…we are starting to acknowledge the ability of modified dialysis procedures (in particular extended dialysis schedules) over the current conventional norms of frequency and duration to provide a range of benefits cutting across the range of relevant domains…”
End-stage renal disease is associated with reduced heart rate variability (HRV), components of which generally are associated with advanced age, diabetes mellitus and left ventricular hypertrophy. We hypothesized that daily in-center hemodialysis (HD) would increase HRV.
The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to receive 12 months of six versus three times per week in-center HD. Two hundred and seven patients had baseline Holter recordings. HRV measures were calculated from 24-h Holter electrocardiograms at both baseline and 12 months in 131 patients and included low-frequency power (LF, a measure of sympathetic modulation), high-frequency power (HF, a measure of parasympathetic modulation) and standard deviation (SD) of the R–R interval (SDNN, a measure of beat-to-beat variation).
Baseline to Month 12 change in LF was augmented by 50% [95% confidence interval (95% CI) 6.1–112%, P =0.022] and LF + HF was augmented by 40% (95% CI 3.3–88.4%, P = 0.03) in patients assigned to daily hemodialysis (DHD) compared with conventional HD. Changes in HF and SDNN were similar between the randomized groups. The effects of DHD on LF were attenuated by advanced age and diabetes mellitus (predefined subgroups). Changes in HF (r = −0.20, P = 0.02) and SDNN (r = −0.18, P = 0.04) were inversely associated with changes in left ventricular mass (LVM).
DHD increased the LF component of HRV. Reduction of LVM by DHD was associated with increased vagal modulation of heart rate (HF) and with increased beat-to-beat heart rate variation (SDNN), suggesting an important functional correlate to the structural effects of DHD on the heart in uremia.
daily hemodialysis; end-stage renal disease; frequent hemodialysis network; heart rate variability; left ventricular mass
Few studies have examined if infectious arteriovenous access complications vary with the cannulation technique and whether this is modified by dialysis frequency. We compared the infection rate between fistulas cannulated using buttonhole versus stepladder techniques for patients treated with short daily (SDH) or nocturnal hemodialysis at home (NHD). We also compared patients receiving conventional intermittent hemodialysis (CIHD) using stepladder cannulation.
Data were prospectively collected from 631 patients dialyzed with a fistula from 2001 to 2010 (Toronto and Ottawa, Canada). We compared the person-time incidence rate of bacteremia and local fistula infections using the exact binomial test.
Forty-six (7.3%) patients received SDH (≥5 sessions/week, 2-4 h/session), 128 (20.3%) NHD (≥4 sessions/week, ≥5 h/session) and 457 (72%) CIHD (3 sessions/week, ≤4 h/session). Fifty percent of SDH and 72% of NHD patients used the buttonhole technique. There were 39 buttonhole-related bacteremias (rate: 0.196/1,000 fistula days) and at least 2 local buttonhole site infections. Staphylococcus aureus accounted for 85% of the bacteremias. There were 5 (13%) infection-related hospitalizations and 3 (10%) serious metastatic infections, including fistula loss. In comparison, there was 1 possible fistula-related infection in CIHD during follow-up (rate: 0.002/1,000 fistula days).
The rate of buttonhole-related infections was high among patients on frequent hemodialysis and more than 50 times greater than that among patients on CIHD with the stepladder technique. Most bacteremias were due to S. aureus – with serious consequences. The risks and benefits of buttonhole cannulation require individual consideration with careful monitoring, prophylaxis and management.
Cannulation; Fistula; Infection; Hemodialysis
NaV1.9 regulates normal colonic afferent mechanosensation and is required for hypersensitivity to noxious inflammatory mediators and those derived from inflammatory bowel disease tissues.
Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9−/− mice. Deletion of NaV1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE2, and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9, and there was a rightward shift in stimulus–response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in NaV1.9−/− afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9−/− mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics.
Distal colon; Inflammatory bowel disease; NaV1.9; Nociceptor sensitivity; Noxious distension; Supernatants; Visceral hypersensitivity; Visceral pain; Voltage-gated sodium channel
The recent synthesis of pyrimidine ribonucleoside-2′,3′-cyclic phosphates under prebiotically plausible conditions has strengthened the case for the involvement of RNA at an early stage in the origin of life. However, a prebiotic conversion of these weakly activated monomers, and their purine counterparts, to the 3′,5′-linked RNA polymers of extant biochemistry has been lacking – previous attempts leading only to short oligomers with mixed linkages. Here we show that the 2′-hydroxyl group of oligoribonucleotide-3′-phosphates can be chemoselectively acetylated in water under prebiotically credible conditions, allowing rapid and efficient template-directed ligation. The 2′-O-acetyl group at the ligation junction of the product RNA strand can be removed under conditions that leave the internucleotide bonds intact. Remarkably, acetylation of mixed oligomers possessing either 2′- or 3′-terminal phosphates is selective for the 2′-hydroxyl group of the latter. This newly discovered chemistry thus suggests a prebiotic route from ribonucleoside-2′,3′-cyclic phosphates to predominantly 3′,5′-linked RNA via partially 2′-O-acetylated-RNA.
It has long been known that circulating levels of IgG and IgM antibodies are elevated in patients with essential and pregnancy-related hypertension. Recent studies indicate these antibodies target, and in many cases activate, G-protein coupled receptors and ion channels. Prominent among these protein targets are AT1 receptors, α1-adrenoceptors, β1-adrenoceptors, and L-type voltage operated Ca2+ channels, all of which are known to play key roles in the regulation of blood pressure through modulation of vascular tone, cardiac output, and/or Na+/water reabsorption in the kidneys. This suggests that elevated antibody production may be a causal mechanism in at least some cases of hypertension. In this brief review, we will further describe the protein targets of the antibodies that are elevated in individuals with essential and pregnancy-related hypertension and the likely pathophysiological consequences of antibody binding to these targets. We will speculate on the potential mechanisms that underlie elevated antibody levels in hypertensive individuals and, finally, we will outline the therapeutic opportunities that could arise with a better understanding of how and why antibodies are produced in hypertension.
Home-based renal replacement therapy (RRT) [peritoneal dialysis (PD) and home hemodialysis (HHD)] offers independent quality of life and clinical advantages compared to conventional in-center hemodialysis. However, follow-up may be less complete for home dialysis patients following a change in care settings such as post hospitalization. We aim to implement a Home Dialysis Virtual Ward (HDVW) strategy, which is targeted to minimize gaps of care.
The HDVW Pilot Study will enroll consecutive PD and HHD patients who fulfilled any one of our inclusion criteria: 1. following discharge from hospital, 2. after interventional procedure(s), 3. prescription of anti-microbial agents, or 4. following completion of home dialysis training. Clinician-led telephone interviews are performed weekly for 2 weeks until VW discharge. Case-mix (modified Charlson Comorbidity Index), symptoms (the modified Edmonton Symptom Assessment Scale) and patient satisfaction are assessed serially. The number of VW interventions relating to eight pre-specified domains will be measured. Adverse events such as re-hospitalization and health-services utilization will be ascertained through telephone follow-up after discharge from the VW at 2, 4, 12 weeks. The VW re-hospitalization rate will be compared with a contemporary cohort (matched for age, gender, renal replacement therapy and co-morbidities). Our protocol has been approved by research ethics board (UHN: 12-5397-AE). Written informed consent for participation in the study will be obtained from participants.
This report serves as a blueprint for the design and implementation of a novel health service delivery model for home dialysis patients. The major goal of the HDVW initiative is to provide appropriate and effective supports to medically complex patients in a targeted window of vulnerability.
Virtual ward; Home dialysis; Patient support; Hospital-avoidance; Peritoneal dialysis; Home hemodialysis; Re-admission; Technique survival; Patient satisfaction
Natural killer cell development and function is regulated by the interaction of inhibitory Ly49 receptors with distinct peptide-laden Major Histocompatibility Complex allotypes (pMHC-I), although whether Ly49 could bind to other MHC-I like molecules was unclear. We show the prototypic inhibitory receptor Ly49A binds the highly conserved non-classical class I molecule, pH2-M3 with similar affinity to that with H-2Dd. Ly49A specific recognition of H2-M3 regulates NK cell licensing and mediates missing-self recognition of H2-M3 deficient-bone marrow. Host-peptide H2-M3 was required for optimal NK cell activity against experimental metastases and carcinogenesis. Accordingly, non-classical MHC-I molecules can act as cognate ligands for Ly49 molecules and provide insight into the various mechanisms that lead to NK cell tolerance.
There is a paucity of information about the views of dialysis nurses towards dialysis modality selection, yet nurses often have the most direct contact time with patients. We conducted a survey to better understand nurses’ attitudes and perceptions, and hypothesized that nurses with different areas of expertise would have differences in opinions.
We administered an electronic survey to all dialysis/predialysis nurses (n = 129) at a large, tertiary care center. The survey included questions about preferred therapy - in-center hemodialysis (CHD), versus home dialysis (home hemodialysis and peritoneal dialysis) and ideal modality mix. Responses were compared between nurses with home dialysis and CHD experience.
The survey response rate was 69%. Both nursing groups ranked patient caregivers and dialysis nurses as having the least impact on patient modality selection. For most patient characteristics (including age > 70 years and presence of multiple chronic illnesses), CHD nurses felt that CHD was somewhat or strongly preferred, while home dialysis nurses preferred a home modality (p < 0.001 for all characteristics studied). Similar differences in responses were noted for patient/system factors such as patient survival, cost to patients and nursing job security. Compared to CHD nurses, a higher proportion of home dialysis nurses felt that CHD was over-utilized (85% versus 58%, p = 0.024).
Dialysis nurses have prevailing views about modality selection that are strongly determined by their area of experience and expertise.
Dialysis; Barriers; Survey; Home dialysis; Peritoneal dialysis; Home hemodialysis
MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTORC1 signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma. Everolimus selectively cleared premalignant B-cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation and strongly protected against lymphoma development. Established Eμ-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B-lymphocytes.
MYC; mTOR; lymphoma; oncogenesis; senescence; everolimus
An increase in left ventricular mass (LVM) is associated with mortality and cardiovascular morbidity in patients with end-stage renal disease.
Methods and Results
The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to 12 months of 6 times per week daily in-center hemodialysis or conventional hemodialysis; the FHN Nocturnal Trial randomized 87 patients to 12 months of 6 times per week nocturnal hemodialysis or conventional hemodialysis. The main cardiac secondary outcome was change in LVM. In each trial, we examined whether several pre-defined baseline demographic or clinical factors, as well as change in volume removal, blood pressure or solute clearance influenced the effect of frequent hemodialysis on LVM. In the Daily Trial, frequent hemodialysis resulted in a significant reduction in LVM (13.1(95% CI 5.0 to 21.3) g, p=0.002), LVM index (6.9 (2.4 to 11.3) g/m2, p=0.003) and percent change in geometric mean of LVM (7.0 (1.0 to 12.6)%, p =0.02). Similar trends were noted in the Nocturnal Trial but did not reach statistical significance. In the Daily Trial, a more pronounced effect of frequent hemodialysis on LVM was evident among patients with left ventricular hypertrophy at baseline. Changes in LVM were associated with changes in blood pressure (conventional hemodialysis: R=0.28, P=0.01, daily hemodialysis: R=0.54, P<0.001) and were not significantly associated with changes in other parameters.
Frequent in-center hemodialysis reduces LVM. The benefit of frequent hemodialysis on LVM may be mediated by salutary effects on blood pressure.
Left Ventricular Mass; Frequent Hemodialysis; Daily Hemodialysis; Nocturnal Hemodialysis; Blood Pressure
Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/Vurea, a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.
hemodialysis; left ventricular mass; nocturnal hemodialysis; RAND physical health composite (PHC) SF-36; randomized clinical trial; vascular access
Poor sleep quality is a common, persistent, and important problem to patients with end-stage renal disease (ESRD). This report examines whether sleep quality is associated with dialysis treatment factors and other modifiable clinical factors in a large group of hemodialysis (HD) patients.
Cross-sectional analyses were conducted on baseline data collected from participants in the Frequent Hemodialysis Network trials. Sleep quality was measured using the Medical Outcomes Study Sleep Problems Index II (SPI II), a 9-item measure of sleep quality with higher scores reflecting poorer sleep quality.
The participants had an age of 51.2 ± 13.6 years, 61% were male, 38% were black, and 42% had diabetes. Higher pre-dialysis serum phosphorus (per 0.5 mg/ml) (OR 0.91; 95% CI 0.85, 0.96) and depression (OR 0.16; 95% CI 0.10, 0.25) were independently associated with decrements in sleep quality. There was also a difference in time to recovery from dialysis for the fourth versus the first SPI II quartile (5.1 h; p < 0.0001).
These findings underscore the link between sleep and daytime function and suggest that improving sleep may provide an opportunity to improve outcomes in ESRD. Whether sleep problems may be improved by reduction of serum phosphorus or treatment of depression in the HD population merits further investigation.
Hemodialysis; Sleep; Quality of life; Cognitive function; Cardiac magnetic resonance imaging
Many nephrology observational studies use renal registries, which have well known limitations. The Canadian Kidney Disease Cohort Study (CKDCS) is a large prospective observational study of patients commencing hemodialysis in five Canadian centers. This study focuses on delineating potentially reversible determinants of adverse outcomes that occur in patients receiving dialysis for end-stage renal disease (ESRD).
The CKDCS collects information on risk factors and outcomes, and stores specimens (blood, dialysate, hair and fingernails) at baseline and in long-term follow-up. Such specimens will permit measurements of biochemical markers, proteomic and genetic parameters (proteins and DNA) not measured in routine care. To avoid selection bias, all consenting incident hemodialysis patients at participating centers are enrolled, the large sample size (target of 1500 patients), large number of exposures, and high event rates will permit the exploration of multiple potential research questions.
Data on the baseline characteristics from the first 1074 subjects showed that the average age of patients was 62 (range; 50-73) years. The leading cause of ESRD was diabetic nephropathy (41.9%), and the majority of the patients were white (80.0%). Only 18.7% of the subjects received dialysis in a satellite unit, and over 80% lived within a 50 km radius of the nearest nephrologist's practice.
The prospective design, detailed clinical information, and stored biological specimens provide a wealth of information with potential to greatly enhance our understanding of risk factors for adverse outcomes in dialysis patients. The scientific value of the stored patient tissue will grow as new genetic and biochemical markers are discovered in the future.
Fluid accumulation in the neck during recumbency might narrow the upper airway (UA) and thereby contribute to its collapse in patients with obstructive sleep apnoea (OSA). It is hypothesised that acute fluid shifts from the legs to the upper body in healthy subjects would increase neck circumference and reduce the cross‐sectional area of the UA (UA‐XSA).
In 27 healthy non‐obese subjects of mean (SE) age 39 (3) years and body mass index 23.2 (0.6) kg/m2 studied while supine, leg fluid volume was measured using bioelectrical impedance, neck circumference using a mercury strain gauge and mean UA‐XSA between the velum and the glottis using acoustic pharyngometry at end expiration. Measurements were made at baseline after which subjects were randomly assigned to a 5 min time control period or to a 5 min application of lower body positive pressure (LBPP) at 40 mm Hg by anti‐shock trousers, separated by a 15 min washout period. Subjects then crossed over to the opposite arm of the study.
Compared with control, application of LBPP significantly reduced leg fluid volume (p<0.001) and increased neck circumference (p<0.001), both at 1 min and 5 min, and reduced UA‐XSA after both 1 min (−0.15 cm2; 95% CI −0.23 to −0.09, p<0.001) and 5 min (−0.20 cm2; 95% CI −0.33 to −0.09, p<0.001).
In healthy subjects, displacement of fluid from the legs by LBPP causes distension of the neck and narrowing of the UA lumen. Fluid displacement from the lower to the upper body while recumbent may contribute to pharyngeal narrowing and obstruction to airflow in patients with OSA. This may have particular pathological significance in oedematous states such as heart and renal failure.
In the title dinuclear complex, [CuGd(C20H22N2O4)(NO3)3], the CuII ion is located in the inner N2O2 cavity of the Schiff base ligand and adopts a distorted square-planar geometry. The GdIII ion is ten-coordinate being bound to ten O atoms, four from the Schiff base ligand and six from three bidentate nitrate anions. The CuII and GdIII ions are linked by two phenolate O atoms of the Schiff base ligand, with a separation of 3.5185 (9) Å.
Prenatal cocaine exposure produces sustained neurobehavioral and brain synaptic changes closely resembling those of animals with defective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamatergic receptors (AMPARs). We hypothesized that prenatal cocaine exposure attenuates AMPAR signaling by interfering with AMPAR synaptic targeting. AMPAR function is governed by receptor cycling on and off the synaptic membrane through its interaction with GRIP, a PDZ domain protein that is regulated by reversible phosphorylation. Our results show that prenatal cocaine exposure markedly reduces AMPAR synaptic targeting and attenuates AMPAR-mediated synaptic long-term depression (LTD) in the frontal cortex of 21-day-old rats. This cocaine effect is the result of reduced GRIP – AMPAR interaction caused by persistent phosphorylation of GRIP by protein kinase C (PKC) and Src tyrosine kinase. These data support the restoration of AMPAR activation via suppressing excessive PKC-mediated GRIP phosphorylation as a novel therapeutic approach to treat the neurobehavioral consequences of prenatal cocaine.
Prenatal; cocaine; AMPA; GRIP1/2; synaptic targeting; scaffolding proteins
Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.
of partially 2′/3′-O-acetylated
oligoribonucleotides has been accomplished by using a 2′/3′-O-acetyl orthogonal protecting group strategy in which non-nucleophilic
strong-base (DBU) labile nucleobase protecting groups and a UV-light
cleavable linker were used. Strong-base stability of the photolabile
linker allowed on-column nucleobase and phosphate deprotection, followed
by a mild cleavage of the acetylated oligonucleotides from the solid
support with UV light. Two 17nt oligonucleotides, which were synthesized
possessing one specific internal 2′- or 3′-acetyl group,
were used as synthetic standards in a recent report from this laboratory
detailing the prebiotically plausible ligation of RNA oligonucleotides.
In order to further investigate the effect of 2′/3′-O-acetyl groups on the stability of RNA duplex structure,
two complementary bis-acetylated RNA oligonucleotides were also expediently
obtained with the newly developed protocols. UV melting curves of
2′-O-acetylated RNA duplexes showed a consistent
∼3.1 °C decrease in Tm per