Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.

BACKGROUND: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. OBJECTIVE: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. METHODS: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. RESULTS: Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. CONCLUSIONS: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.

Long-term measurements of NO3 radical at a semiarid urban site: 2. Seasonal trends and loss mechanisms.

This study is the first to present long-term measurements of the nitrate radical in an urban location. Extensive nitrate radical measurements were conducted together with ancillary parameters during a continuous two year campaign (2005-2007) in the semiarid location of Jerusalem. The average nighttime NO3 concentration was 27.3+/-43.5 ppt, the highest ever reported, with a seasonal average peak during summer (33.3+/-55.8 pptv) with maximum levels exceeding 800 pptv. Significant diurnal changes in NO3 concentrations were observed, caused by an unusual nighttime increase in ozone concentrations. The NO3 loss processes exhibited strong seasonal variability. Homogeneous gas-phase losses were the main removal processes during summer and spring. The heterogeneous losses of N2O5, averaged over the entire campaign, contributed to less than half of the direct losses even though they dominated the winter seasons and part of the autumn months. Statistical regression analysis showed that NO3 was inversely correlated with relative humidity and positively correlated with temperature and to a lesser extent with NO2 and O3, indicating that the heterogeneous removal processes were also important. The diurnal behavior of NO3 was examined using a one-dimensional chemical transport model. The simulations showed that NO3 trends and concentrations were influenced mainly by changes in ozone and nitrogen oxide levels and that the very high levels of NO3 can be explained by the entrainment of fresh ozone from the upper atmospheric levels. After sunset and in the early morning, the homogeneous processes are the major loss pathways, while the heterogeneous N2O5 removal pathway dominates the intermediate times.

Long-term measurements of NO(3) radical at a semiarid urban site: 1. Extreme concentration events and their oxidation capacity.

Nitrate radical (NO(3)), an important nighttime tropospheric oxidant, was measured continuously for two years (July 2005 to September 2007) in Jerusalem, a semiarid urban site, by long-path differential optical absorption spectroscopy (LP-DOAS). From this period, 21 days with the highest concentrations of nitrate radical (above 220 pptv) were selected for analysis. Joint measurements with the University of Heidelberg's LP-DOAS showed good agreement (r = 0.94). For all daytime measurements, NO(3) remained below the detection limit (8.5 pptv). The highest value recorded was more than 800 pptv (July 27, 2007), twice the maximum level reported previously. For this subset of measurements, mean maximum values for the extreme events were 345 pptv (SD = 135 pptv). Concentrations rose above detection limits at sunset, peaked between midnight and early morning, and returned to zero at sunrise. These elevated concentrations of NO(3) were a consequence of several factors, including an increase in ozone concentrations parallel to a substantial decrease in relative humidity during the night; Mean nighttime NO(2) levels above 10 ppbv, which prevented a deficiency in NO(3) precursors; Negligible NO levels during the night; and a substantial decrease in the loss processes, which led to a lower degradation frequency and allowed NO(3) lifetimes to build up to a maximum mean of 25 min. The results indicate that the major sink pathway for NO(3) was direct homogeneous gas phase reactions with VOC, and a smaller indirect pathway via hydrolysis of N(2)O(5). The Jerusalem measurements were used to estimate the oxidation potential of extreme NO(3) levels at an urban location. The 24 h average potential of NO(3), OH, and O(3) to oxidize hydrocarbons was evaluated for 30 separate VOCs. NO(3) was found to be responsible for approximately 70% of the oxidation of total VOCs and nearly 75% of the olefinic VOCs; which was more than twice the VOC oxidation potential of the OH radical. These results establish the NO(3) radical as an important atmospheric oxidant in Jerusalem.