Wm. Jennings Bryan Dorn VA Medical Center

Healthy biological systems exhibit complex patterns of variability that can be described by mathematical chaos. Heart rate variability (HRV) consists of changes in the time intervals between consecutive heartbeats called interbeat intervals (IBIs). A healthy heart is not a metronome. The oscillations of a healthy heart are complex and constantly changing, which allow the cardiovascular system to rapidly adjust to sudden physical and psychological challenges to homeostasis. This article briefly reviews current perspectives on the mechanisms that generate 24 h, short-term (~5 min), and ultra-short-term (<5 min) HRV, the importance of HRV, and its implications for health and performance. The authors provide an overview of widely-used HRV time-domain, frequency-domain, and non-linear metrics. Time-domain indices quantify the amount of HRV observed during monitoring periods that may range from ~2 min to 24 h. Frequency-domain values calculate the absolute or relative amount of signal energy within component bands. Non-linear measurements quantify the unpredictability and complexity of a series of IBIs. The authors survey published normative values for clinical, healthy, and optimal performance populations. They stress the importance of measurement context, including recording period length, subject age, and sex, on baseline HRV values. They caution that 24 h, short-term, and ultra-short-term normative values are not interchangeable. They encourage professionals to supplement published norms with findings from their own specialized populations. Finally, the authors provide an overview of HRV assessment strategies for clinical and optimal performance interventions.

STUDY OBJECTIVES: To evaluate the efficacy of a 12-week exercise training program for reducing obstructive sleep apnea (OSA) severity and improving sleep quality, and to explore possible mechanisms by which exercise may reduce OSA severity. DESIGN: Randomized controlled trial. SETTING: Clinical exercise physiology center, sleep laboratory. PARTICIPANTS: Forty-three sedentary and overweight/obese adults aged 18-55 years with at least moderate-severity untreated OSA (screening apnea-hypopnea index [AHI] ≥ 15). INTERVENTIONS: Participants randomized to exercise training (n = 27) met 4 times/week for 12 weeks and performed 150 min/week of moderate-intensity aerobic activity, followed by resistance training twice/week. Participants randomized to a stretching control (n = 16) met twice weekly for 12 weeks to perform low-intensity exercises designed to increase whole-body flexibility. MEASUREMENTS AND RESULTS: OSA severity was assessed with one night of laboratory polysomnography (PSG) before and following the 12-week intervention. Measures of sleep quality included PSG, actigraphy (7-10 days), and the Pittsburgh Sleep Quality Index. Compared with stretching, exercise resulted in a significant AHI reduction (exercise: 32.2 ± 5.6 to 24.6 ± 4.4, stretching: 24.4 ± 5.6 to 28.9 ± 6.4; P < 0.01) as well as significant changes in oxygen desaturation index (ODI; P = 0.03) and stage N3 sleep (P = 0.03). Reductions in AHI and ODI were achieved without a significant decrease in body weight. Improvements in actigraphic sleep and subjective sleep quality were also noted following exercise compared with stretching. CONCLUSIONS: Exercise training had moderate treatment efficacy for the reduction of AHI in sedentary overweight/obese adults, which suggests that exercise may be beneficial for the management of OSA beyond simply facilitating weight loss. TRIAL REGISTRATION: Clinicaltrials.gov identification number NCT00956423.

Probiotics contain microorganisms, most of which are bacteria similar to the beneficial bacteria that occur naturally in the human gut. Probiotics have been widely studied in a variety of gastrointestinal diseases. The most-studied species include Lactobacillus, Bifidobacterium, and Saccharomyces. However, a lack of clear guidelines on when to use probiotics and the most effective probiotic for different gastrointestinal conditions may be confusing for family physicians and their patients. Probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells. Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication. There is high-quality evidence that probiotics are effective for acute infectious diarrhea, antibiotic-associated diarrhea, Clostridium difficile- associated diarrhea, hepatic encephalopathy, ulcerative colitis, irritable bowel syndrome, functional gastrointestinal disorders, and necrotizing enterocolitis. Conversely, there is evidence that probiotics are not effective for acute pancreatitis and Crohn disease. Probiotics are safe for infants, children, adults, and older patients, but caution is advised in immunologically vulnerable populations.

Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS-treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS-treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control.

Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared with placebo patients (20%; P = 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

Tissue available (bioavailable) testosterone (T) includes circulating free T (FT) and albumin-bound T. A reasonable assessment of bioavailable T can be made by using 50% ammonium sulfate to precipitate sex hormone-binding globulin (SHBG)-bound T. The supernatant non-SHBG-bound T (non-SHBG-T) correlates well with physiological androgen activity. To assess bioavailable T in normal aging men, we analyzed serum samples from seven healthy aged men (65-83 yr old) and compared the results to samples from 13 young men (22-39 yr old). Mean serum T, FT, and LH concentrations were not significantly different in the 2 groups. However, the mean absolute non-SHBG-T level was significantly lower (P less than 0.005) in the older group. In a separate population of 20 impotent but otherwise healthy men (5 27-37 yr old, 10 48-64 yr old, and 5 66-69 yr old), the mean absolute non-SHBG-T concentration was lower in middle-aged (P less than .01) and elderly men (P less than 0.001) than in young men. The absolute FT was lower only in the elderly group (P less than 0.05), while mean LH and T levels were similar in all 3 age groups. These data suggest that serum concentrations of tissue available T are decreased in aged men and that non-SHBG-T measurement is a more sensitive indicator of this decrease than are serum T or serum FT measurements. These changes appear to begin by middle age.

Characterization of insulin and type I insulin-like growth factor (IGF-I) receptors and the effects of insulin and IGF-I on steroidogenesis were evaluated by using purified adult Leydig cells from Sprague-Dawley rats. Purified Leydig cells were found to contain both high and low affinity binding sites for insulin, with Ka values of 1.08 X 10(9) and 1.1 X 10(7) M-1, respectively. Using affinity cross-linking of [125I]iodoinsulin to plasma membrane insulin receptor, several bands were identified by autoradiography under nonreduced conditions with mol wt of 230,000, 280,000, and 300,000. After reduction with 50 mM dithiothreitol, only one band was identified with a mol wt of 130,000, consistent with the alpha-subunit of insulin receptor. Purified Leydig cells also contain specific type I IGF receptors with estimated binding affinity of 0.6 X 10(9) M-1. Multiple high mol wt bands (greater than 250,000) were identified under nonreduced conditions by affinity cross-linking. Under reduced conditions, one band with an approximate mol wt of 135,000 was identified. Purified Leydig cells (10(5) cells/ml) were cultured in Dulbecco's Modified Eagle's Medium-Ham's F-12 Nutrient Mixture (1:1) containing 0.1% fetal calf serum at 37 C in a humidified atmosphere of 5% CO2-95% air. Insulin and IGF-I stimulated testosterone formation as early as 3 h after administration, and their effects were completely blocked by the addition of a protein synthesis inhibitor, cycloheximide (1 microgram/ml). Insulin and IGF-I also significantly potentiated hCG-and 8-bromo-cAMP-induced testosterone formation. Furthermore, insulin and IGF-I potentiated hCG-stimulated cAMP formation. This suggests that insulin and IGF-I have effects at both the LH receptor sites and the steps beyond adenylate cyclase. The ED50 values of insulin and IGF-I-stimulated testosterone formation were comparable (25 ng/ml). In conclusion, we found that Leydig cells contain specific insulin and type I IGF receptors, and both insulin and IGF-I are capable of modulating Leydig cell steroidogenesis.

&lt;i&gt;Background:&lt;/i&gt; Most cases of hyponatremia – serum sodium concentration ([Na&lt;sup&gt;+&lt;/sup&gt;]) &lt;135 mEq/l (&lt;135 m&lt;i&gt;M&lt;/i&gt;) – are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V&lt;sub&gt;1A&lt;/sub&gt;/V&lt;sub&gt;2&lt;/sub&gt;-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. &lt;i&gt;Methods:&lt;/i&gt; Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na&lt;sup&gt;+&lt;/sup&gt;] 115 to &lt;130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na&lt;sup&gt;+&lt;/sup&gt;], measured by the baseline-adjusted area under the [Na&lt;sup&gt;+&lt;/sup&gt;]-time curve. The secondary measures included time from first dose to a confirmed ≧4 mEq/l serum [Na&lt;sup&gt;+&lt;/sup&gt;] increase, total time patients had serum [Na&lt;sup&gt;+&lt;/sup&gt;] ≧4 mEq/l higher than baseline, change in serum [Na&lt;sup&gt;+&lt;/sup&gt;] from baseline to the end of treatment, and number of patients with a confirmed ≧6 mEq/l increase in serum [Na&lt;sup&gt;+&lt;/sup&gt;] or normal [Na&lt;sup&gt;+&lt;/sup&gt;] (≧135 mEq/l). &lt;i&gt;Results:&lt;/i&gt; Both conivaptan doses increased area under the [Na&lt;sup&gt;+&lt;/sup&gt;]-time curve during the 4-day treatment (p &lt; 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean ± standard error serum [Na&lt;sup&gt;+&lt;/sup&gt;] increase associated with placebo was 0.8 ± 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 ± 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 ± 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p &lt; 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. &lt;i&gt;Conclusion:&lt;/i&gt; Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na&lt;sup&gt;+&lt;/sup&gt;] and was well tolerated.

Inflammation and infection induce an acute phase response. The response is characterized by fever and production of interleukin-1 (IL-1). In the present study we evaluated the effects of interleukin-1 on Leydig cell function in primary culture. hCG-stimulated testosterone formation was markedly reduced by IL-1, with an ED50 of 1 U/ml. Basal testosterone production was slightly enhanced in the presence of low concentrations of IL-1, while high concentrations of IL-1 inhibited testosterone formation. Significant inhibition of hCG-stimulated testosterone formation was noted as early as 8 h after the addition of IL-1. IL-1 also inhibited hCG-stimulated cAMP formation, as well as 8-bromo-cAMP- and forskolin-stimulated testosterone synthesis. Furthermore, LH binding to Leydig cells was reduced by human IL-1. The inhibitory effects of IL-1 were reversed only partially by the addition of a cyclooxygenase inhibitor, indomethacin (0.1 mM), even though prostaglandin E2 formation was completely blocked. This indicates that the observed effects of IL-1 are not completely mediated by increased PGE2 formation. The present study suggests that IL-1 is a potent modulator of Leydig cell steroidogenesis. Decreased testosterone formation may modulate the immune response and contribute to the catabolic changes occurring during infection.

A large proportion of individuals affected by sleep disorders are untreated and susceptible to accidents, injuries, long-term sequelae (e.g., risk of cardiovascular disease, cancer, psychiatric disorders), and increased mortality risk. Few studies have examined the scope and magnitude of sleep disorder diagnoses in the United States (US) or factors influencing them. Veterans are particularly vulnerable to factors that elicit or exacerbate sleep disorders. This serial cross-sectional study characterized secular trends in diagnosed sleep disorders among veterans seeking care in US Veterans Health Administration facilities over an eleven-year span (FY2000–2010, n = 9,786,778). Electronic medical records from the national Veterans Administration Informatics and Computing Infrastructure database were accessed. Cases were defined using diagnostic codes specified by the American Academy of Sleep Medicine. Age-adjusted annual prevalence was summarized by sex, race, combat exposure, body mass index, and comorbid diagnoses (cardiovascular disease, cancer, mental disorders). Sleep apnea (47%) and insomnia (26%) were the most common diagnoses among patients with any sleep disorder. There was a six-fold relative increase in total sleep disorder prevalence over the study period. Posttraumatic stress disorder, which tripled over the same time period, was associated with the highest prevalence of sleep disorders (16%) among the comorbid conditions evaluated. The results indicate a growing need for integration of sleep disorder management with patient care and health care planning among US veterans. A commentary on this article appears in this issue on page 1331. Trends in diagnosed sleep disorders were characterized among United States veterans seeking care in Veterans Health Administration facilities between FY2000 and FY2010 (n = 9,786,778). A six-fold relative increase in the age-adjusted prevalence of any sleep disorder diagnosis was observed during the study period. The largest increases were observed among those with posttraumatic stress disorder, other mental health disorders, or combat experience. Veterans with cardiovascular disease, cancer, or other chronic diseases also experienced higher rates of sleep disorder diagnoses relative to those without such conditions. This study identified a growing need for integration of sleep disorder management with veteran care and health care planning.

While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD) has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR) in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC) and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs) decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-γ and IL-17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High-throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-γ production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD.

BACKGROUND: A dramatic increase in the "early start" of dialysis with an estimated glomerular filtration rate (eGFR) at least 10 mL/min/1.73 m(2) has occurred in the United States since at least 1996. Several recent studies have reported a comorbidity-adjusted survival disadvantage of early start of dialysis. The current study examines a relatively "healthy" dialysis cohort to minimize confounding issues and determine whether early initiation of hemodialysis is associated with a survival benefit or harm. METHODS: We examined demographics, year of dialysis initiation, primary etiology of renal failure, and body mass index, hemoglobin, and serum albumin levels in 81,176 nondiabetic, 20- to 64-year-old, in-center incident hemodialysis patients with no reported comorbidity besides hypertension. We compared survival, using a piecewise proportional hazards model to estimate covariate-adjusted mortality hazard ratios (HRs) for eGFR at the time of initiation of dialysis. We also performed time-dependent adjusted analysis stratified by initial serum albumin levels lower than 2.5 g/dL, 2.5 to 3.49 g/dL, and 3.5 g/dL or higher (the "healthiest" group [HG]). RESULTS: Unadjusted 1-year mortality by eGFR ranged from 6.8% in the reference group (eGFR <5.0 mL/min/1.73 m(2)) to 20.1% in the highest eGFR group (≥15.0 mL/min/1.73 m(2)). Compared with the reference group, the HR for the HG was 1.27 (eGFR, 5.0-9.9 mL/min/1.73 m(2)), 1.53 (eGFR, 10.0-14.9 mL/min/1.73 m(2)), and 2.18 (eGFR ≥15.0 mL/min/1.73 m(2)) and ranged from 1.50 to 3.53 mL/min/1.73 m(2) in the first year of dialysis for the early-start group. CONCLUSION: The increased HR during hemodialysis associated with early start in the healthiest group of patients undergoing dialysis indicates that early start of dialysis may be harmful.

A woman receives a diagnosis of diffuse large B-cell lymphoma; a standard chemotherapy regimen is recommended. Use of prophylactic granulocyte CSF is considered. G-CSF stimulates proliferation of neutrophil progenitors and release of mature neutrophils from bone marrow.

The extracellular matrix (ECM) is a complex entity containing a large portfolio of structural proteins, signaling molecules, and proteases. Changes in the overall integrity and activational state of these ECM constituents can contribute to tissue structure and function, which is certainly true of the myocardium. Changes in the expression patterns and activational states of a family of ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), have been identified in all forms of left ventricle remodeling and can be a contributory factor in the progression to heart failure. However, new clinical and basic research has identified some surprising and unpredicted changes in MMP profiles in left ventricle remodeling processes, such as with pressure or volume overload, as well as with myocardial infarction. From these studies, it has become recognized that proteolytic processing of signaling molecules by certain MMP types, particularly the transmembrane MMPs, actually may facilitate ECM accumulation and modulate fibroblast transdifferentiation; both are critical events in adverse left ventricle remodeling. Based on the ever-increasing substrates and diversity of biological actions of MMPs, it is likely that continued research about the relationship of left ventricle remodeling in this family of proteases will yield new insights into the ECM remodeling process and new therapeutic targets.

BACKGROUND: Epidemiologic studies show a curvilinear relationship between inadequate sleep (< 7 or > 8 hours) and obesity (Body Mass Index > 30 kg/m2), which have enormous public health impact. METHODS: Using data from the National Health Interview Survey, an ongoing nationally representative cross-sectional study of non-institutionalized US adults (≥18 years) (1977 through 2009), we examined the hypothesis that inadequate sleep is independently related to overweight/obesity, with adjustment for socio-demographic, health risk, and medical factors. Self- reported data on health risks, physician-diagnosed medical conditions, sleep duration, and body weight and height were used. RESULTS: Prevalence of overweight and obesity increased from 31.2% to 36.9% and 10.2% to 27.7%, respectively. Whereas prevalence of very short sleep (<5 hours) and short sleep (5-6 hours) has increased from 1.7% to 2.4% and from 19.7% to 26.7%, it decreased from 11.6% to 7.8% for long sleep. According to multivariate-adjusted multinomial regression analyses, odds of overweight and obesity associated with very short sleep and short sleep increased significantly from 1977 to 2009. Odds of overweight and obesity conferred by long sleep did not show consistent and significant increases over the years. Analyses based on aggregated data showed very short sleepers had 30% greater odds of being overweight or were twice as likely to be obese, relative to 7-8 hour sleepers. Likewise, short sleepers had 20% greater odds of being overweight or 57% greater odds of being obese. Long sleepers had 20% greater odds of being obese, but no greater odds of being overweight. CONCLUSIONS: Our findings support the hypothesis that prevalence of very short and short sleep has gradually increased over the last 32 years. Inadequate sleep was associated with overweight and obesity for each available year.

For decades the brain was erroneously considered an insulin insensitive organ. Although gaps in our knowledge base remain, conceptual frameworks are starting to emerge to provide insight into the mechanisms through which insulin facilitates critical brain functions like metabolism, cognition, and motivated behaviors. These diverse physiological and behavioral activities highlight the region-specific activities of insulin in the CNS; that is, there is an anatomical context to the activities of insulin in the CNS. Similarly, there is also a temporal context to the activities of insulin in the CNS. Indeed, brain insulin receptor activity can be conceptualized as a continuum in which insulin promotes neuroplasticity from development into adulthood where it is an integral part of healthy brain function. Unfortunately, brain insulin resistance likely contributes to neuroplasticity deficits in obesity and type 2 diabetes mellitus (T2DM). This neuroplasticity continuum can be conceptualized by the mechanisms through which insulin promotes cognitive function through its actions in brain regions like the hippocampus, as well as the ability of insulin to modulate motivated behaviors through actions in brain regions like the nucleus accumbens and the ventral tegmental area. Thus, the goals of this review are to highlight these anatomical, temporal, and functional contexts of insulin activity in these brain regions, and to identify potentially critical time points along this continuum where the transition from enhancement of neuroplasticity to impairment may take place. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

PURPOSE: Azithromycin use has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. The Food and Drug Administration issued a public warning on azithromycin, including a statement that the risks were similar for levofloxacin. We conducted a retrospective cohort study among US veterans to test the hypothesis that taking azithromycin or levofloxacin would increase the risk of cardiovascular death and cardiac arrhythmia compared with persons taking amoxicillin. METHODS: We studied a cohort of US veterans (mean age, 56.8 years) who received an exclusive outpatient dispensation of either amoxicillin (n = 979,380), azithromycin (n = 594,792), or levofloxacin (n = 201,798) at the Department of Veterans Affairs between September 1999 and April 2012. Azithromycin was dispensed mostly for 5 days, whereas amoxicillin and levofloxacin were dispensed mostly for at least 10 days. RESULTS: During treatment days 1 to 5, patients receiving azithromycin had significantly increased risk of death (hazard ratio [HR] = 1.48; 95% CI, 1.05-2.09) and serious arrhythmia (HR = 1.77; 95% CI, 1.20-2.62) compared with patients receiving amoxicillin. On treatment days 6 to 10, risks were not statistically different. Compared with patients receiving amoxicillin, patients receiving levofloxacin for days 1 to 5 had a greater risk of death (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR = 2.43, 95% CI, 1.56-3.79); this risk remained significantly different for days 6 to 10 for both death (HR = 1.95, 95% CI, 1.32-2.88) and arrhythmia (HR = 1.75; 95% CI, 1.09-2.82). CONCLUSIONS: Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.

With appropriate baseline and follow-up safety monitoring, liothyronine augmentation can be a safe and effective treatment for unipolar depression. Larger studies of longer duration assessing liothyronine efficacy with serotonin norepinephrine reuptake inhibitors and multimodal antidepressants are needed.

Inhibin and activin are gonadal glycoproteins that selectively inhibit and stimulate FSH release, respectively. Previously we have reported that transforming growth factor-beta inhibited hCG-stimulated testosterone formation in mature Leydig cells. In the present study we evaluated the effects of other members of the transforming growth factor-beta family, inhibin and activin, on Leydig cell function. We found that activin (0.1-10 ng/ml) had no effect on basal testosterone formation, but inhibited hCG-stimulated testosterone formation in a dose-dependent manner. Activin (10 ng/ml) inhibited hCG-stimulated testosterone formation by 42%. Activin also inhibited hCG-stimulated cAMP formation. In the presence of activin (5 ng/ml), forskolin (10 microM)- and 8-bromo-cAMP (0.1 mM)-induced testosterone formation were reduced about one third. Conversions of pregnenolone and progesterone to testosterone were also blocked by activin. Interestingly, [125I]hCG binding to Leydig cells and forskolin-induced cAMP formation were not affected by the addition of activin. In contrast to activin, inhibin (0.1-10 ng/ml) had no effect on hCG-induced testosterone formation at any concentration used. However, the inhibitory effects of activin on Leydig cell function were reversed by the concomitant addition of inhibin. Our results suggest that activin inhibits testosterone formation by the Leydig cells derived from normal mature rats. Multiple steps of the steroidogenic pathway are affected by testosterone. Inhibin alone has no effect, but reverses the inhibitory action of activin.

Pavlovian eyeblink (EB) conditioning was studied in both trace and delay paradigms in rabbits (Oryctolagus cuniculus) with either medial prefrontal cortex (mPFC) lesions or sham lesions. mPFC lesions of prelimbic cortex (Brodmann's Area 32) retarded EB conditioning in the trace but not the delay paradigm. However, this effect was significant only when the conditioned stimulus (CS) was 500 rather than 100 ms in duration. Lesions of the anterior cingulate cortex (Area 24) did not affect EB conditioning in a trace paradigm. Accompanying CS-evoked heart rate slowing was attenuated under all conditions by the mPFC lesions, although this result was not always statistically significant.