Novel mineralocorticoid receptor mechanisms regulate cardiac tissue inflammation in male mice.

MR activation in macrophages is critical for the development of cardiac inflammation and fibrosis. We previously showed that MR activation modifies macrophage pro-inflammatory signalling, changing the cardiac tissue response to injury via both direct gene transcription and JNK/AP-1 second messenger pathways. In contrast, MR-mediated renal electrolyte homeostasis is critically determined by DNA-binding-dependent processes. Hence, ascertaining the relative contribution of MR actions via DNA binding or alternative pathways on macrophage behaviour and cardiac inflammation may provide therapeutic opportunities which separate the cardioprotective effects of MR antagonists from their undesirable renal potassium-conserving effects. We developed new macrophage cell lines either lacking MR or harbouring a mutant MR incapable of DNA binding. Western blot analysis demonstrated that MR DNA binding is required for lipopolysaccharide (LPS), but not phorbol 12-myristate-13-acetate (PMA), induction of the MAPK/pJNK pathway in macrophages. Quantitative RTPCR for pro-inflammatory and pro-fibrotic targets revealed subsets of LPS- and PMA-induced genes that were either enhanced or repressed by the MR via actions that do not always require direct MR-DNA binding. Analysis of the MR target gene and profibrotic factor MMP12 identified promoter elements that are regulated by combined MR/MAPK/JNK signalling. Evaluation of cardiac tissue responses to an 8-day DOC/salt challenge in mice selectively lacking MR DNA-binding in macrophages demonstrated levels of inflammatory markers equivalent to WT, indicating non-DNA binding-dependent MR signalling in macrophages is sufficient for DOC/salt-induced tissue inflammation. Our data demonstrate that the MR regulates a macrophage pro-inflammatory phenotype and cardiac tissue inflammation, partially via pathways that do not require DNA binding.

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways.

The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling of electrolytes, and induces diverse effects on other tissues. Traditionally, the effects of MR were ascribed to ligand-receptor binding and activation of gene transcription. However, the MR also utilises a number of intracellular signalling cascades, often by transactivating unrelated receptors, to change cell function more rapidly. Although aldosterone is the physiological mineralocorticoid, it is not the sole ligand for MR. Tissue-selective and mineralocorticoid-specific effects are conferred through the enzyme 11ß-hydroxysteroid dehydrogenase 2, cellular redox status and properties of the MR itself. Furthermore, not all aldosterone effects are mediated via MR, with implication of the involvement of other membrane-bound receptors such as GPER. This review will describe the ligands, receptors and intracellular mechanisms available for mineralocorticoid hormone and receptor signalling and illustrate their complex interactions in physiology and disease.

Does the thyroid-stimulating hormone measured concurrently with first trimester biochemical screening tests predict adverse pregnancy outcomes occurring after 20 weeks gestation?

CONTEXT: Maternal hypothyroidism in early pregnancy is associated with adverse outcomes, but not consistently across studies. First trimester screening for chromosomal anomalies is routine in many centers and provides an opportunity to test thyroid function. OBJECTIVE: To determine if thyroid function tests performed with first trimester screening predicts adverse pregnancy outcomes. DESIGN, PARTICIPANTS AND SETTING: A cohort study of 2411 women in Western Australia with singleton pregnancies attending first trimester screening between 9 and 14 weeks gestation. OUTCOME MEASURES: We evaluated the association between TSH, free T4, free T3, thyroid antibodies, free beta human chorionic gonadotrophin (ß-hCG) and pregnancy associated plasma protein A (PAPP-A) with a composite of adverse pregnancy events as the primary outcome. Secondary outcomes included placenta previa, placental abruption, pre-eclampsia, pregnancy loss after 20 weeks gestation, threatened preterm labor, preterm birth, small size for gestational age, neonatal death, and birth defects. RESULTS: TSH exceeded the 97.5th percentile for the first trimester (2.15 mU/L) in 133 (5.5%) women, including 22 (1%) with TSH above the nonpregnant reference range (4 mU/L) and 5 (0.2%) above 10 mU/L. Adverse outcomes occurred in 327 women (15%). TSH and free T4 did not differ significantly between women with or without adverse pregnancy events. On the multivariate analysis, neither maternal TSH >2.15 mU/L nor TSH as a continuous variable predicted primary or secondary outcomes. CONCLUSION: Testing maternal TSH as part of first trimester screening does not predict adverse pregnancy outcomes. This may be because in the community setting, mainly mild abnormalities in thyroid function are detected.

The importance of measuring ionized calcium in characterizing calcium status and diagnosing primary hyperparathyroidism.

CONTEXT: Serum total calcium (tCa) is routinely measured for diagnosing calcium disorders but may not reflect levels of biologically active ionized calcium (iCa) in disease or detect all cases of primary hyperparathyroidism. OBJECTIVE: We investigated the utility of measuring iCa and tCa for diagnosing primary hyperparathyroidism. DESIGN: This was an observational, retrospective, cross-sectional study. PATIENTS: We studied a biochemistry cohort of consecutive ambulatory outpatients with suspected bone or calcium metabolism disorders referred for calcium metabolism biochemistry panels and a surgical cohort of consecutive tertiary hospital patients whose parathyroid specimens were submitted to a single center, and consecutive parathyroidectomy patients of a single surgeon with specimens submitted to a different center. RESULTS: In 5490 biochemistry cohort patients, discordance between iCa and tCa in classifying calcium status occurred in 12.6% of cases overall but was worse in hypercalcemic (whether defined by tCa and/or iCa) cases (49%) and hypocalcemic cases (92%). Reliance on tCa alone would miss 45% with ionized hypercalcemia. In 315 biochemistry cohort cases with PTH-dependent hypercalcemia, 130 (41%) had isolated ionized hypercalcemia at diagnosis. In 143 patients with histologically proven parathyroid disease, 24% had isolated ionized hypercalcemia at diagnosis. These patients were younger (P = 0.022) with milder ionized hypercalcemia and better renal function (both P ≤ 0.001) than patients presenting with concurrently elevated iCa and tCa. CONCLUSION: In abnormal calcium states, tCa frequently disagrees with iCa in classifying calcium status. Histologically proven parathyroid disease can present with isolated ionized hypercalcemia. Measurement of iCa is required to accurately assess calcium status and improve diagnostic accuracy.

Anaphylaxis triggered by benzyl benzoate in a preparation of depot testosterone undecanoate.

We report the first case of an anaphylactic reaction to Reandron 1000 (depot testosterone undecanoate with a castor oil and benzyl benzoate vehicle). While considered to have a favourable safety profile, serious complications such as oil embolism and anaphylaxis can occur. In our patient, skin testing identified benzyl benzoate to be the trigger, with no reaction to castor oil or testosterone undecanoate components. As benzyl benzoate exists in multiple pharmaceuticals, foods, and cosmetics, individual components of pharmaceuticals should be tested when investigating drug allergies. Doctors should be alert to the potential for serious reactions to any of the components of Reandron 1000.

Life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis.

Renal tubular acidosis is an underreported complication of ibuprofen misuse, and can result in life-threatening hypokalaemia. We describe four patients who presented with profound hypokalaemia and muscle weakness associated with excessive ibuprofen ingestion. Ibuprofen cessation and supportive management resulted in complete biochemical resolution within a few days. These cases remind practitioners about potential complications of unmonitored use of over-the-counter analgesics, including those with potential for misuse due to their codeine content.

Therapies for the medical management of persistent hypoglycaemia in two cases of inoperable malignant insulinoma.

OBJECTIVE: Hypoglycaemia poses a significant management challenge in patients with unresectable functional malignant insulinoma. Novel agents such as mammalian target of rapamycin (mTOR) inhibitors and radiolabelled peptides may be effective where there is failure of conventional therapy. DESIGN: We present the cases of two men diagnosed with inoperable malignant insulinoma and hepatic metastases who developed severe symptomatic hypoglycaemia, and review potential therapies for glycaemic support. METHOD: Despite treatment with diazoxide, frequent oral carbohydrate, prednisolone and somatostatin analogue therapy, both men required hospital admission for treatment with continuous i.v. dextrose. Both were treated with Lutetium-177 octreotate. One man was also treated with everolimus, a mTOR inhibitor. RESULT: Use of Lutetium-177 octreotate, and in one case everolimus, successfully achieved normoglycaemia, facilitating safe discharge from hospital. Both men also had regression in the size and number of hepatic metastases. CONCLUSION: Lutetium-177 octreotate and everolimus are options for managing hypoglycaemia due to unresectable malignant insulinoma when refractory to conventional supportive therapies.