Deferiprone Stimulates Aged Dermal Fibroblasts via HIF-1α Modulation.

BACKGROUND: Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In addition to absence of oxygen, sequestration of iron also stimulates HIF-1α. Therefore, we analyzed the efficacy of the iron-chelator deferiprone (DFP) at stimulating dermal fibroblasts. OBJECTIVES: The main objective of this study was to quantify the DFP concentrations capable of stimulating dermal fibroblasts in vitro and to correlate the effective DFP concentrations with the ability of DFP to penetrate the epidermis, reach the dermis, and activate HIF-1α in vivo. METHODS: We measured cell proliferation, metabolic activity, HIF-1α expression, and lactate dehydrogenase levels of both young and aged fibroblasts after a 24-hour in vitro preconditioning with DFP. In addition, we evaluated cell survival rates and morphology with different cellular stainings. Finally, we performed a transdermal permeation study with a 1% DFP topical formulation to quantify the concentration required to reach the dermis. RESULTS: In vitro administration of iron-chelation therapy (156-312.5 µg/mL DFP ) on aged fibroblasts resulted in activation of various antiaging processes. The concentration required to reach the dermis within 24 hours was 1.5% (0.15 mg/mL), which corresponds well with the effective doses of our laboratory analyses. CONCLUSIONS: The activation of HIF-1α by DFP enhances cell metabolism, proliferation, and survival of fibroblasts while reducing lactate dehydrogenase levels. Modulation of HIF-1α is linked to activation of key regeneration enzymes and proteins, and by proxy, antiaging. Therefore, the antiaging properties of DFP and its satisfactory dermal penetration make it a promising regenerative agent.

Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease. The X-PLORER trial.

Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6-8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin-antithrombin complex values at 2 h post-PCI were 3.90 [6.8]µg/l and 3.90 [10.1] µg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin-antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting.

Influenza vaccination coverage among children aged 6-23 months - six immunization information system sentinel sites, United States, 2005-06 influenza season.

Beginning with the 2004-05 influenza season, the Advisory Committee on Immunization Practices (ACIP) recommended that all children aged 6-23 months receive influenza vaccinations annually. Other children recommended to receive influenza vaccinations include those aged 6 months-18 years who have certain high-risk medical conditions, those on chronic aspirin therapy, those who are household contacts of persons at high risk for influenza complications, and, since 2006, all children aged 24-59 months. Previously unvaccinated children aged <9 years need 2 doses administered at least 1 month apart to be considered fully vaccinated. This report assesses influenza vaccination coverage among children aged 6-23 months during the 2005-06 influenza season by using data from six immunization information system (IIS) sentinel sites. The findings demonstrate that vaccination coverage with 1 or more doses varied widely (range: 6.6% to 60.4%) among sites, with coverage increasing from the preceding influenza season in four of the six sites. However, <23% of children in five of the sites were fully vaccinated, underscoring the need for increased measures to improve the proportion of children who are fully vaccinated.

Metabolic alkalosis in a hemodialysis patient--successful treatment with a proton pump inhibitor.

Hemodialysis patients develop metabolic acidosis due to their impaired excretion of daily produced protons (H+). The following report will show a rare case of severe metabolic alkalosis (predialysis pH 7.52, base excess (BE) +17) in a hemodialysis woman caused by self-provoked upper gastrointestinal H+ losses based on an eating disorder. Treatment with a proton pump inhibitor resulted in the normalization of acid/base homeostasis (predialysis pH 7.40, BE +1.6).

Impact of parathyroidectomy on neutrophil cytosolic calcium in chronic kidney disease patients: a prospective parallel group trial.

OBJECTIVES: Polymorphonuclear leucocytes (PMNs) of chronic kidney disease (CKD) patients display elevated basal cytosolic calcium concentrations (iCa(2+)). As parathyroid hormone is considered to substantially contribute to the inappropriate cellular entry of calcium in uraemia, we hypothesized that parathyroidectomy lowers PMN iCa(2+). DESIGN AND SETTING: Prospective parallel group trial at a tertiary care centre. SUBJECTS, INTERVENTION AND MAIN OUTCOME MEASURES: Two patient cohorts (cohort 1: 14 CKD patients; cohort 2: 14 renal transplant recipients) underwent parathyroidectomy for uncontrolled secondary hyperparathyroidism. We assessed PMN iCa(2+) (primary objective) spectrofluorimetrically 1 day before and 20 days after intervention (secondary objective: PMN glucose uptake). Data were compared with those of 16 matched maintenance haemodialysis patients (cohort 3), and to 15 healthy subjects (cohort 4), by generalized estimating equations. RESULTS: PMN iCa(2+) of cohort 1 decreased over time and was significantly higher than that of cohort 3 before but not after parathyroidectomy [mean difference before/after parathyroidectomy: 19.1 nmol L(-1) (95% confidence interval: 9.4-22.4), P =0.0003/-3.2 (-20.9-14.5), P = 0.71]. PMN iCa(2+) of cohort 2 decreased over time, but we found no significant difference in comparison with cohort 3 [mean difference before/after parathyroidectomy: 6.5 nmol L(-1) (-9.4-22.4), P = 0.4/-15.8 (-43.6-12.0), P = 0.25]. PMN iCa(2+) of all CKD patients was substantially higher in comparison with that of healthy subjects [cohort 4 vs. 3: -35.3 (-48.9-21.6), P < 0.001]. PMN glucose uptake increased significantly in both interventional cohorts in comparison with cohort 3. CONCLUSIONS: Parathyroidectomy lowers, but does not normalize PMN iCa(2+) of CKD patients. Further variables, possibly uraemic retention solutes, control both PMN iCa(2+) and functional responses.

The malononitrilamide FK778 inhibits activation of NF-kappaB in human dendritic cells.

FK778, a derivative of the active leflunomide-metabolite, A77 1726, has been shown to be a powerful immunosuppressant in several transplantation models, particularly efficient in prevention of chronic allograft rejection. However, the cellular and molecular mechanisms underlying these effects of FK778 have not been investigated yet in detail. Because dendritic cells (DCs) are a crucial cell type in initiation of immune responses including chronic allograft rejection, we investigated whether FK778 affects this peculiar cell population. NF-kappaB is the essential transcription factor involved in DC activation and function. We found that lipopolysaccharide (LPS)-induced activation of NF-kappaB, as assessed using electromobility shift assay, is markedly inhibited by FK778 in human monocyte-derived DCs. Hence, FK778 could exert its immunosuppressive effects via inhibition of activation and thus function of the central antigen-presenting cell, ie, DC.

Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of various injection intervals on spermatogenesis, reproductive hormones, testis, and prostate.

The goal of this study was to find the most favorable injection interval of norethisterone enanthate (NETE) plus testosterone undecanoate (TU) in terms of gonadotropin, sperm suppression, and prostatic effects. Fifty normal men were randomly assigned to receive NETE 200 mg plus TU 1000 mg every 8 wk (n = 10), every 12 wk (n = 10), every 6 wk for 12 wk and then every 12 wk (n = 10), and every 6 wk for 12 wk and thereafter TU 1000 mg plus placebo every 12 wk (n = 10), and placebo plus placebo every 6 wk for 12 wk and then every 12 wk (n = 10) for 48 wk. Semen analyses, blood drawings, physical examinations, and prostate ultrasounds were performed throughout the study. Of the men in the 8-wk injection group, 90% (nine of 10) achieved azoospermia, compared with 37.5% (three of eight) in the 12-wk injection group (P = 0.019). TU plus placebo injected every 12 wk did not maintain sperm suppression. Prostate volumes did not change significantly in either group. In conclusion, these data suggest that the combined administration of NETE and TU at 8-wk intervals represents an effective hormonal contraceptive regimen.

Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression.

OBJECTIVE: This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression. METHOD: A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) > or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score < or =8 (corresponding to an improvement of > or =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND). RESULTS: The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35). CONCLUSION: The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.

Testosterone undecanoate maintains spermatogenic suppression induced by cyproterone acetate plus testosterone undecanoate in normal men.

In this study we evaluated whether testosterone undecanoate (TU), alone or combined with low dose cyproterone acetate (CPA), can maintain spermatogenic suppression induced by higher doses of CPA plus TU. Twenty-four men received for 12 wk 20 mg/d CPA plus 1000 mg/6 wk TU and then 1000 mg/8 wk TU plus 20 mg/d CPA (n = 8), 2 mg/d CPA (n = 8), or plus placebo (n = 8) for 32 wk. Blood samples, physical examinations, hormones, chemistry, hematology, semen analysis, and sexual/behavioral assessments were performed throughout the study. Sperm counts decreased to less than 1 million/ml in all subjects by wk 12, and 54% of them achieved azoospermia. Suppression of sperm counts was maintained until wk 44. Serum LH and FSH levels were suppressed by wk 12 of hormone administration and remained suppressed until wk 44. No significant changes in any biochemical parameters were detected at wk 44 in any group. There was a slight increase in total prostate volume to within the normal range at wk 44 that returned to baseline 1 yr after stopping hormone administration. In conclusion, TU alone or combined with lower doses of CPA maintains sperm suppression induced by higher dose CPA plus TU for 32 wk. This prototype regimen represents a promising male contraceptive regimen.

Sources of coercive behaviours in psychiatric admissions.

OBJECTIVE: Coercion during psychiatric admissions has been a topic of debate for many years. Although there has been considerable research on patients' perceptions of coercion, there has been no work on who places pressures on patients to be admitted. METHOD: This article integrates interview data from interviews with patients, admitting staff and family and friends to describe the pressures brought to bear on patients to be admitted. RESULTS: Health-care professionals appear to be the most important source of pressures on patients, and to have the most impact on patients' perceptions of coercion. However, there are differences in type of pressure, and the pressures used by family and friends appear to have the most longstanding impact. CONCLUSION: Legal and clinical efforts to reduce the level of coercive pressures on patients need to recognize the importance of mental-health professionals, including especially those who are not legally mandated to participate in the admission process.

Self care for chronic illness: older African Americans and whites.

In-person interviews with two hundred and twenty-one older African Americans and whites in Allegheny County, Pennsylvania on their use of self care activities in the care of one of four chronic illnesses (chronic obstructive pulmonary disease (COPD), heart disease, diabetes mellitus, and arthritis, addressed which types of self care they used for each of these illnesses) the similarities and differences between African Americans and whites in their use of self care and how self care is initiated, modified and integrated into a context that includes help from others. The most common response in each of the illnesses was the use of medications or medical treatments by both African Americans and whites. However, there were some differences in the self care practices used by these two groups by illness type. Whites reported monitoring their illness significantly more than African Americans for diabetes and using assistive devices in the management of COPD significantly more than African Americans. While both African Americans and whites practice self care similarly in the management of heart disease, African Americans reported greater use of exercise in their management of arthritis. The amount of assistance provided by others in support of self care varied by illness and by African American and white. The differences in self care usage may be attributed to many factors, among them, differences in cultural experiences with the illness, health beliefs regarding its efficacy and the amount of assistance received from informal supports.

Factual sources of psychiatric patients' perceptions of coercion in the hospital admission process.

OBJECTIVE: The purpose of this study was to determine what predicts patients' perceptions of coercion surrounding admission to a psychiatric hospital. METHOD: For 171 cases, the authors integrated data from interviews with patients, admitting clinicians, and other individuals involved in the patients' psychiatric admissions with data from the medical records. Using a structured set of procedures, coders determined whether or not nine coercion-related behaviors occurred around the time of admission. Correlation and regression analyses were used to describe the predictors of patients' scores on the MacArthur Perceived Coercion Scale. RESULTS: The use of legal force, being given orders, threats, and "a show of force" were all strongly correlated with perceived coercion. A least squares regression accounted for 43.3% of the variance in perceived coercion. The evidence also suggested that force is typically only used in conjunction with less coercive pressures. CONCLUSIONS: Force and negative symbolic pressures, such as threats and giving orders about admission decisions, induce perceptions of coercion in persons with mental illness. Positive symbolic pressures, such as persuasion, do not induce perceptions of coercion. Such positive pressures should be tried in order to encourage admission before force or negative pressures are used.

The validity of mental patients' accounts of coercion-related behaviors in the hospital admission process.

Although the recent development of a measure for perceived coercion has led to great progress in research on coercion in psychiatric settings, there still exists no consensus on how to measure the existence of real coercive events or pressures. This article reports the development of a system for integrating chart review data and data from interviews with multiple participants in the decision for an individual to be admitted to a psychiatric hospital. The method generates a "most plausible factual account" (MPFA). We then compare this account with that of patients, admitting clinicians and other collateral informants in 171 cases. Patient accounts most closely approximate the MPFA on all but one of nine dimensions related to coercion. This may be due to wider knowledge of the events surrounding the admission.

[Late functional outcome of surgically treated mid-hand fractures]. / Funktionelle Spätergebnisse nach operativ behandelten Mittelhandfrakturen.

The aim of surgical intervention for the treatment of metacarpal fractures is to restore the best possible function. This study of 61 patients who were treated utilizing different osteosynthesis techniques demonstrates out-standing long-term results. Conservative treatment may be adaeqaute for the treatment of uncomplicated and minimally dislocated fractures. For serial fractures and fractures involving joints, however, there is no alternative to osteo-synthesis.

Demonstration of a somatostatin-like activity in retinal cells of the rat.

A somatostatin-like substance is demonstrated by light microscopic immunohistochemistry (PAP-method) in perikarya and cell processes of the retina of adult and infant rats. These perikarya are identified according to their size, arrangement and distribution. Each of the first two neuronal orders (receptors, bipolar cells, ganglionic cells) of the visual pathway can be associated with retinal cells reacting positively with anti-somatostatin. In the adult rat, perikarya and processes of (i) horizontal cells, (ii) amacrine cells and (iii) large neurons in the ganglionic layer are specifically labeled. The staining of middle-sized and small ganglion cells is probably caused by the close attachment of labeled fibers to non-reacting cells. Postnatally, the immunoreactive elements develop in parallel to the differentiation of the corresponding retinal layers. It is discussed whether the three types of retinal cells containing a somatostatin-like substance provide an inhibitory system to each of the two orders of retinal neurons.