Cumulative stress, PTSD, and emotion dysregulation during pregnancy and epigenetic age acceleration in Hispanic mothers and their newborn infants.

Pregnancy can exacerbate or prompt the onset of stress-related disorders, such as post-traumatic stress disorder (PTSD). PTSD is associated with heightened stress responsivity and emotional dysregulation, as well as increased risk of chronic disorders and mortality. Further, maternal PTSD is associated with gestational epigenetic age acceleration in newborns, implicating the prenatal period as a developmental time period for the transmission of effects across generations. Here, we evaluated the associations between PTSD symptoms, maternal epigenetic age acceleration, and infant gestational epigenetic age acceleration in 89 maternal-neonatal dyads. Trauma-related experiences and PTSD symptoms in mothers were assessed during the third trimester of pregnancy. The MethylationEPIC array was used to generate DNA methylation data from maternal and neonatal saliva samples collected within 24 h of infant birth. Maternal epigenetic age acceleration was calculated using Horvath's multi-tissue clock, PhenoAge and GrimAge. Gestational epigenetic age was estimated using the Haftorn clock. Maternal cumulative past-year stress (GrimAge: p = 3.23e-04, PhenoAge: p = 9.92e-03), PTSD symptoms (GrimAge: p = 0.019), and difficulties in emotion regulation (GrimAge: p = 0.028) were associated with accelerated epigenetic age in mothers. Maternal PTSD symptoms were associated with lower gestational epigenetic age acceleration in neonates (p = 0.032). Overall, our results suggest that maternal cumulative past-year stress exposure and trauma-related symptoms may increase the risk for age-related problems in mothers and developmental problems in their newborns.

Increased P450 aromatase levels in post-menopausal women after acute ischemic stroke.

BACKGROUND: Sex differences in stroke have been attributed to the neuroprotective effects of estrogen, yet most clinical trials of estrogen supplementation for stroke prevention have failed. The contribution of sex hormones to stroke outcome remains a subject of debate. Aromatization of testosterone to estradiol in neural tissue leads to sexual differentiation. Emerging data suggests aromatase activity increases in response to brain injury, and increased aromatase expression is seen in the ischemic penumbra in animal models. The objective of this study was to examine the levels of endogenous sex steroids after acute ischemic stroke and determine if levels of sex steroids were associated with acute stroke outcomes. METHODS: Peripheral blood from ischemic stroke patients and controls was collected under an approved IRB within 24 h of symptom onset. 17ß-estradiol, testosterone, and aromatase levels were measured in the serum of both men and women using ELISA. Hormone levels were compared in men vs. women in stroke and control groups and correlated with outcomes (NIHSS and change in the modified Rankin Scale (mRS), defined as the difference of premorbid and discharge mRS) using multivariate regression. RESULTS: We found no significant difference in estradiol levels 24 h after stroke in men (p = 0.86) or women (p = 0.10). In men, testosterone significantly decreased after stroke as compared with controls (1.83 ± 0.12 vs. 2.86 ± 0.65, p = 0.01). Aromatase levels were significantly increased in women after stroke as compared with controls (2.27 ± 0.22 vs. 0.97 ± 0.22, p = 0.002), but not in men (p = 0.84). Estradiol levels positively correlated with change in mRS in both women (r = 0.38, p = 0.02) and men (r = 0.3, p = 0.04). CONCLUSIONS: Estradiol levels correlated with functional outcomes (change in mRS) in both men and women, at least in the acute phase (24 h) of stroke. However, no significant difference in estradiol levels is seen 24 h post-stroke in men or women. Testosterone levels decrease at 24 h after stroke in men. As seen in animal models, aromatase levels increase after acute ischemic stroke, but this was only true for women. These indicate an active aromatization process in post-menopausal women after acute ischemic stroke.

Inner ear protein as a biomarker in circulation?

Serum biomarkers detect the earliest events in disease, monitor management, and provide insight into disease pathogenesis. At this time, there are no biomarkers available for otologic disorders. Otolin-1 is a scaffolding protein exclusively expressed in otoconia and cells of the vestibule and the cochlea; therefore, it may be a biomarker candidate for assessing the health of the inner ear. As a proof of concept, we used serum samples from controls without otologic history and subjects with a history of benign paroxysmal positional vertigo (BPPV), performed enzyme-linked immunosorbent assay for otolin-1, and measured the optical density of the substrate. Otolin-1 was detectable and quantifiable in all subjects, indicating that this inner ear protein crosses the blood-labyrinthine barrier. Furthermore, subjects with BPPV had significantly higher levels, with about one-third being above the control range. This promising preliminary result suggests that inner ear-specific proteins have the potential to serve as biomarkers for otologic disease processes.

Soy proteins and isoflavones reduce interleukin-6 but not serum lipids in older women: a randomized controlled trial.

Soy foods contain several components, notably, isoflavones and amino acids, that may improve cardiovascular health. We evaluated the long-term effect of soy protein and/or soy isoflavones supplementation on serum lipids and inflammatory markers using a 1-year randomized, double-blind, placebo-control, clinical trial in 131 healthy ambulatory women older than 60 years. We hypothesized that soy protein, in combination with isoflavones, would have the largest positive effect on coronary heart disease risk factors (serum lipids and inflammatory markers) compared with either intervention alone and that, within groups receiving isoflavones, equol producers would have more positive effects on coronary heart disease risk factors than nonequol producers. After a 1-month baseline period, participants were randomized into 1 of 4 intervention groups: soy protein (18 g/d) and isoflavone tablets (105 mg/d isoflavone aglycone equivalents), soy protein and placebo tablets, control protein and isoflavone tablets, or control protein and placebo tablets. T Tests were used to assess differences between equol and nonequol producers. Ninety-seven women completed the trial. Consumption of protein powder and isoflavone tablets did not differ among groups, and compliance with study powder and tablets was 79% and 90%, respectively. After 1 year, in the entire population, there were either no or little effects on serum lipids and inflammatory markers, regardless of treatment group. Equol producers, when analyzed separately, had significant improvements in total cholesterol/high-density lipoprotein and low-density lipoprotein/high-density lipoprotein ratios (-5.9%, P = .02; -7.2%, P = .04 respectively). Soy protein and isoflavone (either alone or together) did not impact serum lipids or inflammatory markers. Therefore, they should not be considered an effective intervention to prevent cardiovascular disease because of lipid modification in healthy late postmenopausal women lacking the ability to produce equol.

Continuous renal replacement therapy: cause and treatment of electrolyte complications.

Continuous renal replacement therapy (CRRT) has become the modality of choice for critically ill patients. Although often hemodynamically better tolerated than intermittent dialysis, the continuous nature of this therapy may cause significant electrolyte complications. These complications commonly result from removal of electrolytes from the body without adequate replacement or because of the use of trisodium citrate as the anticoagulant. Both hypophosphatemia and hypokalemia frequently complicate prolonged treatment. These complications can be avoided by adding these electrolytes to the dialysate or replacement fluid. The use of citrate, especially if this anticoagulant is not used routinely following established protocols, can also result in several electrolyte abnormalities. Because citrate works by chelating calcium, hypo- and hypercalcemia occur because of under- or overreplacement of calcium. Because citrate is a base equivalent, if the bicarbonate concentration of the dialysate or replacement fluid is not decreased, a metabolic alkalosis may develop. Less commonly, in patients with severe liver dysfunction who cannot metabolize citrate back to bicarbonate, a metabolic acidosis may develop. Although CRRT may cause electrolyte complication it also can be the treatment of choice for the correction of certain electrolyte complications. In patients with acute or chronic renal failure who present with significant dysnatremias, intermittent hemodialysis may cause overly rapid correction of the serum sodium with serious neurologic sequelae. The ability to manipulate the sodium concentration of the dialysate or replacement fluid and the more sustained nature of the treatment allows for a slower correction thus avoiding complications.

Risedronate prevents early bone loss and increased bone turnover in the first 6 months of luteinizing hormone-releasing hormone-agonist therapy for prostate cancer.

OBJECTIVE: To determine whether increased bone loss and bone turnover during the first 6 months of therapy for prostate cancer with luteinizing hormone-releasing hormone (LHRH)-agonist therapy could be prevented by bisphosphonate therapy with risedronate 35 mg/week, as prostate cancer is commonly treated with LHRH agonists and this often leads to rapid bone loss within the first 6 months of therapy. PATIENTS AND METHODS: A 6-month randomized, double-blind, placebo-controlled trial was conducted, including 40 men aged ≥ 55 years receiving LHRH-agonist treatment for 6 months for locally advanced prostate cancer. Bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip was measured every 6 months. In addition, bone turnover markers including N-telopeptide, serum C-telopeptide and procollagen peptide, and 25-OH vitamin D and intact parathyroid hormone were measured at baseline and at 6 months. RESULTS: After 6 months of LHRH-agonist therapy, the control group had a significant decline at the spine and hip BMD sites; however, the risedronate group had no bone loss at the hip and an increase at the lumber spine. Markers of bone turnover were increased significantly in the control group but unchanged in the risedronate group. CONCLUSIONS: LHRH-agonist treatment for locally advanced prostate cancer produces increased bone turnover and rapid bone loss within the initial 6 months of therapy, and this can be prevented by weekly risedronate treatment.

The effect of short-term estradiol therapy on clotting and inflammatory markers in older men receiving hormonal suppression therapy for prostate cancer.

The cardio protective effect of estrogen in women has come under scrutiny as recent evidence from long-term trials has demonstrated negative findings. In contrast, the effect of endogenous sex hormones, specifically estrogen, on cardiovascular disease, inflammation and clotting parameters in men has not been well-studied. Men receiving androgen deprivation therapy for prostate cancer provide a unique model to study the effect of estrogen alone on inflammation and clotting factors. In a short-term randomized controlled trial of 17-beta estradiol (E(2)) versus placebo, we measured sex hormones, markers of inflammation including homocysteine (HC), C-reactive protein (CRP), interleukin-6 (IL-6) and coagulation factors including fibrinogen, plasminogen activator-inhibitor-1 (PAI-1) and anti-thrombin-III (AT-III) in 27 older men without bone metastases receiving androgen deprivation therapy or neoadjuvant treatment for prostate cancer. After 9 weeks of E(2) treatment, there was no difference in inflammation or clotting parameters between groups, but after 9 weeks of treatment AT-III increased in the E(2) treated group and decreased in the placebo group. CRP, homocysteine and IL-6 did not show any significant differences. We also evaluated the above parameters in 12 men 3 weeks after acute steroid withdrawal with androgen deprivation therapy and found no significant changes. We found an increase in AT-III in men receiving E(2) which may be related to gonadal steroid withdrawal, but no significant differences in other inflammatory or clotting factor parameters. While the current report is very preliminary in a small group of subjects, further studies are needed to determine the long-term effects of E(2) in this population of hypogonadal men.

Polycystic kidney disease.

Polycystic kidney disease, an inherited systemic disorder, is characterized by the development of multiple cysts in the kidneys and other organs. Patients can present at any age, but more often come to clinical attention (unless there is a family history) after age 30. Patients who are diagnosed before age 30 have a worse renal survival. Although palpation of the abdomen occasionally provides a clue to the presence of polycystic kidney disease, radiographic procedures most often suggest the diagnosis. Mutations in the PKD1 or PKD2 genes give rise to cyst formation. Flank pain, hematuria, polyuria, nephrolithiasis, urinary tract infections, and hypertension may be part of the syndrome of polycystic kidney disease. It is the fourth most common cause of end-stage renal disease. Blood pressure treatment goals are less than 130/80 mm Hg. Treatment should include the use of angiotensin-converting enzyme inhibitors.

Lactic acidosis: from sour milk to septic shock.

Lactic acidosis is frequently encountered in the intensive care unit. It occurs when there is an imbalance between production and clearance of lactate. Although lactic acidosis is often associated with a high anion gap and is generally defined as a lactate level >5 mmol/L and a serum pH <7.35, the presence of hypoalbuminemia may mask the anion gap and concomitant alkalosis may raise the pH. The causes of lactic acidosis are traditionally divided into impaired tissue oxygenation (Type A) and disorders in which tissue oxygenation is maintained (Type B). Lactate level is often used as a prognostic indicator and may be predictive of a favorable outcome if it normalizes within 48 hours. The routine measurement of serum lactate, however, should not determine therapeutic interventions. Unfortunately, treatment options remain limited and should be aimed at discontinuation of any offending drugs, treatment of the underlying pathology, and maintenance of organ perfusion. The mainstay of therapy of lactic acidosis remains prevention.

The effect of micronized estradiol on bone turnover and calciotropic hormones in older men receiving hormonal suppression therapy for prostate cancer.

To examine the effect of estradiol (E(2)) without the confounding effect of hypothalamic-pituitary feedback, we studied men with prostate cancer in whom gonadotropin secretion was suppressed by LH-releasing hormone agonists (LHRH-A). Fourteen men over 65 yr of age and receiving established LHRH-A treatment (EST group) without bony metastases and 12 men who received LHRH-A as neoadjuvant therapy for locally advanced prostate cancer (NEO group) were randomized (double blind) to receive either 1 mg/d micronized E(2) (n = 12) or placebo (PL; n = 13) for 9 wk. E(2), estrone, testosterone, SHBG, PTH, and 25-hydroxy- and 1,25-dihydroxyvitamin D levels as well as markers of bone resorption [N- and C-telopeptide cross-links (NTX and CTX) and deoxypyridinoline] and bone formation (bone-specific alkaline phosphatase, osteocalcin, and N-terminal type I collagen) were measured before LHRH-A in the NEO group, before [baseline (BL)] and after 9 wk of E(2) or PL in all patients, and 6 wk after E(2) treatment in the EST group. In the NEO group, hormone levels fell 3 wk after the initial LHRH-A injection, and deoxypyridinoline increased significantly (P = 0.006). At BL, the EST group had higher bone turnover due to the longer duration of LHRH-A treatment. With E(2) treatment, E(2) levels rose into the normal male range, and two resorption markers decreased significantly from BL by 33% for NTX (P < 0.001) and 28% for CTX (P = 0.009). Bone formation markers did not change. PTH increased by 43% from BL (P < 0.01) in the E(2) group and decreased 16% from BL in the PL group (P < 0.01). Ionized calcium did not change in the E(2) group, but increased in the PL group by 2.3% (P < 0.01). NTX and CTX increased 6 wk after E(2) withdrawal in the EST group. We conclude that E(2) inhibits bone resorption in hypogonadal men through a direct skeletal effect that is independent of PTH. Low dose estrogen may be an option for the prevention and/or treatment of bone loss in this population.

Effects of smoking cessation or reduction on hormone profiles and bone turnover in postmenopausal women.

The purpose of this study was to prospectively evaluate the impact of smoking cessation on hormonal concentrations, sex hormone-binding globulin (SHBG) and markers of bone turnover in postmenopausal women. Sixty-six women who were either users or non-users of estrogen replacement therapy (ERT) were randomly assigned, using a weighted randomization scheme, to smoking cessation (SC) or to smoking cessation after 6 weeks of monitoring (wait-list control group, WLC). We measured hormones [estrone, estradiol, testosterone, parathyroid hormone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione] and SHBG, markers of bone turnover [procollagen peptide (PINP), bone alkaline phosphatase (BAP), and osteocalcin (OC), N- and C-terminal collagen cross-links (NTx and CTx)], and cotinine, at baseline and again at 6 weeks in women who reported smoking cessation and in women randomized to the WLC group. Analyses included 20 subjects who quit or significantly reduced their smoking and 18 subjects in the WLC group. After controlling for differences in age and ERT use between groups, we found a significant change in SHBG in the SC vs. the WLC group (-8% vs. +5%, respectively; p = 0.01), and in DHEA (-18% vs. -5%, respectively; p = 0.04), but not in other hormonal concentrations. We also noted a significant change in NTx in the SC vs. WLC group (-5% vs. +56%, respectively, p = 0.01), but not in other markers of bone turnover. Percentage changes in SHBG and NTx were correlated with changes in plasma cotinine (r = 0.48; p = 0.004 and r = 0.36; p = 0.04, respectively). Six weeks of smoking abstinence produces reductions in SHBG and NTx. This may partly explain how smoking contributes to osteoporosis in postmenopausal women.

Multiple myeloma associated with lactic acidosis.

Type B lactic acidosis is rare among patients with malignant diseases. To date only one case report has documented lactic acidosis occurring in a patient with multiple myeloma (MM). Our patient, a 55-year-old black man, was diagnosed with stage IIIA immunoglobulin G-kappa (IgG-kappa) MM in September 1995. He was found to have severe lactic acidosis at the time of second relapse. During the terminal phase of his disease, he required multiple hospitalizations for management of lactic acidosis and other complications of his MM. No other cause of his elevated lactate levels was identified. Although type B lactic acidosis may more commonly occur in patients with leukemia or lymphoma, it may rarely present in patients with rapidly progressive and refractory MM.