The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial

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

Social change and the family: Comparative perspectives from the west, China, and South Asia

This paper examines the influence of social and economic change on family structure and relationships: How do such economic and social transformations as industrialization, urbanization, demographic change, the expansion of education, and the long-term growth of income influence the family? We take a comparative and historical approach, reviewing the experiences of three major sociocultural regions: the West, China, and South Asia. Many of the changes that have occurred in family life have been remarkably similar in the three settings—the separation of the workplace from the home, increased training of children in nonfamilial institutions, the development of living arrangements outside the family household, increased access of children to financial and other productive resources, and increased participation by children in the selection of a mate. While the similarities of family change in diverse cultural settings are striking, specific aspects of change have varied across settings because of significant pre-existing differences in family structure, residential patterns of marriage, autonomy of children, and the role of marriage within kinship systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45661/1/11206_2005_Article_BF01124383.pd

Evidence for Nonacetylcholinesterase Targets of Organophosphorus Nerve Agent: Supersensitivity of Acetylcholinesterase Knockout Mouse to VX Lethality

The possibility that organophosphate toxicity is due to inhibition of targets other than acetylcholinesterase (AChE, EC 3.1.1.7) was examined in AChE knockout mice. Mice (34–55 days old) were grouped for this study, after it was determined that AChE, butyrylcholinesterase (BChE), and carboxylesterase activities had reached stable values by this age. Mice with 0, 50, or 100% AChE activity were treated subcutaneously with the nerve agent VX. The LD50 for VX was 10 to 12 µg/kg in AChE-/-, 17 µg/kg in AChE+/-, and 24 µg/kg in AChE+/- mice. The same cholinergic signs of toxicity were present in AChE-/- mice as in wild-type mice, even though AChE-/- mice have no AChE whose inhibition could lead to cholinergic signs. Wild-type mice, but not AChE-/- mice, were protected by pretreatment with atropine. Tissues were extracted from VX-treated and untreated animals and tested for AChE, BChE, and acylpeptide hydrolase activity. VX treatment inhibited 50% of the AChE activity in brain and muscle of AChE+/+ and +/- mice, 50% of the BChE activity in all three AChE genotypes, but did not significantly inhibit acylpeptide hydrolase activity. It was concluded that the toxicity of VX must be attributed to inhibition of nonacetylcholinesterase targets in the AChE-/- mouse. Organophosphorus ester toxicity in wild-type mice is probably due to inhibition or binding to several proteins, only one of which is AChE

REDUCED ACETYLCHOLINE RECEPTOR DENSITY, MORPHOLOGICAL REMODELING, AND BUTYRYLCHOLINESTERASE ACTIVITY CAN SUSTAIN MUSCLE FUNCTION IN ACETYLCHOLINESTERASE KNOCKOUT MICE

The vertebrate neuromuscular junction is designed for rapid transmission of excitatory signals for initiation of muscle contraction.5 Among the features responsible for the high throughput of this synapse are the close proximity of the presynaptic and postsynaptic membranes,10 the direct coupling of acetylcholine (ACh) binding to the opening of the ion channel associated with the nicotinic acetylcholine receptor (nAChR),27 the brief open time of this channel,21,27 and the presence of cholinesterase (ChE) for hydrolysis of ACh.21,30 At the endplate, there are two distinct ChEs for transmitter hydrolysis: acetylcholinesterase (EC 3.1.1.7, AChE) and butyrylcholinesterase (EC 3.1.1.8, BChE).33 Both enzymes can exist in a multisubunit, collagen-tailed form with selective localization at the endplate basallamina.33 Because of its superior catalytic activity for ACh hydrolysis, AChE is the dominant enzyme, whereas the role of BChE is generally evident only after AChE is inhibited.3,4 Inhibition of ChE results in a progressive accumulation of ACh, especially during periods of repetitive stimulation, leading to desensitization of nAChRs and consequent muscle weakness.12,17 Under this condition, transmitter persists beyond its normal lifetime and is slowly removed from the endplate region by diffusion.21,30 Diffusion is impeded in part by morphological barriers, such as the apposition of the nerve terminal to the postjunctional membrane,5,10 and by the high density of postjunctional nAChRs.21,22,25 If ChE is inhibited pharmacologically or removed by collagenase treatment, repeated binding to nAChR makes diffusional loss of ACh slow and inefficient.21,22,30 The influence of nAChRs on retention of transmitter was termed “buffered diffusion” by Katz and Miledi21 and accounts for findings that elimination of ACh is considerably slower than that expected for free diffusion. 30 Inhibitors of ChE are highly toxic, producing incapacitation and death within minutes.28 The cause of death is complex, involving loss of central respiratory drive,6,29 bronchospasm,1,2 and the inability of the diaphragm muscle to sustain tetanic tension. 19 Because most ChE inhibitors show little selectivity between AChE and BChE, and may have direct actions unrelated to ChE inhibition, it is difficult to establish the role of AChE activity in neuromuscular transmission. To overcome this difficulty, we studied twitch and tetanic tensions in diaphragm muscles from AChE knockout (AChE-/-) mice that fail to express AChE but do contain normal levels of BChE.7,24,36 Stimulation of the phrenic nerve in isolated diaphragm preparations from AChE-/- mice revealed large single twitches and sustained tetanic tensions at 70 and 100 Hz. These findings suggest that, over a limited frequency range, diaphragm muscles from AChE-/- mice are able to compensate for the loss of AChE activity. An understanding of these adaptive mechanisms is expected to provide insight on protection strategies that may be effective against the toxic actions of ChE inhibitors such as the highly lethal nerve agents

REDUCED ACETYLCHOLINE RECEPTOR DENSITY, MORPHOLOGICAL REMODELING, AND BUTYRYLCHOLINESTERASE ACTIVITY CAN SUSTAIN MUSCLE FUNCTION IN ACETYLCHOLINESTERASE KNOCKOUT MICE

The vertebrate neuromuscular junction is designed for rapid transmission of excitatory signals for initiation of muscle contraction.5 Among the features responsible for the high throughput of this synapse are the close proximity of the presynaptic and postsynaptic membranes,10 the direct coupling of acetylcholine (ACh) binding to the opening of the ion channel associated with the nicotinic acetylcholine receptor (nAChR),27 the brief open time of this channel,21,27 and the presence of cholinesterase (ChE) for hydrolysis of ACh.21,30 At the endplate, there are two distinct ChEs for transmitter hydrolysis: acetylcholinesterase (EC 3.1.1.7, AChE) and butyrylcholinesterase (EC 3.1.1.8, BChE).33 Both enzymes can exist in a multisubunit, collagen-tailed form with selective localization at the endplate basallamina.33 Because of its superior catalytic activity for ACh hydrolysis, AChE is the dominant enzyme, whereas the role of BChE is generally evident only after AChE is inhibited.3,4 Inhibition of ChE results in a progressive accumulation of ACh, especially during periods of repetitive stimulation, leading to desensitization of nAChRs and consequent muscle weakness.12,17 Under this condition, transmitter persists beyond its normal lifetime and is slowly removed from the endplate region by diffusion.21,30 Diffusion is impeded in part by morphological barriers, such as the apposition of the nerve terminal to the postjunctional membrane,5,10 and by the high density of postjunctional nAChRs.21,22,25 If ChE is inhibited pharmacologically or removed by collagenase treatment, repeated binding to nAChR makes diffusional loss of ACh slow and inefficient.21,22,30 The influence of nAChRs on retention of transmitter was termed “buffered diffusion” by Katz and Miledi21 and accounts for findings that elimination of ACh is considerably slower than that expected for free diffusion. 30 Inhibitors of ChE are highly toxic, producing incapacitation and death within minutes.28 The cause of death is complex, involving loss of central respiratory drive,6,29 bronchospasm,1,2 and the inability of the diaphragm muscle to sustain tetanic tension. 19 Because most ChE inhibitors show little selectivity between AChE and BChE, and may have direct actions unrelated to ChE inhibition, it is difficult to establish the role of AChE activity in neuromuscular transmission. To overcome this difficulty, we studied twitch and tetanic tensions in diaphragm muscles from AChE knockout (AChE-/-) mice that fail to express AChE but do contain normal levels of BChE.7,24,36 Stimulation of the phrenic nerve in isolated diaphragm preparations from AChE-/- mice revealed large single twitches and sustained tetanic tensions at 70 and 100 Hz. These findings suggest that, over a limited frequency range, diaphragm muscles from AChE-/- mice are able to compensate for the loss of AChE activity. An understanding of these adaptive mechanisms is expected to provide insight on protection strategies that may be effective against the toxic actions of ChE inhibitors such as the highly lethal nerve agents

Recruitment and Training for Home Hemodialysis: Experience and Lessons from the Nocturnal Dialysis Trial

Background and objectives: We assessed perceived barriers and incentives to home hemodialysis and evaluated potential correlates with the duration of home hemodialysis training