bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute effects of cocaine in two models of inhibitory control: implications of non‐linear dose effects
Authors: Fillmore Mark T. , Rush Craig R. , Hays Lon
Published: July 2006

Aims  This study examined dose–response effects of oral cocaine on the inhibitory control of behavior in adult cocaine users using two different behavioral models of inhibitory control.

Design  Adults (n = 12) with a history of cocaine use performed the stop‐signal and cue‐dependent go–no‐go task to measure inhibitory control of behavior in response to a range of oral cocaine HCl doses (0, 100, 200 and 300 mg).

Findings  Although both tasks showed cocaine‐induced facilitation of inhibitory control, dose–response functions differed depending on the measures. The stop‐signal measure revealed a quadratic dose–response function and the cued go–no‐go measure showed a more orderly, linear improvement as a function of dose.

Conclusions  The evidence suggests a two‐phasic dose–response in which facilitating effects of stimulant drugs on inhibitory control might be limited to a range of intermediate doses, above which improvement is no longer evident and impairing effects could possibly emerge.
Prenatal marijuana exposure contributes to the prediction of marijuana use at age 14
Authors: Day Nancy L. , Goldschmidt Lidush , Thomas Carrie A.
Published: July 2006

Aim  To evaluate the effects of prenatal marijuana exposure (PME) on the age of onset and frequency of marijuana use while controlling for identified confounds of early marijuana use among 14‐year‐olds.

Design  In this longitudinal cohort study, women were recruited in their fourth prenatal month. Women and children were followed throughout pregnancy and at multiple time‐points into adolescence.

Setting and participants  Recruitment was from a hospital‐based prenatal clinic. The women ranged in age from 18 to 42, half were African American and half Caucasian, and most were of lower socio‐economic status. The women were generally light to moderate substance users during pregnancy and subsequently. At 14 years, 580 of the 763 offspring–mother pairs (76%) were assessed. A total of 563 pairs (74%) was included in this analysis.

Measurements  Socio‐demographic, environmental, psychological, behavioral, biological and developmental factors were assessed. Outcomes were age of onset and frequency of marijuana use at age 14.

Findings  PME predicted age of onset and frequency of marijuana use among the 14‐year‐old offspring. This finding was significant after controlling for other variables including the child’s current alcohol and tobacco use, pubertal stage, sexual activity, delinquency, peer drug use, family history of drug abuse and characteristics of the home environment including parental depression, current drug use and strictness/supervision.

Conclusions  Prenatal exposure to marijuana, in addition to other factors, is a significant predictor of marijuana use at age 14.
How many drinks does it take you to feel drunk? Trends and predictors for subjective drunkenness
Authors: Kerr William C. , Greenfield Thomas K. , Midanik Lorraine T.
Published: July 2006

Aims To describe and model the sources of the variation and trends in the meaning of subjective drunkenness.

Design Trend analyses of three cross‐sectional surveys.

Setting US general population.

Participants Those who report being drunk in the past year among those in the 1979, 1995 and 2000 National Alcohol Surveys.

Measurements Number of drinks reported to feel drunk (dependent variable), past‐year alcohol consumption measures, beverage preference, state drunk driving blood alcohol concentration (BAC) limit and demographics.

Findings The mean reported number of drinks to feel drunk declined significantly between each survey and was significantly lower for women. Considerable variation was also found within surveys and was explained partially by available variables. Volume of alcohol and heavy drinking occasions were associated positively with the number of drinks to feel drunk. Higher educational attainment was associated negatively as was being a wine drinker, of older age, of African American ethnicity and of becoming drunk more frequently than once per month. Living in a state with aper seBAC limit of 0.08% was associated negatively in models for men.

Conclusions A substantial shift downward in the meaning of drunkenness occurred in the US between 1979 and 2000. This may be explained partly by the increase in educational attainment, the ageing of the population, the decline in per capita alcohol consumption and changes in alcohol policy towards lower BAC limits for drunk driving along with greater penalties, enforcement and awareness.
Ethyl glucuronide in hair: is it a reliable marker of chronic high levels of alcohol consumption?
Authors: Politi Lucia , Morini Luca , Leone Fabio , Polettini Aldo
Published: July 2006

Aims  This study aims to investigate the relationship between ethanol daily intake (EDI) and the levels of ethyl glucuronide in hair.

Design  Ethyl glucuronide concentration was determined in hair samples from different classes of ethanol drinkers and results were compared with the reported information about drinking habits.

Setting  Pavia, Italy.

Participants  Twenty‐two known alcoholics, 21 volunteers self‐reporting an EDI from 2 to 60 g, and seven teetotallers were involved in this study.

Measurements  Ethyl glucuronide determination in hair samples was performed by liquid chromatography‐tandem mass spectrometry (limit of detection: 2 pg/mg, lower limit of quantification: 3 pg/mg).

Findings  Current known alcoholics (n = 21) had ethyl glucuronide hair concentration in the range 4.0–434.7 pg/mg (average: 62.8, median 37.4 pg/mg); ethyl glucuronide was not detected in hair samples from teetotallers (n = 7); all volunteers reporting an EDI of at least 30 g (‘non‐moderate drinkers’ according to the US Department of Health and Human Services) tested positive for ethyl glucuronide (cut‐off: 4 pg/mg). All volunteers declaring an ethanol daily intake higher than 40 g (‘heavy drinkers’ according to the World Health Organization, Regional Committee for Europe) tested positive for this compound (cut‐off: 5 pg/mg). The application of a cut‐off of either 4 pg/mg or 5 pg/mg resulted in one false positive, coming from a volunteer asserting an ethanol daily intake of 30 g. No false negatives were found.

Conclusions  The concentration of ethyl glucuronide in hair appears to correlate with EDI.
Alcohol consumption and out‐patient services utilization by abstainers and drinkers
Authors: Baumeister Sebastian E. , Schumann Anja , Nakazono Terry T. , Alte Dietrich , Friedrich Nele , John Ulrich , Völzke Henry
Published: July 2006

Aims  Previous studies have found that abstainers utilize out‐patient health services more than alcohol consumers. The aim of this study was to investigate this relationship further by including several confounding variables and effect modifiers. It was hypothesized that abstainers utilize more health services because they have less social resources, practice more risky health behaviours, have poorer self‐reported health and suffer more from chronic diseases.

Design and participants  Cross‐sectional health survey of a random sample of adults aged 20–64 in Pomerania, Germany. The response rate was 68.8%. Alcohol consumption was assessed using a quantity–frequency measure and categorized into past‐year abstainers, low‐risk, medium‐risk and high‐risk drinkers. Confounders and effect modifiers included socio‐demographic and health‐related variables.

Findings  Abstainers had a 43% higher rate (rate ratio = 1.43, 95% CI = 1.24, 1.63) of physician visits compared to low‐risk drinkers, adjusting for age and gender. Medium‐risk and high‐risk drinkers did not differ from low‐risk drinkers in terms of out‐patient visits. Further regression adjustment for socio‐economic covariates, self‐reported health status and chronic diseases suggested that abstainers used more out‐patient services because they were more ill than drinkers. The effect of mental health status and the number of chronic diseases on out‐patient visits was greater for abstainers than drinkers.

Conclusions  The relation between alcohol consumption and out‐patient services is explained partly by poorer health among the abstainers. Further research is needed to affirm these results, such as transferring this evidence to the utilization of in‐patient health services.
Review article: scoring systems for assessing prognosis in critically ill adult cirrhotics
Authors: CHOLONGITAS E. , SENZOLO M. , PATCH D. , SHAW S. , HUI C. , BURROUGHS A. K.
Published: July 2006

Background

Cirrhotic patients admitted to intensive care units (ICU) still have poor outcomes. Some current ICU prognostic models [Acute Physiology and Chronic Health Evaluation (APACHE), Organ System Failure (OSF) and Sequential Organ Failure Assessment (SOFA)] were used to stratify cirrhotics into risk categories, but few cirrhotics were included in the original model development. Liver‐specific scores [Child‐Turcotte‐Pugh (CTP) and model for end‐stage liver disease (MELD)] could be useful in this setting.

Aim

To evaluate whether ICU prognostic models perform better compared with liver‐disease specific ones in cirrhotics admitted to ICU.

Methods

We performed a structured literature review identifying clinical studies focusing on prognosis and risk factors for mortality in adult cirrhotics admitted to ICU.

Results

We found 21 studies (five solely dealing with gastrointestinal bleeding) published during the last 20 years (54–420 patients in each). APACHE II and III, SOFA and OSF had better discrimination for correctly predicting death compared with the CTP score. The MELD score was evaluated only in one study and had good predictive accuracy [receiver operator characteristic (ROC) curve: 0.81). Organ dysfunction models (OSF, SOFA) were superior compared with APACHE II and III (ROC curve: range 0.83–0.94 vs. 0.66–0.88 respectively). Cardiovascular, liver and renal system dysfunction were more frequently independently associated with mortality.

Conclusions

General‐ICU models had better performance in cirrhotic populations compared with CTP score; OSF and SOFA had the best predictive ability. Further prospective and validation studies are needed.
Transient elastography: a valid alternative to biopsy in patients with chronic liver disease
Authors: GÓMEZ‐DOMÍNGUEZ E. , MENDOZA J. , RUBIO S. , MORENO‐MONTEAGUDO J. A. , GARCÍA‐BUEY L. , MORENO‐OTERO R.
Published: July 2006

Background

Transient elastography is a novel and non‐invasive technique for the evaluation of fibrosis in chronic liver disease. Few studies that exist value the efficacy of transient elastography, mainly in hepatitis C virus‐infected patients.

Aim

To evaluate the effectiveness, objectivity, reproducibility and safety of this technique.

Methods

We included 103 consecutive patients who underwent a liver biopsy in the last 48 months with a wide spectrum of chronic liver diseases. Median stiffness value (expressed as kilopascals – kPa) was kept as representative of the liver elastic modulus. All biopsy specimens were analysed by the same pathologist according to the METAVIR scoring system.

Results

Median value of stiffness in patients with mild or moderate fibrosis (FI and FII), and severe fibrosis or cirrhosis (FIII and FIV) was of 7, 4 ± 5 and 16, 4 ± 10 kPa, respectively, with a significant difference between them (P < 0.05). The areas under the receiver operating characteristic curves showed the optimal liver stiffness cut‐off values for each group.

Conclusions

We found a positive correlation between the liver stiffness found by transient elastography and fibrosis stage on biopsy in all patients, independently of the liver disease aetiology. Transient elastography is an easy, quick to perform and safe non‐invasive procedure, reliable for assessing liver fibrosis.
Review article: current and emerging therapies for functional dyspepsia
Authors: SAAD R. J. , CHEY W. D.
Published: July 2006

Functional dyspepsia represents a heterogeneous group of gastrointestinal disorders marked by the presence of upper abdominal pain or discomfort. Although its precise definition has evolved over the last several decades, this disorder remains shrouded in controversy. The symptoms of functional dyspepsia may overlap with those of other functional bowel disorders including irritable bowel syndrome and non‐erosive reflux disease.

There may be coexistent psychological distress or disease complicating its presentation and response to therapy. Given the prevalence and chronicity of functional dyspepsia, it remains a great burden to society. Suspected physiological mechanisms underlying functional dyspepsia include altered motility, altered visceral sensation, inflammation, nervous system dysregulation and psychological distress. Yet the exact pathophysiological mechanisms that cause symptoms in an individual patient remain difficult to delineate. Numerous treatment modalities have been employed including dietary modifications, pharmacological agents directed at various targets within the gastrointestinal tract and central nervous system, psychological therapies and more recently, complementary and alternative treatments.

Unfortunately, to date, all of these therapies have yielded only marginal results. A variety of emerging therapies are being developed for functional dyspepsia. Most of these therapies are intended to normalize pain perception and gastrointestinal motor and reflex function in this group of patients.
Interferon‐α therapy in HBeAg‐negative chronic hepatitis B: a long‐term prospective study from north‐western Greece
Authors: BALTAYIANNIS G. , KATSANOS K. , KARAYIANNIS P. , TSIANOS E. V.
Published: July 2006

Aims

To determine the long‐term response to interferon‐α therapy in patients with hepatitis B e antigen‐negative chronic hepatitis B, and the factors independently associated with response and survival.

Methods

Sixty‐three patients with documented hepatitis B e antigen‐negative chronic hepatitis B treated with interferon‐α for a year were followed‐up for a period of 6 years.

Results

Sustained biochemical and virological response was seen in 34.91% and 33.33% of patients at 6 and 12 months of follow‐up, respectively, and histological improvement in 54.5% of sustained responders compared with non‐responders (7.1%, P = 0.004, chi‐squared test), at 6 months of follow‐up. Multivariate analysis showed that patients with hepatitis B virus‐DNA levels at 6 months of treatment <10 000 copies/mL had a low probability of relapse, compared with those with levels >10 000 copies/mL (P = 0.032). Age (>65 years) and hepatitis B virus‐DNA level at 6 months of treatment (>10 000 copies/mL) were the independent factors for disease progression and survival (P = 0.041 and P = 0.044 respectively). At 6 years, a sustained response was still present in 19.04% of patients and 4.8% of them had developed anti‐HBs.

Conclusion

Hepatitis B virus‐DNA monitoring by quantitative polymerase chain reaction at 6 months of treatment may allow for early prediction of response to interferon‐α, and may serve as an indicator of disease progression in the future.
Review article: evolutionary advances in the delivery of aminosalicylates for the treatment of ulcerative colitis
Authors: COHEN R. D.
Published: July 2006

Ulcerative colitis is a chronic and debilitating disease that involves inflammation of the colonic mucosa. Current therapies aim to reduce the symptom burden of ulcerative colitis and maintain disease quiescence. The standard first‐line treatment for mild‐to‐moderate ulcerative colitis is 5‐aminosalicylate therapy, which is available in oral and rectal (topical) formulations.

While current 5‐aminosalicylate formulations are effective in the majority of patients, they are associated with a number of limitations including inconvenient dosing regimens and poor patient acceptability, which may lead to non‐compliance with prescribed therapy. A variety of improved delivery mechanisms have been developed in an effort to overcome these limitations. Micropellet formulations and high‐dose tablets appear to offer comparable efficacy and tolerability to conventional formulations, although any benefit in terms of long‐term patient compliance remains to be proven. Novel methods of delivery, such as those using a combination of hydrophilic and lipophilic matrices, designed to provide once‐daily dosing in a high‐strength tablet, may offer a significant improvement in the therapy of active and quiescent ulcerative colitis.

This review examines the limitations of current 5‐aminosalicylate formulations and reports on the evolution of novel oral formulations designed to overcome these limitations, maximize patient compliance during both induction and maintenance of quiescence, and optimize overall clinical outcomes.
Clinical features of Japanese male patients with type 1 autoimmune hepatitis
Authors: MIYAKE Y. , IWASAKI Y. , SAKAGUCHI K. , SHIRATORI Y.
Published: July 2006

Background

Recently, unusual patients with autoimmune hepatitis, such as male patients, have increased.

Aim

To assess clinical feature of Japanese males with type 1 autoimmune hepatitis compared with females.

Methods

We investigated consecutive 160 patients with type 1 autoimmune hepatitis, who consisted of 20 males and 140 females, with a median age of 55 (16–79) years.

Results

Compared with females, males had a lower frequency of definite diagnosis according to the revised scoring system proposed by the International Autoimmune Hepatitis Group (40% vs. 85%) and lower serum levels of immunoglobulin G [1932 (1085–3850) mg/dL vs. 2624 (1354–6562) mg/dL]. However, they were similar in age, form of clinical onset, symptomatic concurrent autoimmune disease, human leucocyte antigen DR status and frequency of cirrhosis at the time of diagnosis. The normalization of serum alanine aminotransferase levels within 6 months after the introduction of corticosteroid treatment was lower in males compared with females (73% vs. 93%).

Conclusions

In male patients, a diagnosis of autoimmune hepatitis should be made carefully. In Japanese patients with a dominant frequency of human leucocyte antigen DR4, gender may affect the response to corticosteroid treatment.
A double‐blind, placebo‐controlled investigation of the residual psychomotor and cognitive effects of zolpidem‐MR in healthy elderly volunteers
Authors: Hindmarch Ian , Legangneux Eric , Stanley Neil , Emegbo Steve , Dawson Jean
Published: July 2006

Aim

To assess residual psychomotor and cognitive effects of a modified‐release formulation of zolpidem (zolpidem‐MR), developed to provide sustained hypnotic efficacy during the whole night, compared with placebo and flurazepam.

Methods

Twenty‐four healthy elderly volunteers received four study treatments (zolpidem‐MR 6.25 mg and 12.5 mg, placebo and flurazepam 30 mg) using a randomized, cross‐over, double‐blind design. Residual psychomotor and cognitive effects were assessed with a psychometric test battery. Quality of sleep and residual effects were evaluated subjectively with the Leeds Sleep Evaluation Questionnaire.

Results

Psychometric performance was significantly impaired with flurazepam but not with zolpidem‐MR at either dose. Ease of falling asleep and sleep quality were significantly improved with both doses of zolpidem‐MR and with flurazepam. Neither active drug modified perception of well‐being on awakening.

Conclusion

In elderly subjects, zolpidem‐MR showed no residual functional impairment in psychometric or cognitive tests sensitive to flurazepam,
Evidence for extrathymic T cell maturation after thymectomy in infancy
Authors: Torfadottir H , Freysdottir J , Skaftadottir I , Haraldsson A , Sigfusson G , Ogmundsdottir H M
Published: July 2006

Our previous study showed that children who had been partially or completely thymectomized during heart surgery as infants had lower proportions and numbers of total lymphocytes and reduced proportions of T cells (CD3+), helper T cells (CD4+) and naive T cells (CD3+ CD4+ CD45RA+), but normal proportion of cytotoxic T cells (CD8+). In this study T lymphocytes from a selected group of eight of these children and age- and gender-matched controls were characterized further using flow cytometry to determine phenotypes of T cells and T cell subsets related to T cell regulation and phenotypes suggestive of extrathymic maturation. Immune function was assessed by measuring autoantibodies and antibodies against vaccines. The study group had significantly lower numbers of all the main subsets of T lymphocytes and the composition was different. Thus, the proportions of lymphocytes with the following phenotypes: CD3+, CD2+, CD7+, CD4+, CD62L+, CD4+ CD62L+ and CD4+ CD69– were significantly reduced in the study group compared with the control group, but significantly higher proportions were seen of lymphocytes expressing CD8α+ CD8β– and TCRγδ+ CD8α+ CD8β–. The absolute number and proportion of CD4+ CD25+ cells were reduced but the proportions of the subgroup of naive regulatory T cells (CD4+ CD25+ CD62L+) and non-activated regulatory T cells (CD4+ CD25+ CD69–) were not reduced in the thymectomized children. We conclude that the phenotypic characteristics of T lymphocytes of children who have lost their thymus in infancy are indicative of extrathymic maturation. T regulatory cells appear to be less affected than other subsets by the general reduction in T cell numbers.
The emergence of Beijing family genotypes ofMycobacterium tuberculosisand low-level protection by bacille Calmette–Guérin (BCG) vaccines: is there a link?
Authors: Abebe F , Bjune G
Published: July 2006

The world is confronted with major tuberculosis (TB) outbreaks at a time when the protection of bacillus Calmette–Guérin (BCG) vaccine has become inconsistent and controversial. Major TB outbreaks are caused by a group of genetically similar strains of Mycobacterium tuberculosis (Mtb) strains, including the Beijing family genotypes. The Beijing family genotypes exhibit important pathogenic features such high virulence, multi-drug resistance and exogenous reinfection. These family strains have developed mechanisms that modulate/suppress immune responses by the host, such as inhibition of apoptosis of infected macrophages, diminished production of interleukin (IL)-2, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and elevated levels of IL-10 and IL-18. They demonstrate distinct expression of proteins, such as several species of α-crystallin (a known Mtb virulence factor), but decreased expression of some antigens such as heat shock protein of 65 kDa, phosphate transport subunit S and a 47-kDa protein. In addition, the Beijing family strains specifically produce a highly bioactive lipid (a polyketide synthase)-derived phenolic glycolipid. This altered expression of proteins/glycolipids may be important factors underlying the success of the Beijing family strains. The Beijing family strains are speculated to have originated from South-east Asia, where BCG vaccination has been used for more than 60 years. The hypothesis that mass BCG vaccination may have been a selective factor that favoured genotypic and phenotypic characteristic acquired by the Beijing family strains is discussed.
Effect of kidney transplantation on bone
Authors: Kodras K. , Haas M.
Published: July 2006

A broad range of different factors aggravates renal osteodystrophy, which is present in virtually all patients with chronic kidney disease and after successful kidney transplantation. Altered hormonal status, including sex hormones and parathyroid hormone (PTH), a deficit of 1,25(OH)2 vitamin D3(calcitriol), immunosuppressive therapy and post‐operative immobilization contribute to a progressive loss of bone density and structure. The decrease of bone mass is particularly prominent during the first 6 months after kidney transplantation and is associated with an increased number of fractures, both compared with the normal population as well as with dialysis patients. At particular risk are patients with a history of diabetes, long duration of haemodialysis and post‐menopausal women.

To prevent post‐transplant bone loss prescription of steroids should be minimized and withdrawn as early as possible. Additional intake of α‐calcidol [25(OH) vitamin D3] or calcitriol, despite normal serum levels, reduces persistent hyperparathyroidism after kidney transplantation, improves intestinal calcium absorption and activates osteoblasts. Inhibition of osteoclasts by biphosphonate therapy seems to effectively reverse bone loss during the early and late course of kidney transplantation. However, as the majority of transplant recipients have a low‐turnover bone disease, inhibition of osteoclasts, through which bone turnover is impaired, might further reduce osteoblast activity and promote osteoid synthesis.

Most investigations were small‐scale studies with 10–100 participants and a follow up of only 12 months. This makes conclusions on the effect of any intervention on the fracture rate impossible. Larger, randomized multicentre studies investigating bone‐sparing therapy on hard end points are therefore advocated.
Function and effect of bone morphogenetic protein‐7 in kidney bone and the bone‐vascular links in chronic kidney disease
Authors: Mathew S. , Davies M. , Lund R. , Saab G. , Hruska K. A.
Published: July 2006

In two independent and separate studies, we have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreased the serum phosphate. In the first study, the serum Ca PO4, parathyroid hormone (PTH), and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD decreased bone formation rates. More recently, these observations were rediscovered in low‐density lipoprotein receptor null (LDLR‐/–) mice fed high‐fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia and insulin resistance). We demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial calcification. We have also shown that VC is made worse by CKD and ameliorated by bone morphogenetic protein‐7 (BMP‐7). The finding that high‐fat fed LDLR‐/– animals with CKD had hyperphosphatemia which was prevented in BMP‐7‐treated animals lead us to examine the skeletons of these mice. It was found that significant reductions in bone formation rates were associated with high‐fat feeding, and superimposing CKD resulted in the adynamic bone disorder (ABD), while VC was made worse. The effect of CKD to decrease skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The BMP‐7 treatment corrected the ABD and hyperphosphatemia, owing to BMP‐7‐driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action.

Thus, in the metabolic syndrome with CKD, a reduction in bone forming potential of osteogenic cells leads to the ABD producing hyperphosphatemia and VC, processes ameliorated by BMP‐7, in part through increased bone formation and skeletal deposition of phosphate and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury affecting the skeleton before demonstrable hyperphosphatemia and that they are preventable and treatable. Therefore, early intervention in the skeletal disorder associated with CKD is warranted and may affect mortality of the disease.
Vascular calcification and renal osteodystrophy relationship in chronic kidney disease
Authors: Moe S. M.
Published: July 2006

Cardiovascular disease and stroke account for 60–70% of all deaths in patients with end‐stage renal disease (ESRD), at a risk that is 10–20‐fold the age‐ and sex‐matched general population. There is also increased coronary artery calcification and increased cardiovascular mortality in chronic kidney disease (CKD) and dialysis patients compared with the general population. Bone is similarly abnormal in CKD. There is an increased incidence of low bone mass and fractures in dialysis patients compared with the general population. Furthermore, a hip fracture in a dialysis patient is associated with a doubling of the mortality observed in nondialysis patients with a hip fracture. These two problems may be linked, as cross‐sectional studies have demonstrated an inverse relationship between osteoporosis and coronary artery calcification in the general population and in ESRD patients. In vitro and ex vivo, there is clear evidence that vascular calcification is an active cell‐mediated process, made worse by disorders of mineral metabolism. Many factors known to be associated with cardiovascular disease in CKD patients can directly increase calcification in vitro. In addition, in CKD, there are many mechanisms by which bone may adversely affect vascular calcification including disorders of bone remodelling, altered secretion of parathyroid hormone (PTH), hyperphosphatemia, hypercalcaemia, use of calcium based binders, and excessive vitamin D therapy. The coexistence of vascular risk factors and abnormal bone represent a double threat to the well being of patients with CKD.
In situ growth stimulation of a temperate zone liana (Hedera helix) in elevated CO2
Authors: ZOTZ G. , CUENI N. , KÖRNER C.
Published: July 2006

Lianas, which arguably benefit more than other growth forms from elevated CO2, have been associated with increasing turn‐over rates in tropical forests as observed in recent decades. Although rarely as prominent outside the tropics, an increase in abundance of climbing plants is likely to affect forest dynamics in the temperate zone as well. Hedera helix is the most abundant climber in western Europe and previous work in controlled conditions suggested CO2 effects similar to those observed in tropical lianas.

Here we present an in situ test of the hypothesis that this abundant climber will benefit from increasing CO2 concentrations primarily under light limitation in the forest understorey, but much less in the forest canopy. To this end, we studied growth responses to elevated CO2 for an entire growing season at the Swiss Canopy Crane site on the forest floor and 20–25 m above the ground in the forest canopy.

The relative stimulation of length and biomass increment of shoots by elevated CO2 (about 600 µl l−1) was indeed very pronounced in deep shade (c. +60%), about twice as much as in the subcanopy (c. +30%). Given the rapid depletion of non‐structural carbohydrate (NSC) pools at canopy closure in spring, carbon limitation under current ambient CO2 concentrations must be substantial in the understorey. In contrast to the understorey, where CO2 enrichment had no effect on NSC pools, there was a sharp increase in NSC concentration in subcanopy leaves exposed to elevated CO2.

We conclude that rising CO2 concentrations will allow Hedera to explore light‐limited understorey microhabitats more vigorously, which should increase the likelihood of reaching the forest canopy. There, however, Hedera benefits less from elevated CO2. Our results add one more explanation to Hedera's current success in European forests.
Immune challenge reduces reproductive output and growth in a lizard
Authors: ULLER T. , ISAKSSON C. , OLSSON M.
Published: July 2006

A fundamental assumption in evolutionary immunology is that the immune system is costly to develop, maintain or activate.

Two plausible costs of activation of the immune system are decreased resources for growth and reproductive investment. However, few studies have estimated direct effects of an immune challenge, in particular in ectotherm vertebrates. We studied the consequences of an immune challenge in reproductive female dragons,Ctenophorus fordi, and in their offspring by exposing lizards to bacterial lipopolysaccharides (LPS).

The immune challenge led to decreased reproductive investment in terms of egg mass, but with no effect on probability of future reproduction.

Maternal immune challenge did not influence the response of their offspring to the same challenge. However, juveniles that were induced to mount an immune response had a higher thermal preference and showed reduced growth, but the magnitude of the growth effect was dependent on the date of oviposition, indicating maternal effects on offspring immunity.

Our results suggest that costs of immune activation may be important in shaping growth and reproductive strategies in ectotherms.
Presence of shelter reduces maintenance metabolism of juvenile salmon
Authors: MILLIDINE K. J. , ARMSTRONG J. D. , METCALFE N. B.
Published: July 2006

Shelter is of major importance to many animals in providing protection against both the physical environment and potential predators.

We hypothesized that animals without shelter suffer metabolic costs associated with a need for increased vigilance and preparedness to escape attacks from predators or competitors. This possibility was tested by comparing the standard metabolic rates of inactive postdigestive juvenile Atlantic salmon,Salmo salar, held either with or without a shelter, which took the form of a semicircular ledge under which the fish could fit comfortably.

The ledges were semitransparent (so did not substantially reduce light levels) and provided no protection against the minimal water velocities in the testing arena. Nonetheless, absence of ledge shelter resulted in a 30% higher rate of oxygen consumption.

Fish without a ledge shelter typically positioned themselves against vertical walls of the observation arena, which presumably afforded the best available sheltering option, and adopted a significantly darker coloration (indicative of greater stress) than those under ledges. Fish with ledges rested outside and adjacent to rather than beneath the shelter. Therefore, it seems that awareness that a shelter is readily available, rather than the act of sheltering, results in reduced metabolism.

We conclude that the presence of appropriate shelter not only reduces the risk of predation but also provides a metabolic benefit to fish that is likely to have implications for growth performance and activity budgets. Standard metabolic rate can be a function of habitat structure.
Effect of immune serum and role of individual Fcγ receptors on the intracellular distribution and survival of Salmonella enterica serovar Typhimurium in murine macrophages
Authors: Uppington Hazel , Menager Nathalie , Boross Peter , Wood James , Sheppard Mark , Verbeek Sjef , Mastroeni Pietro
Published: July 2006

Immune serum has a protective role against Salmonella infections in mice, domestic animals and humans. In this study, the effect of antibody on the interaction between murine macrophages and S. enterica serovar Typhimurium was examined. Detailed analysis at the single‐cell level demonstrated that opsonization of the bacteria with immune serum enhanced bacterial uptake and altered bacterial distribution within individual phagocytic cells. Using gene‐targeted mice deficient in individual Fc gamma receptors it was shown that immune serum enhanced bacterial internalization by macrophages via the high‐affinity immunoglobulin G (IgG) receptor, Fc gamma receptor I. Exposure of murine macrophages to S. enterica serovar Typhimurium opsonized with immune serum resulted in increased production of superoxide, leading to enhanced antibacterial functions of the infected cells. However, opsonization of bacteria with immune serum did not increase either nitric oxide production in response to S. enterica serovar Typhimurium or fusion of phagosomes with lysosomes.
Altered localization of CXCL13 expressing cells in mice deficient in Pactolus following an inflammatory stimulus
Authors: Hojgaard Andrias , Close Rebecca , Dunn Dianne M. , Weiss Robert B. , Weis Janis J. , Weis John H.
Published: July 2006

The mouse Pactolus gene is an evolutionary paralogue to the CD18/β2 integrin subunit and is preferentially expressed by neutrophils. When first identified, it was assumed Pactolus would function as an adhesion receptor similar to other β integrin subunits. The analysis of mice genetically deficient in Pactolus, however, did not define any lesion in neutrophil migration, adhesion or phagocytosis. Therefore a wider analysis of the Pactolus deficiency was initiated using transcriptional profiling during an inflammatory insult. This screen identified a single transcript, CXCL13, that was elevated in cells from a peritoneal lavage of the wild type animal compared to the Pactolus‐deficient animal. Our analyses confirmed resident macrophages as being responsible for the chemokine using intracellular CXCL13 staining and additional cell markers to phenotypically characterize such cells. The resident CXCL13‐expressing cells (which do not express Pactolus) are functionally distinct from the macrophages recruited into the peritoneal cavity following the inflammatory stimulation since the recruited macrophages do not express detectable levels of the chemokine. The numbers and expression patterns of these resident CXCL13‐expressing cells do not vary in naïve animals of wild type or Pactolus‐deficient origin. Additionally, Pactolus‐deficient neutrophils do not preferentially kill (compared to wild type) CXC13‐expressing macrophages. These data suggest that during an inflammatory response, Pactolus may help retain CXCL13‐expressing cells within the peritoneal environment.
Increased expression of ribosome recycling factor is responsible for the enhanced protein synthesis during the late growth phase in an antibiotic‐overproducing Streptomyces coelicolor ribosomal rpsL mutant
Authors: Hosaka Takeshi , Xu Jun , Ochi Kozo
Published: July 2006

K88E mutation within rpsL, which encodes the S12 ribosomal protein, enhanced the protein synthetic activity of Streptomyces coelicolor during the late growth phase, resulting in overproduction of the deep blue‐pigmented polyketide antibiotic actinorhodin. In vitro cross‐mixing experiments using the ribosomal and S‐150 fractions derived from wild‐type and K88E mutant strains suggested that one or more translation factors are enriched in the mutant's S‐150 fraction, while Western analysis using antibodies against various translation factors revealed ribosome recycling factor (RRF) to be one of the enriched mediators. RRF purified from overexpressing cells stimulated mRNA‐directed green fluorescent protein (GFP) synthesis in an in vitro protein synthesis system. GFP synthesis rates were complemented by RRF addition into wild‐type cell's S‐150 fraction, eliminating the difference between wild‐type and mutant S‐150 fractions. The frr gene encoding RRF was found to be transcribed from two distinct start points (frrp1 and frrp2), and increased expression from frrp1 could account for the elevated level of RRF in the K88E mutant during the late growth phase. Moreover, introduction of a plasmid harbouring a high copy number of frr gene into wild‐type S. coelicolor induced remarkable overproduction of antibiotic, demonstrating that the increased levels of RRF caused by the K88E mutation is responsible for an aberrant stationary‐phase event: overproduction of antibiotic.
The nitrosative stress response of Staphylococcus aureus is required for resistance to innate immunity
Authors: Richardson Anthony R. , Dunman Paul M. , Fang Ferric C.
Published: July 2006

Staphylococcus aureus is a highly virulent human pathogen with an extensive array of strategies to subvert the innate immune response. An important aspect of innate immunity is the production of the nitrogen monoxide radical (Nitric Oxide, NO·). Here we describe an adaptive response to nitrosative stress that allows S. aureus to replicate at high concentrations of NO·. Microarray analysis revealed 84 staphylococcal genes with significantly altered expression following NO· exposure. Of these, 30 are involved with iron‐homeostasis, potentially under the control of the Fur regulator. Another seven induced genes are involved in hypoxic/fermentative metabolism, including the flavohaemoprotein, Hmp. The SrrAB two‐component system has been shown to regulate the expression of many of the NO·‐induced metabolic genes. Indeed, inactivation of hmp, srrAB and fur resulted in heightened NO· sensitivity. Hmp was responsible for c. 90% of measurable staphylococcal NO· consumption and therefore critical for efficient NO· detoxification. While SrrAB was required for maximal hmp expression, srrAB mutants still exhibited significant NO· scavenging and NO·‐dependent induction of hmp. Yet S. aureus lacking SrrAB were more sensitive to nitrosative stress than hmp mutants, indicating that the contribution of SrrAB to NO· resistance extends beyond the regulation of hmp expression. Both Hmp and SrrAB were required for full virulence in a murine sepsis model, however, only the attenuation of the hmp mutant was restored by the abrogation of host NO· production. Thus, the S. aureus Hmp protein has evolved to serve as an iNOS‐dependent virulence determinant.
An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin–piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People's Democratic Republic (Laos)
Authors: Mayxay M. , Thongpraseuth V. , Khanthavong M. , Lindegårdh N. , Barends M. , Keola S. , Pongvongsa T. , Phompida S. , Phetsouvanh R. , Stepniewska K. , White N. J. , Newton P. N.
Published: July 2006

Objective  To determine the efficacy and safety of oral dihydroartemisinin–piperaquine (DP, ArtekinTM) in the treatment of uncomplicated Plasmodium falciparum malaria in southern Laos.

Methods  An open, randomized clinical trial of oral artesunate–mefloquine (AM) vs. DP in 220 patients with acute uncomplicated falciparum malaria in Savannakhet Province, Laos.

Results  The 42‐day cure rates (95% CI), as determined by survival analysis and adjusted for reinfection, were excellent and similar for the two groups [99 (94–100)% and 100 (100–100)% for AM and DP, respectively]. The median (range) fever and parasite clearance times for the AM and DP groups were also similar [20 (4–63) h and 2 (1–4) days vs. 20 (7–57) and 2 (1–4) days, logrank P = 0.4 and 0.17, respectively]. There were more patients with at least one potential side effect following treatment in the AM group when compared with the DP group [64/110 (58%) vs. 48/110 (44%), respectively, P = 0.031].

Conclusion  Dihydroartemisinin–piperaquine did not have superior efficacy to AM for the treatment of uncomplicated falciparum malaria in Laos but was associated with fewer adverse effects.
Cryptic mosaicism for monosomy 20 identified in renal tract cells
Authors: Stefanou E‐G , Crocker M , Boon A , Stewart H
Published: July 2006

We report a post‐natal case of mosaic aneuploidy for chromosome 20 in a 4 months old male baby with an abnormal phenotype including dysmorphic features (asymmetric facial growth), ventricular septal defect, hypotonia and bilateral vesicoureteric reflux. Conventional cytogenetics on peripheral blood showed 1 cell of 200 with 47,XY,+20. Further investigations using fluorescent in situ hybridization (FISH) on a urine sample, with a centromere probe for chromosome 20, revealed 39 of 50 cells giving one signal indicative of monosomy 20. FISH analysis of a buccal smear was consistent with disomy 20 as was conventional cytogenetics on skin fibroblasts. This is the fourth reported case of mosaic monosomy 20, the second case where monosomy 20 is present with a trisomy 20 cell and the first case with each aneuploidy found in two separate tissues. The identification of mosaicism is a difficult task since the abnormal cells can be present only in certain tissues and may disappear with selection as the fetus develops, thus leading to single‐cell abnormalities that may get dismissed (pseudomosaicism). The use of FISH in this case was crucial in identifying the cryptic mosaic monosomy 20 cell line. The likely mechanism of origin is post‐zygotic nondisjunction giving rise to monosomy, disomy and trisomy cell(s) in the same or different tissues. Although no other trisomy 20 cells were found, the abnormal phenotype plus the finding of a monosomy 20 cell line make this mechanism the most plausible explanation. Had we dismissed the single‐cell abnormality, the cryptic mosaicism of monosomy 20 would not have been identified. A detailed analysis of all tissues accessible in conjunction with careful consideration of all clinical information available is the best course of action in suspected mosaicism.
A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2‐q26.31
Authors: Wali A , John P , Gul A , Lee K , Chishti MS , Ali G , Hassan MJ , Leal SM , Ahmad W
Published: July 2006

Congenital alopecia may occur either alone or in association with ectodermal and other abnormalities. On the bases of such associations, several different syndromes featuring congenital alopecia can be distinguished. Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder, clinically characterized by total or partial hair loss and mental retardation. In the present study, a five‐generation Pakistani family with multiple affected individuals with APMR was ascertained. Patients in this family exhibited typical features of APMR syndrome. The disease locus was mapped to chromosome 3q26.2‐q26.31 by carrying out a genome scan followed by fine mapping. A maximum two‐point logarithm of odds (LOD) score of 2.93 at θ= 0.0 was obtained at markers D3S3053 and D3S2309. Multipoint linkage analysis resulted in a maximum LOD score of 4.57 with several markers, which supports the linkage. The disease locus was flanked by markers D3S1564 and D3S2427, which corresponds to 9.6‐cM region according to the Rutgers combined linkage‐physical map of the human genome (build 35) and contains 5.6 Mb. The linkage interval of the APMR locus identified here does not overlap with the one described previously; therefore, this locus has been designated as APMR2.
Expression of wild‐type estrogen receptor β protein in human breast cancer: Specific correlation with HER2/neu overexpression
Authors: Umekita Yoshihisa , Souda Masakazu , Ohi Yasuyo , Sagara Yoshiatsu , Rai Yoshiaki , Takahama Tetsuya , Yoshida Hiroki
Published: July 2006

Expression of estrogen receptor β (ERβ) protein in human breast cancer and correlation with clinicopathological factors have been reported by many investigators, but many of them used ERβ antibodies that react with both wild‐type ERβ (ERβwt) and splicing variant isoform. Therefore, the frequency and correlation with clinicopathological factors of ERβwt expression remain to be established. In the present study a monoclonal antibody EMR02, specific for ERβwt, was used in formalin‐fixed paraffin‐embedded sections from 225 female primary breast cancer patients diagnosed as having invasive ductal carcinoma. Expression of ERα, progesterone receptor (PgR) and HER2/neu were also investigated by immunohistochemistry. For ERβwt, ERα and PgR, positivity was defined as nuclear staining in >10% of the cancer cells. HER2/neu overexpression was defined as a Hercep test score 3+. Positivity for ERβwt, ERα, PgR and HER2/neu overexpression was 55%, 74%, 61% and 25%, respectively. The expression of ERβwt had a positive correlation with ERα (P = 0.018) and PgR (P = 0.02). There was significant positive correlation between ERβwt expression and HER2/neu overexpression (P < 0.0001). According to multivariate logistic regression analysis the most significant association was between ERβwt expression and HER2/neu overexpression (P < 0.0001). These results suggest that clinical significances of ERβwt expression in human breast cancer patients may be more complex.