Arginine: mediator or modulator of sepsis?

Arginine is a conditionally essential amino acid that plays pivotal roles in maintaining body homeostasis. Arginine is a substrate for protein synthesis but can also be metabolized to various bioactive compounds that include nitric oxide, ornithine, polyamines, creatine phosphate, agmatine, and dimethylarginines. Arginine produces physiologic effects via nitric oxide dependent and independent pathways. Nitric oxide is important for the modulation of vascular tone, inflammation, immune function, endothelial function, platelet and leukocyte adherence, and neurotransmission. Nitric oxide modulates many biochemical processes important for the response to sepsis. Arginine, independent of nitric oxide, is important for growth, wound healing, cardiovascular function, immune function, inflammatory responses, energy metabolism, urea cycle function, and other metabolic processes. Arginine supplementation improves outcomes in animals with sepsis, wounds, ischemia-reperfusion injury, and following thermal injury. Enteral administration of arginine improves endothelial function but has little effect upon hemodynamics during human sepsis. An analysis of clinical studies using enteral formulas with supplemental arginine suggests benefits upon outcome, with no evidence of significant detrimental effects.     

Under the Weather: Coping with Alcohol Abuse and Alcoholism

Under the Weather: Coping with Alcohol Abuse and Alcoholism.By John G. Cooney. Newleaf, Dublin, 2002, 176 pp., £9.99.ISBN 0-7171-3424-5. This is a new edition of a book first published in 1991. Ifthat means the original sold well enough to persuade the publishersthat it was worth updating, one     

Body mass index in relation to ovarian cancer survival.

Evidence for an association between indicators of adiposity and survival after ovarian cancer has been inconsistent. A prospective cohort study was conducted in China to examine the relationship between ovarian cancer survival and body mass index (BMI). From the 214 patients recruited in 1999 to 2000 with histopathologically confirmed invasive epithelial ovarian cancer, 207 patients or their close relatives (96.7% of cases) were traced and followed to 2003. Deaths were recorded and Cox proportional hazards regression was used to obtain hazard ratios (HR) and 95% confidence intervals (95% CI) from multivariate models. Reduced survival was observed among patients with BMI > or = 25 kg/m(2) at 5 years before diagnosis (P = 0.001). There were 98 (59.8%) of 164 patients with BMI <25 kg/m(2) survived to the time of interview compared with only 15 women (34.9%) among the 43 patients whose BMI was > or =25 kg/m(2). The HRs significantly increased with higher BMI at 5 years before diagnosis but not at diagnosis nor at age 21 years. The adjusted HR was 2.33 (95% CI, 1.12-4.87) for BMI of > or =25 versus <20 kg/m(2), with a significant dose-response relationship. The HR was 3.31 (95% CI, 1.26-8.73) among patients who had been overweight or obese at age 21 years, but a linear dose-response was not found. We conclude that premorbid BMI may have independent prognostic significance in ovarian cancer.     

Comprehensive analysis of CDKN2A status in microdissected urothelial cell carcinoma reveals potential haploinsufficiency, a high frequency of homozygous co-deletion and associations with clinical phenotype.

PURPOSE: There are significant differences in reported frequencies, modes of inactivation, and clinical significance of CDKN2A in urothelial cell carcinoma (UCC). We aimed to address these issues by investigating all possible modes of inactivation and clinicopathologic variables in a single tumor panel. EXPERIMENTAL DESIGN: Fifty microdissected UCCs were examined. CDKN2A gene dosage (quantitative real-time PCR), allelic status (microsatellite analysis), hypermethylation (methylation-specific PCR), mutation status (denaturing high-performance liquid chromatography and sequencing), protein expression (immunohistochemistry), and clinicopathologic variables (stage, grade, and disease recurrence during follow-up) were assessed. RESULTS: Exon 2 was underrepresented in 20 of 46 (43%) and exon 1beta in 21 of 46 (46%) of cases. Underrepresentation of exon 2 was accompanied by loss of heterozygosity (LOH) of 9p in 6 of 18 (30%) and of exon 1beta in 11 of 19 assessable cases (58%). Overall, LOH of 9p was identified in 15/41 (37%). Homozygous deletion of exons 2 and 1beta was detected in 16 of 46 (35%) and 10 of 46 tumors (22%), respectively. Co-deletion was most common, but exon 2-specific homozygous deletion was also detected. In tumors without homozygous deletion, p16 promoter hypermethylation was detected in 1 of 18 (6%). Hypermethylation of the p14ARF promoter or mutations in CDKN2A were not observed. Homozygous deletion of exon 2 or LOH on 9p were associated with invasion. Homozygous deletion of exon 2 or exon 1beta was associated with recurrent disease. CONCLUSIONS: These results confirm CDKN2A as a clinically relevant target for inactivation in UCC and show that the true frequency of alteration is only revealed by comprehensive analysis. Our results suggest that CDKN2A may be haploinsufficient in human cancer.     

Heterogeneous iodine-organic chemistry fast-tracks marine new particle formation

The gas-phase formation of new particles less than 1 nm in size and their subsequent growth significantly alters the availability of cloud condensation nuclei (CCN, >30–50 nm), leading to impacts on cloud reflectance and the global radiative budget. However, this growth cannot be accounted for by condensation of typical species driving the initial nucleation. Here, we present evidence that nucleated iodine oxide clusters provide unique sites for the accelerated growth of organic vapors to overcome the coagulation sink. Heterogeneous reactions form low-volatility organic acids and alkylaminium salts in the particle phase, while further oligomerization of small α-dicarbonyls (e.g., glyoxal) drives the particle growth. This identified heterogeneous mechanism explains the occurrence of particle production events at organic vapor concentrations almost an order of magnitude lower than those required for growth via condensation alone. A notable fraction of iodine associated with these growing particles is recycled back into the gas phase, suggesting an effective transport mechanism for iodine to remote regions, acting as a “catalyst” for nucleation and subsequent new particle production in marine air.

Marine aerosol formation contributes significantly to the global radiative budget given the high susceptibility of marine stratiform cloud radiative properties to changes in cloud condensation nuclei (CCN) availability. Atmospheric new-particle-formation is thought to involve nucleation of sulfuric acid with water, ammonia, or amines followed by condensation/growth in the presence of organic vapors (1, 2). Unique in the marine boundary layer (MBL), new particle formation involves sequential addition of HIO₃ or clustering of iodine oxides (I_xO_y) (3, 4). In specific source regions such as coastal zones, seaweed beds, or snowpack/pack-ice, iodine oxide nucleation can be a driving force for nucleation (5–7). Over Arctic waters, nonetheless, one study finds insufficient iodic acid vapors to grow nucleated particles to CCN sizes (8), whereas another study finds that both nucleation and growth are almost exclusively driven by iodic acid (9). Over the open ocean, the supply of iodine oxides has been thought to be limited; however, recent measurements suggest that significant reactive iodine chemistry can occur in these regions (10). Moreover, observational evidence exists for open ocean particle formation and growth, especially when oceanic productivity is high (11, 12). An increase in atmospheric iodine levels in the North Atlantic since the mid-20th century has been shown to be driven by growth of anthropogenic ozone and enhanced subice phytoplankton production (13). While the reported IO concentration (0.4–3.1 ppt) in the remote MBL (10, 14, 15) is likely sufficient for formation of prenucleation clusters (∼1 nm), growth of these initial clusters requires the presence of other condensable vapors (16). Since preexisting aerosol particles act as a strong sink for the nucleated clusters, thus inhibiting atmospheric aerosol and CCN formation (17, 18), this early growth phase is essential for their survival. Whereas sulfuric acid vapor is also involved in nucleation, its level in remote open ocean is generally too low (10⁵ molecules cm⁻³) to support subsequent particle growth, leaving organic vapors as the most plausible alternative for particle growth.In the marine atmosphere, condensing organics must originate from the oxidation of marine volatile organic compounds (VOCs), which predominantly comprise C₁–C₅ VOCs (e.g., isoprene) released from phytoplankton. Principal high volatility oxidation products consist of intermediate oxidized organics (IOOs), such as polyhydric alcohols (e.g., tetrols) or polyfunctional carbonyls (e.g., glyoxal) (19–22). Nonetheless, growth of available prenucleation clusters/nanometer particles requires condensing organic molecules of low effective volatilities (i.e., saturation mass concentration, C* < ∼10⁻³ μg m⁻³); otherwise, preferential condensation of the organic mass to larger-diameter particles would occur (23, 24). Formation of such extremely low-volatility organic compounds (ELVOCs) from gas-phase reaction is well established for monoterpene oxidation products (25, 26).A potential pathway for formation of low-volatility organics could also result from particle-phase chemical reactions induced by iodine oxides in the early stages of marine particle formation. When the underlying chemistry is sufficiently fast, kinetic condensation occurs, resulting in particles with diameters smaller than about 50 nm growing at the same rate (e.g., nm h⁻¹) (24). If, however, particle-phase chemistry is preferentially favored in the smallest particles (i.e., stemming from the higher relative concentration of iodine oxides in freshly formed marine particles), growth of the nucleated particles could proceed more rapidly, as compared to that in which gas-phase chemistry is the source of the low-volatility compounds (23).In this paper, we present experimental results from field measurements as well as laboratory studies of nanometer particle growth and derive a plausible chemical mechanism from the results that can explain the observations of ultrafine particle growth in the marine atmosphere. The results suggest that both iodine and condensed organics contribute to particle growth from a nascent nucleation mode into an ultrafine particle mode. Moreover, laboratory studies of the growth of seed iodine oxide particles (IOP) via heterogeneous reactions with organic vapors suggest a hitherto unrecognized mechanism that fast-tracks the growth of nucleation mode clusters into survivable aerosol particles. In this process, a notable fraction of the iodine associated with these growing particles is recycled back to the gas phase, suggesting a transport mechanism for iodine to remote regions.