bluuebunny/crossref_metadata_2025 huggingface dataset:
An injection depot formulation of buprenorphine: extended biodelivery and effects
Authors: Sigmon Stacey C. , Moody David E. , Nuwayser Elie S. , Bigelow George E.
Published: February 2006

Aim  Buprenorphine is an effective medication for treatment of opioid dependence. An injectable depot formulation of buprenorphine has been developed using biodegradable polymer microcapsule technology. This formulation may offer effective treatment of opioid dependence and enhance treatment delivery while minimizing risks of patient non‐adherence or illicit diversion of the medication. This report provides a characterization of the biodelivery of this injectable depot in humans and of the relationship of drug blood levels to pharmacodynamic indices. 

Method and participants  The data are from two studies in which 11 opioid‐dependent volunteers each received a single depot injection containing 58 mg of buprenorphine, and include previously unreported detailed plasma concentration data over a 6‐week time‐course following depot administration and examination of their relationship to pharmacodynamic indices.

Findings  Mean plasma buprenorphine increased gradually following depot administration, peaked at 2–3 days with a mean concentration of 1.25 ng/ml and then decreased gradually, approaching undetectable levels (< 0.10 ng/mL) by 6 weeks. There was substantial between‐subject consistency in several aspects of buprenorphine biodelivery, including time to first detectable blood level (4 hours), peak blood level (2 days) and undetectable blood level (6–6.5 weeks). In contrast, there was marked between‐subject variability in the magnitude of peak buprenorphine concentrations, ranging from 0.17 to 3.47 ng/ml. Extent of opioid blockade was tested by weekly opioid challenges with 3 mg subcutaneous hydromorphone; subjective response and pupillary constriction were related inversely to both buprenorphine and norbuprenorphine plasma concentrations (r = 0.84–0.95).

Conclusion  The data document that this depot formulation provides effective buprenorphine delivery for several weeks and that effects persist even at fairly low buprenorphine plasma concentrations. Suggestions are offered for further research needed to develop this formulation for clinical use as a detoxification and/or maintenance pharmacotherapy for opioid dependence.
‘Handing Over’: transmission of information between nurses in an intensive therapy unit
Authors: Philpin Susan
Published: February 2006

Transferring end of shift information between nurses via both verbal and written routes in an intensive therapy unit (ITU) setting is complex and multifaceted. Some authors have taken ethnographic approaches and explored the verbal handover as an example of a nursing ritual. The written route involves various textual materials, which, in addition to conveying essential information about the patient's status, also represent other messages. This article considers two key areas of end of shift information transmission – verbal bedside handovers and written accounts – arguing that in addition to the manifest purposes of transferring essential information between nurses, both modes of reporting also have important latent functions. It will explore and interpret elements of ritual and symbolism inherent in both forms of handover. The article reports on particular findings from a larger ethnographic study of nursing culture, which was accomplished through participant observation over a 12‐month period in ITU. Subsidiary components of the ethnography were the interviews with 15 nurses and the examination of documentary material. The findings suggest that both verbal and written reports, in addition to ensuring that nurses taking over the care of the patient receive the necessary information to enable them to safely provide continuity of care, also convey essential meanings and articulate group values. Both modes of handover reporting are also visual and/or audible symbolic representations of nursing care in ITU and as such confirm and validate that care, expressing the value of nursing work in this unit.
The nursing role in ICU outreach: an international exploratory study
Authors: Endacott Ruth , Chaboyer Wendy
Published: February 2006

It is widely acknowledged that many critically ill patients are managed outside of designated critical care units. One strategy adopted in Australia and England to assess and manage risk in these patients is the intensive care unit (ICU) outreach or liaison nurse service. This article examines how ICU outreach/liaison roles in Australia and England operate in the context of Manley's theoretical framework for advanced nursing practice. Descriptive case study design using semi‐structured interviews and job descriptions as sources of evidence. Findings of interviews with six Australian ICU Liaison nurses are already published; this study replicated the Australian study with four ICU Consultant Nurses in England and mapped interview and job description data from both countries onto Manley's conceptual framework for advanced practice/consultant nurse. Four themes emerged from the English data: patient interventions, support for ward staff, liaison between ward and ICU staff and hospital‐wide impact. The first three of these comprised the core service common to the roles in both countries. Manley's four subroles (expert practitioner, consultant, educator and researcher) were present across both countries. However, the interview and job description data demonstrated that there were lower expectations in Australia that the roles would lead to staff development and build capacity across the hospital system. Similarly, formal education for ward staff such as ALERT and CRiSP courses were more developed in UK. Our data demonstrate that the role undertaken in England and Australia is sufficiently comparable to use as a research intervention in international studies across the two countries. However, the macro service level differs. Job descriptions across both countries emphasized the need to influence hospital policy; however, the ICU consultant nurses in England might be considered better placed to achieve this through role title and access to the hospital executive. In both countries, the roles would benefit from systematic evaluation of the impact on outcomes. This is particularly important for longer‐term integration of the role in the health services in both countries.
Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma)
Authors: SALLAM H. , MCNEARNEY T. A. , CHEN J. D. Z
Published: February 2006

Gastrointestinal dysmotility in systemic sclerosis (scleroderma) is prevalent in 90% of patients, increasing morbidity and in some cases mortality. The resultant gastrointestinal complications are usually extensive, involving many regions of the gut from the oesophagus to the anus. Collagen replacement of vascular and enteric smooth muscle results in hypomotility, lumen dilatation, tensile rigidity and eventual loss of organ functions.

The aim of this paper is to provide an overview of systemic sclerosis‐related gastrointestinal dysmotility and available/potential therapeutic options.

We evaluated published data on the pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis patients using the MEDLINE database for English and non‐English articles from 1966 to July 2005.

Based on this systematic review, lifestyle and medical therapy approaches are preferred as they often improve and/or ameliorate symptoms. Surgery is only recommended with serious, rare complications such as bowel perforation or ischaemia.

Alternative therapies such as acupuncture‐based therapies are well tolerated, with clinical improvement and may be of potential therapeutic benefit for systemic sclerosis gastrointestinal dysmotility.

Further elucidation of initiating and persistent mechanisms of systemic sclerosis‐related gastrointestinal dysmotility will optimize the development of a multidisciplinary and more directed treatment regimen.
Diverticular disease and migration – the influence of acculturation to a Western lifestyle on diverticular disease
Authors: HJERN F. , JOHANSSON C. , MELLGREN A. , BAXTER N. N. , HJERN A.
Published: February 2006

Background

Diverticular disease of the colon is more common in the Western world, compared with non‐Western countries.

Aim

To investigate the risk of diverticular disease in immigrants of diverse ethnicity and in different phases of acculturation.

Methods

Socio‐demographic indicators and the risk of diverticular disease were investigated. The study population was a prospectively followed national cohort of 4 million residents born between 1925 and 1965. Risk ratios (RRs) of hospital admissions and deaths because of diverticular disease and acute diverticulitis from 1991 through 2000 were calculated.

Results

The risk of hospital admission because of diverticular disease, after adjustment for age, sex and socio‐economic indicators, was lower in non‐Western immigrants (RRs = 0.5–0.7) compared with natives and the risk increased with time after the settlement. Women of all origins had a higher risk compared with men (RR = 1.5). This sex‐difference increased with age (P < 0.001). Socio‐economic status, residency or housing situation were not risk factors.

Conclusion

This population‐based study found that immigrants from non‐Westernized countries had lower relative risks for hospitalization because of diverticular disease than natives, but the risk increased during a relatively short period of time after settlement. Diverticular disease of the colon appears to be an acquired disorder and acculturation to a Western lifestyle has an impact on the risk.
Sustained virological response rates and health‐related quality of life after interferon and ribavirin therapy in patients with chronic hepatitis C virus infection and persistently normal alanine aminotransferase levels
Authors: BINI E. J. , MEHANDRU S.
Published: February 2006

Background

Few studies have evaluated interferon and ribavirin therapy in hepatitis C virus‐infected patients with persistently normal alanine aminotransferase (ALT) levels.

Aim

To determine the efficacy and safety of combination therapy in this population, and to evaluate the impact of treatment on health‐related quality of life.

Methods

Forty‐six hepatitis C virus‐infected patients with persistently normal ALT levels and 92 matched subjects with elevated ALT levels were treated with interferon‐α2b plus ribavirin for up to 48 weeks. Health‐related quality of life was measured prior to therapy and 24 weeks after completion of treatment using the Hepatitis Quality of Life Questionnaire.

Results

Overall, 32.6% of patients with normal ALT levels and 28.3% of those with elevated ALT levels had undetectable hepatitis C virus RNA at 24 weeks after completion of treatment (P = 0.60). Three patients in the normal ALT group had mild transient ALT elevations during therapy. Compared with baseline, treatment was associated with significant improvements in nearly all domains of health‐related quality of life in both groups of patients.

Conclusions

In hepatitis C virus‐infected patients with persistently normal ALT levels, interferon‐α and ribavirin therapy is efficacious, safe, and associated with significant improvements in health‐related quality of life.
Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence
Authors: COOPER B. T. , CHAPMAN W. , NEUMANN C. S. , GEARTY J. C.
Published: February 2006

Background

There is little evidence that treatment of patients with Barrett's oesophagus with proton pump inhibitors over periods up to 6 years results in major regression of Barrett's oesophagus.

Aim

To determine if longer periods of treatment with proton pump inhibitors lead to significant regression of Barrett's oesophagus, and to determine the incidence of oesophageal adenocarcinoma in the proton pump inhibitor‐treated patients.

Methods

We analysed prospectively‐collected data on Barrett's oesophagus patients treated with proton pump inhibitors for 1–13 years.

Results

188 patients with Barrett's oesophagus and intestinal metaplasia, were treated for 1–13 years with a proton pump inhibitor (966 years of treatment; mean 5.1 years). No change in length was seen during treatment but 48% of patients developed squamous islands (25% after 1–3 years; 100% at 12–13 years). Squamous islands correlated with treatment duration and male sex but not with proton pump inhibitor dose or patient age. Six patients developed dysplasia and three males developed adenocarcinoma during treatment (cancer incidence 0.31%).

Conclusions

Proton‐pump inhibitor treatment over 1–13 years does not shorten the Barrett's oesophagus segment but squamous islands appear in many patients. The incidence of oesophageal adenocarcinoma was low in these proton pump inhibitor‐treated patients compared with published series.
Clinical and endoscopic presentation of primary gastric lymphoma: a multicentre study
Authors: ANDRIANI A. , ZULLO A. , DI RAIMONDO F. , PATTI C. , TEDESCHI L. , RECINE U. , CARUSO L. , BONANNO G. , CHIARENZA A. , LIZZANI G. , MIEDICO A. , ROMANELLI A. , COSTA A. , LINEA C. , MARRONE C. , MIRTO S. , MISTRETTA A. , MONTALBANO L. , RESTIVO G. , VINCI M. , BIBAS M. , HASSAN C. , STELLA F. , COTTONE M. , MORINI S.
Published: February 2006

Background

Although the stomach is the most frequent site of intestinal lymphomas, few data are available on both clinical endoscopic presentation of gastric lymphoma and possible differences between low‐grade and high‐grade lymphomas.

Methods

Clinical, histological and endoscopic records of consecutive patients with primary low‐grade or high‐grade lymphoma diagnosed were retrieved. Symptoms were categorized as ‘alarm’ or ‘not alarm’. The endoscopic findings were classified as ‘normal’ or ‘abnormal’.

Results

Overall, 144 patients with primary gastric lymphoma were detected, including 74 low‐grade and 70 high‐grade lymphoma. Alarm symptoms, particularly persistent vomiting and weight loss, were more frequently present in patients with high‐grade lymphoma than in those with low‐grade lymphoma (54% vs. 28%; P = 0.002). Low‐grade lymphomas presented as ‘normal’ appearing mucosa (20% vs. 0%; P = 0.0004) or petechial haemorrhage in the fundus (9% vs. 0%; P = 0.02) more frequently than high‐grade lymphomas, being also more often confined to the antrum (47% vs. 27%, P = 0.03) and associated with Helicobacter pylori infection (88% vs. 52%, P < 0.0001). On the contrary, high‐grade lymphomas presented more commonly as ulcerative type (70% vs. 52%; P = 0.03), being also more frequently diagnosed in stage >I when compared with low‐grade lymphomas (70% vs. 21%, P < 0.0001).

Conclusions

The overall prevalence of alarm symptoms is quite low and may be absent in more than 70% of patients with low‐grade lymphoma.
Predictive factors of irritable bowel syndrome improvement: 1‐year prospective evaluation in 400 patients
Authors: MEARIN F. , BADÍA X. , BALBOA A. , BENAVENT J. , CABALLERO A. M. , DOMÍNGUEZ‐MUÑOZ E. , GARRIGUES V. , PIQUÉ J. M. , ROSET M. , CUCALA M. , FIGUERAS M. ,   FOR THE RITMO GROUP
Published: February 2006

Background

The natural history of the irritable bowel syndrome is poorly understood.

Aim

To assess the clinical course of the irritable bowel syndrome and the factors that might predict it.

Methods

An observational prospective study, involving 400 irritable bowel syndrome patients meeting Rome II criteria. Symptoms were recorded in a diary over four non‐consecutive months (1, 4, 7 and 10). Demographic data, associated disorders, psychological status and health‐related quality of life were obtained.

Results

At 1‐year follow‐up, half of the patients and half of their physicians considered irritable bowel syndrome to have improved, but improvement was minor. Diary data showed that, according to the type of symptom, improvement was small and quite different: diarrhoea in 19% of patients, abdominal pain frequency in 26%, constipation in 33% and abdominal pain intensity in 60%. Factors related to improvement at one year were: severe symptoms and poor health‐related quality of life at first visit, irritable bowel syndrome‐constipation, good improvement at 3 months, anxiety/depression, stress, symptoms related to meals and absence of comorbidity. By multivariate logistic regression, predictors were: severe basal symptoms and good improvement at 3 months (OR:CI 95%, 1.32:1.09–1.59 and 4.44:2.81–7.05).

Conclusions

At 1‐year follow‐up, half the patients and their physicians considered the irritable bowel syndrome to have had some improvement but, symptom diaries demonstrated that improvement was small and heterogeneous. Severe basal symptoms and improvement at 3 months were related to better prognosis.
The prevalence of risk factors for gastrointestinal complications and use of gastroprotection among persons hospitalized for cardiovascular disease
Authors: TARGOWNIK L. E. , AL‐MAMFUD A.
Published: February 2006

Background

Aspirin is often used in patients with cardiovascular disease, but it can also cause gastrointestinal complications. Proton pump inhibitors reduce the risk of gastrointestinal complications in aspirin users with a history of gastrointestinal complications.

Aim

To determine the prevalence of gastrointestinal risk factors in aspirin users and the prevalence of proton pump inhibitor utilization in high‐risk patients.

Methods

We reviewed all patients admitted to hospital between April and October 2004 with a diagnosis of cardiovascular disease. We collected data on demographics, medication use, comorbid illnesses, previous gastrointestinal complications, and medication use on admission and discharge.

Results

A total of 324 patients were admitted with cardiovascular disease of whom 94% were discharged on aspirin. Seventy‐eight per cent of patients admitted had at least one gastrointestinal risk factor in addition to having cardiovascular disease, and 15% had three or more additional gastrointestinal risk factors. Patients with additional gastrointestinal risk factors were more likely to be prescribed proton pump inhibitor therapy (27% vs. 10%, P < 0.001). Only 10% of proton pump inhibitor‐naíve high‐risk aspirin users were prescribed a proton pump inhibitor upon discharge.

Conclusions

The majority of high‐risk aspirin users are not receiving proton pump inhibitors for gastroprotection. Further work is required to encourage providers to consider the use of gastroprotective strategies in appropriate patients.
Characterization of two parvalbumin genes and their association with growth traits in Asian seabass (Lates calcarifer)
Authors: Xu Y. X. , Zhu Z. Y. , Lo L. C. , Wang C. M. , Lin G. , Feng F. , Yue G. H.
Published: February 2006

Parvalbumins are extremely abundant in fish muscle and play an important role in muscle relaxation. In this study, two parvalbumin genes (PVALB1 and PVALB2) were cloned from Asian seabass (Lates calcarifer). The cDNAs for PVALB1 and PVALB2 were 840 and 667 bp respectively. Both genes consisted of five exons and four introns, encoded 109 amino acids, and were of beta lineage. Using real‐time polymerase chain reaction, expression of PVALB1 was detected in all 10 tissues tested, with expression in brain, kidney, muscle and small intestine being 15‐ to 322‐fold higher than in the other tissues. Expression of PVALB2 was detected only in muscle, brain and intestine, and was up to 10‐fold lower than PVALB1 expression. A (CT)17 microsatellite in the 3′‐untranslated region of PVALB1 and three single nucleotide polymorphisms (SNPs) in the third intron of PVALB2 were identified. The microsatellite in PVALB1 was significantly associated with body weight and body length at 90 days post‐hatch (P < 0.01), whereas the SNPs in PVALVB2 were not associated with these traits.
A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients
Authors: Picard Nicolas , Prémaud Aurélie , Rousseau Annick , Le Meur Yannick , Marquet Pierre
Published: February 2006

Aim

To compare the pharmacokinetics of mycophenolic acid when given with either ciclosporin or sirolimus, and investigate in vitro the potential effect of ciclosporin, sirolimus, tacrolimus and everolimus on mycophenolic acid metabolism.

Methods

In renal transplant patients given mycophenolate mofetil in combination with ciclosporin (n = 19) or sirolimus (n = 12), concentration‐time profiles of mycophenolic acid, mycophenolic‐acid‐phenyl‐glucuronide, mycophenolic‐acid‐acyl‐glucuronide and mycophenolic‐acid‐phenyl‐glucoside were determined at one month post‐transplant. The effect of immunosuppressive drugs on mycophenolic acid glucuronidation and glycosylation was investigated in vitro using human liver microsomes.

Results

The mean mycophenolic acid AUC0−9 h in the sirolimus group was 44.9 mg h−1 L−1 (95% CI: 34.7–55.1), vs. 30.5 mg h−1 L−1 (95% CI: 25.4–35.6) in the ciclosporin group, corresponding to 1.5‐fold dose‐normalized difference (95% CI: 1.1–1.9; P < 0.05). In addition, the metabolite/mycophenolic acid AUC0−9 h ratios were significantly higher in patients cotreated with ciclosporin than with sirolimus, giving values of 1.8‐fold (95% CI: 1.3–2.3; P = 0.0009), 2.6‐fold (95% CI: 2.0–3.3; P < 0.0001) and 4.3‐fold (95% CI: 2.6–6.0; P = 0.0016) for mycophenolic‐acid‐phenyl‐glucuronide, mycophenolic‐acid‐acyl‐glucuronide and mycophenolic‐acid‐phenyl‐glucoside, respectively. In vitro, none of the immunosuppressive drugs tested inhibited mycophenolic acid metabolism.

Conclusion

Patients taking mycophenolate mofetil and sirolimus experience a higher exposure to mycophenolic acid and a lower exposure to mycophenolic acid metabolites than those being treated with mycophenolate mofetil and ciclosporin. This interaction is probably not caused by inhibition of mycophenolic acid glucuronidation or glycosylation, but is more likely to be due to the influence of ciclosporin on the excretion of mycophenolic acid metabolites into bile.
Genetic variants in the enhancer region of the thymidylate synthase gene in the Chilean population
Authors: Acuña M. , Eaton L. , Cifuentes L. , Massardo D.
Published: February 2006

Aims

Thymidylate synthase (TYMS) is an important target enzyme for the fluoropyrimidines. The TYMS gene enhancer region possesses tandemly repeated (TSER) sequences that are polymorphic in humans and different among ethnic groups. The aims of this study were to estimate the frequencies of the TSER variants in two hospital samples located in the northern (HSJ) and eastern (CLC) parts of Santiago, Chile, and compare them with the frequencies in other populations of different ethnic origin.

Methods

Genotyping of TSER variants in 368 Chilean subjects (HSJ = 178 and CLC = 190) by polymerase chain reaction; products of amplification were electrophoresed, obtaining fragments of 250 bp for allele TSER*3 and 220 bp for allele TSER*2.

Results

The two hospital samples had different degrees of Amerindian admixture (HSJ 34.5%; CLC 15.9%), which was not reflected in the observed frequencies of the CLC TSER*3: 56.8% and HSJ TSER*3: 53.4%.

Conclusions

Our results are unexpected, considering that genetic markers in the Chilean population generally show allele frequencies between those observed in European Caucasians and Amerindians and that the percentage of Amerindian admixture in CLC is lower than in HSJ. Both hospitals should have had greater frequencies of TSER*3 than were found and the frequency should have been greater in HSJ than in CLC; the only logical explanation of our results is that the frequency of this allele in aboriginal Chilean people is much lower than the 80% estimated for Mongoloid populations.
The effect of chronic tobacco smoking on arterial stiffness
Authors: Rehill Nirandeep , Beck Charles R. , Yeo Karen Rowland , Yeo Wilfred W.
Published: February 2006

Aims

Cardiovascular disease caused by smoking is related to the pathophysiological burden placed on the vascular endothelium. We studied the effect of chronic cigarette smoking on arterial wave reflection (study 1) and smoking cessation on pulse wave analysis (study 2).

Methods

Fifty smokers and 50 age‐ and sex‐matched nonsmokers participated in study 1. Study 2 recruited 20 volunteers from the stop smoking clinic at the Royal Hallamshire Hospital, Sheffield, UK. Systemic augmentation index (AIx) and carotid‐femoral pulse wave velocity (PWV) were measured using the SphygmoCor system. Brachial blood pressure (BP) (Omron 705‐CP‐E), AIx and PWV were recorded at a single visit in study 1. Study 2 measured these variables on ‘quit day’ and 4 weeks later.

Results

In study 1, AIx was significantly higher in smokers than in nonsmokers (median 17.25 vs. 11.75%, P = 0.004). Multiple regression analysis showed a significant correlation between AIx and age, diastolic BP, smoking status (P < 0.001), blood glucose (P = 0.045) and weight (P = 0.049). In study 2, AIx significantly reduced after 4 weeks of abstinence in successful quitters (n = 10) compared with relapsed smokers (n = 4) (median 5.0 vs.− 9.5; P = 0.013). PWV did not reach significance in either study.

Conclusions

Chronic tobacco smoking is associated with endothelial dysfunction and increased AIx in subjects of a wide age range free from additional cardiovascular risk factors, which is partially reversible after 4 weeks of smoking cessation.
Relationship between sedation and pupillary function: comparison of diazepam and diphenhydramine
Authors: Hou Ruihua H. , Scaife Jessica , Freeman Clare , Langley Rob W. , Szabadi Elemer , Bradshaw Chris M.
Published: February 2006

Aims

To examine the relationship between sedation and pupillary function by comparing the effects of diazepam and diphenhydramine on arousal and pupillary activity.

Methods

Fifteen male volunteers participated in three weekly sessions in which they received (i) diazepam 10 mg, (ii) diphenhydramine 75 mg and (iii) placebo, according to a balanced, double‐blind protocol. Pupil diameter was measured with infrared pupillometry under four luminance levels. Alertness was assessed by visual analogue scales (VAS) and by critical flicker fusion frequency (CFFF). Blood pressure, heart rate and skin conductance were recorded by conventional methods. Data were analysed with analysis of variance (anova) with multiple comparisons.

Results

There were significant effects of ambient luminance (F3,42 = 305.7, P < 0.001) and treatment condition (F2,28 = 9.0, P < 0.01) on pupil diameter; diphenhydramine caused miosis at all luminance levels (P < 0.05). The light reflex response was not affected. Both active drugs reduced the pre‐post treatment changes compared with placebo [mean difference from placebo (95% confidence interval)]: in CFFF (Hz), diazepam −0.73 (−1.63, 0.17), diphenhydramine −1.46 (−2.40, −0.52); and VAS alertness (mm), diazepam −11.49 (−19.19, −3.79), diphenhydramine −19.83 (−27.46, −12.20). There were significant effects of both session (F2,26 = 145.1, P < 0.001) and treatment (F2,26 = 5.5, P < 0.01) on skin conductance; skin conductance was reduced by both drugs (P < 0.05).

Conclusions

The miosis by diphenhydramine and the reduction in skin conductance by both drugs may indicate central sympatholytic effects. A lack of a sympatholytic effect of diazepam on the pupil may be due to the masking of the miosis by mydriasis resulting from the inhibition of the parasympathetic output to the iris.
Self-aggregated deglycosylated IgA1 with or without IgG were associated with the development of IgA nephropathy
Authors: Yan Y , Xu L-X , Zhang J-J , Zhang Y , Zhao M-H
Published: February 2006

IgA nephropathy (IgAN) is the most common primary glomerulonephritis, with various pathological phenotypes. Our previous study suggested that aberrant glycosylation of serum IgA1 was associated with different pathological phenotypes of IgAN, and substantial evidence indicated that deglycosylated IgA1 had an increased tendency to form macromolecules. The aim of the current study was to investigate the composition of IgA1-containing macromolecules in different pathological phenotypes of IgAN. Sera from 10 patients with mild mesangial proliferative IgAN (mIgAN), 10 with focal proliferative sclerosing IgAN (psIgAN) and 10 healthy blood donors were collected. The sera were applied and IgA1 binding proteins (IgA1-BP) were eluted from the columns immobilized with desialylated IgA1 (DesIgA1/Sepharose) or desialylated/degalactosylated IgA1 (DesDeGalIgA1/Sepharose), respectively. The amounts of IgA1 and IgG and the glycoform of IgA1 in the IgA1-BP were detected by enzyme-linked immunosorbent assays (ELISAs) and were compared between patients with different pathological phenotypes and normal controls. The amount of IgA1 in IgA1-BP eluted from both columns was significantly higher in patients with both pathological phenotypes of IgAN than in normal controls. In IgA1-BP eluted from DesDeGalIgA1/Sepharose, the desialylation of IgA1 was much more pronounced in patients with both pathological phenotypes of IgAN than in normal controls, while the degalactosylation of IgA1 was much more pronounced only in patients with psIgAN than in normal controls. Furthermore, the amount of IgG in IgA1-BP eluted from DesDeGalIgA1/Sepharose was significantly higher in patients with psIgAN than in normal controls. In patients with psIgAN, the amount of IgG eluted from DesDeGalIgA1/Sepharose was much greater than from DesIgA1/Sepharose. In conclusion, self-aggregated deglycosylated IgA1 with or without IgG were associated with the development of IgAN.
Lipopolysaccharide hyporesponsiveness as a risk factor for intensive care unit hospitalization in infants with respiratory syncitial virus bronchiolitis
Authors: Mandelberg A , Tal G , Naugolny L , Cesar K , Oron A , Houri S , Gilad E , Somekh E
Published: February 2006

Factors such as genetic heterogeneity in the immune response contribute to respiratory syncytial virus (RSV) bronchiolitis severity. Such heterogeneity may manifest by an aberrant proliferation of phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) in response to lipopolysaccharide (LPS). The proliferation of PBMC was analysed in 52 infants: 21 ambulatory infants with mild RSV bronchiolitis (group I), 26 hospitalized infants with RSV bronchiolitis on ward (group II) and five intensive care unit (ICU) hospitalized infants (group III). Proliferation was analysed in response to negative control, PHA (LPS) and LPS/PHA. The TLR4 mutations were genotyped using reverse-transcriptase–polymerase chain reaction. The optical density (OD) post-LPS/PHA of group II (1·27 ± 0·63) was significantly higher than group II (0·65 ± 0·38, P = 0·005) or group I (0·63 ± 0·33, P = 0·003), suggesting hyporesponsiveness to the LPS attenuation effect. None of the ICU hospitalized infants demonstrated OD readings post-LPS/PHA under the 0·75 threshold as opposed to group I (67% under 0·75) and group II (69%) (P < 0·05). The responses to negative-control, LPS and PHA stimulation alone were similar across groups. The presence of TLR4 mutations (Asp299Gly and Thr399Ile) were associated with severe RSV bronchiolitis and were significantly over-represented in groups II and III. These findings suggest that impairments of PBMC function manifested by hyporesponsiveness to LPS as well as the presence of TLR4 mutations are associated with an increased risk for more severe RSV bronchiolitis in previously healthy infants. A certain threshold of LPS hyporesponsiveness may have a very high negative predictive value for ICU hospitalization, even better than the determination of known TLR4 mutations for this purpose.
Yo antibodies in ovarian and breast cancer patients detected by a sensitive immunoprecipitation technique
Authors: Monstad S E , Storstein A , Dørum A , Knudsen A , Lønning P E , Salvesen H B , Aarseth J H , Vedeler C A
Published: February 2006

Onconeural antibodies are found in patients with cancer and are associated with paraneoplastic neurological syndromes (PNS). The objective of the present study was to assess the frequency of Yo antibodies in ovarian and breast cancer using a sensitive immunoprecipitation technique, and to look for any association of Yo antibodies with neurological symptoms and prognostic factors. A multiwell adapted fluid-phase immunoassay using radiolabelled recombinant cerebellar degeneration related protein (cdr2), produced by coupled in vitro transcription/translation was used for the detection of Yo antibodies. This technique combines high specificity and sensitivity with high sample analysing capacity for the antibody in question. Sera or EDTA-blood from 810 ovarian (n = 557) and breast cancer (n = 253) patients were analysed for Yo antibodies by immunoprecipitation, as well as immunofluorescence and immune blots. Two hundred healthy blood donors and sera from 17 patients with paraneoplastic cerebellar degeneration and Yo antibodies served as controls. Immunoprecipitation was more sensitive in detecting Yo antibodies than immunofluorescence and immune blots. The prevalence of Yo antibodies was 13/557 (2·3%) in ovarian cancer and 4/253 (1·6%) in breast cancer using immunoprecipitation. Yo antibodies were not correlated with specific histological subgroups. The Yo index of ovarian cancer patients in FIGO stage IV was higher compared to FIGO stage I-III. The prevalence of Yo antibodies was 3 times higher in patients with stage III breast cancer than in stage I and II. Only 2/17 (11·8%) patients with Yo antibodies detected during the screen of 810 cancer patients had PNS. The results show that the prevalence of Yo antibodies is low in ovarian and breast cancer. Yo antibodies may be associated with advanced cancer, but less often with PNS.
Inhibition of five lipoxygenase activating protein (FLAP) by MK‐886 decreases atherosclerosis in apoE/LDLR‐double knockout mice
Authors: Jawien J. , Gajda M. , Rudling M. , Mateuszuk L. , Olszanecki R. , Guzik T. J. , Cichocki T. , Chlopicki S. , Korbut R.
Published: February 2006

Background  Recent reports point to an important role of leukotrienes in atherogenesis. Leukotrienes are produced by 5‐lipoxygenase co‐operating with five lipoxygenase activating protein (FLAP). We hypothesized that MK‐886, an inhibitor of FLAP, could attenuate the development of atherosclerosis in the atherogenic apolipoprotein E/low density lipoprotein receptor (apoE/LDLR) double knockout (DKO) mouse model.

Materials and methods  Female apoE/LDLR‐DKO mice at the age of 8 weeks were put on Western diet. The experimental group (n = 10) received the same diet as the control group (n = 10), but mixed with MK‐886 (Merck, Rahway, NJ) at a dose of 4 µg per 100 mg of body‐weight per day. At age 6 months the mice were sacrificed under anaesthesia.

Results  Measured by the en face method, the percentage of area occupied by lesions in aortas in the control group was 25·15 ± 2·9%, whereas in the MK‐886‐treated group it was 11·16 ± 0·7% (P < 0·05). Lesion area measured by cross‐section of aortic roots was 455 494 ± 29 564 µm2 in the control group versus 263 042 ± 20 736 µm2 in the MK‐886‐treated group (P < 0·05). The MK‐886 did not change the plasma cholesterol lipoprotein profile as compared with the control mice. Finally, we show that MK‐886 may increase plaque stability by decreasing the macrophage content as well as increasing the collagen and smooth‐muscle cell content.

Conclusions  Our results show for the first time that inhibition of FLAP by MK‐886 reduces development of atherosclerosis in gene‐targeted apoE/LDLR‐DKO mice.
Increased inflammatory markers in children with familial hypercholesterolaemia
Authors: Ueland T. , Vissers M. N. , Wiegman A. , Rodenburg J. , Hutten B. , Gullestad L. , Ose L. , Rifai N. , Ridker P. M. , Kastelein J. J. P. , Aukrust P. , Semb A. G.
Published: February 2006

Background  While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high‐sensitivity C‐reactive protein (hsCRP), and soluble CD40 ligand (sCD40L).

Materials and methods  In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2‐year treatment with pravastatin (20–40 mg qd) or placebo on plasma levels of those markers.

Results  Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high‐density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group.

Conclusion  These findings indicate low‐grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti‐inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults.
Microarray profiling of human white adipose tissue after exogenous leptin injection
Authors: Taleb S. , Van Haaften R. , Henegar C. , Hukshorn C. , Cancello R. , Pelloux V. , Hanczar B. , Viguerie N. , Langin D. , Evelo C. , Zucker J. , Clément K. , Saris W. H. M.
Published: February 2006

Background  Leptin is a secreted adipocyte hormone that plays a key role in the regulation of body weight homeostasis. The leptin effect on human white adipose tissue (WAT) is still debated.

Objective  The aim of this study was to assess whether the administration of polyethylene glycol‐leptin (PEG‐OB) in a single supraphysiological dose has transcriptional effects on genes of WAT and to identify its target genes and functional pathways in WAT.

Materials and methods  Blood samples and WAT biopsies were obtained from 10 healthy nonobese men before treatment and 72 h after the PEG‐OB injection, leading to an approximate 809‐fold increase in circulating leptin. The WAT gene expression profile before and after the PEG‐OB injection was compared using pangenomic microarrays. Functional gene annotations based on the gene ontology of the PEG‐OB regulated genes were performed using both an ‘in house’ automated procedure and GenMAPP (Gene Microarray Pathway Profiler), designed for viewing and analyzing gene expression data in the context of biological pathways.

Results  Statistical analysis of microarray data revealed that PEG‐OB had a major down‐regulated effect on WAT gene expression, as we obtained 1822 and 100 down‐ and up‐regulated genes, respectively. Microarray data were validated using reverse transcription quantitative PCR. Functional gene annotations of PEG‐OB regulated genes revealed that the functional class related to immunity and inflammation was among the most mobilized PEG‐OB pathway in WAT. These genes are mainly expressed in the cell of the stroma vascular fraction in comparison with adipocytes.

Conclusion  Our observations support the hypothesis that leptin could act on WAT, particularly on genes related to inflammation and immunity, which may suggest a novel leptin target pathway in human WAT.
Influence of clinical factors on the haemolysis marker haptoglobin
Authors: Körmöczi G. F. , Säemann M. D. , Buchta C. , Peck‐Radosavljevic M. , Mayr W. R. , Schwartz D. W. M. , Dunkler D. , Spitzauer S. , Panzer S.
Published: February 2006

Background  Plasma haptoglobin determination is clinically used as parameter for haemolysis. To date, however, the influence of the mode of haemolysis (extravascular vs. intravascular) and of nonhaemolytic conditions on haptoglobin concentration and its reliability as a haemolysis marker remain poorly defined.

Materials and methods  In a total of 479 individuals, the influence of haemolytic and nonhaemolytic conditions on plasma haptoglobin levels was investigated.

Results  All studied types of haemolytic disease (n = 16) were associated with markedly decreased plasma haptoglobin levels, without significant differences between intravascular vs. predominantly extravascular haemolysis. Diminished haptoglobin values were also observed in patients with liver cirrhosis, which normalized after liver transplantation. In contrast, markedly increased haptoglobin levels were found in patients with inflammation. In patients with haemolysis and a concomitant acute‐phase response, however, haemolysis‐dependent haptoglobin depletion was not attenuated. Interestingly, patients with a strongly positive direct antiglobulin test or high cold agglutinin titre but no further evidence for haemolysis had normal haptoglobin values. Likewise, anaemia owing to bone marrow failure, acute gastrointestinal or chronic diffuse blood loss, and end‐stage kidney disease were associated with normal haptoglobin levels.

Conclusions  Plasma haptoglobin depletion is a reliable marker for the instant diagnosis of accelerated red cell destruction irrespective of the site of haemolysis or the presence of inflammation. The capacity of this parameter to predict haemolysis appears to be limited in patients with liver cirrhosis and decreased haptoglobin production only.
Defining the limits to local density: alternative views of abundance–environment relationships
Authors: LANCASTER JILL , BELYEA LISA R.
Published: February 2006

1. In many ecosystems, the local abundance of organisms is spatially heterogeneous. Ecologists often seek to explain this variation by modelling the central tendency of abundance as a function of a single dominant factor (central response, CR). An alternative approach is to model maximum and minimum abundance in relation to the dominant factor (limiting response, LR), thereby acknowledging that multiple factors may constrain abundance and create scatter in the relationship. In many ecosystems, including streams, abundance–environment relationships are traditionally expected to be CR models with a single dominant factor determining local abundance, but this hypothesis lacks rigorous test. This omission is of concern because CR modelled relationships form the foundations of many ecological tests, predictive and management tools that, consequently, may provide erroneous interpretations.

2. In a survey designed to minimise variance in the data, we related densities of three taxa of stream invertebrates to near‐bed flow. Data were analysed using both ordinary least squares (OLS) regression and quantile regression, which have different characteristic results depending on whether the relationship is better described as a CR or LR model. For all three taxa, invertebrate responses to flow conformed most closely to LR models and were best described by quantile regression, although OLS regression revealed broadly similar general trends in this case.

3. Based on the statistically modelled relationships, we were able to hypothesise which ecological mechanisms limited maximum abundance at this site, including dislodgement with high flow (Heptageniidae, Leuctridae), reduced oxygen uptake at low flow (Baetidae) and reduced provision of interstitial spaces at high flow (Leuctridae). Scatter in the relationships was attributable to multiple factors that may operate at different scales, including inter‐individual variation, alternative environmental gradients and biotic processes at the patch scale, and potential constraints of dispersal and settlement operating outside the patch.

4. We illustrate how the choice of CR or LR model to describe abundance–environment relationships may affect tests of ecological theory and applied ecology. If our results are typical of other streams and other types of systems, greater use of LR models may transform the way many ecologists view ecosystems, thus having positive consequences for survey and experimental designs and highlighting weaknesses in existing management tools that are underpinned by CR models.
Releases of ingested phytoplankton carbon by Daphnia magna
Authors: HE XUEJIA , WANG WEN‐XIONG
Published: February 2006

1. The carbon budgets and assimilation efficiencies (AEs) of adults and juveniles of Daphnia magna were quantified using 14C as a tracer. Animals were fed pure Chlamydomonas reinhardtii or Scenedesmus obliquus at different food concentrations. Carbon AEs (46–70%) were comparable at food concentrations of 0.03–0.30 mg C L−1 for both algal species, but decreased to 34–49% when the food concentration further increased by 10‐fold. The carbon AEs were significantly and negatively correlated with the food level.

2. During the postdigestive period, partitioning of ingested carbon into different compartments including excretion, respiration and egestion was not influenced by the food species and life stage. There was a negative correlation between respiration (as % of total loss) and food concentration and a positive correlation between egestion (as % of total loss) and food concentration. Dissolved organic carbon (DOC) and CO2 accounted for 55–72% and 9–37%, respectively, of the total carbon loss from juveniles fed both algal diets. For adults, DOC and CO2 contributed to 44–64% and 20–47% of the total carbon loss, respectively. Particulate organic carbon (POC) was a minor pathway for the overall carbon loss.

3. The turnover and release budget of structural carbon (as moults and neonate reproduction) were further evaluated in long‐term experiments at different algal concentrations. Food concentration did not affect the carbon efflux or the carbon allocation into different physiological compartments except for respiration. Juveniles had twofold lower carbon turnover rate (0.12–0.16 day−1) than those of the adults (0.32–0.35 day−1). In adults, comparable carbon was allocated into DOC (35–42%) and reproduction (27–35%), which were the dominant routes for carbon loss. For the juveniles, DOC accounted for 42–64% of the total carbon loss.

4. About 21–38% of the total DOC released by adults and juveniles was associated with the high molecular weight organic carbon fraction (>5 kDa). Our results show that carbon was mainly lost by D. magna in the form of DOC during assimilation process as well as from the structural materials. Reproduction or maternal transfer was another major drain of body carbon for adult D. magna.
The cognitive and behavioural phenotype of Roifman syndrome
Authors: De Vries P. J. , McCartney D. L. , McCartney E. , Woolf D. , Wozencroft D.
Published: February 2006

Background  Roifman syndrome (OMIM 300258) is a multi‐system disorder with a physical phenotype that includes Β‐cell immunodeficiency, intra‐uterine and postnatal growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy and characteristic facial dysmorphism. So far, six cases, all boys, have been reported in the literature. Roifman postulated that the syndrome may be due to a mutation in an X‐linked gene or an autosomal gene giving rise to a sex‐limited trait, but the definitive pathogenetic mechanism has still not been elucidated. Very little is known about the cognitive and behavioural phenotype of Roifman syndrome and no standardized measures of cognitive abilities have been reported.

Methods  We report the seventh case of a boy with Roifman syndrome and present the first systematic documentation of the cognitive and behavioural phenotype of an individual with the syndrome.

Results  In spite of having been reported as appearing intellectually ‘able’, formal evaluation showed very significant intellectual disability and neuropsychological impairment across cognitive domains.

Conclusions  The findings suggest that Roifman syndrome may be an example of an X‐linked mental retardation syndrome (XLMRS).