bluuebunny/crossref_metadata_2025 huggingface dataset:
The Climate and Landscape of the Middle Part of the Weichselian Glaciation in Europe: The Stage 3 Project
Authors: van Andel Tjeerd H.
Published: October 2002

Oxygen isotope stage 3 (OIS 3) was a mild interval between the two cold maxima of the last (Weichselian) glaciation marked by climate changes oscillating on a 100–1000 yr time scale between near-interglacial and peak-glacial conditions. During OIS 3, modern humans entered Europe, and somewhat later their Neanderthal predecessors became extinct. Our understanding of this momentous event depends on an answer to the question, Did the unstable environmental conditions of the time play a significant role in early human history? The Stage 3 Project is an interdisciplinary study with two main goals: (1) to describe with existing data and to simulate the climates and landscapes of typical warm and cold phases between 45,000 and 30,000 yr ago and (2) to compare the results with the spatial and temporal distribution of human beings in this context. This paper introduces the Stage 3 Project and provides background to a set of papers on the climate and landscape aspects of the Project that will appear in Quaternary Research and to studies of their relevance to the Early Upper Paleolithic of Europe to appear in journals yet to be determined.
Deriving Proof Rules from Continuation Semantics
Authors: Audebaud Philippe , Zucca Elena
Published: October 2002

We claim that a continuation style semantics of a programming language can provide a starting point for constructing its proof system. The basic idea is to see weakest preconditions as a particular instance of continuation style semantics, hence to interpret correctness assertions (e.g. Hoare triples {
p
}
C
{
r
}) as inequalities over continuations. This approach also shows a correspondence between labels in a program and annotations.
Cache Coherency in SCI: Specification and a Sketch of Correctness
Authors: Felty Amy , Stomp Frank
Published: October 2002

SCI – Scalable Coherent Interface – is an IEEE standard for specifying communication between multiprocessors in a shared memory model. In this paper we model part of SCI by a program written in a UNITY-like programming language. This part of SCI is formally specified in Manna and Pnueli's Linear Time Temporal Logic (LTL). We give a sketch of our proof that the program satisfies its specification. The proof has been carried out within LTL. It uses history variables. Structuring of the proof has been achieved by careful formulation of lemmata and the use of auxiliary predicates as an abstraction mechanism.
Testing Conformance to a Quasi-Non-Deterministic Stream X-Machine
Authors: Hierons R. M. , Harman M.
Published: October 2002

Stream X-machines have been used in order to specify a range of systems. One of the strengths of this approach is that, under certain well-defined conditions, it is possible to produce a finite test that is guaranteed to determine the correctness of the implementation under test (IUT). Initially only deterministic stream X-machines were considered in the literature. This is largely because the standard test algorithm relies on the stream X-machine being deterministic.

More recently the problem of testing to determine whether the IUT is
equivalent
to a non-deterministic stream X-machine specification has been tackled. Since non-determinism can be important for specifications, this is an extremely useful extension. In many cases, however, we wish to test for a weaker notion of correctness called
conformance
. This paper considers a particular form of non-determinism, within stream X-machines, that will be called quasi-non-determinism. It then investigates the generation of tests that are guaranteed to determine whether the IUT
conforms
to a quasi-non-deterministic stream X-machine specification. The test generation algorithm given is a generalisation of that used for testing from a deterministic stream X-machine.
Generalised Stream X-Machines with Output Delimited Type
Authors: Bălănescu Tudor
Published: October 2002

Some conditions relating to the automata involved in the W-testing method are discussed. It is also shown how to use the method for
reduced automata
instead of minimal automata. New design test conditions (
weak output distinguishable
,
strong test-complete and output delimited type
) are considered for the
generalised stream X-machines
(stream X-machines with basic functions replaced by relations and having as output strings of symbols rather than single symbols). It is proved that testing methods similar to those already developed for ordinary deterministic stream X-machines may be applied for generalised stream X-machines with output delimited types. A particular case of generalised stream X-machine with output delimited type is the X-machine with
output delimiter
, which produces outputs having a distinct right end character.
Using VDMTools to Model and Validate the Cash Dispenser Example
Authors: Larsen Peter Gorm , Mukherjee Paul , Sunesen Kim
Published: October 2002

This document gives a short overview of how VDMTools® can be used in different stages of the system/software development process. The application used is a cash dispensing machine, first introduced at the FM'99 Symposium as the basis for a competition amongst tool vendors. The document provides an overview of how we at IFAD envisage that a problem such as this one should be attacked using VDMTools®.
The ‘Cash-Point’ Service: A Verification Case Study Using STeP
Authors: Browne Anca , Finkbeiner Bernd , Manna Zohar , Sipma Henny
Published: October 2002

STeP, the Stanford Temporal Prover, supports the computer-aided formal verification of concurrent and reactive systems based on temporal specifications [MBB99]. Automated
model checking
is combined with computer-aided
deductive methods
to allow for the verification of a broad class of systems, including parameterised (
N
-component) circuit designs, parameterised (
N
-process) programs, and programs with infinite data domains.
Maximally Concurrent Programs
Authors: Joshi Rajeev , Misra Jayadev
Published: October 2002

Typically, program design involves constructing a program
P
that
implements
a given specification
S
; that is, the set
${\overline P}$
of executions of
P
is a subset of the set
${\overline S}$
of executions satisfying
S
. In many cases, we seek a program
P
that not only implements
S
, but for which
${\overline P}$
=
${\overline S}$
. Then, every execution satisfying the specification is a possible execution of the program; we then call
P maximal
for the specification
S
. We argue that maximality is an important criterion in the context of designing concurrent programs because it disallows implementations that do not exhibit enough concurrency. In addition, a maximal solution can serve as a basis for deriving a variety of implementations, each appropriate for execution on a specific computing platform. This paper also describes a method for proving the maximality of a program with respect to a given specification. Even though we prove facts about possible executions of programs, there is no need to appeal to branching time logics; we employ a fragment of linear temporal logic for our proofs. The method results in concise proofs of maximality for several non-trivial examples. The method may also serve as a guide in constructing maximal programs.
Class Refinement as Semantics of Correct Object Substitutability
Authors: Back Ralph-Johan , Mikhajlova Anna , von Wright Joakim
Published: October 2002

Subtype polymorphism, based on syntactic conformance of objects' methods and used for substituting subtype objects for supertype objects, is a characteristic feature of the object-oriented programming style. While certainly very useful, typechecking of syntactic conformance of subtype objects to supertype objects is insufficient to guarantee correctness of object substitutability. In addition, the behaviour of subtype objects must be constrained to achieve correctness. In class-based systems classes specify the behaviour of the objects they instantiate. In this paper we define the class refinement relation which captures the semantic constraints that must be imposed on classes to guarantee correctness of substitutability in all clients of the objects these classes instantiate. Clients of class instances are modelled as programs making an iterative choice over invocation of class methods, and we formally prove that when a class
C
′ refines a class
C
, substituting instances of
C
′ for instances of
C
is refinement for the clients.
Algebraic Composition of Function Tables
Authors: von Mohrenschildt Martin
Published: October 2002

In general, a program is composed of smaller program segments using composition, conditional constructs or loop constructs. We present a theory which enables us to algebraically define and compute the composition of conditional expressions. The conditional expressions are represented using tabular notation. The formal definition of the composition allows us to compute the close form representation of the composition of tabular expressions. The presented approach is based on a many sorted algebra containing information preserving composition. This formal definition of composition is then “lifted” to an extended algebra containing tabular expressions. The presented theory provides very compact algorithms and proofs.
Value of preoperative coagulation tests: Reappraisal of major noncardiac surgery
Authors: Ng Kwok F. J. , Lai Kin W. , Tsang Suk F.
Published: October 2002

In a retrospective case‐control review, we evaluated preoperative coagulation testing in patients undergoing major noncardiac operations to determine if routine testing benefits this group of patients. The platelet count (PC), prothrombin time (PT), and activated partial thromboplastin time (aPTT) in all patients undergoing major noncardiac surgery over a 22‐month period were reviewed. The review was done both manually and by the computerized hospital information system. Major surgery was defined as procedures usually associated with significant bleeding. For each patient with abnormal results, another two control patients undergoing the same surgery and matched for age and gender were identified. Case and control patients were compared regarding a change in the management plan, use of blood products, blood loss, and bleeding complications by detailed chart review. A total of 828 patients undergoing nine different surgeries were reviewed. The incidence of abnormal PCs was 2.2% [95% confidence interval (CI) 1.2–3.2%] and that of abnormal PT/aPTTs was 2.1% (95% CI 1.1–3.1%). There were only two cases each of thrombocytopenia and prolonged PT/aPTT where the coagulation tests were not indicated clinically. Although (compared to controls) patients with abnormal tests had more changes in their anesthesia plan (36% vs. 2%, p<0.001) and platelet or fresh frozen plasma transfusions (50% vs. 9%, p<0.001), blood loss and the incidence of bleeding complications were not different. We conclude that the use of preoperative coagulation tests in patients undergoing major noncardiac surgery should still be guided by clinical assessment. The surgical procedure itself does not constitute an indication for testing.
Progesterone inhibits chloride transport in human intestinal epithelial cells
Authors: Mayol Julio M. , Arbeo‐Escolar Ana , Alarma‐Estrany Pilar , Adame‐Navarrete Yolanda , Fernández‐Represa Jesús A.
Published: October 2002

Several pieces of evidence suggest that female sex hormones may play a role in the regulation of electrolyte transport. We therefore hypothesized that female sex hormones might impair regulated transcellular chloride transport in human intestinal epithelial cells. The T84 cell line was used for electrophysiological studies. Changes in transepithelial resistance and short‐circuit current (Isc) were measured via a dual voltage/current clamp in epithelial monolayers. Short‐circuit current is equivalent to chloride secretion in T84 cells. Forskolin and 8‐Br‐cyclic adenosine monophosphate (cAMP) were used to activate cAMP‐dependent Cl− transport. Ca2+‐dependent secretion was stimulated by the receptor‐mediated Ca2+ agonist carbachol. Acute exposure (30 minutes) to either progesterone or estradiol did not affect monolayer viability as reflected by transepithelial resistance. Moreover, the secretory response to both cAMP and Ca2+ agonists remained unaffected. In contrast, long‐term exposure (24 hours) to physiological concentrations of progesterone (100 nM), but not estradiol, dose‐dependently reduced the peak Isc induced by the cAMP‐agonist forskolin from 125±2.7 µA · cm−2 in the control group to 96±2.5 µA · cm−2 in monolayers exposed to progesterone (n=6 for each group; p<0.001). When the cAMP‐analogue 8‐Br‐cAMP was used, the same behavior was observed (peak Isc=112±1.6 µA · cm−2 vs 88±1.7 µA · cm−2 for control vs. progesterone‐treated monolayers; n=6 for each group; p<0.001). Taken together, our results suggest that progesterone but not estradiol inhibits cAMP‐stimulated Cl− secretion in intestinal epithelial cells at a site distal to cyclic nucleotide generation.
Clinicopathological prognostic factors and impact of surgical treatment of mass‐forming intrahepatic cholangiocarcinoma
Authors: Suzuki Shohachi , Sakaguchi Takanori , Yokoi Yoshihiro , Okamoto Kazuya , Kurachi Kiyotaka , Tsuchiya Yasuo , Okumura Takuya , Konno Hiroyuki , Baba Satoshi , Nakamura Satoshi
Published: October 2002

The clinicopathological characteristics relevant to prognosis after surgical treatment of intrahepatic cholangiocarcinoma (ICC) remain unclear. In this study, the clinicopathological features of 19 patients with mass‐forming ICC, the most common form of the disease, were reviewed to analyze prognostic determinants. Two or more segmentectomies of the liver with systematic lymphadenectomy were performed in 18 patients. Resection of the extrahepatic bile duct was performed in 14 patients, and reconstruction of the portal vein was accomplished in 5 patients. Stage IVA or IVB tumors were seen in 13 patients, and lymph node (LN) metastasis was present in 14 patients. The estimated 5‐year survival rate after surgery for mass‐forming ICC was 28%, with median survival time of 18 months. In univariate analysis, five variables were determined to be significantly correlated with poor survival of patients with mass‐forming ICC after surgery. These variables include mass‐forming ICC with periductal infiltration, perineural invasion, portal vein invasion, presence of intrahepatic metastasis, and two or more LN metastases. Survival rates of 5 patients without LN metastasis and 6 patients with a single LN metastasis were 80% and 33% at 5 years, respectively, while 8 patients with two or more LN metastasis failed to survive beyond 2 years. Multivariate analysis revealed the presence of intrahepatic metastasis to be an independent prognostic factor of poor survival. Hepatectomy with resection of the extrahepatic bile duct and systematic lymphadenectomy yields a good chance for prolonged survival for patients with mass‐forming ICC when the lesion is singular and LN metastasis is limited to a regional LN. Because the presence of intrahepatic metastasis was closely related to a poor prognosis in patients with mass‐forming ICC, efficacious chemotherapy would be needed to control development of the lesion.
Morphologic Studies of the Placenta and Autopsy Findings in Neonatal-onset Glutaric Acidemia Type II
Authors: Slukvin Igor I. , Salamat M. Shahriar , Chandra Sunita
Published: October 2002

A case of neonatal-onset glutaric acidemia type II with electron-transfer flavoprotein (ETF) deficiency is presented. The morphological pattern of disease in the male infant included hypospadias, cryptorchidism, bilateral 13 ribs, nuclear cataract, cystic dysplasia of kidneys, lipid accumulation in the liver and renal tubular epithelium, and immature brain with white matter gliosis. The morphologic examination of the placenta revealed features of delayed maturation, including large-for-gestational-age size and abundant immature intermediate villi with cellular syncytiotrophoblast, persistent villous cytotrophoblast, and decreased syncytial knots. In addition, immature intermediate villi showed exaggeration of lacunar interstitial spaces consistent with nonhydropic villous edema. Marked lipid accumulation was seen within extravillous trophoblasts of placental septa and cell islands. Light lipid accumulation was also noted within fibroblasts of stem villi. These findings suggest that in glutaric acidemia type II, fatty acid oxidation could also be affected in the placenta.
Signal‐detection models as tools for interpreting judgements of recollections
Authors: Hirshman Elliot , Lanning Kristi , Master Susan , Henzler Amanda
Published: October 2002

This paper considers how the two‐criterion signal‐detection model can be used to interpret judgements of recollection from the remember–know paradigm. We propose that, among other uses, the model can be applied to discriminate results that provide strong evidence for the influence of multiple memory processes from results that are merely consistent with the assumption of such influences. The specific logic motivating this approach is that results falsifying the two‐criterion signal‐detection model provide strong evidence for the influence of multiple‐memory processes on judgements of recollection. We believe that focusing theory construction on results that provide strong evidence of multiple memory processes will lead to the construction of coherent, parsimonious models of the relationship between memory processes and consciousness. We review recent papers by Conway and Dewhurst (1995), Hirshman and Lanning (1999), and Conway et al. (2001) to provide examples of the usefulness of using the two‐criterion signal‐detection model. Copyright © 2002 John Wiley & Sons, Ltd.
Domain specificity of spatial expertise: the case of video game players
Authors: Sims Valerie K. , Mayer Richard E.
Published: October 2002

Two experiments examined whether video game expertise transfers to performance on measures of spatial ability. In Experiment 1, skilled Tetris players outperformed non‐Tetris players on mental rotation of shapes that were either identical to or very similar to Tetris shapes, but not on other tests of spatial ability. The pattern of performance on those mental rotation tasks revealed that skilled Tetris Players used the same mental rotation procedures as non‐Tetris players, but when Tetris shapes were used, they executed them more quickly. In Experiment 2, non‐Tetris players who received 12 hours of Tetris‐playing experience did not differ from matched control students in pretest‐to‐posttest gains on tests of spatial ability. However, Tetris‐experienced participants were more likely to use an alternative type of mental rotation for Tetris shapes than were Tetris‐inexperienced participants. The results suggest that spatial expertise is highly domain‐specific and does not transfer broadly to other domains. Copyright © 2002 John Wiley & Sons, Ltd.
The use of drawings as concrete referents in conditional reasoning problems
Authors: Nelson R.D. , Hannan A.J.
Published: October 2002

A mixed group containing university students, mostly studying mathematics, and some senior school pupils took two paper‐and‐pencil conditional reasoning tests in varying order with a one‐week interval between the tests. One test consisted of five problems presented entirely in written form. The second test took one of two forms, both identical to the first test except that in the first form inessential drawings were added to the presentation of four of the problems and in the second form drawings, which acted as concrete referents and were essential, were added to the same four problems. Irrespective of the order of testing, subjects' performance on the problems with drawings used as concrete referents was significantly worse than on the corresponding problems presented in written form. Furthermore, the results of the initial testing session showed the school group performed significantly worse on both the form of test with inessential drawings and the form with concrete referents than on the written form. In addition, a group of students with recent training in reasoning significantly outperformed all others. Finally, negative conclusion bias was only observed for the Modus Tollens inference. Copyright © 2002 John Wiley & Sons, Ltd.
A test of foreign language acquisition: paired‐association learning
Authors: Krug Kevin , Shafer Ted , Dardick William , Magalis Chris , Parenté Rick
Published: October 2002

This experiment investigated college student difficulties with foreign language acquisition. We developed a word‐sound, paired‐associates learning test that discriminated 92% of the control participants and 95% of the experimental participants. The results are interpreted in terms of an associative model of foreign language learning disability. We discuss how to integrate the test into a larger diagnostic battery for predicting the facility with which a person will be able to learn a foreign language. Copyright © 2002 John Wiley & Sons, Ltd.
Interviewing techniques and the assessment of statement credibility
Authors: Colwell Kevin , Hiscock Cheryl K. , Memon Amina
Published: October 2002

The objective of this study is the development of an applicable comprehensive questioning and statement analysis procedure. One hundred and thirty‐six male residents of the Wynne Unit of the Texas Department of Criminal Justice—Institutional Division (TDCJ—ID) witnessed a staged theft, and provided testimony. Interview formats followed semi‐standardized scripts derived from Structured Interview, Inferential Interview and Cognitive Interview techniques. Participants were randomly assigned to one of six experimental conditions in a 2(honesty of reporting) × 3(interview technique) matrix. Results found a 62% classification accuracy for the Structured Interview, 68% for the Cognitive Interview and 82% for the Inferential Interview, when comparisons were made between treatment phases of each interview condition. When responses given to each interview segment were analysed, 83% of the Structured Interview transcripts were correctly identified, as were 91% of the Inferential and 92.9% of the Cognitive Interview statements. The desire to prevaricate while escaping detection produced statements which were systematically different from honest reporting, as seen in the variables of coherence, response length, type‐token ratio, and verbal hedges. These results indicate a potential forensic utility for strategies which attempt to detect deception through a combination of qualitative and quantitative statement characteristics, and underscore the need for systematic, question‐by‐question analysis of eyewitness statements. Copyright © 2002 John Wiley & Sons, Ltd.
Planning over the day span: memory for the content of plans
Authors: Watanabe Hama , Kawaguchi Jun
Published: October 2002

The purpose of this study was to clarify the effect of the time of day on memory for the content of plans, and to examine the influence of knowledge of daily activities on it. Twenty‐four undergraduates participated as subjects in the experiment. Participants were told to memorize 24 plans of one day (e.g. ‘13:00’, ‘making a telephone call’), and were then asked to recall them in the test phase. Furthermore, we tried to explore their knowledge of everyday activities using a questionnaire. The result showed that plans of night, morning, and evening were recalled better than that of afternoon. This result was explained by the notion that knowledge of one's personal daily activities might affect memory of plans. Copyright © 2002 John Wiley & Sons, Ltd.
Notetaking in non‐academic settings: a review
Authors: Hartley James
Published: October 2002

There is considerable research on notetaking in academic settings but relatively little of it in non‐academic ones. This paper reviews the effects of notetaking in legal situations, counselling and interviewing, and assesses the usefulness of notetaking as a memory aid for older people and as a prospective memory device for brain‐injured persons. The results suggest that: notetaking has no significant effect on recall in ‘real‐life’ jury situations; there is some evidence that notetaking by counsellors in counselling sessions might be harmful for clients; there is some evidence that notetaking in interviews can reduce bias in decision making; there is some evidence that notetaking is helpful for older persons; and that too little research has been conducted on the use of notetaking as a device for aiding the prospective memory for brain‐injured persons to reach any firm conclusions. The general limitations of the research are reviewed and implications for future work considered. Copyright © 2002 John Wiley & Sons, Ltd.
Variation of PDGF, TGFβ, and bFGF levels in essential thrombocythemia patients treated with anagrelide
Authors: Lev P.R. , Marta R.F. , Vassallu P. , Molinas F.C.
Published: October 2002

We studied 15 patients with essential thrombocythemia (ET) before treatment and after normalization of platelet count by anagrelide. Significantly increased plasma levels of PDGF, TGFβ, and bFGF were found. Patients with mild reticulin fibrosis in bone marrow had higher PDGF levels. During treatment, plasma TGFβ and bFGF levels remained elevated in most patients (P < 0.0001 and P < 0.01, respectively). Intraplatelet PDGF levels were low before treatment (P < 0.006) and normal on hematological remission, without relation with the presence or absence of reticulin fibrosis in bone marrow. Intraplatelet TGFβ levels were normal regardless of the platelet count. Intraplatelet bFGF levels were raised before (P < 0.001) and during treatment (P < 0.01). By immunostaining, TGFβ and bFGF were seen in megakaryocytes and lymphocytes with a similar pattern of intensity in patients and controls, suggesting that other cells might also contribute to the raised plasma values. We believe that the plasma increment of these cytokines suggests that they play a role in the pathogenesis of ET. The normal PDGF plasma level found during treatment may be in relation with the platelet count. However, the persistent increase of TGF‐β in plasma and bFGF both in plasma and platelets may indicate dysregulation of cytokine synthesis in TE. Am. J. Hematol. 70:85–91, 2002. © 2002 Wiley‐Liss, Inc.
A reliable plasma marker of platelet activation: Does it exist?
Authors: Gurney David , Lip Gregory Y.H. , Blann Andrew D.
Published: October 2002

Despite the clear importance of the platelet in various conditions and diseases, there are few opportunities to assess the physiological and pathological functions of this cell. Those without access to a flow cytometer or platelet aggregometer rely on secreted or release products of the platelet. Principle among these molecules are alpha granule components beta thromboglobulin and platelet factor four, and membrane constituents such as P selectin, gpV and glycocalicin. However, notwithstanding the ease of measurement of these markers (i.e., by ELISA) each one has its own particular disadvantage, mostly of methodology and specificity. Nevertheless, if our goal is to improve our ability to recognize and treat subjects with thrombotic disorders, then additional studies on these molecules may prove to be a sound investment. Am. J. Hematol. 70:139–144, 2002. © 2002 Wiley‐Liss, Inc.
Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems
Authors: Bombeli Thomas , Basic Adila , Fehr Joerg
Published: October 2002

The prevalence of hereditary thrombophilia is well known in patients with lower‐extremity thrombosis but only poorly studied in patients with thrombosis at unusual sites. Consequently, it is still unclear whether such patients should generally be screened for hereditary thrombophilia. We retrospectively analyzed 260 patients with thrombosis at unusual sites including thrombosis in portal, cerebral, retinal, and upper‐extremity veins with respect to the prevalence of FV Leiden, prothrombin G20210A, protein C, protein S, and antithrombin deficiency. In addition, all thrombotic episodes were analyzed for circumstantial risk factors. Used as controls, healthy volunteers (120) and patients with lower‐extremity thrombosis (292) showed overall prevalence of hereditary thrombophilia of 9.1% and 39.0%, respectively. The corresponding numbers were 33.3%, 34.3%, and 39.0% in patients with portal vein, upper‐extremity, and lower‐extremity thrombosis, respectively. In patients with cerebral vein thrombosis, however, the prevalence was significantly lower (23.5%). Patients with retinal vein occlusion did not show an increased frequency of thrombophilia at all (5.9%). In all five groups FV Leiden was by far the most frequent defect (4.4–27.1%), while prothrombin G20210A occurred rarer (2.5–7.6%). Protein C, protein S, and antithrombin deficiency were much less prevalent (0–3.1%) except for patients with portal vein thrombosis (4.8–7.1%). Compared to healthy individuals, the relative risk of thrombosis was 4.3 (2.2–8.1), 3.8 (1.8–7.7), 2.5 (1.0–6.1), 3.7 (1.5–8.6), and 0.6 (0.2–2.1) for patients with lower‐extremity, upper‐extremity, cerebral vein, portal vein, and retinal vein thrombosis, respectively. Circumstantial risk factors were more frequent in patients without than with hereditary thrombophilia and were found most often in patients with upper‐extremity thrombosis. In each group the most frequent circumstantial risk factor was different. However, oral contraceptives and cancer were found in all five groups. In conclusion, independent upon the presence of circumstantial risk factors, screening for hereditary thrombophilia is warranted in all patients with thrombosis at unusual sites except in those with retinal vein occlusion. Am. J. Hematol. 70:126–132, 2002. © 2002 Wiley‐Liss, Inc.
Testing strategies for diagnosing lupus anticoagulant: Decision analysis
Authors: Segal Jodi B. , Lehmann Harold P. , Petri Michelle , Mueller Lori , Kickler Thomas S.
Published: October 2002

Clinicians commonly evaluate patients with thrombosis or a prolonged activated partial thromboplastin time (aPTT) for the presence of a lupus anticoagulant (LA). We evaluated strategies for detecting LA, in three clinical settings, with decision‐modeling techniques. A decision tree was constructed with 12 strategies, using a combination of aPTT and dilute Russell viper venom times (dRVVT) with confirmatory tests, tissue thromboplastin time (TTI), platelet neutralization procedures, and mixing studies. Probabilities and costs of adverse events and test costs were obtained from the literature. Patient preference for each strategy was evaluated by assigning utilities to each outcome. On the basis of assay results in 90 healthy people and 77 patients, we calculated sensitivities and specificities for each strategy, with true positives defined as suggested by the International Society on Thrombosis and Haemostasis. The least costly strategy for evaluation of patients with a prolonged aPTT, or with thrombosis, is not to test and to assume that LA is absent. For patients with systemic lupus erythematosus (SLE), it is least expensive not to test, although testing with TTI alone can also be considered an efficient strategy. The strategy of highest utility to patients with SLE is testing with TTI, followed by dRVVT. On the basis of these cost and utility results, clinicians' strategies for detecting LA may need modification. These strategies would then optimally be tested in clinical trials. Am. J. Hematol. 70:195–205, 2002. © Wiley‐Liss, Inc.
Phase II trial of sequential therapy with fludarabine followed by cyclophosphamide, mitoxantrone, vincristine, and prednisone for low‐grade follicular lymphomas
Authors: Rohatgi Nitin , LaRocca Renato V. , Bard Vanessa , Sethuraman Gopalan , Foon Kenneth A.
Published: October 2002

Advanced follicular lymphomas, grades I and II, are indolent tumors but are not considered curable with standard therapy. Fludarabine has the highest single‐agent response rates in this disease. However, fludarabine‐based combination chemotherapy regimens have been associated with significant myelotoxicity. Data exist suggesting that the best way to combine partially non‐cross‐resistant agents may be to use them sequentially. Patients with bulky stage II, stage III, or stage IV follicular lymphoma (grade I or II) were entered on this protocol. Patients were treated with 3 cycles of fludarabine followed by 6–8 cycles of cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP). Response was assessed after the 3rd cycle of fludarabine and after the 4th, 6th, and 8th cycles of CNOP. Twenty‐seven patients were entered on the protocol. Median follow‐up was 50 months. Eighteen patients (67%) attained a complete response (CR), and eight patients (30%) attained a partial response (PR), for an overall response rate of 97%. Median relapse‐free survival was 34 months, and median overall survival was not reached for the entire cohort. While all patients who achieved only PR progressed, more than half of those in CR remain free of progression at 39–84 months of follow‐up. The regimen was well tolerated. The sequential combination of fludarabine and CNOP appears to be active and well tolerated in patients with grade I and II follicular lymphoma. Patients who achieve CR fare best, and many remain disease‐free long term. While these results are encouraging, the addition of other active agents such as rituximab to this regimen may further enhance efficacy and is under investigation. Am. J. Hematol. 70:181–185, 2002.© 2002 Wiley‐Liss, Inc.
Outcome in hemoglobin SC disease: A four‐decade observational study of clinical, hematologic, and genetic factors
Authors: Powars Darleen R. , Hiti Alan , Ramicone Emily , Johnson Cage , Chan Linda
Published: October 2002

Over the past 40 years, we observed 284 subjects with hemoglobin SC disease (Hb SC) for 2,837 person‐years. We examined the association of the course of clinical events with hematologic and genetic factors. The mean entry age was 21 years, although 15% entered before one year of age. The mean Hb concentration was 11.3 g/dL, the mean fetal hemoglobin was 2.5%, and the mean MCV was 84.4 fL. Twenty‐five subjects died at a median age of 37 years. Chronic organ‐specific complications occurred in 112 subjects (39.4%), with advanced retinopathy in 65 subjects (22.9%) and osteonecrosis (avascular necrosis) in 42 subjects (14.8%). We identified the β‐globin haplotypes in 82 subjects and the α‐gene status in 79. Twenty‐nine percent had α‐thalassemia‐2. The βCI haplotype was present in 85.4%. We found a decreased incidence of retinopathy in the βCI subjects compared to the non‐βCI subjects (33% vs. 67%; P = 0.049) with a later mean onset age (29 years vs. 21 years; log‐rank test, P= 0.026). We also found a consistent pattern of decreased morbidity in subjects who had α‐thalassemia‐2 in comparison to those who did not. We found a reduced risk of chronic organ‐specific complications (log‐rank test, P= 0.003), lower incidence of sickle crisis (48% vs. 80%, P= 0.001), later onset of gallbladder disease (age of onset: 55 years vs. 34 years; P= 0.055), and lower risk of osteonecrosis (log‐rank test, P= 0.024). Our findings suggest that Hb SC subjects who have not inherited α‐thalassemia‐2 might benefit from erythrocyte rehydration therapy. Am. J. Hematol. 70:206–215, 2002. © 2002 Wiley‐Liss, Inc.
New method to measure minisatellite variant repeat variation in population genetic studies
Authors: Brión M. , Cao R. , Salas A. , Lareu M.V. , Carracedo A.
Published: October 2002

The classical analysis of minisatellite variant repeat (MVR) variation using modular structures is limited by the lack of knowledge of the mutational process involved in the evolution of most of the minisatellites. In this study a new method to measure MVR variation and to calculate genetic distances using MVR codes is proposed. The method is based on the statistical similarity of MVR patterns and considers the complete variability of the minisatellite, enabling meaningful comparisons of closely related populations. As an example, the method has been applied to analyze variation in MSY1 (DYF155S1) in five sets of data from European and North African populations. Am. J. Hum. Biol. 14:421–428, 2002.
Occupational burns from oxygen resuscitator fires: The hazard of aluminum regulators
Authors: Hodous Thomas K. , Washenitz Frank , Newton Barry
Published: October 2002

Background

There have been over 30 incidents of oxygen resuscitator fires over the last 6 years, causing severe burns to a number of fire fighters, emergency medical service personnel, health care workers, and patients. The National Institute for Occupational Safety and Health (NIOSH) was requested to investigate three such incidents.

Methods

NIOSH conducted site investigations of the incidents, and the requesters also sent the involved oxygen resuscitators to a forensic engineering company for a causal analysis.

Results

The investigated fires were associated with aluminum regulators, all from one manufacturer, on compressed pure oxygen cylinders. The investigations indicated that the cause of the fires was an initial small ignition in the high‐pressure area of the aluminum regulator, which then consumed itself in a massive burnout.

Conclusions

Aluminum regulators used with high‐pressure oxygen systems are subject to rare, but potentially catastrophic combustion in normal use. Replacement of such regulators with those made of more fire‐resistant materials or designs, as well as education and improved safety practices are needed to reduce this hazard. Am. J. Ind. Med. 42:63–69, 2002. Published 2002 Wiley‐Liss, Inc.
Interplay between heredity and environment in the recent explosion of type 1 childhood diabetes mellitus
Authors: Laron Zvi
Published: October 2002

The fast increase in the incidence of childhood type 1 diabetes mellitus (T1DM) that cannot be explained by changes in the genetic susceptibility, led us to look for environmental causes. To test the hypothesis that the initiation of the autoimmune process of childhood T1DM in genetically susceptible subjects begins in the perinatal period by a viral infection, we studied the seasonal variations in the month of birth of several cohorts of patients compared to the general population. Population groups with high or low T1DM incidence were analyzed separately by t‐test and the Cosinor methods. In areas with populations with a high incidence (Israeli Jews, Sicily, Sardinia, Slovenia, Germany) we found that the children (in Sicily also young adults) who subsequently developed T1DM, have a higher incidence of births in the summer months than in other seasons of the year, a mirror image of the seasonality of the clinical onset of disease. This pattern differed significantly from the seasonality of the total live births in the same populations. In populations with a low T1DM incidence, (China, Japan and Cuba) no seasonality of month of birth was found. Similar findings have been reported, from five counties in the U.K. and the Netherlands. It is hypothesized that mothers who become pregnant during the period of yearly viral epidemics transmit to the fetus, either a virus or antiviral antibodies, which determine whether an autoimmune process against the pancreatic β is initiated or whether the fetus is protected against that process. © 2002 Wiley‐Liss, Inc.
Environmental factors in the etiology of type 1 diabetes
Authors: Åkerblom Hans K. , Vaarala Outi , Hyöty Heikki , Ilonen Jorma , Knip Mikael
Published: October 2002

Type 1 diabetes is considered to be an autoimmune disease in which T lymphocytes infiltrate the islets of pancreas and destroy the insulin producing beta cell population. Besides antigen specificity, the quality of immune reactivity against islet cell antigen(s) is an important determinant of the beta cell destruction. Much evidence indicates that the function of the gut immune system is central in the pathogenesis, as the regulation of the gut immune system may be aberrant in type 1 diabetes. The role of virus infections in the pathogenesis of type 1 diabetes has been supported by substantial new evidence suggesting that one virus group, enteroviruses, may trigger the beta‐cell damaging process in a considerable proportion of patients. The latest evidence comes from studies indicating the presence of viral genome in diabetic patients and from prospective studies confirming epidemiological risk effect. If this association holds still true in ongoing large‐scale studies, intervention trials should be considered to confirm causality. Of the dietary putative etiological factors, cow's milk proteins have received the main attention. Many studies indicate an association between early exposure to dietary cow's milk proteins and an increased risk of type 1 diabetes. The question will be answered by a large scale, prospective, randomized, international intervention trial. Another dietary factor in need of more studies is the deficiency of vitamin D. Among toxins, N‐nitroso compounds are the main candidates. An interaction of genetic and environmental factors is important in evaluating the possible role of a certain environmental factor in the etiology of type 1 diabetes. © 2002 Wiley‐Liss, Inc.
A 52‐kb deletion in the SOST‐MEOX1 intergenic region on 17q12‐q21 is associated with van Buchem disease in the Dutch population
Authors: Staehling‐Hampton Karen , Proll Sean , Paeper Bryan W. , Zhao Lei , Charmley Patrick , Brown Analisa , Gardner Jessica C. , Galas David , Schatzman Randall C. , Beighton Peter , Papapoulos Socrates , Hamersma Herman , Brunkow Mary E.
Published: October 2002

Van Buchem disease is an autosomal recessive sclerosing bone dysplasia characterized by skeletal hyperostosis, overgrowth of the mandible, and a liability to entrapment of the seventh and eighth cranial nerves. The genetic determinant maps to chromosome 17q12‐q21. We refined the critical interval to the < 1‐Mb region between D17S2250 and D17S2253 in 15 affected individuals, all of whom shared a common disease haplotype. Furthermore, we report here the identification of a 52‐kb deletion located within the interval and encompassing D17S1789 that is 100% concordant with the disorder. Although the deletion itself does not appear to disrupt the coding region of any known or novel gene(s), the closest flanking genes are MEOX1 on the proximal side, and SOST on the distal side of the deletion. MEOX1 is known to be important for the development of the axial skeleton, whereas the SOST gene is the determinant of sclerosteosis, a disorder that shares many features with van Buchem disease, thus raising the possibility that van Buchem disease results from dysregulation of the expression of one or both of these genes. © 2002 Wiley‐Liss, Inc.
Genetic risk assessment in carrier testing for spinal muscular atrophy
Authors: Ogino Shuji , Leonard Debra G.B. , Rennert Hanna , Ewens Warren J. , Wilson Robert B.
Published: October 2002

As evidenced by the complete absence of a functionally critical sequence in exon 7, approximately 94% of individuals with clinically typical spinal muscular atrophy (SMA) lack both copies of the SMN1 gene at 5q13. Hence most carriers have only one copy of SMN1. Combining linkage and dosage analyses for SMN1, we observed unaffected individuals who have two copies of SMN1 on one chromosome 5 and zero copies of SMN1 on the other chromosome 5. By dosage analysis alone, such individuals, as well as carriers of non‐deletion disease alleles, are indistinguishable from non‐carrier individuals. We report that approximately 7% of unaffected individuals without a family history of SMA have three or four copies of SMN1, implying a higher frequency of chromosomes with two copies of SMN1 than previously reported. We present updated calculations for disease and non‐disease allele frequencies and we describe how these frequencies can be used for genetic risk assessment in carrier testing for SMA. © 2002 Wiley‐Liss, Inc.
Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile‐X knockout mice
Authors: Irwin Scott A. , Idupulapati Madhuri , Gilbert Molly E. , Harris Jennifer B. , Chakravarti Aparna B. , Rogers Erica J. , Crisostomo Ralph A. , Larsen Brian P. , Mehta Amit , Alcantara C.J. , Patel Biraju , Swain Rodney A. , Weiler Ivan Jeanne , Oostra Ben A. , Greenough William T.
Published: October 2002

Fragile‐X syndrome is a common form of mental retardation resulting from the inability to produce the fragile‐X mental retardation protein. The specific function of this protein is unknown; however, it has been proposed to play a role in developmental synaptic plasticity. Examination of human brain autopsy material has shown that fragile‐X patients exhibit abnormalities in dendritic spine structure and number, suggesting a failure of normal developmental dendritic spine maturation and pruning in this syndrome. Similar results using a knockout mouse model have previously been described; however, it was noted in retrospect that the mice used in that study may have carried a mutation for retinal degeneration, which may have affected cell morphology in the visual cortex of those animals. In this study, dendritic spines on layer V pyramidal cells of visual cortices, taken from fragile‐X knockout and wild‐type control mice without the retinal degeneration mutation and stained using the Golgi‐Cox method, were investigated for comparison with the human condition. Quantitative analyses of the lengths, morphologies, and numbers of dendritic spines, as well as amount of dendritic arbor and dendritic branching complexity, were conducted. The fragile‐X mice exhibited significantly more long dendritic spines and significantly fewer short dendritic spines than control mice. Similarly, fragile‐X mice exhibited significantly more dendritic spines with an immature‐like morphology and significantly fewer with a more mature type morphology. However, unlike the human condition, fragile‐X mice did not exhibit statistically significant dendritic spine density differences from controls. Fragile‐X mice also did not demonstrate any significant differences from controls in dendritic tree complexity or dendritic arbor. Long dendritic spines with immature morphologies are characteristic of early development or a lack of sensory experience. These results are similar to those found in the human condition and further support a role for the fragile‐X mental retardation protein specifically in normal dendritic spine developmental processes. They also support the validity of these mice as a model of fragile‐X syndrome. © 2002 Wiley‐Liss, Inc.
Complex relationship between Parkin mutations and Parkinson disease
Authors: West Andrew , Periquet Magali , Lincoln Sarah , Lücking Christoph B. , Nicholl David , Bonifati Vincenzo , Rawal Nina , Gasser Thomas , Lohmann Ebba , Deleuze Jean‐François , Maraganore Demetrius , Levey Allan , Wood Nick , Dürr Alexandra , Hardy John , Brice Alexis , Farrer Matt
Published: October 2002

Mutations in the Parkin gene cause juvenile and early onset Parkinsonism. While Parkin‐related disease is presumed to be an autosomal‐recessive disorder, cases have been reported where only a single Parkin allele is mutated and raise the possibility of a dominant effect. In this report, we re‐evaluate twenty heterozygous cases and extend the mutation screening to include the promoter and intron/exon boundaries. Novel deletion, point and intronic splice site mutations are described, along with promoter variation. These data, coupled with a complete review of published Parkin mutations, confirms that not only is recessive loss of Parkin a risk factor for juvenile and early onset Parkinsonism but that Parkin haploinsufficiency may be sufficient for disease in some cases. © 2002 Wiley‐Liss, Inc.