bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Active and Passive Immunization of Male and Female Rats with a Recombinantly Expressed Bonnet Monkey Pituitary GnRH Receptor Fragment
Authors: SANTRA SUMANA , RAO A. JAGANNADHA
Published: March 2003

Gonadotropin releasing hormone (GnRH) exerts its action by binding to the specific receptor which belongs to the family of G‐protein coupled receptors that are characterized by the presence of seven transmembrane domains linked together by extracellular and intracellular loops. A fragment of the pituitary receptor of the bonnet monkey (Macaca radiata) corresponding to amino acids 164–266 was cloned and expressed in Escherichia coli. This was used to raise antibodies to the receptor in rabbits. Active and passive immunization studies in both male and female rats were carried out using, both the `overexpressed' fragment, as well as antibodies raised to the receptor fragment. Both active, as well as passive immunization in the male rats brought about an agonistic effect in terms of increase in serum LH level, as well as increase in serum and testicular testosterone levels. However, in the female rats, active immunization with the receptor fragment did not have any effect on the gonadal steroid levels but had a selective effect on the uterine morphology.
Molecular Genetics of Male Infertility: Stem Cell Factor/c‐kit System
Authors: GRIMALDI PAOLA , ROSSI PELLEGRINO , DOLCI SUSANNA , RIPAMONTI CARLA B. , GEREMIA RAFFAELE
Published: March 2003

PROBLEM: Infertility, affects about 5% of human males and genetic factors are recognized in approximately 30% of them. The mouse represents a good model to study autosomal genes that might play a role in spermatogenesis. In mice, mutations in the c‐kit gene and in the gene encoding stem cell factor (SCF) cause pleiotropic defects among which sterility. A possible involvement of the SCF/c‐kit system in human spermatogenesis was investigated.

METHODS OF STUDY: A group of 65 idiopathic azoospermic patients was screened for the presence of mutations in the human c‐kit gene codon encoding tyrosine 721 (Y721), analogous to Y719 in the murine c‐kit gene (a residue known to be essential for a normal spermatogonial proliferation). Furthermore we have used a mouse model for studying the molecular mechanisms that regulate the transcription of the endogenous SCF gene.

RESULTS: No mutations have been detected on codon encoding Y721 of the human c‐kit gene, in our group of infertile patients.

CONCLUSIONS: A larger group of azoospermic patients, including preferentially patients affected by Sertoli‐cell‐only syndrome, should be screened in order to exclude a role of c‐kit mutations in Y721 in spermatogenesis defects.

In this study we also show that the murine SCF promoter is transcriptionally active and stimulated by follicle stimulating hormone (FSH), 3′‐5′ cyclic adenosine monophosphate (cAMP) analogs, and IBMX in primary mouse Sertoli cells, and that the cAMP effect is cell‐specific, as the SCF promoter is not stimulated in other SCF‐expressing cell types tested.
Part II: Influence of Dimerization of a modified GnRH‐I Peptide Sequence on a Male Antifertility Vaccine
Authors: Ferro Valerie A. , Harvey Michael J. A. , Colston Angela , Stimson William H.
Published: March 2003

Ferro VA, Harvey MJA, Colston A, Stimson WH. Part II: Influence of dimerization of a modified GnRH‐I peptide sequence on a male antifertility vaccine. AJRI 2002; 48: 372–380 © Blackwell Munksgaard, 2002

PROBLEM: In the previous paper, we described how the tetanus toxoid (TT) conjugated monomer, CHWSYGLRPG‐NH2, induced high neutralizing antibody titres, which resulted in decreased levels of testosterone and subsequent antifertility. However, its counterpart HWSYGLRPGC, induced low avidity antibody titres. We wanted to know whether peptide dimerization would improve the efficacy of both peptides.

METHOD OF STUDY: Male Sprague–Dawley rats were immunized with modified dimerized GnRH‐I peptides (HWSYGLRPGCCGPRLGYSWH and GPRLGYSWHCCHWSYGLRPG‐NH2), with or without conjugation to TT.

RESULTS: The unconjugated dimers were not effective in causing castration, although the first peptide dimer did induce production of antibodies. When conjugated to TT, both dimers showed the same level of efficacy in causing castration as each other. However, there were differences in antibody binding to native GnRH.

CONCLUSIONS: Dimerization and conjugation to a carrier improved the antifertility efficacy of HWSYGLRPGC, whereas the conjugated monomer CHWSYGLRPG‐NH2 showed a greater level of consistent castration than its conjugated dimer.
Evolutionary Adaptations to Pre‐eclampsia/Eclampsia in Humans: Low Fecundability Rate, Loss of Oestrus, Prohibitions of Incest and Systematic Polyandry
Authors: ROBILLARD PIERRE‐YVES , DEKKER GUSTAAF A. , HULSEY THOMAS C.
Published: March 2003

Gestational‐hypertension/pre‐eclampsia occurs in approximately 10% of human pregnancies. This persistent complication of pregnancy has been reported to occur more frequently in couples conceiving very shortly after the beginning of their sexual relationship and/or after a change in paternity. Primipaternity may be the leading cause of pre‐eclampsia in women under 30 years of age when genetic susceptibility to cardio‐vascular disease has not yet been expressed, especially in women before their twenties, who for the last 40,000 years have perhaps comprised the age group when the majority of parturients classified as Homo sapiens sapiens initiated their reproductive life. In terms of evolution, the prevalence of pre‐eclampsia represents a distinct reproductive disadvantage in humans as compared with other mammals. Indeed, pre‐eclampsia is a consequence of the defect of the normal human‐specific deep endovascular invasion of the trophoblast. The large size of the human fetal brain imposing this deep trophoblastic invasion induced the need for major immunogenetic compromises in terms of paternal–maternal tissue tolerance. The price that mankind has had to pay to adapt to the pre‐eclampsia risk is a low fecundability rate and therefore loss of oestrus, possibly a step in the deviation between apes and hominids. Further, pre‐eclampsia risk may be a contributing factor leading to the rejection of systematic polyandry in human societies and have influenced prohibition of incest.
A survey of interfacial forces used during filing of root canals
Authors: Regan J. D. , Sherriff M. , Meredith N. , Gulabivala K.
Published: March 2003

Abstract – The pattern of dentine removal during endodontic instrumentation is influenced by many factors including the interfacial forces applied by the operator. The aim of this study was to investigate the influence of operators and different sizes and types of instruments on the magnitude of these interfacial forces. Single‐rooted teeth were mounted on a cantilevered aluminium beam to which two pairs of single element strain gauges were joined in a half‐bridge configuration and mounted at right angles to each other. The strain gauges were connected to an analogue‐to‐digital converter fitted in a micro‐computer via conditioning amplifiers. This enabled strains to be recorded over a period of time. Twenty operators instrumented root canals using a series of hand instruments for 1 min each. The mean interfacial forces used by operators demonstrated a wide variation ranging from 9.06 g to 149.42 g (range of forces from 0–331 g) but there was a consistency in the relative magnitude for each operator. The 20 operators could be divided into 13 groups which were significantly different (α=0.05) from each other. There were significant differences (α=0.05) between the forces used for each of the K‐Flex files (15, 25, 35, 45, and 70), the force increasing with the file size. There was also a significant difference (α=0.05) in the forces used between the Flexofile (#25) and the #25 K‐Flex and Hedström files. However, there was no significant difference between the K‐Flex and Hedström files.
Profile of an orthodontic patient at risk of dental trauma
Authors: Brin I. , Ben‐Bassat Y. , Heling I. , Brezniak N.
Published: March 2003

Abstract – Increased overjet and inadequate lip coverage of the maxillary incisors are considered significant risk factors in many clinical studies. The purpose of the present study was to examine this issue of dental injury by actual cephalometric measurements in orthodontic patients. Pretreatment cephalograms (taken with lips in repose) of consecutive patients were used. The patients were allotted to two groups Group T (trauma): 56 patients who had injured their maxillary incisors prior to their orthodontic treatment, mean age at the start of treatment 11.9 years (SD=1.5); and Group C (control): 98 patients with intact maxillary incisors, mean age at the start of treatment 11.6 years (SD=1.3). Twelve cephalometric landmarks on the soft and hard tissue profile were identified and digitized and the relevant dental, skeletal and soft tissue measurements recorded. The variables in Groups T and C were compared and their predictive values for possible occurrence of trauma were tested by logistic regression analysis. No statistically significant differences between boys and girls were found. Overjet or maxillary incisor exposure or interlabial gap, each as a single variable, could differentiate between the two groups. Logistic regression analysis indicated that only a small percentage (28.7%) of the dependent variable variation (trauma vs control) can be explained by interlabial gap, gender, upper incisor long axis to facial plane (degree), upper incisor long axis to interlabial gap and overjet.
Effect of topical alendronate on root resorption of dried replanted dog teeth
Authors: Levin L. , Bryson E. C. , Caplan D. , Trope M.
Published: March 2003

Abstract – Alendronate (ALN) is a third generation bisphosphonate with demonstrated osteoclast inhibitory activity that may slow down the resorptive process after severe traumatic injuries. Eighty‐two premolar roots of five mongrel dogs were endodontically treated and restored, extracted and treated as follows: 70 roots were bench dried for either 40 or 60 min. Thirty‐eight of these roots were then soaked for 5 min in a 1 mM solution of ALN in Hanks’ Balanced Salt Solution (HBSS) and replanted. Thirty‐two roots were soaked for 5 min in HBSS and replanted. In the remaining 12 roots which were not exposed to the bench drying procedure, a 0.5 mM deep lingual mid‐root cemental defect was made. Six of these roots were soaked in a 1 mM solution of ALN in HBSS for 5 min and replanted. The other six roots were soaked for 5 min in HBSS and replanted. Historical negative and positive controls were used from similarly treated teeth in our previous studies. After 4 months the dogs were killed and the roots prepared for histological evaluation. Five‐μm‐thick cross‐sections of the root and surrounding tissue taken every 70 μm were evaluated for healing according to the criteria of Andreasen. In the 12 roots with cemental defects, healing with cementum of the damaged root surface was evaluated. In addition, residual root mass was also measured to determine the extent of root structure loss for each soaking method. Cemental healing took place in all 12 artificially damaged roots, indicating that these soaking media did not inhibit cementogenesis. The alendronate‐soaked roots had statistically significantly more healing than the roots soaked in HBSS without alendronate. This improvement in healing was seen in all dogs except one and in all teeth except the first premolar. Soaking in alendronate also resulted in significantly less loss in root mass due to resorption compared to those teeth soaked in HBSS without alendronate.
Immediate repositioning of an accidentally extruded immature premolar after extracting root remnants of the primary molar
Authors: Efrat J. , Peretz B.
Published: March 2003

Abstract – This article describes a case where during an extraction of a primary molar’s root remnant, the successor permanent tooth was accidentally extruded. The extruded tooth was immediately repositioned to its right position in the socket and it erupted normally after a short time. After 2 years, a routine clinical examination revealed normal appearance of the premolar in the dental arch. A radiograph demonstrated an obliterated coronal part of the pulp, normal root length, a slightly open apex and no periapical inflammation.
The treatment of an avulsed maxillary central incisor by transplantation of an embedded mandibular premolar
Authors: Khongkhunthian Pathawee , Chantaramungkorn Montri , Waranyuwat Supanit
Published: March 2003

Abstract   –  Avulsion, following traumatic injuries, is relatively infrequent. The treatment of avulsed teeth is by replantation of the avulsed tooth into its own socket. However, sometimes the avulsed tooth cannot be found at the accident site. We report a case in which the avulsed maxillary central incisor is replaced by an embedded lower premolar. A 2‐year follow‐up shows complete periodontal healing and a very satisfactory clinical result.
Intentional surgical repositioning of an ankylosed permanent maxillary incisor
Authors: Moffat Michelle A. , Smart Carrie M. , Fung Diane E. , Welbury Richard R.
Published: March 2003

Abstract –  Replacement resorption (ankylosis) may be a significant complication after replantation of avulsed permanent incisor teeth. This report explains the aetiology, diagnosis, management and current treatment options in ankylosis and then describes an alternative surgical technique, intentional luxation and repositioning. This technique, in the presence of an acceptable root length, may be a realistic treatment option in adolescence until osseointegrated implants can be considered at the age of 18–20 years.
Sports dentistry and dental traumatology
Authors: Ranalli Dennis N.
Published: March 2003

Abstract  – Sports dentistry had its origins in the 1980s. More recently, the Academy for Sports Dentistry joined forces with the International Association of Dental Traumatology in cosponsoring the World Congress on Sports Dentistry and Dental Traumatology. It is the intent of the present paper to introduce readers to the arena of sports dentistry, suggest future areas for collaborative research, and stimulate authors to submit high quality, scientifically based manuscripts on sports dentistry to Dental Traumatology.
Ethanol‐induced activation and rapid development of tolerance may have some underlying genes in common
Authors: Ponomarev I. , Crabbe J. C.
Published: March 2003

Ethanol exerts biphasic effects on behavior, stimulant at low doses and depressant at higher doses. In the present study we used two mouse genetic models to investigate the relationships among activating and depressant responses to alcohol. The first model was a panel of nine isogenic genotypes. FAST and SLOW mice, selectively bred for high and low ethanol‐induced motor activation, respectively, were used as a second model. We used loss of righting reflex to assess initial sensitivity and acute functional tolerance to a hypnotic dose of ethanol (3 g/kg, 20% v/v). Blood ethanol concentration at the onset of loss of righting reflex was used as an estimate of initial sensitivity, while the difference between concentration values at the recovery and loss of righting represented an acute functional tolerance score. Mean initial sensitivity and acute functional tolerance values of the nine strains were correlated with a previously obtained measure of ethanol‐induced locomotor activation. Activation correlated significantly with both initial sensitivity (rg = 0.80; P < 0.05) and acute functional tolerance (rg = 0.77; P < 0.05). Thus, inbred genotypes that were activated more by a low dose of ethanol were also more sensitive to and developed more acute tolerance to a high dose. FAST mice had initial sensitivity values similar to those of SLOW mice, but developed more pronounced tolerance, indicating that ethanol‐induced activation and acute functional tolerance may be regulated by some common genetic mechanisms. In summary, these results supported a genetic association between ethanol‐induced activation and rapid development of tolerance.
Severe cognitive and motor coordination deficits  in Tenascin‐R‐deficient mice
Authors: Montag‐Sallaz M. , Montag D.
Published: March 2003

The extracellular matrix molecule tenascin‐R (TN‐R), predominantly expressed in the central nervous system, has been implied in a variety of functions, e.g. during myelination, cerebellar neurite fasciculation and hippocampal long‐term potentiation. In this study, we investigated in detail the impact of TN‐R deficiency on the living animal by analyzing the behavior of TN‐R‐deficient mice. The general state, gross sensory functions, reflexes and motoric capabilities appeared normal. In contrast, motor coordination on the rota‐rod was compromised in these mice, indicating a deficit in cerebellar functions. In the open field and the hole board, the mutants interact differently with their environment, probably due to differences in their exploratory behavior. TN‐R‐deficient mice were able to learn a reference memory task in the Morris water maze. In contrast to wild‐type mice, the mutants displayed an alternative strategy; swimming around the pool using a stereotypical circling pattern, crossing all possible platform positions after relocation of the escape platform (reversal). These results, confirmed by relocating the platform in the center of the pool, suggest that TN‐R‐deficient mice may be impaired in constructing a goal‐independent representation of space. In addition, a two‐way active avoidance test (shuttle box) revealed a severe deficit in associative learning in TN‐R‐deficient mice. Our results support important functions of TN‐R in vivo in the central nervous system, in particular in the cerebellum and the hippocampus.
Assessment of photoplethysmographic signals for the determination of splanchnic oxygen saturation in humans
Authors: Crerar‐Gilbert A. J. , Kyriacou P. A. , Jones D. P. , Langford R. M.
Published: March 2003

Summary The need for a clinically applicable method of detecting splanchnic hypoxia has led to experimental animal studies which indicated the usefulness of intestinal pulse oximetry. Pulse oximetry relies on detection of photoplethysmographic signals. Before developing a pulse oximeter for the measurement of organ oxygen saturation peri‐operatively, we designed a system based on a reflectance photoplethysmographic probe to investigate photoplethysmographic signals from human viscera (bowel, liver, and kidney). Recordings were obtained simultaneously from the abdominal viscera and the finger using identical probes. The probe was held sequentially for up to 2 min on the surface of viscera of 12 patients during routine laparotomy. Measurable splanchnic photoplethysmographic signals were recorded for the first time in humans. There were no statistically significant differences between photoplethysmographic amplitudes from viscera and those from the finger. Our results indicate the feasibility of pulse oximetry for the measurement of visceral oxygenation in humans.
Remifentanil‐sevoflurane anaesthesia for laparoscopic cholecystectomy: comparison of three dose regimens
Authors: Van Delden P. G. , Houweling P. L. , Bencini A. F. , Ephraim E. P. , Frietman R. C. , Van Niekerk J. , Van Stolk M. A. , Verheijen R. , Wajer O. J. M. , Mulder P. G. H.
Published: March 2003

The objective of this study was to determine a dosing regimen for remifentanil‐sevoflurane anaesthesia that achieves an optimal balance between quality of anaesthesia and time to recovery. Patients undergoing elective laparoscopic cholecystectomy were randomly allocated to receive 0.4, 0.8 or 1.2 MAC (minimal alveolar concentration) of sevoflurane combined with remifentanil as required to maintain stable anaesthesia. For induction of anaesthesia, the remifentanil dose was 25 μg.kg−1.h−1 and the mean propofol dose which was required to obtain loss of consciousness was 1.59 mg.kg−1. During the maintenance phase, the mean remifentanil dose was 16.0, 14.1 and 13.0 μg.kg−1.h−1 for the 0.4, 0.8 and 1.2 MAC groups, respectively. The mean sevoflurane maintenance dose was 0.91, 1.24 and 2.1% end‐tidal for the 0.4, 0.8 and 1.2 MAC groups, respectively. The incidence of somatic responses was significantly higher in the 0.4 MAC sevoflurane group. Recovery times were significantly faster in the 0.4 compared to the 0.8 and 1.2␣MAC groups and in the 0.8 compared to the 1.2 MAC group. The combination of 14 μg.kg−1. h−1 remifentanil and 1.24% end‐tidal sevoflurane achieved the optimal balance between the quality, and recovery from anaesthesia.
Nasopharyngeal airway continuous positive airway pressure: a method to wean from or avoid mechanical ventilation in adults
Authors: Ryan D. W. , Weldon O. G. W. , Kilner A. J.
Published: March 2003

Summary A simple technique using a nasopharyngeal airway and a continuous positive airway pressure circuit␣has proved an effective alternative to a tight fitting nasal or face mask for delivery of continuous positive airway pressure. Nasal trauma, discomfort and mouth breathing are the main disadvantages.
Assessment of the Caradyne WhisperFlow™ for administration of continuous positive airway pressure in a 3 Tesla magnetic resonance scanner
Authors: Steiner L. A. , Chatfield D. A. , Donovan T. , Coles J. P. , Menon D. K.
Published: March 2003

Summary Demand for magnetic resonance investigations in critically ill patients is increasing. While these patients frequently need ventilatory support, not all of them require controlled ventilation and many may be treated with continuous positive airway pressure. Controlled ventilation, with the concurrent need for sedation, may be inappropriate when airway physiology is being studied and may retard weaning. No commercially available ventilator designed for the magnetic resonance environment can deliver high flow continuous positive airway pressure. We tested the Caradyne Whisperflow™ flow generator and five Whisperflow™ valves (2.5–15 cmH2O airway pressure) within a 3 Tesla environment for safety and possible dysfunction. All components had minimal ferromagnetic properties and tests showed no clinically relevant change in flow delivery or oxygen concentration in the magnetic field. In addition, the airway pressure generated by the valves was not affected by the magnetic field. We conclude that the tested system can be safely used in a 3 Tesla magnetic resonance environment.
Prospective ranking of the sonographic markers for aneuploidy: Data of 2143 prenatal cytogenetic diagnoses referred for abnormalities on ultrasound
Authors: Daniel Art , Athayde Neil , Ogle Robert , George Alice M. , Michael Jonathan , Pertile Mark d , Bryan Jennifer , Jammu Vapinder , Trudinger Brian J.
Published: March 2003

Objective: To design a scheme to rank sonographic anomalies as indicators of aneuploidy and record the distribution of data from 2143 prenatal amniotic fluid/chorionic villous sample diagnoses referred for karyotyping because of fetal anomalies detected with ultrasound.

Methods: In all cases the records of sonographic anomalies were obtained prior to karyotyping. A cascade of seven prospective categories of ultrasound anomalies was chosen and the data were included in the highest compatible sonography category. The categories were in descending order: (I) combined central nervous system (CNS)/cranial shape and cardiac anomalies (excluding spina bifida and anencephaly); (II) key anomaly present (exomphalos/intrauterine growth restriction/duodenal atresia/cystic hygroma/fetal hydrops/talipes – with other multiple anomalies); (III) CNS ± other abnormality (excluding choroid plexus cyst, spina bifida, anencephaly); (IVa) increased nuchal translucency – first trimester ± other abnormality; (IVb) increased nuchal thickening – second trimester ± other abnormality; (V) cardiac anomaly ± other abnormality; (VI) other markers of aneuploidy (pyelectasis/two vessel cord/echogenic bowel/short femur); and (VII) other (mostly isolated) malformations.

Results: There were 412/2143 (19.2%) chromosome abnormalities detected in this sonographically abnormal group. Overall, the prevalence of aneuploidy significantly ranged from 51 to 3% according to the above I–VII ultrasound categories and from approximately 1–80% for individual ultrasound anomalies. Likelihood ratios were derived for many ultrasound anomalies for several aneuploidy groups: trisomies of 13; 18; and 21; 45,X and 45,X mosaics; triploidy; other autosomal duplications and/or deletions; and other (than 45,X) sex chromosomal aneuploidies.

Conclusion: It is suggested this data could be used to assist pre‐procedural counselling of patients after the ultrasound scan in tertiary referral centres for prenatal cytogenetic diagnosis.
Incidence of deep vein thrombosis after colorectal surgery in a Chinese population
Authors: Lee Fung Yee , Chu Winnie , Chan Ricky , Leung Yee Fong , Liu Kin Hung , Ng Siu Man , Lai Paul B. S. , Metreweli Constantine , Lau Wan Yee
Published: March 2003

Introduction:  Contemporary studies indicate that the incidence of deep vein thrombosis (DVT) is increasing in the Asian population. The present study aims to evaluate the incidence of postoperative DVT in Chinese patients undergoing surgery for colorectal ­malignancies.

Methods:  Fifty‐one consecutive patients with carcinoma of the rectum or sigmoid colon scheduled for resection were included in the study. None of the study subjects were given any form of DVT prophylaxis. Serial duplex ultrasound of both lower limbs were examined in the preoperative and postoperative periods.

Results:  Three patients were excluded from the study because of the presence of DVT noted preoperatively. A total of 20/48 (41.7%) patients developed asymptomatic calf vein thrombosis. One out of 20 patients required anticoagulation because of thrombus propagation. None of the subjects showed signs or symptoms of DVT or pulmonary embolism. A total of 7/20 thrombi resolved completely at 4 weeks after operation. Only old age and smoking were identified as being associated with a higher incidence of DVT. Disseminated disease, type of operation, duration of operation and postoperative complications did not appear to be risk factors for DVT.

Conclusion:  A high incidence of asymptomatic calf vein thrombosis occurred after colorectal surgery for malignancies in Chinese. The majority did not progress even without anticoagulation.
Modified technique for varus derotation osteotomy of the proximal femur in children
Authors: Wilkinson Andrew J. , Nattrass Gary R. , Graham H. Kerr
Published: March 2003

Background:  The results of a study in which the Richards’ intermediate hip screw and the AO (Association for the Study of­­Internal Fixation (ASIF)) 908 fixed‐angle blade plate were compared for use in proximal femoral osteotomy in children have previously been reported. In that study loss of position at the osteotomy site was reported as a specific complication associated with the use of the Richards’ intermediate hip screw.

Methods:  The authors devised a simple modification of surgical technique using the Richards’ intermediate hip screw to enhance the stability of the fixation. In the present article the results of a prospective study of that modified technique are reported and compared with the results of the previous study.

Results:  During a 2‐year period 24 proximal femoral osteotomies were performed on 12 children with cerebral palsy, using the modified technique by two surgeons. Only two of the 12 patients (16%) required postoperative immobilization in a hip spica cast. This represents a significant reduction in the level of spica casting when compared with the previous cohort study (61%).

Conclusion:  A simple modification of surgical technique improves the stability of fixation in proximal femoral osteotomy in children who have cerebral palsy. This resulted in a decreased need for supplementary hip spica casting and may reduce morbidity.
Genetic polymorphisms in microsomal epoxide hydrolase  and susceptibility to adult acute myeloid leukaemia  with defined cytogenetic abnormalities
Authors: Lebailly Pierre , Willett Eleanor V. , Moorman Anthony V. , Roman Eve , Cartwright Ray , Morgan Gareth J. , Wild Christopher P.
Published: March 2003

Summary.  Acute myeloid leukaemia (AML) cases with different chromosomal abnormalities may reflect different aetiologies. Benzene exposure, from a number of sources including smoking, is one risk factor for AML. Individual susceptibility to benzene may depend on differences in expression of metabolizing enzymes. We tested the hypothesis that smoking as well as genetic polymorphisms in the microsomal epoxide hydrolase gene (HYL1), an enzyme involved in benzene metabolism, could be risk factors for AML with defined chromosomal abnormalities. Twenty‐six AML cases with −7/del(7q) and 24 cases with t(8;21), as well as 43 cases with normal karyotype and 155 age‐, sex‐ and residence‐matched controls, were drawn from a large case–control study on adult acute leukaemia. Current smoking was significantly associated with the cytogenetic abnormalities t(8;21) or −7/del(7q) (OR = 4·9; 95%CI = 2·1–11·5) but not with a normal karyotype, relative to individuals who were not current smokers. A putative high activity HYL1 phenotype [exon 3, residue 113 (Tyr/Tyr) and exon 4, residue 139 (His/Arg or Arg/Arg)] was associated with a significantly increased AML risk in men with −7/del(7q) or t(8;21) (OR = 4·4; 95%CI 1·1–17·0) but not with a normal karyotype. This suggests that AML cases with defined chromosomal abnormalities could be related to specific carcinogen exposures and, furthermore, suggests that smoking and genetic polymorphisms in HYL1 could be risk factors for AML with −7/del(7q) or t(8;21).
Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia
Authors: Smith Franklin O. , King Roberta , Nelson Gene , Wagner John E. , Robertson Kent A. , Sanders Jean E. , Bunin Nancy , Emaunel Peter D. , Davies Stella M.
Published: March 2003

Summary.Children with juvenile myelomonocytic leukaemia (JMML) have a poor outcome, with survival in a minority of patients. The major limitation on success of sibling donor bone marrow transplantation for JMML has been reported to be relapse. A total of 46 children with a diagnosis of JMML underwent unrelated donor marrow (URD) transplantation facilitated by the National Marrow Donor Program. Forty‐three of 46 patients had neutrophil engraftment at a median of 20 d post transplant, with platelet recovery in 28 of 40 evaluable patients at a median of 34·5 d. Thirty‐two of 44 evaluable patients developed acute graft‐versus‐host‐disease (GVHD) (Grades 2–4) and chronic GVHD developed in 14 of 35 evaluable patients. At a median follow‐up of 2·0 years, probabilities of survival and disease‐free survival were 42% and 24% respectively. The probability of relapse was 58% at 2 years and represents the major cause of treatment failure. Multivariate analysis revealed that chronic GVHD was associated with reduced relapse [risk ratio 0·20 (95% CI 0·04–1·02,P = 0·05)] improved survival [risk ratio 0·13 (95% CI 0·03–0·68,P = 0·02)] and event‐free survival [risk ratio 0·23 (95% CI 0·06–0·94,P = 0·04)]. This study demonstrates that relapse is the major cause of treatment failure in patients with JMML undergoing URD transplantation. With lower relapse observed in patients with chronic GVHD, new treatment strategies that focus on enhancing the graft‐versus‐leukaemia effect may improve survival.
CD38 expression and secondary 17p deletion are important  prognostic factors in chronic lymphocytic leukaemia
Authors: Chevallier Patrice , Penther Dominique , Avet‐Loiseau Hervé , Robillard Nelly , Ifrah Norbert , Mahé Béatrice , Hamidou Mohamed , Maisonneuve Hervé , Moreau Philippe , Jardel Henri , Harousseau Jean Luc , Bataille Régis , Garand Richard
Published: March 2003

Summary.CD38 expression and chromosomal abnormalities are novel prognostic factors in chronic lymphocytic leukaemia (CLL). However, their value remains undetermined. CD38 was evaluated in 123 patients and chromosomal aberrations in 111 cases with fluorescencein situhybridization (FISH). CD38 expression was found in 27% ofthe cases. In addition, seven out of 32 CD38– patients became CD38+ during evolution of the disease. Chromosomal abnormalities included isolated 13q deletion (40%), 12q trisomy (14%), 11q deletion (without 17p deletion) (14%) and 17p deletion (7%). CD38 expression was significantly associated with Binet stages B and C, atypical morphology and 11q deletion. On univariate analysis of survival estimates, advanced Binet stages, CD38+ phenotype, atypical morphology and 11q or 17p deletions were associated with shorter event‐free survival (EFS), treatment‐free interval (TFI) and overall survival (OS). Multivariate analysis identified both Binet stages and CD38 as independent prognostic factors with regard to EFS and TFI. However, CD38 appeared as an independent factor for OS when restricted to Binet stage A. Chromosomal aberrations were re‐evaluated during evolution in 31 cases. The 17p deletion was the most frequent new chromosomal abnormality (35%) and significantly associated with death (64%). In conclusion, CD38 expression and secondary 17p deletion are important poor prognostic indicators, especially in Binet stage A CLL.
Expression of the signal transduction molecule ζ in peripheral and tumour‐associated lymphocytes in Hodgkin's disease in relation to the Epstein–Barr virus status of the tumour cells
Authors: Sjöberg Jan , Andersson Margareta , Garcia Carlos , Palucka Karolina A. , Björkholm Magnus , Porwit‐MacDonald Anja , Pisa Pavel
Published: March 2003

Summary. We investigated whether the described immune evasion of Epstein–Barr virus (EBV)‐infected malignant Hodgkin and Reed‐Sternberg (HRS) cells in Hodgkin's disease (HD) is paralleled by a disturbed expression of the signal transduction molecule ζ associated with CD3 and CD16 in tumour‐associated T lymphocytes (TAL). Flow cytometric analysis revealed a significantly lower ζ expression in CD3+/4+, CD3+/8+ and CD16+ patient peripheral blood lymphocytes (PBL; n = 10) compared with normal donor PBLs (n = 11). When patient PBLs were compared with the corresponding TAL, the latter showed a significantly higher (CD3+/4+) or equal (CD3+/8+) ζ expression. The EBV status of the tumours did not correlate with ζ expression in the TAL. Immunohistochemical staining revealed ζ‐positive lymphocytes among the adjacent bystander cells of the HRS cells in all analysed tumours (n = 8), irrespective of tumour EBV status. In conclusion, these results do not support downregulation of ζ in TAL as a critical mechanism contributing specifically to the immune escape of EBV+ HRS cells.
Typical essential thrombocythaemia does not express bcr–abelson fusion transcript
Authors: Damaj G. , Delabesse E. , Le Bihan C. , Asnafi V. , Rachid M. , Lefrère F. , Radford‐Weiss I. , Macintyre E. , Hermine O. , Varet B.
Published: March 2003

Summary. Essential thrombocythaemia (ET) is a chronic myeloproliferative disorder (MPD) characterized by an elevated platelet count and no identifiable underlying primary cause. According to the diagnostic criteria of the Polycythemia Vera Study Group (PVSG), ET lacks features diagnostic for other MPDs, including the Philadelphia chromosome (Ph) or bcr–abl rearrangement. Recently, some authors have reported bcr–abl transcript positivity in ET patients, but these findings remain controversial. The aim of this study was to investigate whether the bcr–abl transcript could be found in ET patients and to verify the hypothesis of a new ET variant. ET patients (n = 121) with a median age at diagnosis of 55 years were enrolled. The bcr–abl transcript status was examined by multiplex reverse transcription–polymerase chain reaction. Only two cases were positive for bcr–abl, one of which had the Ph at diagnosis. The positive bcr–abl transcript was associated, in both cases, with mild basophilia at diagnosis. After a median follow‐up of 43 months (0–309 months), two patients in the bcr–abl‐negative group developed Ph and bcr–abl‐negative acute myeloid leukaemia (AML). In contrast, one of the two patients in the bcr–abl‐positive group died from AML 13 years after diagnosis. In conclusion, our data on a large group of patients shows the rarity of the bcr–abl transcript in well‐established ET. However, a subset of patients with apparent ET and basophilia may express the transcript and may constitute a novel entity intermediate between chronic myeloid leukaemia (CML) and typical ET. A prospective study is warranted in order to define better the clinical and biological characteristics of bcr–abl‐expressing ET.
Effect of nitric oxide modulation on systemic haemodynamics and platelet activation determined by P‐selectin expression
Authors: Ritchie Joan L. , Alexander H. Dennis , Allen Patrick , Morgan David , McVeigh Gary E.
Published: March 2003

Summary. Inhibiting platelet and endothelial nitric oxide production favours platelet adhesion and aggregation, and arterial vasoconstriction. This study investigated the effect of NG‐nitro‐l‐arginine methyl ester (L‐NAME), a stereospecific inhibitor of nitric oxide synthesis, on P‐selectin expression on platelets, platelet‐derived microparticles and platelet–leucocyte aggregates, and on soluble P‐selectin levels. Twelve healthy male volunteers were infused intravenously with L‐NAME and then with a 10% solution of either l‐ or d‐arginine. Blood pressure responses were recorded and whole blood and serum collected at baseline and after each infusion. P‐selectin expression was analysed in all samples by flow cytometry. Serum levels of soluble P‐selectin were batch analysed using an enzyme‐linked immunosorbent assay at the end of the study. P‐selectin expression on platelets, platelet‐derived microparticles and platelet–leucocyte aggregates did not vary significantly from baseline levels following the infusion of L‐NAME or l‐ or d‐arginine. However, endothelial nitric oxide synthase inhibition caused a marked elevation of arterial blood pressure (P < 0·01) that was restored to pretreatment values by l‐ but not d‐arginine. Serum levels of the soluble form decreased significantly (P = 0·001) following the infusion of l‐ and d‐arginine compared with samples taken at baseline and following L‐NAME infusion. In conclusion, inhibition of constitutive nitric oxide synthase in the endothelium and platelets produced significant increases in blood pressure but did not alter platelet membrane expression of P‐selectin.
Genotyping of human platelet antigen‐1 by gene amplification and labelling in one system and automated fluorescence correlation spectroscopy
Authors: Weber Stephanie , Hummel Stefan A. , Weber Artur‐Aron , Zirwes Rudolf F. , Weiner Olaf H. , Reuber Bernadette E.
Published: March 2003

Summary.  Genotyping of human platelet antigen‐1 (HPA‐1) is required for the diagnosis and appropriate therapy of alloimmunization. Recently, the HPA‐1 polymorphism has been identified as an inherited risk factor for thrombosis. Most currently used methods for HPA‐1 genotyping have the disadvantage of time‐consuming post‐polymerase chain reaction (PCR) processes such as ligation (oligonucleotide ligation assay), restriction enzyme digestion (allele‐specific restriction enzyme analysis) and electrophoresis (single‐strand conformation polymorphism). We present a novel method for HPA‐1 genotyping based on a homogeneous PCR strategy (GALIOS®, gene amplification and labelling in one system) combined with automated fluorescence correlation spectroscopy (FCS). The PCR uses one pair of gene‐specific amplification primers and two allele‐specific, semi‐nested labelling primers. The allele‐specific labelling primers differ in a single nucleotide (T for HPA‐1a/1a, C for HPA‐1b/1b) and are coupled to different fluorescent dyes. The quantities of generated fluorescent PCR products are analysed by FCS at 543 nm and 633 nm excitation wavelength respectively. The genotypes determined using this method were in 100% concordance with the results obtained by allele‐specific restriction analysis (n = 380 samples). The assay was validated for specificity, reliability and the dynamic range. This innovative method of rapid HPA‐1 genotyping offers a specific and robust system, which is applicable for routine HPA‐1 genotyping.
Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis
Authors: Passamonti Francesco , Malabarba Lucia , Orlandi Ester , Pascutto Cristiana , Brusamolino Ercole , Astori Cesare , Baratè Claudia , Canevari Angelo , Corso Alessandro , Bernasconi Paolo , Cazzola Mario , Lazzarino Mario
Published: March 2003

Summary. Essential thrombocythaemia (ET) is a disease associated with an elevated risk of thrombosis. This study evaluated the efficacy and safety of pipobroman (PB) in the long‐term control of ET patients who had, at diagnosis, one or more of the following currently known risk factors for thrombosis or haemorrhage (high‐risk patients): age > 60 years, history of thrombosis or haemorrhage, platelets > 1000 × 109/l. From 1978 to 2000, with a median follow‐up of 10 years, 118 previously untreated high‐risk ET patients (median age 62 years, range 25–82), were treated with PB at the starting dose of 0·8–1 mg/kg/d. All patients reached a platelet count < 600 × 109/l and 91% achieved a platelet count < 400 × 109/l. During follow‐up, 13 patients had thrombosis, with a 10‐year cumulative risk of 14%. Acute myeloid leukaemia, myelofibrosis and solid tumours occurred in three, two and seven patients with a 10‐year cumulative risk of 3%, 2% and 7% respectively. Actuarial survival at 20 years was 64% and the standardized mortality ratio was 1·1 (95% CI: 0·7–1·7), not statistically different from the general population (P = 0·54). Age was associated with a higher risk of death (P = 0·00009) and thrombosis (P = 0·003). The duration of PB treatment did not correlate with the occurrence of second malignancies. This study, with a median follow‐up of 10 years, demonstrates that pipobroman is effective and well tolerated. The low cumulative 10‐year risk of thrombosis, leukaemia and solid tumours indicates that pipobroman is an adequate treatment for patients with high risk ET.
Detection of micrometastases in lymph nodes from patients with breast cancer
Authors: Branagan G , Hughes D , Jeffrey M , Crane-Robinson C , Perry P M
Published: March 2003

Background

Sentinel node biopsy affords the opportunity of focused examination of lymph nodes, including the use of the reverse transcriptase–polymerase chain reaction (RT-PCR). The mammaglobin gene is expressed by breast cancers but has not been detected in histologically normal lymph nodes. This study compared mammaglobin RT-PCR with routine histology in the sentinel and non-sentinel nodes of patients with breast cancer.

Methods

Patients with breast cancer underwent tumour excision, sentinel node biopsy and axillary dissection. All nodes were bisected and half of each node was sent for routine histological examination. The other half underwent RNA extraction and mammaglobin RT-PCR.

Results

Sentinel node biopsy was successful in 50 (96 per cent) of 52 patients. Mammaglobin expression was detected in nine (8 per cent) of 119 histologically negative sentinel nodes (Clopper–Pearson 95 per cent confidence interval (c.i.) 4 to 14 per cent) and in 13 (5 per cent) of 247 histologically negative non-sentinel nodes (95 per cent c.i. 3 to 9 per cent). Mammaglobin expression was detected in four (13 per cent) of 31 patients with histologically negative sentinel nodes (95 per cent c.i. 4 to 30 per cent) and in six (14 per cent) of 44 patients with histologically negative non-sentinel nodes (95 per cent c.i. 5 to 27 per cent). The false-negative rate for sentinel node biopsy was zero using histology results and 10 per cent using RT-PCR.

Conclusion

RT-PCR screening of axillary nodes for mammaglobin expression increased the detection of breast cancer metastases compared with routine histology.
Risk-adjusted surgical audit with the POSSUM scoring system in a developing country
Authors: Yii M K , Ng K J
Published: March 2003

Background

The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) is an objective and appropriate scoring system for risk-adjusted comparative general surgical audit. This score was devised in the UK and has been used widely, but application of POSSUM to centres outside the UK has been limited, especially in developing countries. This prospective study validated its application in a surgical practice with a different population and level of resources.

Methods

All general surgical patients who were operated on under regional or general anaesthesia as inpatients over a 4-month period at Sarawak General Hospital in 1999 were entered into the study. All data (12 physiological and six operative factors) were analysed for mortality only with the POSSUM equation and the modified Portsmouth POSSUM (P-POSSUM) equation. Comparisons were made between predicted and observed mortality rates according to four groups of risk: 0–4, 5–14, 15–49 and 50 per cent or more using the ‘linear’ method of analysis.

Results

There were 605 patients who satisfied the criteria for the study. Some 56·7 per cent of patients were in the lowest risk group. The POSSUM predictor equation significantly overestimated the mortality in this group, by a factor of 9·3. The overall observed mortality rate was 6·1 per cent and, again, the POSSUM predictor equation overestimated it at 10·5 per cent (P < 0·01). In contrast, the observed and predicted mortality rates for all risk groups, including the predicted overall mortality rate of 4·8 per cent, were comparable when the P-POSSUM predictor equation was used.

Conclusion

The POSSUM scoring system with the modified P-POSSUM predictor equation for mortality was applicable in Malaysia, a developing country, for risk-adjusted surgical audit. This scoring system may serve as a useful comparative audit tool for surgical practice in many geographical locations.
Late results of selective axillary surgery based on contact cytology in women with operable breast cancer
Authors: Burke M , Burke K I , Boyle S , Shah K , Price A B , Zammit C
Published: March 2003

Background

Interest in the possibility of intraoperative analysis of sentinel lymph nodes to select patients with operable breast cancer for immediate axillary clearance encouraged this review of a long-term experience of selective axillary surgery based on intraoperative contact cytology of conventionally sampled nodes. Survival was assessed as a potential marker for understaging.

Methods

Records of 437 patients who had surgery between 1991 and 1994 were reviewed to compare rates of axillary recurrence in patients who had contact cytology only with those who had contact cytology and axillary clearance.

Results

Axillary recurrence occurred in seven (3 per cent) of 219 patients who had negative contact cytology, three (4 per cent) of 75 patients who had positive contact cytology with axillary clearance and one (1 per cent) of 93 who had axillary clearance alone. In patients with positive contact cytology, 131 (78 per cent) of 168 positive nodes were in the sample specimen, which included all positive nodes on 19 occasions. Survival probability at 36, 72 and 96 months was 92, 87 and 84 per cent respectively for patients with negative contact cytology, and 85, 73 and 71 per cent for patients with positive cytology and axillary clearance.

Conclusion

A selective approach to axillary surgery based on intraoperative contact cytology of sampled lymph nodes gave good long-term control of axillary disease.