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.

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.

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.

A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH).

BACKGROUND AND AIM: This study was conducted in preparation for the Study Evaluating Additional Reduction in Cholesterol and Homocysteine (SEARCH). SEARCH is a 12,000 patient 2X2 factorial study in post-myocardial infarction patients that will compare simvastatin 20 mg with simvastatin 80 mg to evaluate whether greater LDL-C reductions with simvastatin provide greater coronary event reductions. SEARCH will also test the hypothesis that lowering plasma homocysteine with folic acid and vitamin B12 will reduce coronary events. This pilot study was performed to determine whether any clinically meaningful interaction between simvastatin and folic acid/vitamin B12 exists. METHODS AND RESULTS: Following a 2-week diet/placebo run-in period, 141 patients with primary hypercholesterolaemia were randomised to one of three treatments for 6 weeks: 80 mg/day simvastatin and 2 mg folic acid/0.8 mg vitamin B12 daily (combination group); or 80 mg/day simvastatin and placebo vitamins (simvastatin alone group); or 2 mg folic acid/0.8 mg vitamin B12 daily and placebo simvastatin (vitamins alone group). The combination group and simvastatin alone group experienced similar serum lipid changes with reductions in LDL-cholesterol of 55.2% and 51.5% respectively. The combination group and vitamins alone group experienced similar homocysteine lowering with reductions in homocysteine of 25.3% and 23.1% respectively. All therapies were well tolerated. CONCLUSIONS: There was no detectable antagonistic effect when simvastatin and folic acid/vitamin B12 were administered concomitantly.

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.

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.

Treatment guidelines for hypercholesterolaemia: time to consider soluble fibre.

Lowering raised serum cholesterol levels is firmly established as an effective intervention for reducing the mortality and morbidity due to coronary heart disease (CHD). Recent European and British guidelines for the management of hypercholesterolaemia recommend dietary modification as first-line therapy. However, dietary measures alone do not significantly reduce cholesterol levels. There is ample evidence that soluble fibre, such as ispaghula, lowers cholesterol and could therefore potentially reduce the risk of CHD. As CHD management costs spiral upwards, prescribing lipid-lowering drugs for all indicated patients is not sustainable within current NHS resources. It is suggested that treatment guidelines be revised to include a soluble fibre product, such as ispaghula, as an adjunct to diet for patients where diet alone has failed and where lifelong therapy with lipid-lowering drugs is inappropriate.

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.

The effect of cholesterol reduction with fluvastatin on aortic compliance, coronary calcification and carotid intimal-medial thickness: a pilot study.

BACKGROUND: Regression of atheroma with reduction of cholesterol levels is recognized to occur, but less is known about reversal of sclerosis. Non-invasive indices of sclerosis have largely been based on carotid ultrasound measurements. OBJECTIVE: To measure aortic compliance, coronary calcification and carotid intimal-medial thickness during reduction of cholesterol level in patients with and without coronary artery disease. METHODS: We studied 64 hypercholesterolaemic patients, 24 with and 40 without coronary artery disease. All were administered fluvastatin for 1 year. Aortic compliance was assessed using magnetic resonance and coronary calcification score was determined by electron beam computed tomography. Carotid intimal-medial thickness in 34 patients was measured by carotid ultrasound means. RESULTS: There was a rise in high-density lipoprotein cholesterol level and falls in total cholesterol level, low-density lipoprotein cholesterol level, low: high-density lipoprotein ratio, triglyceride level and very-low-density lipoprotein cholesterol level. Coronary artery disease patients had a higher coronary calcification score (442 +/- 551) than did other patients (269 +/- 724, P = 0.0002). For both groups there was a small rise in coronary calcification score during the study. Mean aortic compliance rose and blood pressure and carotid intimal-medial thickness fell. Analysis revealed significant correlations between change in mean aortic compliance and changes in high-density lipoprotein level (r = 0.3, P = 0.036), very-low-density lipoprotein level (r = -0.31, P = 0.038) and low: high-density lipoprotein ratio (r = -0.35, P = 0.014). There was no significant difference in these changes between the two patient groups. CONCLUSION: An improvement in aortic compliance over 1 year indicates that increase in high-density lipoprotein level, decrease in very-low-density lipoprotein level and improvement in low: high-density lipoprotein ratio caused by administration of fluvastatin beneficially influenced vascular pathophysiology in hypercholesterolaemic patients with and without coronary artery disease. In those patients studied with carotid ultrasound means, carotid intimal-medial thickness decreased from 1.09 to 0.87 mm (P = 0.004), corroborating these results.

Ispaghula husk in the treatment of hypercholesterolaemia: a double-blind controlled study.

BACKGROUND: Lowering cholesterol levels by natural dietary modification is an attractive first-line option for the treatment of mild-to-moderate hypercholesterolaemia. However, results have been less than impressive. The addition of soluble fibre - for example, psyllium or oat bran - to a modified diet has produced better results. In this study, the cholesterol-level-lowering effect of ispaghula husk and dietary advice was compared with placebo and dietary advice in treating patients with mild-to-moderate hypercholesterolaemia. METHODS: The double-blind, placebo-controlled, randomized comparison was conducted in 42 general practices and three hospital centres in the UK. There was an initial 8-week diet-only period and then a 1 2-week treatment period. Ispaghula treatment (7.0 or 10.5 g/day) was continued for a further 12 weeks for some patients. A total of 340 patients, aged 18 to 65, with mild-to-moderate hypercholesterolaemia [low-density lipoprotein (LDL) cholesterol levels of 4.1 mmol/l or more] entered the 12-week treatment phase. Levels of LDL cholesterol, total cholesterol, high-density lipoprotein cholesterol, triglycerides and apolipoproteins A1 and B were determined. RESULTS: LDL cholesterol and total cholesterol levels fell during the diet-only period. In members of the intention-to-treat population after the 8-week diet period, LDL cholesterol levels had fallen by 0.42 mmol/l (8.7%) for the 7.0 g ispaghula/day group after 12 weeks of treatment, whereas LDL cholesterol levels had fallen by 0.48 mmol/l (9.7%) for the 10.5 g ispaghula/day group. Ispaghula at both doses produced significantly greater reductions in LDL cholesterol levels than did placebo (7.0 g/day versus placebo, P=0.009; 10.5 g/day versus placebo, P<0.001). Ispaghula and modification of diet together reduced LDL cholesterol levels by 10.6-13.2% and total cholesterol levels by 7.7-8.9% during the 6-month period. CONCLUSIONS: Ispaghula husk as an adjunct to diet is effective and well tolerated in the management of appropriate patients with mild-to-moderate primary hypercholesterolaemia.

Quantification of CMV viraemia in a case of transfusion-related graft-versus-host disease associated with purine analogue treatment.

We report a patient who developed transfusion-associated graft-versus-host-disease (GvHD) and concurrent cytomegalovirus (CMV) infection, both complications thought to be related to severe T lymphocyte depletion induced by treatment with a purine analogue drug, fludarabine. CMV viraemia was detected by qualitative PCR and the viral load in positive samples was measured using a fully quantitative PCR assay. This quantitative assay enabled the evaluation of the efficacy of antiviral interventions based on the qualitative PCR result. The case illustrates the risks associated with the use of purine analogue drugs, as well as the value of quantitative CMV PCR assays for monitoring CMV infection in immunocompromised patients.

A placebo controlled study comparing the efficacy of intranasal azelastine and beclomethasone in the treatment of seasonal allergic rhinitis.

This study compared a new intranasal anti-allergic drug, azelastine (0.56 mg bid) with intranasal beclomethasone (0.2 mg bid) and placebo in the treatment of symptoms associated with seasonal rhinitis. After administering placebo for 3-5 days as a "run-in" period, eligible patients were randomized to treatment for 2 weeks: 83 patients received azelastine, 83 beclomethasone and 77 placebo. Each of six symptoms was assessed daily using a four-point scale. Total symptom scores showed that azelastine-treated patients experienced a more rapid onset of overall symptom relief than beclomethasone-treated patients. This was significant on day 1 (P < 0.003) and continued until day 5. By the end of the 2-week study period, the beclomethasone-treated group showed greater improvement than both the azelastine and placebo groups (P = 0.002 and P = 0.0001, respectively). In contrast, visual analogue scales at this time showed no significant differences between the azelastine and beclomethasone treatment groups, with both groups demonstrating significant reductions in total symptom scores compared to placebo (P = 0.0004 and P = 0.0001, respectively). Differing sensitivities were found in the four-point scales reported by the patients and the investigators and the patients' visual analogue scales in the measurement of symptom severity. However, all three techniques confirmed that both azelastine nasal spray and beclomethasone nasal spray were effective treatments for seasonal rhinitis. While a greater improvement in overall symptoms was found for the beclamethasone-treated patients compared to azelastine-treated patients, diary card data confirmed the more immediate onset of symptom relief provided by azelastine. No serious adverse events were found in the present study and included no complaints of drowsiness.

[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.

Syncope: driving advice is frequently overlooked.

Consecutive referrals to a syncope clinic were asked about the frequency of enquiries about driving status by referring general practitioners and/or hospital specialists. Although 40% were drivers, only 13% of patients had been previously asked about driving, and 12% of drivers had experienced symptoms whilst driving. This represents an important oversight on the part of referring doctors.