Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis

OBJECTIVES: To review the evidence from controlled clinical trials of neonates given equal daily aminoglycoside doses as extended interval dosing (dosage interval typically 24 hours in term and 36-48 hours in immature neonates) compared with traditional dosing (dosage interval typically 8-12 hours in term and 12-24 hours in immature neonates). DESIGN: Systematic review and meta-analysis of controlled trials found in electronic databases, trial registers, and references in reviews and selected trials. SETTINGS: The selected trials were blinded and assessed for methodological quality. Each trial's own predefined criteria for treatment failure, nephrotoxicity, ototoxicity, and therapeutic serum drug concentrations were used. SUBJECTS: Controlled trials of neonatal aminoglycoside treatment in which equal aminoglycoside daily doses were given at traditional and extended dosage intervals. MAIN OUTCOME MEASURES: Serum drug concentrations outside the therapeutic range. Treatment failure and toxicity. RESULTS: Sixteen trials involving 823 neonates met the inclusion criteria for the systematic review. Twelve trials involving 698 neonates were included in the meta-analysis of the pharmacokinetics. Compared with traditional dosing, extended interval dosing was associated with a significantly lower risk of both peak (summary risk ratio 0.50, 95% confidence interval 0.26 to 0.94) and trough (0.36, 0.25 to 0.56) serum drug concentrations outside the therapeutic range. Accurate information on treatment failure was obtained in nine trials involving 555 neonates. One trial reported treatment failure. In this trial two neonates in the traditional dosing group did not respond to treatment within 72 hours. Nephrotoxicity was investigated in 589 neonates in 12 trials and ototoxicity in 210 neonates in four trials, with no significant differences between the two dosing regimens. CONCLUSIONS: Extended interval dosing of aminoglycosides in neonates is safe and effective, with a reduced risk of serum drug concentrations outside the therapeutic range.     

Hangover headache: various manifestations and proposal for criteria. Vågå study of headache epidemiology

Abstract Hangover headache has been focused upon in connection with the Vågå study of headache epidemiology, with 714 cases among 1122 dalesmen (64%). Most frequently the headache was global in location. It was more frequently located in the anterior (frontotemporal) than occipital area. A unilateral headache was present in only 3% of the dalesmen, many of whom were migraineurs. Headache seemed to be more intense in males than females. Headache usually seemed to be of a lower intensity than the pain of migraine, but higher than, or similar to, that of tension-type headache. The headache appeared late in the night/early morning hours, i. e., several hours after discontinuation of drinking. In most cases, headache stopped in the late morning hours, or at high noon, but it could even last until somewhat late in the afternoon; it rarely, if ever, exceeded 12 hours duration. Red wine seemed mostly to provoke headache the same evening (with traits similar to those of the spontaneously occurring headache attacks). Criteria for hangover headache are proposed.     

Detection and genetic typing of type 2 porcine circoviruses in archived pig tissues from the UK

Summary. Porcine circovirus 2 (PCV-2) is implicated as the causative agent of post-weaning multisystemic wasting syndrome (PMWS) and is also associated with porcine dermatitis and nephropathy syndrome (PDNS). The recent emergence of epidemic PMWS in the United Kingdom was predated by sporadic cases of PDNS dating back to the early 1980s. The aim of this study was to investigate whether PCV-2 DNA was present in archival tissues, and if so, to investigate the relatedness of these viruses with contemporary strains of PCV-2. DNA extracted from paraffin wax-embedded tissue blocks (n=68), was subjected to a TaqMan® polymerase chain reaction (PCR) targeting a fragment of ORF1 of PCV-2. Positive results were obtained from 41% (9/22), 31% (4/13) and 32% (8/25) of submissions from the 1990s, 1980s and 1970s respectively. The presence of PCV-2 antigen in some of these tissues was confirmed by immunohistochemistry (IHC). A PCR targeting ORF2 was used to obtain sequence data for phylogenetic analysis. Sequences from 5 archival tissues were unique but showed high genetic identity to PCV-2 sequence obtained from a 2000 PDNS case. These data demonstrate that similar isolates of PCV-2 have been present in the UK pig population for more than 30 years.     

Diagnostic, clinical, and therapeutic aspects of familial hypercholesterolemia in children

The clinical diagnosis of familial hypercholesterolemia (FH) in children is based on family history and laboratory findings. The best available value of low-density lipoprotein cholesterol (LDL-C) for the diagnosis of FH in children is >3.50 mmol/L (>135 mg/dL) when FH runs in the family. Levels below this concentration were only found in 4.3% of children that had a mutation in the LDL-receptor gene. In contrast, children with LDL-C equal to or above 3.50 mmol/L had 0.98 posttest probability of FH. Untreated FH carries a substantial burden of morbidity and mortality if left untreated or if inadequately treated. The guidelines of the American National Cholesterol Education Program suggested that drug treatment should be considered from the age of 10 years if LDL-C levels are greater than or equal to 4.9 mmol/L (190 mg/dL) or greater than or equal to 4.1 mmol/L (158 mg/dL) in the presence of other cardiovascular risk factors, including a positive family history of premature cardiovascular disease. Impaired flow mediated dilatation was more pronounced in FH children with a positive family history of premature cardiovascular disease. The currently prescribed diet is sometimes considered to be monotonous and can lead to problems with compliance. A reduction of the total intake fat and saturated fatty acids is important. Plant sterolesters should be evaluated in young FH children and can supplement drug and diet therapy, with an additional reduction of 10 to 15% of LDL-C. The use of resins leads to poor compliance, and statins are recommended for FH children and adolescents when drug treatment is indicated. Pravastatin, simvastatin, and atorvastatin decrease LDL-C 30 to 40% without serious adverse events and have a high degree of compliance.     

Repeated validation of parental self-reported smoking during pregnancy and infancy: a prospective cohort study of infants at high risk for allergy development

Exposure to environmental tobacco smoke (ETS) during fetal life and infancy is closely related to the smoking habits of the parents. Estimates of exposure to ETS require valid and detailed information on changes in cigarette smoking over time. The objective was to test the validity of self-reported smoking among parents during pregnancy and early childhood in a cohort of children at high risk for allergy development by measurement of exhaled carbon monoxide (CO). The cohort comprised 117 families enrolled from the general population of pregnant women at admission to antenatal care. Data on parental tobacco smoking were obtained by interview and exhaled CO was measured (Micro-Smokerlyzer(R)) in parents twice during pregnancy and when the child was 6 and 18 months old. The median (range) exhaled CO levels were 3 (0-10) parts per million (ppm) for non-smokers and 15 (1-39) ppm for smokers (P < 0.0005). A receiver operating characteristic (ROC) analysis was performed at each examination. The areas under the ROC curve were high for both mothers (between 0.88 and 0.99) and fathers (between 0.87 and 0.89), indicating exhaled CO as a good diagnostic tool for determining smoking status. Comparing the ROC areas obtained for mothers from late pregnancy and during infancy with the area from early pregnancy showed no statistical differences (P = 0.21, 0.43 and 0.44 respectively) and the same was true for fathers during infancy (P = 0.81). The level of 8 ppm was used as the cut-off between smokers and non-smokers, based on data from a pilot study. Using CO as a diagnostic tool for smoker status showed very high specificity (between 97 and 100%), indicating that very few persons claiming to be non-smokers had CO levels higher than 8 ppm. In conclusion, the validity of interview-obtained self-reported smoking among parents during pregnancy and early childhood was high. Repeated interviews and CO measurements in a prospective study design did not change the validity, indicating a low risk of information bias. A structured interview combined with measurement of exhaled CO is a valid and reliable method for estimating ETS exposure to the fetus and young infant.     

Glycine-extended gastrin-17 stimulates acid secretion only via CCK-2 receptor-induced histamine release in the totally isolated vascularly perfused rat stomach

The effects of gastrin precursors have been discussed during recent years. However, the mechanism for their action, whether through a novel receptor on the parietal cell or a cholecystokinin-2 (CCK-2) receptor on the enterochromaffin like (ECL) cells, is still not settled. This study examines the effect of glycine-extended gastrin-17 (Gly-G-17), the main non-amidated gastrin precursor, on gastric acid secretion and histamine release in the totally isolated vascularly perfused rat stomach. Glycine-extended gastrin-17 at the concentrations from 0.52 to 520 nmol L(-1) was administered to the totally isolated vascularly perfused rat stomach. Glycine-extended gastrin-17 at 52 or 520 nmol L(-1), and gastrin-17 at 0.52 nmol L(-1)were co-administered to examine whether glycine-extended gastrin augmented maximal gastrin stimulated acid secretion and histamine release. Both Gly-G-17 at 52 nmol L(-1) and gastrin-17 (G-17) at 0.52 nmol L(-1) were administered together with the histamine-2 receptor antagonist ranitidine at 10 micromol L(-1). Gastric acid and venous histamine output were measured. Glycine-extended gastrin-17 at lower concentrations from 0.52 to 5.2 nmol L(-1) did not stimulate gastric acid output or histamine release, whereas higher concentrations from 52 to 520 nmol L(-1) elicited a concentration-dependent increase in acid secretion and histamine release. The outputs of acid and histamine at 520 nmol L(-1) Gly-G-17 were at the same level as those found for G-17 at its maximally effective concentration of 0.52 nmol L(-1). Glycine-extended gastrin-17 at maximally effective concentration of 520 nmol L(-1) did not augment maximal gastrin stimulated acid secretion or histamine release. Ranitidine inhibited G-17 and Gly-G-17 stimulated acid secretion to a similar degree. This study confirms that the stimulatory effect of Gly-G-17 on gastric acid secretion is via a CCK-2 receptor on the ECL cell.     

Drug-related deaths in a department of internal medicine

BACKGROUND: Drug therapy is associated with adverse effects, and fatal adverse drug events (ADEs) have become major hospital problems. Our study assesses the incidence of fatal ADEs in a major medical department and identifies possible patient characteristics signifying fatal ADE risk. METHODS: During a 2-year period, a multidisciplinary study group examined all 732 patients who died--5.2% of the 13992 patients admitted to the Department of Internal Medicine, Central Hospital of Akershus, Nordbyhagen, Norway. Decisions about the presence or absence of fatal ADEs were based on aggregated clinical records, autopsy results, and findings from premortem and postmortem drug analyses. RESULTS: In 18.2% of the patients (133/732) (95% confidence interval, 15.4%-21.0%), deaths were classified as being directly (64 [48.1%] of 133) or indirectly (69 [51.9%] of 133) associated with 1 or more drugs (this equals 9.5 deaths per 1000 hospitalized patients). Those with fatal ADEs (cases) were older, had more diseases, and used more drugs than those without fatal ADEs (noncases). In 75 of the 133 patients with fatal ADEs, autopsy findings and/or drug analysis data were decisive for recognizing the ADEs; in 62 of the remaining 595 patients, similar data proved necessary to exclude the suspicion of a fatal ADE. Major culprit drugs were cardiovascular, antithrombotic, and sympathomimetic agents. CONCLUSIONS: Fatal ADEs represent a major hospital problem, especially in elderly patients with multiple diseases. A higher number of drugs administered was associated with a higher frequency of fatal ADEs, but whether a high number of drugs is an independent risk factor for fatal ADEs is unsettled. Autopsy results and the findings of premortem and postmortem drug analyses were important for recognizing and excluding suspected fatal ADEs.     

Features indicative of cervical abnormality. A factor to be reckoned with in clinical headache work and research?

The current criteria for cervicogenic headache (CEH) contain an anamnestic and a physical examination part. The latter consists of: 1) range of motion in the cervical spine (1+); 2) mechanical precipitation of head pain (uppermost score: 1.5+). These two factors are included in "Features indicative of cervical abnormality", outlined in the present context, with a view to possibly facilitating CEH diagnosis. These "features" have a wider scope, containing not only the two original factors (1 and 2), but also three additional factors--their relative contribution to the totality also given in parentheses: 3) facet joint tenderness (0.5+); 4) neck muscle tenderness (0.5+); and 5) skin-roll test (1.0+). The sum of the solitary features is, accordingly, 4.5+. An extra 0.5+ can be added if there is extreme positivity of one of the factors, i.e., a maximum of 5.0+. This coarse system concerning cervical function has also been tested out in 1834 parishioners in the V?g? study of headache epidemiology (irrespective of headache diagnoses). The mean number of features increased with increasing intensity of head pain (by a factor of almost 3). In headache-free individuals (n.=246), the mean was 0.42+, against a mean in the whole series of 0.79+. Reproducibility tests demonstrated relatively high consistency.