Hydrochlorothiazide in CLDN16 mutation

BACKGROUND: Hydrochlorothiazide (HCT) is applied in the therapy of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by claudin-16 (CLDN16) mutation. However, the short-term efficacy of HCT to reduce hypercalciuria in FHHNC has not yet been demonstrated in a clinical trial. METHODS: Four male and four female patients with FHHNC and CLDN16 mutation, under long-standing HCT therapy (0.4-1.2 mg/kg, median 0.9 mg/kg, dose according to calciuria), aged 0.7-22.4 years, were included in a clinical study to investigate the effect of HCT on calciuria. The study design consisted of three periods: continued therapy for 4 weeks, HCT withdrawal for 6 weeks and restart of therapy at the same dose for 4 weeks. Calciuria and magnesiuria were assessed weekly as Ca/creat and Mg/creat ratio, every 2 weeks in 24 h urine, and serum Mg, K and kaliuria (s-Mg, s-K and K/creat) at weeks 0, 6, 10 and 14. The data of each study period were averaged and analysed by Friedman and Wilcoxon test. RESULTS: Ca/creat was significantly reduced by HCT (median before/at/after withdrawal 0.76/1.24/0.77 mol/mol creat; n = 8, P<0.05). The reduction of Ca/24 h by HCT was not statistically significant (0.13/0.19/0.13 mmol/kg x 24 h; n = 5). Serum Mg (0.51/0.64/0.56 mmol/l; n = 8, P<0.05) and Serum K (3.65/4.35/3.65 mmol/l; n = 8, P<0.05) were significantly higher during withdrawal. However, Mg/creat (0.98/0.90/0.90 mol/mol creat; n = 8), Mg/24 h (0.14/0.12/0.18 mmol/kg x 24h; n = 5) and K/creat (6.3/8.4/6.2 mol/mol creat; n = 8) remained statistically unchanged during withdrawal. CONCLUSIONS: We demonstrated that HCT is effective in reducing hypercalciuria due to CLDN16 mutation on a short-term basis. However, the efficacy of HCT to attenuate disease progression remains to be elucidated.

Investigation of young water inflow in karst aquifers using SF6–CFC–3H/He–85Kr–39Ar and stable isotope components

Karst aquifers are known for their wide distribution of water transfer velocities. From this observation, a multiple geochemical tracer approach seems to be particularly well suited to provide a significant assessment of groundwater flows, but the choice of adapted tracers is essential. In this study, several common tracers in karst aquifers such as physicochemical parameters, major ions, stable isotopes, and d13C to more specific tracers such as dating tracers – 14C, 3H, 3H–3He, CFC-12, SF6 and 85Kr, and 39Ar – were used, in a fractured karstic carbonated aquifer located in Burgundy (France). The information carried by each tracer and the best sampling strategy are compared on the basis of geochemical monitoring done during several recharge events and over longer time periods (months to years). This study’s results demonstrate that at the seasonal and recharge event time scale, the variability of concentrations is low for most tracers due to the broad spectrum of groundwater mixings. The tracers used traditionally for the study of karst aquifers, i.e., physicochemical parameters and major ions, efficiently describe hydrological processes such as the direct and differed recharge, but require being monitored at short time steps during recharge events to be maximized. From stable isotopes, tritium, and Cl� contents, the proportion of the fast direct recharge by the largest porosity was estimated using a binary mixing model. The use of tracers such as CFC-12, SF6, and 85Kr in karst aquifers provides additional information, notably an estimation of apparent age, but they require good preliminary knowledge of the karst system to interpret the results suitably. The CFC-12 and SF6 methods efficiently determine the apparent age of baseflow, but it is preferable to sample the groundwater during the recharge event. Furthermore, these methods are based on different assumptions such as regional enrichment in atmospheric SF6, excess air, and flow models among others. 85Kr and 39Ar concentrations can potentially provide a more direct estimation of groundwater residence time. Conversely, the 3H–3He method is inefficient in the karst aquifer for dating due to 3He degassing.

Macrofossils as records of plant responses to rapid Late Glacial climatic changes at three sites in the Swiss Alps

Plant macrofossils from the end of the Younger Dryas were analysed at three sites, Gerzensee (603 m asl), Leysin (1230 m asl), and Zeneggen (1510 m asl). For the first two sites an oxygen-isotope record is also available that was used to develop a time scale (Schwander et al., this volume); dates refer therefore to calibrated years according to the GRIP time scale. Around Gerzensee a pine forest with some tree birches grew during the Younger Dryas. With the onset of the isotopic shift initiating the rapid warming (about 11,535 cal. years before 1950), the pine forest became more productive and denser. At Leysin no trees except some juniper scrub grew during the Younger Dryas. Tree birches, pine, and poplar immigrated from lower altitudes and arrived after the end of the isotopic shift (about 11,487 B.P.), i.e., at the beginning of the Preboreal (at about 11,420 B.P.). Zeneggen is situated somewhat higher than Leysin, but single tree birches and pines survived the Younger Dryas at the site. At the beginning of the Preboreal their productivity and population densities increased. Simultaneously shifts from Nitella to Chara and from silt to gyttja are recorded, all indicating rapidly warming conditions and higher nutrient levels of the lake water (and probably of the soils in the catchment). At Gerzensee the beginning of the Younger Dryas was also analysed: the beginning of the isotopic shift correlates within one sample (about 15 years) to rapid decreases of macrofossils of pines and tree birches.

Isotope signature of the Younger Dryas and two minor oscillations at Gerzensee (Switzerland): palaeoclimatic and palaeolimnologic interpretation based on bulk and biogenic carbonates

Oxygen- and carbon-isotope ratios in the carbonate of benthic ostracodes (Pseudocandona marchica) and molluscs (Pisidium ssp.) were measured across the transitions bordering the Younger Dryas chronozone in littoral lacustrine cores from Gerzensee (Switzerland). The specific biogenic carbonate records confirm the major shifts already visible in the continuous bulk-carbonate oxygen-isotope record (δ18OCc). If corrected for their vital offsets, oxygen-isotope ratios of Pisidium and juvenile P. marchica, both formed in summer, are almost identical to δ18OCc. This bulk carbonate is mainly composed of encrustations of benthic macrophythes (Chara ssp.), also mainly produced during summer. Adult P. marchica, which calcify in winter, show consistently higher δ18O, larger shifts across both transitions, and short positive excursions compared with the summer forms, especially during early Preboreal. Despite such complexity, the δ18O of adult P. marchica probably reflects more accurately the variations of the δ18O of former lake water because, during winter, calcification temperatures are less variable and the water column isotopically uniform. The difference between normalised δ18O of calcite precipitated in winter to that formed in summer can be used to estimate the minimum difference between summer and winter water temperatures. In general, the results indicate warmer summers during the late Allerød and early Preboreal compared with the Younger Dryas. Altogether, the isotopic composition of lake water (δ18OL) and of the dissolved inorganic carbonate (δ13CDIC) reconstructed from adult Pseudocandona marchica, as well as the seasonal water temperature contrasts, indicate that the major shifts in the δ18O of local precipitation at Gerzensee were augmented by changes of the lake's water balance, with relatively higher evaporative loss occurring during the Allerød compared with the Younger Dryas. It is possible that during the early Preboreal the lake might even have been hydrologically closed for a short period. We speculate that such hydrologic changes reflect a combination of varying evapotranspiration and a rearrangement of groundwater recharge during those climatic shifts.