Interspecific differences in the bioaccumulation of arsenic of three Patagonian top predator fish: Organ distribution and arsenic speciation.

Interspecific differences in arsenic bioaccumulation and organ distribution (muscle, liver, kidney and gills) in three predator fish (creole perch, rainbow trout and brown trout) from a Patagonian lake impacted by volcanic eruptions were studied. Arsenic in fish organs were compared analyzing: 1) temporal (before and after volcanic eruption) and spatial (near and far from the volcano) influence of Puyehue-Cordón Caulle volcanic complex activity on arsenic concentrations; 2) the influence of growth (as total length), organ type and their interactions over arsenic accumulation; and 3) arsenic speciation and total arsenic relationship with carbon to nitrogen ratios (C:N), as a proxy of lipid presence, in fish muscle. In general, total arsenic concentrations in creole perch organs were 2-7 times higher than those recorded in the corresponding organs of salmonids. Arsenic was preferentially accumulated in liver and kidney in the three fish species. The influence of the volcanic activity over arsenic concentrations was more evident in creole perch: organs from creole perch captured closest to the volcano exhibited higher arsenic concentrations. Temporal variations were not so consistent. No clear relationship between arsenic and fish length was observed. Positive and linear relationship between arsenic in all pair of organs was found in creole perch, while rainbow trout showed a quadratic relationship between muscle and the remaining organs, indicating different arsenic assimilation-elimination relationships between organs and fish. The arsenic liver:muscle ratio in the three fish species was greater than 1, suggesting some level of arsenic stress. Arsenobetaine (AB) and dimethylarsinic acid (DMA) were the dominant arsenic species in muscle of these fish, having creole perch 3-4 times higher AB than rainbow trout. A positive relationship between C:N ratio and total arsenic concentrations was found, with higher C:N in creole perchs near the volcano. In terms of food safety, no inorganic arsenic compound were detected, therefore arsenic levels in fish from Lake Nahuel Huapi does not represent any health risk to consumers.

Surgery in ovarian cancer - Brazilian Society of Surgical Oncology consensus.

Surgical management in epithelial ovarian cancer (EOC) has a significant impact in overall survival and progression-free survival. The Brazilian Society of Surgical Oncology (BSSO) supported a taskforce of experts to reach a consensus: experienced and specialised trained surgeons, in cancer centres, provide the best EOC surgery. Laparoscopic and/or radiological staging prognosticates the possibility of complete cytoreduction (CC0) and helps to reduce unnecessary laparotomies. Surgical techniques were reviewed. Multidisciplinary input is essential for treatment planning. Quality assurance criteria are proposed and require national consensus. Genetic testing is mandatory. This consensus states the final recommendations from BSSO for management of EOC. TWEETABLE ABSTRACT: Brazilian Society of Surgical Oncology consensus for surgery in epithelial ovarian cancer patients.

A qualitative study: potential benefits and challenges of traditional healers in providing aspects of palliative care in rural South Africa.

INTRODUCTION: This article draws on selected palliative care providers' views and experiences to reflect on the potential benefits and possible challenges of involving traditional healers in palliative care in rural areas of South Africa. There is increasing consensus that palliative care should be offered by a range of professional and non-professional healthcare givers. Including non-professionals such as traditional healers in a palliative care team may strengthen care provisioning as they have intimate knowledge of patients' local culture and spiritual beliefs. METHODS: Employing the qualitative method of photo-elicitation, one-on-one discussions about the photographs taken by participants were conducted. The participants - 4 palliative care nurses and 17 home-based care workers - were purposively selected to provide in-depth information about their experiences as palliative caregivers in rural homes. RESULTS: Healthcare workers' experiences revealed that the patients they cared for valued traditional rituals connected to illness, dying, death and bereavement. Participants suggested that traditional healers should be included in palliative care training programs as they could offer appropriate psychological, cultural and spiritual care. A challenge identified by participants was the potential of traditional healers to foster a false sense of longevity in patients facing death. DISCUSSION: The importance of recognising the value of traditional practices in palliative care should not be underrated in rural South Africa. Traditional healers could enhance palliative care services as they have deep, insider knowledge of patients' spiritual needs and awareness of cultural practices relating to illness, death, dying and bereavement. Incorporating traditional healers into healthcare services where there are differences in the worldviews of healthcare providers and patients, and a sensitivity to mediate cultural differences between caregivers and patients, could have the benefit of providing appropriate care in rural spaces. CONCLUSIONS: Considering the influences of cultural and spiritual beliefs on the wellbeing of patients living in rural areas, the inclusion of traditional healers in a palliative care team is a sensible move. It is, nevertheless, important to note that unanticipated challenges may arise with respect to power differentials within the palliative care team and to beliefs that contradict medical prognosis.

Arsenic, cobalt and chromium food web biodilution in a Patagonia mountain lake.

Mussels, Diplon chilensis, from Lake Moreno, a double-basined mountain lake in southern Argentina, is known to have elevated concentrations of chromium (Cr, > 25 µg g⁻¹ dry weight DW) and arsenic (As, 35 µg g⁻¹ DW), attributed to untreated sewage. To further understand the trophodynamics of Cr, As and cobalt (Co), we investigated concentrations and transfer throughout the food web in each basin of Lake Moreno. Each basin differs in morphology in that the gently-sloping Lake Moreno West has more littoral habitat than deeper Lake Moreno East with its higher proportion of pelagic habitat. Despite the morphological differences, both basins share similar water quality parameters and species assemblages. As a result, Lake Moreno provides an exceptional opportunity to compare trophodynamics of elements that enable us to hypothesize pelagic-littoral habitat coupling in response to lake morphology as the underlying factor influencing both Cr pathway and Co and As trophodynamic modeling. Using stable isotopes of nitrogen (δ¹5N) and carbon (δ¹³C) to characterize metals trophodynamics in each basin, biodilution of As, Cr and Co were indicated by negative regressions. This is confirmed by elevated As, Co and Cr concentrations in phytoplankton (11.3±5.7, 7.4±4.9, 44.5±40.7 µg g⁻¹ DW respectively), while zooplankton and biofilm had the next elevated concentrations. Those elevated concentrations are in contrast with lower concentrations in sport fish such as rainbow trout (0.5±0.5, 0.2±0.3, 1.8±1.2 µg g⁻¹ DW). Higher concentrations of Cr in fish were associated with higher proportion of benthic/littoral prey items in western basin, and were confirmed by significant correlation with δ¹³C values. Arsenic, Co and Cr concentrations in fish, while elevated, do not post health risks to human or wildlife consumers.

Trophodynamics and distribution of silver in a Patagonia mountain lake.

Silver (Ag) ions are among the most toxic metallic ions to aquatic biota. In southern Argentina, fish from Patagonian lakes have liver Ag concentrations [Ag] among the highest ever reported globally. Silver concentration in phytoplankton from Lake Moreno (1.82±3.00µgg(-1) dry weight, DW) was found to be significantly higher than [Ag] in zooplankton (0.25±0.13µgg(-1)). Values in snails and decapods (0.60±0.28µgg(-1) and 0.47±0.03µgg(-1) respectively), were higher than in insect larvae (0.28±0.39µgg(-1) for Trichoptera). We examined trophic transfer of Ag in the biota using stable nitrogen and carbon isotopes ratios (δ(15)N and δ(13)C respectively). Silver concentrations in the biota of Lake Moreno were not associated with any particular C source, as assessed by δ(13)C. Hepatic [Ag] significantly increased with trophic position, as measured by δ(15)N, within the brook trout sample set. Biodilution of Ag was observed between primary producers and small forage fish when whole body [Ag] was analyzed. Nevertheless, when considering whole food web biomagnification and hepatic [Ag] of top predator fish, a significant positive regression was found between [Ag] and trophic position, as measured by δ(15)N. The importance of species-specific and tissue-specific considerations to obtain more information on Ag trophodynamics than that usually presented in the literature is shown. To the best of our knowledge, this is the first study in assessing Ag trophodynamics and tissue-specific biomagnification in a whole freshwater food web.

Comparison of the efficacy and tolerability of topically administered azelastine, sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis and rhino-conjunctivitis.

OBJECTIVE AND SETTING: Azelastine (AZE) in a novel, eye drop, formulation, was compared with topically applied sodium cromoglycate (SCG) and placebo (PLA) in the treatment of seasonal allergic conjunctivitis or rhino-conjunctivitis in a multicentre, parallel group study. RESEARCH DESIGN: 144 subjects ranging in age from 16 to 65 years participated. All had at least a 2-year history of seasonal allergic conjunctivitis and were symptomatic at the time of inclusion. Medications were administered topically either twice daily (AZE/PLA) or four times daily (SCG) over a 2-week treatment period. Method and outcome measures: Azelastine and placebo were compared double-blind; the comparison versus SCG was carried out in an open manner. Itching, redness, flow of tears, eyelid swelling, foreign-body sensation, photophobia, soreness and discharge were scored on a 4-point severity scale. RESULTS: Results for the decrease of main conjunctivitis symptoms (itching, tearing and conjunctival redness) showed a marked effect for both active treatments on day 3 with a sustained improvement on days 7 and 14. A clear response to treatment (an improvement of sum scores for day 3 of >/=3 points compared to baseline) occurred in 85.4% of azelastine-treated patients, 83.0% of sodium cromoglycate patients and 56.3% of placebo patients. Response rates for both active treatments were statistically superior to those for placebo (azelastine p = 0.005; sodium cromoglycate p = 0.007). Global assessment of efficacy was at least 'satisfactory' for 90.0% of azelastine patients, 81.3% of sodium cromoglycate patients and 66.3% of placebo-treated patients. The most frequent adverse effects were transient application site reactions which tended to disappear with increasing duration of treatment, and, less frequently, taste perversion. CONCLUSION: The results of this study indicate that the therapeutic use of azelastine eye drops in patients with seasonal allergic conjunctivitis or rhino-conjunctivitis can be recommended.

Mercury in fish from three rift valley lakes (Turkana, Naivasha and Baringo), Kenya, East Africa.

Total mercury (THg) concentrations were measured for various fish species from Lakes Turkana, Naivasha and Baringo in the rift valley of Kenya. The highest THg concentration (636 ng g(-1) wet weight) was measured for a piscivorous tigerfish Hydrocynus forskahlii from Lake Turkana. THg concentrations for the Perciformes species, the Nile perch Lates niloticus from Lake Turkana and the largemouth bass Micropterus salmoides from Lake Naivasha ranged between 4 and 95 ng g(-1). The tilapiine species in all lakes, including the Nile tilapia Oreochromis niloticus, had consistently low THg concentrations ranging between 2 and 25 ng g(-1). In Lake Naivasha, the crayfish species, Procambrus clarkii, had THg concentrations similar to those for the tilapiine species from the same lake, which is consistent with their shared detritivore diet. THg concentrations in all fish species were usually consistent with their known trophic position, with highest concentrations in piscivores and declining in omnivores, insectivores and detritivores. One exception is the detritivore Labeo cylindricus from Lake Baringo, which had surprisingly elevated THg concentrations (mean=75 ng g(-1)), which was similar to those for the top trophic species (Clarias and Protopterus) in the same lake. Except for two Hydrocynus forskahlii individuals from Lake Turkana, which had THg concentrations near or above the international marketing limit of 500 ng g(-1), THg concentrations in the fish were generally below those of World Health Organization's recommended limit of 200 ng g(-1) for at-risk groups.

From adrenaline to formoterol: advances in beta-agonist therapy in the treatment of asthma.

Long-acting beta2-agonists (formoterol and salmeterol) represent the latest advance in a series of improvements in beta-agonist asthma therapy since the introduction of isoprenaline. Traditional inhaled short-acting beta2-agonists (salbutamol and terbutaline) provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. Where symptoms are not adequately controlled by corticosteroids alone, inhaled selective long-acting beta2-agonists are used additionally for maintenance. Salmeterol and formoterol are well tolerated, provide effective long-term symptom control and reduce the incidence of exacerbations; any development of tolerance or masking of underlying inflammation with continual use does not appear to be clinically relevant. Formoterol is both rapid acting (as fast as salbutamol) and long acting (similar to salmeterol). Increasing clinical evidence suggests that inhaled formoterol is a convenient and well-tolerated treatment that is effective both for regular maintenance and as-needed relief of symptoms.

Candesartan cilexetil is not associated with cough in hypertensive patients with enalapril-induced cough. Multicentre Cough Study Group.

The aim of this study was to evaluate the occurrence of dry cough during treatment with candesartan cilexetil, enalapril, or placebo in patients with hypertension and a history of angiotensin converting enzyme (ACE)-inhibitor-related cough. Patients with confirmed cough during an enalapril (10 mg) challenge period, followed by no cough during a placebo dechallenge period were randomized to 8 weeks of double-blind treatment with candesartan cilexetil (8 mg) (n = 62), enalapril (10 mg) (n = 66), or placebo (n = 26). Incidence and severity of dry cough was evaluated by the symptom assessment questionnaire, frequency of dry cough by a visual analog scale, and the possible impact on quality of life by the minor symptom evaluation (MSE) profile. The percentage of patients with cough was significantly lower with candesartan cilexetil (35.5%) than with enalapril (68.2%, P < .001), and did not differ between candesartan cilexetil and placebo (26.9%, P > .20). Patients coughed less frequently and with less severe cough with candesartan cilexetil than with enalapril, and similarly with candesartan cilexetil and placebo. Changes in the MSE profile were minor, although candesartan cilexetil had better scores for contentment than placebo (P = .03), and also tended to be associated with better sleep than enalapril (P = .08). In hypertensive patients with ACE-inhibitor-induced cough, the incidence, frequency, and severity of dry cough was significantly lower with candesartan cilexetil than with enalapril, and no different from that found with placebo.

Candesartan Cilexetil is not Associated with Cough in Patients with Enalapril-induced Cough.

Treatment with angiotensin-converting enzyme (ACE) inhibitors is frequently associated with persistent dry cough. This side effect is thought to be due to the non-specific action of ACE inhibitors, which, in addition to suppressing the renin-angiotensin system (RAS), leads to the accumulation of kinins, encephalins and other biologically active peptides. Candesartan cilexetil is a new, long-acting angiotensin II type 1 (AT 1 ) receptor blocker, which offers a more specific means of suppressing the RAS than can be achieved with ACE inhibitors. In this study, we compared the incidence and severity of cough during treatment with candesartan cilexetil, enalapril and placebo in patients with hypertension and enalapril-induced cough. Men and women, aged 20-80 years, with a history of medically treated primary hypertension and ACE-inhibitor-related cough were enrolled. The presence of cough was confirmed during a 4-week challenge period with enalapril, 10 mg, which abated during a subsequent 4-week washout period with placebo. Patients with confirmed ACE-inhibitor-related cough were then randomized to double-blind treatment with candesartan cilexetil, 8 mg once daily ( n = 62), enalapril, 10 mg once daily ( n = 66), or placebo ( n = 26). Baseline blood pressure was similar in all groups. Although blood pressure was recorded during the study, this was for safety monitoring, and the measurements were not standardized in relation to study drug intake or time of day. The frequency of dry cough was recorded on a visual analogue scale (VAS). For each assessment, patients marked a cross on a straight horizontal 100 mm line, rating cough frequency from 'none of the time( at one end of the line to 'all of the time( at the other end. The impact of treatment on quality of life was also studied, using the Symptom Assessment (SA) questionnaire and the Minor Symptom Evaluation (MSE) profile. The SA questionnaire assessed the severity of nine symptoms, including dry cough, by means of a five-graded Likert scale (not at all, a little, moderately, quite a bit, extremely). Changes in the three dimensions of the MSE profile - contentment, vitality and sleep - were recorded using a VAS. Candesartan cilexetil was superior to enalapril regarding the change in frequency ( p = 0.001) and severity ( p < 0.001) of dry cough. After 8 weeks of treatment, the proportions of patients with cough were 26.9% for placebo, 35.5% for candesartan cilexetil and 68.2% for enalapril ( p < 0.001, candesartan cilexetil versus enalapril; p > 0.20, candesartan cilexetil versus placebo). Treatment with candesartan cilexetil did not compromise patients' well-being. Compared with placebo, candesartan cilexetil was superior in terms of its effect on contentment; similar trends were noted for vitality and sleep, although the differences were not significant. When all adverse events were considered, candesartan cilexetil was very well tolerated. No serious adverse events occurred in the candesartan cilexetil or placebo groups, while three patients in the enalapril group reported serious adverse events (chest pain, agranulocytosis, accidental fracture). No treatment-related changes of clinical relevance could be found with regard to laboratory variables, ECG or vital signs/physical findings, except the anticipated blood pressure reduction in the active treatment groups. In conclusion, candesartan cilexetil is not associated with cough in hypertensive patients with previous ACE-inhibitor-induced cough. The incidence of dry cough in patients treated with candesartan cilexetil was similar to that of placebo and lower than that of enalapril.

Clinical skills assessment.

BACKGROUND: From September 1996, all GP registrars completing vocational training in the United Kingdom must demonstrate competence by means of a four-part assessment procedure. AIM: To look at the accuracy of one of the components of vocational training: the trainer's report. METHOD: Seventy-five registrars completing their general practice training at the end of July 1997 were invited to take part in a practical skills workshop. Eight stations were designed to test practical skills and diagnostic interpretations that were included in the trainer's report, and a clinical vignette accompanied each task. The marking schedule used was developed from the minimum standards required in the trainer's report. Twenty-nine registrars (38%) took part in the workshop. RESULTS: Only one registrar passed all eight stations. The maximum number of stations failed by any one individual was five and this doctor was the only one of the sample to ultimately fail summative assessment. The majority of registrars failed by being unable to interpret clinical findings. Twenty-five registrars (86%) responded to the follow-up questionnaire. Of these, only six felt that the stations were unrealistic. All but two registrars had spent at least six months in their hospital training doing obstetrics and gynaecology but, in spite of this, only 31% of registrars were above minimum competence for vaginal and speculum examination. CONCLUSION: With one exception, registrars passed all aspects of the trainer's report. Discrepancy was found between the trainer's report and the doctor's ability to carry out clinical procedures. There is an assumption that many of these clinical skills are being taught and assessed at undergraduate level and during the hospital component, but this cannot be taken for granted. Doubt must also be cast on whether the trainers are using the trainer's report appropriately, and whether this is a valid and reliable tool to identify skills deficient in registrars for summative assessment.

A comparison of the efficacy of long-acting beta 2-agonists: eformoterol via Turbohaler and salmeterol via pressurized metered dose inhaler or Accuhaler, in mild to moderate asthmatics. Force Research Group.

Four hundred and sixty nine patients were randomized to receive either 12 micrograms bd of eformoterol (Oxis, Astra Pharmaceuticals Ltd., Kings Langley, U.K.) delivered via Turbohaler or 50 micrograms bd salmeterol (Serevent, Glaxo-Wellcome Ltd., Uxbridge, U.K.) via either the Accuhaler (Glaxo-Wellcome Ltd.) or pressurized metered dose inhaler (pMDI, Glaxo-Wellcome Ltd.) for 8 weeks. This was followed by a 4-week cross-over period when patients who had received salmeterol in the previous 8 weeks were given eformoterol and patients who had received eformoterol were given either salmeterol via the Accuhaler or pMDI to assess patient device and treatment preference. For the primary efficacy variable, the increase in peak expiratory flow (PEF) rate from run-in to 8 weeks, similar significant improvements were seen in all three treatment groups. Eformoterol Turbohaler (FT) achieved a greater increase in morning PEF than salmeterol Accuhaler (SA) from randomisation to 4 weeks; the increase shown in the eformoterol Turbohaler group was 28.9 1 min-1 compared to 19.91 min-1 for the salmeterol Accuhaler group. The addition of eformoterol Turbohaler 12 micrograms bd, to patients' existing asthma therapy was found to have a significantly more beneficial effect on the severity of patients' daytime asthma symptoms than had salmeterol Accuhaler 50 micrograms bd (P = 0.014). Eformoterol Turbohaler reduced the severity of daytime asthma symptoms by 42% after only 4 weeks of treatment. The patients in the eformoterol Turbohaler treated group experienced a higher percentage of days when they were symptom-free and did not use their short-acting bronchodilator to relieve symptoms (32.8, 24.1 and 28.0% in the FT, SA and SM groups, respectively). At 8 weeks there were no significant differences in any of these variables between the three groups. Patients in all the treatment groups gained an additional 1-1.5 nights undisturbed by asthma per week. The changes in sleep disturbance were not significantly different between the three treatment groups. In addition to the therapeutic benefits provided by eformoterol Turbohaler the device (Turbohaler) was the significant preference of patients given both Turbohaler and pMDI (P = 0.0168) and was also considered to be significantly more convenient to carry around than the Accuhaler (P < 0.0001). No other differences were found between the three devices. The results of this study demonstrate that the addition of a long-acting beta 2-agonist is an effective tool for achieving the goals of asthma treatment. Eformoterol via the Turbohaler is at least as effective as salmeterol via either the Accuhaler or the pMDI in achieving these goals.

A comparison of the efficacy of long-acting beta 2-agonists: eformoterol via Turbohaler and salmeterol via pressurized metered dose inhaler or Accuhaler, in mild to moderate asthmatics. Force Research Group.

Four hundred and sixty nine patients were randomized to receive either 12 micrograms bd of eformoterol (Oxis, Astra Pharmaceuticals Ltd., Kings Langley, U.K.) delivered via Turbohaler or 50 micrograms bd salmeterol (Serevent, Glaxo-Wellcome Ltd., Uxbridge, U.K.) via either the Accuhaler (Glaxo-Wellcome Ltd.) or pressurized metered dose inhaler (pMDI, Glaxo-Wellcome Ltd.) for 8 weeks. This was followed by a 4-week cross-over period when patients who had received salmeterol in the previous 8 weeks were given eformoterol and patients who had received eformoterol were given either salmeterol via the Accuhaler or pMDI to assess patient device and treatment preference. For the primary efficacy variable, the increase in peak expiratory flow (PEF) rate from run-in to 8 weeks, similar significant improvements were seen in all three treatment groups. Eformoterol Turbohaler (FT) achieved a greater increase in morning PEF than salmeterol Accuhaler (SA) from randomisation to 4 weeks; the increase shown in the eformoterol Turbohaler group was 28.9 l min-1 compared to 19.9 l min-1 for the salmeterol Accuhaler group. The addition of eformoterol Turbohaler 12 micrograms bd, to patients' existing asthma therapy was found to have a significantly more beneficial effect on the severity of patients' daytime asthma symptoms than had salmeterol Accuhaler 50 micrograms bd (P = 0.014). Eformoterol Turbohaler reduced the severity of daytime asthma symptoms by 42% after only 4 weeks of treatment. The patients in the eformoterol Turbohaler treated group experienced a higher percentage of days when they were symptom-free and did not use their short-acting bronchodilator to relieve symptoms (32.8, 24.1 and 28.0% in the FT, SA and SM groups, respectively). At 8 weeks there were no significant differences in any of these variables between the three groups. Patients in all the treatment groups gained an additional 1-1.5 nights undisturbed by asthma per week. The changes in sleep disturbance were not significantly different between the three treatment groups. In addition to the therapeutic benefits provided by eformoterol Turbohaler the device (Turbohaler) was the significant preference of patients given both Turbohaler and pMDI (P = 0.0168) and was also considered to be significantly more convenient to carry around than the Accuhaler (P < 0.0001). No other differences were found between the three devices. The results of this study demonstrate that the addition of a long-acting B2-agonist is an effective tool for achieving the goals of asthma treatment. Eformoterol via the Turbohaler is at least as effective as salmeterol via either the Accuhaler or the pMDI in achieving these goals.

Once-daily inhaled corticosteroids in mild to moderate asthma: improving acceptance of treatment.

Despite the established efficacy of inhaled corticosteroids in improving lung function in asthma, there has not been a corresponding improvement in morbidity and mortality associated with the disease, which, in part, may result from non-compliance with the prescribed regimen. The reasons for this are many and varied, but an important measure in improving the level of compliance in asthma patients is simplification of the treatment regimen, which may be achieved by reducing the dose frequency and improving the ease of administration. In clinical trials designed to determine whether a reduction in dose frequency to once daily is associated with similar efficacy to that with more frequent administration, a number of studies have shown that once-daily administration of inhaled corticosteroids in both adults and children is as effective in controlling asthma as twice-daily administration of the same dosage, both when given as initial therapy in corticosteroid-naïve patients and in patients already receiving an inhaled corticosteroid. The drug for which most evidence to support a dosage change from twice-daily to once-daily therapy currently exists is budesonide, though limited evidence with other inhaled corticosteroids such as beclomethasone dipropionate, fluticasone propionate and flunisolide also supports once-daily use. Despite the larger single dosage with once-daily budesonide therapy, there has been no evidence in clinical trials of a greater incidence of local adverse effects such as hoarseness, throat irritation or oropharyngeal candidosis, and no evidence of adrenal suppression or growth retardation. Since compliance is an important factor that can affect the success or failure of asthma therapy, a reduction in the frequency of administration to once daily offers the potential advantage of improved compliance with treatment and hence better control of asthma. In the short term clinical trials conducted to date, patient preferences have favoured the once-daily regimen over twice-daily administration. When combined with other (e.g. educational) measures to improve patient compliance, a switch from twice-daily (or more frequent) administration to once-daily inhaled corticosteroid therapy seems likely to be beneficial in improving the long term outcome of treatment.

Once-daily budesonide: 400 micrograms once daily is as effective as 200 micrograms twice daily in controlling childhood asthma. PETITE Research Group.

One hundred and sixty seven children on 0-200 microgram/day of inhaled steroid with asthma symptoms and sub-optimal peak flow values (less than 90% of that predicted for their height) were randomly allocated either 400 microgram once daily (nocte with placebo o.m.) or 200 mircrogram twice daily of budesonide Turbohaler for 8 weeks. Bronchdilator usage and symptoms were reduced in both groups at 4 and 8 weeks compared with baseline. There was a significant increase within both groups in morning and evening PEF after 4 and 8 weeks. The increase in evening PEF after 8 weeks was greater in the once-daily group than in the twice-daily group but there were no other significant differences between the groups (morning: +24.6 l/min vs 15.2 l/min, p = 0.059; evening: + 19.7 l/min vs +8.31 l/min; p = 0.013). Budesonide Turbohaler 400 microgram once daily is therefore as effective as 200 microgram twice daily in achieving asthma control in children.

Adrenal hormone modulation of type 1 and type 2 cytokine production by spleen cells: dexamethasone and dehydroepiandrosterone suppress interleukin-2, interleukin-4, and interferon-gamma production in vitro.

Our previous work has documented that physical or psychological stress can alter interleukin (IL)-2, IL-4, and interferon (IFN)-gamma production by spleen or lymph node cells in vitro. To determine if adrenal hormones might be mediating these stress-induced changes in type 1 and type 2 cytokines and immune effector functions, we cultured spleen cells in vitro with either the synthetic glucocorticoid dexamethasone (DEX) or the putative restorative hormone dehydroepiandrosterone (DHEA). Spleen cells were obtained from either young (5-6 weeks old) or mature (7-8 months old) BALB/c mice that were either unimmunized or immunized with the T-cell-dependent antigen keyhole limpet hemocyanin (KLH). We determined that DEX suppressed production of all three cytokines examined. DHEA was not associated with any enhancement of cytokine production. These data challenge the hypothesis that glucocorticoids can differentially regulate Th1-like versus Th2-like cytokine production. Further, they suggest that in stress paradigms in which differential regulation of cytokine production and effector function has been observed, other neuroendocrine factors in addition to glucocorticoids must be relevant.

Initial loading (400 micrograms twice daily) versus static (400 micrograms nocte) dose budesonide for asthma management. PLAN Research Group.

This double-blind study aimed to determine whether superior asthma control is achieved with budesonide (Pulmicort Turbohaler) at a loading dose (LD) (400 micrograms b.d.) for 6 weeks, followed by step down to 400 micrograms nocte for 12 weeks, compared with a static dose (SD) (400 micrograms nocte) for 18 weeks. A total of 682 patients (mean peak expiratory flow rate (PEFR) 413 l/min), who demonstrated > or = 15% reversibility in PEFR, were randomised into the study. After 18 weeks, patients experienced improvements in morning PEFR (+45 l/min, both groups), symptom score (LD -0.57, SD -0.49, on a scale of 0-3), sleep disturbance (LD -1.21 nights/week, SD -1.06 nights/week) and beta 2-agonist use (LD -1.36 puffs/day, SD -1.06 puffs/day), within both groups (each p = 0.0001). At 18 weeks, 82% (LD) and 84% (SD) of patients benefited from no nocturnal wakening in the previous 7 days. Overall, at 18 weeks, asthma control was not significantly different between the groups. After 6 weeks, improvements in morning PEFR (LD +36 l/min, SD +26 l/min) and beta 2-agonist use (LD -1.10 puffs/day, SD -0.94 puffs/day) were greater in the loading dose than in the static dose group (each p < 0.05). The greater improvement in morning PEFR in the loading dose group was significant by day 7 (p < 0.05). While both regimens are equally effective in achieving asthma control at 18 weeks, early clinical advantage is gained with initial loading dose budesonide (400 micrograms b.d.).

Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia.

Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained > or = 3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P < 0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of < 3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (P < 0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.