High lactate dehydrogenase levels at admission for painful vaso-occlusive crisis is associated with severe outcome in adult SCD patients

Objectives

The aim of this study is to assess biological prognostic factors at the onset of vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD).

Methods

A monocentric prospective study including all patients admitted for VOC in a reference center for SCD was utilized. We used multivariate logistic regression to find independent predictors of severe evolution, defined by death or a worsening clinical state indicating transfusion or transfer to the intensive care unit.

Results

Eighty eight patients were included, 63% were women, median age of 23 years, and 90% of patients were homozygous SCD, 10% compound heterozygous. VOC became severe in 17 patients. Patients with severe VOC were more frequently males, who also had higher white blood cell (WBC) count, procalcitonin (PCT), and lactate dehydrogenase (LDH) levels. LDH level was the best predictor of the outcome; WBC and PCT had no significant added predictive values when coupled with LDH in multivariable models, even in patients with fever or acute chest syndrome. Severe evolution always occurred when LDH levels were over 4 times the upper limit of the normal range at admission and never occurred when LDH levels were within the normal range.

Conclusion

Further studies should confirm the predictive value of LDH before its widespread use as a prognostic factor. If it is confirmed, the benefit of preemptive transfusion when LDH levels at admission are very high could be investigated.     

Beta cell function: the role of macrophage migration inhibitory factor

During evolution, beta cells adapted to a sole aim: the production and stimulus-dependent secretion of insulin. This acquired specificity was accompanied by a loss of protection mechanisms predisposing beta cell to a high vulnerability. Among beta cell-damaging molecules, a new one has been identified recently: macrophage migration inhibitory factor (MIF). MIF was at first designated as a T-cell product that inhibits random movement of macrophages. Over the years, the number of functions attributed to this protein increased significantly, positioning MIF at the top of inflammatory cascade in the combat against infection and in immunoinflammatory and autoimmune diseases. This exceptionally versatile molecule regulates insulin secretion in physiological conditions, while in pathological states it alters beta cell function and induces their apoptosis or necrosis and affects beta cell neoplasia.     

Global phosphorus retention by river damming

More than 70,000 large dams have been built worldwide. With growing water stress and demand for energy, this number will continue to increase in the foreseeable future. Damming greatly modifies the ecological functioning of river systems. In particular, dam reservoirs sequester nutrient elements and, hence, reduce downstream transfer of nutrients to floodplains, lakes, wetlands, and coastal marine environments. Here, we quantify the global impact of dams on the riverine fluxes and speciation of the limiting nutrient phosphorus (P), using a mechanistic modeling approach that accounts for the in-reservoir biogeochemical transformations of P. According to the model calculations, the mass of total P (TP) trapped in reservoirs nearly doubled between 1970 and 2000, reaching 42 Gmol y⁻¹, or 12% of the global river TP load in 2000. Because of the current surge in dam building, we project that by 2030, about 17% of the global river TP load will be sequestered in reservoir sediments. The largest projected increases in TP and reactive P (RP) retention by damming will take place in Asia and South America, especially in the Yangtze, Mekong, and Amazon drainage basins. Despite the large P retention capacity of reservoirs, the export of RP from watersheds will continue to grow unless additional measures are taken to curb anthropogenic P emissions.The systematic damming of rivers began with the onset of the Industrial Revolution and peaked in the period from 1950 to 1980 (1, 2). After slowing down during the 1990s, the pace of dam building has recently risen again sharply (3). As a consequence, the number of hydroelectric dams with generating capacity >1 MW is expected to nearly double over the next two decades (2). The current surge in dam construction will increase the proportion of rivers that are moderately to severely impacted by flow regulation from about 50% at the end of the 20th century to over 90% by 2030 (3). Homogenization of river flow regimes resulting from damming is a growing, worldwide phenomenon and has been invoked as one of the reasons for the decline in freshwater biodiversity (4).Another major global driver of environmental change of river systems is enrichment by anthropogenic nutrients, in particular phosphorus (P) (5, 6). Fertilizer use, soil erosion, and the discharge of wastewater have more than doubled the global P load to watersheds compared with the inferred natural baseline (7–10). Because P limits or colimits primary productivity of many aquatic ecosystems, increased river fluxes of P have been identified as a main cause of eutrophication of surface water bodies, including lakes and coastal marine environments (6, 11, 12). River damming and P enrichment are interacting anthropogenic forcings, because sediments accumulating in reservoirs trap P and, thus, reduce the downstream transfer of P along the river continuum (13–15). This raises the question to what extent P retention by dams may offset anthropogenic P enrichment of rivers.The number of published studies from which P retention efficiencies in dam reservoirs can be obtained is small: an extensive literature search only yields useable data for 155 reservoirs (Dataset S1), that is, less than 0.2% of the ∼75,000 dam reservoirs larger than 0.1 km² (16). The existing data nonetheless clearly show that even a single dam can significantly alter the flow of P along a river. For example, dam-impounded Lake Kariba (Zambezi River), Lake Diefenbaker (South Saskatchewan River), and Lac d’Orient (Seine River) sequester ∼87%, 94%, and 71% of their total P inflows, respectively (17–19). For the 1 million km² Lake Winnipeg watershed, 28 reservoirs and lakes accumulate over 90% of the total P load (18). The global retention of P by dams, however, remains poorly constrained (20, 21). Previous estimations have simply applied a correction factor to river P loads to represent retention by dams (22–24). This approach does not distinguish between the various chemical forms of P, nor does it account for differences in reservoir hydraulics or provide information about uncertainties on retention estimates.Here, we follow a mass balance modeling approach developed previously to calculate the global retention of nutrient silicon by dams (25). The mass balance model represents the key biogeochemical processes controlling P cycling in reservoirs (Fig. 1). The model separates total P (TP) into the following pools: total dissolved P (TDP); particulate organic P (POP); exchangeable P (EP); and unreactive particulate P (UPP). UPP consists mostly of crystalline phosphate minerals that are inert on reservoir-relevant timescales (≤100 y); TDP comprises inorganic and organic forms of P, whereas EP includes orthophosphate and organic P molecules sorbed to or coprecipitated with oxides, clay minerals, and organic matter. Reactive P (RP) is defined as the sum of TDP, EP, and POP; RP represents the potentially bioavailable fraction of TP.Open in a separate windowFig. 1.Mass balance model used to estimate retention of P in reservoirs. F_in,i is the influx of the ith P pool into the reservoir, F_i,out is the corresponding efflux out of the reservoir, F₁₂ represents P fixation by primary productivity, F₂₁ represents mineralization of POP, F₁₃ and F₃₁ are the sorption and desorption rates of dissolved P, and F_i,bur is the permanent burial flux of the ith particulate P pool in the reservoir’s sediments.Global predictive relationships for the retention of TP and RP in reservoirs are derived from a Monte Carlo analysis of the model, which accounts for parameter variability within expected ranges. The relationships are applied to the reservoirs in the Global Reservoirs and Dams (GRanD) database (16), to estimate the sequestration of TP and RP by dams in each of the major river basins of the world. Throughout, P retention efficiencies in a reservoir are defined asRX=Xin−XoutXin,[1]where R_X is the fractional retention of TP or RP, and X_in and X_out are the input and output fluxes of TP or RP in units of mass per unit time. Annual amounts of TP and RP retained in a reservoir are then calculated by multiplying the R_X values with the corresponding TP and RP input fluxes from the dam’s upstream watershed. The latter are obtained from the Global-NEWS-HD model, which estimates emission yields for dissolved inorganic P (DIP), dissolved organic P (DOP), and particulate P (PP), of which 20% is assumed to be reactive (7, 26). The Global-NEWS-HD yield estimates are based on the biogeophysical characteristics, population density, socioeconomic status, land use, and climatic conditions within the drainage basin (20).Because the biogeochemical mass balance model explicitly represents the in-reservoir transformations between the different forms of P, it allows us to estimate how dams modify both the total and reactive fluxes of P along rivers. With the proposed approach, we reconstruct global TP and RP retentions by dams in 1970 and 2000 and make projections for 2030. For the latter, we apply the nutrient P loading trends developed for the four Millennium Ecosystem Assessment (MEA) scenarios (27). The results illustrate the evolving role of damming in the continental P cycle and, in particular, the ongoing geographical shift in P retention resulting from the current boom in dam construction.     

Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations

Hereditary inclusion body myopathy (HIBM) is an adult onset neuromuscular disorder associated with mutations in the gene UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), whose product is the rate limiting bi-functional enzyme catalyzing the first two steps of sialic acid biosynthesis. Loss of GNE activity in HIBM is thought to impair sialic acid production and interfere with proper sialylation of glycoconjugates, but it remains unclear how such a defect would lead to muscle destruction and muscle weakness. Hypoglycosylation of alpha-dystroglycan, a central protein of the skeletal muscle dystrophin-glycoprotein complex, results in disturbed interactions with extracellular matrix proteins. This has recently been identified as the pathomechanism involved in several congenital muscular dystrophies. We examined the glycosylation status of alpha-dystroglycan in muscle biopsies of four HIBM patients of non-Iranian Jewish origin (one American, two Indians, and one Greek). Two of these patients carry novel compound heterozygous GNE mutations on exon 2 and exon 9. All four muscle biopsies showed absent or markedly reduced immunolabeling with two different antibodies (VIA4 and IIH6) to glycosylated epitopes of alpha-dystroglycan. Normal labeling was found using antibodies to the core alpha-dystroglycan protein, beta-dystroglycan, and laminin alpha-2. These findings resemble those found for other congenital muscular dystrophies, suggesting that HIBM may be a "dystroglycanopathy," and providing an explanation for the muscle weakness of patients with GNE mutations.     

Supplementation with Guanidinoacetic Acid in Women with Chronic Fatigue Syndrome

A variety of dietary interventions has been used in the management of chronic fatigue syndrome (CFS), yet no therapeutic modality has demonstrated conclusive positive results in terms of effectiveness. The main aim of this study was to evaluate the effects of orally administered guanidinoacetic acid (GAA) on multidimensional fatigue inventory (MFI), musculoskeletal soreness, health-related quality of life, exercise performance, screening laboratory studies, and the occurrence of adverse events in women with CFS. Twenty-one women (age 39.3 ± 8.8 years, weight 62.8 ± 8.5 kg, height 169.5 ± 5.8 cm) who fulfilled the 1994 Centers for Disease Control and Prevention criteria for CFS were randomized in a double-blind, cross-over design, from 1 September 2014 through 31 May 2015, to receive either GAA (2.4 grams per day) or placebo (cellulose) by oral administration for three months, with a two-month wash-out period. No effects of intervention were found for the primary efficacy outcome (MFI score for general fatigue), and musculoskeletal pain at rest and during activity. After three months of intervention, participants receiving GAA significantly increased muscular creatine levels compared with the placebo group (36.3% vs. 2.4%; p < 0.01). Furthermore, changes from baseline in muscular strength and aerobic power were significantly greater in the GAA group compared with placebo (p < 0.05). Results from this study indicated that supplemental GAA can positively affect creatine metabolism and work capacity in women with CFS, yet GAA had no effect on main clinical outcomes, such as general fatigue and musculoskeletal soreness.     

Inhibitory effect of the novel anti-estrogen EM-800 and medroxyprogesterone acetate on estrone-stimulated growth of dimethylbenz[a]anthracene-induced mammary carcinoma in rats

The novel anti-estrogen EM-800 and medroxyprogesterone acetate (MPA) inhibit estrone (E₁)-stimulated growth of dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in a rat model. After 65 days, ovariectomy (OVX) decreased total tumor area to 9.6 ± 3.9% of initial size, while E₁ (1.0 μg, s.c., twice daily) stimulated tumor growth to 225 ± 40.9% of initial size. Daily oral administration of 2.5 mg/kg body weight of EM-800 completely abolished E₁-stimulated tumor growth. A low daily dose of EM-800 (0.25 mg/kg body weight) or MPA (1 mg, s.c., twice daily) used alone partially reversed the stimulatory effect of E₁ on the growth of DMBA-induced tumors. The combination of both compounds, however, caused a more potent inhibitory effect than each compound used alone. A high dose of EM-800 completely or almost completely inhibited the E₁-stimulated vaginal and uterine weights, respectively. The same dose of EM-800 completely reversed the inhibitory effect of E₁ on serum luteinizing hormone levels. Uterine, vaginal and tumoral estrogen and progesterone receptor levels were reduced markedly following treatment with EM-800. Our data show that the combination of the pure anti-estrogen EM-800 with the androgenic compound MPA achieves greater inhibition of the growth of DMBA-induced mammary carcinoma than that achieved by each compound used alone. Int. J. Cancer 73:580–586, 1997. © 1997 Wiley-Liss, Inc.     

Concurrent Accelerated Hyperfractionated Radiation Therapy and Carboplatin/etoposide in Patients With Malignant Glioma: Long-term break Results of A Phase II Study

Purpose: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. Material and methods: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200mg/m², and VP 16, 200mg/m², both given once weekly during the RT course. Results: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. Conclusions: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.     

Chronic liver inflammation and hepatocellular carcinogenesis are independent of S100A9

The S100A8/A9 heterodimer (calprotectin) acts as a danger signal when secreted into the extracellular space during inflammation and tissue damage. It promotes proinflammatory responses and drives tumor development in different models of inflammation‐driven carcinogenesis. S100A8/A9 is strongly expressed in several human tumors, including hepatocellular carcinoma (HCC). Apart from this evidence, the role of calprotectin in hepatocyte transformation and tumor microenvironment is still unknown. The aim of this study was to define the function of S100A8/A9 in inflammation‐driven HCC. Mice lacking S100a9 were crossed with the Mdr2^?/? model, a prototype of inflammation‐induced HCC formation. S100a9^?/? Mdr2^?/? (dKO) mice displayed no significant differences in tumor incidence or multiplicity compared to Mdr2^?/? animals. Chronic liver inflammation, fibrosis and oval cell activation were not affected upon S100a9 deletion. Our data demonstrate that, although highly upregulated, calprotectin is dispensable in the onset and development of HCC, and in the maintenance of liver inflammation.     

200 Hz flying-spot technology of the LaserSight LSX excimer laser in the treatment of myopic astigmatism: six and 12 month outcomes of laser in situ keratomileusis and photorefractive keratectomy

PURPOSE: To evaluate safety, efficacy, predictability, and stability in the treatment of myopic astigmatism with laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) using the 200 Hz flying-spot technology of the LaserSight LSX excimer laser. SETTING: SynsLaser Clinic, Troms?, Norway. METHODS: This retrospective study included 110 eyes treated with LASIK and 87 eyes treated with PRK that were available for evaluation at 6 and 12 months, respectively. The mean preoperative spherical equivalent (SE) was -5.35 diopters (D) +/- 2.50 (SD) (range -1.13 to -11.88 D) in the LASIK eyes and -4.72 +/- 2.82 D (range -1.00 to -15.50 D) in the PRK eyes. The treated cylinder was 4.00 D in both groups. Eleven (8.5%) LASIK eyes and 8 (7.4%) PRK eyes had secondary surgical procedures before 6 and 12 months, respectively, and were excluded when the 6 and 12 month outcomes were analyzed. RESULTS: None of the eyes lost 2 or more lines of best spectacle-corrected visual acuity. Seventy-seven percent of the LASIK eyes and 78% of the PRK eyes achieved an uncorrected visual acuity of 20/20 or better; 98% in both groups achieved 20/40 or better. The SE was within +/-0.5 D of the desired refraction in 83% of the LASIK eyes and 77% of the PRK eyes; it was within +/-1.0 D in 97% and 98%, respectively. The cylinder correction had a mean magnitude of error of 0.04 +/- 0.31 D (range -0.96 to +0.85 D) in the LASIK eyes and 0.02 +/- 0.37 D (range -1.44 to +0.72 D) in the PRK eyes. Refractive stability was achieved at 1 month and beyond in the LASIK eyes and at 3 months and beyond in the PRK eyes. CONCLUSION: The outcomes of this study are comparable to those achieved with lasers that use small-beam technology with a lower frequency, as well as with other types of delivery systems. They suggest that the 200 Hz technology used in the LaserSight LSX excimer laser is safe, effective, and predictable and that with LASIK and PRK the results are stable when treating low to moderate myopia and astigmatism up to 4.0 D.