GSK-3beta inhibitors reduce protein degradation in muscles from septic rats and in dexamethasone-treated myotubes.

Sepsis is associated with muscle wasting, mainly reflecting increased muscle proteolysis. Recent studies suggest that inhibition of GSK-3beta activity may counteract catabolic stimuli in skeletal muscle. We tested the hypothesis that treatment of muscles from septic rats with the GSK-3beta inhibitors LiCl and TDZD-8 would reduce sepsis-induced muscle proteolysis. Because muscle wasting during sepsis is, at least in part, mediated by glucocorticoids, we also tested the effects of GSK-3beta inhibitors on protein degradation in dexamethasone-treated cultured myotubes. Treatment of incubated extensor digitorum longus muscles with LiCl or TDZD-8 reduced basal and sepsis-induced protein breakdown rates. When cultured myotubes were treated with LiCl or one of the GSK-3beta inhibitors SB216763 or SB415286, protein degradation was reduced. Treatment of incubated muscles or cultured myotubes with LiCl, but not the other GSK-3beta inhibitors, resulted in increased phosphorylation of GSK-3beta at Ser9, consistent with inactivation of the kinase and suggesting that the other inhibitors used in the present experiments inhibit GSK-3beta by phosphorylation-independent mechanisms. The present results suggest that GSK-3beta inhibitors may be used to prevent or treat sepsis-induced, glucocorticoid-regulated muscle proteolysis.

Preoperative evaluation of thyroid nodules with 18FDG-PET/CT.

BACKGROUND: Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)FDG-PET/CT) has become an important tool in the postoperative management of de-differentiated thyroid cancer. The utility of this imaging modality in the preoperative assessment of thyroid nodules is unclear. This study was designed to determine whether (18)FDG-PET/CT improves the preoperative diagnosis of thyroid nodules. METHODS: A total of 31 patients with 48 lesions underwent fine-needle aspiration and (18)FDG-PET/CT before surgical resection of thyroid nodules. PET/CT images were obtained 1 hour after intravenous administration of (18)FDG. Standard uptake values were calculated for regions of increased (18)FDG uptake. CT scans were evaluated to identify thyroid pathology. Final pathologic diagnoses were compared with PET/CT findings. RESULTS: Fifteen of 48 lesions were malignant and 33 were benign. Nine of 15 malignant lesions were (18)FDG-avid (sensitivity 60%). Thirty of 33 benign lesions were (18)FDG-cold (specificity 91%). Positive and negative predictive values were 75% and 83%, respectively. CONCLUSIONS: (18)FDG-PET/CT provides a high negative predictive value for malignancy, making this a potentially useful tool in the evaluation of thyroid nodules with indeterminate fine-needle aspiration. However further studies with larger sample sizes are needed to determine the true efficacy of this test.

Angiogenesis in benign and malignant thyroid disease.

CONTEXT: Angiogenesis has been recognized as an important process contributing to the pathophysiology of many benign and malignant diseases. It is not surprising, therefore, that this complex process is proving to be an important regulator of both benign and malignant disease processes in the thyroid gland. This paper will review the general principles of angiogenesis and lymphangiogenesis, as well as the importance of the balance between angiogenic stimulators and inhibitors in the normal thyroid gland. We will also review how this balance is disturbed in benign and malignant thyroid conditions. Finally, we will address the role manipulation of this process may play in the development of novel treatment strategies for diseases of the thyroid. OBJECTIVE: To review the literature concerning the role of angiogenesis in the thyroid gland. CONCLUSIONS: Angiogenesis is an important process which has been shown to be involved in the pathophysiology of benign and malignant diseases of the thyroid gland. Manipulation of this process holds great promise for the development of novel treatments for these disorders. As the mechanisms regulating angiogenesis in the thyroid become increasingly clear, researchers will come ever closer to turning this promise into clinical reality.

The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from the electronic medical record.

BACKGROUND: The electronic medical record (EMR) of a large, tertiary referral center was examined to study the prevalence of undiagnosed and unrecognized primary hyperparathyroidism (PHPT). METHODS: The EMR was queried for outpatient serum calcium >10.5 mg/dL over a 2-year period. RESULTS: Of 2.7 million patients, 54,198 (2%) had hypercalcemia (>10.5 mg/dL). In a 2-year sample of 7,269 patients, 1.3% (95 patients) had a recorded diagnosis of PHPT, and 0.3% (16 patients) had parathyroidectomy. Of the remaining patients, parathyroid hormone (PTH) values were recorded in 32% (2,337 patients). Of patients with PTH measured, 71% (1,662 patients) had PHPT (PTH > 30 pg/mL). Patients with calcium of 11.1­11.5 mg/dL were most likely to have PHPT (55%). Patients with calcium >12 mg/dL were most likely to have PTH measured (52%). Of hypercalcemic patients, 67% never had PTH obtained, 28% of whom were likely to have PHPT. It is estimated that 43% of hypercalcemic patients are likely to have PHPT. The estimated prevalence of PHPT in the general population is 0.86%. CONCLUSION: PHPT is a more common disorder than previously documented. It is crucial to evaluate even mild hypercalcemia, because 43% of these patients have PHPT. PHPT is underdiagnosed and undertreated.

The phenotype of primary hyperparathyroidism with normal parathyroid hormone levels: how low can parathyroid hormone go?

BACKGROUND: While normocalcemic hyperparathyroidism is well recognized in primary hyperparathyroidism (PHP), less is known about patients with high calcium but normal intact parathyroid hormone (iPTH). We aimed to describe this entity and designated it normohormonal primary hyperparathyroidism (NHPHP). METHODS: From a prospectively maintained database of patients undergoing bilateral parathyroid exploration for PHP, we identified and compared those with preoperative iPTH levels below (NHPHP) and above (typical PHP) normal reference peak (60 pg/mL). RESULTS: NHPHP occurred in 46 of 843 patients (5.5%) undergoing initial parathyroidectomy for PHP. All had hypercalcemia (11.1 mg/dL). Regarding preoperative iPTH, 7 patients (15%) had values <40 pg/mL, 19 (41%) had values <60 pg/mL; and 20 (44%) had intermittent values >60 pg/mL. Unlike patients with elevated iPTH, nearly all NHPHP patients had additional testing delaying the operation. Imaging correctly localized NHPHP parathyroid disease in 80%. At the time of operation, 74% of NHPHP patients had single adenomas. Intraoperatively postmobilization, using the same assay that was used preoperatively, 82% had PTH levels >60 pg/mL (mean, 279 pg/mL). During the follow-up period, iPTH levels remained lower among NHPHP patients (21 pg/mL) compared to 41 pg/mL for patients with preoperative iPTH 60 to 100 pg/mL and 56 pg/mL for patients with preoperative iPTH 100 to 200 pg/mL (P < .0001). CONCLUSION: Lower PTH set points may exist in some patients with otherwise typical PHP features. Although high normal iPTH is inappropriate for hypercalcemia and should suggest PHP, this disorder may occur with iPTH levels as low as 5 pg/mL. Awareness of the unusual phenotype of NHPHP may facilitate earlier diagnosis and surgery.