bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomechanical Analysis of a Modification of Tang Method of Tendon Repair
Authors: WANG B. , XIE R. G. , TANG J. B.
Published: July 2003

We report a modification of the original Tang technique of tendon repair which uses fewer sutures and has fewer knots on the tendon surface. The modified method consists of six longitudinal and two horizontal strands that form an “M” configuration within the tendon and four dorsal longitudinal strands made with a single looped suture. Thirty-six fresh pig flexor tendons were divided and repaired with either the modified Tang or the Tang method. The tendons were subjected to linear or 90° angular loading in an Instron tensile machine. The gap formation strength and ultimate strength of the modified Tang repair was statistically identical to those of the Tang method under linear tension. Under angular tension, the ultimate strength of the modified Tang method was greater than that of the Tang method.
The Natural History of an Untreated Isolated Scapholunate Interosseus Ligament Injury
Authors: O’MEEGHAN C. J. , STUART W. , MAMO V. , STANLEY J. K. , TRAIL I. A.
Published: July 2003

The natural history of an untreated isolated scapholunate interosseus ligament injury remains unclear, although it is commonly assumed that patients continue to suffer with pain, stiffness and weakness of the wrist and ultimately develop secondary osteoarthritis (SLAC wrist). In this study, we evaluated the clinical condition of 11 patients with an arthroscopically proven interosseus scapholunate ligament injury, but without any radiological signs of either DISI deformity or scapholunate gapping, who had declined further treatment at an average follow-up of 7 years. Whilst there was on going pain and functional limitation in all cases, there was no rapid progression to degenerative change (SLAC wrist).
Influence of Core Suture Material and Peripheral Repair Technique on the Strength of Kessler Flexor Tendon Repair
Authors: MISHRA V. , KUIPER J. H. , KELLY C. P.
Published: July 2003

The purpose of our study was to determine the most favourable combination of core suture material and peripheral repair technique for Kessler tendon repair. Thirty freshly thawed pig flexor tendons were repaired by a Kessler technique, either with braided polyester or monofilament nylon suture. A peripheral augmentation was done using one of the three techniques – running, cross-stitch and Halsted. All repairs were tested by cyclic loading, followed by load-to-failure. During cyclic loading six of the 15 tendons with a nylon core failed, but none with a braided polyester core. Irrespective of peripheral technique, the monofilament nylon core suture allowed early central cyclic gapping, resulting in failure of the repair. During load-to-failure testing, the running stitch proved weakest and the cross-stitch repair toughest.
Outcome of Hand Trauma: The Hand Injury Severity Scoring System (HISS) and Subsequent Impairment and Disability
Authors: MINK VAN DER MOLEN A. B. , ETTEMA A. M. , HOVIUS S. E. R.
Published: July 2003

This study was designed to evaluate correlations between the hand injury severity scoring system (HISS) and measures of impairment and disability obtained 6 months after a hand injury. A statistically significant positive correlation was found between the severity of the injury (HISS) and residual impairment, as measured with the American Medical Association’s (AMA) “Guides to the evaluation of permanent impairment, 4th edition”. No statistically significant correlation was found between the severity of the injury (HISS) and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, which measures disability from the patient’s perspective. There was however a statistically significant correlation between AMA total body impairment measured and the results of the DASH questionnaire. The results indicate the potential of the HISS for predicting the final impairment after hand injuries.
The Rheumatoid Wrist in Black South African Patients
Authors: MARITZ N. G. J. , GERBER A. J. , GREYLING S. J. , SANDA B. B.
Published: July 2003

The wrist and hand X-rays of 75 black patients with rheumatoid arthritis were scored according to the Larsen criteria. The mean Larsen score for left hands was 9.6 (range 0–100) and for the right hands was 10:3 (range 0–100), whereas the score for the wrists were 2.5 (range 0–5) for the left and 2.7 (range 0–5) for the right. Our conclusion is that rheumatoid wrist involvement in black patients was more or less the same as reported in other series, but finger joint involvement was considerably less. This finding must influence surgical decision-making and also the interpretation of results of drug trials, whenever black patients are involved.
Miniplate Fixation for Avulsion Injuries of the Flexor Digitorum Profundus Insertion
Authors: KANG N. , PRATT A. , BURR N.
Published: July 2003

This article describes the use of a miniplate and cortical screws in the treatment of five cases of flexor digitorum profundus (FDP) tendon avulsion. One case was type II, three cases were type III and one case was type IV. Near normal joint congruity was restored together with bony union in all cases. Six months after surgery four cases had near normal range of motion at the distal interphalangeal joint compared with the contralateral uninjured finger. These four patients were to return to their previous activities without restriction by 3 months. One repair of a type III avulsion ruptured but the distal interphalangeal joint was pain free and stable and the patient declined further surgery. Miniplate fixation offers some advantages over existing methods of repair and adds to the range of techniques available for reattachment of the FDP tendon in these injuries.
Hand Injuries in Young Children
Authors: LJUNGBERG E. , ROSBERG H. E. , DAHLIN L. B.
Published: July 2003

Four hundred and fifty five young children (0–6 years old) were treated for hand injuries between 1996 and 2000. Boys (61%) were injured more often and a higher number of injuries occurred during May and September. Fingertip injuries were the most common injuries (37%), and were often caused by jamming in doors at home. Fractures were caused by falls and punches and tendon/nerve injuries by sharp objects. The incidence of hand injuries increased from 20.4/10,000/year in 1996 to 45.3/10,000/year in 2000. Only 4% of the children had complex injuries but these placed a high demand on resources. The incidence of injuries was not higher amongst children from immigrant families.
A Biomechanical Study of Reattachment Versus Distal Multistrand Repair in Distal Division of the Flexor Digitorum Profundus
Authors: IWUAGWU F. C. , SHAABAN H. , LEES V. C.
Published: July 2003

Distal division of the flexor digitorum profundus (FDP) within 10 mm of its insertion is commonly treated in the same manner as avulsion of the FDP, using the “button” technique or bone suture anchor fixation. Button and bone suture anchor fixation techniques have been associated with significant complications. Importantly, both lead to shortening of the FDP which may cause flexion contracture at the distal interphalangeal joint. This study compared the breaking strength of a multistrand distal suture with reattachment using the “button-on-the-nail” technique in a laboratory cadaver model of distal FDP division. The data showed that multistrand distal suture repair was at least as strong as reattachment and has the theoretical advantage of avoiding some of the acknowledged complications of reattachment techniques.
Assessing Outcome after Hand Surgery: the Current State
Authors: BINDRA R. R. , DIAS J. J. , HERAS-PALAU C. , AMADIO P. C. , CHUNG K. C. , BURKE F. D.
Published: July 2003

An overview of the current state of outcome measurement after hand surgery is presented. The paper focuses on the development, application and strengths and weaknesses of subjective assessment techniques. It also reviews the existing questionnaires and suggests recommendations for use in research or clinical practice.
The Different Characteristics of Dupuytren’s Disease Fibroblasts Derived from Either Nodule or Cord: Expression of α-Smooth Muscle Actin and the Response to Stimulation by TGF-β1
Authors: BISSON M. A. , MCGROUTHER D. A. , MUDERA V. , GROBBELAAR A. O.
Published: July 2003

Mechanisms behind the onset and progression of Dupuytren’s disease are poorly understood. Both myofibroblasts and transforming growth factor beta 1 (TGF-β1) have been implicated. We studied fibroblast cultures derived from nodules or cords of Dupuytren’s contracture tissue to determine the proportion of myofibroblasts present in comparison with flexor retinaculum fibroblast cultures. We identified myofibroblasts by immunohistochemical staining for α-SMA. We then investigated the effects of TGF-β1 stimulation on these fibroblasts.

Basal myofibroblast/fibroblast proportions were 9.7% in nodule cell cultures, 2.7% in cord cell cultures and only 1.3% in flexor retinaculum cell cultures. Nodule and cord myofibroblast proportions increased to 25.4% and 24.2%, respectively, in response to TGF-β1 treatment. Flexor retinaculum cell cultures showed no response to TGF-β1 stimulation.

Fibroblasts cultured from specific regions of Dupuytren’s tissue retain myofibroblast features in culture. TGF-β1 stimulation causes an increased myofibroblast phenotype to similar levels in both nodule and cord, suggesting that previously quiescent cord fibroblasts can be reactivated to become myofibroblasts by TGF-β1. This could be an underlying reason for high recurrence rates seen after surgery or progression following injury.
Trauma-Related Distress and Mood Disorders in the Early Stage of an Acute Traumatic Hand Injury
Authors: GUSTAFSSON M. , AMILON A. , AHLSTRÖM G.
Published: July 2003

The aim of the study was to estimate the incidence of trauma-related distress and mood disorders in the early stages after acute traumatic hand injuries and identify characteristics associated with these reactions. Data were obtained from 112 patients by means of mailed questionnaires and medical records. Nearly half of the patients had increased levels of intrusive and avoidance symptoms, indicating trauma-related distress. One-third showed signs of a mood disorder. Mood disorders were associated with the need for help with activities of daily living, pain and avoidance symptoms. The study showed that emotional problems in the early stages after injury are related to the consequences of both the injury and the traumatic experience. Negative reactions to the sight of the hand were associated with both trauma-related distress and mood disorders, suggesting that observation of the reactions to the sight of the hand could help to identify patients in need of psychological support.
A comparison of direct macrofaunal mortality using three types of clam dredges
Authors: Gaspar M.B , Leitão F , Santos M.N , Chícharo L , Dias M.D , Chícharo A , Monteiro C.C
Published: July 2003

The white clam Spisula solida is harvested along the entire coast of Portugal using mechanical dredges. In this study, the total direct mortality of the macrobenthic community caused by three types of clam dredges (north dredge—ND, traditional dredge—TD, and the metallic grid dredge—GD) used in the S. solida fishery was determined and compared. The relationship between mortality and catching efficiency for each type of dredge was also assessed. Our results showed significant differences for total direct mortality between the ND and both the GD and TD dredges. This difference was largely attributed to the mortality of animals that died in the dredge track as a direct result of the physical damage inflicted by the dredge passing. It was also found that the damage to uncaught individuals is directly related to gear efficiency. The lower catching efficiency of the ND (64%) led to a higher proportion of damaged individuals being left in the dredge path, when compared with the more efficient GD (98%) and TD (90%) dredges. Short and long-term implications of the impact of dredging on the composition of benthic communities are discussed. From fisheries management and ecological points of view, there are obvious advantages to introduce into the bivalve dredge fisheries more efficient and selective dredges in order to reduce the number of damaged individuals and by-catch, and consequently decreasing the impact on the macrobenthic communities.
Winter and spring changes in condition factor and energy reserves of wild cod compared with changes observed during food-deprivation in the laboratory
Authors: Dutil Jean-Denis , Lambert Yvan , Chabot Denis
Published: July 2003

Atlantic cod were food-deprived for a period of 84 days at three temperatures (2, 6, 10°C), and changes in the liver, gonads and somatic weights, and muscle and liver water contents were monitored and compared with changes observed in wild cod over winter in the northern Gulf of St. Lawrence. Total lack of food during the period January–April would have caused condition to decline to a level at which very high mortality takes place. Actual changes in condition in wild cod were less than predicted from the laboratory experiments except during the period April–May at the onset of spawning. Thus, wild cod were able to meet part of the metabolic costs during winter through occasional feeding, as confirmed by stomach content data. We conclude that previous estimates of natural mortality associated with poor condition in spring were not biased by the selective mortality of poor-condition fish in winter.
Using AMOEBAs to display multispecies, multifleet fisheries advice
Authors: Collie Jeremy S. , Gislason Henrik , Vinther Morten
Published: July 2003

In multispecies fish communities, predation levels change dynamically in response to changes in the abundance of predator and prey species, as influenced by the fisheries that exploit them. In addition to community-level metrics, it remains necessary to track the abundance of each species relative to its biological reference point. In situations with many interacting species, exploited by multiple fishing fleets, it can be complicated to illustrate how the effort of each fleet will affect the abundance of each species. We have adapted the AMOEBA approach to graph the reference levels of multiple interacting species exploited by multiple fleets. This method is illustrated with 10 species and eight fishing fleets in the North Sea. We fit a relatively simple response-surface model to the predictions of a fully age-structured multispecies model. The response-surface model links the AMOEBA for fishing effort to separate AMOEBAs for spawning stock biomass, fishing mortality, and yield. Ordination is used to give the shape of the AMOEBAs functional meaning by relating fish species to the fleets that catch them. The aim is to present the results of dynamic multispecies models in a format that can be readily understood by decision makers. Interactive versions of the AMOEBAs can be used to identify desirable combinations of effort levels and to test the compatibility of the set of single-species biological reference points.
Influence of improved performance monitoring on the consistency of a bottom trawl survey
Authors: Zimmermann Mark , Wilkins Mark E , Weinberg Kenneth L , Lauth Robert R , Shaw Franklin R
Published: July 2003

Numerous trawl hauls, made during the triennial bottom trawl surveys (1977–1998) conducted by the National Marine Fisheries Service off the U.S. West Coast, had unusually small catch rates of benthic fish and invertebrates (cpueB), probably because the trawl failed to contact the seabed (off-bottom). Technological advances in the equipment used to monitor trawl performance since 1986 have increased our ability to recognize off-bottom tows, and cpueB has risen. As direct trawl performance measurements were not available in earlier surveys, a minimum cpueB derived from the survey with the best monitoring of bottom contact of the time-series (1998) was used as a criterion to eliminate trawls with poor bottom contact from earlier surveys. The truncated data sets produce significantly larger biomass indices, especially in 1980, with increases of 43, 45, and 56% for Dover sole, petrale sole, and Pacific sanddab, respectively. The analysis suggests that changes in cpueB over the time-series may be related more to changing survey fishing methods than to changes in abundance. Other bottom trawl surveys, which have also added trawl monitoring equipment during their time-series, may have experienced similar changes in trawl performance.
Acoustic Doppler current profiler observations of herring movement
Authors: Zedel Len , Knutsen Tor , Patro Ranjan
Published: July 2003

Observations were made of over-wintering (December 1997) and migrating (January 1998) Norwegian, spring-spawning herring (Clupea harengus) using a moored 307 kHz acoustic Doppler current profiler (ADCP). The location of herring in ADCP data is identified by regions of volume-backscatter strength greater than −60 dB re 1 m−1. The presence of herring was verified using net trawls and 38 kHz, EK500 data. While the ADCP cannot make speed measurements of individual fish, the system does provide a measure of the swimming speed and direction of large herring schools. Herring were observed to move both horizontally and vertically: horizontal speeds were from 0 to 50 cm s−1. Higher speeds were observed during daylight hours for both deployments with somewhat increased activity at both dawn and dusk. At night-time, over-wintering herring demonstrated no well-defined velocity.
The role of inorganic and organic nutrients on the development of phytoplankton along a transect from the Daugava River mouth to the Open Baltic, in spring and summer 1999
Authors: Põder Tõnis , Maestrini Serge Y , Balode Maija , Lips Urmas , Béchemin Christian , Andrushaitis Andris , Purina Ingrida
Published: July 2003

The importance of dissolved silicate (DSi), dissolved inorganic nitrogen (DIN), dissolved organic nitrogen (DON), phosphate and dissolved organic phosphorus (DOP) on algal growth is analysed for the Gulf of Riga and the adjacent open Baltic Sea. The results of three cruises (May, June, and July, 1999) along a transect across the Gulf of Riga from the entrance to the Daugava River to the open Baltic are presented. Nutrient-limitation was identified on the basis of available nutrient concentrations and stoichiometric analysis. In spring, phosphate appeared to be the algal-growth-potential-limiting nutrient at the entrance of the Daugava River, DSi in the central Gulf, and DIN at the open Baltic station. There was no correlation between limiting nutrient and spring phytoplankton community structure. Both the DIN and phosphate pools of the upper mixed layer were exhausted by mid-May, except at the river mouth. In summer there was a good correlation between phytoplankton biomass and DOP along the transect. Contrary to the situation in the open Baltic, the lower layer DIN/phosphate ratio in the Gulf of Riga significantly exceeds the Redfield ratio, and upwelling likely does not favour nitrogen-fixing species. Therefore, the upper layer DOP pool should be regarded as potentially the main source of phosphorus for nitrogen-fixing cyanobacteria in the Gulf of Riga.
Acoustic observations of the swimming behavior of the euphausiid Euphausia pacifica Hansen
Authors: De Robertis Alex , Schell Chad , Jaffe Jules S
Published: July 2003

A high-resolution, 445 kHz, multi-beam sonar and new data-processing techniques were used to characterize the swimming behavior of the euphausiid Euphausia pacifica Hansen, in Saanich Inlet, British Columbia. The instrument was deployed when the euphausiids were at depth during the day and during dusk periods of population ascent. Three-dimensional swimming paths of individual euphausiids were reconstructed by linking successive, acoustically determined positions. Median swimming speeds were 1.8 cm s−1 during the day and 2.2–3.5 cm s−1 during dusk periods of vertical ascent. The presence of a fish at distances of 20–300 cm did not affect the swimming speed or turning of the euphausiids, suggesting that they did not respond to the presence of a potential predator at these distances. Euphausiids moved primarily obliquely in the vertical plane, with few individuals moving directly up or down, even during periods of vertical migration at dusk. We hypothesize that oblique swimming trajectories of euphausiids may reduce vulnerability to visual predators by allowing them to maintain bioluminescent counter-illumination during vertical migration.
The quantitative definition of the Barents Sea Atlantic Water: mapping of the annual climatic cycle and interannual variability
Authors: Smolyar I. , Adrov N.
Published: July 2003

The Barents Sea Atlantic Water (AW) is defined in eight different ways in the literature. These definitions can be consolidated into one statement (decision rule) that allows the separation of the AW of the Barents Sea from the rest of the water masses there. The decision rule defines AW as a straight-line function of temperature and salinity and non-Atlantic Water and Mixed Water by their proximity to AW on a temperature–salinity diagram. This rule is used to map the monthly-mean distribution of AW in the Barents Sea at 0, 30, 50 and 100 m depths. These maps demonstrate two stable seasons (winter and summer) of AW intrusion into the Barents Sea. The average duration of the AW-winter season is five months (January to May), whilst that of the AW-summer season is four months (July to October). During the winter, the area coverage of the AW at the surface equals 23% and varies slightly with depth. During summer, there is zero areal coverage of the AW at the surface, and with depth it varies considerably. The decision rule was used to map the monthly distribution of AW along latitude 74°30′N in the Barents Sea for the period 1975–1989. The maximum inflow of AW into the Barents Sea along 74°30′N occurs during March. The minimum inflow of AW occurs in August. The March/August inflow ratio is 1.55.
Spatial variation in growth of the green tiger prawn (Penaeus semisulcatus) along the coastal waters of Kuwait, eastern Saudi Arabia, Bahrain, and Qatar
Authors: Ye Y. , Bishop J.M. , Fetta N. , Abdulqader E. , Al-Mohammadi J. , Alsaffar A.H. , Almatar S.
Published: July 2003

Shrimp (Penaeus semisulcatus) length-frequency data collected from the coastal waters of Kuwait, Saudi Arabia, Bahrain, and Qatar during a 23-month study from 1999 to 2001 were analyzed to estimate parameters of von Bertalanffy growth equation. All growth curves show a strong seasonal oscillation and a difference in size between males and females. The estimates of l∞ exhibit a southward decreasing trend with increasing temperature and salinity. A single variable of annual mean temperature explains 94 and 81% of the variations in l∞ for males and females, respectively. Likelihood ratio tests compared growth parameters among survey areas. A significant difference in growth was found between Kuwait and Kufji, and between Manifa and Dareen. Based on these results, we conclude that three separate populations of P. semisulcatus are present in the western Arabian Gulf: one in Kuwait, one in Kufji and Manifa, Saudi Arabia, and a third occupying Dareen, Saudi Arabia, Bahrain, and Qatar waters. Countries sharing unit stocks should implement a cooperative approach to the management of each.
Time scale of ovarian maturation in Greenland halibut (Reinhardtius hippoglossoides, Walbaum)
Authors: Junquera S , Román E , Morgan J , Sainza M , Ramilo G
Published: July 2003

Evidence for a prolonged ovarian development phase in Greenland halibut is presented. The reproductive cycle in this species was originally described based on the assumption that this phase should last about one year. The results of the present study, which involves data series covering a long time period and different geographic areas, show instead that there is more than one year between the mean age of the females that are at the onset of ovarian development and the mean age of the females that are actually spawning. There are two possible interpretations for this observation. One is that the ovarian development phase (vitellogenesis) could last more than one year and thus as a consequence, individual spawning would not necessarily occur on an annual basis. The other would be the existence of a high proportion of non-spawning females every year for other reasons not related with the natural rhythm of oocyte development.
A bioeconomic multispecies analysis of an estuarine small-scale fishery: spatial structure of biovalue
Authors: Rueda Mario , Defeo Omar
Published: July 2003

We estimated the spatial population structure by size and the economical potential (biovalue) of a multispecies fish resource in an estuarine lagoon in Colombia, based on fishery-dependent (catch and effort) and independent (seasonal fishing surveys) data. Model-based (geostatistics, kriging) estimations of such performance variables were used to quantify the uncertainty in abundance, individual price by size and variable costs per haul. Monte Carlo analysis was used to assess the status of the fishery. The spatial dimension of risk analysis was explored by indicator kriging, whereas effects of biovalue on the spatial allocation of fishing effort were evaluated using contingency tables. Fish abundance, individual sizes and biovalue were spatially structured, but the spatial patterns varied between seasons and species. Analysis of biovalue showed a moderate risk that fishers had economic losses derived from the fishing activity. Spatial risk analysis showed that no more than 30% of the total area from the lagoon registered profitable levels of fish abundance, which affected the spatial allocation of fishing effort. Management implications supported by our study suggest seasonal and spatial fishing closures to protect juveniles and spawning stock of fish species.
A cellular model for myeloma cell growth and maturation based on an intraclonal CD45 hierarchy
Authors: Bataille Regis , Robillard Nelly , Pellat‐Deceunynck Catherine , Amiot Martine
Published: July 2003

Summary:  Multiple myeloma (MM) is a plasma cell malignancy mainly characterized by the accumulation of malignant plasma cells within the bone marrow. This review shows that the biology of CD45 illuminates that of MM and, more specifically, provides a better delineation of a tumor cell ‘hierarchy’ of clinical interest. We show that in MM, as in normal plasma cell differentiation, there is an intraclonal CD45 hierarchy that is a gradient of CD45 expression on myeloma cells directly related to their proliferation rate and differentiation status. This CD45 hierarchy allows for the design of a cellular model for MM‐cell growth and maturation in which CD45 bright myeloma cells represent the proliferating compartment and CD45 low myeloma cells the quiescent compartment. This model includes an aberrant phenotype that is annihilation rather than decline of CD45, annihilation reflecting the terminal phase of the disease and/or an aggressive presentation of MM. Data from the literature suggest that CD45 bright myeloma cells are targeted by interleukin (IL)‐6, whereas CD45 negative myeloma cells with a high clonogenic capacity are targeted by insulin/insulin‐like growth factor 1 (IGF‐1). This model will be useful for both a better understanding of the basic biology of MM and a better stratification of and therapeutic approach to the patients. Finally, this model presents MM as a self‐renewing plasma cell disease, although the first oncogenic events such as 14q32 translocations clearly occur earlier in a B cell.
Transcriptional regulatory cascades controlling plasma cell differentiation
Authors: Lin Kuo‐I , Tunyaplin Chainarong , Calame Kathryn
Published: July 2003

Summary:  Plasma cells are the terminally differentiated effector cells of the B lymphocyte lineage. Recently, studies using genetically altered mice and analyses of global gene expression programs have significantly expanded our understanding of the molecular mechanisms regulating plasmacytic differentiation. Specific molecular components of a multistep cascade of transcriptional regulators have been identified. Furthermore, two transcriptional regulators, X box binding protein‐1 (XBP‐1) and B lymphocyte induced maturation protein‐1 (Blimp‐1), have been shown to be necessary for plasmacytic differentiation. In addition to providing a mechanistic basis for the induction of genes necessary for immunoglobulin secretion, cessation of cell cycle and other phenotypic changes characteristic of terminally differentiated plasma cells, these studies have led to the important concept that plasmacytic differentiation involves repression of regulators, such as Bcl‐6 and Pax5, that are necessary to maintain the earlier developmental phenotype of activated, germinal center B cells. This review describes our current understanding of the transcriptional cascades regulating terminal differentiation of B cells.
Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma
Authors: Bergsagel P. Leif , Kuehl W. Michael
Published: July 2003

Summary:  Multiple myeloma (MM) is a tumor of long‐lived bone marrow plasma cells (PCs). Nearly 40% of MM tumors have immunoglobulin H (IgH) translocations involving four recurrent chromosomal loci (oncogenes): 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (MMSET and FGFR3), and 16q23 (c‐maf). Other MM tumors have Ig translocations involving different loci, none of which is involved in more than 1% of tumors. At least 25% of MM tumors have no Ig translocation. Unlike normal PCs, MM tumors usually express one of the three cyclin D genes at a high level. Translocations involving 4p16 and 16q23 do not directly target a cyclin D gene, but they are associated with a high level of cyclin D2 expression. Although cyclin D1 is not expressed in normal hematopoietic cells, one‐third of MM tumors ectopically express cyclin D1 in the absence of t(11;14). Despite a low proliferation index in MM, dysregulation of a cyclin D gene seems to be a unifying oncogenic event. Analysis of 34 MM cell lines indicates that tumors having an IgH translocation are significantly over‐represented, whereas tumors that ectopically express cyclin D1 are not represented. We speculate that ectopic cyclin D1 expression without t(11;14) is dependent on tumor‐specific interaction with bone marrow stromal cells.
Novel therapeutic approaches for multiple myeloma
Authors: Hideshima Teru , Richardson Paul , Anderson Kenneth C.
Published: July 2003

Summary:  Multiple myeloma (MM) affects 15 000 new patients annually in the US, with 50 000 total patients, and remains incurable. Our preliminary in vitro and animal studies suggest a role for MM–host interactions in regulating MM cell growth, drug resistance, and migration in the bone marrow. Importantly, treatment strategies which target mechanisms whereby MM cells grow and survive in the bone marrow, including thalidomide and its potent immunomodulatory derivatives and proteasome inhibitor PS‐341, can overcome classical drug resistance in preclinical and early clinical studies.
Interpreting the molecular biology and clinical behavior of multiple myeloma in the context of global gene expression profiling
Authors: Shaughnessy John D. , Barlogie Bart
Published: July 2003

Summary:  Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody‐secreting plasma cells (PCs). Although several key molecular events in disease initiation or progression have been confirmed (e.g. FGFR3/MMSET activation) or implicated (e.g. chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Importantly, although generally being indistinguishable morphologically, MM exhibits a tremendous degree of variability in clinical course, with some patients surviving only months and others many years. However, current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti‐MM effect are also mostly unknown. In addition, the mechanisms by which MM cells contribute to serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, are also poorly understood. Finally, very little knowledge exists concerning the molecular events leading to benign hyperplasia and/or overt malignancy of PCs. Given that abnormal gene expression lies at the heart of most, if not all, cancers, high‐throughput global gene expression profiling has become a powerful tool for investigating molecular biology and clinical behavior of diseases. Here, we discuss recent progress made in addressing many of the above issues through the molecular dissection of the transcriptome of normal PCs and MM.
The rise and fall of long‐lived humoral immunity: terminal differentiation of plasma cells in health and disease
Authors: O'Connor Brian P. , Gleeson Michael W. , Noelle Randolph J. , Erickson Loren D.
Published: July 2003

Summary:  Long‐lived humoral immune responses are a hallmark of thymus‐dependent immunity. The cellular basis for enduring antibody‐mediated immunity is long‐lived memory B cells and plasma cells (PCs). Both of these cell populations acquire longevity as a result of antigen‐specific, CD40–dependent, cognate interactions with helper T cells within germinal centers (GCs). At the molecular level, defined functional domains of CD40 control the post‐GC fate of B cells. PC precursors that emerge from these GC reactions are highly proliferative and terminally differentiate to end‐stage cells within the bone marrow (BM). The striking phenotypic similarities between the PC precursors and the putative malignant cell in multiple myeloma (MM) suggests that MM may result from the transformation of PC precursors. Within the domain of autoimmune disease, recent studies have shown that dysregulated migration of PCs to the BM may impact immune homeostasis and the development of lupus. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of differentiated B‐cell disorders.
Monoclonal gammopathies of undetermined significance: a review
Authors: Kyle Robert A. , Rajkumar S. Vincent
Published: July 2003

Summary:  Monoclonal gammopathy of undetermined significance (MGUS) denotes the presence of a monoclonal protein (M‐protein) in patients without evidence of multiple myeloma (MM), macroglobulinemia, amyloidosis (AL), or a related plasma cell proliferative disorder. MGUS is found in approximately 3% of persons older than 70 years and in about 1% of those older than 50 years. In a series of 1384 patients from south‐eastern Minnesota in whom MGUS was diagnosed at Mayo Clinic from 1960 through 1994, the risk of progression was 1% per year. Patients were at risk of progression even after 25 years or more of a stable monoclonal gammopathy. The risk of development of MM was increased by 25‐fold, the risk of macroglobulinemia was 46‐fold, and the risk of primary AL was 8.4‐fold when compared with a similar population (Surveillance, Epidemiology and End Results). The concentration of the serum M‐protein was the major independent predictor of progression. Patients with an immunoglobulin M (IgM) or an IgA monoclonal gammopathy had a higher risk of progression than those with an IgG monoclonal gammopathy. The presence of a urine M‐protein or the reduction of one or more uninvolved Igs was not a risk factor for progression. MGUS may be associated with many different disorders, including lymphoproliferative diseases, leukemia, connective tissue disorders, dermatologic diseases, and neurologic disorders.
The X‐box binding protein‐1 transcription factor is required for plasma cell differentiation and the unfolded protein response
Authors: Iwakoshi Neal N. , Lee Ann‐Hwee , Glimcher Laurie H.
Published: July 2003

Summary:  X‐box binding protein‐1 (XBP‐1) is a transcription factor essential for plasma cell differentiation. XBP‐1 transcripts are found at high levels in plasma cells from rheumatoid synovium and myeloma cell lines. Lymphoid chimeras deficient in XBP‐1 have a profound defect in plasma cell differentiation, with few plasma cells in their periphery and severely reduced serum immunoglobulin levels. When introduced into B‐lineage cells, XBP‐1 initiates plasma cell differentiation. XBP‐1 is also the mammalian homologue of the yeast transcription factor Hac1p, an important component of the unfolded protein response (UPR). The UPR allows cells to tolerate conditions of endoplasmic reticulum (ER) stress caused by misfolded proteins. Studies examining the relationship between plasma cell differentiation, XBP‐1, and the UPR demonstrate that this novel signaling system is vital for plasma cell differentiation. Signals that induce plasma cell differentiation and the UPR cooperate via XBP‐1 to induce terminal B‐cell differentiation. Additionally, XBP‐1 plays an important role in the regulation of interleukin‐6 production, a cytokine essential for plasma cell survival.
The role of DNA breaks in genomic instability and tumorigenesis
Authors: Mills Kevin D. , Ferguson David O. , Alt Frederick W.
Published: July 2003

Summary: DNA double‐strand breaks (DSBs) represent dangerous chromosomal lesions that can lead to mutation, neoplastic transformation, or cell death. DSBs can occur by extrinsic insult from environmental sources or may occur intrinsically as a result of cellular metabolism or a genetic program. Mammalian cells possess potent and efficient mechanisms to repair DSBs, and thus complete normal development as well as mitigate oncogenic potential and prevent cell death. When DSB repair (DSBR) fails, chromosomal instability results and can be associated with tumor formation or progression. Studies of mice deficient in various components of the non‐homologous end joining pathway of DSBR have revealed key roles in both the developmental program of B and T lymphocytes as well as in the maintenance of general genome stability. Here, we review the current thinking about DSBs and DSBR in chromosomal instability and tumorigenesis, and we highlight the implications for understanding the karyotypic features associated with human tumors.
Neoplastic development in plasma cells
Authors: Potter Michael
Published: July 2003

Summary:  An increasing number of model systems of plasma cell tumor (PCT) formation have been and are being developed. Discussed here are six models in mice and multiple myeloma (MM) in humans. Each model illustrates a unique set of biological factors. There are two general types of model systems: those that depend upon naturally arising mutagenic changes (pristane‐induced PCTs, 5TMM, and MM) and those that are associated with oncogenes (Eµ‐v‐abl), growth factors [interleukin‐6 (IL‐6)], and anti‐apoptotic factors (Bcl‐xL/Bcl‐2). PCTs develop in several special tissue microenvironments that provide essential cytokines (IL‐6) and cell–cell interactions. In mice, the activation and deregulation of c‐myc by chromosomal translocations is a major feature in many of the models. This mechanism is much less a factor in MM and the 5T model in mice. Genetically determined susceptibility is involved in many of the mouse models, but only a few genes have been implicated thus far.
Cell‐cycle control of plasma cell differentiation and tumorigenesis
Authors: Chen‐Kiang Selina
Published: July 2003

Summary:  Cell‐cycle control is a major determinant of homeostasis during B‐cell development, differentiation, and tumorigenesis. The generation of an antibody response requires activation and expansion of antigen‐specific B cells and terminal differentiation of these cells into plasma cells. Plasma cells arrest in the G1 phase of the cell cycle, but the mechanism that underlies timely cell‐cycle entry and exit in the humoral immune response is not known. The mammalian cell‐cycle is regulated primarily at the G1 to S transition by the balance between positive regulators, the cyclin‐dependent kinases (CDK) together with cyclins, and negative regulators, the CDK inhibitors. One such inhibitor, p18INK4c, has been shown to be required for cell‐cycle termination and final differentiation of non‐secreting plasmacytoid cells to antibody‐secreting plasma cells. This finding provides the first direct evidence for cell‐cycle control of B‐cell immunity. It also raises important questions regarding cell‐cycle control of cellular differentiation, apoptosis, and earlier steps of B‐cell terminal differentiation. This article discusses the biochemical mechanism of cell‐cycle control in the context of antibody response and plasma cell differentiation along with the role of cell‐cycle dysregulation in the pathogenesis of multiple myeloma, the plasma cell cancer.
Botulinum toxin in the therapy of gastrointestinal motility disorders
Authors: Gui D. , Rossi S. , Runfola M. , Magalini S. C.
Published: July 2003

Since 1980, botulinum toxin has been employed for the treatment of various voluntary muscle spastic disorders in the fields of neurology and ophthalmology. More recently, botulinum toxin has been proved to be effective in the therapy of dyskinetic smooth muscle disorders of the gastrointestinal tract. Achalasia and anal fissure are the gastrointestinal disorders in which botulinum toxin therapy has been most extensively investigated. Botulinum toxin is the best treatment option for achalasia in patients whose condition makes them unfit for pneumatic dilation or surgery. In anal fissure, botulinum toxin is highly effective and may become the treatment of choice. In the future, botulinum toxin application in the gastrointestinal tract will be extended to many other gastrointestinal disorders, such as non‐achalasic motor disorders of the oesophagus, dysfunction of Oddi's sphincter, achalasia of the internal anal sphincter and others. This article describes the mechanism of action, rationale of employment, indications and side‐effects of botulinum toxin application in smooth muscle disorders of the gastrointestinal tract, and compares the results of different techniques of botulinum toxin therapeutic application.
Is a 9‐month treatment sufficient in tuberculous enterocolitis? A prospective, randomized, single‐centre study
Authors: Kim S. G. , Kim J. S. , Jung H. C. , Song I. S.
Published: July 2003

Background : Tuberculosis has increased in parallel with the acquired immunodeficiency syndrome epidemic and the use of immunosuppressive therapy, and the growing incidence of extra‐pulmonary tuberculosis, especially with intestinal involvement, reflects this trend. However, the duration of anti‐tuberculous therapy has not been clarified in intestinal tuberculosis.

Aim : To compare the efficacy of different treatment durations in tuberculous enterocolitis in terms of response and recurrence rates.

Methods : Forty patients with tuberculous enterocolitis were randomized prospectively: 22 patients into a 9‐month and 18 into a 15‐month group. Diagnosis was made either by colonoscopic findings of discrete ulcers and histopathological findings of caseating granuloma and/or acid‐fast bacilli, or by clinical improvement after therapeutic trial. Patients were followed up with colonoscopy every other month until complete response or treatment completion, and then every 6 months for 1 year and annually. Complete response was defined as a resolution of symptoms and active tuberculosis by colonoscopy.

Results : Complete response was obtained in all patients in both groups. Two patients in the 9‐month group and one in the 15‐month group underwent operation due to intestinal obstruction and perianal fistula, respectively. No recurrence of active intestinal tuberculosis occurred during the follow‐up period in either group.

Conclusions : Tuberculous enterocolitis can be managed by 9‐month chemotherapy without disease recurrence. Further investigations are needed in immunocompromised patients.
Development and validation of a patient‐assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index
Authors: Revicki D. A. , Rentz A. M. , Dubois D. , Kahrilas P. , Stanghellini V. , Talley N. J. , Tack J.
Published: July 2003

Background : Patient‐based symptom assessments are necessary to evaluate the effectiveness of medical treatments for gastroparesis.

Aim : To summarize the development and measurement qualities of the Gastroparesis Cardinal Symptom Index (GCSI), a new measure of gastroparesis‐related symptoms.

Methods : The GCSI was based on reviews of the medical literature, clinician interviews and patient focus groups. The measurement qualities (i.e. reliability, validity) of the GCSI were examined in 169 gastroparesis patients. Patients were recruited from seven clinical centres in the USA to participate in this observational study. Patients completed the GCSI, SF‐36 Health Survey and disability day questions at a baseline visit and again after 8 weeks. Clinicians independently rated the severity of the patients' symptoms, and both clinicians and patients rated the change in gastroparesis‐related symptoms over the 8‐week study.

Results: The GCSI consists of three sub‐scales: post‐prandial fullness/early satiety, nausea/vomiting and bloating. The internal consistency reliability was 0.84 and the test–re‐test reliability was 0.76 for the GCSI total score. Significant relationships were observed between the clinician‐assessed symptom severity and the GCSI total score, and significant associations were found between the GCSI scores and SF‐36 physical and mental component summary scores and restricted activity and bed disability days. Patients with greater symptom severity, as rated by clinicians, reported greater symptom severity on the GCSI. The GCSI total scores were responsive to changes in overall gastroparesis symptoms as assessed by clinicians (P = 0.0002) and patients (P = 0.002).

Conclusion: The findings of this study indicate that the GCSI is a reliable and valid instrument for measuring the symptom severity in patients with gastroparesis.
Bioavailability of oral vs. subcutaneous low‐dose methotrexate in patients with Crohn's disease
Authors: Kurnik D. , Loebstein R. , Fishbein E. , Almog S. , Halkin H. , Bar‐Meir S. , Chowers Y.
Published: July 2003

Background : Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter.

Aim : To determine the relative bioavailability of oral low‐dose methotrexate administered with and without concomitant folic acid vs. subcutaneous administration in patients with stable Crohn's disease.

Methods : Ten patients were randomized to receive their regular maintenance dose of methotrexate (15–25 mg) for three consecutive weeks: orally, orally with 5 mg folic acid or subcutaneously. Blood samples were drawn at specified intervals during 24 h, and methotrexate levels were determined by fluorescence immunoassay. Areas under the curve extrapolated to infinity (AUC∞) were compared between the three routes.

Results : The geometric mean AUC∞ values (95% confidence intervals) were 360 nmol.h/L (301–430 nmol.h/L), 261 nmol.h/L (214–318 nmol.h/L) and 281 nmol.h/L (209–377 nmol.h/L) per milligram of methotrexate administered for subcutaneous, oral and oral with folic acid administration, respectively (P < 0.05 and P < 0.01 for oral with folic acid and oral vs. subcutaneous administration, respectively). The geometric mean relative bioavailabilities (95% confidence intervals) were 0.73 (0.62–0.86) and 0.77 (0.60–0.99) for oral and oral with folic acid administration, respectively (difference not significant).

Conclusions : In patients with stable Crohn's disease, the oral bioavailability of methotrexate is highly variable and averages 73% of that of subcutaneous administration. Concomitant folic acid has no significant effect on the bioavailability. Dose adjustments based on individual pharmacokinetic assessment should be considered when switching patients from parenteral to oral therapy.