Central venous pulse pressure analysis using an R-synchronized pressure measurement system

Objective. The information derived from central venous catheters is underused. We developed an EKG-R synchronization and averaging system to obtained distinct CVP waveforms and analyzed components of these. Methods. Twenty-five paralyzed surgical patients undergoing CVP monitoring under mechanical ventilation were studied. CVP and EKG signals were analyzed employing our system, the mean CVP and CVP at end-diastole during expiration were compared, and CVP waveform components were measured using this system. Results. CVP waveforms were clearly visualized in all patients. They showed the a peak to be 1.8+/- 0.7 mmHg, which was the highest of three peaks, and the x trough to be lower than the y trough (-1.6+/- 0.7mmHgand-0.9+/- 0.5mmHg, respectively), withameanpulsepressureof3.4mmHg.ThedifferencebetweenthemeanCVPandCVPatend-diastoleduringexpirationwas0.58+/- 0.81 mmHg. Conclusions. The mean CVP can be used as an index of right ventricular preload in patients under mechanical ventilation with regular sinus rhythm. Our newly developed system is useful for clinical monitoring and for education in circulatory physiology.

Individualization of 5-fluorocytosine therapy

Using a convenient and fast HPLC procedure we determined serum concentrations of the fungistatic agent 5-fluorocytosine (5-FC) in 375 samples from 60 patients treated with this drug. The mean trough concentration (n = 127) was 64.3 mg/l (range: 11.8-208.0 mg/l), the mean peak concentration (n = 122) was 99.9 mg/l (range: 25.6-263.8 mg/l), the mean nonpeak/nontrough concentration (n = 126) was 80.1 mg/l (range: 10.5-268.0 mg/l). Totally 134 (35.7%) samples were outside the therapeutic range (25-100 mg/l), 108 (28.8%) being too high, 26 (6.9%) being too low. Forty-four (73%) patients showed 5-FC serum concentrations outside the therapeutic range at least once during the treatment course. In a prospective study we performed 65 dosage predictions on 30 patients by use of a 3-point method previously developed for aminoglycoside dosage adaptation. The mean absolute prediction error of the dosage adaptation was +0.7 mg/l (range: -26.0 to +28.0 mg/l). The root mean square prediction error was 10.7 mg/l. The mean predicted concentration (65.3 mg/l) agreed very well with the mean measured concentration (64.6 mg/l). The frequency distribution of 5-FC serum concentrations indicates that 5-FC monitoring is important. The applied pharmacokinetic method allows individual adaptations of 5-FC dosage with a clinically acceptable prediction error.

A Global Climatology of Baroclinically Influenced Tropical Cyclogenesis*

Tropical cyclogenesis is generally considered to occur in regions devoid of baroclinic structures; however, an appreciable number of tropical cyclones (TCs) form in baroclinic environments each year. A global climatology of these baroclinically influenced TC developments is presented in this study. An objective classification strategy is developed that focuses on the characteristics of the environmental state rather than on properties of the vortex, thus allowing for a pointwise “development pathway” classification of reanalysis data. The resulting climatology shows that variability within basins arises primarily as a result of local surface thermal contrasts and the positions of time-mean features on the subtropical tropopause. The pathway analyses are sampled to generate a global climatology of 1948–2010 TC developments classified by baroclinic influence: nonbaroclinic (70%), low-level baroclinic (9%), trough induced (5%), weak tropical transition (11%), and strong tropical transition (5%). All basins other than the North Atlantic are dominated by nonbaroclinic events; however, there is extensive interbasin variability in secondary development pathways. Within each basin, subregions and time periods are identified in which the relative importance of the development pathways also differs. The efficiency of tropical cyclogenesis is found to be highly dependent on development pathway. The peak efficiency defined in the classification subspace straddles the nonbaroclinic/trough-induced boundary, suggesting that the optimal environment for TC development includes a baroclinic contribution from an upper-level disturbance. By assessing the global distribution of baroclinically influenced TC formations, this study identifies regions and pathways whose further study could yield improvements in our understanding of this important subset of TC developments.

The implications of arterial Po2 oscillations for conventional arterial blood gas analysis

In a surfactant-depletion model of lung injury, tidal recruitment of atelectasis and changes in shunt fraction lead to large Pao2 oscillations. We investigated the effect of these oscillations on conventional arterial blood gas (ABG) results using different sampling techniques in ventilated rabbits. In each rabbit, 5 different ventilator settings were studied, 2 before saline lavage injury and 3 after lavage injury. Ventilator settings were altered according to 5 different goals for the amplitude and mean value of brachiocephalic Pao2 oscillations, as guided by a fast responding intraarterial probe. ABG collection was timed to obtain the sample at the peak or trough of the Pao2 oscillations, or over several respiratory cycles. Before lung injury, oscillations were small and sample timing did not influence Pao2. After saline lavage, when Po2 fluctuations measured by the indwelling arterial Po2 probe confirmed tidal recruitment, Pao2 by ABG was significantly higher at peak (295 +/- 130 mm Hg) compared with trough (74 +/- 15 mm Hg) or mean (125 +/- 75 mm Hg). In early, mild lung injury after saline lavage, Pao2 can vary markedly during the respiratory cycle. When atelectasis is recruited with each breath, interpretation of changes in shunt fraction, based on conventional ABG analysis, should account for potentially large respiratory variations in arterial Po2.

Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease

OBJECTIVE: The aetiology of Crohn's disease (CD) has been related to nucleotide-binding oligomerisation domain containing 2 (NOD2) and ATG16L1 gene variants. The observation of bacterial DNA translocation in patients with CD led us to hypothesise that this process may be facilitated in patients with NOD2/ATG16L1-variant genotypes, affecting the efficacy of anti-tumour necrosis factor (TNF) therapies. DESIGN: 179 patients with Crohn's disease were included. CD-related NOD2 and ATG16L1 variants were genotyped. Phagocytic and bactericidal activities were evaluated in blood neutrophils. Bacterial DNA, TNFα, IFNγ, IL-12p40, free serum infliximab/adalimumab levels and antidrug antibodies were measured. RESULTS: Bacterial DNA was found in 44% of patients with active disease versus 23% of patients with remitting disease (p=0.01). A NOD2-variant or ATG16L1-variant genotype was associated with bacterial DNA presence (OR 4.8; 95% CI 1.1 to 13.2; p=0.001; and OR 2.4; 95% CI 1.4 to 4.7; p=0.01, respectively). This OR was 12.6 (95% CI 4.2 to 37.8; p=0.001) for patients with a double-variant genotype. Bacterial DNA was associated with disease activity (OR 2.6; 95% CI 1.3 to 5.4; p=0.005). Single and double-gene variants were not associated with disease activity (p=0.19). Patients with a NOD2-variant genotype showed decreased phagocytic and bactericidal activities in blood neutrophils, increased TNFα levels in response to bacterial DNA and decreased trough levels of free anti-TNFα. The proportion of patients on an intensified biological therapy was significantly higher in the NOD2-variant groups. CONCLUSIONS: Our results characterise a subgroup of patients with CD who may require a more aggressive therapy to reduce the extent of inflammation and the risk of relapse

CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients

BACKGROUND After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and under-immunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients. METHODS Associations between 7 functional genetic variants and blood dose-adjusted trough (C0) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively. RESULTS Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2- to 2.6-fold higher daily TAC doses to reach the targeted C0 concentration at all studied time points (P ≤ 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement. CONCLUSIONS The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.

The behaviour of incompatible elements during hydrous melting of metasomatized peridotite at 4–6 GPa and 1000 °C–1200 °C

Trace element behavior during hydrous melting of a metasomatized garnet–peridotite was examined at pressures of 4–6 GPa and temperatures of 1000 °C–1200 °C, conditions appropriate for fluid penetrating the mantle wedge atop the subducting slab. Experiments were performed in a rocking multi-anvil apparatus using a diamond-trap setup. The compositions of the fluid and melt phases were measured using the cryogenic LA-ICP-MS technique. The water-saturated solidus of the K-lherzolite composition is located between 900 °C and 1000 °C at 4 GPa and between 1000 °C and 1100 °C at 5 and 6 GPa. The partition coefficients between fluid or melt and clinopyroxene reveal an asymmetric MREE trough with a minimum at Dy. The clinopyroxene in equilibrium with aqueous fluids is characterized by DUfluid–cpx > DThfluid–cpx while DUmelt–cpx tends to be similar to DThmelt–cpx. The partition coefficients between fluid or melt and garnet reveal very strong light to heavy REE fractionation, DLa/DLu from 95 (hydrous melt) to 1600 (aqueous fluid). The LILE are highly incompatible with partition coefficients > 50. The behavior of HFSE are decoupled, with DZr,Hf close to 1 while DNb,Ta > 10. Garnet is characterized by DUmelt/fluid–garnet < DThmelt/fluid–garnet. A comparison of our experimental partitioning results for trivalent cations as well as the results from the literature and the calculations carried out using the lattice strain model adapted to the presence of water in the bulk system indicates that H2O in the fluid or melt phase has a prominent effect on trace element partitioning. Garnet in mantle rocks in equilibrium with an aqueous fluid is characterized by significantly higher Do(3 +) for REE in the X site of the garnet compared with the partitioning values of the optimal cation in garnet in equilibrium with hydrous melts. Our data show for the first time that the change in the nature of the mobile phase (fluid vs. melt) does affect the affinities of trace elements into the garnet crystal at conditions below the second critical endpoint of the system. The same also applies for clinopyroxene, although this is less clear. Consequently, our new data allow for refinements in predictive modeling of element transfer from the slab to the mantle wedge and of possible compositions of metasomatized mantle that sources OIB magmatism.

The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers

Mutations in the vacuolar–type H+-ATPase B1 subunit gene ATP6V1B1 cause autosomal–recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G.A; p.E161K) that causes greatly diminished pump function in vitro. To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in theDallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild–type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low–Ca and low–Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P,0.01). Kidney stones of p.E161K carriers were more likely to contain calcium phosphate than stones of wild-type patients. In acute NH4Cl loading, p.E161K carriers displayed a higher trough urinary pH (5.34 versus 4.89; P=0.01) than wild-type patients. Overall, 14.6% of wild-type patients and 52.4% of p.E161K carriers were unable to acidify their urine below pH 5.3 and thus, can be considered to have incomplete dRTA. In summary, our data indicate that recurrent stone formers with the vacuolar H+-ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphate– containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.

Overdeepened glacial basins as archives for the Quaternary landscape evolution of the Alps

The Alps and the Alpine foreland have been shaped by repeated glaciations during Quaternary glacial-interglacial cycles. Extent, timing and impact on landscape evolution of these glaciations are, however, poorly constrained due to the fragmentary character of terrestrial archives. In this context, the sedimentary infills of subglacially eroded, ‘overdeepened’, basins may serve as important archives to complement the Quaternary stratigraphy over several glacial-interglacial cycles. In this thesis, the infills of deep subglacial basins in the Lower Glatt valley (N Switzerland) are explored to better constrain the Middle- to Late Pleistocene environmental change. Five drill cores gave direct insight into to the up to ~200 m thick valley fill at the study site and allowed for detailed analysis of sedimentary facies, age and architecture of the basin fills. A first focus is set on the sedimentology of coarse-grained diamicts with sorted interbeds overlying bedrock in the trough center, which mark the onset of deposition in many glacial bedrock troughs. Evidence from macro- and microsedimentology suggests that these sediments are emplaced subglacially and reflect deposition, reworking and deformation in response to repeated coupling and decoupling of the ice-bed interface promoted by high basal water pressures. Overlying these subglacial sediments, large volumes of sandy glacio-deltaic, fine-grained glacio-lacustrine and lacustrine sediments document sedimentation during glacier retreat from the basins. On these thick valley fill sequences the applicability and reliability of luminescence dating is investigated in a second step on the basis of experiments with several different luminescence signals, protocols and experiments to assess the signal stability. The valley fill of the Lower Glatt valley is then grouped into nine depositional cycles (Formations A-I), which are related to the Birrfeld Glaciation (~MIS2), the Beringen Glaciation (~MIS6), and up to three earlier Middle Pleistocene glaciations, tentatively correlated to the Hagenholz, Habsburg, and Möhlin Glaciations, according to the regional glaciation history. The complex bedrock geometry and valley fill architecture are shown to be the result of multiple erosion and infilling cycles and reflect the interplay of subglacial erosion, glacial to lacustrine infilling of overdeepened basins, and fluvial down-cutting and aggradation in the non-overdeepened valley fill. Evidence suggests that in the study area deep bedrock incision, and/or partial re-excavation, occurred mainly during the Beringen and Hagenholz Glaciation, while older structures may have existed. Together with the observation of minor, ‘inlaid’ glacial basins, dynamic changes in the magnitude and focus of subglacial erosion over time are documented.