bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical evaluation in treatment of oral lichen planus with topical fluocinolone acetonide: a 2‐year follow‐up
Authors: Thongprasom K. , Luengvisut P. , Wongwatanakij A. , Boonjatturus C.
Published: June 2003

Background:  Oral lichen planus (OLP) is a chronic inflammatory disease which is recalcitrant to medical treatment. The purpose of this study was to compare the effectiveness of various forms of the topical steroid fluocinolone acetonide applications in patients with OLP.

Methods:  Data of OLP patients were collected retrospectively from the chart record and the 97 OLP patients were divided into three groups. The first group (n = 28) was treated with a 0.1% solution of fluocinolone acetonide (FAS), the second group (n = 22) with 0.1% fluocinolone acetonide in orabase (FAO), and the third group (n = 47) with both FAS and FAO (FAS/FAO) throughout the study. Each group was clinically evaluated as complete remission (CR), partial remission (PR), or no response (NR), following the treatment. Also, the side‐effect of oral candidiasis was recorded in each group.

Results:  Two years of treatment resulted in complete remission of 77.3, 21.4, and 17.0% of patients in the FAO, FAS, and FAS/FAO groups, respectively. There was a statistically significant difference in disease remission (P < 0.05), but not in oral candidiasis appearance (P > 0.05) among various forms of topical steroid application.

Conclusion:  The study concluded that FAO or FAS can produce improved results in the management of OLP by long‐term follow‐up.
Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint‐blind DNA damage
Authors: Redon Christophe , Pilch Duane R , Rogakou Emmy P , Orr Ann H , Lowndes Noel F , Bonner William M
Published: June 2003

Cells maintain genomic stability by the coordination of DNA‐damage repair and cell‐cycle checkpoint control. In replicating cells, DNA damage usually activates intra‐S‐phase checkpoint controls, which are characterized by delayed S‐phase progression and increased Rad53 phosphorylation. We show that in budding yeast, the intra‐S‐phase checkpoint controls, although functional, are not activated by the topoisomerase I inhibitor camptothecin (CPT). In a CPT‐hypersensitive mutant strain that lacks the histone 2A (H2A) phosphatidylinositol‐3‐OH kinase (PI(3)K) motif at Ser 129 (h2a‐s129a), the hypersensitivity was found to result from a failure to process full‐length chromosomal DNA molecules during ongoing replication. H2A Ser 129 is not epistatic to the RAD24 and RAD9 checkpoint genes, suggesting a non‐checkpoint role for the H2A PI(3)K site. These results suggest that H2A Ser 129 is an essential component for the efficient repair of DNA double‐stranded breaks (DSBs) during replication in yeast, particularly of those DSBs that do not induce the intra‐S‐phase checkpoint.
X‐ray structure of human acid‐β‐glucosidase, the defective enzyme in Gaucher disease
Authors: Dvir Hay , Harel Michal , McCarthy Andrew A , Toker Lilly , Silman Israel , Futerman Anthony H , Sussman Joel L
Published: June 2003

Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid‐β‐glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. No clear correlation exists between the ∼200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with non‐ neuronopathic and neuronopathic disease, respectively. We report the X‐ray structure of GlcCerase at 2.0 Å resolution. The catalytic domain consists of a (β/α)8 TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest α‐helix (helix 7), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin‐like domain on which L444 is located, suggesting an important regulatory or structural role for this non‐catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme‐replacement therapy, and for designing structure‐based drugs aimed at restoring the activity of defective GlcCerase.
Horizontal transfer of drug‐resistant aminoacyl‐transfer‐RNA synthetases of anthrax and Gram‐positive pathogens
Authors: Brown James R , Gentry Daniel , Becker Julie A , Ingraham Karen , Holmes David J , Stanhope Michael J
Published: June 2003

The screening of new antibiotics against several bacterial strains often reveals unexpected occurrences of natural drug resistance. Two examples of this involve specific inhibitors of Staphylococcus aureus isoleucyl‐transfer‐RNA synthetase 1 (IleRS1) and, more recently, Streptococcus pneumoniae methionyl‐tRNA synthetase 1 (MetRS1). In both cases, resistance is due to the presence of a second gene that encodes another synthetase (IleRS2 or MetRS2). Here, we show that both S. pneumoniae MetRS2 and S. aureus IleRS2 have closely related homologues in the Gram‐positive bacterium Bacillus anthracis, the causative agent of anthrax. Furthermore, similar to drug‐resistant pathogens, strains of B. anthracis and its closest relative, B. cereus, also have wild‐type ileS1 and metS1 genes. Clostridium perfringens, the causative agent of gangrene, also has two metS genes, whereas Oceanobacillus iheyensis isolated from deep‐sea sediments has a single ileS2‐type gene. This study shows the importance of understanding complex evolutionary networks of ancient horizontal gene transfer for the development of novel antibiotics.
Media composition and narrative performance at school
Authors: Fusai C. , Saudelli B. , Marti P. , Decortis F. , Rizzo A.
Published: June 2003

Abstract  POGO is a distributed learning environment that allows children to create stories by connecting physical and virtual worlds. The environment is composed of several interactive tools that children use to compose, edit and perform stories. Together with teachers, five pedagogical objectives were defined as goals to be achieved in narrative. The pedagogical objectives drove the entire POGO design process and constituted a solid reference for the different evaluations undertaken during the project. This paper, after a brief introduction and a presentation of the POGO world, illustrates how the interaction with the POGO Tools supports the fulfilment of the pedagogical objectives.
Computer supported collaborative writing in an early learning classroom
Authors: Lingnau A. , Hoppe H.U. , Mannhaupt G.
Published: June 2003

Abstract This paper describes a collaborative experiment in an early learners' classroom, equipped with special software and hardware to support the acquisition of initial reading and writing skills. This ‘Computer‐integrated Classroom’ originated from the EU project NIMIS. Here, a new method to teach ‘reading through writing’ is supported by a specific software tool (T3) in the general framework of the classroom environment. Particularly, a collaborative writing task facilitated by a shared workspace system has been evaluated with a group of first graders using the T3 application. The speciality of this experiment lies in the study of domain‐specific collaboration in a rich real world learning setting.
Concept development for kindergarten children through a health simulation
Authors: Andrews G. , Woodruff E. , MacKinnon K.A. , Yoon S.
Published: June 2003

According to many dental professionals, the decay process resulting from the accumulation of sugar on teeth is a very difficult concept for young children to learn. Playing the dental hygiene game with Thinking Tags not only brings context into the classroom, but also allows children to work with digital manipulatives that provide rich personal experiences and instant feedback. Instead of watching a demonstration of the accumulation of sugars on a computer screen, or being told about dental health, this simulation allows pre‐school children to experience improving or decaying dental health without any real adverse health effects. Small, wearable, microprocessor‐driven Tags were brought into the kindergarten classroom to simulate the decay process, providing information about sugars in foods and creating a discussion about teeth. Preliminary analyses suggest that this program was effective and enthusiastically received by this age group.
Understanding children's collaborative interactions in shared environments
Authors: Scott S.D. , Mandryk R.L. , Inkpen K.M.
Published: June 2003

Traditional computer technology offers limited support for face‐to‐face, synchronous collaboration. Consequently, children who wish to collaborate while using computers must adapt their interactions to the single‐user paradigm of most personal computers. Recent technological advances have enabled the development of co‐located groupware systems offering support for concurrent, multi–user interactions around a shared display. These systems provide a unique collaboration environment in which users share both the physical and the virtual workspace. This paper examines how such technology impacts children's collaboration. Findings from this research show that when concurrent, multi–user interaction is supported on a shared display, children exhibit collaborative behaviour similar to their interactions during paper‐based activities. The findings also suggest strengths and weaknesses of various mechanisms for supporting synchronous interactions that have implications for the design of computer systems to support children's face‐to‐face collaboration.
A collaborative digital library for children
Authors: Druin A. , Revelle G. , Bederson B.B. , Hourcade J.P. , Farber A. , Lee J. , Campbell D.
Published: June 2003

Abstract  Over the last three years, a digital library interface has been developed where two children can collaborate using multiple mice on a single computer to access multimedia information concerning animals. This technology, SearchKids, supports past work in copresent collaborative zoomable interfaces for young children. This paper describes the differences in children's collaborative behaviour and dialogue when using two different software conditions to search for animals in the digital library. In this study, half the children had to ‘confirm’ their collaborative activities (e.g. both children had to click on a given area to move to that area). The other half used an ‘independent’ collaboration technique (e.g. just one mouse click allowed the pair to move to that area). The participants in this study were 98 second and third grade children (ages 7–9 year‐old) from a suburban public elementary school in Prince George's County, Maryland. The results of the study show distinct differences between conditions in how children discussed their shared goals, collaborative tasks, and what outcomes they had in successfully finding multimedia information in the digital library.
Test and treat or test and scope for Helicobacter pylori infection. Any change in gastric cancer prevention?
Authors: Mc Loughlin R. M. , Sebastian S. S. , O'Connor H. J. , Buckley M. , O'Morain C. A.
Published: June 2003

A ‘test and treat’ strategy is advocated for patients with dyspepsia under the age of 45 years, with endoscopy reserved for those with alarm symptoms or aged over 45 years. One of the consequences of this strategy will be a reduction in population infection rates of Helicobacter pylori. It is now clear that H. pylori is one of the prime initiators of gastric cancer with up to 70% of gastric cancers attributable to H. pylori. What remains unclear is if H. pylori reduction will lead to a reduction in gastric cancer.
Hepatocellular carcinoma: indications for liver transplantation
Authors: Mela M. , Mancuso A. , Burroughs A. K.
Published: June 2003

The role of liver transplantation for hepatocellular carcinoma has evolved over the years and currently is one of the curative therapies for small tumours. The survival rates are similar with those for nonmalignant liver disease after transplantation. The treatment of small tumours eligible for both resection and transplantation depends on the experience of the transplant centre and the waiting time for a liver graft. With waiting times for liver transplant becoming gradually longer, prioritization of the tumour patients has been suggested. Adjuvant therapies may delay the tumour progression while patients wait for a transplant. The living donor and the domino liver transplantation are useful alternatives given the shortage of organs but the experience is still limited in the Western world and the selection for the domino livers is fairly restricted.
Crohn's disease: monitoring disease activity
Authors: Sostegni R. , Daperno M. , Scaglione N. , Lavagna A. , Rocca R. , Pera A.
Published: June 2003

A global measurement of Crohn's disease activity, comprising clinical, endoscopic, biochemical and pathological features is not available yet and perhaps is unobtainable. In this review we analyse the most used and validated clinical indices (Crohn's Disease Activity Index [CDAI], Perianal Disease Activity Index [PDAI], fistula drainage assessment), quality of life scores (Inflammatory Bowel Disease Questionnaire [IBDQ]), sub‐clinical markers (C‐reactive protein, faecal calprotectin, intestinal permeability) and endoscopic indices (Crohn's Disease Endoscopic Index of Severity [CDEIS]/Simple Endoscopic Score for Crohn's Disease [SES‐CD], Rutgeeerts' score for postsurgical recurrence). We also review the main advantages and disadvantages of each of these scoring systems. All these indices are rather complex and time‐consuming, therefore their use is limited to clinical trials. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision‐making.
Medical treatment of severe ulcerative colitis
Authors: Rizzello F. , Gionchetti P. , Venturi A. , Campieri M.
Published: June 2003

Severe colitis is a life‐threatening complication of ulcerative colitis. Early recognition of the severity of the colitis and intensive treatment and monitoring have all contributed to improved outcome. Since their introduction in 1950s, corticosteroids are the first line therapy for severe active ulcerative colitis (UC). Several prognostic parameters (such as stools movement per day, C‐reactive protein, increased amount of intestinal gas or small bowel dilation, hypoalbuminemia, fever etc) help the physician to quickly introduce cyclosporin or to refer the patient to the surgeon. This decision requires a careful evaluation of the patient and a medical /surgical team. Infliximab seems to be a promising drug but more controlled trial are needed.
Medical treatment of mild to moderately active Crohn's disease
Authors: Löfberg R.
Published: June 2003

Crohn's disease is a chronic, debilitating subset of inflammatory bowel diseases, which may affect any part of the gastrointestinal tract. The most common sites of inflammation are the terminal ileum and/or the colon. Fistulous disease is present in up to 20% of patients, particularly in those having rectal involvement.

The aetiology of Crohn's disease still remains obscure, therefore medical therapy is directed towards symptomatic relief in active disease and relapse prevention in the long‐term setting. Contemporary Crohn's disease management comprises individual treatment depending mainly on Crohn's disease localization in the gastrointestinal tract and the disease severity.

The mainstay of current medical treatment for mild to moderately active stages of Crohn's disease includes aminosalicylates, antibiotics, glucococorticosteroids and immunomodulators. Biologics such as anti TNF‐compounds and anti‐integrins are being introduced.
Medical treatment of moderate to severe Crohn's disease
Authors: Scribano M. , Prantera C.
Published: June 2003

The treatment for patients with Crohn's disease of moderate to severe activity includes traditional drugs, such as corticosteroids, the primary therapy for these forms of disease, able to induce the remission of symptoms in a high percentage of patients. Because of the side‐effects produced by systemic steroids, a new glucocorticoid derivative, budesonide, which acts locally in the mucosa, has recently been introduced with positive results. On the assumption that intestinal bacteria play a role in the causing Crohn's disease symptoms, antibiotics are often used in the treatment of active phases, as an alternative to or in association with steroids. The most widely employed antibiotics are metronidazole and ciprofloxacin. Immunosuppressors, such as azathioprine and 6‐mercaptopurine, are useful for the treatment of chronic active disease and for maintaining remission, but they have only a marginal role in the therapy of an acute flare‐up of Crohn's disease. Methotrexate acts more rapidly and its use in patients with active disease resistant to standard therapy is of interest. The discovery of biological agents represents a new era in the management of patients. To date, infliximab is the more extensively studied biological therapy in the treatment of Crohn's disease and clinical studies have demonstrated its efficacy in inducing remission of refractory disease.
Diagnosis and treatment of Helicobacter: a 2002 updated review
Authors: Basset C. , Holton J. , Ricci C. , Gatta L. , Tampieri A. , Perna F. , Miglioli M. , Vaira D.
Published: June 2003

The year 2002 saw advances on many fronts in the study of Helicobacter and gastroduodenal disease. Several studies have confirmed endoscopy as a valuable management procedure with confirmation of the diagnostic utility of the rapid urease test and the description of a new formulation of the test, which is more rapid in giving a result. Serology has been re‐confirmed as a useful investigation in selected populations. Some commercial kits for near patient testing have also been assessed and although generally regarded as less accurate than laboratory based tests some have shown acceptable accuracy. The recent exciting development in diagnostic serology is the availability of the faecal antigen test; further studies have confirmed its usefulness as recommended screening tests.

There have been several studies demonstrating that a test and treat policy has a significant patient benefit, both economic and medical, although there is some doubt if eradication of Helicobacter leads to regression of atrophy and metaplasia. However, in low Helicobacter‐prevalence areas the test and treat policy is being challenged as an effective management strategy. Further studies have shown that compliance with treatment regimens is an important determinant of successful eradication. Finally several new eradication regimens have been reported particularly for use in patients who have had previous unsuccessful eradication attempts.
Rapidly repeated intravenous boluses of salbutamol for acute severe asthma
Authors: Sellers W. F. S. , Messahel B.
Published: June 2003

Summary We describe the use of intravenous boluses of salbutamol given rapidly (over 1–2 min) in children (5 µg.kg−1) and young adults (250 µg) with acute severe asthma who were not improving with doses of nebulised salbutamol. Intravenous boluses were repeated within a short time until improvement was seen. Two of the seven patients required tracheal intubation and ventilation.
Startin's pneumatic inhaler
Authors: Walmsley D. A. , Zuck D.
Published: June 2003

This apparatus was seen by one of us (DAW) in a private collection. Although it was one of the first ether inhalers to be manufactured commercially, and was described in the medical literature of the time, it is not mentioned in any of the histories of anaesthesia. Its genesis was unusual, and it presents a number of interesting features, not least being the purpose for which it was originally designed.
Factors affecting the spread of bupivacaine in the adult thoracic paravertebral space
Authors: Cheema S. , Richardson J. , McGurgan P.
Published: June 2003

Factors affecting the spread of bupivacaine in the paravertebral space were investigated in patients undergoing paravertebral nerve blocks for the treatment of chronically painful conditions. Injections of bupivacaine 0.5%, 10–15 ml mixed with depomedrone up to 80 mg were repeated at 2‐wk intervals up to a maximum of four times. A blinded observer mapped out the subsequent distribution of sensory loss to cold on both sides of the torso at 5‐min intervals after each injection. Age, sex, height and weight did not correlate with the block; nor did injectate volume, mass of bupivacaine, previous posterolateral thoractomy and spread of radiocontrast. Injections repeated at 2‐wk intervals in the same patient resulted in different degrees of spread that were unrelated to one another. Time to peak onset of blockade was 40 min in 95% of patients. A single bolus of bupivacaine produces a safe but unpredictable block. Yet to be defined physical properties and anatomical factors are probably key determinants of the spread of bupivacaine in the paravertebral space. This single bolus technique may be better supplanted by a reversion to the older multiple level injection technique.
Day of surgery cancellations after nurse‐led pre‐assessment in an elective surgical centre: the first 2 years
Authors: Rai M. R. , Pandit J. J.
Published: June 2003

We describe a nurse‐led pre‐assessment system at an elective surgical centre. A targeted referral system was used by trained nurses to direct referrals to a supervising consultant anaesthetist or to the surgical team. Of 2726 patients pre‐assessed in the first 2 years, 105 patients (3.9%) were cancelled or postponed for medical optimisation after pre‐assessment. There were 137 cancellations (5.0%) on the day of surgery, despite pre‐assessment, but only 36 were for anaesthetic or medical reasons. Only eight of these 36 were considered a ‘failure’ of the pre‐assessment system. These results are much better than the cancellation rate of about 11% in the Trust as a whole. There were 18 transfers of patients postoperatively from the elective centre to another hospital. A review suggested that four of these transfers could have been reasonably predictable from the patients' medical history. We conclude that a pre‐assessment clinic has an important role to play in minimizing cancellations on the day of surgery and also in reducing the number of patients transferred to other hospitals. This last conclusion has an important implication for the planning of systems in hospitals that perform only elective surgery.
New aspects of ventilation in acute lung injury
Authors: Malarkkan N. , Snook N. J. , Lumb A. B.
Published: June 2003

Recent recognition that artificial ventilation may cause damage to the acutely injured lung has caused renewed interest in ventilation techniques that minimise this potential harm. Many ventilation techniques have proved beneficial in small trials of very specific patient groups, but most have subsequently failed to translate into improved patient outcome in larger trials. An exception to this is ‘protective ventilation’ using reduced tidal volumes (to lower airway pressure) and increased PEEP (to reduce pulmonary collapse). Results of trials of protective ventilation have been encouraging, and the technique should now be adopted more widely. High frequency ventilation, inverse ratio ventilation, prone positioning and inhaled nitric oxide are all techniques that may be considered when, in spite of optimal artificial ventilation, the patient's gas exchange remains dangerously poor. Under these circumstances, the choice of technique is dependent on their availability, local expertise and individual patient needs.
The rigid nasendoscope as a tool for difficult tracheal intubation: A manikin study*
Authors: Goodwin N. , Latto I. P. , Hodzovic I. , Williams G. , Hall J. E.
Published: June 2003

Summary We examined the use of the 30° rigid nasendoscope in aiding difficult tracheal intubations. A Cormack and Lehane grade 4 difficult intubation (no view of glottis or epiglottis) was set up on a manikin. After 10 s of tuition, 40 anaesthetists attempted to pass a standard gum elastic bougie between the cords, with and without the nasendoscope, in randomised order. A bougie curved to an ‘optimal curve’ was also tested. Using the standard bougie 13/40 (33%) passed the bougie between the cords without the nasendoscope, compared with 31/40 (78%) when using the nasendoscope (p < 0.001). The ‘optimal curve’ bougie resulted in 29/40 (73%) and 39/40 (98%) success rates without and with the nasendoscope, respectively (p = 0.004). The nasendoscope is a simple and easy to use tool in grade 4 intubation, and results are improved further by the use of an ‘optimal curve’ bougie.
Long‐term survival following intensive care: Subgroup analysis and comparison with the general population*
Authors: Wright J. C. , Plenderleith L. , Ridley S. A.
Published: June 2003

Summary This study aimed to compare the very long‐term survival of critically ill patients with that of the general population, and examine the association among age, sex, admission diagnosis, APACHE II score and mortality. In a retrospective observational cohort study of prospectively gathered data, 2104 adult patients admitted to the intensive care unit (ICU) of a teaching hospital in Glasgow from 1985 to 1992, were followed until 1997. Vital status at five years was compared with that of an age‐ and sex‐matched Scottish population. Five‐year mortality for the ICU patients was 47.1%, 3.4 times higher than that of the general population. For those surviving intensive care the five‐year mortality was 33.4%. Mortality was greater than that of the general population for four years following intensive care unit admission (95% confidence interval included 1.0 at four years). Multivariate analysis showed that risk factors for mortality in those admitted to ICU were age, APACHE II score on admission and diagnostic category. Mortality was higher for those admitted with haematological (87.5%) and neurological diseases (61.7%) and septic shock (62.9%). A risk score was produced: Risk Score = 10 (age hazard ratio + APACHE II hazard ratio + diagnosis hazard ratio). None of the patients with a risk score > 100 survived more than five years and for those who survived to five years the mean risk score was 57. Long‐term survival following intensive care is not only related to age and severity of illness but also diagnostic category. The risk of mortality in survivors of critical illness matches that of the normal population after four years. Age, severity of illness and diagnosis can be combined to provide an estimate of five‐year survival.
Monitoring long‐term efficacy of iron chelation therapy by deferiprone and desferrioxamine in patients with β‐thalassaemia major: application of SQUID biomagnetic liver susceptometry
Authors: Fischer Roland , Longo Filomena , Nielsen Peter , Engelhardt Rainer , Hider Robert C. , Piga Antonio
Published: June 2003

Summary. In this non‐randomized prospective study, liver and spleen iron concentrations were monitored annually over a 4‐year period by non‐invasive Superconducting Quantum Interference Device biomagnetometry in 54 β‐thalassaemia major patients (age, 7–22 years) receiving treatment with deferiprone (75 mg/kg/d). Median liver iron concentrations increased significantly from 1456 to 2029 and 2449 µg/gliver at baseline, after 2·0 and 3·2 years respectively. Another group of 51 thalassaemic patients (aged 4–34 years) who received desferrioxamine s.c. for 1·9 years increased their liver iron concentration from 1076 to 1260 µg/gliver. Taking into account the increase of the daily iron input from transfusions of 3·6 mg/d, caused by weight gain in 67% of the patients treated with deferiprone, a larger total body iron elimination rate was achieved after 2 years than at baseline. A negative ferritin change was observed in 51% of the patients. In 15 non‐splenectomized patients, liver iron significantly increased from 1260 to 1937 µg/gliver (P < 0·01), but serum ferritin remained stable at 2100 µg/l, as did the spleen iron concentration at 1200 µg/gspleen. A two‐compartment model may predict an average chelation efficacy for desferrioxamine and deferiprone, with a saturation effect of the latter, for a certain chelation and transfusion regimen by a single liver iron quantification.
Decreased treatment failure in recipients of HLA‐identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses
Authors: Ringdén Olle , Barrett A. John , Zhang Mei‐Jie , Loberiza Fausto R. , Bolwell Brian J. , Cairo Mitchell S. , Gale Robert Peter , Hale Gregory A. , Litzow Mark R. , Martino Rodrigo , Russell James A. , Tiberghien Pierre , Urbano‐Ispizua Alvaro , Horowitz Mary M.
Published: June 2003

Summary. We studied the association between CD34 cell dose and transplant outcomes in 359 bone marrow (BM) and 511 peripheral blood stem cell (PBSC) transplant recipients from human leucocyte antigen (HLA)‐identical siblings, reported to the International Bone Marrow Transplant Registry (IBMTR). Transplants for leukaemia were performed between 1995 and 1998. Patients were divided into those receiving below or above the median CD34+ dose, for BM (3 × 106/kg) and PBSC (6 × 106/kg) grafts respectively. Cox proportional hazards regression was used to adjust for baseline patient‐, disease‐ and transplant‐related characteristics. Analysis of the BM recipients showed that high CD34 cell dose was associated with lower transplant‐related mortality [relative risk (RR) = 0·60, P = 0·033] and treatment failure (inverse of leukaemia‐free survival, RR = 0·69, P = 0·032). Among PBSC recipients, high CD34 dose was associated with faster recovery of neutrophils to > 0·5 × 109/l (RR = 1·38, P < 0·001) and platelets to > 20 × 109/l (RR = 1·34, P = 0·003), lower risk of relapse (RR = 0·62, P = 0·029) and treatment failure (RR = 0·74, P = 0·03). We conclude that higher CD34 cell doses decrease treatment failure in recipients of HLA‐identical sibling BM and PBSC transplants.
Protein kinase C‐delta is commonly expressed in multiple myeloma cells and its downregulation by rottlerin causes apoptosis
Authors: Ni Hongyu , Ergin Melek , Tibudan Shalini S. , Denning Mitch F. , Izban Keith F. , Alkan Serhan
Published: June 2003

Summary. The growth and proliferation of multiple myeloma (MM) cells are influenced by various cytokines produced by bone marrow stromal cells. As cytokine interaction between malignant plasma cells and neighbouring stromal cells is important in the pathogenesis of MM, the understanding of intracellular signalling events elicited by this interaction is of central importance. Recent reports have shown that protein kinase C (PKC) is directly involved in modulating apoptosis in different cells types, including those of haematopoietic neoplasms. In the present study, we analysed the expression patterns of PKC isoforms in the myeloma cell lines U266, RPMI‐8226 and K620. This analysis demonstrated common expression of PKC‐δ, PKC‐ι, PKC‐µ and PKC‐ζ in all three myeloma cell lines. PKC‐δ expression in plasma cells from 11 patients with MM was also shown by immunohistochemistry, utilizing a monoclonal mouse anti‐human PKC‐δ antibody. U266 cells treated with the broad PKC inhibitor safingol (l‐threo‐dihydrosphingosine) or the PKC‐δ‐specific inhibitor rottlerin (3′‐[(8‐Cinnamoyl‐5,7‐dihydroxy‐2,2‐dimethyl‐2H‐1‐benzopyran‐6‐yl)methyl]‐2′,4′,6′‐trihydroxy‐5′‐methylacetophenone) showed decreased PKC‐δ in the particulate fraction and resulted in significant apoptosis. Primary myeloma cells also showed apoptosis after treatment with the PKC inhibitors, as detected by both flow cytometric and morphological evaluation. Our results indicate that PKC‐δ is commonly expressed in myeloma cells and plays an important role in plasma cell survival.
Flow cytometry detection of serotonin content and release in resting and activated platelets
Authors: Gobbi Giuliana , Mirandola Prisco , Tazzari Pier Luigi , Ricci Francesca , Caimi Luigi , Cacchioli Antonio , Papa Stefano , Conte Roberto , Vitale Marco
Published: June 2003

Summary. Early detection of platelet activation is important for the diagnosis and follow‐up of several pathological conditions that primarily or secondarily involve platelets in their pathogenesis. The golden standard assay to detect thrombocyte activation is represented by the release of serotonin, classically performed by demanding methodologies, such as high‐performance liquid chromatography, 14C‐labelling and enzyme‐linked immunosorbent assay (ELISA). We developed a non‐radioactive method, based on individual cells, for the detection of serotonin content in activated and resting platelets by flow cytometry. The assay was standardized on cells activated by Ca2+ ionophore or by sera from patients with heparin‐induced thrombocytopenia (HIT). Cells were identified by CD41a surface staining and their serotonin content measured by specific antiserotonin intracytoplasmic staining, while their activation was independently shown by annexin V binding. Cellular degranulation was detected by flow cytometry in all the cases that were also positive by standard ELISA. Moreover, multiparametric flow cytometry analysis revealed that, although virtually all activated cells bind annexin V, serotonin was released only by the platelet subset that downmodulates surface CD41a.
Reassessment of von Willebrand factor (VWF), VWF propeptide, factor VIII:C and plasminogen activator inhibitors 1 and 2 during normal pregnancy
Authors: Sie Pierre , Caron Claudine , Azam Jany , Goudemand Jenny , Grandjean Helene , Boneu Bernard , Fournié Alain
Published: June 2003

Summary. The use of von Willebrand factor [VWF antigen (WF:Ag)] measurement as a marker of endothelial cell activation for monitoring hypertensive pregnancies is limited by the poor definition of reference values. We reassessed these reference values using different assays, and those of the propeptide (VWF:Ag II) and factor VIII coagulant activity (factor VIII:C), in a large population of normal pregnancies, at 3‐week intervals of gestational age. Plasminogen activator inhibitors (PAI‐1 and PAI‐2) were measured in parallel. Blood was collected at single time points between 12 weeks and delivery in 306 women undergoing normal singleton pregnancy. For clinical purposes, the VWF:Ag reference values were assay independent and the influence of ABO blood group on VWF:Ag or factor VIII:c was found to be limited during the third trimester. VWF:Ag II was not influenced by the ABO blood group. The ratio, VWF:Ag/factor VIII:C was close to 1·0 throughout pregnancy. In contrast, VWF:Ag II increased more slowly than VWF:Ag and the ratio of VWF:Ag II to VWF:Ag in plasma decreased from 1·00 to 0·5 at term. PAI‐1 and PAI‐2 increased with gestational age, but PAI‐2 decreased during the last 2 weeks, indicating physiological placental regression at the very end of pregnancy.
Viral antigen‐specific CD8+ T‐cell responses are impaired in multiple myeloma
Authors: Maecker Britta , Anderson Karen S. , Von Bergwelt‐Baildon Michael S. , Weller Edie , Vonderheide Robert H. , Richardson Paul G. , Schlossman Robert L. , Menezes Isaura A. , Xia Zhinan , Munshi Nikhil C. , Anderson Kenneth C. , Nadler Lee M. , Schultze Joachim L.
Published: June 2003

Summary. Multiple myeloma (MM) is associated with defects of humoral and cellular immunity, however, little is known about the frequency and function of antigen‐specific CD8+ T cells. Such information might be critical for the development of immunotherapy for MM patients. As a model, we assessed the frequency and proliferation of CD8+ T cells specific for HLA‐A*0201‐restricted immunodominant epitopes from influenza A (Inf A) and Epstein–Barr virus (EBV). Experiments in identical twins demonstrated reduced numbers of antigen‐specific T cells after ex‐vivo antigenic challenge in the MM twin when compared with the healthy twin. Similarly, the proliferation and frequency of EBV‐ and Inf A‐specific T cells was also significantly reduced in a cohort of 24 previously untreated or conventionally treated MM patients when compared with 19 healthy individuals. In contrast, MM patients studied after receiving an autologous stem cell transplantation showed strikingly higher frequencies of EBV‐specific T cells with potential to proliferate ex vivo, suggesting that EBV‐specific T cells are readily expandable under these circumstances. These data identify an impaired response of CD8+ T cells in MM patients, which might in part explain the relatively limited success of anti‐MM immunisations. Prospective studies will determine whether such immune assessment strategies may identify patients more likely to benefit from cancer immunotherapy.
Risks of mortality in children admitted to the paediatric intensive care unit after haematopoietic stem cell transplantation
Authors: Tomaske Maren , Bosk Axel , Eyrich Matthias , Bader Peter , Niethammer Dietrich
Published: June 2003

Summary. The risk of mortality in children admitted to the paediatric intensive care unit (PICU) after haematopoietic stem cell transplantation is felt to be very high. Life‐threatening complications leading to PICU admission are due to organ toxicity caused by conditioning regimes and graft‐versus‐host disease (GVHD), systemic infections and other organ dysfunctions. Data collected between October 1998 and December 2001 of paediatric patients undergoing haematopoietic stem cell transplantation and thereafter admitted to the PICU were retrospectively analysed in order to reveal the possible causes and risk factors related to death while in the PICU. Twenty‐six PICU admissions were recorded. We found a mortality rate of 57·7% and a 6‐month survival rate of 23·1%. Univariate analysis identified an oncological paediatric risk of mortality (O‐PRISM) score above 10 points, sustained renal failure and a failed negative fluid balance as significant predictors to non‐survival.
Prognostic significance of soluble interleukin‐2 receptor levels in patients with dilated cardiomyopathy
Authors: Limas C. J. , Hasikidis C. , Iakovou J. , Kroupis C. , Haidaroglou A. , Cokkinos D. V.
Published: June 2003

Background Activation of T lymphocytes is thought to mediate myocardial dysfunction in dilated cardiomyopathy (CMP), probably through cytotoxic cytokines, but its value as a prognostic factor has not been evaluated.

Methods For 2 years we prospectively followed 76 patients (65 males, 11 females, age 49 ± 7 years) with CMP and New York Heart Association(NYHA) Class II–III heart failure; left ventricular (LV) function was assessed echocardiographically. Thirty‐three patients (28 males, five females, age 52 ± 6 years) with ischaemic heart disease (IHD) and similar NYHA and LV function characteristics were used as controls. Serum sIL‐2R levels, peripheral blood lymphocyte proliferation (basal, + concanavalin A) and HLA‐DQB1 genotyping was carried out in all patients.

Results The CMP patients had increased sIL‐2R levels (1259 ± 130 pg mL−1) compared with the IHD patients (703 ± 80 pg mL−1, P < 0·01, only 3 > 800 pg mL−1). In the CMP patients, there was a significant (r = +0·45, P= 0·04) correlation between sIL‐2R and the LV end‐diastolic diameter but not with the LV ejection fraction or NYHA Class. During the 24‐month follow up, 17 of the CMP patients had an adverse clinical course (death, need for cardiac transplantation, or worsening heart failure). Of these, 14 (75%) had elevated (≥ 800 pg mL−1) sIL‐2R levels (Group I) compared with only five (6%) with a stable clinical course (Group II). Neither [3H] thymidine incorporation into the peripheral blood lymphocytes nor the excess of HLA‐DQB1‐30 histidine homozygotes in the Group I patients (38% vs. 17%, P < 0·05) could predict the clinical outcome.

Conclusion Increased sIL‐2R levels in CMP patients are an independent predictor of a more aggressive clinical course.
Broad identification of bacterial type from pus by 1H MR spectroscopy
Authors: Garg M. , Misra M. K. , Chawla S. , Prasad K. N. , Roy R. , Gupta R. K.
Published: June 2003

Background  Abscess formation is a common bacterial infection and requires an immediate antimicrobial approach for apposite treatment. Delay in patient treatment is usually a common feature, as the bacterial identification of clinical samples is based on the culture, which is a time‐consuming exercise. The current study was aimed at developing an alternative technique with the potential for rapid bacterial group identification.

Materials and methods  In the present study we performed ex vivo proton magnetic resonance spectroscopy of 40 pus samples collected from abscesses in different locations and the results have been retrospectively compared with the microorganism identified in the pus culture. In addition, the microbes obtained from the culture have been further subcultured and studied with magnetic resonance spectroscopy to identify the bacterial fingerprint in the pus sample seen on spectroscopy.

Results  On reviewing the spectra obtained from the various abscesses, they were found to be qualitatively similar for a particular bacterium. The similar spectral pattern of the pus with obligate aerobes/anaerobes and pure cultures of the same bacteria suggests its strict metabolism under in vivo and in vitro conditions, respectively.

Conclusions  The characteristic metabolite pattern of obligate anaerobes may be used as a prototype for its rapid identification. This information may be of value for more appropriate clinical management of such cases.
Urinary excretion of complement C3d in patients with renal diseases
Authors: Branten A. J. , Kock‐Jansen M. , Klasen I. S. , Wetzels J. F.
Published: June 2003

Introduction  Complement‐mediated tubular injury may play an important role in the progression of renal diseases. C3d is a presumed marker of complement activation. Its precursor C3dg has been detected in the urine of patients with membranous nephropathy. However, little is known of the renal handling of C3d or its excretion in other renal diseases.

Methods  We measured the urinary excretion of albumin, IgG, β2‐microglobulin (β2m), and of complement C3d in patients with tubulo‐interstitial nephritis (TIN; n= 8), in patients with membranous nephropathy (n = 35) and in patients with nonmembranous glomerular diseases (23 nonproliferative and 21 proliferative). Fractional excretions (FE) were calculated using creatinine clearance as marker of GFR.

Results  C3d was not measurable in the urine of the healthy controls, but was detectable in seven out of eight of the TIN patients (median excretion 0·11 mU min−1, range 0·006–2·4 mU min−1). In these patients the urinary excretion of β2m was clearly elevated (median 26·6 µg min−1, range 1·0–103 µg min−1). The FE of C3d correlated with the FE of β2microglobulin (r = 0·83, P = 0·01), and their ratio amounted to 0·03 (range 0·003–0·06), a value in agreement with the expected sieving coefficient. Urine C3d was detectable in all but three of the patients with glomerular diseases (median excretion 0·36 mU min−1, range 0·004–7·9 mU min−1); C3d‐excretion did not differ between the three subgroups of patients with glomerular diseases. FEC3d correlated with FEIgG (r = 0·88, P < 0·01). The ratio FEC3d/FEβ2m was 0·78 (range 0·04–9·99). Selected patients with membranous nephropathy were re‐analyzed after (partial) remission of proteinuria. Reduction of proteinuria resulted in a decrease of C3d excretion.

Conclusion  Urinary excretion of C3d is elevated in patients with TIN, most likely as a mere consequence of decreased tubular reabsorption. In patients with glomerular diseases urinary excretion of C3d is increased and related to proteinuria, independent of the underlying glomerular disease. In these patients there is evidence of increased local formation of C3d.
Variable expression of CYP and Pgp genes in the human small intestine
Authors: Lindell M. , Karlsson M. O. , Lennernäs H. , Påhlman L. , Lang M. A.
Published: June 2003

Background  The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome P450 and P‐Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes.

Methods  The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT‐PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed.

Results  Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively.

Conclusions  Extensive interindividual variability is characteristic for the expression of drug‐metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation.
Nesidioblastosis in adults: a challenging cause of organic hyperinsulinism
Authors: Kaczirek K. , Soleiman A. , Schindl M. , Passler C. , Scheuba C. , Prager G. , Kaserer K. , Niederle B.
Published: June 2003

Background Nesidioblastosis in adults has been reintroduced into the differential diagnosis of organic hyperinsulinism by the description of ‘noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS)’.

Materials and methods Pathologic specimens of all adult patients (n = 66) operated on for organic hyperinsulinism were re‐examined. Five patients fulfilled the histomorphological criteria of nesidioblastosis. Retrospective review of clinical presentation, results of 72‐h fasts, intravenous tolbutamide tolerance tests, pre‐ and intraoperative localization studies and surgical therapy was performed.

Results In contrast to NIPHS, fasting tests became positive after 8–14 h. Tolbutamide tests were positive and preoperative imaging showed negative results in all patients. At first operation distal pancreatic resections were performed in three patients, resection of the pancreatic body in one patient and biopsy of the pancreatic tail in one patient. Two of three patients with recurrent disease had to be reoperated. One patient showed a coexistence of nesidioblastosis and multiple small insulinomas and is part of a kindred with autosomal dominantly inherited ‘familial islet‐cell adenomatosis’.

Conclusions Surgical exploration is indicated only after thorough biochemical diagnosis. An aggressive strategy for preoperative localization including selective arterial calcium stimulation testing seems justified. There may be a combination of nesidioblastosis and islet cell tumours. A link between β‐cell hyperplasia and progression to insulinoma based on not yet known genetic causes can be suspected.