Changes in survival among elderly patients initiating dialysis from 1990 to 1999

Background

Over the past decade, there has been a steep rise in the number of people with complex medical problems who require dialysis. We sought to determine the life expectancy of elderly patients after starting dialysis and to identify changes in survival rates over time.

Methods

All patients aged 65 years or older who began dialysis in Canada between 1990 and 1999 were identified from the Canadian Organ Replacement Register. We used Cox proportional hazards models to examine the effect that the period during which dialysis was initiated (era 1, 1990–1994; era 2, 1995–1999) had on patient survival, after adjusting for diabetes, sex and comorbidity. Patients were followed from initiation of dialysis until death, transplantation, loss to follow-up or study end (Dec. 31, 2004).

Results

A total of 14 512 patients aged 65 years or older started dialysis between 1990 and 1999. The proportion of these patients who were 75 years or older at the start of dialysis increased from 32.7% in era 1 (1990–1994) to 40.0% in era 2 (1995–1999). Despite increased comorbidity over the 2 study periods, the unadjusted 1-, 3- and 5-year survival rates among patients aged 65–74 years at dialysis initiation rose from 74.4%, 44.9% and 25.8% in era 1 to 78.1%, 51.5% and 33.5% in era 2. The respective survival rates among those aged 75 or more at dialysis initiation increased from 67.2%, 32.3% and 14.2% in era 1 to 69.0%, 36.7% and 20.3% in era 2. This survival advantage persisted after adjustment for diabetes, sex and comorbidity in both age groups (65–74 years: hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.72–0.81; 75 years or more: HR 0.86, 95% CI 0.80–0.92).

Interpretation

Survival after dialysis initiation among elderly patients has improved from 1990 to 1999, despite an increasing burden of comorbidity. Physicians may find these data useful when discussing prognosis with elderly patients who are initiating dialysis.Within general medical and subspecialty areas, chronic kidney disease is increasingly recognized as an important comorbid condition that is often associated with prolonged hospital stays and increased morbidity and mortality.^1–3 As a result, internists and other specialists are more likely than before to be involved with the care of patients for whom dialysis needs to be started because of end-stage kidney disease. The majority of patients starting dialysis are 65 years or older at the time of their first treatment, and many are over 75 years.⁴ Given the heightened awareness of chronic kidney disease, its high prevalence, the association with multiple comorbidity, and the impact of dialysis on survival and quality of life, we sought to calculate the mean life expectancy of elderly patients who began dialysis at either 65–74 years of age or at 75 years or more, and to identify whether there was any change in survival probability, or in the effect of comorbidity characteristics, on dialysis over the past decade.     

Structural biology

A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in structural biology.     

Recapitulation and design of protein binding peptide structures and sequences

An important objective of computational protein design is the generation of high affinity peptide inhibitors of protein-peptide interactions, both as a precursor to the development of therapeutics aimed at disrupting disease causing complexes, and as a tool to aid investigators in understanding the role of specific complexes in the cell. We have developed a computational approach to increase the affinity of a protein-peptide complex by designing N or C-terminal extensions which interact with the protein outside the canonical peptide binding pocket. In a first in silico test, we show that by simultaneously optimizing the sequence and structure of three to nine residue peptide extensions starting from short (1-6 residue) peptide stubs in the binding pocket of a peptide binding protein, the approach can recover both the conformations and the sequences of known binding peptides. Comparison with phage display and other experimental data suggests that the peptide extension approach recapitulates naturally occurring peptide binding specificity better than fixed backbone design, and that it should be useful for predicting peptide binding specificities from crystal structures. We then experimentally test the approach by designing extensions for p53 and dystroglycan-based peptides predicted to bind with increased affinity to the Mdm2 oncoprotein and to dystrophin, respectively. The measured increases in affinity are modest, revealing some limitations of the method. Based on these in silico and experimental results, we discuss future applications of the approach to the prediction and design of protein-peptide interactions.     

A New Locus for Dominant “Zonular Pulverulent” Cataract, on Chromosome 13

Inherited cataract is a clinically and genetically heterogeneous disease that most often presents as a congenital autosomal dominant trait. Here we report the linkage of a new locus for dominant “zonular pulverulent” cataract (CZP) to chromosome 13. To map the CZPlocus we performed molecular-genetic linkage analysis using microsatellite markers in a five-generation English pedigree. After exclusion of eight known loci and several candidate genes for autosomal dominant cataract, we obtained significantly positive LOD scores (Z) for markers D13S175 (maximum Z [Z_max] å 4.06; maximum recombination frequency [u_max] å 0) and D13S1236 (Z_max å 5.75, u_max å 0). Multipoint analysis gave Z_maxå 6.62 (u_max å 0) at marker D13S175. Haplotype data indicated that CZP probably lies in the centromeric region of chromosome 13, provocatively close to the gene for lens connexin46.     

Failed medical management in ovarian pregnancy despite favorable prognostic factors--a case report

Primary ovarian pregnancy is a rare form of ectopic pregnancy that must be demonstrated with use of 4 Spiegelberg criteria. It is usually diagnosed at laparotomy or laparoscopy, although it may resemble a hemorrhagic corpus luteum. Successful conservative management of ovarian pregnancy with methotrexate has been reported only occasionally. This may be partly because of the rarity of this condition and partly because when medical treatment is successful, the patient does not need to undergo laparotomy or laparoscopy, and an occasional ovarian pregnancy may have been diagnosed as a tubal pregnancy. We present a case of ovarian pregnancy (diagnosed at laparotomy) for which initial medical management with methotrexate failed despite favorable prognostic factors. Whether the unusual location (ovary) could have contributed toward treatment failure is unknown.     

The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease

Background

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD.

Results

Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels.

Conclusions

Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.

     

Ethanol Alters Proliferation and Differentiation of Normal and Chromosomally Abnormal Human Embryonic Stem Cell‐Derived Neurospheres

Ethanol is a powerful substance and, when consumed during pregnancy, has significant psychoactive and developmental effects on the developing fetus. These abnormalities include growth retardation, neurological deficits, and behavioral and cognitive deficiencies, commonly referred to as fetal alcohol spectrum disorder. The effect of ethanol has been reported to affect cellular development on the embryonic level, however, not much is known about mutations contributing to the influence of ethanol. The purpose of our study was to determine if mutation contribute to changes in differentiation patterning, cell‐cycle regulatory gene expression, and DNA methylation in human embryonic stem cells after ethanol exposure. We exposed human embryonic stem cells (with and without know DNA mutations) to a low concentration (20 mM) of ethanol and measured neurosphere proliferation and differentiation, glial protein levels, expression of various cell‐cycle genes, and DNA methylation. Ethanol altered cell‐cycle gene expression between the two cell lines; however, gene methylation was not affected in ether lines.. Birth Defects Res (Part B) 98:283–295, 2013. © 2013 Wiley Periodicals, Inc.     

Development of gallic acid formazans as novel enoyl acyl carrier protein reductase inhibitors for the treatment of tuberculosis

The enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel antitubercular agents. A series of gallic acid formazans, were computationally designed and docked into the active site of InhA to understand their binding mode and potential to inhibit InhA. Nine compounds from the designed series were identified as potential InhA inhibitors, on the basis of good Glide score. These compounds were synthesized in the laboratory and evaluated for in vitro antitubercular activity against drug-sensitive and multi-drug resistant strains of MTB. Out of nine compounds, three compounds exhibited the most promising MIC of <2 μM against the sensitive strain of MTB, H37Rv. The compounds were evaluated against five resistant strains of MTB. Most of the compounds exhibited activity superior to the standard, linezolid, against all these resistant strains. The mechanism of action of these compounds was concluded to be InhA inhibition, through InhA enzyme inhibition study. Insignificant cytotoxicity of these compounds was observed on RAW 264.7 cell line. Inactivity of all these compounds against gram positive and gram negative bacteria indicated their specificity against MTB. The compounds were further analyzed for ADME properties and showed potential as good oral drug candidates. The results clearly identified some novel, selective and specific InhA inhibitors against sensitive and resistant strains of MTB.