ABSTRACT
CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. OBJECTIVE: This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT. DESIGN, SETTING, AND PATIENTS: This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured. RESULTS: In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped. CONCLUSION: In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.
Subject(s)
Adaptor Protein Complex 2/genetics , Adaptor Protein Complex sigma Subunits/genetics , GTP-Binding Protein alpha Subunits/genetics , Hypercalcemia/congenital , Hyperparathyroidism, Primary/genetics , Receptors, Calcium-Sensing/genetics , Adult , Calcium/blood , Cross-Sectional Studies , DNA Mutational Analysis , Female , Genotype , Humans , Hypercalcemia/blood , Hypercalcemia/genetics , Hyperparathyroidism, Primary/blood , Male , Middle Aged , Mutation , Parathyroid Hormone/blood , PhenotypeABSTRACT
A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/ß-pregnane-3,20-dione or 5ß-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2'R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/ß-pregnane-3,20-dione, among which the 5ß-H-7α-benzoyloxy-11α-(2'R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 µM versus 1.2 and 10.6 µM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5ß-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 µM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Leukemia, Erythroblastic, Acute/drug therapy , Leukemia, Erythroblastic, Acute/metabolism , Progesterone/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cell Survival/drug effects , Crystallography, X-Ray , Humans , K562 Cells , Leukemia, Erythroblastic, Acute/pathology , Models, Molecular , Molecular Conformation , Progesterone/chemical synthesis , Progesterone/chemistry , Tumor Cells, CulturedABSTRACT
The aim of this cross-sectional multicenter study was to determine the prevalence of and risk factors for hypothyroidism in human immunodeficiency virus (HIV)-infected patients. Free T4, free T3, and thyroid-stimulating hormone levels were determined. Data on age, sex, weight variation, smoking status, duration of HIV infection, Centers for Disease Control and Prevention disease stage, CD4 cell count, HIV RNA load, lipodystrophy, HIV-hepatitis C virus coinfection, and antiretroviral treatment (type of drugs and total cumulative dose) were collected. The prevalence study included 350 HIV-infected patients. Sixteen percent of patients had hypothyroidism: 2.6% had overt hypothyroidism, 6.6% had subclinical hypothyroidism, and 6.8% had a low free T4 level. The prevalence of subclinical hypothyroidism was higher among HIV-infected men than among HIV-infected women. A case-control study was conducted that compared hypothyroid (n=56) and euthyroid (n=287) patients. In the multivariate analysis, receipt of stavudine and low CD4 cell count were associated with hypothyroidism. Therefore, screening may be indicated for patients, especially men, who have received stavudine or have decreased CD4 cell counts.
