bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted gene delivery using humanized single‐chain antibody with negatively charged oligopeptide tail
Authors: Suzuki Masataka , Takayanagi Atsushi , Shimizu Nobuyoshi
Published: August 2005

We have recently developed the so‐called recombinant immunoporter as a non‐viral vector based on a single‐chain antibody (scFv) derived from a monoclonal antibody B4G7 against epidermal growth factor (EGF) receptor. This immunoporter (mBBD20) was composed of single‐chain antibody and negatively charged oligopeptide tail [5 units of Asn4Ser (D20)], and was expressed in yeast as a secreted protein. The purified mBBD20 was converted to an immunogene by mixing it with DNA and a cationic polymer, polyethyleneimine (PEI). The resulting complex, namely recombinant immunogene, exhibited gene transfer activity with EGFRspecificity in vitro (Suzuki et al., Gene Ther. 2003). In this paper, we further improved various conditions necessary for the formation of the proper recombinant immunogene, retaining receptor specificity of its binding, intracellular processing of the receptorbound gene, and efficient gene expression. Moreover, we provided evidence that the recombinant immunoporter made with humanized scFv could be used as a potent gene transfer vehicle to target particular tumor cells. This approach seems worthy of clinical trial.
Late resistance to adenoviral p53‐mediated apoptosis caused by decreased expression of Coxsackie‐adenovirus receptors in human lung cancer cells
Authors: Tango Yasuhisa , Taki Masaki , Shirakiya Yoshiko , Ohtani Shoichiro , Tokunaga Naoyuki , Tsunemitsu Yosuke , Kagawa Shunsuke , Tani Toru , Tanaka Noriaki , Fujiwara Toshiyoshi
Published: August 2005

Adenovirus‐mediated wild‐type p53 gene transfer induces apoptosis in a variety of human cancer cells. Although clinical trials have demonstrated that a replication‐deficient recombinant adenovirus expressing the wild‐type p53 gene (Ad‐p53) is effective in suppressing growth of non‐small cell lung cancer (NSCLC), we often experienced late resistance to this treatment. To elucidate the mechanism of late resistance to Ad‐p53 in human lung cancer cells, we generated 5 different resistant variants from p53‐susceptible H1299 NSCLC cells by repeated infections with Ad‐p53. We first examined the transduction efficiency of adenoviral vector by Ad‐LacZ transduction followed by X‐gal staining in parental and 5 resistant H1299 cell lines. Their sensitivity to viral infection decreased in correlation with the magnitude of resistance, and Ad‐p53‐mediated tumor suppression could be restored by dose escalation of Ad‐p53 in the resistant variants. The expression of Coxsackie and adenovirus receptor (CAR) and αV integrins, which are cellular receptors for attachment and internalization of the virus, respectively, was next investigated in these cell lines. Flow cytometry revealed that αVβ3 and αVβ5 integrin expression was consistent, while p53‐resistant cell lines showed that diminished CAR expression correlated with the magnitude of the resistance. Our results demonstrated that decreased CAR expression could be one of the mechanisms of late resistance to Ad‐p53, which may have a significant impact on the outcome of adenovirus‐based cancer gene therapy.
In vitro conversion of irinotecan to SN‐38 in human plasma
Authors: Shingyoji Masato , Takiguchi Yuichi , Watanabe‐Uruma Reiko , Asaka‐Amano Yoshiko , Matsubara Hiroshi , Kurosu Katsushi , Kasahara Yasunori , Tanabe Nobuhiro , Tatsumi Koichiro , Kuriyama Takayuki
Published: August 2005

Irinotecan is an active cytotoxic agent for various cancers, and is converted to SN‐38, its most active metabolite, by carboxy‐lesterase converting enzyme (CCE) in vivo. Although the primary metabolic site is in the liver, ex vivo studies have proven that irinotecan is also converted to SN‐38 in intestines, plasma and tumor tissues. The present study attempted to elucidate the in vitro conversion efficiency in human plasma, and to examine possible inter‐individual variability and its clinical significance. Plasma samples were taken from 57 patients with lung cancer, 3 patients with benign pulmonary diseases and 9 healthy volunteers. After addition of 157 μM irinotecan to plasma, time courses of SN‐38 concentration, measured by high‐performance liquid chromatog‐raphy (HPLC), were investigated. All subjects showed linear increase in SN‐38 concentration during the first 60‐min period, followed by a plateau. Mean and standard deviation of the conversion rate in the first 60 min were 515.9±50.1 pmol/ml/h (n=69), with a coefficient of variation of 0.097. Although most of the subjects showed comparable conversion rates, 3 subjects had significantly higher conversion rates. In conclusion, the results of this study suggest that the enzyme activity of CCE in human plasma may show inter‐individual variability.
The critical role of type‐1 innate and acquired immunity in tumor immunotherapy
Authors: Ikeda Hiroaki , Chamoto Kenji , Tsuji Takemasa , Suzuki Yoshinori , Wakita Daiko , Takeshima Tsuguhide , Nishimura Takashi
Published: August 2005

The discovery of a large array of tumor antigens has demonstrated that host lymphocytes can indeed recognize and destroy tumor cells as originally proposed in the cancer immunosurveillance hypothesis. Recent reports that led to the cancer immuno‐editing concept also strongly support the immunosurveillance hypothesis, and they further indicate that the host immune system plays a critical role not only in promoting host protection against cancer but also in selecting tumors that can better escape from immune attack. Thus, it is now clear that T cells have the ability to recognize and destroy spontaneously arising tumors. However, the generation of antitumor immunity is often difficult in the tumor‐bearing host because of various negative regulatory mechanisms. Here, we review our recent work on tumor immunotherapy, which utilizes the activation of type‐1 innate and/or acquired immunity as a potent strategy to overcome immunosuppression in the tumor‐bearing host. We have established a variety of tumor therapeutic protocols that aim to activate type‐1 immunity, such as tumor‐vaccine therapy with CpG encapsulated in liposomes, cell therapy using tumor‐specific Th1 cells, and gene therapy using gene‐engineered Th1 cells. We found that CpG encapsulated in liposomes stimulated IL‐12‐producing DC and induced IFN‐γ‐producing NK cells, NKT cells, and tumor‐specific CTL. Th1 cell therapy was also shown to be beneficial for acceleration of APC/Th1 cell‐cell interaction in the DLN, which was critical for inducing tumor‐specific CTL at the tumor site. Therefore, we conclude that the activation of type‐1 innate and acquired immunity is crucial for tumor immunotherapy in order to overcome strong immunosuppression in the tumor‐bearing host.
Promoter hypermethylation of DAP‐kinase is associated with poor survival in primary biliary tract carcinoma patients
Authors: Tozawa Tomohiro , Tamura Gen , Honda Teiichiro , Nawata Shin‐ichi , Kimura Wataru , Makino Naohiko , Kawata Sumio , Sugai Tamotsu , Suto Takayuki , Motoyama Teiichi
Published: August 2005

To clarify the clinicopathological significance of promoter hypermethylation of tumor suppressor and tumor‐related genes in biliary tract carcinomas, we examined the promoter methylation status of multiple genes in primary biliary tract carcinomas. These consisted of carcinomas of the bile duct, gallbladder, and duodenal ampulla. Surgical specimens were obtained from a total of 37 patients with biliary tract carcinoma. The cohort consisted of 23 patients with bile duct carcinoma, 9 patients with gallbladder carcinoma, and 5 patients with ampullary carcinoma. The methylation status of CHFR, DAP‐kinase, E‐cadherin, hMLH1, p16, RASSF1A, and RUNX3 was examined by methylation‐specif ic polymerase chain reaction (MSP). The correlation between methylation status and clinicopathological characteristics was then assessed. The methylation frequencies of CHFR, DAP‐kinase, E‐cadherin, hMLH1, p16, RASSF1A, and RUNX3 genes were 16.2%, 21.4%, 27.0%, 8.1%, 24.3%, 27.0%, and 56.8%, respectively, in primary biliary tract carcinomas. The number of methylated genes per sample was 2.17±0.28 (average±SD) in bile duct carcinomas, 1.80±0.97 in ampullary carcinomas, and 0.89±0.35 in gallbladder carcinomas, with a statistically significant difference between bile duct carcinomas and gallbladder carcinomas (P=0.02). As for clinicopathological significance, patients with a methylated RUNX3 promoter were significantly older than those with unmethylated RUNX3 (P=0.01), and DAP‐kinase methylation was more frequent in poorly differentiated tumors than in well to moderately differentiated ones (P=0.04). The overall survival rate was significantly lower in patients with methylated DAP‐kinase (P=0.009) or RUNX3 (P=0.034) compared to those with unmethylated genes. Furthermore, DAP‐kinase methylation‐positive status was independently associated with poor survival in multivariate analyses (hazard ratio=8.71, P=0.024). A significant proportion of primary biliary tract carcinomas exhibited promoter hypermethylation of tumor suppressor and tumor‐related genes, although bile duct carcinomas are more prone to being affected by promoter methylation than are gallbladder carcinomas. Hypermethylation of DAP‐kinase appears to be a significant prognostic factor in primary biliary tract carcinomas.
Therapeutic drug monitoring of atazanavir: surveillance of pharmacotherapy in the clinic
Authors: Ray John E. , Marriott Debbie , Bloch Mark T. , McLachlan Andrew J.
Published: August 2005

Background

Therapeutic failure with antiretroviral therapy (ART) is a substantial issue where viral rebound, viral resistance and drug‐related toxicity remain serious concerns. Drug exposure‐response relationships have been described for the protease inhibitors, pharmacokinetic variability is substantial for this class of drugs and drug interactions can also alter ART exposure. Given this background we established a therapeutic drug monitoring (TDM) service to monitor atazanavir (ATV) plasma concentrations early after the therapy was made available to treatment‐experienced people infected with HIV who were managed in a clinical setting.

Methods

This was a prospective observational study which evaluated plasma samples from 110 highly treatment‐experienced people with HIV using TDM and applied pharmacokinetic analysis over a five month period.

Results

ATV trough concentrations exhibited substantial intersubject variability (<25–2108 µg l−1). A substantial number of subjects (50%,13/26) who received ATV400 mg daily had low exposure to ATV. Serum bilirubin concentrations correlated significantly with higher ATV trough concentrations (ρ = 0.803; P < 0.001) and 55% (29/53) of subjects who received ATV300/100 mg RTV daily had plasma concentrations above a proposed target concentration associated with elevated bilirubin concentrations. This study confirmed low ATV exposure in eight subjects with HIV receiving ATV 400 mg daily. Reasons for low ATV exposure in this cohort include administration of interacting drugs, including a possible interaction with ritonavir, fluticasone and ATV, impaired ATV absorption secondary to suspected achlorhydria and potential interactions with colchicine and nandrolone. Viral load remained undetectable in most of these subjects with low ATV exposure.

Conclusions

TDM and targeted pharmacokinetic studies should be viewed as fundamental tools in the development and clinical application of ART, to improve pharmacotherapy for people with HIV.
Concomitant use of analgesics and psychotropics in home‐dwelling elderly people‐Kuopio 75 + study
Authors: Hartikainen Sirpa , Mäntyselkä Pekka , Louhivuori‐Laako Kirsti , Enlund Hannes , Sulkava Raimo
Published: August 2005

Aims

To investigate the extent of concomitant use of analgesic and psychotropic medicines among home‐dwelling elderly people aged at least 75 years in Finland.

Methods

This was a population‐based study in Finland, performed as part of Kuopio 75 + study focusing on the clinical epidemiology of diseases, medication and functional capacity. A random sample of 700 persons was drawn from the total population of the city of Kuopio, eastern Finland, aged 75 years on January 1, 1998 (n = 4518). Ninety‐nine persons could not be examined and 78 were living in long‐term institutions, so that the number of home‐dwelling elderly persons amounted to 523. A trained nurse interviewed the participants about their use of medicines, and a geriatrician examined their overall physical and mental status. Dementia and depression were diagnosed according to the DSM IV criteria. Both regular and irregular prescribed and nonprescribed drug use was recorded.

Results

Every fourth elderly person (27.2%) used analgesics and psychotropics concomitantly, this use becoming twice as common with advancing age (19.6% in the age group 75–79 years, 38.2% among the oldest, aged 85 + years). Concomitant use of psychotropics and opioids also became more common with increasing age (2.8% in age group 75–79 years and 9.6% in the oldest group, aged 85 + years). The use of opioids was nearly twice as common among concomitant users (19.7%) than among those using only analgesics (11.3%). Concomitant users suffered from interfering daily pain and daily pain at rest more commonly than nonusers of analgesics. Depression, sleeping problems and polypharmacy were more common among the concomitant users, who had also had more hip fractures than the rest.

Conclusions

Concomitant use of analgesics and psychotropics becomes more common with advancing age and is a potential risk factor for adverse drug effects.
Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain
Authors: Reznikov Igor , Pud Dorit , Eisenberg Elon
Published: August 2005

Aims

Previous research has reported on reduced paw withdrawal latencies to heat and mechanical stimuli after parenteral administration of opioids in animals and on increased pain sensitivity in humans subsequent to postoperative infusions of short‐acting opioids or in drug addicts. The aim of the present study was to explore the possibility that oral opioid treated patients with cancer‐related or chronic nonmalignant pain differ in their pain sensitivity from patients treated with non‐opioid analgesics.

Methods

The study population consisted of 224 patients, including 142 in the opioid‐treated group and 82 in the non‐opioid‐treated group. Pain thresholds for punctuate measured by von Frey filaments (g), mechanical pressure measured by pressure algometer (mmHg), heat stimuli measured by quantitative sensory testing (°C), as well as suprathreshold tonic heat pain intensity (46.5 °C for 1 min) measured by 0–10 numerical pain scale (NPS) were obtained at a nonpainful site (thenar eminence) in all patients.

Results

No differences between the groups were found for gender, age, duration of pain, or duration of treatment (independent variables). No significant differences between the groups were found in punctuate (difference = 17.0 g (95% CI −8.8, 42.8), P = 0.19), pressure (2.2 mmHg (−28.7, 33.2), P = 0.89) and heat (−0.3 °C (−1.5, 0.9), P = 0.70) pain thresholds, or in suprathreshold heat pain intensity (difference between maximal pain intensities −0.4 NPS units (95% CI −1.2, 0.4), P = 0.31). Pearson correlations within the opioid‐treated group failed to show significant relationships between any of the independent variables and the outcome measures. A further comparison of the outcomes between the ‘weak’ opioid‐treated subgroup and the ‘strong’ opioid‐treated subgroup again revealed insignificant results.

Conclusions

These results suggest that the administration of ‘commonly used’ dosages of oral opioids does not result in abnormal pain sensitivity beyond that of patients receiving non‐opioid analgesia.
Ziprasidone decreases cortisol excretion in healthy subjects
Authors: Meier Andreas , Neumann Anna‐Catharina , Jordan Wolfgang , Huether Gerald , Rodenbeck Andrea , Rüther Eckart , Cohrs Stefan
Published: August 2005

Aims

To determine the influence of the atypical antipsychotic ziprasidone on cortisol excretion.

Methods

In a double‐blind, placebo‐controlled, randomized cross‐over design 11 healthy male subjects were studied twice for 2 consecutive nights (N1, undisturbed sleep conditions; N2, exposure to acoustic stress) 5 days apart. Placebo or ziprasidone 40 mg was administered orally 2 h before bedtime on N1 and N2. Urine was collected during three fractionated collection periods (evening; night; morning) for the later determination of cortisol concentrations by standard radioimmunoassays.

Results

Ziprasidone decreased the total amount of cortisol excreted by 4.9 (95% CI 3.3, 6.5) µg during N1 and by 10.8 (95% CI 5.7, 15.8) µg during N2 (P < 0.002). This effect was still detectable in the morning (P < 0.02), with decreases of 5.8 (95% CI −2.8, 14.4) µg after N1 and by 12.1 (95% CI 2.8, 21.4) µg after N2. The effect subsided in the evening. A significant intervention–condition interaction (P < 0.02), was found. The significant increase in cortisol excretion during acoustic stress observed with placebo was absent after treatment with ziprasidone.

Conclusions

The significant decrease in nocturnal cortisol excretion following ziprasidone reflects a decreased activity of the HPA‐axis in healthy subjects. This effect may be an important contributor to the mode of action of ziprasidone in different patient populations, particularly in the treatment of depression and in cognitive impairment in schizophrenia.
Population pharmacokinetics of indinavir alone and in combination with ritonavir in HIV‐1‐infected patients
Authors: Kappelhoff Bregt S. , Huitema Alwin D. R. , Sankatsing Sanjay U. C. , Meenhorst Pieter L. , Van Gorp Eric C. M. , Mulder Jan W. , Prins Jan M. , Beijnen Jos H.
Published: August 2005

Aims

The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir.

Methods

HIV‐1‐infected patients being treated with an indinavir‐containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM).

Results

The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h−1 (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h−1, respectively. An absorption lag‐time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100–400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co‐administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males.

Conclusions

The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non‐nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.
Diversity‐dependent productivity in semi‐natural grasslands following climate perturbations
Authors: KAHMEN A. , PERNER J. , BUCHMANN N.
Published: August 2005

The consequences of globally declining biodiversity and climate change for ecosystem functions are intensively debated topics in ecological research. However, few studies have investigated potential interactions, or the combined effects of both scenarios, for ecosystem functioning. In the work presented here we tested the hypothesis that increasing plant diversity acts as insurance for ecosystem functions during extreme weather events which are predicted by climate change scenarios.

We measured the effect of plant diversity on above‐ and below‐ground productivity in semi‐natural grasslands following experimentally induced early summer drought. To test the insurance hypothesis directly, we determined in each community the range of δ13C values of individual plant species as drought stress indicators.

Increasing plant diversity significantly enhanced below‐ground productivity as a consequence of simulated drought, while above‐ground productivity was reduced independently of plant diversity.

Plants shifting carbon allocation to below‐ground compartments during drought maintain various aspects of ecosystem services and functions. Although we were not able to detect physiological evidence for the insurance hypothesis, we conclude from our below‐ground results that plant diversity is an essential entity of ecosystems for maintaining ecosystem functions in a changing climate.
Factors affecting the expression of inducible defences in Euplotes: genotype, predator density and experience
Authors: DUQUETTE S. L. , ALTWEGG R. , ANHOLT B. R.
Published: August 2005

Inducible defences alter the strength of interaction in food webs. Their effectiveness depends both on the maximum level of induction and the speed at which induction happens. Maximum level and speed of induction should therefore evolve in concert.

We examined the effect of genotype, number of predators and previous exposure to predators on speed and maximum level of induction in a morphological defence expressed by eight clones in three species of the ciliate Euplotes.

Both speed and maximum level of induction, and the reaction to predator density varied among genotypes. These results show that there is genetic variance for all aspects of this inducible defence and the potential for complex evolutionary change under selection.

Higher predator densities led to higher maximum levels of defence and, for one measure of induction speed, more rapid induction. Previous exposure to predators had no detectable effect on either speed or maximum level of induction.

Our results demonstrate that Euplotes can precisely and rapidly adjust their morphological defence to the magnitude of predation risk. The speed of induction and the maximum level of defence varied among genotypes and this will lead to variation in defence level and vulnerability under natural conditions. Variation in prey vulnerability is a key factor promoting stability in food webs.
Competition increasingly dominates the responsiveness of juvenile beech and spruce to elevated CO2 and/or O3 concentrations throughout two subsequent growing seasons
Authors: Kozovits Alessandra R. , Matyssek Rainer , Blaschke Helmut , Göttlein Axel , Grams Thorsten E. E.
Published: August 2005

Saplings of Fagus sylvatica and Picea abies were grown in mono‐ and mixed cultures in a 2‐year phytotron study under all four combinations of ambient and elevated ozone (O3) and carbon dioxide (CO2) concentrations. The hypotheses tested were (1) that the competitiveness of beech rather than spruce is negatively affected by the exposure to enhanced O3 concentrations, (2) spruce benefits from the increase of resource availability (elevated CO2) in the mixed culture and (3) that the responsiveness of plants to CO2 and O3 depends on the type of competition (i.e. intra vs. interspecific).

Beech displayed a competitive disadvantage when growing in mixture with spruce: after two growing seasons under interspecific competition, beech showed significant reductions in leaf gas exchange, biomass development and crown volume as compared with beech plants growing in monoculture. In competition with spruce, beech appeared to be nitrogen (N)‐limited, whereas spruce tended to benefit in terms of its plant N status.

The responsiveness of the juvenile trees to the atmospheric treatments differed between species and was dominated by the type of competition: spruce growth benefited from elevated CO2 concentrations, while beech growth suffered from the enhanced O3 regime. In general, interspecific competition enhanced these atmospheric treatment effects, supporting our hypotheses. Significant differences in root : shoot biomass ratio between the type of competition under both elevated O3 and CO2 were not caused by readjustments of biomass partitioning, but were dependent on tree size.

Our study stresses that competition is an important factor driving plant development, and suggests that the knowledge about responses of plants to elevated CO2 and/or O3, acquired from plants growing in monoculture, may not be transferred to plants grown under interspecific competition as typically found in the field.
Glia maturation factor‐β is produced by thymoma and may promote intratumoral T‐cell differentiation
Authors: Yamazaki H , Tateyama H , Asai K , Fukai I , Fujii Y , Tada T , Eimoto T
Published: August 2005

Aims : To investigate whether Glia maturation factor‐β (GMFB) is expressed in thymomas and is associated with T‐cell development.

Methods and results : We investigated the expression of GMFB by immunohistochemistry in 86 cases of thymoma classified into five type A, 35 type AB, 11 type B1, 26 type B2, and nine type B3 thymomas according to the World Health Organization classification system. Immunoblotting and in situ hybridization (ISH) studies were also performed in selected cases. The results of the immunoblot analysis were in accordance with those of immunohistochemical scoring. The ISH study ascertained the tumour cells producing the protein. Immunohistochemically, GMFB expression was observed in one (20%) of type A, 32 (80%) of type AB, all (100%) of type B1 and B2, and eight (89%) of type B3 thymoma with statistically significant differences between type A and type AB, type B1, or type B2 thymoma, and between type B3 and type AB or type B2 thymoma. There was a significant correlation between GMFB expression and the amount of accompanying non‐neoplastic T cells. GMFB promoted T‐cell differentiation into CD4–/CD8+ cells when analysed by two‐colour flow cytometry.

Conclusions : The present study suggests that T‐cell development in thymoma may be maintained partly by GMFB produced by the tumour cells.
Reconstruction of the colonization of southern Madagascar by introducedRattus rattus
Authors: Hingston Melanie , Goodman Steven M. , Ganzhorn Jörg U. , Sommer Simone
Published: August 2005

Aim Description of the genetic differentiation ofRattus rattuspopulations in southern Madagascar. Reconstruction of the colonization pattern ofR. rattusin southern Madagascar and of the origin of introducedR. rattus.

Location Southern Madagascar.

Methods We analysed the variation in the non‐coding hypervariable region 1 (HVR I) of the mitochondrial control region in 93 individuals from six different sampling sites. The origin of the introduced individuals was examined by comparing MalagasyR. rattussequences to data available from outside Madagascar.

Results Thirteen distinct mtDNA control region haplotypes (H1–H13) were distinguished. Only 11 sites (2.6%) were variable within a 419‐bp sequence. Three haplotypes were shared between the sampling areas, though only one haplotype was ubiquitous accounting for 63.4% of all individuals. Population genetic differences (ΦST) between sampling sites ranged from 0.13 to 0.31.amovaresults showed that the majority of variation (86.1%) was assigned to diversity within populations. Except for twoR. rattussequences from India, all other outgroup samples (New York, Great Britain, France and French Polynesia) belonged to an identical haplotype.

Main conclusions The spatial distribution and frequency of haplotypes and associated phylogenetic analysis provisionally suggest the Tolagnaro harbour as the place of the founder population from whichR. rattusspread into southern Madagascar. Given currently available samples, these populations are most closely related to rats from the Indian subcontinent. Corroboration of each of these hypotheses will require additional geographical sampling, particularly from northern Madagascar and Africa.
Cigarette smoking and the risk of goitre and thyroid nodules amongst parous women
Authors: GALANTI M. R. , GRANATH F. , CNATTINGIUS S. , EKBOM‐SCHNELL A. , EKBOM A.
Published: August 2005

Objectives.  To clarify the mechanisms by which smoking is associated to toxic and nontoxic goitre and thyroid nodules.

Design.  Cohort study.

Setting.  Sweden.

Subjects.  A cohort of 874 507 parous women identified through the Medical Birth Registry, with smoking behaviour assessed through self‐reported information at the first pre‐natal visit, and follow‐up between 1983 and 1997.

Main outcome measures.  Hospital diagnoses of toxic and nontoxic goitre and thyroid nodules, identified by record‐linkage with the national Inpatient Registry. Cox regression was employed to estimate the hazard ratio (HR) of smokers compared with nonsmokers and the corresponding 95% confidence limits (CL).

Results.  There was a significantly increased risk of goitre and nodules amongst smokers. The positive association was stronger for toxic (age adjusted HR = 1.94, CL = 1.74–2.16) than for nontoxic goitre and nodules (age‐adjusted HR = 1.26; CL = 1.14–1.38). There was generally no clear risk trend with regard to amount smoked (below and above 10 cigarettes per day). Elevated body mass attenuated these associations, whilst being born in Swedish areas of endemic goitre enhanced the association with nontoxic goitre and nodules.

Conclusions.  Smoking enhances the risk of thyroid goitre and nodules requiring hospital admission. Iodine deficiency and body weight are likely to be important modifiers of the risk of thyroid hyperplastic diseases amongst smokers.
NmlR ofNeisseria gonorrhoeae: a novel redox responsive transcription factor from the MerR family
Authors: Kidd Stephen P. , Potter Adam J. , Apicella Michael A. , Jennings Michael P. , McEwan Alastair G.
Published: August 2005

A MerR‐like regulator (NmlR –NeisseriamerR‐likeRegulator) identified in theNeisseria gonorrhoeaegenome lacks the conserved cysteines known to bind metal ions in characterized proteins of this family. Phylogenetic analysis indicates that NmlR defines a subfamily of MerR‐like transcription factors with a distinctive  pattern  of  conserved  cysteines  within their primary structure. NmlR regulates itself and three other genes inN. gonorrhoeaeencoding a glutathione‐dependent dehydrogenase (AdhC), a CPx‐type ATPase (CopA) and a thioredoxin reductase (TrxB). AnnmlRmutant lacked the ability to survive oxidative stress induced by diamide and cumene hydroperoxide. It also had >  50‐fold lower NADH‐S‐nitrosoglutathione oxidoreductase activity consistent with a role for AdhC in protection against nitric oxide stress. The upstream sequences of the NmlR regulated genes contained typical MerR‐like operator/promoter arrangements consisting of a dyad symmetry located between the −35 and −10 elements of the target genes. The NmlR target operator/promoters were cloned into a β‐galactosidase reporter system and promoter activity was repressed by the introduction of NmlRin trans. Promoter activity was activated by NmlR in the presence of diamide. Under metal depleted conditions NmlR did not repress PAdhC(or PCopA) promoter activity, but this was reversed in the presence of Zn(II), indicating repression was Zn(II)‐dependent. Analysis of mutated promoters lacking the dyad symmetry revealed constitutive promoter activity which was independent of NmlR. Gel shift assays further confirmed that NmlR bound to the target promoters possessing the dyad symmetry. Site‐directed mutagenesis of the four NmlR cysteine residues revealed that they were essential for activation of gene expression by NmlR.
A non‐RD1 gene cluster is required for Snm secretion in Mycobacterium tuberculosis
Authors: MacGurn Jason A. , Raghavan Sridharan , Stanley Sarah A. , Cox Jeffery S.
Published: August 2005

The Snm secretion system is a crucial virulence determinant of Mycobacterium tuberculosis. Genes encoding all known components of this alternative secretion pathway are clustered at the same genetic locus, known as RD1. Here, we show that a mutant M. tuberculosis strain containing a transposon insertion in the Rv3615c gene, which is situated outside the RD1 locus, results in loss of Snm secretion. Complementation analysis revealed that both Rv3615c and the downstream gene Rv3614c are required for Snm secretion. Thus, we have renamed the two genes snm9 and snm10 respectively. The snm9::Tn mutant phenocopies bona fide snm mutants, exhibiting attenuation in mice, macrophage growth defects and failure to suppress cytokine induction. Furthermore, yeast two‐hybrid analysis revealed a physical interaction between Snm10 and Snm7 (Rv3882c), suggesting that Snm10 may function in complex with other Snm proteins during secretion. Thus, snm9 and snm10 are the first genes located outside the RD1 locus identified as critical components of Snm secretion. These data indicate that Snm secretion consists of an elaborate network of interactions that likely arose from multiple  duplication  events  during  the  evolution  of M.  tuberculosis.
An investigation of folate‐related genetic factors in the determination of birthweight
Authors: Relton Caroline L. , Pearce Mark S. , Burn John , Parker Louise
Published: August 2005

Recent evidence suggests that maternal folate status in early gestation is a significant determinant of infant birthweight. Folate metabolism is known to be controlled by genetic factors, with a number of polymorphic variations in folate metabolising genes identified, several of which have well‐documented functional effects. The current study investigated whether folate‐related polymorphic variation, in association with low maternal folate status, influences birthweight. Red blood cell (RBC) folate analysis and genotyping of five polymorphisms in folate‐related genes [Methylenetetrahydrofolate reductase (MTHFR) 677C>T; MTHFR 1298A>C; cystathionine‐β‐synthase (CβS) 844ins68bp; serine hydroxymethyltransferase (SHMT) 1420C>T; reduced folate carrier‐1 (RFC‐1) 80G>A] were undertaken in mothers and infants from 998 pregnancies. These data were analysed in relation to infant birthweight, adjusted for gender and gestational age (z‐score).

Low maternal RBC folate status was associated with reduced infant birthweight. None of the genetic variants studied showed an independent association with infant birthweight. However, two genetic variants were shown to have a significant effect on birthweight when found in association with low maternal RBC folate status. When individuals with variant genotypes and mothers with folate in the lowest quintile were compared with wild‐type individuals and mothers with folate in the highest quintile, the following differences in mean birthweight (z‐score) were observed; maternal MTHFR 677C>T (−0.56 [95% CI −1.00, −0.12]P = 0.01) and infant CβS 844ins68bp (−0.71 [95% CI −1.97, −0.07]P = 0.03). The findings of this study suggest that folate‐related genetic polymorphisms do not directly influence infant birthweight. However, when placed on a background of deficient maternal nutritional status, they may detrimentally affect fetal growth.
Changing patterns of inequality in birthweight and its determinants: a population‐based study, Scotland 1980–2000
Authors: Fairley Lesley
Published: August 2005

Birthweight is used as an indicator of individual and population health and is known to be strongly correlated with adult cardiovascular disease. This paper uses routinely collected maternity discharge data from Scotland between 1980 and 2000 to look at birthweight trends and the changes in the distribution of maternal risk factors for birthweight. We also examine the contributions of each of the risk factors to birthweight trends and investigate whether there has been a reduction in inequality in birthweight over time. Data from 1 282 172 singleton live births were used in the analysis. Both mean birthweight and low birthweight (LBW: < 2500 g) were used as outcomes. The risk factors studied were maternal age, parity, maternal height, marital status and occupational social class of the father. The slope and relative indices of inequality were used to measure the change in inequalities over time.

Mean birthweight increased from 3320 g in 1980 to 3410 g in 2000, while the percentage LBW decreased slightly from 5.7% in 1980 to 5.4% in 2000. The prevalence of many risk factors changed; there has been an increase in the proportion of older mothers, single mothers, taller mothers and mothers with undetermined social class. Although most risk factors had a significant change in effect over time, the inequalities in birthweight between groups did not appear to diminish over time. Both the slope and relative index of inequality had a quadratic relationship over time, with the inequalities in birthweight being greatest in the early 1980s and late 1990s.
Lifespan and patterns of accumulation and mobilization of nutrients in the sugar‐fed phorid fly, Pseudacteon tricuspis
Authors: Fadamiro Henry Y. , Chen LI , O. Onagbola Ebenezer , Graham Lawrence ‘FUDD’
Published: August 2005

Abstract.  The effect of sugar feeding on the survival of adult phorid fly Pseudacteon tricuspis is investigated. Flies fed 25% sucrose in aqueous solution continuously throughout their lifespan have greater longevity (mean ± SE longevity: female = 7.9 ± 0.8 days, male = 8.9 ± 0.9 days) than completely starved (provided no water and no sugar solution) flies, sugar‐starved (provided water only) flies, or flies fed sugar solution only on their first day of adult life. Completely starved flies rarely lived beyond one day. Provision of water increases longevity by 2 days, and one full day of sugar feeding further increases longevity by an additional 1–2 days. Flies fed 50% sucrose have similar survivorship as those fed 25% sucrose. The temporal patterns of nutrient accumulation and utilization are also compared in P. tricuspis fed different diets: sugar‐starved, sucrose‐fed on the first day of adult life only, and sucrose‐fed continuously. Adult P. tricuspis emerge with no gut sugars, and only minimal amounts of body sugars and glycogen. Although the levels of body sugars and glycogen decline gradually in sugar‐starved flies, a single day of sugar feeding results in the accumulation of maximum amounts of gut sugars, body sugars and glycogen. High levels of these nutrients are maintained in female and male phorid flies fed on sucrose continuously over the observation period, whereas nutrient levels decline in flies fed only on the first day of life, beginning 1 day postfeeding. Female and male P. tricuspis emerge with an estimated 12.3 ± 2.3 and 7.2 ± 1 g of lipid reserves per fly, respectively. These teneral amounts represent the highest lipid levels detected in adult flies, irrespective of their diet, and are maintained over the life times of sucrose‐fed female and male flies, but declined steadily in sugar‐starved females. These data suggest that adult P. tricuspis are capable of converting dietary sucrose to body sugars and glycogen, but not lipids.
Population history and its impact on medical genetics in Quebec
Authors: Laberge A‐M , Michaud J , Richter A , Lemyre E , Lambert M , Brais B , Mitchell GA
Published: August 2005

Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French‐Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle‐France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix–Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French‐Canadian‐type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).
Choice of oxytocic preparation for routine use in the management of the third stage of labour: an overview of the evidence from controlled trials
Authors: ELBOURNC DIANA , CHALMERS IAIN , PRENDIVILLE WAITER
Published: August 2005

Summary. Prophylactic use of oxytocics reduces the risk of postpartum haemorrhage by about 40%. The analysis presented in this paper assesses which oxytocic preparation is associated with the least risk of postpartum haemorrhage and examines the relative effects of different preparations on the length of the third stage, the risk of manual removal of the placenta, blood pressure and other side‐effects. A mixture of oxytocin and ergometrine (Syntometrine) appears to be the safest and most effective prophylactic of the alternatives which have been compared, but the quality of the evidence is not satisfactory. There is scope for a randomized comparison of Syntometrine with oxytocin to obtain unbiased and more precise estimates of their relative effects on postpartum haemorrhage, blood pressure and unpleasant side‐effects.
Magnetic resonance imaging (MRI) in obstetrics. I. Maternal anatomy
Authors: POWELL M. C. , WORTHINGTON B. S. , BUCKLEY J. M. , SYMONDS E. M.
Published: August 2005

Summary. We assessed the ability of magnetic resonance, a recently introduced imaging technique, to demonstrate the maternal anatomy in obstetrics. The signal intensity of different maternal tissues using T1 and T2 weighted sequences was examined. The bony pelvis is depicted with sufficient clarity to provide an alternative to conventional X‐ray pelvimetry. The placenta and cervix have a distinctive appearance facilitating the diagnosis of placenta praevia. The unique demonstration of cervical morphology will offer the potential for investigation into the illunderstood conditions of cervical dystocia and cervical incompetence.
Magnetic resonance imaging (MRI) in obstetrics. II. Fetal anatomy
Authors: POWELL M. C. , WORTHINGTON B. S. , BUCKLEY J. M. , SYMONDS E. M.
Published: August 2005

Summary. Magnetic resonance imaging (MRI) was performed in 36 patients at between 10 and 38 weeks gestation to determine the fetal anatomy that could be identified at different gestations. Fetal motion significantly degraded the image quality in the first and second trimesters, but in the final trimester fetal anatomy was clearly demonstrated. T2 weighted sequences showed the fetal brain and lungs to have a high signal intensity. Shorter TR leading to a T1 weighting gave better resolution of the overall anatomy. MRI has revealed the potential for assessment of lung maturity and the growth‐retarded fetus.
Pulmonary metastases in gestational trophoblastic disease: a review of 97 cases
Authors: KUMAR JOTHI , ILANCHERAN A. , RATNAM S. S.
Published: August 2005

Summary. Metastatic gestational trophoblastic disease poses problems in diagnosis and management and has a poorer prognosis than the nonmetastatic variant. The lung is the most common site of metastases. This paper reviews 97 patients with pulmonary metastasis developing after gestational trophoblastic disease who were seen at one centre over 26 years. Most patients had an antecedent molar pregnancy but an associated choriocarcinomatous lesion in the uterus was absent in the majority. In many patients the pulmonary lesion was asymptomatic. Whilst chemotherapy was the treatment of choice, selective thoracotomy in cases with solitary lung nodules reduced the treatment time and need for aggressive multi‐drug combination regimens. The overall survival rate at 2 years after diagnosis was 65%. A higher mortality was found when the antecedent pregnancy ended at term, when the time interval between the preceding pregnancy and diagnosis of pulmonary metastases was > 1 year, when multiple pulmonary secondaries were present or when cerebral metastases occurred. The main causes of death were cerebral haemorrhage, respiratory failure and pulmonary embolism.
A study comparing transcervical with transabdominal chorionic villus sampling (CVS)
Authors: MACKENZIE WILLIAM E. , HOLMES DEBORAH S. , NEWTON JOHN R.
Published: August 2005

Summary. Chorionic villus sampling (CVS) was performed in 50 anaesthetized patients before therapeutic abortion by the transabdominal route and then by the transcervical route. The two methods of villus sampling were equally successful in obtaining villi but the transcervical method was significantly better at obtaining chorionic villi >10 mg in weight (x2 13·92 P<0·001). Placental position did not affect villus recovery with either sampling method.
Plasma corticotrophin‐releasing factor (CRF) in abnormal pregnancy
Authors: WOLFE C. D. A. , CAMPBELL E. A. , ANDERSON J. , JONES M. T. , PATEL S. P. , DORNHORST A. , LINTON E. A. , LOWRY P. J.
Published: August 2005

Summary. Maternal plasma levels of cortiocotrophin‐releasing factor (CRF) have been measured in abnormal pregnancy states to assess their potential as biochemical markers for at‐risk pregnancies. CRF levels were not significantly altered in patients with hydatidiform mole, polyhydramnios or diabetes. CRF levels were elevated in pregnancies complicated by accidental antepartum haemorrhage at 28 weeks (P<0·03) but not for the rest of the third trimester. In twin pregnancies CRF levels were significantly raised throughout the third trimester (28–32 weeks, P<0·01; 34–36 weeks, P<0·001). In patients with pregnancy‐induced hypertension (28 weeks, P<0·001; 32–36 weeks, P<0·001; and 38–40 weeks, P<0·01), preterm labour and premature rupture of the membranes (28 weeks, P<0·004; 30–32 weeks, P<0·002; and 34–36 weeks, P<0·001), CRF levels were significantly raised and in some patients levels were elevated 11 weeks before the onset of signs or symptoms. These observations raise the possibility that maternal CRF measurement may be of use as a predictive indicator of certain at‐risk pregnancies.
Vaginal cones: a conservative method of treating genuine stress incontinence
Authors: PEATTIE A. B. , PLEVNIK S. , STANTON S. L.
Published: August 2005

Summary. A set of weighted vaginal cones designed to exercise the pelvic floor muscles was used by a group of 39 premenopausal patients with genuine stress incontinence who were awaiting corrective surgery. The effectiveness of the exercises in reducing urinary loss was assessed with a standard urine pad test before and after 1 month of training. Of the 30 women who completed 1 month of the exercises 70% felt they were improved or cured and 90% found it an acceptable method of treatment. Of the 30 women only 11 (37%) opted for surgery after training. There was a highly significant correlation (P<0·001, rs= ‐0·21) between decreased urine loss and increase in retained cone weight.
Maternal blood viscosity and uteroplacental blood flow velocity waveforms in normal and complicated pregnancies
Authors: STEEL S. A. , PEAKCE J. M. F. , NASH G. , CHRISTOPHER B. , DORMANDY J. , BLAND J. M.
Published: August 2005

Summary. According to the Poiseuille‐Hagen law, viscosity influences flow resistance. A possible effect of blood viscosity upon the resistance index of the uteroplacental circulation as measured by continuous wave Doppler ultrasound was investigated in 50 pregnant women. It was found that blood viscosity variables explained only about 10% of the variation in the resistance index in all patients, which was not statistically significant. It is suggested, therefore, that the vascular contribution to flow resistance may be more important.