National variation between clinical commissioning groups in referral criteria for primary total hip replacement surgery.

The referral criteria used by the UK clinical commissioning groups for primary total hip replacement surgery appear inconsistent; the criteria rarely follow National Institute for Health and Care Excellence criteria. With established guidelines available, it is unclear why the clinical commissioning groups have referral criteia with less evidence base, without obviously addressing particular issues in their locality.

Quantification of the effects of audible rattle and source type on the human response to environmental vibration.

The present research quantifies the influence of source type and the presence of audible vibration-induced rattle on annoyance caused by vibration in residential environments. The sources of vibration considered are railway and the construction of a light rail system. Data were measured in the United Kingdom using a socio-vibration survey (N = 1281). These data are analyzed using ordinal logit models to produce exposure-response relationships describing community annoyance as a function of vibration exposure. The influence of source type and the presence of audible vibration-induced rattle on annoyance are investigated using dummy variable analysis, and quantified using odds-ratios and community tolerance levels. It is concluded that the sample population is more likely to express higher levels of annoyance if the vibration source is construction compared to railway, and if vibration-induced rattle is audible.

Human annoyance, acceptability and concern as responses to vibration from the construction of Light Rapid Transit lines in residential environments.

The aim of this paper is to investigate the use of different self-reported measures for assessing the human response to environmental vibration from the construction of an urban LRT (Light Rapid Transit) system. The human response to environmental stressors such as vibration and noise is often expressed in terms of exposure-response relationships that describe annoyance as a function of the magnitude of the vibration. These relationships are often the basis of noise and vibration policy and the setting of limit values. This paper examines measures other than annoyance by expressing exposure-response relationships for vibration in terms of self-reported concern about property damage and acceptability. The exposure-response relationships for concern about property damage and for acceptability are then compared with those for annoyance. It is shown that concern about property damage occurs at vibration levels well below those where there is any risk of damage. Earlier research indicated that concern for damage is an important moderator of the annoyance induced. Acceptability, on the other hand, might be influenced by both annoyance and concern, as well as by other considerations. It is concluded that exposure-response relationships expressing acceptability as a function of vibration exposure could usefully complement existing relationships for annoyance in future policy decisions regarding environmental vibration. The results presented in this paper are derived from data collected through a socio-vibration survey (N=321) conducted for the construction of an urban LRT in the United Kingdom.

Design of measurement methodology for the evaluation of human exposure to vibration in residential environments.

Exposure-response relationships are important tools for policy makers to assess the impact of an environmental stressor on the populace. Their validity lies partly in their statistical strength which is greatly influenced by the size of the sample from which the relationship is derived. As such, the derivation of meaningful exposure-response relationships requires estimates of vibration exposure at a large number of receiver locations. In the United Kingdom a socio-vibrational survey has been conducted with the aim of deriving exposure-response relationships for annoyance due to vibration from (a) railway traffic and (b) the construction of a new light rail system. Response to vibration was measured via a questionnaire conducted face-to-face with residents in their own homes and vibration exposure was estimated using data from a novel measurement methodology. In total, 1281 questionnaires were conducted: 931 for vibration from railway traffic and 350 for vibration from construction sources. Considering the interdisciplinary nature of this work along with the volume of experimental data required, a number of significant technical and logistical challenges needed to be overcome through the planning and implementation of the fieldwork. Four of these challenges are considered in this paper: the site identification for providing a robust sample of the residents affected, the strategies used for measuring both exposure and response and the coordination between the teams carrying out the social survey and the vibration measurements.

Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA): a randomized double-blind placebo-controlled trial of high- vs. low-dose atorvastatin(1).

AIMS: To compare the renal effects of low- vs. high-dose atorvastatin in patients with Type 2 diabetes mellitus and optimally managed early renal disease. METHODS: We compared the 2-year progression of nephropathy in a double-blind randomized controlled trial of atorvastatin 80 mg/day (n = 60) vs. 10 mg/day (n = 59) in patients with Type 2 diabetes with microalbuminuria or proteinuria [mean (sd): age 64 years (10 years); HbA(1c) 7.7% (1.3%), 61 mmol/mol (10 mmol/mol); blood pressure 131/73 mmHg; renin-angiotensin system blocker use > 80%; dual blockade > 67%] recruited from diabetes clinics in Greater Manchester. RESULTS: Over (mean) 2.1 years of follow-up, the Modification of Diet in Renal Disease estimated glomerular filtration rate declined by 3 ml min(-1) 1.73 m(-2) in the combined group. The mean (95% CI) between-group difference during follow-up was not significant [2.2 ml min(-1) 1.73 m(-2) (-1.1 to 5.4 ml min(-1) 1.73: m(-2) ), P = 0.20] after adjusting for baseline differences in renal function; positive difference favours 80 mg dose. Similarly, there was no significant difference in creatinine clearance by Cockcroft and Gault [2.5 ml/min (-2.4 to 7.3 ml/min), P = 0.32]; serum creatinine/24-h urine collections [4.0 ml/min (-4.8 to 12.7 ml/min), P = 0.38]; cystatin C (P = 0.69); or 24-h urine protein or albumin excretion (P = 0.92; P = 0.93). We recorded no significant between-group differences in deaths or adverse events. CONCLUSIONS: In patients with Type 2 diabetes with early renal disease, we found no statistical difference in renal function between those taking high- or low-dose atorvastatin over 2 years. We cannot exclude a beneficial effect of < 1.6 ml min(-1) 1.73 m(-2) year(-1) on Modification of Diet in Renal Disease estimated glomerular filtration rate, or if blood pressure management or if renin-angiotensin system blocker use had not been optimized.

A dimensionless mobility formulation for evaluation of force and moment excitation of structures.

The problem addressed is the simultaneous excitation of a structure by a force and moment. These two forms of excitation are dimensionally incompatible, and so their relative importance is normally difficult to assess. Here, a dimensionless form of the mobility matrix is developed thereby allowing proper comparison. The off-diagonal elements of the matrix quantify the coupling between two excitations of whatever dimensions, in other words the extent to which an applied force or moment affects the power input by another force or moment. It is shown that off-diagonals of unit magnitude indicate the maximum possible extent of coupling between the corresponding excitations. A precise definition of weak and strong coupling is therefore possible. Illustrative examples of dimensionless mobilities for infinite, semi-infinite, and finite plates are given. It is also shown that the eigenvalues of the dimensionless mobility matrix relate the actual delivered power to the "point-by-point" power input. The results are shown to have wider relevance than originally intended; specifically, the dimensionless mobilities provide a measure of the suitability for active vibration control of different points on a structure, or mixed excitations.

Anomalous mole-fraction effects in recombinant and native cyclic nucleotide-gated channels in rat olfactory receptor neurons.

Anomalous mole-fraction effects (AMFE) were studied, using the inside-out configuration of the patchclamp technique, in both recombinant wild-type alpha-homomeric rat olfactory adenosine 3',5'-cyclic monophosphate (cAMP)-gated channels (rOCNC1) expressed in human embryonic kidney cells (HEK 293) and native cyclic nucleotide-gated (CNG) channels in acutely isolated rat olfactory receptor neurons. Single-channel and macroscopic currents were activated by 200 microM and 500 microM cAMP, respectively. Macroscopic currents, measured with mixtures of Na(+)-NH(4)(+) or Cs(+)-Li(+) in the cytoplasmic bathing solution, displayed AMFE in the rOCNC1 channels at both positive and negative membrane potentials. The rOCNC1 single-channel conductance showed a distinct minimum (or maximum) in an 80% Na(+)-20% NH(4)(+) mixture (or a 60% Cs(+)-40% Li(+) mixture), but only at positive membrane potentials. Macroscopic measurements in native olfactory CNG channels with mixtures of Na(+)-NH(4)(+) indicated similar AMFE. These results suggest that both native CNG channels and recombinant alpha-homomeric channels allow several ions to be present simultaneously within the channel pore. They also further validate the dominant role of the alpha-subunit in permeation through these channels, provide the first evidence to suggest that rOCNC1 channels have multi-ion properties and further justify the use of the rOCNC1 channel as an effective model for structure-function studies of ion permeation and selectivity in olfactory CNG channels.

IP3-gated channels and their occurrence relative to CNG channels in the soma and dendritic knob of rat olfactory receptor neurons.

Olfactory receptor neurons respond to odorants with G protein-mediated increases in the concentrations of cyclic adenosine 3',5'-monophosphate (cAMP) and/or inositol-1,4,5-trisphosphate (IP3). This study provides evidence that both second messengers can directly activate distinct ion channels in excised inside-out patches from the dendritic knob and soma membrane of rat olfactory receptor neurons (ORNs). The IP3-gated channels in the dendritic knob and soma membranes could be classified into two types, with conductances of 40 +/- 7 pS (n = 5) and 14 +/- 3 pS (n = 4), with the former having longer open dwell times. Estimated values of the densities of both channels from the same inside-out membrane patches were very much smaller for IP3-gated than for CNG channels. For example, in the dendritic knob membrane there were about 1000 CNG channels x microm(-2) compared to about 85 IP3-gated channels x microm(-2). Furthermore, only about 36% of the dendritic knob patches responded to IP3, whereas 83% of the same patches responded to cAMP. In the soma, both channel densities were lower, with the CNG channel density again being larger ( approximately 57 channels x microm(-2)) than that of the IP3-gated channels ( approximately 13 channels x microm(-2)), with again a much smaller fraction of patches responding to IP3 than to cAMP. These results were consistent with other evidence suggesting that the cAMP-pathway dominates the IP3 pathway in mammalian olfactory transduction.

A study of live supervisory phone-ins in collaborative family therapy: correlates of client cooperation.

The behavior of five supervisors, 19 trainee family therapists, and 20 clients before, during, and after 88 live supervisory phone-in events was examined in this study to determine the correlates of client cooperation. Following supervisory phone-in conversations, client cooperation was associated exclusively with the presence and quality of the collaborative behavior shown by the therapist. Isomorphism between the behavior of the supervisor and therapist was not associated with subsequent client cooperation, nor was any particular category of supervisor behavior. Surprisingly, isomorphism between the quality of supervisor and therapist behavior preceded those events where client resistance occurred.

When CPR is not an option.

What is to be learned from this situation? First, although Mr. Lockwood's consent for the DNR order is not needed, there is an obligation to communicate openly and clearly with the family and ensure that Mrs. Lockwood's advance directive is respected. This might mean a DNR order needs to be written. Also, there is an obligation to discuss goals of care with the family. The second lesson is that you should reflect on your employer's CPR policies and practice, and ask the following questions: Do the policy and/or practices support saying "no" in a situation such as Mrs. Lockwood's? Also, how does the policy support staff when there is a request for futile CPR, either from a competent patient or from a patient's family? What are the expectations about communication with the family when there is an advance directive and/or when CPR is found to be futile? Knowing what you ought to do for patients is not sufficient. Often you cannot act on these decisions because of the environment. If the policies are not in accord with the CNA Statement on Resuscitative Interventions, you should collaborate with colleagues to revise the CPR policy and practices. By doing so, you will be meeting your obligation to help foster and support a practice environment that promotes ethical, competent and compassionate nursing care.

Ion permeation and selectivity of wild-type recombinant rat CNG (rOCNC1) channels expressed in HEK293 cells.

The permeation properties of adenosine 3', 5'-cyclic monophosphate (cAMP)-activated recombinant rat olfactory cyclic nucleotide-gated channels (rOCNC1) in human embryonic kidney (HEK 293) cells were investigated using inside-out excised membrane patches. The relative permeability of these rOCNC1 channels to monovalent alkali cations and organic cations was determined from measurements of the changes in reversal potential upon replacing sodium in the bathing solution with different test cations. The permeability ratio of Cl(-) relative to Na(+) (P(Cl)/P(Na)) was about 0.14, confirming that these channels are mainly permeable to cations. The sequence of relative permeabilities of monovalent alkali metal ions in these channels was P(Na) > or = P(K) > P(Li) > P(Cs) > or = P(Rb), which closely corresponds to a high-strength field sequence as previously determined for native rat olfactory receptor neurons (ORNs). The permeability sequence for organic cations relative to sodium was P(NH3OH) > P(NH4) > P(Na) > P(Tris) > P(Choline) > P(TEA), again in good agreement with previous permeability ratios obtained in native rat ORNs. Single-channel conductance sequences agreed surprisingly well with permeability sequences. These conductance measurements also indicated that, even in asymmetric bi-ionic cation solutions, the conductance was somewhat independent of current direction and dependent on the composition of both solutions. These results indicate that the permeability properties of rOCNC1 channels are similar to those of native rat CNG channels, and provide a suitable reference point for exploring the molecular basis of ion selectivity in recombinant rOCNC1 channels using site-directed mutagenesis.

M2 pore mutations convert the glycine receptor channel from being anion- to cation-selective.

Three mutations in the M2 transmembrane domains of the chloride-conducting alpha1 homomeric glycine receptor (P250Delta, A251E, and T265V), which normally mediate fast inhibitory neurotransmission, produced a cation-selective channel with P(Cl)/P(Na), = 0.27 (wild-type P(Cl)/P(Na) = 25), a permeability sequence P(Cs) > P(K) > P(Na) > P(Li), an impermeability to Ca(2+), and a reduced glycine sensitivity. Outside-out patch measurements indicated reversed and accentuated rectification with extremely low mean single channel conductances of 3 pS (inward current) and 11 pS (outward current). The three inverse mutations, to those analyzed in this study, have previously been shown to make the alpha7 acetylcholine receptor channel anion-selective, indicating a common location for determinants of charge selectivity of inhibitory and excitatory ligand-gated ion channels.

Very negative potential for half-inactivation of, and effects of anions on, voltage-dependent sodium currents in acutely isolated rat olfactory receptor neurons.

Previous measurements with CsF pipette solutions using whole-cell patch-clamp techniques in dissociated rat olfactory receptor neurons (ORNs) indicated that the sodium currents had very negative inactivation characteristics with the implication that the cell resting potential must also normally have a very negative value. This study supports the conclusions that such an effect was real and not dependent on either the nature of the pipette anions or the recording situation previously used. For all pipette solutions, sodium currents showed a threshold activation approximately -80 mV and half-maximal activation voltages approximately -55 with half-inactivation potential < or =-100 mV, without being significantly affected by the replacement of F(-) by other pipette anions (H(2)PO(-)(4) and acetate(-)) or the addition of nucleotides and glutathione (which did cause a very slight positive shift). F(-), followed by H(2)PO(-)(4) and to a much lesser extent by acetate(-), was the most favorable pipette anion for obtaining good seals and whole-cell sodium currents in these extremely small ORNs. These results implied that resting potentials, for viable responsive cells, should be more negative than about -90 mV, as supported by the observation that action potentials could only be evoked from holding potentials more negative than -90 mV.

Glycine receptors: what gets in and why?

1. The glycine receptor channel (GlyR), a member of the ligand-gated ion channel superfamily, shares many similar permeation properties with the GABAA receptor channel. 2. The GlyR is anion permeable, with PK/PCl < 0.05, has a 5-6 A minimum pore diameter and a permeation selectivity sequence dominated by hydration energies. 3. The channels, which display multiple subconductance states, can be multiply occupied. 4. Two positive arginine rings at the ends of the pore region may contribute to the anion selectivity of the GlyR. 5. Mutation of the extracellular charged arginine ring can impair channel function by decreasing the sensitivity of glycine activation, reducing channel conductance, shifting the normal multi-subconductance states to lower values and by decoupling the link between ligand binding and channel gating. 6. These and other site-directed mutagenesis studies of recombinant GlyR, together with studies of native GlyR, are providing further insights into what controls gating and ion permeation and selectivity through this channel.

Measurement of the limiting equivalent conductivities and mobilities of the most prevalent ionic species of EGTA (EGTA2- and EGTA3-) for use in electrophysiological experiments.

In many experimental biological situations, chelating agents like EGTA (ethylene glycol-bis-(beta-amino-ethyl ether) N,N,N',N'-tetra-acetic acid) are commonly used to control or suppress the concentration of divalent ions like Ca2+. The evaluation of liquid junction potentials in electrophysiological measurements, and particularly in patch-clamp situations, requires information about the ions within the solution. Where there is a significant concentration of EGTA present, it is necessary to know the values of the relative mobility of at least the most predominant ionic species of EGTA in order to complete these calculations. EGTA, with four negative charges with different pKas, can therefore exist as four differently charged ions in solution (EGTA-, EGTA2-, EGTA3- and EGTA4-) or as uncharged, although between pH 5.5 and 8 it is almost exclusively EGTA2-. We have measured limiting equivalent conductivities of the most common ionic forms of EGTA (EGTA2- and EGTA3-) encountered at physiological pHs. These were 35.9 +/- 0.7 and 56 +/- 2.5 S cm2 equiv(-1) respectively. Their mobilities relative to K+ were 0.24 +/- 0.01 for EGTA2- and 0.25 +/- 0.01 for EGTA3-. Thus for typical electrophysiological solutions, the contribution of EGTA to the liquid junction potential should be small (e.g. approximately 0.4 mV).

Direct effects of tolbutamide on mitochondrial function, intracellular Ca2+ and exocytosis in pancreatic beta-cells.

Using the whole-cell voltage-clamp method to measure ATP-sensitive K+(KATP) currents, changes in cell capacitance to measure secretion and microfluorimetry to monitor intracellular Ca2+ and mitochondrial function, we have investigated the direct effect of sulphonylureas on exocytosis in pancreatic beta-cells. Tolbutamide (100 microM) and 100 nM 4-beta-12-phorbolmyristate-13-acetate (PMA), which activates the protein kinase C (PKC) isoforms found in beta-cells, potentiated exocytosis in a non-additive manner. These effects were blocked by down-regulation of PKC. Our data support the idea that tolbutamide can potentiate secretion from beta-cells via a PKC-dependent pathway. Because PKC and sulphonylureas can modulate the activity of KATP channels, we explored whether the above effects are caused by inhibition of this channel. PMA increased whole-cell KATP currents but did not affect their sensitivity to tolbutamide. Down-regulation of PKC affected neither the magnitude nor the tolbutamide sensitivity of the KATP current. Both tolbutamide and the mitochondrial uncoupler FCCP (1 microM) mobilized intracellular Ca2+ and prolonged Ca2+ transients elicited by cholinergic mobilization of intracellular Ca2+ stores. Tolbutamide (0.1-0.5 mM), like FCCP, depolarized the mitochondrial membrane potential and activated KATP currents. We suggest that sulphonylureas can directly potentiate exocytosis by impairing mitochondrial function and Ca2+ handling, which ultimately leads to activation of Ca2+-dependent enzymes such as PKC.

The startle disease mutation Q266H, in the second transmembrane domain of the human glycine receptor, impairs channel gating.

Hyperekplexia (startle disease) results from mutations in the glycine receptor chloride channel that disrupt inhibitory synaptic transmission. The Q266H missense mutation is the only hyperekplexia mutation located in the transmembrane domains of the receptor. Using recombinant expression and patch-clamping techniques, we have investigated the functional properties of this mutation. The ability of glycine and taurine to open the channel was reduced in the mutated channel, as shown by a 6-fold shift in the concentration-response curve for both agonists. This was not accompanied by similar changes in agonist displacement of strychnine binding, suggesting that the mutation affects functions subsequent to ligand binding. Taurine was also converted to a weak partial agonist and antagonized the actions of glycine, consistent with changes in its channel gating efficacy. Because the Q266H mutation is within the pore-forming second transmembrane domain, we tested for a direct interaction with permeating ions. No change in either the cation/anion selectivity ratio or in single channel conductance levels was observed. No differential effects of Zn++, pH, and diethylpyrocarbonate were observed, implying that the histidine side chain is not exposed to the channel lumen. Single-channel recordings revealed a significant reduction in open times in the mutant receptors, at both high and low agonist concentrations, consistent with the open state of the channel being less stable. This study demonstrates that residues within the second transmembrane domain of ligand-gated ion channel receptors, even those whose side chains do not directly interact with permeating ions, can affect the kinetics of channel gating.

An integrated model of discharge planning for acutely-ill elderly patients.

Prior research has demonstrated that current discharge-related practices present resource-related and ethical problems for all those involved. The purpose of this 9-month qualitative study was to develop a more resource efficient and compassionate discharge planning model for acutely-ill, elderly patients. The focus group interviewing method was used to elicit 99 participants' perceptions of an ideal approach to discharge planning. Focus group participants included professionals from acute-care hospitals and community organizations. Telephone interviews were also completed with 25 patients and 6 family members. Themes identified in the analysis revealed that an ideal approach to discharge planning would incorporate seven elements. According to participants, the approach is ideal because it potentially addresses both resource utilization and ethical issues. Program evaluation of the model is underway in order to determine its effectiveness.

The sulphonylurea receptor confers diazoxide sensitivity on the inwardly rectifying K+ channel Kir6.1 expressed in human embryonic kidney cells.

1. We have examined the effects of diazoxide and intracellular ATP (ATPi) on whole-cell currents in HEK293 cells transfected transiently with the inwardly rectifying K+ channel Kir6.1 (uKATP1) or cotransfected with Kir6.1 and the sulphonylurea receptor (SUR1). 2. Kir6.1 currents were unaffected by the K+ channel opener diazoxide or by dialysis with 0.3 mM ATPi. 3. Kir6.1-SUR1 currents increased in amplitude when cells were dialysed with 0.3 mM ATP, but not with 5 mM ATP. This activation may be explained by the loss of endogenous ATP from the cell when the intracellular solution contains 0.3 mM ATP. Kir6.1-SUR1 currents were also activated by diazoxide; this activation was greater with 0.3 mM ATP1 than with 5 mM ATP1. 4. We conclude that SUR1 is required to confer both diazoxide and ATP sensitivity on Kir6.1.