bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimation of the impact of noncompliance on pharmacokinetics: an analysis of the influence of dosing regimens
Authors: Hughes Dyfrig A.
Published: April 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Patient compliance is better with formulations that require less frequent dosing than with formulations that require more frequent dosing.

• Intramuscular risperidone and long‐acting oxybutynin are two examples of medicines reformulated for less frequent dosing.

• However, it is not clear whether better compliance with less frequent dosing regimens translates to improved therapeutic outcome.

WHAT THIS STUDY ADDS

• At equivalent daily doses and typical patterns of compliance, fortnightly intramuscular depot administrations of risperidone provide better pharmacokinetic coverage than once‐daily oral dosing.

• Once‐daily dosing of oxybutynin is no better at maintaining pharmacokinetic exposure than twice‐daily dosing at half strength.

• The use of simulated compliance data as input to pharmacokinetic models is useful to assess the impact of noncompliance on internal drug exposure.

AIMS

To determine whether, for oxybutynin and risperidone, drug exposure is better with less frequent dosing regimens than with regimens that require more frequent dosing.

METHODS

Pharmacokinetic models of oxybutynin (5 mg twice‐daily and 10 mg once‐daily) and risperidone (2 mg once‐daily orally and 25 mg fortnightly intramuscular injection) were developed. Simulations of multiple doses were performed by use of stochastic models of dose‐taking compliance and clinic visit attendance.

RESULTS

At therapeutic concentrations and with typical patterns of noncompliance, intramuscular injections of risperidone resulted in a 41% (SD 12%) greater pharmacokinetic coverage than the oral dose, 76% (SD 10%) vs. 35% (SD 7%). No discernable differences were evident between once‐ and twice‐daily formulations of oxybutynin, 29.2% (SD 10%) vs. 29.0% (SD 13%).

CONCLUSIONS

For equivalent doses for each drug, the longer acting preparation of risperidone, but not oxybutynin, is pharmacokinetically more forgiving of noncompliance than the shorter acting counterparts. Further analysis is required to confirm whether these observations are valid clinically.
Thrombolysis or nothing for acute myocardial infarction? It's all the same!
Authors: Bertele' Vittorio , Angelici Laura , Barlera Simona , Garattini Silvio
Published: April 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The methodological and ethical value of equivalence and non‐inferiority trials is questioned.

• These studies are still increasingly used in drug evaluation and accepted by the scientific community and the regulatory authorities.

WHAT THIS STUDY ADDS

• By applying the hypothesis of an equivalence trial of saruplase and streptokinase (SK) we proved that the no‐thrombolysis approach in the GISSI trial was equivalent to thrombolysis with SK, i.e. death rates in patients given SK or not were similar enough to consider the no‐thrombolysis regimen equivalent to thrombolytic treatment.

• These data illustrate the unreliability of equivalence trials, which can even disprove consolidated clinical evidence such as the efficacy of thrombolysis in acute myocardial infarction.

• Equivalence trials should not be considered an option by the scientific community and should not be accepted as a basis for marketing authorization by the regulatory authorities.

AIMS

To assess the reliability of equivalence trials we tested whether the no‐thrombolysis approach was equivalent to thrombolysis with streptokinase (SK) in acute myocardial infarction.

METHODS

We applied the hypothesis of an equivalence trial of a recombinant plasminogen activator and SK to the GISSI‐1 control group.

RESULTS

In at least one of three subsets randomly extracted from the GISSI database the equivalence criterion was satisfied, i.e. death rates in patients given SK or not were similar enough to consider the no‐thrombolysis regimen equivalent to thrombolytic treatment. Two‐thirds of 100 replications of the sampling gave this result.

CONCLUSIONS

These findings suggest the unreliability of equivalence trials, which should neither be adopted by the scientific community nor accepted by the regulatory authorities.
Prognostic importance of T and NK‐cells in a consecutive series of newly diagnosed patients with chronic lymphocytic leukaemia
Authors: Palmer Shanique , Hanson Curtis A. , Zent Clive S. , Porrata Luis F. , LaPlant Betsy , Geyer Susan M. , Markovic Svetomir N. , Call Timothy G. , Bowen Deborah A. , Jelinek Diane F. , Kay Neil E. , Shanafelt Tait D.
Published: April 2008

Patients with chronic lymphocytic leukaemia (CLL) have a variable clinical course. The identification of modifiable characteristics related to CLL‐specific survival may provide opportunities for therapeutic intervention. The absolute number of T‐cell and natural killer (NK)‐cells was calculated for 166 consecutive patients with CLL evaluated by flow cytometry at Mayo Clinic ≤2 months of diagnosis. The size of the T‐cell/NK‐cell compartment relative to the size of the malignant monoclonal B‐cell (MBC) compartment was evaluated by calculating NK:MBC and T:MBC ratios. Patients exhibited substantial variation in the absolute number of T‐ and NK‐cells as well as T:MBC and NK:MBC ratios at diagnosis. Higher T:MBC and NK:MBC ratios were observed among patients with early stage and mutated IGHV genes (all P ≤ 0·0003). As continuous variables, both T:MBC ratio (P‐value = 0·03) and NK:MBC ratio (P‐value = 0·02) were associated with time to treatment (TTT). On multivariate Cox modelling including stage, CD38, absolute MBC count, NK:MBC ratio and T:MBC ratio, the independent predictors of TTT were stage, T:MBC ratio and NK:MBC ratio. These findings suggest that measurable characteristics of the host immune system relate to the rate of disease progression in patients with newly diagnosed CLL. These characteristics can be modified and continued evaluation of immunomodulatory drugs, vaccination strategies and cellular therapies to delay/prevent disease progression are warranted.
Detection of chromium allergy by cellular in vitro methods
Authors: Lindemann M. , Rietschel F. , Zabel M. , Grosse‐Wilde H.
Published: April 2008

Background
The standard assay for the detection of chromium sensitization, the patch test, does not allow discrimination between patients with and without clinical symptoms of allergy.

Objective
The aim of this study was to prove whether cellular in vitro tests are predictive of chromium allergy.

Methods
Chromium‐sensitized volunteers with and without clinically manifest allergy and non‐sensitized healthy controls (n=37, 19, and 26, respectively) were analysed by cellular in vitro methods using tri‐ and hexavalent chromium (chromium chloride and potassium dichromate) as stimuli. The results were correlated with clinical and anamnestic data.

Results
Sensitized individuals with an allergy displayed significantly higher lymphocyte transformation test (LTT) responses than sensitized volunteers without allergy and controls (P<0.05 and P<0.01, respectively). 12.5 μg/mL of chromium chloride and 50 ng/mL of potassium dichromate were found to be optimal to discriminate between sensitized individuals with and without allergy. Combining the results of chromium chloride and potassium dichromate LTT, a positive reaction to at least one of the stimuli was highly predictive of allergy [sensitization with vs. without allergy: Odds ratio (OR)=6.4, P=0.004; sensitization with allergy vs. controls: OR=11.5, P<0.0001]. On the contrary, IFN‐γ, IL‐2, IL‐4, IL‐10, and IL‐12 production to the ELISpot, patch test results, sensitization against other metals, and atopy score did not significantly discriminate between sensitization with and without allergy. However, IFN‐γ responses towards chromium chloride were significantly correlated with the strength of patch test reactivity (r=0.49, P=0.002). By IFN‐γ ELISpot, the average precursor cell frequency reactive to trivalent chromium could be defined as 26, 15, and 11 : 106 in volunteers with sensitization and allergy, with sensitization without allergy, and controls, respectively.

Conclusions
In contrast to the patch test, the LTT appears to be a method that is predictive of chromium allergy.
Inhibition of inducible nitric oxide synthase activity prevents liver recovery in rat thioacetamide‐induced fibrosis reversal
Authors: Lukivskaya O. , Patsenker E. , Lis R. , Buko V. U.
Published: April 2008

Background  Stimulation of nitric oxide (NO) synthesis similar to the application of NO donors could be of benefit in liver fibrosis. Many authors believe that activation of NO synthesis by pharmacological agents is promising in the treatment of liver fibrosis. However, there is considerable controversy in understanding the role of NO in fibrogenesis and fibrolysis. The aims of our study were to evaluate the effects of L‐arginine, as an NO metabolic precursor, and those of NO synthase (NOS) inhibitors, L‐nitroarginine methyl ester (L‐NAME) and aminoguanidine (AG) in rats with thioacetamide (TAA)‐induced liver fibrosis reversal.

Materials and methods  Male Wistar rats, 230–240 g, received TAA (200 mg kg−1, intraperitoneally) twice a week for 3 months. Liver resolution was simulated by withdrawal of TAA administration. Thereafter the animals were subdivided into five groups and treated by intragastric intubation with: L‐arginine (100 and 300 mg kg−1); L‐NAME as an inhibitor of both constitutively expressed NOS (eNOS) and inducible NOS (iNOS) (20 mg kg−1), AG as a specific inhibitor of iNOS (100 mg kg−1) or placebo. The severity of liver fibrosis was assessed by morphometric evaluation of liver slides stained with Azan‐Mallory, hydroxyproline (Hyp) determination and mRNA steady state levels of collagen I, transforming growth factor (TGF)‐β1, metalloproteinases (MMP)‐13, ‐14, tissue inhibitor of MMP (TIMP)‐1 and plasminogen activator inhibitor (PAI)‐1 were quantified by real time PCR. The activities of serum marker enzyme, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, were measured.

Results  TAA treatment during 3 months induced micronodular liver fibrosis with a pronounced deposition of collagen fibres. L‐Arginine did not affect this deposition nor did it affect both relative and total liver hydroxyproline content. Both NOS inhibitors significantly increased the square of the liver connective tissue stained by Azan‐Mallory and the above parameters characterizing liver hydroxyproline content. Both NOS inhibitors up‐regulated procollagen α1 (I), MMP‐13, TIMP‐1 and PAI‐1 mRNA expression. The AG effects were more pronounced. than those of L‐NAME. AG treatment also increased mRNA expression of TGF‐β1 and PAI‐1.

Conclusions  Both NOS inhibitors developed a clear pro‐fibrotic effect in the liver. Aminoguanidine was more fibrotic than L‐NAME. Our data suggest a significant anti‐fibrotic role for iNOS rather than for eNOS. L‐Arginine did not show any anti‐fibrotic properties in the TAA‐model used.
Evaluation of the one‐minute exercise test to detect peripheral arterial disease
Authors: Hoogeveen E. K. , Mackaay A. J. C. , Beks P. J. , Kostense P. J. , Dekker J. M. , Heine R. J. , Nijpels G. , Rauwerda J. A. , Stehouwer C. D. A.
Published: April 2008

Background   Asymptomatic peripheral arterial disease (PAD) is common amongst the elderly and is a risk factor for cardiovascular morbidity and mortality. PAD can be assessed by non‐invasive tests such as the ankle/brachial pressure index (ABPI) at rest and Doppler flow velocity (DFV) scanning, but these tests may underestimate the prevalence of PAD. The aim of this study was to estimate the added value, for the detection of PAD, of the one‐minute exercise test, defined as positive if the drop of the ankle systolic pressure was more than 30 mmHg. We also investigated whether the combination of the ABPI at rest and the one‐minute exercise test could replace DFV scanning.

Materials and methods   We studied this in a random sample (n = 631) of a 50‐ to 75‐year‐old population.

Results   Of these subjects 11% (66/631) had an abnormal ABPI (< 0·9) and 16% (102/631) had an abnormal DFV curve. Of this sample 72% of the subjects performed a one‐minute exercise test. Of all subjects 6% (27/451) had an abnormal ABPI (< 0·9) and 12% (54/451) had an abnormal DFV curve. The one‐minute exercise test revealed seven cases of PAD (beyond the 67 already identified) which were not detected by an abnormal ABPI at rest and/or DFV scanning. As a result the prevalence of PAD increased by 2%. All patients with an aortoiliac or femoropopliteal obstruction had an ABPI at rest < 0·9. The sensitivity of the combination of the ABPI at rest and the one‐minute exercise test to detect abnormal DFV curves was low for crural obstructions.

Conclusion   The one‐minute exercise test slightly improves the detection of peripheral arterial disease in the general population.
Evidence that viral abundance across oceans and lakes is driven by different biological factors
Authors: CLASEN JESSICA L. , BRIGDEN SEAN M. , PAYET JÉRÔME P. , SUTTLE CURTIS A.
Published: April 2008

1. Samples from 16 lakes in central (n = 145) and western (n = 12) North America, the coastal northeast Pacific (n = 302) and the western Canadian Arctic Oceans (n = 142) were collected and analysed for viral, bacterial and cyanobacterial abundances and chlorophyll‐a concentration.

2. Viral abundance was significantly different among the environments. It was highest in the coastal Pacific Ocean and lowest in the coastal Arctic Ocean. The abundances of bacteria and cyanobacteria as well as chlorophyll‐a concentrations also differed significantly among the environments, with both bacterial abundance and chlorophyll‐a concentration highest in lakes. As a consequence, the association of these variables with viral abundance varied among the environments.

3. Discriminant analyses with the abundance data indicated that the marine and freshwater environments were predictably different from each other. Multiple‐regression analysis included bacterial and cyanobacterial abundances, and chlorophyll‐a concentration as significant variables in explaining viral abundance in lakes. In regression models for the coastal Pacific Ocean, bacterial and cyanobacterial abundances were significant variables, and for the coastal Arctic Ocean viral abundance was predicted by bacterial abundance and chlorophyll‐a concentration.

4. The relationship of viral and bacterial abundance differed between the investigated freshwater and marine environments, probably because of differences in viral production and loss rates. However, freshwaters had fewer viruses compared to bacteria, despite previously documented higher burst sizes and frequencies of infected cells, suggesting that loss rates may be more important in lakes.

5. Together, these findings suggest that there are different drivers of viral abundance in different aquatic environments, including lakes and oceans.
Courseware evaluation: where's the intelligence?*
Authors: MacKenzie I. Scott
Published: April 2008

Abstract  Questions are explored that courseware evaluators may pose in establishing the extent to which ‘intelligence’ is present in Intelligent Computer Assisted Instruction and Intelligent Tutoring Systems. The focus is on key features of intelligent systems including a knowledge base which grows, knowledge of student progress and interaction style, feedback or self‐reflection of activities, tolerance of user input errors, learner control, and resources for attaining higher cognitive states. Ways in which courseware evaluators may establish the presence of these features are examined.
Why is science difficult to learn? Things are seldom what they seem
Authors: Johnstone A. H.
Published: April 2008

Abstract The difficulties of learning science are related to the nature of science itself and to the methods by which science is customarily taught without regard to what is known about children's learning. An information processing model is proposed to guide thinking and research in this area.
The effect of altered dietary carbohydrate content on the metabolic responses to physical exercise in insulin‐dependent diabetic subjects
Authors: Torrance A. D. , Sharpe G. R. , Cooper B. G. , Alberti K. G. M. M.
Published: April 2008

The effects of two isoenergetic 8.4 MJ (2000 kcal) diets containing 40% and 65% of total energy from carbohydrate, respectively, were studied in six insulindependent diabetics in relation to the metabolic responses to physical exercise. Each subject followed both diets in turn for one week. Additionally, the effects of a pre‐exercise supplement of either 50 g carbohydrate (as glucose polymer) or placebo were measured.

Exercise induced a marked fall in blood glucose levels of similar magnitude on both diets (P < 0.05) in the absence of supplementary carbohydrate and a significant increase (P < 0.01) when the supplement was provided. Insulin concentrations were virtually unaltered on either diet or supplement when compared before and after exercise (P < 0.5).

Blood levels of the gluconeogenic precursors (lactate, pyruvate, alanine and glycerol) were significantly increased after exercise in the case of both diets with or without supplementary carbohydrate (0.02 < P < 0.05).

Basal and post‐exercise levels of glucagon, cortisol, 3‐hydroxybutyrate, catecholamines and free fatty acids (FFA) were generally similar and not significantly different in any of the treatment conditions.

These data demonstrate that the metabolic and hormonal response to exercise is similar in insulin‐dependent diabetics receiving conventional injection therapy on standard diets (40% carbohydrate) and high carbohydrate containing diets (65% carbohydrate).
The eating and snacking patterns of young people in Brisbane, Australia
Authors: Dugdale A. E. , Townsend Beris , Rigsby Barbara
Published: April 2008

The frequencies of intakes of food and drink have been found in 591 subjects in Brisbane, Queensland, Australia who ranged in age from 11 to 25 years and came from upper‐ and lower‐class suburbs. The younger subjects were at primary and high schools, while the older subjects were either at technical college, university, employed as apprentices or unemployed.

Most subjects ate at the time of the traditional three meals but also had additional snacks so that most ate/drank 5–6 times a day. Confectionery was eaten more often by young boys than young girls, but the biggest difference was between employed women who ate sweets very often and unemployed women who ate them much less frequently. By contrast, ‘finger snacks' and soft drinks were consumed with similar frequencies by the employed and unemployed. More children consumed these products frequently in lower‐class suburbs than in the upper‐class suburbs.

These results suggest that soft drinks and ‘finger snacks' are regarded as part of the normal daily intake to be consumed regardless of income, but that sweets are seen as a discretionery pleasure to be indulged when money is available.
Predictable and unpredictable evolution of antibiotic resistance
Authors: Courvalin P.
Published: April 2008

Evolution of bacteria towards antibiotic resistance is unavoidable as it represents a particular aspect of the general evolution of bacteria. Thus, at the very best, the only hope we can have in the field of resistance is to delay dissemination of resistant bacteria or resistance genes. Resistance to antibiotics in bacteria can result from mutations in resident structural or regulatory genes or from horizontal acquisition of foreign genetic information. In this review, we will consider the predictable future of the relationship between bacteria and antibiotics.
The role of immune responses in the pathogenesis of hepatitis C virus infection
Authors: Koziel M. J.
Published: April 2008

Summary. Hepatitis C virus (HCV) is notable for the high rate of chronic infection, which occurs in nearly all individuals who become infected. Liver biopsies from individuals with chronic HCV infection are notable for the presence of numerous mononuclear cells, at least some of which are CD4+ and CD8+ T lymphocytes. The immune response to HCV is polyclonal and multispecific, both in terms of antibody and cellular immune responses. Individuals who recover from acute HCV infection appear to have quantitatively more vigorous CD4+ proliferative responses against one or more HCV proteins compared with those individuals who develop chronic disease. CD8+ responses are less well characterized, in part because of the technical difficulties involved in isolating and characterizing these cells. HCV‐specific CTL can be readily isolated from the liver and PBMC of chronically infected individuals, and recognize multiple epitopes. Even individuals with the same HLA type do not consistently recognize the same epitope. Thus, there does not appear to be an immunodominant response on the CD8+ level in this infection. CD8+ cells do appear to play some role in limiting viral replication. These responses are insufficient to eradicate virus completely, however, and may cause liver injury once chronic infection is established. Cytokines produced by both CD4+ and CD8+ cells may play an important role in both inhibiting viral replication and causing liver injury. A better understanding of the role of cellular immunity in the pathogenesis of HCV infection may aid in the development of vaccines and immunotherapeutic intervention strategies.
The longitudinal study of the Northern Finland birth cohort of 1966
Authors: Rantakallio Paula
Published: April 2008

Summary. The Northern Finland birth cohort comprises 12058 live births in 1966–96.3% of all births in the region. The investigation was started during pregnancy and the last follow‐up of the total series was at the age of 14 years, when the coverage was still large. Smaller samples of the children and data for the study population from national registers were also examined for the older age groups. The health and development of the children was studied, with special emphasis placed on obtaining reliable incidence figures for neurological handicaps and their correlation with perinatal events. In particular, the correlation between low birthweight and handicapping conditions was documented thoroughly. The indicators predictive of low birthweight among the biological characteristics of the mother and the social conditions of the mother and family, included maternal smoking during pregnancy. The latter was associated not only with adverse perinatal outcome but also with reduction in educational achievement and height among survivors.
Use of antibiotics and prescription drugs in general during the first 9 years of life in a Swedish community
Authors: Rasmussen Finn
Published: April 2008

Summary. The use of antibiotic drugs and of prescription drugs in general during the first 9 years of life was studied among all 1701 children born in a Swedish municipality. Cumulative proportions of children who had received one or more prescriptions for any type of drug and for different groups of antibiotic drugs were estimated by life‐table methods. The effects on drug use of the gender and the birth order of the child along with the age, citizenship and marital status of the mother were analysed by Cox's proportional hazards regression model. Half of the children had received at least one prescription for any drug after 0.6 years and at least one prescription for any antibiotic drug after 1.8 years. Higher proportions of children with prescriptions for all drugs and for all antibiotic drugs were found among males than females, among those with older siblings compared with first‐borns and among children of younger mothers compared with those of older mothers.
Cystic fibrosis in the United Kingdom, 1968–1988: incidence, population and survival
Authors: Dodge J.A. , Morison S. , Lewist P.A. , Coles E.C. , Geddes D. , Russell G. , Jackson A.D. , Bentley B.
Published: April 2008

Summary. A thorough survey was conducted of patients with cystic fibrosis living in the UK from 1977 onwards. This was supplemented with death certificate data back to 1968. There was one case identified for each 2475 births. The total number of cases in the UK rose linearly from 4086 in 1977 to 5426 in 1988 and is estimated to be 6000 in 1992.

The probability of survival improved in the period under study for all age groups and in both sexes. It was worst in the first year of life, dropped sharply thereafter but then increased steadily with age. There has been a very marked improvement over the years in survival in the first year of life, but a lesser one in older age groups.

Male mortality was greater than that in females in the first year of life, but less in subsequent years giving, overall, worse survival for females. A set of cohort and ‘current’ survival graphs for the two sexes are given.
Symptoms and health problems in pregnancy: their association with social factors, smoking, alcohol, caffeine and attitude to pregnancy
Authors: Meyer Lesley C. , Peacock Janet L. , Bland J. Martin , Anderson H. Ross
Published: April 2008

Summary. This paper describes the prevalence and correlates of symptoms and health problems in pregnancy using data from a prospective population study in London. Data on the prevalence of 11 symptoms and 12 health problems were obtained at three points in pregnancy from a consecutive sample of 1513 white women. Relationships were examined between these symptoms and a range of psychosocial factors including social class, education, marital status, income, smoking, alcohol, caffeine, attitude to pregnancy and whether the pregnancy was planned.

Most women reported nausea and breast tenderness in early pregnancy. Heartburn, backache, constipation and headaches were also common. The prevalence of symptoms tended to increase with gestation except for nausea and vomiting. Women with manual occupations, minimum education, low income, single marital status and unplanned pregnancy reported more of most symptoms except nausea which was associated with higher social status. A negative attitude to pregnancy was associated with more headaches but was unrelated to nausea. Women who smoked reported more ‘nerves and depression’ but less nausea. In general, nausea and vomiting showed a different pattern of associations from all other symptoms.
Survival of infants with neural tube defects in Western Australia 1966–1990
Authors: Kalucy Megan , Bower Carol , Stanley Fiona , Burton Paul
Published: April 2008

Summary. To investigate the survival of infants with neural tube defects in Western Australia from 1966 to 1990, cases of neural tube defects were ascertained from multiple sources. Survival of infants with anencephaly, spina bifida, and encephalocoele was examined separately, and four birth cohorts were compared: 1966–1972 (when most surviving infants were actively treated), 1973–1979 (a period of stringent application of selection criteria for treatment), 1980–1985 (some relaxation of selection criteria), and 1986–1990 (further relaxation of selection criteria).

There was an increase in terminations of pregnancies affected with anencephaly over the study period, and a fall in the proportion of both liveborn and stillborn infants with anencephaly. Most liveborn infants (76.4%) died in the first 24 hours, and none survived longer than 5 days. Most infants with encephalocoele (76.4%) were liveborn, and survival was poorest in the 1973–1979 cohort, although the difference in survival across cohorts just failed to attain a formal level of significance. For spina bifida, there was an increase in terminations of affected pregnancies over the study period. Survival of liveborn infants with spina bifida was poorest in the 1973–1979 cohort, and greatest in the most recent cohort. These improvements in survival are likely to be the result of relaxation of selection criteria for treatment, improvements in treatment and, to a lesser extent, selective termination of affected pregnancies.
The widening gap in low birthweight rates between extreme social groups in Poland during 1985–90
Authors: Brzezinski Zbigniew J. , Szamotulska Katarzyna
Published: April 2008

Summary. An attempt was made to identify the reasons for the increase in low birthweight (LBW) rates in Poland from 8.1% in 1985 to 8.4% in 1990. It was found that there was a differential increase in the LBW rates among the social groups. The highest increase was observed among the least educated mothers, especially in large cities. The LBW rate among the newborns of mothers who had finished their education at primary school level increased from 10.6% (in large cities from 14.7%) in 1985 to 12.5% (in large cities to 16.2%) in 1990. Controlling for maternal age, parity, education and place of residence did not change the significance of the increase in the LBW rate. The decline in birthweight was probably largely related to negative changes in socially differentiated levels of consumption of basic nutrients in Poland.
Low birthweight and the risk for mental retardation later in childhood
Authors: Mervis Cynthia A. , Decoufle Pierre , Murphy Catherine C. , Yeargin‐Allsopp Marshalyn
Published: April 2008

Summary. Data from the population‐based Metropolitan Atlanta Developmental Disabilities Study were used in a case‐control study to assess the association between low birthweight and mental retardation (intelligence quotient ≤70) among 10‐year‐old children who were born in 1975 or 1976. Children with mental retardation were identified from existing records at multiple sources and control children were selected from public school rosters. Data on birthweight and other covariates (sex, birth order, maternal age, maternal race, maternal education and gestational age) came from birth certificates. We used multiple logistic regression modelling to obtain adjusted odds ratios for mental retardation, with normal birthweight children (those weighing ≥2500g) as the referent group. For low birthweight children as a whole, the odds ratio for mental retardation was 2.8 (95% CI 1.9‐4.2). The risk was higher for very low birthweight (<1500 g) children than for moderately low birthweight (1500–2499 g) children, and higher for severe mental retardation (intelligence quotient <50) than for mild mental retardation (intelligence quotient 50–70). Adding gestational age to the models revealed that normal birthweight children who were born preterm also were at increased risk of having mental retardation at age 10 years.
Maternal body mass, proportional weight gain, and fetal growth in parous women
Authors: Shepard Mary Jo , Bakketeig Leiv S. , Jacobsen Geir , O'Connor Theresa , Bracken Michael B.
Published: April 2008

Summary. This study is designed to examine the impact of maternal body mass index (BMI), proportional weight gain, and other variables on fetal growth. From a 10% random sample of 5722 Norwegian and Swedish para one and two women (n = 561), three hundred and sixty‐nine women for whom prepregnant weight and height were recorded and for whom four fetal ultrasound measurements were taken at 17,25,33, and 37 weeks of gestation, were divided into low, average, and high body mass index groups (weight/height2). Fetal growth rate (mm/day) was determined by taking the mean of three measurements of the sagital and transverse diameters of the fetal abdomen (MAD) in each of three study time periods: weeks 17 to 25, first period; weeks 25 to 33, second period; weeks 33 to 37, third period. Proportional weight gain (kilograms gained within a specific time period/prepregnant weight) was measured in those same intervals. Fetal growth rate was significantly slower in the first and second periods, and significantly faster in the third time period for women with a low BMI, compared with those of average BMI. Fetal growth also significantly increased with increases in proportional weight gain in the second and third periods, but not in the first. Fetal growth appears to be independently associated with maternal BMI and proportional maternal weight gain.
Stress, social support and pregnancy outcome: a reassessment based on recent research
Authors: Hoffman Susie , Hatch Maureen C.
Published: April 2008

Summary.We present an assessment of studies published in the last decade that consider the relationship of stress and social support to preterm delivery or fetal growth retardation. Included in the review are all reports on the direct effects of stressors or psychological distress; the indirect effects of stressors or distress through health behaviours such as smoking; and the direct and buffering effects of social support. Although an important stimulus for recent stress research has been the attempt to explain racial and social class differences in birth outcome, the recent data show that stressful life events during pregnancy, though more common in disadvantaged groups, do not increase the risk of preterm birth. In contrast, intimate social support from a partner or family member appears to improve fetal growth, even for women with little life stress. Questions unanswered by the research to date are whether elevated levels of depressive symptoms affect pregnancy outcome, either directly or by encouraging negative health behaviours, and whether chronic (vs. acute) stressors are harmful. Additional research is also needed to determine whether psychosocial factors interact with specific clinical conditions to promote adverse pregnancy outcomes. Focusing on intimate support and how it benefits pregnancy outcome could lead to the design of more effective interventions.
Urticaria Neonatorum: Accumulation of tryptase‐expressing mast cells in the skin lesions of newborns with Erythema Toxicum
Authors: Nelson Annika , Ulfgren Ann‐Kristin , Edner Josefine , Ståbi Berit , Brismar Hjalmar , Hultenby Kjell , Marchini Giovanna
Published: April 2008

Erythema Toxicum, a rash frequently present in the healthy newborn infant is an innate, immune response to the first commensal micro flora. Flushing and urtication are seen in this manifestation suggesting mast cell (MC) activation and MC derived mediator release. It has recently become evident that MCs participate in the protective, innate immune response against microbes also by secreting products toxic to pathogens such as cathelicidin peptide antibiotics. We hypothesized that MCs contribute to the process of inflammation in Erythema Toxicum and that skin MCs of human newborns express the cathelicidin peptide antibiotic LL‐37. Skin sections were immunostained for MC tryptase. Double immunofluorescence was performed by staining LL‐37 in combination with tryptase. We studied ultra structure of skin MCs with transmission (TEM) and immunoelectron microscopy (IEM). Seven infants with and six infants without the rash, as well as three adults were included. We found numerous tryptase‐expressing MCs recruited around the hair follicles in the lesions of Erythema Toxicum. TEM analysis of MCs exhibited signs of degranulation in the lesion. Neither skin MCs from newborns nor adults did express LL‐37 as judged by confocal and IEM. MCs participate in the inflammatory responses of Erythema Toxicum by taking an active part in the immune system of the hair follicle. However, their immunological activity is not linked to the expression of the cathelicidin antimicrobial peptide LL‐37. A pivotal role of MCs in the innate, inflammatory response at the site of pathogen invasion during the critical time of perinatal colonization is suggested.
The stress of birth enhances in vitro spontaneous and IL‐8‐induced neutrophil chemotaxis in the human newborn
Authors: Yektaei‐Karin Elham , Moshfegh Ali , Lundahl Joachim , Berggren Veronica , Hansson Lars‐Olof , Marchini Giovanna
Published: April 2008

The birth process induces fetal stress. Stress has profound effects on the immune system, also by acting on the trafficking of leukocytes, a process in which adhesion and chemotaxis are primordial and critical events for the development of effective antimicrobial defenses. The newborn is rapidly challenged by a microflora at the epithelia linings and therefore depending on early, innate immunity onset. The objective of the study was to investigate the immune response in cord blood from newborns in relation to different degrees of fetal stress, with focus on neutrophil chemotaxis. We analyzed in vitro transmigration ability of neutrophils and their CD11b expression, measured total white blood count (WBC) and the major leukocyte populations, interleukin (IL)‐8, interferon (IFN)‐γ, and soluble E‐Selectin, as well as relevant immuno‐modulating hormones in infants born at term after Cesarean section prior to the start of labor (n = 55), normal vaginal delivery (n = 87), and assisted delivery (n = 26). Arterial pH and lactate were used as stress markers. We found that spontaneous and IL‐8‐induced transmigration ability of neutrophils from newborns after normal delivery was significantly higher compared with that of neutrophils from Cesarean section or from adults. With a progressive increase in fetal stress, there were significant elevations in total WBC, in particular neutrophils and monocytes, as well as an enhanced IL‐8 and soluble E‐Selectin level. Assisted delivery, associated with the highest degree of fetal stress in addition had an enhanced lymphocyte and monocytes count as well as an increased IFN‐γ level. There were significant direct correlations between neutrophils and monocytes, respectively, with cortisol, β‐endorphin, and prolactin. Interferon‐γ was directly related to dopamine, as well as to the lymphocyte and monocyte count. The setting of the HPA‐axis at birth is a promoter of an alarm response and a surge of neuroendocrine immuno‐modulating factors that enhances antimicrobial defenses of the newborn. We speculate that IL‐8 induced by normal labor may be a priming factor for an increased neutrophil chemotaxis through the pre‐activated endothelium of the fetus. Assisted delivery may trigger excessive recruitment of additional inflammatory cells and IFN‐γ release.
Case of fulminant‐SSPE associated with measles genotype D7 from India: An autopsy study
Authors: Mahadevan Anita , Vaidya Sunil R. , Wairagkar Niteen S. , Khedekar Deepika , Kovoor Jerry M.E. , Santosh Vani , Yasha T.C. , Satishchandra P. , Ravi V. , Shankar S.K.
Published: April 2008

Subacute sclerosing panencephalitis (SSPE), a post‐measles progressive neurological disorder is still common in India because of indifferent vaccination compliance. However, the acute fulminant form of SSPE is extremely rare. An unusual case of fulminant SSPE in an 18‐year‐old man from south India with an ultra‐short course of 19 days presenting with hemiparesis in absence of myoclonus and progressive cognitive decline, is reported. MRI showed frontal and parieto‐occipital demyelination extending to nuclear areas. Antimeasles antibodies were demonstrable in CSF and serum with oligoclonal bands in CSF despite normal CSF protein and cell count. At autopsy, unlike classical SSPE, oligodendroglia containing measles viral antigen was sparse despite florid necrotizing leukoencephalitis with acute demyelination. Measles virus was isolated from the brain with hypermutation in M gene confirming the diagnosis. Phylogenetic analysis of the viral genotype indicated that it belonged to D7 genotype which is considered rare in India.
Galectin‐3: A useful biomarker for differential diagnosis of brain tumors
Authors: Park Sung‐Hye , Min Hye Sook , Kim Bomi , Myung Jaekyung , Paek Sun Ha
Published: April 2008

Galectin‐3 (gal‐3) is a 31 kDa β‐galactoside‐binding lectin that is immunohistochemically expressed in macrophages, lymphocytes, and endothelial cells, and also in some neoplastic cells. Gal‐3's expression in and significance to brain tumors has not been fully addressed. Here, we investigated its immunohistochemical expression in 409 cases of surgically resected primary brain tumors, including various glioneuronal tumors, pituitary adenomas, meningiomas and Schwannomas, among others. In normal brain tissues, gal‐3 was robustly expressed in normal astrocytes, endothelial cells and macrophages. It showed consistent and diffuse positivity in 100% of the pilocytic astrocytomas, pleomorphic xanthoastrocytomas (PXA), Schwannomas, meningiomas, capillary hemangioblastomas, as well as in ependymomas, but it was completely negative in the diffuse astrocytomas, anaplastic astrocytomas, both low‐ and high‐grades of the oligodendrogliomas, central neurocytomas, and medulloblastomas. Definitely positive but heterogeneous expression was found in various tumors including subependymal giant cell astrocytomas (SEGA), classic glioblastoma multiforme, anaplastic oligoastrocytomas, CNS primitive neuroectodermal tumors (CNS PNETs), and hemangiopericytomas. Eighty percent of small cell glioblstomas were completely negative, but 20% showed heterogeneous positivity for gal‐3. Focal positivity for gal‐3 was also found in dysembryoplastic neuroepithelial tumors (DNTs) and gangliogliomas, in which the positive cells were the astrocytic component. On the basis of our immunohistochemical data in conjunction with previous reports, we therefore conclude that gal‐3 is differentially expressed in various brain tumors, and thereby, is a helpful biomarker in making differential diagnoses, especially in cases where a morphological diagnosis is controversial.
Complication rates of ultrasound‐guided prostate biopsy: A nation‐wide survey in Japan
Authors: Kakehi Yoshiyuki , Naito Seiji ,   Japanese Urological Association
Published: April 2008

Objective:  To assess the morbidity secondary to ultrasound‐guided systematic prostate biopsy in Japan.

Methods:  Five hundred and forty‐eight principal urological training institutions certified by the Japanese Urological Association participated in the survey. A retrospective analysis of complications after prostate biopsy was conducted.

Results:  Medical records of 212 065 procedures carried out between 2004 and 2006 were reviewed. Seventy‐six percent of procedures had been carried out transrectally, and 23% transperineally. Hematuria, rectal bleeding and hematospermia occurred in 12%, 5.9% and 1.2% of cases, respectively. Voiding symptoms were reported after biopsy in 1.9% of cases and urinary retention in 1.1%. Fever (>38°C) was observed in 1.1% and sepsis occurred in 0.07%. Hospitalization was required in 0.69% of cases for the treatment of biopsy‐related complications.

Conclusions:  Overall, contemporary ultrasound‐guided systematic prostate biopsy is safely carried out in Japan. However, minor complications are not infrequent, whereas major ones remain very rare but life‐threatening if they occur. Thus, adequate information should be provided to patients undergoing prostate biopsy.
The effect of a preoperative education programme on perioperative anxiety in children: an observational study
Authors: RICE MARIAM , GLASPER ALAN , KEETON DIANA , SPARGO PAUL
Published: April 2008

The distress of children at the induction of anesthesia (DAI) is unpleasant for all involved and potentially harmful. Many strategies such as premedication or parental presence at induction have been described to minimize it. A preoperative education programme [the ‘Saturday Morning Club’ or (SMC)] has been in existence in our institution for a number of years and an observational study of children undergoing day case surgery was undertaken to assess the influence of attendance at the SMC on DAI. Ninety‐four children aged between 2 and 16 years of age were included in the study; 21 attended the SMC and 73 did not. Patient anxiety using the modified Yale Preoperative Anxiety Scale was measured by blinded observers on the day ward, in the preoperative waiting room and at induction of anesthesia. Parental anxiety at the same locations was self reported using a visual analogue scale. Attendance at the SMC had a favorable effect on patient anxiety levels in all three locations but only reached statistical significance in the waiting room (P = 0.007, Mann–Whitney U‐test). At present there is little evidence to support the use of preoperative education programmes in the UK and further studies are required to determine their benefit.
Hepatic tolerance of repeated intravenous paracetamol administration in neonates
Authors: ALLEGAERT KAREL , RAYYAN MAISSA , DE RIJDT THOMAS , VAN BEEK FRANK , NAULAERS GUNNAR
Published: April 2008

Introduction:  An intravenous (i.v.) formulation of paracetamol is available, but reports on its hepatic tolerance in neonates are limited. We therefore assessed hepatic tolerance of i.v. paracetamol in neonates.

Methods:  In a single centre retrospective study, clinical data and hepatic enzyme profiles (ALT, AST, γGT) were collected in neonates treated with i.v. paracetamol between January 1, 2006 and October 1, 2007. Hepatic enzyme profiles were retrieved from 2 days before until 2 days after i.v. paracetamol administration. Mann–Whitney U‐test was used to compare hepatic enzymes before, during, and after i.v. treatment. Correlations (Spearman rank) of hepatic enzymes with duration of treatment during i.v. administration were investigated.

Results:  In 189 cases, 2360 administrations {postmenstrual age 38 (range 30–55) weeks, postnatal age 5 (1–182) days} were documented and 1132 hepatic enzyme observations were available in 149/189 cases. There was no significant increase in ALT, AST, or γGT when pretreatment observations (n = 310) were compared with observations during (n = 649) or during with after (n = 173) treatment, nor was there a significant increase during administration.

Conclusions:  This retrospective study on hepatic tolerance provides evidence on safety aspects of i.v. paracetamol in neonates. Future studies should focus on dose‐findings and pharmacodynamics of this formulation in neonates.
Diversity of the Southeast Asian leaf turtle genus Cyclemys: how many leaves on its tree of life?
Authors: Fritz U , Guicking D , Auer M , Sommer R. S , Wink M , Hundsdörfer A. K
Published: April 2008

In the present study, we use mtDNA sequence data (cyt b gene) in combination with nuclear DNA sequences (C‐mos, Rag2 genes, R35 intron), nuclear genomic fingerprints (ISSR) and morphological data to reveal species diversity within the Southeast Asian leaf turtle genus Cyclemys, a morphologically difficult group comprising cryptic species. Two morphologically distinct major groupings exist, a yellow‐bellied species group with three taxa (Cyclemys atripons, C. dentata, C. pulchristriata) and a dark‐bellied species group. The latter contains besides the morphologically variable C. oldhamii three additional new species (C. enigmatica n. sp., C. fusca n. sp., C. gemeli n. sp.). According to mtDNA data, C. fusca and C. gemeli constitute with high support the sister group of a clade comprising all other species, indicating that the dark‐bellied species are not monophyletic, despite morphological similarity. mtDNA sequences of C. enigmatica, being highly distinct in nuclear genomic markers, do not differ from the sympatric C. dentata, suggesting that the original mitochondrial genome of C. enigmatica was lost due to introgressive hybridization. Morphological discrimination of Cyclemys species is possible using multivariate methods. However, gross morphology of most dark‐bellied species on the one hand and of C. atripons and C. pulchristriata on the other is so similar that reliable species determination is only possible when genetic markers are used. The high diversity within Cyclemys requires revision of the IUCN Red List Categories for leaf turtles because the former assessment was based on the wrong assumption that in the entire range of the genus occurs only a single species.