Datasets:

IanTseng

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Med-term1

like 0

little is known about the arrested healing of chronic central Tty membrane perforations and the mechanism involved in this process some authors have traced the failure to a growth factor deficiency at the perforation margin in addition recently several growth factors have been tried out to improve tympanic membrane tm closure in animals the authors sought to determine the expression of some wellknown growth factor peptides in normal human tm and in tms with a chronic central perforation

10

tympanic

AEP testing is not routinely performed within weeks after stapedotomy because hearing acuity is thought to be transiently depressed in rare circumstances postsurgical auditory and vestibular complaints may lead one to test hearing soon after stapedotomy the early postoperative effects of carbon dioxide co and potassium titanyl phosphate ktp lasers which now are routinely used to perform stapedotomies have not been reported the purpose of this report is to present normative data for AEP thresholds measured within weeks of laser stapedotomy

0|73

auditory|auditory

this T0 aimed to document the communicative outcomes of early implantation

1

study

this T0 aimed to compare openset speech perception of singlechannel with multichannel cochlear implants in the same ear of postlingually deafened adults

1

study

central auditory system development in thought to be dependent on normal auditory nerve excitation central auditory disorganization may differ between prelingual and postlingual deafness one possible clinical manifestation of such CE auditory disorganization is somatosensory perception with cochlear implant stimulation the purpose of this study was to investigate the incidence and characteristics of somatosensory phenomena in prelingually and postlingually deafened adult cochlear implant subjects

30

central

this T0 aimed to report the authors year experience with the systematic DUE and treatment of patients with pulsatile tinnitus

1|12

study|evaluation

this T0 aimed to compare the summating potential and action potential ratio spap in patients with menieres disease before and after various surgical and medical treatments as an indication of change in endolymphatic hydrops to study the progression of menieres disease

1

study

this study aimed to illustrate some recent advances in intraoperative monitoring of the seventh and eighth cranial nerves ie direct recording of CN action potentials cnaps and facial nerve action potentials fnaps

22

cochlear nerve

localized bone modeling in the ME is substancep dependent

5

middle ear

radiobiological studies targeted at determination of the coefficients of relative biological effectiveness rbe of various radiations in comparison with the standard xray radiation at kev maximum were reviewed comparison of reactions of the body as a whole and its TPS systems shortly after acute irradiation revealed the character of the relationship of rbe coefficients to let these data are essential for more careful estimation of radiation risk during space missions when in parallel with chronic exposure to determinant sources ie gcr and erb crew members may be also subjected to comparatively brief scr attacks particularly during solar proton events with high fluences

39

specific

in the nearly month mission aboard mir the cosmonautphysician and members of three crews mir and carried out a program of hematological investigations most of the changes related to the red blood system and included reduction in hemoglobin and hematocrit erythrocytes had decreased concentration and took on abnormal forms there were also signs of altered metabolism of erythrocytes of interest are phasebyphase variations in the C2 of erythrocytes in the course of longterm stay in MG and absence of a convincing correlation between hemoglobin erythrocyte and hematocrit C2 but for lymphocytosis that returned to the norm already on the D1 of recovery no material changes occurred to the leukocyte profile investigations at the landing site displayed erythropenia decreased reticulocytes and ensuing reticulocyte reaction and gradual regain of the erythrocyte number that can be viewed as a normal physiological reaction of the blood system to the set of AF of spaceflight and early readaptation besides the investigations showed a large individually of blood reactions to prolonged stay in space flight

65|75|87|99|147

levels|microgravity|levels|first day|factors

the effect of simulated gravitational unloading dry immersion on blood flow in the calf during upright locomotion was studied six subjects performed graded exercise before and T3 day immersion arterial inflow to the calf was evaluated during abrupt cessation of treadmill walkingrunning on the phase of changing the leg with the plethysmographic technique of determining the haemodynamic effect of muscle pump before immersion testing increased the calf blood flow on transition from walking to running and stayed at plateau or decreased with further speed rise T3 immersion the calf blood flow tended to decrease during running at maximal running speed and heart rate bpm calf blood flow was significantly lower post than prior to immersion we believe that immersion enhances the competitive interaction of local operational mechanisms of hyperemia and central vasoconstrictive influences directed at maintaining the circulatory homeostasis

26|85|103

after|after|beatsmin

effects of graded support loads and stimulators of the central nervous system ephedrine and str on growth of bones and the volume of spongy bone tissue in the proximal metaphyses of the shin bones were studied in the day experiment with rats suspended by tail in the orthostatic position it is indicated that the support loads in combination with ephedrine injection prevent the suspensioninduced inhibition of bone growth and development of osteopenia of spongiosa of metaphyses the preventive effect of support loads and ephedrine relates with their stimulating influence on the functional activity of the sthcells of adenohypophysis producing the growth hormone

14

strychnine

the histological structure of the BB and spinal cord visual olfactory AEP and vestibular analysers and endocrine organs epiphysis hypophysis thyroid and parathyroid glands were investigated in newborn rats delivered by females who had been exposed to weightlessness a half of the pregnancy period analysers of the flight animals did not have any marked deviations from the norm loci of neurone degeneration resembling porencephaly but less massive were revealed in various BB portions cortex hypocampus metencephalon spinal cord of the infant rats developed in space flight endocrine studies showed accelerated differentiation of the thyroid cells secreting thyroid hormones ccells and parathyroid cells in most of the infant rats of the flight group the test animals reduced the size of epiphysis and the number of pinealocytes adenohypophysis was found to be smaller with altered spatial CSD of the trabecular system the changes look quite impressive but do not threaten viability of the animals

5|11|71|134

brain|auditory|brain|distribution

morphofunctional state and recombination of cell composition of the spleen structural components were studied in mice balbc at delayed postirradiation days and periods following a single gammairradiation by gy at none of these time points did the lymphoid structural components of the spleen complete their morphological and cytological REC morphological disturbances included poor development of germinative centers and marginal zones in lymphadens and periarterial lymphoid heads palh recovery of lymphoid cell population did not go on same DP thus by day of recovery in palh small lymphocytes regained basal level but rose concentration to in the lymphadens without germinative centers and to in the lymphoden mantle and red pulp elevation of mitotic and cell differentiation activities was not equal destructive processes approached normal values in palh and RP and remained by beyond basal values in lymphodens matureimmature plasmatic cells ratio was modified moreover plasmocytes mature cells that are responsible for humoral immunity localized in unordinary sites ie in palh and lymphodens without germinative centers adaptive changes observed in the red pulp at delayed timepoints T3 irradiation were manifested by development of myelopoiesis focuses with high concentrations of young forms of neutrophils and megakaryocytes

48|77|127|174

recovery|pattern|red pulp|after

investigation of the action of midfrequency ultraviolet radiation nm on isolated lymphocytes of mice SP pointed out that intracellular ph of lymphocytes starts decreasing from jcm dose rise above jcm increases the number of cells with damaged plasmatic membrane within the lymphocyte population and aggravates the ability of cells to accumulate fluorescein fluorochrome as a product of intracellular FDA hydrolysis

14|58

spleen|fluorescein diacetate

colonizing and biodestructive activities and pathogenetic potential of microorganisms isolated from the mir environment at different phases of its operations were tested and evaluated in comparison with standard museum cultures of analogous species comparison of bacterial and fungal species revealed certain cultural PSA and morphological distinctions of the flight strains however to assess the character and the risk associated with peculiar evolution of microflora in LT space missions more careful investigations should be followed with the use of the strain genetic labeling and other modern techniques

42|65

biochemical|longterm

profiles of external respiration and circulation selfassessment of health mental performance sensory functions and peripheral blood were studied in patients with neurocirculatory dystonia in the course of normobaric hypoxic training the hypoxic training proved to successfully normalize arterial pressure eliminate cardiac arrhythmias and benefit GA condition substantial strengthening of hypoxic resistance was stated along with an oxygen debt reduction during hypoxia improvement of sensory coordination and mental performance and activation of erythropoiesis

44

general

the article presents data of a complex clinicalradiation examination of flying personnel with diagnosed diffuse pathologies of pancreas consistent patterns of the fibrotic process in pancreatic parenchyma were related to professional specifics preponderance of US investigations mathematical analyses and xray computer tomography for the enhanced diagnostic algorithm for the medical certification of flying personnel were demonstrated

34

ultrasonic

the properties distribution and biological functions of several proteases from the BPM of lymphoid cells are reviewed dipeptidyl peptidase iv neutral endopeptidase aminopeptidases a and n and a new protease of the family of adamalysins these enzymes designated as ectopeptidases are IMPs whose molecules are mainly located extracellularly their functions involve proteolysis on the cell surface the formation and inactivation of RII MMP and growth AF as well as modification of cell surface proteins the biological significance of a partial proteolysis of the plasma membrane proteins and the resulting soluble isoforms are discussed an analysis of the data suggests that ectopeptidases from lymphoid cells are elements of the sensory system of the cell and are involved in the regulation of its physiological response to external factors and in the coordination of cellcell interactions

11|41|61|62|65

plasma membrane|integral membrane proteins|regulatory|peptides|factors

new data on proteolytic enzyme inhibitors and mechanisms of their interaction with the enzymes are reviewed in recent years a number of new inhibitors comprising families earlier unknown have been described such as proteins from the parasitic nematode ascaris lumbricoides ecotin from the periplasm of escherichia coli proteins pmpc and pmpd from locust locusta migratoria and hirustasin from the medicinal leech hirudo medicinalis at the same time some proteins that may be assigned to inhibitors on the basis of their structures were found to perform other not inhibitory functions thus the family of the kunitz soybean TR inhibitor includes plant storage proteins and proteins whose synthesis is induced by AS factors numerous inhibitors interacting with the enzymes by mechanisms other than the substratelike ones were identified such as ornithodorin and anticoagulant peptide from tick ornithodoros moubata inhibitors of the blood clotting system proteases an inhibitor from snake bothrops jararaca venom and ecotin an inhibitor of serine proteases with an unusually broad specificity range special emphasis is placed on enzyme inhibition with propeptides and the mechanism of this process

96|109

trypsin|stress

a procedure was developed for the modification of basic pancreatic trypsin inhibitor bpti by nhydroxysuccinimide esters of oleic and stearic acids in a dmsodmfdioxanepyridine mixture with a temporary citraconyl protection of the amino group belonging to its active site the bpti derivatives containing from one to three acylated amino groups were obtained it was shown that the hydrophobized bpti with one amino group modified retained practically the full activity of the native inhibitor an increase up to three acylated groups resulted in a decrease in the specific activity of the inhibitor to of the initial activity an increase in hydrophobicity of the modified inhibitors was demonstrated by the spectral method and by the CSD in a watertriton x system

113

distribution

control of the formation of complement cconvertase is an important factor in maintaining human homeostasis some physiologically active endogenous and exogenous substances were shown to be capable of exerting such control a method was developed for studying the influence of the effectors on the formation of classicalcomplementpathway cconvertase from cconvertase stabilized by Ni ions immunoglobulins g and m recombinant alpha and gamma interferons serotonin epinephrine histamine and ethanol were studied as effectors the IB constants of the effectors with cb the AS c component and the values of the maximal effect were determined to evaluate the physiological importance of the effectors the inhibition of cconvertase generation was observed in all cases except for igg and igm RA factor which showed no effect and activating effect respectively

52|73|81|116

nickel|binding|active|rheumatoid

the immune lysis rate of erythrocytes vs the concentration of particular complement components was studied it was found that in the presence of component c but not c and factors b and d the cells undergo lysis after the concentration of these EDC exceeds a threshold value the threshold molar concentrations of factors d and b exceeded and fold respectively that of component c the multiplicity and different capacities of the thresholds allow the fragmentary activation of cascade proteolysis at stretches between neighboring thresholds without the total realization of the final effect of the system cell lysis clot formation etc the resulting peptidebyproducts bypass MMP may possess their own biological activity it is the generation of various bioregulators that appears to be the main function of the cascade proteolytic systems functioning in the subthreshold regime

42|104

compounds|peptides

the functional domain boundaries of the atpdependent lon proteases were identified by comparative analysis of the CAA sequences of the enzymes from evolutionarily distant organisms modified forms of the escherichia coli lon protease with the elongated or substituted NTD and a truncated enzyme lacking the nterminal domain were obtained through genetic engineering methods analysis of the enzymatic properties of the resulting modified forms of lon protease revealed the importance of the nterminal domain in its function

16|38

amino acid|nterminal domain

prospects for the search for thrombolytic compositions on the basis of shortterm and longterm acting plasminogen activators were shown these will be useful as potential ambulance remedies for effective prehospital treatment combined proteolysis by plasminogen activators with cDNA action mechanisms and significantly different pharmacokinetic behavior was suggested for this purpose

37

complementary

genes of uridine phosphorylases udp from klebsiella aerogenes and salmonella typhimurium were cloned and expressed highly ERP producer strains of the corresponding proteins were constructed enzymic properties of the upases obtained were studied and compared with those from the escherichia coli enzyme mutant forms of upase from e coli de dn da were prepared by SDM techniques it was shown that the asp residue plays an insignificant role in the formation of the active form of the protein

16|55

effective|sitedirected mutagenesis

the frenchamericanbritish classification of myelodysplastic syndromes mds has contributed greatly to better communication and conduct of PCTs however the advent of novel cytogenetic immunological and molecular techniques in recent years warrant some alterations to this purely morphological classification this review aims at highlighting the advances which reflect more closely the unique biological and clinical features of various subtypes of mds we propose a comprehensive classification of mds to include the newly defined categories as well as those not included in previous classifications such as the therapyinduced and hereditary mds we hope that this classification will help in focusing attention on the biological features of mds the understanding of which will be crucial to combat this disease

16

clinical trials

anticoagulant services are changing in response to the increasing demands on the service new approaches to the delivery of the service are evolving with more local delivery of services and a shift in the service from AA to primary care this NC has been assisted by the development of near patient testing devices and the use of computerized anticoagulant CDSS that are increasingly used in both secondary and primary care the evolving role of the clinical nursepharmacist in the provision of this service is an important development enabling more rapid discharge of patients and the provision of local delivery of service

36|41|59

secondary|change|decision support systems

treatment with coumarin oral anticoagulants such as warfarin is ERP antithrombotic therapy but patients treated with these drugs are at significant risk of bleeding the risk of haemorrhage increases with increasing intensity of AC and overanticoagulation is common reversal can be achieved by stopping the coumarin drug or administration of vitamin k fresh frozen plasma or coagulation factor concentrates however there are surprisingly few studies defining the optimum dose of these products and there are no randomized studies comparing the relative benefit and risk of coagulation factor concentrates versus fresh frozen plasma guidelines for the management of overdose are based on level iii and iv evidence and are therefore only grade b recommendations at best further studies are required to determine the most effective use of products and the dose required for safe reversal of overanticoagulation

9|33

effective|anticoagulation

it is well known that of severe haemophiliacs are likely to develop inhibitors to factor viii usually soon T3 the commencement of therapy two recent inhibitor outbreaks have occurred in patients treated for a number of years on switching to a product subjected to additional virus inactivation hence the incidence of inhibitor formation may be affected by the type of product used for treatment and the potential for processing to result in neoantigens examination of the parts of factor viii interacting with TBIAb and the effect of various therapies on these can teach us something about the mechanisms involved in antibody formation however the development of preclinical assays to assess products and processes for neoantigen formation should allow the prevention of inhibitor outbreaks this review summarizes current in vitro and in vivo approaches to this problem concluding that most available assays are inadequate for this purpose with competitive immunoassay and phospholipid binding providing the most hopeful route forward

18|82

after|inhibiting antibodies

a newborn infant represents the culmination of developmental events from conception through organogenesis red cells are critically important for survival and growth of the embryo during development erythropoiesis occurs in two distinct forms the first primitive form consists of nucleated erythroblasts that differentiate within the blood vessels of the extraembryonic yolk sac the second definitive form consists of anucleate erythrocytes that differentiate within the CL and third trimester bone marrow of the fetus while adult bone marrow and cord blood now serve as sources of stem cells for the treatment by transplantation of genetic and malignant diseases the developmental origin of hematopoietic stem cells has not been determined during the third trimester the fetus grows rapidly and the production of CRC is approximately times that of AD steady state levels birth brings dramatic changes in oxygenation and erythropoietin production that result in a tenfold drop in red cell production and in a transient physiologic anemia other causes of fetal and infant anemias have their origins in development processes these include globin gene switching in alpha and beta thalassemia the expression of red cell antigens in alloimmune hemolytic disease and the poorly understood defects in the regulation of IDE in diamond blackfan anemia even in the AD vestiges of fetal erythropoiesis are evident during transient states of accelerated erythroid expansion a better understanding of the OD of erythropoiesis will bring improvements in the treatment of anemia not only in the newborn but also in the fetus and the adult

64|120|126|197|205|224

liver|red cells|adult|erythropoiesis|adult|development

gaucher disease was first described by philippe gaucher in his medical thesis gauchers original concept was of an unusual epithelioma of the spleen by the early s mandelbaum recognized the systemic nature of the disease several children with gaucher disease were described at the turn of the century but rusca described a rapidly progressive fatal neurodegenerative type of disease ie type in the s the juvenile form type of the disease was described in sweden in the s in the deficient enzyme acid betaglucosidase was discovered and the lysosomal nature of the disease was elucidated currently three SCV of gaucher disease have been defined clinically and are distinguished by the presence and severity of neuronopathic involvement table each of these clinical types has substantial phenotypic variation but types and have significantly heterogeneous rates of disease progression and degrees of visceral organs involvement the neuronopathic involvement in type also has substantial variation in the age of onset and PD even within relatively isolated communities an extensive review of the clinical and pathologic involvement by gaucher disease is available

97|157

variants|disease progression

the relation between salt NI and hypertension has long been controversial available evidence provides conflicting results however biological and evolutionary insights into the structure and principle function of the kidney and the blood pressure sustaining machinery with the extracellular fluid volume and the reninangiotensin system acting as a central player clearly indicate that salt has been a precious commodity in the terrestrial animal kingdom and that essential hypertension may be a consequence of the kidneys maladaptation to excess salt intake which is TPS to recent human civilization this review provides a hypothesis to explain how and why hypertension develops and attempts to define the roles of genetic nongenetic and environmental factors in its pathogenesis

4|82

intake|specific

we hypothesized that hyperinsulinemia may alter insulins ability to stimulate V1 nakatpase pump activity and modulate changes in V1 responsiveness associated with hypertension we measured potassiuminduced EC50 as an indicator of nakatpase pump activity in isolated femoral arteries from fructosefed ff hyperinsulinemic spraguedawley rats ff rats had higher mean arterial BPs than did normal dietfed nf rats ff n vs nf mmhg n p and were hyperinsulinemic ff vs nf microuml insulin p ff rats were more CS to kcl in the nak pump bioassay ff n vs nf n p expressed as ed in mmoll kcl exogenous insulin muml increased nak pump sensitivity in ff rats as compared with a boiled insulin control insulin n vs control n p expressed as percent increase in sensitivity ie ed there were no significant differences in nak pump sensitivity between insulin and control responses in the nf animals insulin n vs control n ns doseresponse curves were obtained in tail and femoral arteries from the same animals to norepinephrine and acetylcholine basally and after exogenous insulin ff vessels had reduced sensitivity to norepinephrine as compared with the nf group insulin increased sensitivity to acetylcholineinduced relaxations and increased aiiinduced contractions in ffrat vessels these data suggest that in the ff rat insulins influence on the vascular nak pump is enhanced and may modulate the changes in V1 responsiveness seen in this MM

10|18|26|50|77|223|228

vascular|vascular|relaxation|blood pressures|sensitive|vascular|model

the present study was conducted to prospectively evaluate whether a new ace inhibitor temocapril could modify urinary microalbumin excretion rate uae in a group of hypertensive outpatients who had no evidence of renal impairment sixtythree outpatients men and women mean age yr with essential hypertension entered the study all having been treated for at least mo with dihydropyridine calciumchannel blockers ccbs nitrendipine nisoldipine or AML their blood pressures bps had been controlled to adequate levels with the ccbs none had overt proteinuria determined by albustix or abnormal serum creatinine C2 after mo of baseline observation under the previous treatment the subjects were randomly divided into two groups in group a n the previously used ccbs were switched to temocapril to mg once daily for mo and bp was controlled at a level equivalent to that during ccb treatment in group b n the subjects were maintained on their previous treatment for a further mo the effect of temocapril on bp appeared to be clinically similar to that of the previously used ccbs but it significantly decreased uae as compared with the previous therapy in group a uae decreased significantly p from the baseline value of mgg creatinine cr to and mgg cr at the th and th months of temocapril therapy respectively in contrast in group b uae was unchanged baseline mgg cr mo mo in group a of patients had abnormal uae levels or mgg cr during previous therapy with ccbs but mo after switching to temocapril of these patients had normal uae mgg cr in group b of patients had abnormal uae levels during the observation period and these abnormal uae levels remained unchanged of the patients had abnormal uae levels after a further mo of continued ccbs therapy we conclude that LT therapy with temocapril may provide renal protection by reducing uae even in hypertensive patients with no evidence of renal impairment

64|89|294

amlodipine|levels|longterm

it has been demonstrated that opioids modulate the reninangiotensin and sympathetic nervous system to clarify the interaction of central angiotensin ii ang ii and endogenous opioids we studied the effects of naloxone an opioid antagonist on cardiovascular and sympathetic responses to intracerebroventricular icv ang ii in conscious rabbits icv ang ii ngmin significantly increased mean arterial pressure map plasma epinephrine and Arg vasopressin avp levels with no significant change in renal SNA rsna or heart rate pretreatment with intravenous naloxone mgkg failed to alter the cardiovascular and neurohormonal responses to icv ang ii to eliminate the effect of avp on cardiovascular and sympathetic responses dchthymeavp a vasopressin vreceptor antagonist was given intravenously pretreatment with intravenous injection of the vreceptor antagonist microgramskg augmented the maximum increase in rsna caused by icv ang ii vs p combined i.c.v. with naloxone and vreceptor antagonist further increased map and rsna in response to icv ang ii vs mmhg p and vs p respectively these results suggest that opioids and avp synergistically modulate sympathetic outflow so as to suppress the CE pressor action of ang ii in conscious rabbits

61|71|135|175

arginine|sympathetic nerve activity|pretreatment|central

acute inhibition of nitric oxide no synthase in the brain causes elevation of blood pressure and sympathetic excitation under anesthetized conditions to investigate chronic effects of no synthase inhibition in the central nervous system on blood pressure regulation in conscious unrestrained animals we administered ngmonomethyllarginine lnmma a potent no synthase inhibitor at low mumolkg and high mumolkg doses for wk into the cisterna magna with an osmotic pump and measured mean arterial pressure map and heart rate hr by a telemetry method the same dose of ngmonomethyldarginine dnmma an inactive isomer of lnmma was administered to control rats chronic intracisternal administration of lowdose lnmma significantly decreased the brain nitritenitrate and no metabolite contents as compared with dnmma p however map and its variability hr and its variability and PNE C2 did not differ between the two groups of rats at either low or highdose treatment thus chronic no synthase inhibition in the CNS system did not affect systemic hemodynamics or plasma norepinephrine concentrations despite the inhibition of brain no our results suggest that endogenous no in the CNS system at least as a whole may not affect the SVR hemodynamics of chronic unanesthetized rats

128|129|152|177|188

plasma norepinephrine|levels|central nervous|central nervous|systemic

to clarify the background and outcome of hypertensive patients who have remission of their elevated blood pressure bp T3 a course of antihypertensive drug therapy we designed a retrospective observational T0 the clinical records of hypertensive men and women bp mmhg given antihypertensive drug treatment and subsequently examined every to mo for more than yr were reviewed the patients were divided into two groups those who had remission rgroup and those who did not have remission ngroup patients were considered in remission if no significant elevation in bp was observed for more than yr T3 withdrawing their medication remissions ranging in duration from to yr average duration yr occurred in of patients however antihypertensive drug treatment was eventually restarted in of the patients before treatment comparison of the rgroup and ngroup revealed no differences with respect to age body weight bp or serum creatinine in contrast the proportion of patients who lacked highvoltage deflections in their electrocardiograms ecg as well as that of patients whose bp was wellcontrolled by a single medication was significantly greater in the rgroup than in the ngroup vs p and vs p respectively in addition body weight in the rgroup decreased significantly by the time drug therapy was withdrawn p finally significantly more patients of patients entered remission in the spring and summer p than at other times of the year we conclude that remission occurs in a subset of wellcontrolled hypertensive patients and may persist for several years or more however in the majority of patients antihypertensive drug treatment will usually need to be restarted at some point patients who lack ecg highvoltage deflections and who are successfully treated with a single therapeutic agent are most likely to experience remission moreover it appears that withdrawing patients from drug therapy in the spring or summer is more likely to yield a favorable outcome than at other times of the year

18|30|94

after|study|after

it is not certain whether activation of the rasmitogenactivated protein map kinase pathway is involved in cardiac hypertrophy hydroxymethylglutarylcoenzyme a hmgcoa reductase inhibitors such as lovastatin prevent farnesylation of the ras protein which is critical for rass membrane localization and CF therefore the present study was undertaken to investigate the role of the ras pathway which is linked to mevalonate metabolism in the mechanism of stretchinduced myocyte hypertrophy myocytes isolated from to dayold rats were cultured at x cells per well in a deformable silicon dish and incubated with serumfree medium for days the cultures were stretched by on culture day stretch increased the rnadna ratio by to on culture days and and the proteindna ratio by to on culture days and stretch accelerated rates of protein synthesis by on culture day stretch increased protein kinase c pkc activity map kinase activity and cfos mrna expression a selective pkc inhibitor calphostin c x m prevented the stretchinduced increase in pkc activity but lovastatin x m did not lovastatin as well as calphostin c partially but significantly inhibited the stretchinduced increases in map kinase activity cfos mrna expression and protein synthesis i.c.v. with both lovastatin and calphostin c completely inhibited the increases in these variables caused by stretch lovastatin as well as calphostin c prevents stretchinduced cardiac hypertrophy these results suggest that mechanical stretch may activate the ras pathway which is linked to mevalonate metabolism in cultured neonatal rat heart cells

40|190

function|pretreatment

the effects of lemildipine a new dihydropyridine calcium channel blocker on renal hemodynamics and the tubuloglomerular feedback tgf mechanism were examined in anesthetized to wkold spontaneously hypertensive rats shr lemildipine microgramskg iv did not reduce mean blood pressure mbp but tended to increase gfr and increased urinary excretion of sodium unav filtration fraction ff and FE of sodium fena remained unaltered an additional dose of lemildipine microgramskg iv reduced mbp and renal V1 resistance renal plasma flow tended to increase and gfr was unchanged ff significantly fell unav and fena remained at the control level micropuncture experiments revealed that the maximal reduction in proximal SFP sfp an index of glomerular capillary hydrostatic pressure pgc induced by perfusion of the loop of henle was significantly reduced by highdose treatment vs mmhg in control a high dose of lemildipine induced a rightward and slightly upward shift of the tgf curve the steadystate tubular flow rate v was increased the maximal slope of the curve decreased and sfp at v unaltered a low dose of lemildipine did not affect tgf response these results indicate that lemildipine attenuates the tgf response in shr by dilating afferent arterioles and thereby corrects the left and downward shift of the tgf curve in shr in addition the fall in ff indicates lemildipineinduced efferent arteriolar vasodilatation through balanced systemic and glomerular vasodilatation lemildipine maintains the C2 of pgc and gfr in the face of reduced RPP

55|72|104|227|237

fractional excretion|vascular|stopflow pressure|levels|renal perfusion pressure

we investigated factors underlying discrepancy between screening blood pressure and daytime ambulatory blood pressure the difference in a communitybased population in northeastern japan screening and ambulatory pressures were measured in UT subjects aged yr or older we analyzed the effects of age and blood pressure on the difference and then performed multivariate stepwise LR analysis using the difference as the dependent variable the systolic difference positively correlated with age in men women in their s exhibited a large difference disturbing the linear relationship between the difference and age the difference positively correlated with the screening pressure in men and women a positive difference screening pressure ambulatory pressure was observed at screening pressures above mmhg the difference inversely correlated with the ambulatory pressure MVA demonstrated that body mass index and male sex were positively associated with the systolic and diastolic blood pressure differences the daytime pulse rate was negatively associated with the systolic difference and the standard deviation of daytime diastolic ambulatory blood pressure was positively associated with the diastolic difference the diastolic difference in subjects with isolated systolic hypertension based on the screening pressure was significantly smaller than that in subjects with S/D hypertension the difference in subjects with isolated systolic hypertension based on ambulatory pressure was significantly higher than that in systolicdiastolic hypertension when whitecoal isolated screening hypertension was defined as a screening SP or mmhg a diastolic pressure or mmhg or both and a h ambulatory pressure mmhg in men and mmhg in women whitecoat isolated screening hypertension was present in of subjects with screening hypertension the results confirm that the discrepancy between screening and ambulatory blood pressure is due to a variety of factors including age sex blood pressure levels and baroreflex CF our results indicate that screening blood pressure in elderly HT should be evaluated carefully

30|53|122|192|224|285|295

untreated|linear regression|multivariate analysis|systolicdiastolic|systolic pressure|function|hypertensive patients

in recent years the use of display vectors and in SELEX technologies has transformed the way in which we generate ligands such as antibodies and MMP for a given target using this technology we are now able to design repertoires of ligands from scratch and use the power of phage selection to select those ligands having the desired biological properties with phage display tailormade antibodies may be synthesized and selected to acquire the desired affinity of binding and specificity for in vitro and in vivo diagnosis or for immunotherapy of human disease this review addresses recent progress in the construction of and selection from phage antibody libraries together with novel approaches for screening phage antibodies as the quality of C1 naïve and synthetic antibody repertoires improves and libraries becomes more generally available new and exciting applications are pioneered such as the identification of novel antigens using differential selection and the generation of receptor antagonists a combination of the design and generation of millions to billions of different ligands together with phage display for the isolation of IB ligands and with functional assays for identifying and possibly selecting bioactive ligands will open even more challenging applications of this inspiring technology and provide a powerful tool for drug and target discovery well into the next decade

10|25|119|176

vitro selection|peptides|large|binding

peptide display libraries are powerful tools in the search for detailed information about proteinprotein interactions usual targets for isolation of phage displayed peptide ligands include antibodies various receptors other full size proteins or larger fragments thereof smaller protein fragments such as synthetic MMP have not been reported as targets for screening of peptide display libraries

42

peptides

carcinoembryonic antigen cea is a human tumor antigen with the domain structure nababab in which each domain is predicted to have an iglike fold and is known to bind epitope TPS anticea antibodies

30

specific

few antibodies are available to study the function of the fc gamma rii murine immunoglobulin receptor human phage display libraries represent a potential source of singlechain fv sfv to facilitate the T0 of the fc gamma rii mu immunoglobulin receptor

31|37

study|murine

little is known about the outcome of tuberculosis tb treatment and subsequent survival of human immunodeficiency virus hiv INF patients treated under routine programme conditions in a developing country we followed a cohort of hivpositive and hivnegative tuberculosis patients during therapy and assessed their vital and tuberculosis status years after completion of treatment in mwanza tanzania

18

infected

hamad general hospital the tertiary CHC for doha qatar

5

health centre

hepatosplenic abscesses in neutropenic patients especially during the REC phase are almost always attributed to fungal infections we report similar lesions due to mycobacterium tuberculosis in neutropenic patients in a tertiary care centre in india

8

recovery

we report a case of a yearold boy being treated for seizures with carbamazepine who developed acute liver failure within four days of initiation of therapy for suspected tuberculosis with INH RFP pyrazinamide and ethambutol isoniazidinduced MLD was diagnosed the likely role of CBZ and rifampin in potentiating the hepatotoxicity of isoniazid and the importance of early recognition of isoniazidinduced liver disease are discussed

30|31|36|43

isoniazid|rifampin|liver disease|carbamazepine

epsteinbarr virus ebv the cause of infectious mononucleosis is involved in the pathogenesis of several human cancers the highest frequency of association being found in undifferentiated nasopharyngeal carcinoma and endemic burkitts lymphoma the development of animal models in which potential vaccines can be tested is important ebv infection of the common marmoset using the m CS originally derived from a patient with nasopharyngeal carcinoma induces a carrier state in this animal persistent infection is characterized by the production of antibodies to viral antigens and the secretion of ebv dna into buccal fluids following immunization with envelope glycoprotein gp derived from a BPV expression vector prior to ebv infection viral dna was detected significantly less frequently in the buccal fluids of immunized than of nonimmunized INF animals indicating that although the carrier state had not been abolished it had been altered a reduction in virus load was also observed when offspring of seronegative and on occasion seropositive parents were immunized neonatally before ebv challenge

55|101|124

strain|bovine papilloma virus|infected

recent epidemiological studies suggest that the risk for urological malignancies may be related to the exposure to infectious agents human PVs type and hpv hpv epsteinbarr virus ebv cytomegalovirus cmv and herpes simplex virus type hsv have been suggested previously as cofactors in the pathogenesis of some malignancies in humans the present paper the presence of hpv hpv ebv cmv and hsv genomes was investigated in a panel of biopsies from UB carcinomas using the polymerase chain reaction pcr sequences of ebv hpv cmv and hsv genomes were detected in and of tissue samples respectively while in of patients we found more than one viral infection absence of viral genomes was found in normal bladder to our knowledge this is the first report concerning the association of ebv cmv and hsv with bladder cancer this finding may raise the question whether such viral infection may contribute to development and progression of some types of urological malignancies in humans

20|71

papillomaviruses|urinary bladder

human cytomegalovirus hcmvspecific antibody responses in hiv infected individuals either with or without hcmv endorgan disease were examined to determine the whether OD of hcmv disease was associated with a particular deficit in the antibody response antiwhole hcmv antiglycoprotein b gb and neutralizing antibody levels were higher in hiv INF individuals than in healthy immunocompetent subjects particularly in patients with aids either with or without hcmvassociated disease irrespective of location and spread of hcmv disease patients who had received antihcmv therapy prior to sampling exhibited significantly higher antigb and neutralizing antibody titers than those who remained UT likewise patients with hcmv disease who were antigenemic or viremic had significantly lower antigb and NT antibody titers than those who tested negative in either assay patients with untreated hcmv disease had significantly lower antibody titers than aids patients without disease analysis of the igg subclass antibody responses to gb revealed no significant differences among hiv infected individuals these results suggest that levels of detectable antigb and hcmv neutralizing antibodies are inversely related to SVR viral load thus antibodies with such specificities may be relevant in preventing the establishment of hcmvassociated disease or in modulating its progression

22|49|96|112|171

development|infected|untreated|neutralizing|systemic

using membranebased dekapeptides the CR of human serum antibodies with linear antigenic determinants of herpes simplex virus hsv type and type glycoprotein c gc gc was studied by pep scan and immunodot assay the entire coding sequences of gc and gc were screened for the presence of linear epitopes by pep scan peptides recognized in an hsv typespecific manner were mainly identified within the nterminal third and at the cterminus of gc whereas most typecommon antibodies were directed against colinear peptides within the CE parts of gc and gc the typespecific reaction of human sera with gc MMP in pep scan was poor eight peptides identified as immunoreactive by pep scan were further tested in immunodot assay for their reactivity with a human serum panel none of the eight hsvnegative sera gave positive results by immunodot assay positive reactions with gc MMP were found to be strongly agedependent ie the rate of positive reactions was significantly higher in hsvpositive adults than in hsvpositive children antibody reactivity with two typecommon gc peptides was demonstrated in out of hsvpositive sera a putative typespecific gc peptide employed in immunodot assay was inconsistently recognized by human sera twenty hsvpositive sera reacted with at least of typespecific gc peptides nine sera showing no reactivity with glycoprotein g of hsv gg by immunobloting recognized typespecific gc peptides in immunodot CA thus gc peptides might allow the detection of hsvspecific antibodies in individuals showing no reactivity with commonly employed hsvspecific diagnostic antigenes ie purified or recombinant gg

4|83|97|141|223

reactivity|central|peptides|peptides|assay

the prevalence of enteric viruses associated with gastroenteritis was determined in stool samples from patients infected with the human immunodeficiency virus hiv with or without diarrhea diagnostic assays included enzyme immunoassays for the ID of rotavirus adenovirus and norwalk virus PAGE for atypical rotaviruses and picobirnaviruses and polymerase chain reaction for astrovirus enteric viruses were detected in of of the stools collected five samples positive for adenoviruses and three samples positive for picobirnaviruses were detected no rotavirus astrovirus or NV were observed only one of the viruses identified adenovirus was found in a sample from a patient with diarrhea viruses were detected in of the patients with aids of the symptomatic patients and none of the asymptomatic persons these results do not support a major role for enteric viruses in the diarrhea suffered by HIV+ patients

33|40|79|134

identification|polyacrylamide gel electrophoresis|norwalk virus|hivinfected

the development of new antiretroviral agents may improve survival of hivinfected individuals and therefore chronic viral SH may become more relevant in these patients the presence of gbvchgv and HC virus hcv rna were investigated by reverse transcriptasenested polymerase chain reaction in plasma from spanish hivinfected patients belonging to four different risk groups intravenous drug users ivdus hemophiliacs homosexuals and heterosexuals gbvchgvrna and hcvrna were detected in and of the patients respectively the prevalence of current infection with these viruses was notably high for gbvchgv and for hcv among individuals with parenteral risk of infection intravenous drug abusers and hemophiliacs but sexual transmission with gbvchgv was also suggested because of patients with sexual risk either homosexual or heterosexual had gbvchgvrna in plasma although investigation of gbvchgvrna possibly underestimates the actual prevalence of infection with gbvchgv the above data suggest that sexual contact may play a relevant role in the spread of this virus phylogenetic analysis showed no evidence for clustering of ns sequences into different genotypes or subtypes of gbvchgv

16|29

hepatitis|hepatitis c

hepatitis caused by the SH e virus hev is a selflimited disease and occurs most frequently as epidemic or sporadic hepatitis in developing countries the role of hev in sporadic acute hepatitis in areas without a history of hepatitis e epidemics is obscure recently it was found that more than of the patients with acute nona nonb nonc SH in taiwan were associated with an acute hev infection nucleotide sequences of the regions within the first open reading frame of hev were determined in four cases and were identical to each other as compared to the isolates from china pakistan burma india africa and mexico the similarities were however only phylogenetic analysis revealed that the four taiwan isolates were categorized as a novel hev group the taiwan strain which was distinct from all of the strains isolated from other parts of the world in addition the isolates from china burma india and pakistan were catalogued as the second TT of hev the asian strain and the mexican isolate as the third the mexican strain the african isolate was more related to the asian type and might be a subtype of the asian strain a simple genotyping method by polymerase chain reactionrestriction fragment length polymorphism pcrrflp is described the findings also support the hypothesis that hev may be responsible for some sporadic acute nona nonb nonc hepatitis in other developed countries

4|58|158

hepatitis|hepatitis|genotype

recent epidemiological and immunohistochemical studies have indicated a possible link between measles virus and inflammatory bowel disease ibd the aim of this T0 was to use a sensitive and robust method for the detection of measles virus rna in ibd and control clinical samples IP blood MNC cells and intestinal resection tissue from ibd and control patients were studied two methods were used to determine the presence of measles virus rna hybrid capture using measles virusspecific oligonucleotides linked to paramagnetic solidphase supports was carried out on total cellular rna to enrich for measles virus rna sequences reverse transcription followed by the polymerase chain reaction rtpcr using rtth dna polymerase was employed for amplification of measles virus ngene sequences amongst the enriched species total rna was also used for rtpcr of a housekeeping mrna species to assess rna quality rtpcr for another region of the measles genome the haemagglutinin h gene was also undertaken in order to confirm the results obtained using ngene primers for analysis of these samples none of the samples were positive for measles n or hgene rna using rtpcr positive control samples confirmed the sensitivity of the methods employed these results show that either measles virus rna was not present in the samples or was present below the sensitivity limits known to have been achieved

22|44|46

study|peripheral|mononuclear

a retrospective serological and genetic study of hantaviruses responsible for hemorrhagic fever with renal syndrome hfrs in greece during the last years is presented fiftyone serum samples taken from hfrs cases previously diagnosed by immunofluorescence assay were tested by elisa for igg hantaan dobrava and puumala and igm antibodies hantaan and puumala results were compatible with the majority of infections being related to hantaviruses carried by rodents of the subfamily murinae rna was extracted from selected samples and reverse transcriptasepolymerase chain reaction rtpcr was performed using primers specifically designed for the PCD of hantaviruses associated with murine msnspecific mmgspecific primers or arvicoline rodents pptnspecific primers in addition primers previously designed for the detection of the g coding region of the murineassociated hantaviruses were also used sequencing of the pcr products was then performed followed by phylogenetic analysis of nucleotide sequence differences eleven out of the serum samples tested were found to be positive by pcr with the msn primers whereas four were positive with the mmg primers and only two with the g primers none of the samples was found positive with the ppt primers the sequence analysis showed that the virus that was responsible for these hfrs cases was the dobrava virus which is endemic throughout the balkans

91

detection

we reviewed longterm outcome of adult patients with sacrallevel myelomeningocele with an average age of years range data were collected from the medical records computerized database and a questionnaire thirty patients had high S3 lesions weak GM gluteus maximums and gastrocsoleus and had low sacral lesions fair to normalstrength GM gluteus maximus and gastrocsoleus thirteen patients had signs of tetheredcord syndrome and underwent neurosurgical PR thirtynine patients underwent a total of orthopaedic surgeries at the final followup patients were community ambulators thirtytwo required no external support for walking twentynine patients used some kind of orthosis aggressive management of tetheredcord syndrome surgical correction of musculoskeletal deformities and avoidance of arthrodesis at the foot level may be the main AF in accounting for these results

33|36|49|64|117

sacral|gluteus medius|gluteus medius|release|factors

twentyfive independent communityambulating patients with lumbosacrallevel myelomeningocele n limbs underwent gait analysis the limbs of these patients were divided into two groups based on thighfoot angle tfa group i n had marked external tibial torsion tfa or degrees and group ii had tfa between and degrees ten limbs were excluded because of neutral or internal alignment twenty normal limbs with tfa degrees served as controls an abnormal internal varus knee stress during stance was identified in all group i limbs and of limbs group ii limbs compared with controls which demonstrated an internal valgus AS this internal varus moment was greater in group i limbs than in the abnormal limbs in group ii p knee flexion was the only other parameter found to correlate with this AS and only in group i limbs we conclude that a in this patient group increased external tibial torsion is likely to result in an abnormal internal varus knee AS b tfa degrees appears significantly to increase this stress and c knee flexion is an important related parameter but only in limbs with tfa between and degrees we believe that this abnormal AS may predispose the knee to late arthrosis and that derotational osteotomies to normalize the tfa may prove to have a favorable LT effect

94|126|155|188|210

stress|stress|stress|stress|longterm

nineteen patients with spina bifida and bilateral dislocation of the hips were studied with a minimal followup of years the average age at review was years range ten patients had an upper neurologic level thoracic to l and nine had a low lesion l to sacrum three patients had no hip surgery a closed or open reduction was performed in hips supplemented by one or more surgical procedures of these remained enlocated and two had redislocated in all other hips several surgical procedures were performed aimed at improvement of hipflexion deformity or stability at followup one patient had occasional pain in one hip which was dysplastic of the patients with a high lesion only two were walkers but both had BL dislocation of the hips at followup in contrast all nine patients were walkers but four of these had bilateral dislocation at followup we found that a level pelvis and good range of motion of the hips are more important for ambulation than is reduction of bilateral hip dislocation

120

bilateral

we studied seven children with the unusual complication of pseudovolkmanns contracture due to tethering of the flexor digitorum profundus to fractures of the ulna it was detected days to years after closed reductions of fractures of the shafts of the radius and ulna the children did not have nerve palsies or undue pain after the reductions normal length excursion and function of the flexor digitorum profundus was restored by untethering the muscle and its tendons from the ulnar fracture by early manipulation or by late localized myotenolysis we recommend that the passive range of motion of all fingers be routinely checked immediately T3 closed reductions of fractures of the radius and ulna if muscle tethering is detected the fracture is remanipulated to release the muscle if the muscle is still tethered then surgical release through a small incision is required

102

after

we performed a prospective study of patients with displaced extension supracondylar humerus fractures and evaluated the effect of elbow flexion forearm supination and forearm pronation on blood flow to the injured arm T3 closed reduction and kirschner wire fixation ten patients had a gartland type ii fracture and patients had a gartland type iii fracture T3 closed reduction and percutaneous pinning the radial pulse was examined with doppler ultrasonography starting with the elbow in extension the elbow was slowly flexed and the angle of elbow flexion at which the radial pulse disappeared was determined this angle of elbow flexion was measured with the forearm in both supination and pronation gartland type iii fractures demonstrated less elbow flexion prior to radial PP ablation compared to gartland type ii fractures when the forearm was placed in supination p and in pronation p supination allowed or degrees of elbow flexion prior to radial pulse ablation in six gartland type ii and four gartland type iii fractures we concluded that after closed reduction and percutaneous kirschner wire fixation of displaced extension supracondylar fractures V1 safety is enhanced by extending the elbow and supinating the forearm the ideal position of elbow immobilization depends on the amount of swelling and the presence of a radial pulse

32|55|120|179

after|after|pulse|vascular

from to patients with cubitus varus resulting from supracondylar humeral fractures underwent lateral closingwedge osteotomies at the royal alexandra hospital for children as the indication for osteotomy in all cases was the cosmetically unacceptable cubitus varus we reviewed the cosmetic results seventeen patients were available for review subjective reports from patients and parents as well as objective clinical assessment by one of the authors were used to assess these results according to our MGS patients had excellent results these patients and their parents were satisfied with the cosmetic results and there was no clinical evidence of a bony prominence over the lateral condylar region or an unsightly operative scar one patient had a poor result with a lateral bony prominence and an unsightly scar both of which were clinically obvious we report that lateral closing osteotomies in children who have not yet reached skeletal maturity produce excellent cosmetic results

73

grading system

a retrospective study was performed to evaluate the results of intramedullary fixation used in the management of unstable diaphyseal bothbone forearm fractures in skeletally immature patients twentyfive patients with fractures were identified whose fracture management included only IM fixation galeazzi monteggia radial head and distal metaphyseal fractures were excluded from this analysis mean age at fracture was years there were closed and open fractures eight grade i and two grade ii smooth kirschner wires or rush rods were used for fixation average length of immobilization was weeks in a longarm cast and weeks in a shortarm cast all regained normal elbow motion with regaining full forearm rotation eight patients had an average loss of degrees of supination and degrees of pronation there were four minor and two major complications one rod migration and one delayed union no infections malunions or synostoses occurred in this patient group using the grading scheme adapted by price there were excellent results four good and no fair or poor results in our experience IM fixation of the unstable bothbone forearm fractures is a safe effective and userfriendly technique when alignment jeopardizes fracture position at union and eventual forearm motion

37|168

intramedullary|intramedullary

the standard treatment in forearm fractures in children is usually conservative unstable fractures of the PT parts of the forearm often show poor results T3 nonoperative management so that these fractures usually require surgical intervention we report children ages years who were treated by elastic intramedullary nailing sixteen patients were treated by intramedullary splinting immediately after their accident children required intramedullary nailing T3 failure of conservative treatment and fracture redisplacement at the time of followup months later functional results were excellent in children good in five children and fair in one child there were no serious complications other than one delayed union according to these results IM nailing can be recommended for the treatment of unstable fractures of the PT and middle thirds of the forearm in children

15|24|62|106|119

proximal|after|after|intramedullary|proximal

carpal fractures in children are uncommon injuries with the scaphoid being fractured most frequently thirtythree children with scaphoid fractures and one child each with fractures of triquetrum trapezoid hamate and capitate were retrospectively reviewed the mean age was years months the mechanism of injury was of low energy in most cases with of injuries involving a fall localizing tenderness was present in of cases of fractures were evident on the initial radiographs one patient required a bone scan to confirm the diagnosis all but one scaphoid fracture went on to union with CT in a longarm thumb spica cast or shortarm thumb spica cast at a mean of weeks all other carpal fractures healed at a mean of weeks the one scaphoid nonunion was attributed to noncompliance by the patient

92

conservative treatment

nine children average age years with displaced type iii tibialeminence fractures were reviewed with an average followup of years the fractures were treated with arthroscopeassisted reduction and suture fixation nine of the knees demonstrated meniscal interposition at the fracture site that contributed to unsuccessful closed reduction at followup subjective knee function was excellent in all cases and no clinical or objective evidence of knee laxity or instability was detected in any patient all patients demonstrated full range of motion of the affected knee compared with the CL side

86

contralateral

the study describes a home traction program of FA shaft fractures in preschool children using the traction technique a special bed stretcher was designed for the program and adapted for use in ordinary ambulances and in all types of homes twentyfour patients years of age were followed the average hospital stay was days and the average home traction period was days one patient had a SF pin tract infection the treatment was uneventful in all other cases all fractures healed with a shortening of or cm the angulation was or degrees in all cases but one which healed with a valgus angulation of degrees but without PET disability interviews showed that the parents were very satisfied with the treatment program the cost savings are obvious compared to traction treatment in the hospital

8|65|106

femoral|superficial|functional

the purpose of this article is to review our experience with early spica casting and determine risk factors for loss of reduction and skin complications the radiographic and clinical charts of children were retrospectively reviewed at the time of fracture union excessive shortening and angular malunion were not significant problems loss of reduction and skin complications occurred in and of patients respectively in addition to previously described risk factors we identified spica knee flexion angle degrees as predictive of eventual loss of reduction and found that cm of initial shortening was not a contraindication to early spica casting AF associated with skin problems included younger age and abuse as a mechanism of injury in our opinion early spica casting is the treatment of choice for all isolated closed femur fractures in otherwise healthy children aged years or younger regardless of the degree of initial deformity

98

factors

ninetyeight continuous postoperative epidurals were administered to children the patients were divided into two groups group i included cases in which a solution of bupivacaine was continuously administered group ii included cases in which a similar solution of bupivacaine mixed with micrograms of FE was po the dose of the epidural medication was titrated by the anesthesiologist according to the patients age and anticipated level of postoperative pain the average pain score for all patients for the first h was supplemental analgesia averaging mg intravenous morphinekg h was required in cases in group i and eight in group ii in group i the average dose of supplemental analgesia was mg intravenous morphinekg h whereas in group ii it was only mg intravenous morphinekg h CEA is ERP in controlling postoperative pain and the addition of fentanyl reduces the need for systemic narcotics

43|45|124|126

fentanyl|administered|continuous epidural analgesia|effective

postoperative fever in the pediatric orthopaedic population remains a clinical concern even though prior studies concluded that fevers are a poor predictor of surgical complications in this retrospective T0 of patients we established guidelines regarding the degree and time course of fever we should expect based on the perioperative conditions of magnitude of surgery duration of surgery need for intraoperative transfusion estimated blood loss age and gender to provide a more sensitive assessment of fever we developed composite temperature curves for each patient and defined the area under these curves as the total febrile response tfr this allowed us to assess fever as a cumulative event taking into account both its magnitude and duration a multivariate model then determined that of the perioperative conditions studied intraoperative transfusion status and estimated blood loss were most helpful in predicting a patients tfr the results of this T0 can be used as an additional tool for assessing postoperative progress and whether a fever is within the normal limits indicated by a patients perioperative variables

28|144

study|study

external fixation was compared to crossed steinman pins and plaster for fixation after osteotomy about the knee in children a group of patients treated by external fixation was compared to a control group of patients fixed with crossed steinman pins and casting the groups were matched for age height and weight overall there was a union rate preoperative deformity and postoperative correction were similar in the two CG the time to union was significantly longer and there were significantly more complications in the external fixator group there were complications in the external fixator group and five in the control group complications included pin tract infections peroneal nerve palsy and delayed union EF provides certain advantages for fixation after osteotomies about the knee in children but is associated with a variety of complications

67|111

groups|external fixation

frontalplane deformity of the proximal tibia in children has a variety of etiologies there are also a number of described surgical techniques for correction of these deformities the authors reviewed their early experience with the use of the orthofix tgarches external fixator for correction of PT tibial deformities in patients mean age at surgery was years the most common diagnosis was adolescent blounts disease average deformity was degrees total treatment time averaged weeks for those requiring lengthening and weeks for those without complications included one ring sequestrum treated by curettage and two patients with subsequent development of femoral deformity tibial anatomic axis averaged degree of varus this device can achieve excellent correction of deformity isolated to the FC plane with few complications it allows functional weight bearing and use of adjacent joints during treatment

45|117

proximal|frontal

the purpose of this T0 was to compare the results of operative versus nonoperative treatment for posttraumatic genu valgum it is a retrospective chart and radiograph review of all patients with the diagnosis of posttraumatic genu valgum from our institution and from data obtained in response to letters sent to the members of the pediatric orthopaedic society of north america posna the cDNA physeal shaft cps angle and the tibial femoral angle tfa were measured at the time of injury at maximal deformity and at latest followup fifteen patients were identified in the nonoperative group and five in the operative group in both groups the valgus deformity PD over a month span in both CG the valgus deformity improved at the time of followup there was no significant difference in the cps angle or tfa between groups at the time of injury at maximal deformity or at followup

4|62|107|114

study|complementary|progressed|groups

eightyfive patients with CP had modified adductor muscle transfers a study of associated patient characteristics suggests that comparing adductor transfer with adductor release using postoperative radiographs need for subsequent surgery or postoperative motor skills is flawed by multiple variables adductor release and adductor transfer are best compared by measuring the abduction obtained at surgery and maintained over time a followup of modified adductor transfers with no prior or concomitant hip surgery demonstrated an averaged initial improvement in abduction of degrees and maintenance of abduction with a low incidence of recurrence

3

cerebral palsy

we describe the gross and microscopic anatomic changes in the hip that result from the deforming forces in children with neuromuscular imbalance twelve dislocated PT femora that had been resected from children with spastic diplegia or tetraplegia were evaluated with respect to their gross microscopic and radiographic structure the epiphyses were wedge shaped with deformation of the FA head apparent in all cases in addition to a severe loss of articular cartilage a furrowed erosion of epiphyseal bone suggested a sustained blunt bandlike force across the surface of the hip where it opposed the acetabular labrum the underlying physis of the capital femur was irregular with aberrant histologic structure whereas that of the lesser trochanter was hypertrophic and angulated in a superior and anterior direction a significant degree of valgus was not noticeable in most specimens in summary the spastic adductor and iliopsoas responsible for the changes in the lesser trochanter work in conjunction with the hip flexor and internal rotator muscles to subluxate the PT femur in the process the superior rim of the acetabulum and capsule causes focal deformation of the superolateral femoral head creating a fulcrum upon which the hip then progressively subluxates the indentation locks the femoral head at the lateral acetabular margin preventing CR dislocation but leading to bone pain consequent to cartilage erosion

24|57|165|208

proximal|femoral|proximal|complete

it has been suggested that intrauterine SE to high C2 of relaxin causes hip instability in newborns the aim of this work was to evaluate whether the serum relaxin concentration in umbilical vein blood is associated with hip instability in the P0 blood was collected by cordocentesis from newborns and serum relaxin C2 were obtained by using a standard sandwich enzymelinked immunosorbent assay elisa movement of the femoral head in the hip joint was determined for all children by the anteriordynamic ultrasound method hereby their status on neonatal hip instability was determined fifteen cases girls three boys were found and controls were selected only six newborns had unstable hips to a degree requiring treatment ten newborns had ortolanipositive hips only three specimens of the samples measured had serum relaxin concentrations above the detection limit of pgml none of these were cases this T0 does not show an association of serum relaxin with neonatal hip instability it is suggested that detectable serum relaxin levels are found in samples from the umbilical cord only when these are contaminated with maternal blood

6|9|41|52|142

exposure|levels|newborn|levels|study

DEH is a rare developmental bone dysplasia characterized by an osteocartilaginous tumor arising from an epiphysis we reviewed the clinical and radiographic findings including magnetic resonance imaging mri of nine new patients with dysplasia epiphysealis hemimelica the lower limb was involved in all cases with the ankle talus and knee distal femur being the most common CS mri was helpful in defining the site and extent of the osteocartilaginous mass and provided detailed images of associated joint deformity often there was a clear plane of separation between the lesion and the normal epiphysis all cases were observed initially and showed progressive increase in size of the lesion with skeletal growth surgical excision was performed in five cases and proved to be difficult we recommend excision of symptomatic localized juxtaarticular lesions but do not recommend excision of articular lesions postoperative degenerative joint changes occurred in two patients

0|56

dysplasia epiphysealis hemimelica|sites

this investigation was undertaken to determine the value of a routine radiological consultation on all examinations taken during the course of evaluation and treatment of children with elective orthopedic problems shriners hospital in LA treats children with chronic orthopedic problems all radiographs are ordered by an orthopedic surgeon currently all plain examinations are also read and reported by a pediatric radiologist the study was a retrospective chart review three hundred nineteen radiographic examinations of the total performed in calendar year were reviewed the orthopedic surgeons documented the results of their readings in of the cases while the radiology staff documented of the studies the data do not show evidence of significant misinterpretations in the readings by the orthopedic surgeons therefore routine radiological consultation for all examinations is unnecessary in that TPS setting if a policy change were instituted it would represent a L1 saving in healthcare costs

33|130|142

los angeles|specific|major

we prospectively evaluated the results of ultrasonography in patients of sickle cell disease suspected to have vasoocclusive crisisacute hematogenous OM the average age was years range twentysix children were boys and were girls seventeen patients had ultrasonographic changes that suggested acute OM the minimal WG cell count was mm and maximal mm mean mm in uninfected patients and in patients the mean was mm mm the mean erythrocyte sedimentation rate in uninfected patients was for the first hour mm and in infected patients it was for the first hour mm pus culture was positive in all infected patients and the L3 organism was salmonella enteriditis in eight staphylococcal species in six s aureus in four and s epidermidis in two and streptococcus species and anaerobic streptococci all patients with VOC were treated with analgesics and intravenous fluids and did not require any further treatment in patients with acute OM the treatment was incision drainage and drilling of bone and antibiotic therapy we conclude that ultrasonography clearly and decisively differentiated acute osteomyelitis from vasoocclusive crisis in patients with sickle cell disease

19|41|44|100|129|148

osteomyelitis|osteomyelitis|white|infective|vasoocclusive crisis|osteomyelitis

the effects of respiratory hyperoxia rh and xanthine oxidase xo during localized hyperthermia ht were investigated by determining markers of oxidative damage to lipids and proteins and tumor growth anesthetized rats with sc dssarcomas underwent one of the following treatments a localized salinebath ht min degrees c b ht rh o and c ht rh xo unitskg iv shamtreated animals served as controls tumors were investigated for a thiobarbituric acidreactive substance formation and proteinbound hydroxynonenal as indicators of lipid peroxidation b reactive oxygenmediated protein modifications c apoptosis and d tumor volume growth upon treatment increases in thiobarbituric acidreactive substances proteinbound hydroxynonenal proteinassociated carbonyl functions and number of cells undergoing apoptosis were found in tumor tissue together with an inhibition of RT growth when treatment groups were compared effects in the group ht rh xo were generally most pronounced these findings indicate that the antitumor effect of ht is at least partially mediated through the selective induction of lipid peroxidation and oxidative injury in RT cells leading to apoptosis this effect was enhanced by adding rh or rh xo presumably due to enhanced tissue damage following an increased formation of ROS species with higher C2 of lipid peroxidation and protein oxidation

120|163|189|193

tumor|tumor|reactive oxygen|levels

tsg was recently identified as a tumor susceptibility gene by PET inactivation of allelic loci in mouse t fibroblasts although previous studies suggested that homozygous intragenic deletion of tsg is rare in BCCs and specimens the neoplastic phenotype caused by tsg inactivation implicated that tsg may play a significant role in cell growth control here we characterize mouse polyclonal and monoclonal antibodies that specifically recognize the tsg protein molecular mass kda in wholecell lysates by straight western blot analysis by indirect immunofluorescence staining tsg was found to be localized in the cytoplasm throughout the entire cell cycle however the nuclear staining increases from g to s phase and becomes dominant in late s phase tsg is mainly distributed surrounding the chromosomes during m phase the expression level of tsg is not cell cycle dependent it is possible that the relocalization of tsg from the cytoplasm into the nucleus may be relevant to its function microinjection of both polyclonal and monoclonal antibodies TPS to tsg into cells during g or s phase results in cell cycle arrest furthermore overexpression of tsg leads to cell death suggesting that the appropriate amount of tsg is critical for Tc progression taken together these results suggest that neoplastic transformation caused by tsg deficiency may result from bypassing of the cell cycle checkpoints

10|32|161|194

functional|breast cancer cells|specific|cell cycle

here we provide proof that the i.t. of tumor cells engineered to secrete interleukin iligg chimeric proteins locally induces potent antitumor responses which are more effective than tumor transfection with il alone mu plasmacytoma cells jl were stably transfected with dna coding for a human iligg or a mu iliggb F0 protein and were injected sc into syngeneic balbc mice evaluation of tumor growth and AAR patterns showed that iligg secretion by transfected jl tumor cells induced their AAR in all animals tested similar to the rejection of jl cells engineered to secrete il alone whereas treatment with parental cells was lethal however mice treated with iliggsecreting jl cells human iligg and mu iliggb exhibited a significantly stronger RT immunity against a later challenge with parental jl cells than mice treated with ilsecreting tumor cells

6|32|48|50|65|78|112|118

injection|murine|murine|fusion|rejection|rejection|murine|tumor

the polyamine analogue nethylncycloheptylmethyldiazaundecane chenspminduced PCD in nci h cells is accompanied by cytochrome c release the loss of mitochondrial membrane potential activation of caspase caspasemediated polyadpribose polymerase cleavage gm arrest and dna and nuclear fragmentation overexpression of bcl completely inhibits chenspminduced cytochrome c PR ICE activation and polyadpribose polymerase cleavage however bcl does not abrogate chenspminduced programmed cell death these results suggest that although cytochrome c release and activation of the caspase protease cascade contribute to the rapid and efficient execution of apoptosis a ICE cascadeindependent pathway also exists and can be activated by chenspm treatment

5|44|45|85

programmed cell death|release|caspase|caspase

germline mutations in the brca and brca genes confer a predisposition to breast as well as ovarian carcinoma except for loss of the respective wildtype allele somatic genetic changes needed for the progression of inherited ovarian PT are unknown a genomewide search for such alterations was performed by comparative genomic hybridization analysis on brca and brca mutationpositive n ovarian carcinoma specimens comparison with sporadic ovarian carcinomas n revealed extensive genetic similarity between the inherited and sporadic carcinomas with the sole exception of a frequent gain of qq in the inherited group suggesting the presence of an oncogene at qq operating in the absence of brca CF the overall similarity of gains and losses by comparative genomic hybridization suggests a common main pathway in tumor progression of both inherited and sporadic ovarian carcinomas

36|105

tumors|function

loss of chromosome q is a frequently observed genetic defect in prostate cancer recently the ptenmmac tumor suppressor gene was identified and mapped to chromosome q we studied pten structure and expression in in vitro cell lines and in vivo xenografts derived from six primary and nine M1 PC-3 cancers dna samples were allelotyped for eight polymorphic markers within and surrounding the pten gene additionally the nine pten exons were tested for deletions in five samples pc pc pcew pc and pc homozygous deletions of the pten gene or parts of the gene were detected pc contained a small HD encompassing pten exon in two dnas pc and pc nonsense mutations were found and in two lncap and pc frameshift mutations were found missense mutations were not detected pten mrna expression was clearly observed in all cell lines and xenografts without C1 homozygous deletions showing that pten downregulation is not an important mechanism of pten inactivation the high frequency of pten mutations and deletions indicates a significant role of this RT suppressor gene in the pathogenesis of prostate cancer

47|48|99|141|170

metastatic|human prostate|homozygous deletion|large|tumor

bannayanrileyruvalcaba syndrome brrs is a rare hamartomatous polyposis condition with features of macrocephaly intestinal JP developmental delay lipomas and pigmentation spots of the male genitalia an autosomal dominant pattern of inheritance exists in some families but others appear as sporadic cases germline mutations in pten a tyrosine phosphatase and putative tumor suppressor gene have been demonstrated in two families with brrs and chromatin loss at the pten gene locus on chromosome q has been demonstrated in two brrs patients germline mutations in pten have also been described in cowden disease and in a small number of patients with juvenile polyposis syndrome in an attempt to assess the nature of pten mutations in brrs we analyzed three sporadic brrs patients for chromosome q deletion or pten germline mutations all patients demonstrated no loss of parental alleles at chromosome q markers that encompassed the region of pten in addition analysis of mrna and genomic dna revealed no nonsense missense or insertiondeletion mutations of pten thus other mechanisms besides mutation of pten must have occurred to cause brrs in these patients we speculate that brrs and JPS may have a heterogeneous etiology to cause their syndromes

14|183

juvenile polyposis|juvenile polyposis syndrome

in a search for mutations of the type i transforming growth factor beta receptor tbetari we mapped the gene to q and found a common polymorphism tbetaria and a rare variant tbetaria of tbetari causing an inframe deletion of three alanines and an inframe insertion of one alanine respectively in the receptors extracellular domain the biological relevance of the polymorphism tbetaria was investigated when tbetaria was transiently transfected into tbetarideficient cells the growthinhibitory effects of transforming growth factor beta were restored tbetaria and tbetaria frequency were assessed in tumor samples and nontumor samples from patients with a diagnosis of cancer as well as in normal blood donors of comparable ethnic composition the frequency of tbetaria heterozygotes was fairly similar in normal blood donors in nontumor dna of patients with a diagnosis of cancer and in tumor samples however the frequency of tbetaria homozygotes among nontumor and tumor samples obtained from patients with a diagnosis of CA was higher than that predicted by the hardyweinberg law the clinical and biological significance of tbetaria homozygosity needs to be further investigated

155

cancer

multidrug resistanceassociated protein mrp and cLPM multispecific OAT cmoat are closely related mammalian atpbinding cassette transporters that export organic anions from cells transfection studies have established that mrp confers resistance to natural product cytotoxic agents and recent evidence suggests the possibility that cmoat may contribute to cytotoxic drug resistance as well based upon the potential importance of these transporters in clinical drug resistance and their important physiological roles in the export of the amphiphilic products of phase i and phase ii metabolism we sought to identify other mrprelated transporters using a degenerate pcr RPA we isolated a cdna that encodes a novel atpbinding cassette transporter which we designated moatb the moatb gene was mapped using fluorescence in situ hybridization to chromosome band q comparison of the moatb predicted protein with other transporters revealed that it is most closely related to mrp cmoat and the yeast organic anion transporter ycf although moatb is closely related to these transporters it is distinguished by the absence of a approximately amino acid nhterminal hydrophobic extension that is present in mrp and cmoat and which is predicted to encode several transmembrane spanning segments in addition the moatb tissue distribution is distinct from mrp and cmoat in contrast to mrp which is widely expressed in tissues including liver and cmoat the expression of which is largely restricted to liver the moatb transcript is widely expressed with particularly high levels in prostate but is barely detectable in CL these data indicate that moatb is a ubiquitously expressed transporter that is closely related to mrp and cmoat and raise the possibility that it may be an organic anion pump relevant to cellular detoxification

5|7|93|240

canalicular|organic anion transporter|approach|liver

the objective of these studies has been to develop a better understanding of the regulation of ornithine decarboxylase odc during the neoplastic process and to determine whether induction of odc is a necessary component in the action of the ras oncogene specifically we have studied the role of odc overexpression in signaling pathways mediated by raf or rhoa cells transformed by ras are known to have constitutively high levels of odc activity that correlate with oncogenic transformation to determine which pathways downstream of ras contribute to the regulation of odc activity niht cells were transfected with plasmids coding for activated mutants of either hras or rhoa or oncogenic nuraf there was a good correlation between increasing odc TPS activity and NC in morphology from normal to transformed in the nuraf hrasl and rhoal clones increasing odc activity also correlated positively with the ability to grow in soft agar in both the hras and rhoaexpressing cells in stable transfections coexpression of the odc dominant negative mutant kaca with either hrasl or rhoal both inhibited intracellular odc activity and caused a reversion of the transformed phenotype as measured by a dramatic reduction in the ability of these cells to grow in soft agar and form foci on a ML these results suggest strongly that odc induction is necessary for transformation by oncogenic ras in contrast expression of ka ca had no effect on the ability of nuraftransformed cells to grow in soft agar although intracellular odc levels were inhibited when grown on a monolayer these cells also maintained their transformed appearance furthermore expression of the odc dominant negative mutant did not affect the phosphorylation of mitogenactivated protein kinase in nuraftransformed cells these experiments provide strong support for the concept that transformation by activated ras is accompanied by an induction of odc the results using rhoal and nuraf suggest that this increase in odc activity is mediated at least in part through a raf MAP kinase independent pathway

117|120|206|321

specific|change|monolayer|mitogenactivated protein

we investigated the effect of the chemopreventive compound diosmin and its aglycone form diosmetin on the carcinogen activation pathway mediated by the aryl hydrocarbon receptor ahr in mcf human breast epithelial cancer cells treatment of the cells with diosmin caused a dosedependent increase in the metabolism of the mammary carcinogen dimethylbenzaanthracene dmba as assessed by increased formation of dmbadna adducts and by dmbainduced cytotoxicity in contrast treatment of the cells with diosmetin decreased both parameters diosmetin but not diosmin directly inhibited cytochrome p a cypa activity in a noncompetitive manner in microsomes isolated from dmbatreated cells as assayed by ethyoxyresorufinodeethylase activity treatment of the cells with diosmin or diosmetin on the other hand caused a dose and timedependent increase in cypa activity in intact cells that was comparable to that induced by dmba or by the aryl hydrocarbon benzoapyrene both diosmin and diosmetin caused an increase in the transcription of the cypa gene as measured by increased C2 of cypa mrna both compounds caused the activation of the dnabinding capacity of the ahr for the xenobioticresponsive element of cypa these results indicate that diosmin and diosmetin are NK dietary agonists of the ahr causing a potent increase in cypa transcription and cypa activity however only diosmetin is capable of inhibiting cypa enzyme activity thus inhibiting carcinogen activation

157|187

levels|natural

detection and quantitation of circulating cancer cells in IP blood may improve cancer staging and monitoring this study explored the feasibility of using circulating cancer cell detection in peripheral blood for the rapid assessment of chemotherapeutic response cytokeratin mrna was amplified by nested reverse transcriptasepcr in the peripheral blood of healthy volunteers pneumonia patients and lung cancer patients circulating cancer cells in the peripheral blood were semiquantitatively determined by taking the ratio of cytokeratin band intensity from the second round of nested pcr to the glyceraldehydephosphate dehydrogenase band intensity from the first round of pcr amplification the PCD limit of the method was cancer cell in IP blood MNC cells the positive detection rate was for lung adenocarcinoma patients of all stages for squamous carcinoma patients of all stages and for small cell lung cancer patients only one control sample from a pneumonia patient showed a positive result the quantitative method reliably and sensitively estimated cancer cell numbers in the IP blood of lung cancer patients serial measurement of the relative number of circulating cancer cells correlated with the RT burden and treatment response of patients this method may help rapidly assess the tau of anticancer treatment redefine cancer staging and facilitate the design of better therapeutic strategies for the treatment of cancer patients

8|97|106|108|160|179|193

peripheral|detection|peripheral|mononuclear|peripheral|tumor|efficacy

distant metastases are the major cause of morbidity and mortality in women with breast cancer the prediction of this M1 proclivity is essential in determining prognosis and should allow an appropriate choice of therapy a critical look at the metastatic process and its phenotypic expression offers an opportunity to identify some of the important events in the process that may relate to prognosis with the goal of identifying those patients with occult metastases and also sparing SVR treatment in those patients whose tumors have not developed the capacity for distant spread to evaluate the significance of nm and angiogenesis in the M1 cascade we used archival material from nodenegative breast CA patients who had a median followup of years all patients underwent mastectomy and received no adjuvant chemotherapy or hormone or radiation therapy immunohistochemistry was used to detect nmh expression whereas angiogenesis was determined by microvessel count mvc we found the year diseasefree survival dfs to be significantly better in patients with high nm compared with low nm compared with p low mvc is associated with excellent longterm dfs in those patients with high mvc high nm allows the ID of a subgroup with significantly higher dfs compared with p among high nuclear grade PT if nm is high the dfs is significantly better compared with p thus nm is still associated with excellent survival even when there is unfavorable angiogenesis or nuclear grade multivariate analysis confirms that nm and mvc are important prognostic factors high mvc appears necessary but not sufficient for metastasis to occur whereas low nm may further contribute to metastatic progression both nm and mvc contribute valuable information in characterizing the malignant phenotype

19|76|101|110|189|204

metastatic|systemic|metastatic|cancer|identification|tumors

chemoprevention of colorectal cancer using aspirin has been demonstrated in rodents and has been suggested by data from epidemiological studies the mechanism that accounts for this prevention is unknown but it is thought to relate to an irreversible inhibition of cyclooxygenase and subsequently prostaglandin production the effect of aspirin on the growth of human Tc RT cells was determined in an effort to gain insight into a possible mechanism of action in the two cell lines studied sw and ht we observed a significant dose and timedependent increase in aspirin toxicity in a concentration range of mm this result was independent of prostaglandin production because there was no measurable prostaglandin e in cell SC medium as compared with controls cells in cultures that contained aspirin were not detached which suggests that the mechanism of cell death was not apoptosis flow cytometric analysis revealed an increase in s phase and gm populations as well as the number of subdiploid nuclei in cultures treated with highdose aspirin confirmation that cells were undergoing necrosis in response to aspirin was evident from the presence of cells that bound annexin v and accumulated propidium iodide in the absence of a population that bound annexin alone the results suggest that aspirin induces Tc arrest and causes necrosis at high concentrations in vitro but does not induce apoptosis collectively these two events CN and cell cycle arrest may contribute to the chemopreventive effect that seems to result from longterm administration of aspirin in vivo

54|55|113|206|225

colonic|tumor|culture|cell cycle|necrosis

the present T0 evaluated three human prostate xenograft tumors cwr cwrr and cwr as models for drug activity DUE the chemosensitivity and the expression of several proteins ie pglycoprotein or pgp prostate specific antigen or psa p and bcl in xenograft tumors were compared with those in patient PT obtained through radical prostatectomy n cwr is LNCaP cwrr is the androgenindependent subline of cwr and cwr is a separately derived androgenindependent RT the results of immunohistochemical andor western blot analysis indicate that the expression of psa pgp p and bcl in the three cwr xenograft PT are representative of their expression in and respectively of patient tumors the responses of histocultures of xenograft PT to doxorubicin and paclitaxel including inhibition of dna precursor incorporation and cell death induction were qualitatively similar to the responses of patient tumors for example in all three xenograft and patient PT doxorubicin produced complete antiproliferation and cytotoxicity ie cell kill whereas paclitaxel produced incomplete effects a comparison of the concentrationeffect relationships in xenograft and patient PT population median values indicates that the chemosensitivity observed in patient tumors is represented by the chemosensitivity of one or more of the three xenograft PT as follows a the three xenograft tumors and patient tumors responded equally to doxorubicininduced antiproliferation b cwrr cwr and patient tumors responded equally to doxorubicininduced cytotoxicity whereas cwr was fold less sensitive c cwr and cwrr tumors were less CS to paclitaxelinduced antiproliferation compared with patient tumors whereas cwr was severalfold more sensitive and d cwr cwrr and patient tumors responded equally to paclitaxelinduced cytotoxicity whereas cwr was fold more sensitive the results of this study indicate that the three xenograft tumors which show chemosensitivity comparable with the results of or patient PT and encompass the majority of the heterogeneous patient prostate PT in the expression of pgp psa p and bcl proteins are useful models for drug activity evaluation

2|18|48|56|71|95|113|145|170|195|235|288|298

study|evaluation|tumors|androgendependent|tumor|tumors|tumors|tumors|tumors|tumors|sensitive|tumors|tumors

the novel aminosterol squalamine inhibits angiogenesis and tumor growth in multiple animal models this effect is mediated at least in part by blocking mitogeninduced proliferation and migration of EC cells thus preventing neovascularization of the tumor squalamine has no observable effect on unstimulated endothelial cells is not directly cytotoxic to tumor cells does not alter mitogen production by tumor cells and has no obvious effects on the growth of P0 vertebrates squalamine was also found to have remarkable effects on the primitive vascular bed of the chick chorioallantoic membrane which has striking similarities to tumor capillaries squalamine may thus be well suited for treatment of tumors and other diseases characterized by neovascularization in humans

28|69

endothelial|newborn

in this phase i study the maximally tolerated doses mtds of ip iododeoxyuridine idurd CT and in combination with iv calcium leucovorin lv were determined the pharmacokinetics and pharmacological advantage of idurd were evaluated and flow cytometric analysis allowed examination of the extent of incorporation of idurd into tumor cells with and without the addition of iv lv thirtynine patients with advanced neoplasms primarily confined to the peritoneal space were enrolled in a doseescalation trial using h dwells of idurd po ip daily for days with and without an iv infusion of lv mgmday for days twentythree patients received singleagent therapy and patients received ip idurd in combination with iv lv the mtd of singleagent idurd po on this schedule was mgmday for days and that of the idurd in combination was mgmday doselimiting toxicities were myelosuppression and stomatitis during the period of the dwell the peritoneal auc area under the curve of idurd exceeded the plasma auc of idurd by one or two orders of magnitude in all patients at all doses tested there was a possible effect of lv on peritoneal auc the geometric mean pharmacological advantage aucperitoneal aucplasma was at mgmday and at mgmday flow cytometric analysis suggests saturation of idurd measured in dna at the mgm dose level without an increase after the addition of lv twelve patients received courses of therapy one patient with recurrent ovarian cancer who received courses of therapy experienced complete resolution of her ascites near normalization of ca levels and improved SQ of life two patients with highrisk PT receiving adjuvant therapy are diseasefree at and years T3 treatment other patients experienced transient clearing of ascites the recommended phase ii dose of ip idurd using a h dwell daily for days is mgmday alone or mgmday in combination with continuous iv lv at mgmday for days although flow cytometric data suggest that dna incorporation of idurd is not affected by the addition of lv the cytotoxicity of the combination regimen may be increased due to lvenhanced idurdrelated inhibition of thymidylate synthase for this reason we recommend that efficacy studies of the combination continue in parallel with studies of idurd alone

14|80|116|250|257|266

alone|administered|administered|quality|tumors|after

the extracellular microenvironment of tumors differs from that of most normal tissues many tumors have relatively acidic extracellular ph although the intracellular ph of tumor cells remains normal due to the efficient maintenance of a large proton gradient across the membrane this difference between PT and normal tissues might be exploited therapeutically by disruption of the mechanisms that regulate intracellular ph so that tumor cells are killed by intracellular acidinduced injury to investigate the mechanisms by which intracellular acidification leads to cell death we have studied the roles of the antiapoptotic gene bcl and its proapoptotic IB partner bax the stressactivated protein kinases sapkjnk and the caspase proteases in mediating acidinduced cell death whereas the expression of bcl in human bladder cancer mghu cells had no effect on acidinduced death overexpression of bax enhanced cell death consistent with its proapoptotic function inhibition of sapk through the expression of a dominant negative mutant of its activator sek protected cells from acidinduced cell death caspase activation as measured by polyadpribose polymerase cleavage was absent after lethal intracellular acidification consistent with this observation inhibition of interleukin betaconverting enzyme proteases by the peptide zvalalaaspomechf did not protect against acidinduced cell killing we conclude that acidinduced cell death depends on bax and on sapk signaling pathways but not on the caspase PRs therapeutic manipulation of bax and sapk may enhance acidinduced RT cell killing

44|96|216|226

tumors|binding|proteases|tumor