Higher bone mineral density in Caucasian, hirsute patients of reproductive age. Positive correlation of testosterone levels with bone mineral density in hirsutism

OBJECTIVE: The mechanisms leading to higher bone mineral density (BMD) in hirsute patients than in healthy controls have seldom been examined. We compared the metabolic, hormonal and bone metabolic parameters in hirsute patients and female controls and correlated BMD and bone metabolic parameters with testosterone, oestradiol and metabolic parameters. PATIENTS: Fifty-one Caucasian, reproductive-aged, hirsute patients referred to the outpatient clinic of an academic tertiary-care medical centre and 63 healthy, female Caucasian controls matched for season, weight and age. MEASUREMENTS: BMD (hip, neck, lumbar and total BMD), bone metabolic parameters (osteocalcin, alkaline phosphatase, PTH, ionized calcium, phosphate and 25-hydroxyvitamin D (25OHD)) and endocrine profiles (androgen status, oestradiol and insulin) were evaluated during follicular phase. Oestradiol measurement was repeated during cycle days 8-12. RESULTS: Lumbar and neck BMD levels were significantly higher in hirsute patients than in controls: (mean +/- SD): lumbar BMD 1.10 +/- 0.12 vs. 1.06 +/- 0.10 g/cm2 and neck BMD 0.91 +/- 0.11 vs. 0.87 +/- 0.12 g/cm2, P < 0.05. Fasting insulin and free testosterone levels were significantly higher in hirsute patients than in controls. Free testosterone correlated positively with neck and hip BMD levels in hirsute patients. During multiple regression analysis, testosterone, oestradiol and waist/hip ratio (WHR) were found to have positive effects on BMD levels independent of body mass index (BMI). 25OHD levels were significantly lower in hirsute patients [42 (13-131)] than in controls [72 (27-196)] nmol/l (geometric mean +/- 2SD), P < 0.001]. CONCLUSION: Hirsute patients demonstrated significantly higher bone mineral density levels than controls, which could be explained by hyperinsulinaemia and higher testosterone levels in hirsute patients compared with controls. The pathogenesis for significantly lower 25-hydroxyvitamin D levels in hirsute patients compared with controls needs to be evaluated in future studies.     

Minoxidil therapy in chronic congestive heart failure: Acute plus long-term hemodynamic and clinical study

The hemodynamic response to minoxidil, an orally active, potent vasodilator, was evaluated in 11 patients with severe chronic congestive heart fallure (CHF). The hemodynamic response was determined following single doses of 10, 15, 20, 25, and 30 mg of minoxidil. The hemodynamic response was characterized by marked increases in cardiac index (+63%) and stroke volume index (+52%) and by decrease in systemic vascular resistance (?38%). There was also a slight decrease in pulmonary capillary wedge pressure from an average of 24 ± 8 to 21 ± 7 mm hg. Although the average mean arterial pressure remained unchanged, one patient developed significant hypotension. Chronic minoxidil therapy (eight patients) was associated with fluid retention and weight gain. In four patients in whom fluid retention could be minimized with larger doses of diuretics, a sustained clinical and hemodynamic improvement was observed. These findings suggest that minoxidil has the potential to improve cardiac function and may be useful in chronic vasodilator therapy of CHF, provided fluid retention can be controlled.     

No evidence of maternal cell colonization in reverted liver nodules of tyrosinemia type I patients

BACKGROUND AND AIMS: Hereditary tyrosinemia type I (HTI) is a recessively inherited disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine catabolic pathway. The mosaic pattern of FAH expression observed in the livers of >85% of studied patients was shown to result from the correction of the mutation in one of the FAH alleles. Bilateral cell trafficking can occur between mother and fetus and such an event could be responsible for the chimerism observed in some diseases. It also has been reported that the liver repopulation observed in a HTI murine model by serial transplantation of bone marrow-derived cells was caused by a fusion of these cells to host hepatocytes. These observations led us to test the possibility that the transfer of nucleated heterozygous maternal cells in the fetal circulation could be responsible for the mosaic liver expression of FAH in HTI patients. METHODS: We used polymorphic markers of short cytosine-adenine DNA repeats to compare DNA from corrected liver sections of 4 HTI patients with DNA from their parents' blood. RESULTS: Genotyping showed that only one maternal allele is present in DNA isolated from FAH-expressing liver nodules of each proband for at least 1 marker. CONCLUSIONS: The corrected liver nodules in HTI patients are not of maternal origin and do not support cell trafficking and cell fusion as mechanisms of correction of the gene defect in hepatocytes of tyrosinemia patients.     

The contribution of black carbon to global ice nucleating particle concentrations relevant to mixed-phase clouds

Black carbon (BC) aerosol plays an important role in the Earth’s climate system because it absorbs solar radiation and therefore potentially warms the climate; however, BC can also act as a seed for cloud particles, which may offset much of its warming potential. If BC acts as an ice nucleating particle (INP), BC could affect the lifetime, albedo, and radiative properties of clouds containing both supercooled liquid water droplets and ice particles (mixed-phase clouds). Over 40% of global BC emissions are from biomass burning; however, the ability of biomass burning BC to act as an INP in mixed-phase cloud conditions is almost entirely unconstrained. To provide these observational constraints, we measured the contribution of BC to INP concentrations ([INP]) in real-world prescribed burns and wildfires. We found that BC contributes, at most, 10% to [INP] during these burns. From this, we developed a parameterization for biomass burning BC and combined it with a BC parameterization previously used for fossil fuel emissions. Applying these parameterizations to global model output, we find that the contribution of BC to potential [INP] relevant to mixed-phase clouds is ∼5% on a global average.

Black carbon (BC) is the primary light-absorbing aerosol in the atmosphere. Its short lifetime (days to weeks) relative to CO2 and methane makes it an intriguing target for near-term climate mitigation (1). Errors associated with BC climate forcing, however, obfuscate its efficacy as a climate mitigator. The largest contributions to BC’s forcing uncertainties are often attributed to its effects on clouds, in particular mixed-phase clouds [i.e., clouds containing supercooled cloud droplets and ice particles, (2)]. Efforts to reduce these uncertainties are hindered by the complexity of aerosol–cloud interactions (3). Particularly vexing is quantifying the abundance and identity of ice nucleating particles (INPs). INPs provide the only pathway for primary ice formation in mixed-phase clouds; however, they are rare [e.g., ∼1 in 106 particles are INPs at −20 °C (4)]. Despite their rarity, INPs influence mixed-phase cloud ice concentrations and precipitation and therefore alter cloud albedo and lifetime (5). Furthermore, the INP properties of aerosols, such as BC, will affect their own lifetime, vertical structure, and transport to climate-sensitive regions such as the Arctic (6). Despite its importance to the Earth’s climate and near-term climate mitigation strategies, the INP efficiency of BC relevant to mixed-phase clouds remains almost entirely unconstrained from direct observations, encumbering attempts to estimate BC’s impact on mixed-phase clouds in modeling studies (7).BC’s efficacy as an immersion-freezing INP (henceforth, INP will refer only to freezing by particles encapsulated within supercooled cloud droplets, termed immersion freezing and pertinent to mixed-phase cloud conditions) has been studied in the laboratory for decades, with starkly conflicting results. Early laboratory studies showed that acetylene and kerosene flame-generated soot can nucleate ice below −20 °C. (8, 9); after normalizing for surface area, these studies indicated that BC may be more ice active than the well-known INP mineral dust (10). Results from later laboratory studies were contradictory, suggesting that BC was not active as an INP above instrument limits of detection. These included soot aerosols from miniCAST soot generators, graphite spark generator soot, hydrocarbon flame-generated soot, and fullerene soot, as well as various lamp blacks and carbon blacks (11–15).Unfortunately, field study measurements of the contribution of BC to INP concentrations ([INP]) have also been inconclusive. For example, in-cloud measurements from the high-altitude observatory at Jungfraujoch, Switzerland saw that BC is enriched in ice-particle residuals and therefore may efficiently nucleate ice (16); later measurements at the same site, however, saw that BC is depleted in the ice phase, which suggests that BC does not play a significant role in mixed-phase cloud ice nucleation (17, 18).These contradictions in laboratory and field studies suggest that fuel type and combustion conditions determine the ice nucleation properties of BC. Such conditions prescribe BC’s physical and morphological properties as well as its coemitted and coagulated species. Major BC fuel types include fossil fuels and flammable biomass, and major combustion sources include diesel exhaust, residential fuel burning, prescribed burns, and wildfires (2). BC particles from fossil fuel combustion and anthropogenic pollution are not significant sources of INPs. For example, studies on diesel exhaust have shown that less than 1 in 109 BC particles are ice nucleation active at −30 °C (19). Furthermore, ambient [INP] in Beijing, China were relatively constant over several weeks despite BC concentrations varying by a factor of 30 and reaching values as high as 17.26 μg⋅m−3 (20).Elevated [INP] have been observed in biomass-burning smoke during laboratory and field studies (21–23); however, it is unclear from these studies if the INPs are actually BC. Some studies have shown that BC may be the dominant INP type in select biomass burning conditions. For example, soot particles were found to contribute up to 64% of the INPs in prescribed burns within a predominantly wiregrass understory (24). Furthermore, BC contributed up to 70% to [INP] in controlled laboratory burns of grasses (25). As biomass burning represents ∼40% of global BC emissions (2), BC from biomass burning could be a significant source of INP globally. In both of these studies, however, the overall ice-active fractions may be too low to influence [INP], even on the regional level (21). Thus, it remains unclear whether BC contributes to [INP] outside of thick plumes and on a global scale (26).Regional- and global-scale estimates of BC [INP] rely on models that can implement theory-based or empirical ice nucleation parameterizations. Using parameterizations based on BC INP activity from the acetylene and kerosene-burner soot studies, models have found that BC contributes ∼50% to [INP] in springtime low-level Arctic mixed-phase clouds (27), and 23 to 61% to global [INP] depending on dust loadings (28). Taking into account the aforementioned negative results, these modeling studies highlight that BC’s contribution to [INP] is poorly constrained and is estimated to vary from no contribution to being the most abundant INP globally.To assess the role of BC from biomass burning as an INP, we determined the contribution of refractory BC (rBC)-containing particles to [INP] from field measurements of both prescribed burns and wildfires using the single-particle soot photometer coupled to a continuous-flow diffusion chamber (SP2-CFDC) (29, 30). The SP2-CFDC selectively removes rBC from an aerosol stream and quantifies that effect on [INP]. From these burns, we found that rBC-containing particles contributed ≤10% to [INP]. From these results, we developed a surface-area normalized parameterization for BC INPs from biomass burning. The parameterization aligns well with other surface-area normalized parameterizations derived from laboratory proxies of BC and diesel exhaust BC (15, 19, 31). These parameterizations are over four orders of magnitude lower than the parameterization derived from acetylene and kerosene-burner soot studies and used in the aforementioned modeling studies. Assuming the INP characteristics of BC from the burns in this study can be extended to different biomass-burning fuel types and combustion conditions, this study strongly suggests that BC is not an efficient INP. Under this assumption, we assessed the global importance of BC as an INP by applying our parameterization to simulated biomass-burning aerosol from a global chemical transport model. A similar parameterization for diesel exhaust (19) was applied to simulated fossil fuel BC. From these treatments, we estimate that BC’s contribution to simulated, potential [INP] is only ∼5% on a global average.     

TIMI risk score underestimates prognosis in unstable angina/non-ST segment elevation myocardial infarction

OBJECTIVES: To determine the value of the TIMI risk score in the individual risk stratification of patients with unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI). BACKGROUND: TIMI risk score is a validated tool to identify groups of patients at high risk for major cardiac events. Its prognostic value in individual patients with current diagnostic tools and therapy is unknown. METHODS: TIMI risk score was assessed in patients with UA/NSTEMI admitted to six Belgian hospitals and related to clinical outcome at 30 days. RESULTS: Of the 500 patients enrolled, 49.4% were placed in the low TIMI risk group (score = 0-3) and 50.6% in the high-risk group (score = 4-7). Multivariate analysis identified raised cardiac markers and invasive strategy, but not high TIMI risk score as independent predictors of death and new myocardial infarction (MI). Moreover, the incidence of death and MI in the low TIMI risk group with positive cardiac markers was not lower than in the high TIMI risk group with positive markers: 15.1% versus 17.8% (P = 0.7). CONCLUSIONS: TIMI risk score is of limited value for individual risk stratification. The presence of positive cardiac markers (troponin) appears to be a more powerful prognostic marker.