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This work presents the results of kinetic measurements for the reactions of atomic bromine with the three isomers of trimethylbenzene at temperatures from 295 K to 354 K and at pressures close to atmospheric. The atomic bromine was produced by photolysis of Br 2 in a thermostated Pyrex chamber as described in our previous work. The reactants were present as dilute mixtures in argon with Br 2 in sufficient excess to scavenge the free radical products of the initiation step. Chemical analysis was by gas chromatography and the rate coefficients were calculated from the chromatographic results using the relative rate method. The experimentally measured temperature dependence of the rate coefficients for the reactions of Br with the trimethylbenzenes is given in the units cm 3 molec. -1 s -1 by: 1,2,3-trimethylbenzene + Br, log 10 ( k ) = -9.57 ± 0.43 - (996 ± 134)/ T ; 1,2,4-trimethylbenzene + Br, log 10 ( k ) = -9.74 ± 0.29 - (968 ± 91)/ T ; 1,3,5-trimethylbenzene + Br, log 10 ( k ) = -9.87 ± 0.26 - (1079 ± 85)/ T . The enthalpies and entropies of activation for these reactions are compared to those for the reactions of Br with toluene and the xylenes.

Population genetic studies of North Asian ethnic groups have focused on genetic variation of sex chromosomes and mitochondria. Studies of the extensive variation available from autosomal variation have appeared infrequently. We focus on relationships among population samples using new North Asia microhaplotype data. We combined genotypes from our laboratory on 58 microhaplotypes, distributed across 18 autosomes, on 3945 individuals from 75 populations with corresponding data extracted for 26 populations from the Thousand Genomes consortium and for 22 populations from the GenomeAsia 100 K project. A total of 7107 individuals in 122 total populations are analyzed using STRUCTURE, Principal Component Analysis, and phylogenetic tree analyses. North Asia populations sampled in Mongolia include: Buryats, Mongolians, Altai Kazakhs, and Tsaatans. Available Siberians include samples of Yakut, Khanty, and Komi Zyriane. Analyses of all 122 populations confirm many known relationships and show that most populations from North Asia form a cluster distinct from all other groups. Refinement of analyses on smaller subsets of populations reinforces the distinctiveness of North Asia and shows that the North Asia cluster identifies a region that is ancestral to Native Americans., (© 2022. The Author(s).)

This work reports the temperature dependence of the rate coefficients for the reactions of atomic bromine with the xylenes that are determined experimentally and theoretically. The experiments were carried out in a Pyrex chamber equipped with fluorescent lamps to measure the rate coefficients at temperatures from 295 K to 346 K. Experiments were made at several concentrations of oxygen to assess its potential kinetic role under atmospheric conditions and to validate comparison of our rate coefficients with those obtained by others using air as the diluent. Br 2 was used to generate Br atoms photolytically. The relative rate method was used to obtain the rate coefficients for the reactions of Br atoms with the xylenes. The reactions of Br with both toluene and diethyl ether (DEE) were used as reference reactions where the loss of the organic reactants was measured by gas chromatography. The rate coefficient for the reaction of Br with diethyl ether was also measured in the same way over the same temperature range with toluene as the reference reactant. The rate coefficients were independent of the concentration of O 2 . The experimentally determined temperature dependence of the rate coefficients of these reactions can be given in the units cm 3 molecule -1 s -1 by: o -xylene + Br, log 10 ( k ) = (-10.03 ± 0.35) - (921 ± 110)/ T ; m -xylene + Br, log 10 ( k ) = (-10.78 ± 0.09) - (787 ± 92/ T ); p -xylene + Br, log 10 ( k ) = (-9.98 ± 0.39) - (956 ± 121)/ T ; diethyl ether + Br, log 10 ( k ) = (-7.69 ± 0.55) - (1700 ± 180)/ T ). This leads to the following rate coefficients, in the units of cm 3 molecule -1 s -1 , based on our experimental measurements: o -xylene + Br, k (298 K) = 7.53 × 10 -14 ; m -xylene + Br, k (298 K) = 3.77 × 10 -14 ; p -xylene + Br, k (298 K) = 6.43 × 10 -14 ; diethyl ether + Br, k (298 K) = 4.02 × 10 -14 . Various ab initio methods including G3, G4, CCSD(T)/cc-pV(D,T)Z//MP2/aug-cc-pVDZ and CCSD(T)/cc-pV(D,T)Z//B3LYP/cc-pVTZ levels of theory were employed to gain detailed information about the kinetics as well as the thermochemical quantities. Among the ab initio methods, the G4 method performed remarkably well in describing the kinetics and thermochemistry of the xylenes + Br reaction system. Our theoretical calculations revealed that the reaction of Br atoms with the xylenes proceeds via a complex forming mechanism in an overall endothermic reaction. The rate determining step is the intramolecular rearrangement of the pre-reactive complex leading to the post-reactive complex. After lowering the relative energy of the corresponding transition state by less than 1.5 kJ mol -1 for this step in the reaction of each of the xylenes with Br, the calculated rate coefficients are in very good agreement with the experimental data.

The endoplasmic reticulum (ER) has emerged as a source of hydrogen peroxide (H 2 O 2 ) and a hub for peroxide-based signaling events. Here we outline cellular sources of ER-localized peroxide, including sources within and near the ER. Focusing on three ER-localized proteins-the molecular chaperone BiP, the transmembrane stress-sensor IRE1, and the calcium pump SERCA2-we discuss how post-translational modification of protein cysteines by H 2 O 2 can alter ER activities. We review how changed activities for these three proteins upon oxidation can modulate signaling events, and also how cysteine oxidation can serve to limit the cellular damage that is most often associated with elevated peroxide levels.

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). Loss of PGRN leads to lysosome dysfunction during aging. TMEM106B, a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM106B affects FTLD disease progression remains to be determined. Here, we report that TMEM106B deficiency in mice leads to accumulation of lysosome vacuoles at the distal end of the axon initial segment in motor neurons and the development of FTLD-related pathology during aging. Ablation of both PGRN and TMEM106B in mice results in severe neuronal loss and glial activation in the spinal cord, retina, and brain. Enlarged lysosomes are frequently found in both microglia and astrocytes. Loss of both PGRN and TMEM106B results in an increased accumulation of lysosomal vacuoles in the axon initial segment of motor neurons and enhances the manifestation of FTLD phenotypes with a much earlier onset. These results provide novel insights into the role of TMEM106B in the lysosome, in brain aging, and in FTLD pathogenesis., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Microhaplotypes have become a new type of forensic marker with a great ability to identify and deconvolute mixtures because massively parallel sequencing (MPS) allows the alleles (haplotypes) of the multi-SNP loci to be determined directly for an individual. As originally defined, a microhaplotype locus is a short segment of DNA with two or more SNPs defining three or more haplotypes. The length is short enough, less than about 300 bp, that the read length of current MPS technology can produce a phase-known sequence of each chromosome of an individual. As part of the discovery phase of our studies, data on 130 microhaplotype loci with estimates of haplotype frequency data on 83 populations have been published. To provide a better picture of global allele frequency variation, we have now tested 13 more populations for 65 of the microhaplotype loci from among those with higher levels of inter-population gene frequency variation, including 8 loci not previously published. These loci provide clear distinctions among 6 biogeographic regions and provide some information distinguishing up to 10 clusters of populations.

Genetic data on North and Central Asian populations are underrepresented in the literature, especially for autosomal markers. In the present study we used 812 single nucleotide polymorphisms (SNPs) distributed across all the human autosomes and extensively studied at Yale to examine the affinities of two recently collected samples of populations: rural and cosmopolitan Mongolians from Ulaanbaatar and nomadic, Turkic-speaking Tsaatan from Mongolia near the Siberian border. We compare these two populations with each other and with a global set of populations and discuss their relationships to New World populations. Specifically, we analyze data on 521 autosomal loci (single SNPs and multi-SNP haplotypes) studied in 57 populations representing all the major geographical regions of the world. We conclude that these North and Central Asian populations are genetically distinct from all other populations in our study and may be close to the ancestral lineage leading to the New World populations.

A detailed theoretical analysis of the reaction of atomic bromine with tetrahydropyran (THP, C5H10O) was performed using several ab initio methods and statistical rate theory calculations. Initial geometries of all species involved in the potential energy surface of the title reaction were obtained at the B3LYP/cc-pVTZ level of theory. These molecular geometries were reoptimized using three different meta-generalized gradient approximation (meta-GGA) functionals. Single-point energies of the stationary points were obtained by employing the coupled-cluster with single and double excitations (CCSD) and fourth-order Møller-Plesset (MP4 SDQ) levels of theory. The computed CCSD and MP4(SDQ) energies for optimized structures at various DFT functionals were found to be consistent within 2 kJ mol(-1). For a more accurate energetic description, single-point calculations at the CCSD(T)/CBS level of theory were performed for the minimum structures and transition states optimized at the B3LYP/cc-pVTZ level of theory. Similar to other ether + Br reactions, it was found that the tetrahydropyran + Br reaction proceeds in an overall endothermic addition-elimination mechanism via a number of intermediates. However, the reactivity of various ethers with atomic bromine was found to vary substantially. In contrast with the 1,4-dioxane + Br reaction, the chair form of the addition complex (c-C5H10O-Br) for THP + Br does not need to undergo ring inversion to form a boat conformer (b-C4H8O2-Br) before the intramolecular H-shift can occur to eventually release HBr. Instead, a direct, yet more favorable route was mapped out on the potential energy surface of the THP + Br reaction. The rate coefficients for all relevant steps involved in the reaction mechanism were computed using the energetics of coupled cluster calculations. On the basis of the results of the CCSD(T)/CBS//B3LYP/cc-pVTZ level of theory, the calculated overall rate coefficients can be expressed as kov.,calc.(T) = 4.60 × 10(-10) exp[-20.4 kJ mol(-1)/(RT)] cm(3) molecule(-1) s(-1) for the temperature range of 273-393 K. The calculated values are found to be in excellent agreement with the experimental data published previously.

Background: Despite adverse effects such as constipation, vascular calcification, and hypercalcemia, calcium-based salts are relatively affordable and effective phosphate binders that remain in widespread use in the dialysis population. We conducted a pilot study examining whether the use of a combined magnesium/calcium-based binder was as effective as calcium carbonate at lowering serum phosphate levels in peritoneal dialysis (PD) patients., Methods: This was a cross-over, investigator-masked pilot study in which prevalent PD patients received calcium carbonate alone (200 mg calcium per tablet) or calcium magnesium carbonate (100 mg calcium, 85 mg magnesium per tablet). Primary outcome was serum phosphate level at 3 months. Analysis was as per protocol., Results: Twenty patients were recruited, 17 completed the study. Mean starting dose was 11.35 ± 7.04 pills per day of MgCaCO3 and 9.00 ± 4.97 pills per day of CaCO3. Mean phosphate levels fell from 2.13 mmol/L to 2.01 mmol/L (95% confidence interval (CI): 1.76 - 2.30, p = 0.361) in the MgCaCO3 group, and 1.81 mmol/L (95% CI: 1.56 - 2.0, p = 0.026) in the CaCO3 alone group. Six (35%) patients taking MgCaCO3 and 9 (54%) taking CaCO3 alone achieved Kidney Disease Outcomes Quality Initiative (KDOQI) serum phosphate targets at 3 months. Diarrhea developed in 9 patients taking MgCaCO3 and 3 taking CaCO3. Serum magnesium exceeded 1.4 mmol/L in 5 patients taking MgCaCO3 while serum calcium exceeded 2.65 mmol/L in 3 patients receiving CaCO3. When compared to the initial dose, the prescribed dose at 3 months was reduced by 44% (to 6.41 tablets/day) in the MgCaCO3 group and by 8% (to 8.24 pills per day) in the CaCO3 alone group., Conclusion: Compared with CaCO3 alone, the preparation and dose of MgCaCO3 used in this pilot study was no better at lowering serum phosphate levels in PD patients, and was associated with more dose-limiting side effects., (Copyright © 2015 International Society for Peritoneal Dialysis.)

Background and Objectives: Infectious complications remain a significant cause of peritoneal dialysis (PD) technique failure. Topical ointments seem to reduce peritonitis; however, concerns over resistance have led to a quest for alternative agents. This study examined the effectiveness of applying topical Polysporin Triple ointment (P(3)) against mupirocin in a multi-centered, double-blind, randomized controlled trial., Design, Setting, Participants, & Measurements: PD patients routinely applied either P(3) or mupirocin ointment to their exit site. Patients were followed for 18 months or until death or catheter removal. The primary study outcome was a composite endpoint of exit-site infection (ESI), tunnel infection, or peritonitis., Results: Seventy-five of 201 randomized patients experienced a primary outcome event (51 peritonitis episodes, 24 ESIs). No difference was seen in the time to first event for P(3) (13.2 months; 95% confidence interval, 11.9-14.5) and mupirocin (14.0 months; 95% confidence interval, 12.7-15.4) (P=0.41). Twice as many patients reported redness at the exit site in the P(3) group (14 versus 6, P=0.10). Over the complete study period, a higher rate per year of fungal ESIs was seen in patients using P(3) (0.07 versus 0.01; P=0.02) with a corresponding increase in fungal peritonitis (0.04 versus 0.00, respectively; P<0.05)., Conclusions: This study shows that P(3) is not superior to mupirocin in the prophylaxis of PD-related infections. Colonization of the exit site with fungal organisms is of concern and warrants further study. As such, the use of P(3) over mupirocin is not advocated in the prophylaxis of PD-related infections.

The rate coefficients for the reaction of 1,4-dioxane with atomic chlorine were measured from T = 292-360 K using the relative rate method. The reference reactant was isobutane and the experiments were made in argon with atomic chlorine produced by photolysis of small concentrations of Cl2. The rate coefficients were put on an absolute basis by using the published temperature dependence of the absolute rate coefficients for the reference reaction. The rate coefficients for the reaction of Cl with 1,4-dioxane were found to be independent of total pressure from p = 290 to 782 Torr. The experimentally measured rate coefficients showed a weak temperature dependence, given by k(exp)(T) = (8.4(-2.3)(+3.1)) × 10(-10) exp(-(470 ± 110)/(T/K)) cm3 molecule (-1) s(-1). The experimental results are rationalized in terms of statistical rate theory on the basis of molecular data obtained from quantum-chemical calculations. Molecular geometries and frequencies were obtained from MP2/aug-cc-pVDZ calculations, while single-point energies of the stationary points were computed at CCSD(T) level of theory. The calculations indicate that the reaction proceeds by an overall exothermic addition-elimination mechanism via two intermediates, where the rate-determining step is the initial barrier-less association reaction between the chlorine atom and the chair conformer of 1,4-dioxane. This is in contrast to the Br plus 1,4-dioxane reaction studied earlier, where the rate-determining step is a chair-to-boat conformational change of the bromine-dioxane adduct, which is necessary for this reaction to proceed. The remarkable difference in the kinetic behavior of the reactions of 1,4-dioxane with these two halogen atoms can be consistently explained by this change in the reaction mechanism.

The reactions of Cl with tetrahydrofuran, tetrahydropyran, and dimethyl ether have been studied as a function of temperature, pressure, and O(2) concentration. The temperature was varied from approximately 280 to 360 K, the mole fraction of O(2) ranged from zero to approximately 0.6, and the experiments were made in a bath of argon at total pressures ranging from approximately 300 to 760 Torr. The rate coefficients were measured using the relative rate method with gas chromatographic analysis. The reaction of Cl with isobutane was the reference reaction, the rate coefficients for which were calibrated against the reaction of propane with chlorine atoms as a function of temperature. The rate coefficients were unaffected by the concentration of O(2) or by variation in pressure. The rate coefficient for the reaction of Cl with isobutane increased slightly with decreasing temperature. This weak temperature dependence of the rate coefficient was in satisfactory agreement with information in the literature and is represented in Arrhenius form by k(T) = (1.02(-0.25)(+0.32)) x 10(-10) exp(99 +/- 88/T) cm(3) molecule(-1) s(-1), where the uncertainties represent two standard deviations. The rate coefficients for the reactions of Cl with the ethers did not show a statistically significant dependence on temperature. Their average values over our range of temperature are: for Cl + tetrahydrofuran, k = (2.71 +/- 0.34) x 10(-10) cm(3) molecule(-1) s(-1); for Cl + tetrahydropyran, k = (2.03 +/- 0.82) x 10(-10) cm(3) molecule(-1) s(-1); and for Cl + dimethyl ether, k = (1.73 +/- 0.22) x 10(-10) cm(3) molecule(-1) s(-1), in which the uncertainties are again two standard deviations.

The rate coefficient for the reaction of atomic bromine with 1,4-dioxane was measured from approximately 300 to 340 K using the relative rate method. Iso-octane and iso-butane were used as reference compounds, and the experiments were made in a bath of argon containing up to 210 Torr of O(2) at total pressures between 200 and 820 Torr. The rate coefficients were not affected by changes in pressure or O(2) concentration over our range of experimental conditions. The ratios of rate coefficients for the reaction of dioxane relative to the reference compound were put on an absolute basis by using the published absolute rate coefficients for the reference reactions. The variation of the experimentally determined rate coefficients with temperature for the reaction of Br with 1,4-dioxane can be given by k(1)(exp)(T) = (1.4 +/- 1.0) x 10(-11)exp[-23.0 +/- 1.8) kJ mol(-1)/(RT)] cm(3) molecule(-1) s(-1). We rationalized our experimental results in terms of transition state theory with molecular data from quantum chemical calculations. Molecular geometries and frequencies were obtained from MP2/aug-cc-pVDZ calculations, and single-point energies of the stationary points were obtained at CCSD(T)/CBS level of theory. The calculations indicate that the 1,4-dioxane + Br reaction proceeds in an overall endothermic addition-elimination mechanism via a number of intermediates. The rate-determining step is a chair-to-boat conformational change of the Br-dioxane adduct. The calculated rate coefficients, given by k(1)(calc)(T) = 5.6 x 10(-11)exp[-26.6 kJ mol(-1)/(RT)] cm(3) molecule(-1) s(-1), are in very good agreement with the experimental values. Comparison with results reported for the reactions of Br with other ethers suggests that this multistep mechanism differs significantly from that for abstraction of hydrogen from other ethers by atomic bromine.

The rate coefficients for the reactions of atomic bromine with toluene, tetrahydrofuran, and tetrahydropyran were measured from approximately 295 to 362 K using the relative rate method. Iso-octane was used as the reference compound for the reaction with toluene, and iso-octane and toluene were used as the reference compounds for the reaction with tetrahydrofuran; tetrahydrofuran was used as the reference compound for the reaction with tetrahydropyran. The rate coefficients were found to be unaffected by changes in pressure and oxygen concentration. The rate coefficient ratios were converted to absolute values using the absolute rate coefficient for the reaction of Br with the reference compound. The absolute rate coefficients, in the units cm(3) molecule(-1) s(-1), for the reaction of Br with toluene are given by k(T) = (3.7 +/- 1.7) x 10(-12) exp(-(1.63 +/- 0.15) x 10(3)/T), for the reaction of Br with tetrahydrofuran by k(T) = (3.7 +/- 2.7) x 10(-10) exp(-(2.20 +/- 0.22) x 10(3)/T), and for the reaction of Br with tetrahydropyran by k(T) = (3.6 +/- 1.8) x 10(-10) exp(-(2.35 +/- 0.16) x 10(3)/T). The uncertainties represent one standard deviation. The Arrhenius parameters for these reactions are compared with results in the literature for dimethyl ether, diethyl ether, and a series of saturated hydrocarbons, and the effects of structural variation on these parameters are identified.

The rate constants for the reactions of atomic bromine with dimethyl ether and diethyl ether were measured from approximately 300 to 350 K using the relative rate method. Both isooctane and isobutane were used as the reference reactants, and the rate constants for the reactions of these hydrocarbons were measured relative to each other over the same temperature range. The kinetic measurements were made by photolysis of dilute mixtures of bromine, the reference reactant, and the test reactant in mixtures of argon and oxygen at a total pressure of 1 atm. The resulting ratios of rate constants were combined with the absolute rate constant as a function of temperature for the reference reaction of Br with isobutane to calculate absolute rate constants for the reactions of Br with isooctane, dimethyl ether, and diethyl ether. The absolute rate constant, in the units cm3 molecule(-1) s(-1), for the reaction of Br with dimethyl ether was given by k = (3.8 +/- 2.4) x 10(-10) exp(-(3.54 +/- 0.21) x 10(3)/T) while for the reaction of Br with diethyl ether the rate constant is given by k = (2.8 +/- 2.7) x 10(-10) exp(-(2.44 +/- 0.32) x 10(3)/T). On the same basis, the rate constant for the reaction of Br with isooctane is given by k = (3.34 +/- 0.59) x 10(-12) exp(-(1.80 +/- 0.11) x 10(3)/T). In each case, the activation energy of the reaction is significantly smaller than the endothermicity of the reaction. This is discussed in terms of a complex mechanism for these reactions.

The interaction of ozone with alumina has been examined at ambient temperature as a function of ozone concentration and relative humidity. The experiments used diffuse reflectance FTIR spectroscopy in a small flow reactor, which provided control of the temperature, pressure, and composition of the gas mixture to which the sample was continuously exposed. Treatment of alumina with ozone produced a new spectroscopic feature at 1380 cm(-1), which we attribute to an aluminum oxide species formed by interaction of O3 with Lewis acid sites on the alumina surface. After exposure of the alumina sample to O3 was stopped, subsequent exposure of the sample to humidified nitrogen resulted in the slow removal of the peak at 1380 cm(-1). Simultaneously, the uptake of water by the alumina increased as indicated by the growth of the adsorbed water features which extend from approximately 3700 to 2500 cm(-1). Treatment of dry alumina with humidified ozone strongly inhibited both the rate of formation of the spectral feature at 1380 cm(-1) and its limiting extent of formation. These observations are analyzed in terms of the adsorption and surface reaction properties of ozone on alumina. The observation that the new oxide feature on alumina, produced by reaction with ozone, can be removed by water is important for assessing the ability of mineral dust aerosols to process atmospheric trace gases over a significant time scale. We believe the work reported here to be the first direct and quantitative kinetic study of the competition between O3 and water for adsorption sites on alumina.

Transplantation offers superior life expectancy and quality of life compared with dialysis in young patients with end-stage renal failure. However, the initial risks of mortality and morbidity are high. This study used a decision analysis model to evaluate the costs and benefits of kidney transplantation versus continued dialysis for older patients with renal failure. A decision analytic model comparing cadaveric renal transplantation to continued hemodialysis treatment was developed. The base case considered a theoretical cohort of patients aged 65 yr without known comorbidity or contraindications to transplantation who would have to wait 2 yr for a cadaveric transplant. Separate models were constructed for patients with diabetes or cardiovascular disease and for patients receiving an organ after a variety of wait-list times. Probability, utility, and survival data were obtained from published reports and renal registries. For 65-yr-old patients, quality-adjusted life expectancy increased by 1.1 quality-adjusted life years (QALY) at an incremental cost of $67,778 per QALY. Assuming a 2-yr wait-listed time, transplantation remained economically attractive for 70-yr-old patients (incremental cost effectiveness [ICE], $79,359 per QALY) but was less economically attractive for those over 75 yr of age (ICE, $99,553) or for 70-yr-olds with either cardiovascular disease or diabetes (ICE, $126,751 and $161,090 per QALY, respectively). The analytic results were sensitive only to the time spent waiting for the graft. The cost-effectiveness reduced such that the costs associated with one QALY were in excess of $100,000/yr when the probability of a complication was > or = 50% per 3-mo cycle and when the utility of transplantation fell below 0.62. If available within a timely period, transplantation may offer substantial clinical benefits to older patients at a reasonable financial cost. Prolonged waiting times dramatically decrease the clinical benefits and economic attractiveness of transplantation, suggesting that living donor transplantation may be of particular benefit in this population.

In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO&#95;SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.

Factor Xa, a critical serine protease in the blood coagulation cascade, has become a target for inhibition as a strategy for the invention of novel anti-thrombotic agents. Here we describe the development of phenylglycine containing benzamidine carboxamides as novel, potent and selective inhibitors of factor Xa.

Previous studies have demonstrated venous stenosis and thrombosis in hemodialysis patients who had repeated or prolonged cannulation of the subclavian vein. Early reports, however suggested that patients with catheters placed in the internal jugular vein were not at risk of such complications. We conducted a retrospective case series to determine if this was correct. We report a series of seven patients who were found to have stenosis of the upper neck veins despite having never had subclavian vein cannulation. We suggest that previous reports suggesting a superior safety profile with internal jugular catheters may have been misleading and propose that all measures be taken to encourage wider use of arteriovenous grafts and fistulae.

Objective: To develop a set of comprehensive, standardized, evidence-based guidelines for the use of antiviral therapy to prevent cytomegalovirus disease in adult patients having undergone renal transplantation., Options: The use of medication, at the time of induction therapy or at the earliest sign of viremia. Treatments were evaluated by patient and donor serologic groups and the induction regimen used., Outcomes: The control of symptoms and features of cytomegalovirus disease over the first 6 mo to 1 yr after transplantation., Evidence: Articles, compiled using a MEDLINE search from 1976 to July 1997, were reviewed by representatives of nephrology, microbiology, pharmacy, and epidemiology. Additional information was obtained from recent review articles and conference abstracts, and from experts in the field., Values: The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examinations were used. High value was placed on studies with a randomized controlled design and blinded outcome observers. Study quality was classified as poor when cointervention was present (especially with regard to immunosuppressive regimens), when more than 20% of patients were lost to follow-up, and when intention to treat analysis was not performed. Recommendations were made with a graded system (grades A and B: Use of the intervention advised, based on high or fair quality evidence, respectively; grades D and E: Use of the intervention not advised, based on high or fair quality evidence, respectively: grade C: No recommendation made because of insufficient or conflicting evidence)., Recommendations: (1) Seropositive recipient; donor seropositive or seronegative; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation). (2) Seronegative recipient; seropositive donor; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation) (3) Seronegative recipient; seropositive donor; conventional immunosuppression. Prophylaxis with antiviral therapy recommended (grade B recommendation). (4) Seronegative recipient; seronegative donor; any immunosuppressive regimen. No prophylaxis with antiviral therapy required (grade D/E recommendation). (5) Seropositive recipient: donor seropositive or seronegative; conventional immunosuppression. Prophylaxis left to the discrimination of the physician in charge (grade C recommendation).

Background: At least 40% of those starting onto renal dialysis at the present time are aged over 65 years old. With old age comes increased comorbidity and decreased functional status. The long term management of older patients is limited by the need for rehabilitation and by placement concerns. We describe a 5-year experience of a pilot program, created in 1991 on the recommendation of the Metropolitan Toronto District Health Council, to rehabilitate and care for elderly and disabled patients on either hemodialysis or peritoneal dialysis., Methods and Results: This retrospective, observational study reports on a total of 185 patients admitted over a 5-year period to the Riverdale Chronic Dialysis Unit for chronic care or rehabilitation. The mean age of patients admitted was 67 years (quartiles 61 and 75 years). Eighty-five percent of patients had 2 or more severe comorbidities, while 60% had 3 or more active medical issues. The most commonly used dialysis modality was hemodialysis (80%). Of the 185 patients followed 34% were discharged home, 35% died and 13% were still resident at the time of completion of the study. The most common acute medical problems seen in these patients related to their vascular access and necessitated temporary transfer to an acute nephrology center. A total of 4.7 transfers were recorded for each patient-year of follow up., Conclusions: This study describes the adaptation of facilities already present in our area, to allow better management and placement of older dialysis patients. Transfer of patients from a high level acute care facility to a chronic care facility makes economic and practical sense and may allow better long term health care planning as well as more stability for the family or care-givers.

Objective: To investigate the cost and quality of life associated with the first specialized chronic care facility for disabled dialysis patients., Design: A case controlled study in dialysis patients admitted to a specialized chronic dialysis unit (RCDU)., Setting: The study compares the cost of care in a specialized chronic care facility with that of a tertiary hospital., Patients: All dialysis patients with severe chronic disability, resident in Greater Toronto, who were unable to be discharged into the community and who were admitted to the RCDU in the first year of the program., Interventions: Chronic care and rehabilitation services in a specialized dialysis unit., Outcome Measures: Costs are expressed as $Cdn per patient year. Quality of life scores were measured using SIP and SF-36 questionnaires., Results: The data show a saving of $37,022 Cdn over the 618 day study period with care in the RCDU compared with that of a tertiary hospital. Quality of life measures show no difference in scores., Conclusions: We conclude that this preliminary report confirms a cost benefit of a specialized chronic care dialysis unit.

This study describes the Toronto, Ontario experience with autosomal dominant polycystic kidney disease (ADPKD). Patients were divided into three groups: Group 1, 19 families studied with genetic markers; Group 2, 80 pre-dialysis ADPKD patients followed by Toronto nephrologists in whom the incidence of non-renal complications and the mean age of onset of symptomatology is documented; Group 3, 4,449 individuals who entered end-stage renal failure (ESRF) in the Toronto region between the years 1981 and 1992, 320 with ADPKD and 4129 with other diseases. In this third group age of onset of ESRF, frequency, age and cause of death is compared between ADPKD and non-ADPKD. ADPKD caused by a gene different from that linked to chromosome 16 short-arm probes occurred at a frequency of between 8 and 17%. Incidence of hepatic cysts in ADPKD was similar to that of previous series, other organ involvement was underdiagnosed without deliberate screening, and incidence of symptomatic intracranial aneurysm was 1.25%. A 5% excess of patients with ADPKD died of cerebro-vascular accident. Years of survival after ESRF measured by life table analysis was significantly greater for ADPKD patients than for non-ADPKD patients. A high frequency of death due to infection still exists in ADPKD despite the reduction of invasive procedures in diagnosis and treatment, and despite the presumably improved recent methods of managing infection. The average age of onset of ESRF has been delayed by over six years, and average age of death of ADPKD patients at 63.9 years-old by 12.4 years since 1960.

Clinical information was collected on 118 adolescents who developed ESRF at age 143 months or older and were treated between 1966 and 1986 at the Toronto Hospital for Sick Children. The cumulative survival rate in transplanted patients (N = 109) was 80.1% after 15 years. Survival rates after four years were 93.9% in transplanted and 46.9% in nontransplanted patients (P less than 0.001). No patient receiving dialysis alone (N = 9) was followed longer than four years. Nine patients received three transplants and had an 89% survival rate. Six of these had a functioning graft at end of the follow-up. The cumulative survival of the entire group was 76.4% at eighteen years. Forty-two (35.6%) patients had a height below the third percentile. Functional status obtained by a structure telephone interview with a member of the present treating nephrology service was good (G) or excellent (E) for 66.7% of all patients (73.5% of transplant patients (N = 68) and 45% of dialysis patients (N = 20). Hemodialysis patients functioned less well [25% G/E (N = 12)] than peritoneal dialysis patients [75% G/E (N = 8)]. Most patients achieved an appropriate level of formal education although more slowly than normal adolescents. Only 11 patients were neither enrolled in an educational institution nor employed. We conclude that aggressive treatment for adolescents with ESRF is an appropriate application of health care resources.

A family segregating for autosomal dominant polycystic kidney disease (ADPKD) is reported. The clinical picture was typical for ADPKD in some family members, although others showed mild involvement. DNA from family members was probed with seven chromosome 16 single-copy DNA sequences that mapped to the telomere of the short arm of the chromosome. The most likely order of six of the probes from the telomere is palpha3'HVR.64 at the designated locus D16S85, CRI-0327 at D16S63, CRI-090 at D16S45, CRI-0129 at D16S56, CRI-0133 at D16S58, and CRI-0136 at D16S60, with the PKD1 locus for ADPKD between D16S85 and D16S63. The seventh probe 24-1 at D16S80 had not been ordered in relation to the other sequences, but PKD1 had been mapped between it and D16S85. The three probes that were informative in our family, palpha3'HVR.64, CRI-090, and CRI-0136 had been linked to the disease locus at recombination frequencies of 4% and approximately 6 and 12%, respectively. Linkage was excluded between the ADPKD locus in our family and palpha3'HVR.64 at a recombination value of up to 6%. Linkage was also excluded between CRI-090 and the disease locus at a recombination value of up to 5%. The data for linkage between CRI-0136 and the ADPKD locus in our family were inconclusive. Multipoint analysis excluded the possibility that the disease in this family lies between the flanking genetic markers that have previously been used to define the genetic interval in which the most common form of polycystic kidney disease, PKD1, lies. We have not made a positive assignment of the ADPKD mutation in this family.(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary tumor cells require thyroid hormones for growth in vivo [Sorrentino, J. M., Kirkland, W. L., & Sirbasku, D. A. (1976) J. Natl. Cancer Inst. 56, 1155-1158]. In vitro, GH1 rat pituitary tumor cells were studied in a serum-free defined medium (PCM-10) formulated with Ham's F12 and Dulbecco's modified Eagle's media (1:1, v/v) supplemented with 2.2 g/L sodium bicarbonate, 15 mM 4-(2-hydroxy-ethyl)-1-piperazineethanesulfonic acid (pH 7.2), 10 micrograms/mL human transferrin, 50 microM ethanolamine, 10 micrograms/mL insulin, 10 ng/mL selenous acid, 0.1 nM 3,5,3'-triiodothyronine (T3) and 500 micrograms/mL bovine serum albumin and in the same medium without T3 (PCM-0). The cells only grew in PCM-10 when low concentrations of horse serum were added. Attempts to replace the serum factor requirement with known growth factors and adhesion proteins were unsuccessful. The Mr 65,000-72,000 serum factor regulating T3-induced growth (thyromedin) was purified to homogeneity and identified as equine transferrin R and/or D by amino acid sequencing. The ED50 in PCM-10 was 17-40 micrograms/mL (260-620 nM) while in PCM-0 half-maximum growth was not achieved at 200 micrograms/mL. Concentrations of 75 micrograms/mL in PCM-10 caused 80% of serum-stimulated growth rate. Removal of iron from thyromedin, and assay in iron salts reduced PCM-10, increased the specific activity 110-270-fold to ED50 150 ng/mL (2.3 nM); at 1.0 micrograms/mL, growth in PCM-10 was 16-fold greater than in PCM-0. Iron saturation of thyromedin caused total loss of biological activity. We conclude that the horse transferrin variant isolated in this report is active as apotransferrin.

A prospective randomized drug trial was carried out on 59 patients with confirmed membranoproliferative glomerulonephritis (MPGN). The treatment group (27 patients) received cyclophosphamide, coumadin, and dipyridamole for 18 months, and the control group (32 patients) received no specific therapy. Complications of the renal disease such as hypertension and fluid retention were treated similarly in both groups. Entrance criteria included confirmed renal pathology demonstrating either types I or II MPGN, a corrected creatinine clearance (CCr) of less than 80 ml/min/1.73 m2, and/or proteinuria greater than 2 g/day. Actuarial survival was not different between the treatment and the control groups in either MPGN type and was 85% in type I and 90% in type II at 2 years. The change in renal function, as measured by both the slope of CCr and the plasma creatinine reciprocal (1/Cr) at 6, 12, and 18 months was not significantly different between treatment and control groups in either types I or II when tested by both parametric and nonparametric analysis. The age, sex, and initial level of CCr did not influence the rate of decline. Control and treatment group proteinuria was not different at any time point in either types I or II MPGN. The small numbers of type II MPGN cases do not give sufficient power to allow conclusions regarding this therapy in type II. We can conclude that this treatment is ineffective in altering the natural history of type I MPGN.

The purpose of this study was to clarify the means by which lithium induced a disorder of urine acidification. Rats infused with hydrochloric acid (1 mEq/kg) developed acute metabolic acidosis (blood Ph = 7.32; bicarbonate, 18 mEq/liter) with a urine pH of approximately 5.85. The addition of lithium chloride (4 mEq/kg i.p) caused an increase in the urine pH (6.38) and a further decrease in blood bicarbonate (11.0 mEq/liter). During bicarbonate loading, lithium caused the urine PCO2 to fall significantly (urine minus blood PCO2 decreased from 25.3 +/-2.8 To 14.4 +/- 2.3 mm Hg) These changes were not seen following equimolar i.p. administration of sodium chloride. Similarly, lithium administration depressed bicarbonate reabsorption by 11.1% (from 30.6 to 27.2muEq/ml of GFR) during alkali infusion, while saline caused only a 5% decrease (30.0 to 28.5muEq/ml of GFR). The combination of an increase in urine PCO2 in alkaline urine indicates that lithium produced a defect in distal nephron hydrogen ion secretion. The fall in bicarbonate reabsorption following lithium administration oculd be due to a mild hydrogen ion secretory defect located in the proximal tubule or a severe defect in the distal nephron.

It has been proposed that distal renal tubular acidosis is a gradient-limited disorder an that the low urine Pco2 observed in this condition is caused by back diffusion of carbonic acid. This study was designed to examine this hypothesis using the amphotericin B model of gradient-limited distal renal tubular acidosis in rats. After induction of acute metabolic acidosis the minimum urine pH in 12 of 24 amphotericin B-treated rats exceeded 5.63 (mean 5.76 +/- 0.04), whereas it was 5.41 +/-0.04 in control rats. These animals with impaired urine acidification were presumed to have a gradient lesion and were studied in bicarbonate-loading experiments. The urine minus blood Pco2 gradient in these rats was 24.9 +/- 1.5 mm. Hg, a value similar to that of the control rats (26.7 +/- 2.1 mm. Hg). The presence of a normal urine minus blood Pco2 value in this experimentally induced gradient-limited type of acidification lesion indicates that a permeability defect for hydrogen ions was not associated with a similar defect for carbonic acid and that the urine minus blood Pco2 gradient is a valid index of distal nephron hydrogen ion secretion in amphotericin B-like gradient-type lesions.

Hyperglycemia is associated with a decrease in serum sodium concentration. Previous methods of estimating the degree of decrease have not considered the fact that glucose will enter certain cells despite relative insulin deficiency; thus, glucose will not contribute directly to the osmotic gradient responsible for water shifts into or out of these tissues. The expected decrease in serum sodium concentration is 1.35 meg/l for every 100mg/dl increase in blood glucose concentration - the metabolic correction factor. Although the numerical difference between this factor and that calculated by others is small, the metabolic implications could be critical. In the hyperglycemic state the water content of tissues not requiring insulin for glucose transport could increase, and where tissue swelling is physically restricted (for example, in the brain) this expansion could seriously affect organ function.