Transcripts for the beta2 and the beta4 nicotinic acetylcholine receptor (nAChR) subunits are found throughout the CNS and the peripheral nervous system. These two beta subunits can form heteromultimeric channels with any of the alpha2, alpha3, alpha4, or alpha5 subunits in heterologous expression systems. Nonetheless, the subunit composition of native nAChRs and the role of different nAChR subtypes in vivo remain unclear. We prepared null mutations for the beta2 and the beta4 genes and bred beta2-/-beta4-/- mice by mating mice of identical beta2-/-beta4+/- or beta2+/-beta4-/- genotype. The beta2-/- and the beta4-/- single-mutant mice grow to adulthood with no visible phenotypic abnormalities. The beta2-/-beta4-/- double mutants survive to birth but have impaired growth and increased perinatal mortality. They also present enlarged bladders with dribbling urination and develop urinary infection and bladder stones. The ocular pupils are widely dilated and do not constrict in response to light. Histological studies revealed no significant abnormalities of brain or peripheral tissues except for hyperplasia in the bladder mucosa of beta4-/- and beta2-/-beta4-/- mutants. Bladder strips from beta2-/-beta4-/- mice did not respond to nicotine but contracted when stimulated with a muscarinic agonist or electric field stimulation. Bladder strips from beta4 mutants did not respond to nicotine despite the absence of major bladder dysfunction in vivo. Acetylcholine-activated whole-cell currents were absent in superior cervical ganglion neurons from beta2-/-beta4-/- mice and reduced in neurons from beta4-/- mice. Although there is apparent redundancy and a superficially normal phenotype in beta2-/- and beta4-/- mice, physiological studies indicate major deficits in the beta4-/- mice. Our previous description of a similar phenotype in alpha3-/- mice and the current data suggest that the alpha3 and the beta4 subunits are major components in autonomic nAChRs. The phenotype of the beta2-/-beta4-/- and alpha3-/- mice resembles the autosomal recessive megacystis-microcolon-hypoperistalsis syndrome in humans.

Dialysis-to-dialysis variability in blood pressure is a predictor of cardiovascular mortality in hemodialysis patients, and blood pressure variability may be used in managing hypertension and predicting outcomes in dialysis patients.

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During hemodialysis, amino acids (AA) are lost in the ultrafiltrate with consequent modification of their plasma profile. The aim of this cross-sectional study was to evaluate intradialytic changes of plasma AA levels during a single session of hemodiafiltration with endogenous reinfusion (HFR) versus acetate-free biofiltration (AFB). 48 patients chronically treated with HFR or AFB were matched 1:1 for age, gender, Kt/V and diabetes. Blood samples were collected at the beginning and the end of dialysis. Baseline plasma levels (µmol/l) of total AA (3,176 ± 722), essential AA (889 ± 221), and branched chain AA (459 ± 140) levels in HFR were similar to those in AFB (3,399 ± 621, 938 ± 277, and 463 ± 71, respectively). Plasma intradialytic AA levels did not change in HFR, while in AFB there was a reduction by about 25%. In conclusion, as compared with AFB, HFR has a sparing effect on AA loss due to the lack of adsorption by cartridge and to their complete reinfusion in blood.

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We have already demonstrated that in chronic hemodialysis (HD) patients, the cyclic variations in both hydration status and blood pressure are responsible for changes in pulse wave velocity (PWV). The aim of this study is to verify whether the cyclic variation of PWV influences mortality in dialysis patients. We studied 167 oligoanuric (urinary output <500 mL/day) patients on chronic standard bicarbonate HD for at least 6 months. They performed 3 HD sessions of 4 hours per week. Patients were classified into 3 groups: normal PWV before and after dialysis (LL); high PWV before and normal PWV after dialysis (HL); and high PWV before and after dialysis (HH). The carotid-femoral PWV was measured with an automated system using the foot-to-foot method. Analysis of variance was used to compare the different groups. The outcome event studied was all-cause mortality and cardiovascular mortality. The PWV values observed were LL in 44 patients (26.3%); HL in 53 patients (31.8%); and HH in 70 patients (41.9%). The 3 groups of patients are homogenous for sex, age, and blood pressure. The HH group had a higher prevalence of (P<0.001) ASCVD. It is interesting that the distribution of patients in the 3 groups is correlated with the basal value of PWV. In fact, when the basal measure of PWV is elevated, there is a higher probability that an HD session cannot reduce PWV (<12 ms). A total of 53 patients (31.7%) died during the follow-up of 2 years: 5 patients in the LL group (11.4%); 16 in the HL group (30.2%); and 32 in the HH group (50.7%) (LL vs. HL, P=0.047; LL vs. HH, P<0.00001; HL vs. HH, P=0.034). We evidence for the first time that different behaviors of PWV in dialysis subjects determine differences in mortality.

Chronic inflammation is widely diffuse in maintenance hemodialysis (MHD) patients and is associated with poor survival. Hemodiafiltration with endogenous reinfusion (HFR) is a dialysis technique, highly biocompatible, able to adsorb proinflammatory cytokines and to decrease amino acids and antioxidants loss. These features could be helpful in MHD patients affected by idiopathic chronic inflammation, but this issue remains to be elucidated. We performed a multicenter longitudinal study to assess the effect of the switching from bicarbonate HD to HFR in patients with serum C-reactive Protein (CRP) > 5 mg/L coupled with albumin <4.0 g/dL in the last 6 months. We enrolled 24/176 (14%) patients, of which 20 patients were assessed at 4 months and 18 completed the study. We excluded 11 patients with evident causes of inflammation. At baseline, serum levels of CRP (18.7[7.0-39.4] mg/L) and albumin (3.5[3.3-3.7] g/dL) were significantly correlated (r = -0.49; P = 0.028). The effect on CRP and albumin was almost evident in the first 4 months and remained stable until to eighth month. A strict correlation (R = -0.49; 0.040) between percentage change of CRP (-35%) and albumin (+14%) after 8 months of HFR. These effects were associated with the reduction of IL-6, IL-1β, and TNF-α and the increment of pre-albumin and leptin, whereas the serum levels of Branched Chain Amino Acid (BCAA) remained unchanged. In MHD patients affected by idiopathic chronic inflammation the switching from BHD to HFR is associated with improvement of inflammation. Whether these favorable effects may modify the outcomes of these high-risk patients needs to be confirmed by studies ad hoc.