67.04 mIU/L and free T4 0.4 ng/dl. CONCLUSION: The temporal relationship between COVID-19 infection in the patients described here raises the question of possible effects of COVID-19 on the immune system and the thyroid gland.

The incremental benefit of functional imaging in pheochromocytoma/paraganglioma: a systematic review.

Computed tomography (CT) and magnetic resonance imaging (MRI) are the major imaging modalities used for the localization of catecholamine-producing tumors (pheochromocytoma and paraganglioma). Functional imaging (FI) offers an alternative approach to localize, evaluate, and stage these tumors. Our objective was to describe the additive benefit of FI studies for patients with pheochromocytoma and paraganglioma (PPG) who have undergone MRI or CT scan evaluation. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from database inception through June 2012 for studies that included patients with biochemically proven PPGs who underwent CT or MRI and additional FI for the localization of PPGs. We included 32 studies enrolling a total of 1,264 patients with a mean age of 43-years old. The studies were uncontrolled and evaluated six FI modalities. FI tests provided small additive value to CT/MRI, aiding in the localization of only 24/1,445 primary cases (1.4 %) and 28/805 metastatic cases (3.5 %). In metastatic cases, 6-[F-18]fluoro-L-dihydroxyphenylalanine (DOPA) and fluorodopamine-PET (FDA) were the FI tests most successful at identifying disease missed by CT/MRI, providing additional benefit in 6/60 (10 %) and 5/78 (6.4 %) cases, respectively. No clinically significant findings were observed in any of the predefined subgroups. No study evaluated the impact of FI on the completeness of surgical resection or other patient-important outcomes. Observational evidence suggests that FI tests have a limited additional role in patients with PPGs who have undergone CT/MRI evaluation. However, the role of FI tests in specific subgroups of patients with atypical presentations (metastatic, extra-adrenal) as well as the use of hybrid FI tests should be explored. Further research should also evaluate the impact of FI tests on patient-important outcomes.

Estradiol regulates GH-releasing peptide's interactions with GH-releasing hormone and somatostatin in postmenopausal women.

OBJECTIVE: Estrogen stimulates pulsatile secretion of GH, via mechanisms that are largely unknown. An untested hypothesis is that estradiol (E2) drives GH secretion by amplifying interactions among GH-releasing hormone (GHRH), somatostatin (SS), and GH-releasing peptide (GHRP). DESIGN: The design comprised double-blind randomized prospective administration of transdermal E2 vs placebo to healthy postmenopausal women (n=24) followed by pulsatile GHRH or SS infusions for 13 h overnight with or without continuous GHRP2 stimulation. METHODS: End points were mean concentrations, deconvolved secretion, and approximate entropy (ApEn; a regularity measure) of GH. RESULTS: By generalized ANOVA models, it was observed that E2 vs placebo supplementation: i) augmented mean (13-h) GH concentrations (P=0.023), GHRH-induced pulsatile GH secretion over the first 3 h (P=0.0085) and pulsatile GH secretion over the next 10 h (P=0.054); ii) increased GHRP-modulated (P=0.022) and SS-modulated (P<0.001) GH ApEn; and iii) did not amplify GHRH/GHRP synergy during pulsatile GH secretion. By linear regression, E2 concentrations were found to be positively correlated with GH secretion during GHRP2 infusion (P=0.022), whereas BMI was found to be negatively correlated with GH secretion during GHRH (P=0.006) and combined GHRH/GHRP (P=0.015) stimulation. E2 and BMI jointly determined triple (combined l-arginine, GHRH, and GHRP2) stimulation of GH secretion after saline (R²=0.44 and P=0.003) and pulsatile GHRH (R²=0.39 and P=0.013) infusions. CONCLUSION: In summary, in postmenopausal women, E2 supplementation augments the amount (mass) and alters the pattern (regularity) of GH secretion via interactions among GHRH, SS, GHRP, and BMI. These outcomes introduce a more complex model of E2 supplementation in coordinating GH secretion in aging women.

Short-term estradiol supplementation potentiates low-dose ghrelin action in the presence of GHRH or somatostatin in older women.

CONTEXT: Ghrelin is a potent gastric-derived GH-releasing peptide. How ghrelin interacts with sex steroids, GHRH, and somatostatin (SS) is not known. OBJECTIVE: Our objective was to test the hypotheses that ghrelin's interactions with GHRH (synergistic) and SS (disinhibitory) are ghrelin dose-dependent and amplified by estrogen. SUBJECTS, SETTING, AND DESIGN: Healthy postmenopausal women were treated with placebo (n=12) or 17ß-estradiol (E2) (n=12) at the Center for Translational Science Activities in a randomized double-blind prospective study. METHODS: Ghrelin dose-dependence was assessed by nonlinear curve fitting of the relationship between deconvolved GH secretory-burst mass and 5 randomly ordered ghrelin doses (0, 0.03, 0.135, 0.6, and 2.7 µg/kg bolus iv) during saline, GHRH, and SS infusion. RESULTS: Under placebo, neither GHRH nor SS altered the ED50 of ghrelin (range 0.64-0.67 µg/kg). Under E2 (median E2 88 pg/mL), the ED50 of ghrelin declined in the presence of GHRH to 0.52 µg/kg. In contrast, the efficacy of ghrelin rose markedly during GHRH vs saline exposure with and without E2: placebo and saline 52±1.0 vs GHRH 173±3.8 µg/L; and E2 and saline 56±0.90 vs GHRH 174±3.7 µg/L. Sensitivity to ghrelin was similar under all conditions. SUMMARY: Short-term E2 supplementation in postmenopausal women reduces the ED50 (increases the potency) of ghrelin when GHRH is present, without altering ghrelin efficacy (maximal effect) or hypothalamo-pituitary sensitivity (slope of dose response) to ghrelin. The data suggest possible physiological interactions among sex steroids (endogenous), ghrelin, and GHRH during E2 replacement in postmenopausal women.

Sex steroids, GHRH, somatostatin, IGF-I, and IGFBP-1 modulate ghrelin's dose-dependent drive of pulsatile GH secretion in healthy older men.

CONTEXT: Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined. OBJECTIVE: The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin's action. DESIGN/PARTICIPANTS/SETTING: Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center. INTERVENTIONS: To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant i.v. infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus i.v. doses of ghrelin (0.03, 0.135, 0.60, and 2.7 µg/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression. OUTCOME MEASURES/RESULTS: The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions. CONCLUSIONS: These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-I on ghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.

Measurement of calcium dissociation rates from troponin C in rigor skeletal myofibrils.

Ca2+ dissociation from the regulatory domain of troponin C may influence the rate of striated muscle relaxation. However, Ca(2+) dissociation from troponin C has not been measured within the geometric and stoichiometric constraints of the muscle fiber. Here we report the rates of Ca(2+) dissociation from the N-terminal regulatory and C-terminal structural domains of fluorescent troponin C constructs reconstituted into rabbit rigor psoas myofibrils using stopped-flow technology. Chicken skeletal troponin C fluorescently labeled at Cys 101, troponin C(IAEDANS), reported Ca(2+) dissociation exclusively from the structural domain of troponin C at ∼0.37, 0.06, and 0.07/s in isolation, in the presence of troponin I and in myofibrils at 15°C, respectively. Ca(2+) dissociation from the regulatory domain was observed utilizing fluorescently labeled troponin C containing the T54C and C101S mutations. Troponin [Formula: see text] reported Ca(2+) dissociation exclusively from the regulatory domain of troponin C at >1000, 8.8, and 15/s in isolation, in the presence of troponin I and in myofibrils at 15°C, respectively. Interestingly, troponin [Formula: see text] reported a biphasic fluorescence change upon Ca(2+) dissociation from the N- and C-terminal domains of troponin C with rates that were similar to those reported by troponin [Formula: see text] and troponin C(IAEDANS) at all levels of the troponin C systems. Furthermore, the rate of Ca(2+) dissociation from troponin C in the myofibrils was similar to the rate of Ca(2+) dissociation measured from the troponin C-troponin I complexes. Since the rate of Ca(2+) dissociation from the regulatory domain of TnC in myofibrils is similar to the rate of skeletal muscle relaxation, Ca(2+) dissociation from troponin C may influence relaxation.

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities.

We investigated whether changing thin filament Ca(2+) sensitivity alters the rate of contraction, either during normal cross-bridge cycling or when cross-bridge cycling is increased by inorganic phosphate (P(i)). We increased or decreased Ca(2+) sensitivity of force production by incorporating into rat skinned cardiac trabeculae the troponin C (TnC) mutants V44QTnC(F27W) and F20QTnC(F27W). The rate of isometric contraction was assessed as the rate of force redevelopment (k(tr)) after a rapid release and restretch to the original length of the muscle. Both in the absence of added P(i) and in the presence of 2.5 mM added P(i) 1) Ca(2+) sensitivity of k(tr) was increased by V44QTnC(F27W) and decreased by F20QTnC(F27W) compared with control TnC(F27W); 2) k(tr) at submaximal Ca(2+) activation was significantly faster for V44QTnC(F27W) and slower for F20QTnC(F27W) compared with control TnC(F27W); 3) at maximum Ca(2+) activation, k(tr) values were similar for control TnC(F27W), V44QTnC(F27W), and F20QTnC(F27W); and 4) k(tr) exhibited a linear dependence on force that was indistinguishable for all TnCs. In the presence of 2.5 mM P(i), k(tr) was faster at all pCa values compared with the values for no added P(i) for TnC(F27W), V44QTnC(F27W), and F20QTnC(F27W). This study suggests that TnC Ca(2+) binding properties modulate the rate of cardiac muscle contraction at submaximal levels of Ca(2+) activation. This result has physiological relevance considering that, on a beat-to-beat basis, the heart contracts at submaximal Ca(2+) activation.

Effects of thin and thick filament proteins on calcium binding and exchange with cardiac troponin C.

Understanding the effects of thin and thick filament proteins on the kinetics of Ca(2+) exchange with cardiac troponin C is essential to elucidating the Ca(2+)-dependent mechanisms controlling cardiac muscle contraction and relaxation. Unlike labeling of the endogenous Cys-84, labeling of cardiac troponin C at a novel engineered Cys-53 with 2-(4'-iodoacetamidoanilo)napthalene-6-sulfonic acid allowed us to accurately measure the rate of calcium dissociation from the regulatory domain of troponin C upon incorporation into the troponin complex. Neither tropomyosin nor actin alone affected the Ca(2+) binding properties of the troponin complex. However, addition of actin-tropomyosin to the troponin complex decreased the Ca(2+) sensitivity ( approximately 7.4-fold) and accelerated the rate of Ca(2+) dissociation from the regulatory domain of troponin C ( approximately 2.5-fold). Subsequent addition of myosin S1 to the reconstituted thin filaments (actin-tropomyosin-troponin) increased the Ca(2+) sensitivity ( approximately 6.2-fold) and decreased the rate of Ca(2+) dissociation from the regulatory domain of troponin C ( approximately 8.1-fold), which was completely reversed by ATP. Consistent with physiological data, replacement of cardiac troponin I with slow skeletal troponin I led to higher Ca(2+) sensitivities and slower Ca(2+) dissociation rates from troponin C in all the systems studied. Thus, both thin and thick filament proteins influence the ability of cardiac troponin C to sense and respond to Ca(2+). These results imply that both cross-bridge kinetics and Ca(2+) dissociation from troponin C work together to modulate the rate of cardiac muscle relaxation.