Preoperative Calcium and Parathyroid Hormone Values Are Poor Predictors of Gland Volume and Multigland Disease in Primary Hyperparathyroidism: A Review of 2000 Consecutive Patients.

OBJECTIVE: Calcium and parathyroid hormone (PTH) values are believed to have a linear relationship in patients with primary hyperparathyroidism and correlate with parathyroid gland size, with higher values predicting single-gland disease. In this modern series, these preoperative values were correlated with operative findings to determine their utility in predicting the gland involvement at parathyroid exploration. METHODS: Two thousand consecutive patients who underwent initial surgery for sporadic primary hyperparathyroidism from 2000 to 2014 were reviewed. All patients underwent a 4-gland exploration. Relationships between preoperative calcium and PTH values with the total gland volume of each patient were examined and stratified using the number of involved glands: single adenoma (SA), double adenoma (DA), and hyperplasia (H). RESULTS: There were 1274 (64%) SA, 359 (18%) DA, and 367 (18%) H cases. There was a poor correlation between preoperative calcium and PTH values (R = 0.37) and both poorly correlated with the total gland volume (R < 0.40). Similarly, subgroup analysis using the number of involved glands showed poor correlation. The mean total gland volume was similar among all subgroups (SA = 1.28 cm3, DA = 1.43 cm3, and H = 1.27 cm3; P = .52), implying that individual glands were smaller in multigland disease. SA was found in 271 (53%) of patients with calcium levels of ≤10.5 mg/dL and 122 (78%) with levels of ≥12 mg/dL (P < .001). CONCLUSION: This is the largest series correlating preoperative calcium and PTH values with operative findings of gland size and number of diseased glands. Although a lower calcium value predicts somewhat more multigland disease, the overall poor correlation should make the parathyroid surgeon aware that gland size and multigland disease cannot be predicted by preoperative laboratory testing.

Targeted FGFR/VEGFR/PDGFR inhibition with dovitinib enhances the effects of nab-paclitaxel in preclinical gastric cancer models.

Standard chemotherapy regimens for gastric adenocarcinoma (GAC) have limited efficacy and considerable toxicity profiles. Nab-paclitaxel has shown promising antitumor benefits in previous GAC preclinical studies. Dovitinib inhibits members of the receptor tyrosine kinase family including FGFR, VEGFR and PDGFR, and has exhibited antitumor effects in many solid tumors including GAC. Based on the antimitotic, antistromal and EPR effects of nab-paclitaxel, we investigated augmentation of nab-paclitaxel response by dovitinib in multiple GAC preclinical models. In MKN-45 subcutaneous xenografts, inhibition in tumor growth by nab-paclitaxel and dovitinib was 75% and 76%, respectively. Dovitinib plus nab-paclitaxel had an additive effect on tumor growth inhibition and resulted in tumor regression (85% of its original value). Dovitinib monotherapy resulted in minimal improvement in animal survival (25 days) compared to control (23 days), while nab-paclitaxel monotherapy or dovitinib plus nab-paclitaxel combination therapy led to a clinically significant lifespan extension of 83% (42 days) and 187% (66 days), respectively. IHC analysis of subcutaneous tumors exhibited reduced tumor cell proliferation and tumor vasculature by dovitinib. In vitro studies demonstrated that dovitinib and nab-paclitaxel individually reduced tumor cell proliferation, with an additive effect from combination therapy. Immunoblot analyses of MKN-45 and KATO-III cells revealed that dovitinib decreased phospho-FGFR, phospho-AKT, phospho-ERK, phospho-p70S6K, phospho-4EBP1, Bcl-2 and increased cleaved PARP-1, cleaved-caspase-3, p27, Bax, Bim, with an additive effect from combination therapy. These results demonstrate that the FGFR/VEGFR/PDGFR inhibitor, dovitinib, has the potential to augment the antitumor effects of nab-paclitaxel, with implications for use in the advancement of clinical GAC therapy.

Selective parathyroid venous sampling in reoperative parathyroid surgery: A key localization tool when noninvasive tests are unrevealing.

BACKGROUND: Preoperative localization studies are essential for parathyroid re-exploration. When noninvasive studies do not regionalize the abnormal parathyroid gland, selective parathyroid venous sampling may be employed. We studied the utility of parathyroid venous sampling in reoperative parathyroid surgery and the factors that may affect parathyroid venous sampling results. METHODS: Patients with hyperparathyroidism and previous cervical surgery undergoing evaluation for reoperative parathyroidectomy over a 20-year period were identified. Patients with indeterminate or negative noninvasive studies underwent parathyroid venous sampling. Parathyroid hormone values were mapped with a ≥2-fold increase above peripheral signifying positive parathyroid venous sampling. These results were correlated with reoperative findings. RESULTS: Parathyroid venous sampling was positive in 113 of 140 (81%). Re-exploration occurred in 75 (66%). Parathyroid venous sampling correctly detected the region of abnormal glands in 58 (77%). With 1 gradient, 1 abnormal gland was found in 81%. With multiple gradients, 1 abnormal gland was found in 78%, most often at the site with the largest gradient. Eighty percent of patients who underwent reoperative parathyroidectomy were biochemically cured. CONCLUSION: Parathyroid venous sampling can guide parathyroid re-exploration when noninvasive localizing studies are indeterminate. Expectation of 1 versus multiple remaining glands was key in interpreting the results.

APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1.

Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A to A3H These genes have either one or two cytidine deaminase domains, and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a "super restriction factor" that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein resulted in an even greater increase in the antiviral activity-recapitulating a similar evolution seen in A3F and A3G (double domain A3s that use only a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity but instead inhibit formation of reverse transcription products, which correlates with their ability to form large higher-order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein Vif.IMPORTANCE As a part of the innate immune system, humans encode proteins that inhibit viruses such as HIV-1. These broadly acting antiviral proteins do not protect humans from viral infections because viruses encode proteins that antagonize the host antiviral proteins to evade the innate immune system. One such example of a host antiviral protein is APOBEC3C (A3C), which weakly inhibits HIV-1. Here, we show that we can improve the antiviral activity of A3C by duplicating the DNA sequence to create a synthetic tandem domain and, furthermore, that the proteins thus generated are relatively resistant to the viral antagonist Vif. Together, these data give insights about how nature has evolved a defense against viral pathogens such as HIV.

Review of 2017 Diabetes Standards of Care.

Diabetes is a complex medical condition that requires evidence-based care. This article discusses the current diabetes screening, diagnostic criteria, and treatment recommendations for patients with type 1 diabetes, type 2 diabetes, gestational diabetes, and prediabetes.

The effectiveness of a novel neuromuscular electrostimulation method versus intermittent pneumatic compression in enhancing lower limb blood flow.

OBJECTIVE: This study compares the effectiveness of a neuromuscular electrostimulation device (geko T-1; Firstkind Ltd, High Wycombe, UK) in enhancing lower limb blood perfusion with two leading intermittent pneumatic compression (IPC) devices, the Huntleigh Flowtron Universal (Huntleigh Healthcare Ltd, Cardiff, UK) and the Kendall SCD Express (Covidien plc, Dublin, Ireland). The subjects' tolerance of the devices was also compared. METHODS: Ten healthy subjects were recruited. The devices were fitted bilaterally, in a sequential manner, for 30 minutes. Ultrasound and laser Doppler fluxmetry assessments were performed. RESULTS: The geko T-1 device was superior to both IPC devices in increasing both venous and arterial blood volume flow by ∼30% (95% confidence interval [CI], 23.7%-82.4%; P ≤ .001). The geko T-1 increased arterial blood velocity by 24% (95% CI, 9.7%-24.5%; P ≤ .001). A substantial increase in the total microcirculatory blood velocity by ∼370% (95% CI, 13.5%-39.7%) was reported after the use of the geko T-1 (P ≤ .001). With use of the visual analog scale, no significant differences in discomfort were found between the geko T-1 device and the IPC devices (P >.05). CONCLUSIONS: The geko T-1 device is more effective than the IPC devices in increasing venous, arterial, and microcirculatory blood velocity. The devices studied were safe and well tolerated by healthy subjects.

End-of-life care: legal and ethical considerations.

OBJECTIVE: To prepare the oncology nurse, under the Patient Self-Determination Act, to analyze and discuss legal and ethical issues that may arise in the clinical area when end-of-life decisions are made. DATA SOURCES: Nursing textbooks, scholarly articles, court cases, and internet publications. CONCLUSIONS: The dying patient has the right to die with dignity, respect, and the right treatment choices. IMPLICATIONS FOR NURSING PRACTICE: Nurses need to understand how to implement the Patient Self-Determination Act regarding living wills, do not resuscitate orders, euthanasia, and whether or not to use feeding tubes.