Good publication practice guidelines for medical communications agencies: a MedComm perspective.

BACKGROUND: Physicians and other health care personnel rely on the peer-reviewed biomedical literature as a key source for making clinical decisions. Thus, ensuring that the nonclinical and clinical findings published in biomedical journals are reported accurately and clearly, without undue influence from commercial interests, is essential. Accordingly, beginning in the mid-1990s and continuing to the present, various organizations, including the International Committee of Medical Journal Editors, the American Medical Association, the Council of Science Editors, the American Medical Writers Association, and the International Society for Medical Publication Professionals, have published guidelines to strengthen and uphold ethical standards in biomedical communications. SCOPE: A task force of staff members from the AXIS group of companies reviewed these and other guidelines to assess the need for a good publication practices (GPP) document specific to medical communications agencies. As this review demonstrated an unmet need, the task force was charged with developing GPP guidelines for the AXIS group of agencies in the United States. FINDINGS: Although such guidelines have been previously published on behalf of medical journal editors and publishers, medical writers, academic centers, and pharmaceutical companies, there has been no prior publication in the peer-reviewed literature of good publication practices for medical communications agencies, which face unique challenges in negotiating a balance among authors, sponsoring companies, and biomedical publishers. CONCLUSION: This article presents and discusses these GPP guidelines. To our knowledge, this is the first publication of guidelines developed from the perspective of a medical communications agency.

Neuraminidase inhibitors for preventing and treating influenza in children.

BACKGROUND: During epidemic years, influenza attack rates in children exceed 40%. Options for prevention and treatment include the neuraminidase inhibitors: zanamivir and oseltamivir. OBJECTIVES: To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza infection in children. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005); MEDLINE (1966 to April 2005); EMBASE (January 1980 to December 2004); the on-line GlaxoSmithKline Clinical Trials Register; the on-line Roche Clinical Trial Protocol Registry and Clinical Trial Results Database (August 2005); and reference lists of articles. We also scrutinised web sites of European and US regulatory bodies and contacted manufacturers and authors. SELECTION CRITERIA: Double-blind, randomised, controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs in children less than 12 years of age. Additional safety and tolerability data from other sources were also included. DATA COLLECTION AND ANALYSIS: Four authors applied the inclusion criteria to the retrieved studies, assessed trial quality and extracted data. Data were analysed separately for oseltamivir and zanamivir. MAIN RESULTS: Three trials involving 1500 children with a clinical case definition of influenza were included, of whom 977 had laboratory-confirmed influenza. Overall, trial quality was good. Oseltamivir reduced the median duration of illness by 26% (36 hours) in healthy children with laboratory-confirmed influenza (P value less than 0.0001). The reduction was only 7.7% (10 hours) in 'at risk' (asthmatic) children, and this did not reach statistical significance (P value = 0.54). Zanamivir reduced the median duration of illness by 24% (1.25 days) in healthy children with laboratory-confirmed influenza (P value less than 0.001). No data in 'at risk' children were available. Only oseltamivir produced a significant reduction in the complications of influenza (particularly otitis media), although there was a trend to benefit for zanamivir. We identified one randomised, controlled trial of oseltamivir for the prevention of influenza transmission in households, reporting data from 222 paediatric contacts. Where index cases had laboratory-confirmed influenza, a protective efficacy of 55% was observed, but this did not reach statistical significance (P value = 0.089). The adverse events profile of zanamivir was no worse than placebo, but vomiting was more common in children treated with oseltamivir. AUTHORS' CONCLUSIONS: Neuraminidase inhibitors are effective in shortening illness duration in healthy children with influenza, but efficacy in 'at risk' children remains to be proven. Oseltamivir is also effective in reducing the incidence of secondary complications, and may be effective for influenza prophylaxis.

Vaccines for preventing influenza in healthy children.

BACKGROUND: In children and adults the consequences of influenza are mainly absences from school and work, however the risk of complications is greatest in children and people over 65 years old. OBJECTIVES: To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children; assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness) and document adverse events associated with receiving influenza vaccines. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005); OLD MEDLINE (1966 to 1969); MEDLINE (1969 to December 2004); EMBASE (1974 to December 2004); Biological Abstracts (1969 to December 2004); and Science Citation Index (1974 to December 2004). We wrote to vaccine manufacturers and a number of corresponding authors of studies in the review. SELECTION CRITERIA: Any randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years old. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: Fifty-one studies involving 263,987 children were included. Seventeen papers were translated from Russian. Fourteen RCTs and 11 cohort studies were included in the analysis of vaccine efficacy and effectiveness. From RCTs, live vaccines showed an efficacy of 79% (95% confidence interval (CI) 48% to 92%) and an effectiveness of 33% (95% CI 28% to 38%) in children older than two years compared with placebo or no intervention. Inactivated vaccines had a lower efficacy of 59% (95% CI 41% to 71%) than live vaccines but similar effectiveness: 36% (95% CI 24% to 46%). In children under two, the efficacy of inactivated vaccine was similar to placebo. Thirty-four reports containing safety outcomes were included, 22 including live vaccines, 8 inactivated vaccines and 4 both types. The most commonly presented short-term outcomes were temperature and local reactions. The variability in design of studies and presentation of data was such that meta-analysis of safety outcome data was not feasible. AUTHORS' CONCLUSIONS: Influenza vaccines are efficacious in children older than two years but little evidence is available for children under two. There was a marked difference between vaccine efficacy and effectiveness. That no safety comparisons could be carried out emphasizes the need for standardisation of methods and presentation of vaccine safety data in future studies. It was surprising to find only one study of inactivated vaccine in children under two years, given recent recommendations to vaccinate healthy children from six months old in the USA and Canada. If immunisation in children is to be recommended as public-health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required.

Neuraminidase inhibitors for preventing and treating influenza in children.

BACKGROUND: During epidemic years, influenza attack rates in children exceed 40%. Options for prevention and treatment include immunisation, amantadine and rimantadine, and the neuraminidase inhibitors: zanamivir and oseltamivir. OBJECTIVES: Our objective was to assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prophylaxis of influenza infection in children. SEARCH STRATEGY: We searched the Cochrane Acute Respiratory Infections Group Specialised Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the GlaxoSmithKline Clinical Trials Register, generally from inception through to December 2002. We also screened the references of retrieved articles and scrutinised relevant web sites. We also screened references of retrieved articles and other systematic reviews, scrutinised web sites of European and US regulatory bodies, and contacted manufacturers and authors. SELECTION CRITERIA: Double-blind randomised controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs in children less than 12 years of age. Additional safety and tolerability data from other sources were also included. DATA COLLECTION AND ANALYSIS: Four reviewers applied the inclusion criteria to the retrieved studies, assessed trial quality and extracted data. Data were analysed separately for oseltamivir and zanamivir. MAIN RESULTS: We identified three randomised controlled trials reporting data from 1500 children with a clinical case definition of influenza, of whom 798 had laboratory confirmed influenza infection. Two were trials of oseltamivir (in healthy children and in children with asthma) and one was a trial of zanamivir (in healthy children). Overall, trial quality was good. Oseltamivir reduced the median duration of illness by 26% (36 hours) in previously healthy children with laboratory confirmed influenza (p < 0.0001) and by 17% (21 hours) in the intention-to-treat population (p = 0.0002). Zanamivir reduced the median duration of illness by 24% (1.25 days) in previously healthy children with laboratory confirmed influenza (p < 0.001) and by 10% (0.5 days) in the intention-to-treat population (p = 0.011). Both drugs also significantly reduced the time to return to normal activity. Only oseltamivir produced a significant reduction in the complications of influenza (particularly otitis media), although there was a trend to benefit for zanamivir. No data on the use of zanamivir in 'at risk' children were available. The reduction in time to resolution of illness in 'at risk' children (with asthma) treated with oseltamivir was not statistically significant. Although we identified three trials of neuraminidase inhibitors in the prevention of influenza in families (including children), Roche and GlaxoSmithKline were not willing to break-out data for paediatric populations, and so no data were eligible for inclusion in the review. The adverse events profile of zanamivir was no worse than placebo and we found no reports of zanamivir-induced bronchospasm in children. Vomiting was more common in children treated with oseltamivir (p = 0.008), but study withdrawals were similar (<2%) between oseltamivir and placebo. REVIEWER'S CONCLUSIONS: Neuraminidase inhibitors were effective in shortening illness duration and hastening return to normal activity in previously healthy children with a clinical or laboratory diagnosis of influenza. Oseltamivir was effective in reducing the incidence of secondary complications. Efficacy in 'at risk' children remains to be proven. The drugs are safe, but oseltamivir can cause vomiting.

Use of an ethanol sensor for feedback control of growth and expression of TBV25H in Saccharomyces cerevisiae.

A process for production of a malaria transmission blocking vaccine candidate under the control of the ADH2 promoter in Saccharomyces cerevisiae was developed. Monitoring and controlling the ethanol concentration during the process is essential for successful expression of the recombinant protein. A simple sensor accomplishing this task has been developed, the principle of its operation is the following: air-flow through silicone tubing submerged in the media picks up ethanol, which is detected by an alcohol sensor that relays a signal to a controller regulating the amount of ethanol added to the culture. The sensor was used successfully in high cell density cultures of various scales.

Purification and characterization of a novel peptidase (IImes) from mesquite (Prosopis velutina) pollen.

Although the mesquite plant (Prosopis velutina) is not as widely distributed as some other allergenic species, its pollen can induce serious pollinosis in areas where it is localized. We previously isolated and characterized a peptidase from mesquite pollen with trypsin-like specificity (peptidase Imes) (Matheson, N., Schmidt, J., and Travis, J. (1995) Am. J. Respir. Cell Mol. Biol. 12, 441-448). Now we have characterized a second enzyme with specificity for hydrophobic residues (mesquite pollen peptidase IImes). This enzyme has a molecular mass near 92 kDa and activity that was not affected by reducing or chelating agents but was inhibited by specific synthetic serine proteinase inhibitors and the aminopeptidase inhibitor bestatin. However, it was not inhibited by human plasma proteinase inhibitors, nor did it inactivate any of those tested. The enzyme possessed amidolytic activity against p-nitroanilide substrates most effectively after alanine residues and also displayed aminopeptidase activity against non-p-nitroanilide peptides with a preference for phenylalanine. This specificity for hydrophobic amino acid residues was corroborated by inhibition studies with chloromethyl ketone and organophosphonate inhibitors. More interesting from a physiological point of view is that the bioactive peptides, angiotensins I and II and vasoactive intestinal peptide, were also hydrolyzed rapidly, indicating an ability of peptidase IImes to act also as an oligopeptidase. Because these bioactive peptides play a role in the inflammatory responses in allergic asthma, our data suggest that the purified mesquite pollen peptidase IImes may be involved in the degradation of neuro- and vasoactive peptides during pollen-initiated allergic reactions.

Induction of histamine release from non-immunized guinea pigs: a possible involvement of lectin-like factor(s) in pollinosis.

To investigate nonimmune pathogenic functions of pollens, vascular permeability enhancement (VPE) activity of pollen extracts was examined using guinea pigs nonimmunized against pollens. Ryegrass, ragweed, mesquite and almond, but not common cattail and sumac, induced VPE which was inhibited primarily by an anti-histamine drug. Ryegrass pollen VPE activity was extracted more at pH 7.3 than at pH 6.5 or 8.0 and the maximal activity was extracted in 30 min. Interestingly, more than 60% of the maximal activity was extracted in 5 min. The maximal VPE activity had a dose-dependency similar to histamine (3 x 10(-5) M) but lasted longer than the histamine activity. The VPE activity was inhibited by oligomannose-glycosylated ovalbumin or avidin, as well as the oligosaccharides but not by the deglycosylated proteins. These results indicate that some pollens contain lectin-like, histamine-releasing factor(s), which may be involved in part in pollinosis, by inducing mast cell degranulation through a nonimmune mechanism and resulting in allergy-like symptoms.

The chemical structure of amylose and amylopectin fractions of starch from tobacco leaves during development and diurnally-nocturnally.

Starches, isolated from rapidly expanding tobacco leaves four times during the day and night and once from fully expanded leaves, were fractionated with concanavalin A. From an examination of the amounts and properties of amylose, the diurnal decrease in iodine absorption of the starches on illumination appeared to be due to an increase in its branched character, and possibly the presence of unbranched polymer of low dp, combined with a decrease in the proportion of amylose fraction. The increase in apparent amylose content with age was due to an increase in the proportion of amylose. The amylose fractions at different times had only small differences in average mol size in solution and relative mol wt (M(r) near 4 x 10(5)) which were lower than those of storage organs. The average mol size in solution and relative mol wt of the amylopectins decreased during illumination, increased in darkness, and were lower (M(r) 2-2.7 x 10(6)) at all times than those from storage organs. Debranching followed by size-exclusion chromatography [on Fractogel TSK 50(S)] gave similar proportions of long, medium, and short chains for all amylopectin samples, and these proportions differed from those for debranched amylopectin from n-maize seed starch. On debranching and chromatography of the amylopectin beta-limit dextrins (which gives an estimate of the proportions of core chains) differences persisted. Structural characteristics of amylopectin from tobacco leaf starch were similar to those of normal genotypes from storage organs. The proportion of glucosyl units in core chains, the external-to-core chain ratio, and indices of compactness were calculated for a number of (1-->4)(1-->6) alpha-glucans. A plot of the index of compactness for glycogens and amylopectins showed that the decrease in compactness and the increase in total average chain length that occurs from glycogen to normal and then to amylose extender amylopectins involves a proportionate increase in average internal, external, and core chain lengths and not a selective increase in one type of chain.

Proteinases from pollen and pests.

An examination of the proteinases present in two very different systems is described, in order to illustrate the diversity in function of this class of enzymes. In the first case we have noted the importance of gut proteinases from the fire ant Solenopsis invicta in relation to the nutritional requirements of the entire colony. In the second we have investigated the properties of endoproteases from both ragweed and mesquite pollen, relative to their role in the development of allergies and asthma. If the function of each type of enzyme(s) is correct, then it is clear that addition of exogenous inhibitors might be useful in a) controlling the infestation associated with the fire ant, and b) reducing the deleterious effects associated with the development of asthma.

Nesidioblastosis in an elderly patient.

We report an 84-year-old woman with hypoglycaemia and hyperinsulinaemia caused by diffuse nesidioblastosis. This is the oldest case of nesidioblastosis so far recorded. The case illustrates some of the difficulties in diagnosing inappropriate hyperinsulinaemia and the benefits of surgery, even in old age. Hypoglycaemia should be considered in patients with variable mental function.

Changes in bone mass and metabolism after surgery for primary hyperparathyroidism.

BACKGROUND AND OBJECTIVE: Bone mass is often reduced in patients with primary hyperparathyroidism (pHPT) and is usually partially reversible after parathyroidectomy. However, site specific and overall skeletal benefits of surgery in mild asymptomatic pHPT remain uncertain. DESIGN: Cross-sectional and longitudinal studies. PATIENTS: Fourteen patients (12 women and 2 men) with pHPT. MEASUREMENTS: Baseline bone mass was assessed at the lumbar spine, left hip and whole body using dual-energy X-ray absorptiometry, and at the left os calcis using broad-band ultrasound attenuation. Changes in bone mass, serum intact PTH and osteocalcin, and urinary pyridinium cross-link excretion were recorded in 10 patients followed for 6 months after surgery. RESULTS: (1) Cross-sectional study: Baseline measurements at the lumbar spine and hip were inversely related to both the serum PTH concentration and the weight of the parathyroid gland removed at surgery. (2) Longitudinal study: Six months after adenectomy, bone mass had increased significantly at the femoral neck, greater trochanter, whole body and os calcis, but not at the lumbar spine or Ward's area. Serum PTH, osteocalcin and pyridinium cross-link excretion all fell significantly after surgery. The percentage increment in whole body bone mineral content at 6 months was proportional to the baseline PTH. CONCLUSION: In primary hyperparathyroidism, preoperative reductions and post-operative gains in bone mass are proportional to the initial serum PTH concentration. Mild primary hyperparathyroidism probably does not cause appreciable bone loss at clinically relevant fracture sites such as the spine and hip, and in such cases the overall skeletal benefits of surgery are likely to be negligible.

Isolation and properties of an angiotensin II-cleaving peptidase from mesquite pollen.

Biochemical studies of pollen proteins have been focused, primarily, in investigating their roles as allergens. These molecules, some of which have enzymatic activity, act as antigens and initiate the production of IgE antibodies, leading to allergic and/or asthmatic responses. Included in this mixture of proteins are proteinases which, although they may or may not be allergenic, could still be involved in airway dysfunction. We have isolated an arginine-specific endopeptidase to homogeneity from mesquite (Prosopis velutina) pollen, a known wind-borne allergen, which has a molecular mass near 84 kDa by NaDodSO4-gel electrophoresis, a pH optimum in the neutral to alkaline range, and a requirement for Ca2+ for stabilization. The enzyme is inhibited by diisopropyl fluorophosphate (DFP) and N-p-tosyl-L-lysine chloromethylketone but not by N-p-tosyl-L-phenylalanine chloromethylketone, EDTA, or iodoacetamide. It was also not inhibited by human plasma proteinase inhibitors nor several other naturally occurring plant and animal inhibitors. Cleavage by the endopeptidase was primarily on the carboxy-terminal side of arginine residues in peptides, whereas proteins such as kallikrein and prothrombin were only activated and/or degraded extremely slowly. Several bioactive peptides that may be involved in maintaining normal lung function were readily fragmented, including angiotensin II, a vasoconstrictor, and atrial natriuretic peptide, a modulator of vascular permeability, both of which were rapidly cleaved at low enzyme:substrate molar ratios. Thus, the pollen endopeptidase could be involved in exacerbating the development of asthma by inactivating bioactive peptides that have ameliorating effects in maintaining lung airway homeostasis.

Things to come: postmodern digital knowledge management and medical informatics.

The overarching informatics grand challenge facing society is the creation of knowledge management systems that can acquire, conserve, organize, retrieve, display, and distribute what is known today in a manner that informs and educates, facilitates the discovery and creation of new knowledge, and contributes to the health and welfare of the planet. At one time the private, national, and university libraries of the world collectively constituted the memory of society's intellectual history. In the future, these new digital knowledge management systems will constitute human memory in its entirety. The current model of multiple local collections of duplicated resources will give way to specialized sole-source servers. In this new environment all scholarly scientific knowledge should be public domain knowledge: managed by scientists, organized for the advancement of knowledge, and readily available to all. Over the next decade, the challenge for the field of medical informatics and for the libraries that serve as the continuous memory for the biomedical sciences will be to come together to form a new organization that will lead to the development of postmodern digital knowledge management systems for medicine. These systems will form a portion of the evolving world brain of the 21st century.

The idea of the library in the twenty-first century.

The fundamental idea of the library must change. The nineteenth-century idea of the library as the embalming of dead genius and the twentieth-century idea of the library as the repository for second-hand knowledge must give way to the idea of the library as the owner and the librarian as the manager of first-hand knowledge. In the coming era of knowledge capitalism, those individuals and organizations will flourish who are able to apply knowledge to create knowledge and to organize it to produce knowledge. The roles of present-day librarians and libraries will begin to differentiate sharply over the next decade. Some must seize the opportunity to participate in the transformation of libraries into online knowledge servers.

Hexose-6-kinases in germinating honey locust cotyledons: substrate specificity of D-fructo-6-kinase.

Extracts of the cotyledons of germinated honey locust (Gleditsia triacanthos) seeds, which contain galactomannan as a reserve polysaccharide in the endosperm, were fractionated by chromatography and the fractions examined for the presence of a specific manno-6-kinase which could phosphorylate the D-mannose released by hydrolysis of galactomannan. One particulate hexokinase (the major hexose-6-kinase fraction) and two soluble hexokinase fractions (the minor portion), as well as a soluble fructo-6-kinase fraction, were initially separated. From chromatography, electrophoresis and kinetic studies, no evidence for a specific manno-kinase was obtained. This and the level and kinetic behaviour of the particulate hexokinase implicated it as the enzyme catalysing the phosphorylation of released D-mannose. The fructo-kinase activity was further separated into three fractions. Kinetic studies on one of these with native and synthetic substrates indicated that the structural requirements for the monosaccharide substrate were a beta-D-anomeric 2-OH in the furanose ring, a 4-OH trans to the D-5-CH2OH and a -CH2OH substituent on C2 (trans to the 5-CH2OH) which could be modified. The orientation of the hydroxyl on C-3 had only a limited effect.

Thyroid neoplasia coexistent with chronic lymphocytic thyroiditis.

During a 6-year period 115 patients presenting with thyroid enlargement had evidence of chronic lymphocytic thyroiditis on fine-needle aspiration cytology. Of 27 patients in whom histological analysis was carried out, 16 had neoplasms (follicular adenoma, four; follicular carcinoma, one; papillary carcinoma, four; lymphoma, seven). Assuming that neoplasia was not overlooked in the absence of histological examination, the overall incidence was 14 per cent and that of malignant disease 10 per cent. All patients with carcinoma had cytological features suspicious of neoplasia on the first or subsequent aspirates in addition to those of thyroiditis. Cytology was suspicious of lymphoma in only two of seven patients but increasing size of the thyroid swelling was a consistent feature. Evidence of chronic lymphocytic thyroiditis may lead to neoplasia being overlooked. Repeated cytological analysis is helpful in identifying coexistent carcinoma but unreliable in excluding lymphoma.