The Practice of Vitamin D Deficiency Assessment in a Geriatric Day Hospital.

There has been no clear consensus on the assessment and treatment of vitamin D deficiency prior to the publication of the National Osteoporosis Society (NOS) Vitamin D Guideline in 2014. The aim of our study was to assess the practice in a medicine for the older person day hospital setting relative to this guideline. A 6-month retrospective analysis of all new patients who attended service from January to July 2013 was carried out. Seventy-six patients were included in the final analysis. Mean age was 83 years. 39 (51%) patients had sufficient levels while 37 (49%) patients had insufficient levels; 14 (19%) being inadequate and 23 (30%) deficient. Eighteen patients who had insufficient levels were subsequently prescribed supplements; 13 (72%) received vitamin D3 in combination with calcium while 5 (28%) received vitamin D3 alone. Based on the findings of this study, we have made some recommendations and adopted the guideline.

Immediate post-anaesthesia recovery 2013: Association of Anaesthetists of Great Britain and Ireland.

1. After general, epidural or spinal anaesthesia, all patients should be recovered in a specially designated area (henceforth 'post-anaesthesia care unit', PACU) that complies with the standards and recommendations described in this document. 2. The anaesthetist must formally hand over the care of a patient to an appropriately trained and registered PACU practitioner. 3. Agreed, written criteria for discharge of patients from the PACU to the ward should be in place in all units. 4. An effective emergency call system must be in place in every PACU and tested regularly. 5. No fewer than two staff (of whom at least one must be a registered practitioner) should be present when there is a patient in a PACU who does not fulfil the criteria for discharge to the ward. 6. All registered practitioners should be appropriately trained in accordance with the standards and competencies detailed in the UK National Core Competencies for Post Anaesthesia Care. 7. All patients must be observed on a one-to-one basis by an anaesthetist or registered PACU practitioner until they have regained control of their airway, have stable cardiovascular and respiratory systems and are awake and able to communicate. 8. All patients with tracheal tubes in place in a PACU should be monitored with continuous capnography. The removal of tracheal tubes is the responsibility of the anaesthetist. 9. There should be a specially designated area for the recovery of children that is appropriately equipped and staffed. 10. All standards and recommendations described in this document should be applied to all areas in which patients recover after anaesthesia, to include those anaesthetics given for obstetric, cardiology, imaging and dental procedures, and in psychiatric units and community hospitals. Only registered PACU practitioners who are familiar with these areas should be allocated to recover patients in them as and when required. 11. Patients' dignity and privacy should be respected at all times but patients' safety must always be the primary concern. When critically ill patients are managed in a PACU because of bed shortages, the primary responsibility for the patient lies with the hospital's critical care team. The standard of nursing and medical care should be equal to that in the hospital's critical care units. Audit and critical incident reporting systems should be in place in all PACUs.

Common nonsense mutations in RAD52.

RAD51, RAD52, and RAD54 encode proteins that are critical to the repair of double-strand DNA breaks by homologous recombination. The physical interactions among the products of RAD51, BRCA1, and BRCA2 have suggested that the BRCA1 and BRCA2 breast cancer susceptibility genes may function, at least in part, in this DNA damage repair pathway. Given the observation that different genes within a common functional pathway may be targeted by mutations in human cancers, we analyzed RAD51, RAD52, and RAD54 for the presence of germ-line mutations in 100 cases with early-onset breast cancer and for somatic mutations in 15 human breast cancer cell lines. Two premature stop codons, Ser346ter and Tyr415ter, were identified in germ-line RAD52 alleles from 5% of early-onset breast cancer cases. Together, these two heterozygous mutations were also found in 8% of a healthy control population, indicating that they do not confer an increased risk for breast cancer. A rare germ-line missense mutation was identified in RAD54, whereas no sequence variants were found in RAD51. None of the three RAD genes demonstrated somatic mutations in breast cancer cell lines. We conclude that, despite their potential functional association with the BRCA gene products, RAD51, RAD52, and RAD54 are not themselves targeted by mutations in human breast cancer. The presence of common nonsense mutations in RAD52 within the population may have significance for other conditions associated with potential alterations in DNA damage repair pathways.

Safety, pharmacokinetics, and immunogenicity of single-dose rFXIII administration to healthy volunteers.

BACKGROUND: Factor XIII (FXIII) is a transglutaminase that cross-links fibrin and other proteins to improve clot strength and resistance to fibrinolysis. Both congenital and acquired FXIII deficiency may result in a bleeding diathesis, and plasma-derived FXIII has been used to treat many of these clinical conditions. OBJECTIVES: A clinical study was designed and performed to evaluate the safety, pharmacokinetics, and immunogenicity of recombinant FXIII (rFXIII) administration to healthy adult volunteers. PATIENTS AND METHOD: Fifty healthy adult volunteers were enrolled in this randomized, double-blinded, placebo-controlled study. A single dose of rFXIII, ranging from 2 U kg(-1) to 50 U kg(-1), or placebo was administered. Safety was evaluated by capturing adverse events, clinical safety laboratory studies, and clinical score for deep venous thrombosis. Blood samples were taken for pharmacokinetic and immunogenicity analysis throughout the 28-day follow-up period. RESULTS: Recombinant FXIII was well tolerated, with no serious adverse events or dose-related toxicities. Following a single i.v. injection of 50 U kg(-1) rFXIII, the estimated terminal half-life was 270-320 h, the volume of distribution ranged from 40 to 75 mL kg(-1), and FXIII activity increased 1.77% per 1 U kg(-1) rFXIII administered. Increase in circulating A2B2 and decrease in free FXIII-B subunit indicate in vivo formation of FXIII heterotetramer. An immunogenic response to rFXIII or yeast, the production host, was not observed. CONCLUSIONS: Recombinant FXIII was well tolerated at doses of up to 50 U kg(-1) in healthy adult volunteers. The safety, pharmacological and immunological profile of rFXIII suggests it should be studied in patients with congenital FXIII deficiency as well as evaluated as a systemic hemostat in patients with acquired FXIII deficiency or hemorrhage.

Haemodynamics, cardiac conduction and pharmacokinetics of mibefradil (Ro 40-5967), a novel calcium antagonist.

OBJECTIVES: Mibefradil (Ro40-5967) is a chemically novel non-dihydropyridine calcium antagonist. In this phase II study we compared its acute and chronic effects on blood pressure, heart rate and atrioventricular conduction (electrocardiographic PQ interval) with those of verapamil and diltiazem. PATIENTS AND METHODS: After a 4-week placebo run-in, 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinetics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days. Seventeen of the same patients subsequently underwent 4 weeks of treatment with either mibefradil (100 mg daily; n = 10) or verapamil SR (240 mg daily; n = 7), and on the last day, they attended a further 10-h study day. Two studies were conducted: an acute, single-dose, double-blind, randomly allocated, placebo-controlled, crossover study and a chronic, open-label, randomly allocated, parallel-group study. RESULTS: Mibefradil was well tolerated. In the acute study, the antihypertensive effect (difference from placebo) of mibefradil 150 mg was of slower onset than that of verapamil or diltiazem, but comparable blood pressure reductions had been achieved by 6 h. The mean +/- SD maximal PQ prolongation (difference from placebo) was 15.6 +/- 16.1 ms, compared with 44.0 +/- 22.6 ms for verapamil and 56.0 +/- 48.9 ms for diltiazem (P<0.05 mibefradil versus verapamil; P<0.01 mibefradil versus diltiazem). In the chronic study there were no significant differences during steady-state conditions between mibefradil at 100 mg and verapamil SR at 240 mg in their effects on blood pressure, PQ and heart rate. The mean +/- SD elimination half-life (t1/2) of mibefradil under steady-state conditions was 26.8 +/- 5.5 h (versus an apparent t1/2 of 16.9 +/- 11.1 h for verapamil SR, P<0.05). CONCLUSIONS: Mibefradil is a well-tolerated and efficacious antihypertensive agent well suited to single daily dosing because of its intrinsic long plasma half-life. The effects on both blood pressure and PQ interval are of more gradual onset than those of unmodified verapamil and diltiazem after single doses.

Low-dose antihypertensive therapy with 1.5 mg sustained-release indapamide: results of randomised double-blind controlled studies. European study group.

OBJECTIVE: In accordance with international recommendations on the need to decrease doses of antihypertensive drugs, a low-dose (1.5 mg) sustained-release (SR) formulation of indapamide was developed to optimize the drug's efficacy : safety ratio. The aim of this work was to evaluate the benefit of a low-dose diuretic by consolidating the efficacy and safety results of two clinical trials with a similar design. PATIENTS AND METHODS: Clinical data were obtained in two European randomized double-blind studies with 690 mild to moderate hypertensive patients (95 mmHg < or = supine diastolic blood pressure < or = 114 mmHg using a mercury sphygmomanometer) treated respectively for 2 and 3 months, with a mean age of 53 and 57 years, 44 and 57% males, mean supine diastolic blood pressure of 100.6 and 102.5 mmHg and mean supine systolic blood pressure of 161.0 and 164.5 mmHg. RESULTS: The first study, a dose-finding study with indapamide SR at 1.5, 2 and 2.5 mg versus placebo and the immediate-release (IR) formulation of indapamide, showed that the 1.5 mg dosage of the new indapamide formulation had an improved antihypertensive efficacy : safety ratio. The second study confirmed the equivalence of blood pressure reductions with 1.5 mg indapamide SR and 2.5 mg indapamide IR, and better acceptability with 1.5 mg indapamide SR, particularly in the number of patients with serum potassium levels < 3.4 mmol/l, which was reduced by more than 50%. The long-term efficacy of 1.5 mg indapamide SR was observed through a 9-month open-treatment follow-up to the second study. CONCLUSION: The 1.5 mg SR formulation of indapamide has an improved antihypertensive efficacy : safety ratio, which is in accordance with international recommendations for the use of low-dose antihypertensive drugs and diuretics in first-line therapy of hypertension.

Small intestinal bacterial overgrowth--an incidental finding?

OBJECTIVES: To assess the prevalence of typical clinical features and need for treatment of small intestinal bacterial overgrowth (SIBO) in the elderly. DESIGN: Random selection of patients, regardless of their nutritional status. SETTING: Acute admissions ward in the Dept. of Medicine for the Elderly. PATIENTS: Thirty elderly patients between 68 and 90 years of age. MEASUREMENTS: Active clinical problems, including the presence of recent weight loss and diarrhea, were recorded. Routine blood tests, including serum vitamin B12, red cell folate, albumin and calcium, and qualitative small bowel bacteriology results, were analyzed. The effect of age on all variables was studied. RESULTS: Twenty of the 30 small bowel aspirates had proven SIBO, and strict anaerobes were isolated in 15. The mean blood test values did not differ significantly between culture-positive and culture-negative patients. There was no significant correlation between those variables and the total bacterial counts. Of the 20 proven SIBO cases, eight had anemia, five had hypoalbuminemia, five had diarrhea, four complained of recent weight loss, and none had B12 deficiency. Alternative causes other than SIBO were identified for many of these abnormalities. Advancing age correlated significantly with rising counts of small bowel strict anaerobes. CONCLUSIONS: These data suggest that age may be a predisposing factor in the development of anaerobic overgrowth but that SIBO is a benign entity in the elderly. Contrary to previous recommendations, treatment of this condition is not routinely indicated.

Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia.

The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia (type IIb). After a two-month placebo phase, patients were randomized to receive either Bezafibrate Slow Release (SR) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy. Total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol were measured at monthly intervals. Apolipoproteins (apo) A1 and B, lipoprotein (a) [Lp(a)] and fibrinogen were measured before and after each treatment. Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol (2.0 vs. 1.1 mmol/l, p = 0.003) and lowering LDL cholesterol (1.7 vs. 0.4 mmol/l, p = 0.0001) whereas Bezafibrate SR was more effective in reducing triglycerides (by 41% vs. 17%, p = 0.001) and fibrinogen (by 23% vs. 3%, p = 0.004). Compared with simvastatin monotherapy, combined drug therapy induced further reductions in triglycerides (by 26%, p = 0.0003) and apoB (by 11 mg/dl, p = 0.03) and an increase in apoA1 (by 21 mg/dl, p = 0.0008). Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy. The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events.

Pharmacodynamics and pharmacokinetic-pharmacodynamic relationships of atorvastatin, an HMG-CoA reductase inhibitor.

The objective of this study is to determine the relationships between plasma atorvastatin concentrations, LDL (low-density lipoprotein) cholesterol reduction, and atorvastatin dose; the earliest time at which lipid levels change when atorvastatin treatment is initiated or discontinued; and alterations in LDL particle composition. Twenty-four subjects with elevated LDL-cholesterol were treated with escalating daily doses of 5, 20, and 80 mg atorvastatin for 6 weeks each. Serial plasma lipid and lipoprotein analyses were performed during the initiation and discontinuation of atorvastatin therapy, as well as at steady state. LDL-apolipoprotein B and LDL-cholesterol were measured directly after ultracentrifugation, and LDL-cholesterol also was estimated by the method of Friedewald. Steady-state atorvastatin pharmacokinetic parameters were estimated on the last day of each dosing period. LDL-cholesterol (Friedewald) reductions of 34%, 43%, and 57% were produced by atorvastatin doses of 5, 20, and 80 mg, respectively. The mean dose-response relationship was log linear, and almost all individual dose-response curves paralleled the mean curve. LDL-apolipoprotein B reductions were slightly less than those of LDL-cholesterol. Atorvastatin area under the curve (AUC(0-24) values increased proportionally with dose, while values of Cmax (maximum concentration) increased more than proportionally, and Cmin (minimum concentration) increased less than proportionally. Following initiation of dosing, statistically significant decreases in total cholesterol, LDL-cholesterol (beta quant), and LDL-apolipoprotein B were observed within 24 hours and in LDL-C (Friedewald) within 72 hours. Following discontinuation of drug dosing, statistically significant increases were observed in total cholesterol and LDL-cholesterol (Friedewald) within 48 hours and in LDL-cholesterol (beta quant) and LDL-apolipoprotein B within 72 hours. At each dose, an individual's LDL-cholesterol response was not correlated with AUC(0-24). In conclusion, atorvastatin produces marked LDL-cholesterol reductions, the mean dose-response relationship is log linear, almost all individual dose-response curves parallel the mean dose-response curve, onset and cessation of action are rapid, the estimated and measured LDL-cholesterol are the same, LDL-cholesterol and LDL-Apo B reductions are similar, and plasma concentrations are not correlated with LDL-cholesterol reduction at a given dose.

Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir.

Zanamivir is a potent and specific inhibitor of influenza A and B virus neuraminidase, that is now approved for the treatment, and is currently under development for the prophylaxis of influenza. To assess the safety of this drug in asthmatics, 13 subjects with mild/moderate asthma [forced expiratory volume in 1 sec (FEV1)> or =70% predicted, reversibility of FEV1 to salbutamol > or =15%, concentration of methacholine causing a drop of 20% in the FEV1 (PC20FEV1)< or =8 mg ml(-1)], were recruited to a double-blind, randomized, placebo controlled, two way cross-over study. Subjects received 10 mg zanamivir as a dry powder (2 x 5 mg blisters via a Diskhaler Sovnn Plastics Ltd., Berkshire, U.K.), or a matching placebo, twice daily on day 1 and then four times daily from day 2 to day 14, in two separate periods separated by a washout period of 7 days. PC20FEV1 to methacholine was determined pre-study, on day 1 after the evening dose and on day 14 after the last dose of the study drug. FEV1 was measured pre-study and at regular intervals on days 1 and 14. Laboratory safety tests were performed on days 1, 7 and 15. Morning and evening peak expiratory flow rate (PEFR) and any adverse events were recorded in a diary card. Eleven subjects completed the study. One was withdrawn due to non-compliance, and one due to an adverse event that occurred during the placebo period. On day 1 the geometric mean PC20 for zanamivir was 36% lower than for placebo [ratio to placebo 0.64, (90% CI 0.44, 0.93)] and on day 14 this was 33% lower with zanamivir [ratio to placebo 0.67 (90% CI 0.38, 1.15)]. Both these confidence intervals were within the pre-defined interval of 'no clinically significant effect' of 0.25-4 (i.e. a change of two doubling doses of methacholine PC20FEV1 which was considered clinically significant). The time weighted mean FEV1 was 0.15 l (5.4%) lower for zanamivir on day 1 compared to placebo (90% CI 0.03, 0.28; P=0.050) and 0.01 l higher compared to placebo on day 14 (90%CI -0.12, 0.10; P=0.912). The day 1 changes were not associated with any significant symptoms or requirement for rescue bronchodilator therapy. Furthermore there was no apparent treatment difference over the 14 day dosing period in FEV1 data (90% CI: -0.11, 0.05, P=057). The mean morning PEFR was 4 l min(-1) less for zanamivir than for placebo (90% CI: -11, 3) and mean evening PEFR was 9 l min(-1) less (90% CI: -24, 5). The study treatments were well tolerated by the subjects with no clinically significant adverse events attributable to zanamivir treatment. Zanamivir inhaled as a dry powder does not significantly affect the pulmonary function and airway responsiveness of subjects with mild/moderate asthma and therefore its use in such patients subjects is not precluded.

Measurement of arterial closing pressure.

It has been suggested that certain artifacts in blood pressure measurement by auscultation stem from stiffness of the tissues underneath the pressure cuff, resulting in a component of cuff pressure being required to overcome resistance to brachial artery collapse. This paper describes a technique for measuring the pressure required to collapse a segment of the brachial artery which has been isolated from central arterial pressure. This measurement is termed the arterial closing pressure. In a study of eleven elderly subjects, the artery collapsed spontaneously (zero closing pressure) after being isolated from central pressure in seven subjects. The remaining four required external pressures ranging from 4.6 to 10.7 kPa (35 to 81 mmHg) in order to collapse the artery. Thus arterial closing pressure may frequently be a significant fraction of arterial blood pressure in the elderly population, and may contribute to error in the measurement of blood pressure by auscultation. Arterial closing pressure may be a useful tool for investigating the origin of differences between indirect and direct blood pressure measurements, and also in the investigation of spontaneous arterial closure.

Observing the brachial artery through a pressure cuff.

A technique is described which enables ultrasonic imaging of the brachial artery whilst pressure is applied via a pressure cuff. This involves a new instrument--a sphygmomanometer, which uses water as opposed to air as the pressure medium, in order to permit ultrasonic imaging through the cuff. The technique was found to be acceptable in the clinical setting, and gave a measurement of the systolic blood pressure which correlated with the conventional cuff measurement in eleven elderly subjects (r = 0.89, p < 0.001). The technique should have an important role to play in studying the origin of differences which occur between direct and indirect blood pressure measurements.

[Evaluation of trough/peak ratio of indapamide 1.5 mg sustained-release form assessed by ambulatory blood pressure monitoring]. / Evaluation du rapport vallée/pic de l'indapamide 1,5 mg comprimé enrobé a libération prolongée par la mesure ambulatoire de la pression artérielle.

Because of the high variability of casual blood pressure measurements. ABPM has become a complementary clinical tool for evaluating antihypertensive treatment. Nevertheless, there is still a lack of practical guidelines to interpret the data. A review of the literature shows that ABPM efficacy data are analyzed differently, especially the trough-to-peak ratio proposed by the Food and Drug Administration. Published trough-to-peak ratios are widely disparate due to the diversity of the calculation methods which are most often not justified. Thus inappropriate comparisons of these results can easily produce incorrect conclusions. The aim of this review is to select, through the literature, basic methodological requirements commonly agreed on for accurate assessment of trough-to-peak ratio, and to apply them to the ABPM data on indapamide, a diuretic related to the thiazides. Six methodological requirements commonly agreed on at this time are the following: 1. study design: placebo-controlled study with a placebo run-in period; 2. patients selection: compliance with the study protocol, record obtained before and after treatment for each patient; 3. population analysis: whole and responder population: 4. quality control of the records: 5. placebo effect subtraction; 6. global and individual calculation with the indication of median values. Given that, no T/P ratio, especially for a diuretic, has yet been calculated according to these requirements, the above methodological points were taken into account for the T/P calculation of indapamide, from a placebo-controlled dose-finding study involving 285 patients.

Management of Parkinson's disease in the acute hospital environment.

There have been a number of exciting developments in the management of Parkinson's disease (PD) in the past decade. However the objective for the vast majority of patients remains the maintenance of quality of life through the achievement of steady levels of dopaminergic stimulation within the target neurones of the basal ganglia. While there is a great deal of guidance available for the PD specialist, it remains a challenge for the generalist to know which patients require specialist input, how urgently that input should be obtained and what steps should be taken while awaiting review. Diagnosis can be difficult in the acute setting. While a high index of suspicion is important, it is not a diagnosis that should be made lightly and all cases should be reviewed by a specialist who will then advise on initial treatment. Management of PD medication during intercurrent illness is a challenge, particularly when the gastrointestinal tract is dysfunctional. Some guidance on dealing with this situation is available and has been summarised in this article. Problems that may present to the general physician include aspiration pneumonia, uncontrolled dyskinesias, psychosis, dopamine agonist withdrawal syndrome and rarely, neuroleptic malignant-like syndrome. These conditions will be reviewed, along with general guidance for managing patients on more sophisticated regimes such as continuous intrajejunal levodopa infusion (Duodopa) and patients with a deep brain stimulator in situ.