Efficacy of a basal bolus insulin protocol to treat prednisolone-induced hyperglycaemia in hospitalised patients.

BACKGROUND/AIM: Few studies have specifically investigated treatment of prednisolone-induced hyperglycaemia. AIM: To determine if a basal bolus insulin (BBI) protocol for inpatient hyperglycaemia is effective in patients prescribed acute prednisolone for an inflammatory disease. METHODS: In a cross-sectional study, 66 patients with type 2 diabetes admitted to a general medical ward and treated with BBI for up to 5 days were studied. Twenty-four patients were taking prednisolone ≥10 mg/day to treat an acute inflammatory disease. The remaining 42 patients were a control group. The primary outcome was mean daily blood glucose level. RESULTS: There were no significant differences in glycosylated haemoglobin (8.1 ± 1.0 vs 8.1 ± 1.6%, P = 0.88), age (77 ± 11 vs 75 ± 14 years, P = 0.57), male sex (63 vs 60%, P = 0.81) or body mass index (30.0 ± 5.3 vs 30.2 ± 11.5 kg/m(2) , P = 0.90) between patients taking prednisolone and controls. Mean daily glucose concentration was higher in patients taking prednisolone than in controls (12.2 ± 0.3 vs 10.0 ± 0.1 mmol/L, P < 0.001). Blood glucose level was higher in patients on prednisolone at 1700 h (14.6 ± 0.6 vs 10.3 ± 0.3 mmol/L, P < 0.001) and 2100 h (14.5 ± 0.6 vs 10.5 ± 0.3 mmol/L, P < 0.001), with no significant differences at 0700 h and 1200 h. These findings occurred despite patients taking prednisolone receiving a higher daily insulin dose than controls (0.67-0.70 vs 0.61-0.65 U/kg, P = 0.001) because of higher doses of ultra-rapid-acting insulin at 1200 h and 1700 h. CONCLUSIONS: Hospitalised patients taking prednisolone had substantial afternoon and evening hyperglycaemia despite receiving BBI via a protocol for inpatient hyperglycaemia. Specific insulin regimens for prednisolone-induced hyperglycaemia are needed that recommend more insulin during this time period.

Relationship between glycaemia and length of hospital stay during an acute exacerbation of chronic obstructive pulmonary disease.

We have assessed whether glucose concentration and patient outcome are related in hospitalised patients when glycaemia is quantified in detail. Continuous glucose monitoring was performed on 47 consecutive subjects with an acute exacerbation of chronic obstructive pulmonary disease. Length of hospital stay increased by 10% for each mmol/L increase in mean glucose (P = 0.01). In a multivariable analysis, mean glucose was independently associated with length of hospital stay (P = 0.02). These data add weight to evidence that hyperglycaemia may adversely affect patient outcomes in hospitalised patients.

Efficacy of once-daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: a preliminary study.

Our objective was to compare the efficacy, safety, and microbiology of once-daily intravenous (IV) tobramycin with conventional 8-hourly tobramycin/ceftazidime IV therapy for acute Pseudomonas aeruginosa (PA) pulmonary exacerbations in cystic fibrosis (CF). CF patients with PA-induced pulmonary exacerbations were allocated to receive either once-daily tobramycin (Mono) or conventional therapy with tobramycin/ceftazidime given 8-hourly (Conv). The two longitudinal groups received therapy in a double-blind, randomized manner over a period of 2 years. Tobramycin doses were adjusted to achieve a daily area under the time-concentration curve of 100 mg x hr/L in both groups. Results were assessed for both short-term changes (efficacy and safety after 10 days of IV antibiotics during acute exacerbations) and long-term changes (efficacy, safety, and sputum microbiology between study entry and exit). Pulmonary function tests (PFTs) on admission were similar in both groups. After 10 days of IV antibiotics, absolute mean improvements in percent of predicted PFTs were 12.8, 12.1, and 13.7 for forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), and forced expired flow between 25--75% of FVC (FEF(25--75%)) in the Conv group (n = 51 admissions) compared to 10.6, 9.9, and 10.6 in the Mono group (n = 47)(P<0.05 for all). Sixteen percent in the Conv group and 15% of patients in the Mono group did not respond to therapy by day 10. Long-term PFT patterns were similar for the Conv and Mono groups. The time between admissions did not differ. The Mono group showed a significant increase in tobramycin minimum inhibitory concentrations (MICs) against PA from study entry to study exit (P = 0.02, n = 27 strains); this failed to reach significance in the Conv group (P = 0.08, n = 25). There was no significant increase in the number of isolates, with MIC> or =8 mg/L in both groups. No short- or long-term changes in audiology or serum creatinine were found in either group. After 10 days of IV therapy, the urinary enzyme N-acetyl-beta-d-glucosaminidase/creatinine ratios increased in both groups (P0.05). This increase was greater in the Conv compared to the Mono group (P < 0.05). We conclude that this pilot study indicates once-daily tobramycin therapy to be as effective and safe as conventional 8-hourly tobramycin/ceftazidime therapy. Combination antibacterial therapy appears to offer no clinical advantage over once-daily tobramycin monotherapy. Tobramycin once-daily monotherapy is a potential alternative to conventional IV antibacterial therapy which deserves further investigation, including the impact on susceptibility of PA to tobramycin.

Identifying the factors influencing minority language use in health care education settings: a European perspective.

The recent enhanced status of many minority languages across the European Community has led to increasing demands for their use within the public sector. This is particularly evident in health care, where, in circumstances of stress and vulnerability, denying opportunities for clients to communicate in their preferred language may place them at a personal disadvantage and compromise their health chances. In view of the exclusion of many minority languages from the public domain over the years, their re-introduction demands adaptations to health care education programmes in order to promote language sensitivity in practice. Before embarking on developments which establish such languages within the professional sphere, valuable insight may be gained by examining their current use in practice education. Furthermore, comparing their use across language communities enables the sharing of common experiences and furthers opportunities for developing networks across Europe. This paper describes an ethnographic study of the use, within midwifery education, of the Welsh language in north Wales, the Catalan language in Barcelona and the Irish language in Western Ireland. Semi-structured interviews were conducted with key lecturers, clinical mentors and students across the three communities in order to determine patterns of language use within a range of learning environments. Focus groups were also held in order to confirm the findings. The data reveal many commonalities in terms of language use across the three settings and important factors are identified which support the use of minority languages in practice education. The findings are invaluable for guiding future bilingual initiatives across health care education programmes.

Repeated dose inhaled budesonide versus placebo in the treatment of croup.

OBJECTIVE: To investigate the efficacy and tolerance of 12-hourly dosing with 2 mg 4 mL-1 of inhaled budesonide versus placebo in patients admitted to hospital with moderate/severe croup. METHOD: Eighty-two children hospitalised with croup received either 2 mg 4 mL-1 of budesonide or placebo 12 hourly (maximum four doses) via Ventstream nebuliser in a randomised, double-blind manner. Croup scores were performed at 0, 2, 6, 12, 24, 36 and 48 h from initial nebulisation whilst the patient remained hospitalised. Follow-up assessments were made 1 and 3 days after discharge. RESULTS: Improvement was observed in the budesonide group over the 12-h dosing interval when compared to placebo (P = 0.04). Time to attain a significant clinical improvement was superior in the budesonide group (P = 0.01). Three days after discharge seven of 32 placebo-treated patients and one of 34 budesonide-treated patients had sought further medical follow-up (P = 0.02). CONCLUSION: Twelve-hourly dosing with inhaled budesonide significantly improved symptoms of croup as well as decreased relapse rates when compared with placebo.

Is there a genetic basis for the deposition of beta-amyloid after fatal head injury?

1. Alzheimer's disease is a heterogeneous disorder that may be caused by genetic or environmental factors or by a combination of both. Abnormalities in chromosomes 1, 14, and 21 have all been implicated in the pathogenesis of the early-onset form of the disease, while the epsilon 4 allele of the apolipoprotein E gene (on chromosome 19) is now recognized as a risk factor for early- and late-onset sporadic and familial Alzheimer's disease. 2. The best-established environmental trigger for the disease is a head injury, based on epidemiological and neuropathological evidence. Approximately 30% of patients who die after a single episode of severe head injury show intracerebral deposition of beta-amyloid protein (A beta), a protein that is thought to be central to the pathogenesis of Alzheimer's disease. 3. Recent studies have revealed an over-representation of the apoE epsilon 4 allele in those head-injured patients displaying A beta pathology, thus providing the first evidence for a link between a genetic susceptibility (apoE epsilon 4) and an environmental trigger (head injury) in the development of Alzheimer-type pathology.

Patient-selected dosing in a six-month open-label study evaluating oral sumatriptan in the acute treatment of migraine. Sumatriptan Tablets S2CM10 Study Group.

BACKGROUND: Dosing recommendations for oral sumatriptan as acute treatment for migraine have ranged from 25 mg to 100 mg. Patient dose preferences have not been studied in a setting mimicking clinical practice. METHODS: In an open-label study evaluating patient acceptance and the relative efficacy and safety of 25 mg, 50 mg, and 100 mg doses of oral sumatriptan over a period of six months, 338 patients treated three migraine attacks with 50 mg sumatriptan and then were allowed to double or halve the dose. After treating another three attacks, they were again allowed to adjust the dose by one level. RESULTS: After migraine attack 3, 37% of patients chose to continue with the 50 mg dose, 50% increased the dose to 100 mg, and 12% decreased it to 25 mg. After attack 6, 8%, 33%, and 58% of patients chose the 25 mg, 50 mg, and 100 mg doses, respectively; only 3% of those taking the 100 mg dose chose to reduce it. Overall, the mean percentages of attacks per patient in which headache relief had been obtained 4 h after dosing were 71%, 71%, and 80% for the 25 mg, 50 mg, and 100 mg doses, respectively. Patients who decreased the dose to 25 mg after attack 3 experienced decreases both in adverse events and percentage of attacks with headache relief, whereas in those who increased the dose to 100 mg, likelihood of headache relief increased but the incidence of adverse events did not. CONCLUSIONS: More patients chose the 50 mg or 100 mg dose than the 25 mg dose. All three doses had similar efficacy and tolerability.

Comparison of an age adjusted warfarin loading protocol with empirical dosing and Fennerty's protocol.

AIM: A warfarin loading protocol adjusting doses for age was compared to both Fennerty's protocol (Fenn) and empirical dosing (Emp). METHODS: Patients beginning warfarin were randomised to receive doses according to either the age adjusted (Age) protocol or Fenn. Data were retrospectively collected for patients who had begun warfarin in the previous six months to represent empirical dosing. The study was performed on inpatients being commenced on warfarin for the first time at two teaching hospitals. MAIN OUTCOME MEASURES: Endpoints were time to reach a stable, therapeutic International Normalised Ratio (INR) between 2-3, the number of patients experiencing an INR > or =4 in the first week and the number of patients who had a dose held in the first week. RESULTS: Thirty-five patients were assessed in the Age group, 28 in the Fenn group, and 123 patients for the Emp group. Patients using the Age protocol achieved a stable, therapeutic INR more rapidly than either the Fenn (p=0.003, log rank test) or Emp (p<0.001) group. The Age group had a lower proportion of patients experiencing an INR > or =4 in the first week (p<0.05) as well as a lower proportion having doses held in the first week (p<0.01). There were no differences between Emp and Fenn for any of the endpoints. CONCLUSION: Adjustment of warfarin loading doses for age exhibits clear superiority over the use of Fenn or Emp. This becomes increasingly important as the average age of patients being warfarinised increases, with the recognition that atrial fibrillation requires anticoagulation. Fenn consistently overdosed elderly patients, especially those aged 80 years and older.

Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression.

The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the beta-amyloid precursor protein, thus favoring continuing deposition of beta-amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100beta, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.

Life-long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis.

Chronic overexpression of the neurite growth-promoting factor S100beta has been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. Such plaques are virtually universal in middle-aged Down's syndrome, making Down's a natural model of Alzheimer's disease. We determined numbers of astrocytes overexpressing S100beta, and of neurons overexpressing beta-amyloid precursor protein (beta-APP), and assayed for neurofibrillary tangles in neocortex of 20 Down's syndrome patients (17 weeks gestation to 68 years). Compared to controls, there were twice as many S100beta-immunoreactive (S100beta+) astrocytes in Down's patients at all ages: fetal, young, and adult (p = 0.01, or better, in each age group). These were activated (i.e., enlarged), and intensely immunoreactive, even in the fetal group. There were no neurofibrillary changes in fetal or young Down's patients. The numbers of S100beta+ astrocytes in young and adult Down's patients correlated with the numbers of neurons overexpressing beta-APP (p < 0.05). Our findings are consistent with the idea that conditions--including Down's syndrome--that promote chronic overexpression of S100beta may confer increased risk for later development of Alzheimer's disease.

Alzheimer's disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment.

The recently identified Alzheimer's disease-associated presenilin 1 and 2 (PS1 and PS2) genes encode two homologous multi membrane-spanning proteins. Rabbit antibodies to the N-terminal domain of PS1 detected PS1 in human neuroblastoma SH-SY5Y wild type and PS1 transfectants (SY5Y-PS1) as well as in mouse P19, in CHO-K1 and CHO-APP770 transfected cells, in rat cerebellar granule and hippocampal neurons, and astrocytes. Immunoblotting detected full-length protein of 50 kDa, and a major presumptive cleavage product of 30 kDa. The immunofluorescence pattern resembled labeling of the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) marker protein ERGIC-53. PS1 distribution showed slight condensation after brefeldin A and more marked condensation after incubation of cells at 16 degrees C, characteristic of the ERGIC compartment. Double labeling showed colocalization of ERGIC-53 with PS1 in the SY5Y-PS1 cells. PS1 labeling of SY5Y-PS1 and P19 cells showed overlap of the cis-Golgi marker p210 and colocalization with p210 after brefeldin A which causes redistribution of p210 to the ERGIC. Expression of PS1 did not change in level or cellular distribution during development of neurons in culture. Double labeling for the amyloid precursor protein (APP) and PS1 on SY5Y-PS1 cells and CHO-APP770 cells showed some overlap under control conditions. These results indicate that PS1 is a resident protein of the ERGIC and could be involved in trafficking of proteins, including APP, between the ER and Golgi compartments.

Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides.

The Alzheimer amyloid precursor protein (APP) is cleaved by several proteases, the most studied, but still unidentified ones, are those involved in the release of a fragment of APP, the amyloidogenic beta-protein A beta. Proteolysis by gamma-secretase is the last processing step resulting in release of A beta. Cleavage occurs after residue 40 of A beta [A beta(1-40)], occasionally after residue 42 [A beta(1-42)]. Even slightly increased amounts of this A beta(1-42) might be sufficient to cause Alzheimer's disease (AD) (reviewed in ref. 1, 2). It is thus generally believed that inhibition of this enzyme could aid in prevention of AD. Unexpectedly we have identified in neurons the endoplasmic reticulum (ER) as the site for generation of A beta(1-42) and the trans-Golgi network (TGN) as the site for A beta(1-40) generation. It is interesting that intracellular generation of A beta seemed to be unique to neurons, because we found that nonneuronal cells produced significant amounts of A beta(1-40) and A beta(1-42) only at the cell surface. The specific production of the critical A beta isoform in the ER of neurons links this compartment with the generation of A beta and explains why primarily ER localized (mutant) proteins such as the presenilins could induce AD. We suggest that the earliest event taking place in AD might be the generation of A beta(1-42) in the ER.

A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury.

Fatal head injury results in the formation of diffuse parenchymal deposits of amyloid beta-protein (A beta) in the brains of approximately 30% of individuals. We used carboxyl terminal-specific antisera to examine the exact nature of these deposits in paraffin sections of neocortex from seven head-injured patients. Immunostaining for A beta 42 was observed in all parenchymal deposits whereas staining for A beta 40, the form of the protein which predominates in serum and cerebrospinal fluid, was seen in only a small proportion of deposits. The relative paucity of A beta 40 suggests that post-traumatic deposits do not arise as a result of passive leakage from damaged cerebral blood vessels but are similar to the early A beta 42 parenchymal deposits seen in Down's syndrome and Alzheimer's disease.

Behavioral scientists at the Centers for Disease Control and Prevention. Evolving and integrated roles.

The behavioral sciences offer theories and methods that are critical to fulfilling the mission of the Centers for Disease Control and Prevention (CDC). Behavioral scientists have been integrated into the epidemiological and biomedical traditions of the agency, thereby broadening the effectiveness of prevention strategies that rely on behavior change. The diversity and changing nature of the roles of CDC behavioral scientists are presented, along with a discussion of how they connect to ongoing public health efforts. Psychological theories and methods, especially, have relevance for tackling many of the challenges facing public health. Some of these challenges, and the opportunities they present for psychologists and other behavioral scientists, are discussed.

Systematic screening of the LDL-PLA2 gene for polymorphic variants and case-control analysis in schizophrenia.

Systematic scans of the genome using microsatellite markers have identified chromosome 6p21.1 as a putative locus for schizophrenia in multiply affected families. There is also evidence from a series of studies for a role of abnormal phospholipid metabolism in schizophrenia. In light of these findings, and the role of platelet activating factor in neurotransmission and neurodevelopment, we have examined the LDL-PLA2 (plasma PAF acetylhydrolase, PAF-AH) gene, a serine dependent phospholipase that has been mapped by hybrid mapping to chromosome 6p21.1, as a positional candidate gene for schizophrenia. The gene was systematically screened using SSCP/HD analysis for polymorphisms associated with the disease. Four polymorphic variants were found within the gene and studied in a group of 200 schizophrenic patients and 100 controls. The variant in exon 7 (Iso195Thr) was found to be weakly associated with schizophrenia (p = 0.04) and the variant in exon 11 (Val379Ala) almost reached significance (p = 0.057). After correcting for multiple testing no significant associations were detected. Haplotype analysis combining pairs of polymorphisms also provided no evidence for association of this gene with schizophrenia in our sample of patients.

A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders.

The serotonin transporter (5-HTT) is a candidate locus for aetiological involvement in affective disorders. Biochemical studies in suicides and depressed patients suggest that 5-HT uptake function is frequently reduced in affective illness. Furthermore, 5-HTT is targeted by widely used antidepressant drugs such as fluoxetine. We have performed an association study of a short variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which restricts transcriptional activity of the 5-HTT promoter leading to low functional expression of the 5-HTT, in 454 patients with bipolar or unipolar affective disorder and 570 controls, derived from three European Centres (London, Milan and Würzburg). In all three centres, the frequency of the low activity allele was higher in patients than in controls (50% vs 45% in London, 45% vs 43% in Milan, 47% vs 40% in Würzburg). Although these differences were not individually significant, a stratified analysis of all three samples gave a significant overall odds ratio of 1.23 (95% confidence interval 1.02-1.49, P = 0.03). The excess of the homozygous low-activity genotype among the patients was even greater (odds ratio 1.53, 95% confidence interval 1.04-2.23, P = 0.02), suggesting partial recessively of the low-activity allele. Given the functional role of 5-HTT, our findings suggest that 5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders. If this finding is replicated, further work on genetic variants with low 5-HTT activity may facilitate the differential diagnosis of affective disorders, the assessment of suicidal behaviour, and the prediction of good clinical response to antidepressants.

Presenilin-1 is processed into two major cleavage products in neuronal cell lines.

Presenilin-1 (PS-1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). Using PS-1 transfected SHSY5Y neuroblastoma cells, we have demonstrated by immunodetection, using polyclonal antibodies, that PS-1 is processed to give two fragments: an N-terminal 28 kDa fragment, and a C-terminal 18 kDa fragment. In a number of non-transfected cell types, most PS-1 is detected as the cleaved products. The molecular weights of the PS-1 cleavage products suggest that the cleavage point will most probably be within a region of the hydrophilic loop domain coded for by either exon 8 or 9 of the PS-1 gene. The clustering of FAD mutations within exon 8 strongly suggests that it encodes a key functional domain. It seems likely that the cleavage of PS-1 is crucial to some aspect of its functionality. An understanding of this process will give insights into the pathology of AD, and may offer new opportunities for therapeutic intervention.

Prion diseases: transmission from mad cows?

Prion diseases in humans show considerable clinical and pathological heterogeneity. The identification of a new variant of Creutzfeldt-Jakob disease, and its interpretation as evidence of transmission of mad cow disease to man, rely critically on our understanding of the epidemiology of prion diseases.

A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease.

Recent studies suggest that mutations in the presenilin 1 gene, which encodes a polypeptide predicted to be a multispanning membrane protein, are responsible for the majority of cases of early onset, autosomal dominant Alzheimer's disease. Here we describe a further mutation in the presenilin 1 gene (R269G) in a family with early onset Alzheimer's disease. This mutation is in exon 8 which appears to be a favoured region for pathogenic mutations. In the presenilin protein the region coded for by this exon is likely to comprise a domain located on the membrane surface. We discuss the likely effects of the exon 8 mutations on the structure of the exon and in the pathogenesis of the disease.

Alteration in brain presenilin 1 mRNA expression in early onset familial Alzheimer's disease.

The expression of the presenilin 1 (PS-1) gene has been investigated by in situ hybridization in early onset familial Alzheimer's disease (FAD), late onset Alzheimer's disease (AD) and normal control brain. Mutations in this gene are responsible for chromosome 14-linked FAD. We have found that presenilin 1 mRNA is present throughout the human brain with a distribution consistent with both a glial and neuronal localization. The in situ hybridization pattern was similar for the controls, the early onset FAD cases and the late onset AD cases. However, one of the two forms of the mRNA for PS-1, the long form (which contains a sequence encoding a four amino acid (VRSQ) insert at its 5' end) was significantly reduced in early onset FAD brain compared with late onset AD. We suggest that this long transcript may alter the normal pathway for processing of amyloid precursor protein, the protein which appears to be central in the pathogenesis of AD.