MRC trial of alpha2b-interferon maintenance therapy in first plateau phase of multiple myeloma. MRC Working Party on Leukaemia in Adults

We have recently reported the isolation of a rat cDNA encoding a receptor-type tyrosine phosphatase, which appears to be a marker of thyroid differentiation. To elucidate the molecular mechanisms underlying r-PTPeta expression in normal thyroid cells both in vitro and in vivo, we investigated the regulation of r-PTPeta expression in cultured thyrocytes (the rat cell line PC Cl 3) and in an animal model of TSH-dependent thyroid goitrogenesis. In vitro studies showed that mRNA expression of r-PTPeta in thyroid cells is induced in a time- and dose-dependent manner by the activation of growth- and differentiation-linked PKA pathways (TSH and forskolin), whereas it is down-regulated by the activation of the proliferative dedifferentiating PKC-dependent transduction pathway (TPA). However, the regulation of r-PTPeta expression by TSH and TPA, respectively, is observed only in normal thyroid cells, but is lost in transformed thyroid cells. In vivo studies with thiouracil-fed rats demonstrated that increased serum levels of TSH up-regulated r-PTPeta mRNA expression in parallel with the stimulation of thyroid growth and function. The reduction of blood TSH levels due to iodide refeeding to goitrous rats determined a marked down-regulation of r-PTPeta expression, in parallel with involution of thyroid hyperplasia. Taken together these results demonstrate that the phosphatase r-PTPeta is regulated by the two main thyroid regulatory pathways and suggest that it may play an important role in the growth and differentiation of thyroid cells.     

Analysis of the immunophenotype of children treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia Trial XI (MRC UKALLXI). Medical Research Council Childhood Leukaemia Working Party

Despite many years of meticulous immunophenotyping of childhood acute lymphoblastic leukaemia (ALL) cases the prognostic significance of some subtypes remains unclear. The Medical Research Council UKALLXI trial (1990-1996) in which uniform treatment has been given to 2090 children with ALL below the age of 18 years and above the age of 1 year, has afforded the opportunity to review these issues. Children with ALL of mature B cell type were not entered into this trial. Immunophenotype analysis was performed in each individual trial centre, but results were centrally reviewed in all cases, and were both available and considered adequate in 1934 (93%) of the first 2090 patients entered. The main diagnostic categories were early pre-B or null reported in 60 cases (3.1%), common ALL in 1242 (64.2%), pre-B in 252 (13.0%), 'common' or pre-B in 172 (8.9%) and T cell in 207 (10.7%) cases. Children with T cell disease were significantly more likely to be over the age of 10 years, with central nervous system disease at diagnosis and to be CD34 negative. They also had a higher incidence of high white cell count and were more likely to be of the French-American-British (FAB) L2 morphological subtype. Patients with 'null' cell disease tended to be less than 2 years or greater than 10 years of age, and CD13 and CD33 positive. CD10 was associated with lower white cell count (WBC) at diagnosis, younger age and FAB L1 morphological subtype. The presence of cytoplasmic immunoglobulin in pre-B cells was not associated with any specific clinical or laboratory features. CD34 positivity was less common in T cell patients and was associated with low WBC. Disease-free survival (DFS) and 95% confidence intervals (CI) at 5 years from diagnosis was 52% (95% CI: 44-59%) for T cell disease, 58% (95% CI: 43-73%) for early pre-B (or null cell) disease and 65% (95% CI: 62-68%) for common or pre-B disease; there being no significant difference between common and pre-B disease with regard to disease outcome. Patients with T cell disease had a worse prognosis than any other immunophenotype group (P < 0.00005). However this worse outcome was no longer significant after allowing for the other principal prognostic factors of age, gender and white cell count at diagnosis except for the very small number with WBC <20 x 10(9)/l and T cell disease. Those with CD10-positive leukaemia did better than those who were CD10 negative (P < 0.00005), with DFS at 5 years 64% (95% CI: 62-67%) for positive vs 56% (95% CI: 49-62%) for CD10 negative. CD10 positivity did not have independent significance when white count, gender and age were taken into account. CD13, CD33, and cytoplasmic mu positivity carried no prognostic significance.     

Intensification of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA. Medical Research Council Working Party on Leukaemia in Adults

The effects of short-chain alcohols (methanol, ethanol and n-propanol) on the fast-inactivating, A-type, potassium current of Lymnaea neurons were examined using macroscopic recording techniques. Alcohols produced a blockade of the current and modified its inactivation mechanism. The extracellular concentrations of methanol, ethanol and n-propanol causing 50% suppression of the current were 2970, 830 and 230 mM, respectively. The main effects of alcohols on inactivation were a decrease in the amplitude of the fast component and a simultaneous increase in the amplitude of the slow component of inactivation. In a model, the suppression of the fast component could be reproduced by an increase of the backward rate constant related to the dissociation of the inactivation particle from its binding site. The blockade and modification of inactivation reveal similar dependences on ethanol concentration, indicating that the same type of interaction of ethanol with the channel underlies both of these events. Ethanol was effective only in extracellular applications. The data support an action of alcohols at a hydrophobic site near the extracellular portion of the channel.     

Surgery for congenital dislocation of the hip in the UK as a measure of outcome of screening. MRC Working Party on Congenital Dislocation of the Hip. Medical Research Council

BACKGROUND: Universal clinical screening for congenital dislocation of the hip to detect hip instability in neonates was introduced in the UK as a national policy in 1969, but its effectiveness is not known. We aimed to assess the extent to which surgery for congenital dislocation of the hip is the result of a failure of detection through screening or follows non-surgical treatment after detection by screening. METHODS: We established a national orthopaedic surveillance scheme and used routine hospital data for inpatients for 20% of births in the UK (Scotland and the Northern and Wessex regions) to ascertain the number of children aged under 5 years per 1000 livebirths who had received at least one operative procedure for congenital dislocation of the hip from April, 1993, to April, 1994. Estimates of the incidence of operative procedures were adjusted for under-ascertainment by capture-recapture techniques. FINDINGS: The ascertainment-adjusted incidence of a first operative procedure for congenital dislocation of the hip in the UK was 0.78 per 1000 livebirths (95% CI 0.72-0-84). Congenital dislocation of the hip had not been detected by routine screening in 222 (70%) of 318 children reported to the national orthopaedic surveillance scheme. In 112 (35%) children the diagnosis was made primarily as a result of parental concern. 67 (21%) children had previously received non-surgical treatment. In Scotland and the Northern and Wessex regions, 81 cases were notified to the national orthopaedic surveillance scheme, 62 cases were identified only through routine hospital data on inpatients, and an estimated 20 cases were not identified by either source, making a total of 163 cases. Thus, 81 (50%) of these 163 cases were identified by surveillance, 125 (77%) by routine data, and 143 (88%) by both sources. INTERPRETATION: The incidence of a first operative procedure for congenital dislocation of the hip in the UK was similar to that reported before screening was introduced. In most children who received surgery, congenital dislocation of the hip was not detected by screening. Formal evaluation of current and alternative screening policies, including universal primary ultrasound imaging, is needed.     

Influence of psychiatric history on physicians' response to a new patient.

Investigated the possibility that former mental patients, often treated unfavorably by society, are given inadequate attention by medical practitioners. In visits to 32 practitioners, 16 were told by the "patient" that he had stomach pains which first occurred 9 mo previously when he was a mental patient. Results indicate that a former mental patient receives the same medical treatment as anyone else. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The natural history of problem gambling from age 18 to 29.

Aggregate-level prevalences and individual-level developmental trajectories of untreated problem gambling were examined in an 11-year, 4-wave longitudinal study spanning the adolescent through young adult years. The past-year prevalences, 3-4 year incidences, and lifetime prevalences of problem gambling from adolescence through young adulthood were relatively stable at 2%-3%, 1%-2%, and 3%-5%, respectively. Despite the stability of the prevalences at the aggregate level, problem gambling appeared to be more transitory and episodic than enduring and chronic at the individual level. The present study is consistent with the limited evidence available on the natural history of problem gambling in the community in suggesting that natural recovery may be the rule rather than the exception. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The physiological characteristics of genetic predisposition to catalepsy in rats depending on the stage of selection

Male rats with a genetic predisposition to cataleptic reactions revealed a reduced motor activity and a diminished activation of mineralocorticoid and testosterone synthesis in response to a mild stress as compared with the Wistar rats. The reactions, however, were exactly opposite in the Wistar rats with signs of cataleptic features. The data obtained suggest that, when creating genetic animal models of human diseases, the initial stages of breeding should correspond to early stages of the disease whereas advanced stages of breeding are similar to later, chronic phases of the disease.     

Complete remission in acute promyelocytic leukemia. The advantages of all-trans-retinoic acid compared to conventional chemotherapy

In all of seven patients (six men, one woman; mean age 43 [24-55] years) with newly diagnosed acute promyelocytic leukaemia, treated between 1989 and 1993, complete remission was achieved. In three of these patients, treated between 1989 and 1991, remission was induced with conventional chemotherapy (cytarabine and anthracycline), after this in four patients with all-trans retinoic acid (tretinoin). The seventh patient who had a very rapid increase in leucocytes during tretinoin administration, was as a precaution also given conventional chemotherapy. All seven patients received consolidating chemotherapy with an intensive treatment cycle. Retrospective analysis indicated that induction with tretinoin had marked advantages: quicker regression of the clotting abnormalities (mean of 9 vs 25 days), shorter period of leukopenia (mean of 3.5 vs 30 days), shorter time until complete remission (mean of 38 vs 48 days). There were no specific side effects ascribable to tretinoin. Toxicity after chemotherapy corresponded to WHO grades 2-4. The results indicate that tretinoin markedly reduces the two main risks in the treatment of acute promyelocytic leukaemia: bleeding and infection.     

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

BACKGROUND: Transplantation of blood or bone-marrow stem cells is the treatment of choice for selected patients with chronic myeloid leukaemia (CML). Transplantation is used with increasing frequency and success, but remains associated with substantial risks of morbidity and mortality. Other treatments with satisfactory short-term outcome are available. For appropriate counselling of patients, a rapid and simple way to assess risk is needed. METHODS: Data from 3142 patients (1873 [60%] male, 1269 [40%] female; mean age 34 years, range <1-60 years) treated with allogeneic blood or marrow transplants for CML between 1989 and 1997, reported to the European Group for Blood and Marrow Transplantation (EBMT), were used to develop and test a simple risk score based on previously reported major pretransplant risk factors: histocompatibility, stage of disease at time of transplantation, age and sex of donor and recipient, and time from diagnosis to transplantation. We analysed probabilities of survival, leukaemia-free survival, transplant-related mortality, and relapse incidence with respect to these risk factors. FINDINGS: At the time of analysis, 1922 (61%) of the 3142 patients were alive-1567 (65%) of those with HLA-identical sibling donors and 417 (57%) of those with unrelated donors. 1682 (54%) were alive without relapse. 1220 (39%) patients had died, 1013 (83%) of transplant-related causes, 207 (17%) of relapse. 447 (14%) patients had relapsed. The final scoring system was highly predictive for leukaemia-free survival, survival and transplant-related mortality. Survival at 5 years was 72%, 70%, 62%, 48%, 40%, 18%, and 22% for patients with scores 0, 1, 2, 3, 4, 5, and 6, respectively. Risk of transplant-related mortality was 20%, 23%, 31%, 46%, 51%, 71%, and 73%. Data showed the same trends for HLA-identical sibling transplants and unrelated transplants for transplants done in 1989-93 and 1994-96. INTERPRETATION: Pretransplant risk factors are cumulative for individual patients with CML having blood or marrow transplantation. A simple system based on five main factors gives adequate risk assessment for counselling of patients and taking decisions.     

Influence of SDZ-PSC833 on daunorubicin intracellular accumulation in bone marrow specimens from patients with acute myeloid leukaemia

From August 1987 through February 1995 we performed 42 surgical procedures in 29 patients with occluded or stenotic radiocephalic arteriovenous fistulae. Operations were designed to preserve native veins for cannulation (Group I) or to preserve access in the same forearm, bypassing the failed fistula (Group II). For 27 procedures in 22 Group I patients, cumulative primary patency was 70%, 57%, and 47% at 6, 12, and 18 months, respectively. A subgroup of patients was identified, however, in whom excellent results could be reliably predicted. Among 19 hemodynamically stable patients with mature fistulae amendable to more proximal arteriovenous anastomoses, cumulative primary patency was 100%, 81%, and 67% at 6, 12, and 18 months, respectively. Secondary patency for 17 such patients was 100%, 89% and 89% for these same intervals. In Group II only two of ten patients required use of other access sites (9 1/2, 18 1/2 months). We believe that all occluded or stenotic radiocephalic arteriovenous fistulae should be considered for surgical salvage. Excellent results can be predicted for (1) hemodynamically stable patients with (2) mature fistulae that (3) fail near the arterial anastomosis and are (4) amendable to new more proximal arteriovenous anastomoses.     

Influence of drinking history on food-deprived drinking in the rat.

Investigated the role of drinking during development in 40 male hooded Long-Evans rats. Experimental Ss were deprived of water during rearing; ingestion of lettuce provided for sufficient fluids. Body weight, feeding, drinking, and urine volume over successive food deprivation periods were compared with normally reared controls. The lettuce-reared Ss drank less water and ate less lettuce when food deprived, but did not differ from normal Ss in drinking or in lettuce intake when food was available ad lib. It is suggested that lettuce-reared animals drink water principally in response to fluid deficits. Other research indicates that the drinking of normally reared rats anticipates fluid deficits and is not initiated by events related to the need for water. The present results suggest that this anticipatory drinking is acquired. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Time-of-day effects on response of natural killer cells to acute stress in men and women.

Diurnal influences on natural killer (NK) cell changes to acute stress were assessed in 21 men and 21 women assigned to either an acute stress (mental arithmetic) or control task condition. Sessions began at either 8 a.m. or 2 p.m. Number of NK (CD3–CD56+) cells and NK activity were measured at baseline, during the 5-min task, and 60 and 90 min after the task. Both morning and afternoon stress participants had elevated NK cell numbers during the task. After the task, number of NK cells decreased in morning stress participants but remained significantly above baseline levels 60 and 90 min posttask. NK cell numbers in afternoon stress participants decreased to below baseline levels 60 and 90 min after the task. Changes in NK activity were driven primarily by diurnal influences. NK activity increased in all morning participants and stayed increased 60 and 90 min posttask. NK activity of all afternoon participants also increased during the task but dropped below baseline 60 and 90 min later. Greater increases in NK levels and activity during the task were associated with greater heart rate changes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

From genes to public health: the applications of genetic technology in disease prevention. Genetics Working Group

OBJECTIVES: With advances in the Human Genome Project, the implications of genetic technology in disease prevention should be assessed. METHODS: The paradigm suggested in The Future of Public Health--assessment, policy development, and assurance--was used to examine the continuum from genetic technology to public health practice. RESULTS: First, important public health functions are to (1) assess the impact of genes and their interactions with modifiable disease risk factors on the health status of the population and (2) assess the impact and safety of genetic testing on the population. Second, given the many implications of genetic testing, the public health community should participate in policy development related to the timing and use of genetic testing in disease prevention. Third, whenever appropriate, the public health community needs to ensure the development of public health genetics programs (e.g. newborn screening) and evaluate the quality and effectiveness of the use of genetic testing in disease prevention. CONCLUSIONS: Although most current genetic tests are not ready for disease prevention, there is an important role for the public health community in translating genetic technology into disease prevention.     

Party Over Policy: The Dominating Impact of Group Influence on Political Beliefs.

Four studies demonstrated both the power of group influence in persuasion and people's blindness to it. Even under conditions of effortful processing, attitudes toward a social policy depended almost exclusively upon the stated position of one's political party. This effect overwhelmed the impact of both the policy's objective content and participants' ideological beliefs (Studies 1-3), and it was driven by a shift in the assumed factual qualities of the policy and in its perceived moral connotations (Study 4). Nevertheless, participants denied having been influenced by their political group, although they believed that other individuals, especially their ideological adversaries, would be so influenced. The underappreciated role of social identity in persuasion is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Significant reduction of medical costs by differentiation therapy with all-trans retinoic acid during remission induction of newly diagnosed patients with acute promyelocytic leukemia. The Japan Adult Leukemia Study Group

OBJECTIVE: For resuscitation of hemorrhagic hypovolemia, we compared the effectiveness of (1) isotonic lactated Ringer's solution (LRS), (2) 2400 mOsm of 7.5% NaCl:6% dextran 70 (HSD), and (3) 2400 mOsm of 7.9% sodium acetate:1.9% NaCl:6% dextran 70 (HAD). DESIGN: In six randomized, blinded experiments for each solution, conscious instrumented adult sheep were hemorrhaged by removing approximately 1.8 L (42 +/- 3 mL/kg) of blood, while maintaining the mean arterial pressure (MAP) at 50 mm Hg for 2 hours. METHODS: Test solutions were infused as needed to restore the cardiac index to baseline. RESULTS: Volume requirements with HAD (236 +/- 29 mL) and HSD (244 +/- 39 mL) were significantly less (p < 0.05) than LRS (3463 +/- 234 mL). Mean arterial pressure was normalized with HSD and LRS, but not with HAD, which resulted in MAPs of 20 to 25 mm Hg less than baseline resulting from a reduced peripheral resistance. Oxygen delivery, however, was significantly higher with HAD during the resuscitation period. Acid-base balance (pH) and oxygen consumption were normalized within 5 minutes of infusion only with HAD. CONCLUSIONS: Small-volume infusion with HAD resulting in "high-flow-low-pressure" resuscitation may offer unique hemodynamic and metabolic advantages for the initial treatment of hemorrhage from trauma.     

Clinical trials of antibacterial agents: a practical guide to design and analysis. Statisticians in the Pharmaceutical Industry Working Party

Guidelines on the conduct of clinical trials of antibacterial agents produced by the US Food and Drug Administration, the British Society for Antimicrobial Chemotherapy, the Infectious Diseases Society of America and a European Working Party have been reviewed. Although very informative, these guidelines provide limited practical guidance on the design and statistical aspects of phase III studies of antimicrobial agents. This paper describes the differences between antibacterial trials and clinical studies in other therapeutic areas with regard to subjective endpoints, dual clinical and bacteriological endpoints, frequent protocol violations and difficulty of using placebo controls. The importance of a detailed protocol and planned analysis strategy is emphasized. The choice of comparator agents, practical issues with the blinding of trial materials and the documentation of patients excluded from study entry are discussed. The use of different patient groups and different endpoints in analyses are described. The principles of equivalence and their application to trials of antibacterial agents are discussed, together with an approach to calculating sample size. A variety of statistical analyses of results are compared for different situations indicating some of the problems that can arise. Different methods of presentation of study data are included with emphasis on regulatory submissions rather than scientific publications. Some graphical presentations are recommended and issues regarding data across different studies are discussed.     

Ascites, pleural, and pericardial effusions in acute pancreatitis. A prospective study of incidence, natural history, and prognostic role

Ascites and pleural and pericardial effusions can be observed during acute pancreatitis. The aims of this study were to evaluate their incidence, natural history, and prognostic role in patients with acute pancreatitis. One hundred patients consecutively admitted with a diagnosis of acute pancreatitis were prospectively submitted to abdominal, pleural, and cardiac ultrasonography at admission and during follow-up. Ascites was found in 18 patients, pleural effusion in 20, and pericardial effusion in 17. Twenty-four patients of this series had severe pancreatitis; three of them died. All effusions disappeared spontaneously in patients who survived pancreatitis up to two months after dismissal. At multivariate analysis ascites and pleural effusion were demonstrated to be accurate independent predictors of severity. The respective odds ratios were 5.9 [95% confidence interval (CI), 1.5-23.0%) and 8.6 (95% CI, 2.3-32.5%). Furthermore the presence of pleural effusion, ascites, and pericardial effusion were associated with an increased incidence of pseudocyst during follow-up. Ascites and pleural and pericardial effusions are frequent during acute pancreatitis. Pleural effusion and ascites are accurate predictors of severity in these patients.     

Patients surviving more than 10 years on haemodialysis. The natural history of the complications of treatment

BACKGROUND: The purpose of this survey was to describe the natural history of complications in 52 long-surviving haemodialysis patients to obtain a clearer picture of the impact these patients have on the dialysis population. This is important as they are often no longer suitable for transplantation and therefore are destined to remain on dialysis for the rest of their lives. METHODS: The patients who survived for more than 10 years on haemodialysis alone were studied. Information was obtained from patients' records and from the renal unit computer. RESULTS: Mean age at start of dialysis was 43 years and mean duration of HD 14.5 years. Renal failure was most commonly due to polycystic kidney disease or glomerulonephritis. Sixty-two per cent of patients developed cardiovascular disease, 78% complained of joint pains, 72% had a parathyroidectomy, and 50% developed carpal-tunnel syndrome. Two hundred and forty-five episodes of infection were recorded, 41% related to vascular access acquired in hospital or on immunosuppression. Only three infections occurred which could be described as opportunistic. Twelve patients were hepatitis C positive. In the 37 patients who have died, cardiovascular disease was the most common cause of death. Compared to other patients who started on dialysis before 1986 but who had a successful transplant the survival of patients on haemodialysis is much worse. CONCLUSION: Long-term survival on renal replacement therapy is dependent on successful transplantation. Complications, morbidity, and mortality are high after 10 years of dialysis.