Population pharmacokinetics of acyclovir in children and young people with malignancy after administration of intravenous acyclovir or oral valacyclovir.

Acyclovir is effective in the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The aim of this study was to characterize the population pharmacokinetics of acyclovir observed following treatment with intravenous acyclovir and oral valacyclovir (valaciclovir) in young people with malignancy. Plasma acyclovir concentration-time data were collected from 43 patients (age range, 9 months to 20 years) who had been given multiple doses of acyclovir (5 mg/kg of body weight) and/or valacyclovir (10 mg/kg). Nonlinear mixed-effect modeling was employed to analyze acyclovir population pharmacokinetics and identify influential covariates. Simulations (n = 1,000) were conducted to explore the ability of the current doses to maintain acyclovir concentrations above the recommended 50% inhibitory concentration for HSV or VZV (0.56 mg/liter or 1.125 mg/liter, respectively) for more than 12 h. A one-compartment pharmacokinetic model with first-order elimination best described the acyclovir concentration-time data. The population mean estimates for clearance (CL), volume of distribution (V), absorption rate (k(a)), and bioavailability (F) were 3.55 liters/h, 7.36 liters, 0.63 h(-1), and 0.60, respectively. Inclusion of body weight and estimated creatinine CL (CL(CR)) in the final model reduced the interindividual variabilities in CL and V from 61% to 24% and from 75% to 36%, respectively. Simulations revealed that with the use of the current doses, maximal efficacy can be achieved in over 45% of patients weighing 25 to 50 kg and with CL(CR) levels of 2.0 to 4.0 liters/h/m(2), but only in a much smaller proportion of patients, with low weights (10 kg) and high CL(CR)s (5.5 liters/h/m(2)), suggesting that higher doses are required for this subgroup. This validated population pharmacokinetic model for acyclovir may be used to develop dosing guidelines for safe and effective antiviral therapy in young people with malignancy.

Aerosols and climate.

To determine the effects of atmospheric aerosols on the radiative heating of the earth-atmosphere system, the radiative transfer equation is solved analytically in the two-stream approximation. It is found that the sign of the heating is independent of optical thickness of an aerosol layer and the amount of heating approaches a finite limit with increasing thickness of a layer. Limitations of the two-stream approximation are discussed.

Effect of ship-stack effluents on cloud reflectivity.

Under stable meteorological conditions the effect of ship-stack exhaust on overlying clouds was detected in daytime satellite images as an enhancement in cloud reflectivity at 3.7 micrometers. The exhaust is a source of cloud-condensation nuclei that increases the number of cloud droplets while reducing droplet size. This reduction in droplet size causes the reflectivity at 3.7 micrometers to be greater than the levels for nearby noncontaminated clouds of similar physical characteristics. The increase in droplet number causes the reflectivity at 0.63 micrometer to be significantly higher for the contaminated clouds despite the likelihood that the exhaust is a source of particles that absorb at visible wavelengths. The effect of aerosols on cloud reflectivity is expected to have a larger influence on the earth's albedo than that due to the direct scattering and absorption of sunlight by the aerosols alone.

Direct and remote sensing observations of the effects of ships on clouds.

Under certain conditions ships can affect the structure of shallow layer clouds. Simultaneous observations of two ship track signatures in stratus clouds from a satellite and in situ from an aircraft show that in the ship tracks the droplet sizes were reduced and total concentrations of both droplets and particles were substantially increased from those in adjacent clouds. In situ measurements of the upwelling radiance within the ship tracks was significantly enhanced at visible wavelengths, whereas radiance at 2.2 micrometers was significantly reduced. Cloud reflectivity along the tracks was enhanced at 0.63 and 3.7 micrometers. These observations support the contention that ship track signatures in clouds are produced primarily by particles emitted from ships.

Climate forcing by anthropogenic aerosols.

Although long considered to be of marginal importance to global climate change, tropospheric aerosol contributes substantially to radiative forcing, and anthropogenic sulfate aerosol in particular has imposed a major perturbation to this forcing. Both the direct scattering of shortwavelength solar radiation and the modification of the shortwave reflective properties of clouds by sulfate aerosol particles increase planetary albedo, thereby exerting a cooling influence on the planet. Current climate forcing due to anthropogenic sulfate is estimated to be -1 to -2 watts per square meter, globally averaged. This perturbation is comparable in magnitude to current anthropogenic greenhouse gas forcing but opposite in sign. Thus, the aerosol forcing has likely offset global greenhouse warming to a substantial degree. However, differences in geographical and seasonal distributions of these forcings preclude any simple compensation. Aerosol effects must be taken into account in evaluating anthropogenic influences on past, current, and projected future climate and in formulating policy regarding controls on emission of greenhouse gases and sulfur dioxide. Resolution of such policy issues requires integrated research on the magnitude and geographical distribution of aerosol climate forcing and on the controlling chemical and physical processes.

A fatal case of Lassa fever in London, January 2009.

In January 2009, the eleventh [corrected] case of Lassa fever imported to the United Kingdom was diagnosed in London. Risk assessment of 328 healthcare contacts with potential direct exposure to Lassa virus - through contact with the case or exposure to bodily fluids - was undertaken. No contacts were assessed to be at high risk of infection and no secondary clinical cases identified.

Chlorinated persistent organic pollutants in serum of New Zealand adults, 2011-2013.

A national survey was conducted in 2011-2013 to assess serum concentrations of persistent organic pollutants (POPs) in adult New Zealanders. Participants were randomly selected from the 2010 Electoral Roll within 64 demographic strata according to 4 age groups, 4 regions, 2 ethnic groups (Maori/non-Maori) and gender. Eligible subjects (n=734) donated up to 30ml of blood, after which serum was pooled (n=49) according to demographic strata prior to analysis by GC-HRMS. Associations between demographic variables (age, region, ethnicity, gender) and serum POPs were assessed using linear regression. The weighted geometric mean (GM) of PCDD/Fs was 5.3pg/g lipid toxic equivalents using the WHO 2005 toxic equivalence factors (TEQ05), which increased by age (3.2, 4.4, 4.8, and 8.1pg/g lipid for the 19-24, 25-34, 35-49, and 50-64year age groups, respectively). The weighted GM of dioxin-like PCBs was 1.4pg TEQ05/g lipid which also increased by age (0.82, 0.86, 1.4, and 2.3pg/g lipid for the same age groups, respectively). Of the detected OCPs, the highest concentration was observed for p,p'-DDE (weighted GM, 220ng/g lipid) followed by hexachlorobenzene (HCB; 7.3ng/g lipid), beta-HCH (7.0ng/g lipid), and dieldrin (4.7ng/g lipid). For most Cl-POPs, concentrations were lowest in the youngest age group, and were similar for men and women and Maori and non-Maori. Serum Cl-POPs were, on average, 50% lower than those measured 15years earlier in 1997. This survey provides evidence of declining serum concentrations of chlorinated POPs in the New Zealand adult population. Age was the most important determinant of POPs concentrations. Body burdens of PCDD/Fs and PCBs in New Zealand are relatively low by international comparison, while for OCPs they are similar or lower compared to those reported for other developed countries.

Polybrominated diphenyl ethers and perfluorinated alkyl substances in blood serum of New Zealand adults, 2011-2013.

A national survey was conducted in 2011-2013 to assess serum concentrations of brominated flame retardants (BFRs) and perfluorinated alkyl substances (PFASs) in adult New Zealanders. Participants were randomly selected from the 2010 Electoral Roll within 64 demographic strata according to 4 age groups, 4 geographic regions, 2 ethnic groups (Maori/non-Maori) and sex. Eligible participants (n = 734; response rate of contacted individuals = 37%) donated up to 30 mL of blood, after which serum was pooled (49 pools for BFRs, 63 pools for PFASs) according to demographic strata. BFRs were analysed by GC-HRMS and PFASs by LC-MS/MS. Associations between serum BFRs and PFASs and demographic variables (age, region, ethnicity, sex) were assessed using regression analysis. The weighted geometric mean (GM) serum concentrations of BDE47, BDE99, BDE100, and BDE153 were 2.0, 0.66, 0.43, and 1.2 ng/g lipid, respectively. The weighted geometric mean (GM) serum concentrations of PFOS, PFOA, PFHxS, and PFNA were 3.4, 2.4, 1.0, and 0.66 ng/mL, respectively. The majority of BFRs showed higher serum concentrations in younger age groups. Conversely, the four PFASs showed higher serum concentrations in older age groups. Concentrations of BFRs and PFASs were generally lower in females compared to males. In New Zealand, both age and sex are important determinants of BFR and PFAS serum concentrations.

Novel mutations in abetalipoproteinaemia and homozygous familial hypobetalipoproteinaemia.

Abetalipoproteinaemia (ABL) and homozygous familial hypobetalipoproteinaemia (FHBL) are rare inherited disorders associated with low or undetectable levels of apolipoprotein B (apoB)-containing lipoproteins. Patients present with the symptoms and sequelae of fat malabsorption, including fat-soluble vitamin deficiencies. We describe two novel mutations: one an APOB gene mutation causing FHBL and the other a microsomal triglyceride transfer protein (MTP) gene mutation causing ABL. Two siblings of consanguineous parents were homozygous for an apoB mutation 4339delT causing an apoB-30.9 truncation. In another family, a boy born to consanguineous parents was homozygous for a 319 bp in-frame deletion of MTP exon 15 (c.2076-39_2303 + 52del319). All three children presented with malabsorption and liver dysfunction and had similar very low serum lipid, apoB, and fat-soluble vitamin levels. The FHBL parents had low serum lipid and apoB profiles distinguishing the disorder from the normal levels in ABL parents. Future patients presenting with FHBL or ABL should be genotyped to provide further insight into the varying clinical severity related to molecular heterogenicity in these two conditions.

The potential of toxin-based drug delivery systems for enhanced nucleic acid therapeutic delivery.

INTRODUCTION: The potential of gene replacement therapy has been underscored by the market authorization of alipogene tiparvovec (Glybera) and GSK2696273 (Strimvelis) in the EU and recombinant adenovirus-p53 (Gendicine) in China. Common to these systems is the use of attenuated viruses for 'drug' delivery. Whilst viral delivery systems are being developed for siRNA, their application to antisense delivery remains problematic. Non-viral delivery remains experimental, with some notable successes. However, stability and the 'PEG dilemma', balancing toxicity and limited (often liver-tropic) pharmacokinetics/oharmacodynamics, with the membrane destabilizing activity, necessary for nucleocytosolic access and transfection remain a problem. Areas covered: Here we review the use of attenuated protein toxins as a delivery vehicle for nucleic acids, their relationship to the PEG dilemma, and their biological properties with specific reference to their intracellular trafficking. Expert opinion: The possibility of using attenuated toxins as antisense and siRNA delivery systems has been demonstrated in vitro. Systems based upon attenuated anthrax toxin have been shown to have high activity (equivalent to nucleofection) and low toxicity whilst not requiring cationic 'helpers' or condensing agents, divorcing these systems from the problems associated with the PEG dilemma. It remains to be seen whether these systems can operate safely, efficiently and reproducibly, in vivo or in the clinic.

Molecular heterogeneity in McArdle's disease.

Biopsies were taken from a group of eleven patients with McArdle's disease, a congenital deficiency in muscle glycogen phosphorylase. The biopsies were screened by Western and Northern blotting for phosphorylase protein, phosphorylase-bound pyridoxal-5'-phosphate (the cofactor of the enzyme) and for phosphorylase mRNA. Of the eleven patients, three expressed phosphorylase mRNA at near normal levels and at the expected size. One of these patients also expressed low levels of phosphorylase protein that correlated with a small amount of measurable phosphorylase activity. These data support the contention of molecular heterogeneity in the presentation of this phenotype.

Interpretation of alpha-fetoprotein concentrations in cerebrospinal fluid of infants.

BACKGROUND: There are no published reference intervals for concentrations of alpha-fetoprotein (AFP) in the cerebrospinal fluid (CSF) of normal infants. The presence of abnormal concentrations of AFP in plasma or CSF may indicate the presence of a teratoma or a germ cell tumour with yolk sac elements. We measured CSF AFP in infants who did not have malignancy in order to determine its reference intervals. METHODS: AFP was measured in the CSF and/or plasma in 128 infants. Of these, 91 infants had CSF AFP measurements, 94 infants had plasma AFP measurements and in 60 infants AFP concentrations were determined in paired CSF and plasma samples. The patients ranged in age from 1 to 110 days. Both CSF and plasma AFP concentrations were measured by a microparticle enzyme immunoassay using an AxSYM analyser. RESULTS: Using ages corrected for prematurity, the median CSF AFP concentration for babies -69 to 31 days old was 61 kIU/L (5th-95th centile: 2-889 kIU/L), while the median CSF AFP concentration for infants 32 to 110 days was 1.2 kIU/L (5th-95th centile: 0.1-12.5 kIU/L). By age 6 weeks, the concentrations were close to those found in adult plasma and all CSF AFP concentrations from infants with a corrected age over 2 months were <3 kIU/L. CONCLUSION: We have defined reference intervals for CSF AFP concentrations in infants. These results may assist in the diagnosis of CNS tumours, particularly congenital CNS tumours containing yolk sac elements.

Selenium metabolism and supplementation in patients with muscular dystrophy.

We studied selenium metabolism in patients with Duchenne muscular dystrophy and in contrast to previous reports found no significant abnormalities in these patients. Supplementation of muscular dystrophy patients and control subjects with sodium selenite (1 mg selenium/day) induced a variable rise in the activity of the selenium-dependent enzyme glutathione peroxidase in plasma and red cells, but no significant change in muscle glutathione peroxidase activities. There was no effect of selenium supplementation on disease activity in the patients with muscular dystrophy. Thiobarbituric acid-reacting substances (an index of free radical-mediated lipid peroxidation) were elevated in the muscle of patients with Duchenne muscular dystrophy in contrast to patients with other forms of muscular dystrophy and control subjects. This elevation was unaffected by selenium supplementation.

Prolonged neurogenic weakness in patients requiring mechanical ventilation for acute airflow limitation.

We describe three patients who required mechanical ventilation for severe acute exacerbations of obstructive airways disease. When treatment with sedatives and muscle relaxants was withdrawn, they exhibited profound generalized weakness and consequently required prolonged ventilation despite resolution of the airway obstruction. Clinical features were variable, but none of the patients developed failure of other organs and infection was confined to the lungs. All had electrophysiologic evidence of a predominantly motor axonal syndrome. One patient in whom sensory action potentials were abnormal may represent an unusually severe case of critical illness neuropathy occurring in the absence of systemic sepsis and multiple organ failure. In the other two cases, this diagnosis is made less likely by the complete absence of sensory involvement and in these patients the lesion appeared to be either in the most distal portion of the motor neuron or at the neuromuscular junction. In all three patients, resolution was slow but eventually complete. The etiology of the condition is not clear, but it seems to be distinct from the acute myopathy previously described in asthmatics who had received mechanical ventilation. It is important to recognize this phenomenon to avoid erroneous conclusions about the likelihood of the patient recovering from ventilator dependence. A prolonged weaning period is to be expected in such cases.

Cardiac failure in children with pneumonia in Papua New Guinea.

BACKGROUND: Cardiac failure is suspected of contributing to mortality from pneumonia in children in developing countries, but its role has not been clearly defined. METHODS: A convenience sample of 47 children admitted to Goroka Hospital in Papua New Guinea was studied prospectively with ultrasound, chest radiographs and assays of creatine kinase and lactate dehydrogenase. Results. Seven (15%) of the 47 children died. Of the 43 children who had a chest radiograph, 31 (72%) had severe or very severe pneumonia. No child had poor contractility of the heart on ultrasound examination or unequivocally raised cardiac isoenzymes; therefore no evidence of myocardial injury from sepsis was found. However, ultrasound examination showed dilatation of the right ventricle or hepatic veins in 12 (26%) of the children (both were dilated in 7 children) and 4 (33%) of these children died; this suggests that right ventricular cardiac failure secondary to pulmonary hypertension was present in 26% (95% confidence interval, 14 to 40%) of these children with severe pneumonia. Tachycardia was not associated with right ventricular dilatation on ultrasound, but 3 of the 4 children with more than 3 cm of liver palpable in the abdomen had right ventricular dilatation. Only 4 of the 12 children with right heart failure had hepatomegaly, tachycardia, raised jugular venous pressure or peripheral edema. CONCLUSIONS: Right ventricular failure is common in children with severe pneumonia, and it is probably caused by pulmonary hypertension rather than septic toxemia. The clinical signs of heart failure are unreliable. There is no evidence that digoxin is effective treatment for right ventricular failure secondary to pulmonary hypertension.

Plasma intestinal alkaline phosphatase isoenzymes in neonates with bowel necrosis.

AIM: To determine if the intestinal isoenzymes of alkaline phosphatase (ALP) are biochemical markers of bowel necrosis in neonates. METHODS: Plasma ALP isoenzymes were measured in 22 babies with bowel necrosis, histologically confirmed, and in 22 matched controls. The isoenzymes were also measured in 16 infants with signs of necrotising enterocolitis, who recovered without histological confirmation of bowel necrosis. The isoenzymes were separated by polyacrylamide gel electrophoresis. Auxiliary tests for identification included neuraminidase digestion and treatment with monoclonal and polyclonal antiplacental antibodies. RESULTS: Intestinal ALP was detected in 16 infants with bowel necrosis--13 had fetal intestinal ALP (FI-ALP) and three had adult intestinal ALP (AI-ALP). FI-ALP was detected in nine of the controls. In the babies with bowel necrosis intestinal ALP was found over all gestations, but in the controls only in those less than 34 weeks. The percentages of total ALP activity due to intestinal ALP were significantly higher in those with bowel necrosis compared with matched controls (p = 0.028). In babies of all gestations diagnostic sensitivity for the presence of intestinal ALP as a marker of bowel necrosis was 73% and diagnostic specificity 59%. In babies greater than 34 weeks' gestation, diagnostic sensitivity fell to 60% but the test became completely specific. In two babies FI-ALP increased from zero/trace to high activity coincident with the episode of bowel necrosis. In 16 babies with signs of necrotising enterocolitis but unconfirmed bowel necrosis FI-ALP was detected in four. CONCLUSION: Intestinal ALP seems to be released into the circulation in some babies with bowel necrosis, but its detection does not have the diagnostic sensitivity and specificity to be a reliable biochemical marker of the condition.

Preliminary observations on the neuromuscular abnormalities in patients with organ failure and sepsis.

OBJECTIVE: To estimate the incidence and nature of neuromuscular abnormalities in a representative group of ITU patients. DESIGN: Prospective sequential study. SETTING: Teaching hospital ITU. PATIENTS: 23 patients who eventually stayed > 7 days on ITU who had no contraindication to muscle biopsy and whose relatives gave informed consent. MEASUREMENTS AND RESULTS: Muscle histopathology, neurophysiological studies, record of all drugs administered, APACHE II score, organ system failure score, presence or absence of sepsis, clinical evaluation of neuromuscular problems, time to hospital discharge. Heterogeneous neuromuscular abnormalities were present in 22 out of 23 patients studied and included axonal neuropathy, denervation, generalised fibre atrophy, non-specific myopathy and necrotising myopathy. CONCLUSION: Neuromuscular abnormalities are almost invariable in longstay intensive care patients and the resulting weakness may seriously delay hospital discharge. Various abnormalities were seen but no obvious aetiological factors were identified. The origin of the abnormalities is probably multifactorial.

Patterns of neurophysiological abnormality in prolonged critical illness.

OBJECTIVE: To describe the various patterns of neurophysiological abnormalities which may complicate prolonged critical illness and identify possible aetiological factors. DESIGN: Prospective case series of neurophysiological studies, severity of illness scores, organ failures, drug therapy and hospital outcome. Some patients also had muscle biopsies. SETTING: General intensive care unit (ICU) in a University Hospital. PATIENTS: Forty-four patients requiring intensive care unit stay of more than 7 days. The median age was 60 (range 27-84 years), APACHE II score 19 (range 8-33), organ failures 3 (range 1-6), and mortality was 23%. RESULTS: Seven patients had normal neurophysiology (group I), 4 had a predominantly sensory axonal neuropathy (group II), 11 had motor syndromes characterised by markedly reduced compound muscle action potentials and sensory action potentials in the normal range (group III) and 19 had combinations of motor and sensory abnormalities (group IV). Three patients had abnormal studies but could not be classified into the above groups (group V). All patients had normal nerve conduction velocities. Electromyography revealed evidence of denervation in five patients in group III and five in group IV. There was no obvious relationship between the pattern of neurophysiological abnormality and the APACHE II score, organ failure score, the presence of sepsis or the administration of muscle relaxants and steroids. A wide range of histological abnormalities was seen in the 24 patients who had a muscle biopsy; there was no clear relationship between these changes and the neurophysiological abnormalities, although histologically normal muscle was only found in patients with normal neurophysiology. Only three of the eight patients from group III in whom muscle biopsy was performed had histological changes compatible with myopathy. CONCLUSIONS: Neurophysiological abnormalities complicating critical illness can be broadly divided into three types -- sensory abnormalities alone, a pure motor syndrome and a mixed motor and sensory disturbance. The motor syndrome could be explained by an abnormality in the most distal portion of the motor axon, at the neuromuscular junction or the motor end plate and, in some cases, by inexcitable muscle membranes or extreme loss of muscle bulk. The mixed motor and sensory disturbance which is characteristic of 'critical illness polyneuropathy' could be explained by a combination of the pure motor syndrome and the mild sensory neuropathy. More precise identification of the various neurophysiological abnormalities and aetiological factors may lead to further insights into the causes of neuromuscular weakness in the critically ill and ultimately to measures for their prevention and treatment.

Reversible tetraplegia due to polyneuropathy in a diabetic patient with hyperosmolar non-ketotic coma.

Critical illness polyneuromypathy has not previously been reported as a complication of diabetic coma. We describe a patient with hyperosmolar non-ketotic coma (HONK) complicating gram-negative sepsis in whom persistent coma and profound tetraplegia caused considerable concern. Although, initially, it was feared that the patient had suffered a central neurological complication such as stroke or cerebral oedema, a diagnosis of critical illness motor syndrome (CIMS) was subsequently confirmed neurophysiologically. Profound limb weakness associated with HONK is not necessarily due to a catastrophic cerebral event, rather it may be a result of CIMS, which has an excellent prognosis for full neurological recovery.