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Biomedical subjects

J Berger

Publications and source records attributed to J Berger.

At least 127 records · Page 7Linked to original sources
PubMed2000

CFU-Mk content of immunoselected CD34+ peripheral blood progenitor cells, evaluated with an adapted serum-free methylcellulose assay, is predictive of platelet lineage reconstitution in children with solid tumors.

Immunoselected CD34+ peripheral blood progenitor cell (PBPC) transplantation is now frequently used to support autologous hematopoiesis after myeloablative therapy, its feasability having been proved by several groups. However, we and others observed delayed platelet recovery. We hypothesized that immunoselection processing might induce selective loss of megakaryocyte progenitors, or a decrease in their proliferation. We used a colony-forming units megakaryocyte (CFU-Mk) assay to evaluate these consequences and predict platelet recovery in patients. In CD34+ PBPCs from 10 children with solid tumors, we observed no selective loss in CFU-Mk numbers during immunoselection processing and no impairment of clonogenicity. The CFU-Mk yield (59.2 +/- 11.3%) was at least similar to the CD34+ yield (44.2 +/- 3.8%). We assessed the predictive value of CFU-Mk numbers infused for recovery of platelet lineage. We found an inverse correlation between the time taken to reach a platelet count greater than 50 x 10(9)/L and only the CFU-Mk dose (r = -0.71; p = 0.022) among the different type of progenitors, including colony-forming units granulocyte-macrophage (CFU-GM), burst-forming units erythrocyte (BFU-E) and colony-forming units-mixed (CFU-Mix). These findings suggest that CFU-Mk number could be used as sole predictive functional parameter for platelet reconstitution in children after immunoselection of CD34+ cells, in particular for low CD34+ cell dose, and thus as an indicator for initial quality of hematopoietic cells before in vitro expansion.

Adolescent↗
PubMed2000

Expression of retinoic acid receptors in non-neoplastic epithelial disorders of the vulva and normal vulvar skin.

Retinoids and their nuclear retinoic receptors (RARs) are important modulators of epidermal cell proliferation and terminal differentiation. Aberrant expression of RARs in the epidermis has been found to be associated with altered differentiation capacity of keratinocytes. In this study, the expression of the various types of RARs (RAR-alpha, RAR-beta, and RAR-gamma) was investigated in surgical specimens from 17 patients with vulvar lichen sclerosus, 12 patients with vulvar squamous cell hyperplasia, and 11 specimens of normal vulvar skin by nonradioactive in situ hybridization. The results demonstrate that RAR-alpha expression is significantly decreased in lichen sclerosus (p < 0.0001) and squamous cell hyperplasia (p = 0.007) compared with normal vulvar skin. Furthermore, in normal vulvar skin RAR-alpha mRNA is mainly located in the suprabasal epidermal cell layers, whereas in lichen sclerosus RAR-alpha is expressed predominantly in the basal cell layers. In squamous cell hyperplasia RAR-alpha expression occurs in all cell layers. Compared with normal vulvar skin, RAR-gamma expression is higher in lichen sclerosus (p = 0.026), but no statistically significant differences are seen in squamous cell hyperplasia. These results suggest that partial loss and abnormal localization of RAR-alpha expression as well as increased RAR-gamma expression may play a role in the etiology of non-neoplastic epithelial disorders of the vulva.

Epidermis↗
PubMed2000

Fulminant hepatic failure from heat stroke requiring liver transplantation.

A 16-year-old man developed heat stroke during football practice when the temperature was 33.8 degrees C (heat index, 44.4 degrees C). Resuscitation with ice water lavage, external cooling, and intravenous fluids was initially successful, but the patient again became obtunded. Liver chemistry tests and the prothrombin time and serum ammonia increased markedly, and rhabdomyolysis and renal failure became evident, necessitating hemodialysis. He underwent liver transplantation for fulminant hepatic failure approximately 72 hours after admission. Rhabdomyolysis with renal failure and severe electrolyte disturbances continued despite aggressive hemodialysis and the patient had a cardiopulmonary arrest and died 10 days after transplantation. This case shows that liver transplantation cannot always overcome the generalized toxic effects of heat stroke. More aggressive hemodialysis or combined liver/kidney transplantation might result in a positive outcome in selected cases.

Adolescent↗
PubMed2000

Electric field distributions in a phased-array applicator with 12 channels: measurements and numerical simulations.

In this paper we examine the SIGMA-Eye hyperthermia applicator (BSD Medical Corp., Salt Lake City, Utah 84119) with respect to the control of electric field distributions. This applicator is equipped with 12 pairs of antennas fed by 12 amplifiers, allowing the individual adjustment of phase and power for each of them. Measurements were conducted using phantoms with well-defined electrical properties. Specific electro-optical sensors, capable of measuring both electric field amplitudes and phases, have been developed, and a system for data acquisition and analysis has been set up. In its initial state the applicator appeared not to be satisfactorily matched at 100 MHz for the phantom used, with return losses up to 20% in power. By tuner readjustments we achieved values below 5%. For various settings of the amplifiers' control parameters we measured field distributions, both in the phantom and in the surrounding water bolus. The experimental results were compared with numerical simulations based on finite difference and finite element methods. Measured and calculated electric fields exhibit deviations of 10% on average, allowing, in principle, a satisfactory prediction of fields by numerical simulations or as well by on-line measurements at selected locations of the applicator at antenna proximity. However, to obtain this satisfactory agreement a modification of the control parameters in the calculations (phases and amplitudes in the feed points of the antennas) was necessary. The origin of these problems is mainly attributed to cross-talk phenomena and other characteristics of the transforming network, which need to be scrutinized further for a full understanding.

Computer Simulation↗
PubMed2000

Prevalence of arylsulfatase A pseudodeficiency allele in metachromatic leukodystrophy patients from Poland.

Arylsulfatase A (ASA) pseudodeficiency (PD) allele was searched for in 22 patients originating from Poland and suffering from different types of metachromatic leukodystrophy (MLD). Four of them carried the PD allele in a heterozygous state. The prevalence of the PD allele among investigated MLD patients was revealed to be 9%, while the frequency of the PD allele in healthy controls was estimated at 6-7%. One of the examined MLD patients was additionally a carrier of an isolated mutation leading to the loss of the N-glycosylation site. The question arises whether and how MLD mutations create a convenient milieu for PD mutations to occur (or inversely).

Alleles↗
PubMed2000

The law of unintended consequences in action: increase in incidence of hypokalemia with improved adequacy of dialysis.

In 1996, we raised our peritoneal dialysis (PD) dose to meet new DOQI adequacy targets. Concurrently, we noted an increase in the frequency of K+ levels below 3.5 mEq/L. A continuous quality improvement (CQI) project was initiated to quantify the impact of increasing dialysis dose on the prevalence of hypokalemia in our unit. Measurements of serum K+, blood urea nitrogen (BUN), creatinine, residual renal function, and the number and type of clinical interventions required to maintain eukalemia were abstracted from the charts of 62 patients enrolled in our program for more than 6 months and having more than two adequacy data points. In the seven consecutive 6-month periods from January 1996 to June 1999, dialysis dose progressively increased while median serum K+ decreased, and the percentage of patients requiring either diet counselling or K+ supplementation rose from 9% to 42%. We conclude that the increased clearance of K+ that occurs with increasing dialysis dose may lead to significant hypokalemia in a large proportion of PD patients dialyzed to DOQI adequacy targets. Maintenance of eukalemia in this population often requires increased K+ intake and or oral supplementation. Further studies are needed to ascertain whether the prevalence of hypokalemia is sufficient to warrant routine addition of K+ to PD dialysis solutions.

Creatinine↗
PubMed1999

Anthropogenic extinction of top carnivores and interspecific animal behaviour: implications of the rapid decoupling of a web involving wolves, bears, moose and ravens.

The recent extinction of grizzly bears (Ursus arctos) and wolves (Canis lupus) by humans from 95-99% of the contiguous USA and Mexico in less than 100 years has resulted in dramatically altered and expanded prey communities. Such rampant ecological change and putative ecological instability has not occurred in North American northern boreal zones. This geographical variation in the loss of large carnivores as a consequence of anthropogenic disturbance offers opportunities for examining the potential consequences of extinction on subtle but important ecological patterns involving behaviour and interspecific ecological interactions. In Alaska, where scavengers and large carnivores are associated with carcasses, field experiments involving sound playback simulations have demonstrated that at least one prey species, moose (Alces alces), is sensitive to the vocalizations of ravens (Corvus corax) and may rely on their cues to avoid predation. However, a similar relationship is absent on a predator-free island in Alaska's Cook Inlet and at two sites in the Jackson Hole region of the Rocky Mountains (USA) where grizzly bears and wolves have been extinct for 50-70 years. While prior study of birds and mammals has demonstrated that prey may retain predator recognition capabilities for thousands of years even after predation as a selective force has been relaxed, the results presented here establish that a desensitization in interspecific responsiveness can also occur in less than ten generations. These results affirm (i) a rapid decoupling in behaviour involving prey and scavengers as a consequence of anthropogenic-caused predator-prey disequilibriums, and (ii) subtle, community-level modifications in terrestrial ecosystems where large carnivores no longer exist. If knowledge about ecological and behavioural processes in extant systems is to be enhanced, the potential effects of recently extinct carnivores must be incorporated into current programmes.

Animals↗
PubMed1999

The human homolog of Sex comb on midleg (SCMH1) maps to chromosome 1p34.

Polycomb group genes were originally identified in Drosophila as repressors required to maintain the silenced state of homeotic loci. About ten Polycomb group genes have been cloned in Drosophila, and mammalian homologs have been identified for most of these. Here, we isolate cDNAs encoding two isoforms of a human homolog of Drosophila Sex comb on midleg (Scm), named Sex comb on midleg homolog-1 (SCMH1). Overall, SCMH1 has 94% identity to its mouse counterpart Scmh1, and 41% identity to Scm, and contains two 1(3)mbt domains, and the SPM domain that are characteristic of Scm. SCMH1 is widely expressed in adult tissues, and maps to chromosome 1p34.

Amino Acid Motifs↗
PubMed1999

Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators.

BACKGROUND: In patients with refractory unstable angina, the platelet glycoprotein IIb/IIIa-receptor antibody abciximab reduces the incidence of cardiac events before and during coronary angioplasty. We investigated whether serum troponin T levels identify patients most likely to benefit from therapy with this drug. METHODS: Among 1265 patients with unstable angina who were enrolled in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, serum samples drawn at the time of randomization to abciximab or placebo were available from 890 patients; we used these samples for the determination of troponin T and creatine kinase MB levels. Patients with postinfarction angina were not included. RESULTS: Serum troponin T levels at the time of study entry were elevated (above 0.1 ng per milliliter) in 275 patients (30.9 percent). Among patients receiving placebo, the risk of death or nonfatal myocardial infarction was related to troponin T levels. The six-month cumulative event rate was 23.9 percent among patients with elevated troponin T levels, as compared with 7.5 percent among patients without elevated troponin T levels (P<0.001). Among patients treated with abciximab, the respective six-month event rates were 9.5 percent for patients with elevated troponin T levels and 9.4 percent for those without elevated levels. As compared with placebo, the relative risk of death or nonfatal myocardial infarction associated with treatment with abciximab in patients with elevated troponin T levels was 0.32 (95 percent confidence interval, 0.14 to 0.62; P=0.002). The lower event rates in patients receiving abciximab were attributable to a reduction in the rate of myocardial infarction (odds ratio, 0.23; 95 percent confidence interval, 0.12 to 0.49; P<0.001). In patients without elevated troponin T levels, there was no benefit of treatment with respect to the relative risk of death or myocardial infarction at six months (odds ratio, 1.26; 95 percent confidence interval, 0.74 to 2.31; P=0.47). CONCLUSIONS: The serum troponin T level, which is considered to be a surrogate marker for thrombus formation, identifies a high-risk subgroup of patients with refractory unstable angina suitable for coronary angioplasty who will particularly benefit from antiplatelet treatment with abciximab.

Abciximab↗
PubMed1999

Full length cDNA cloning, promoter sequence, and genomic organization of the human adrenoleukodystrophy related (ALDR) gene functionally redundant to the gene responsible for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a functional defect of the ALD Protein (ALDP), an ABC half-transporter localized in the peroxisomal membrane. It is characterized by defective, very long chain fatty acid (VLCFA) beta-oxidation, resulting in progressive cerebral demyelination. Since individual mutations in the ALD gene may result in a variety of clinical phenotypes, the existence of modifying genetic factors has been proposed. The adrenoleukodystrophy related protein (ALDRP), a close homolog of ALDP, has been shown to complement the defect of VLCFA oxidation if transfected into X-ALD cells or chemically induced in ALDP-deficient mice. Chemical ALDRP induction holds a potential for a novel therapeutic strategy. We report here the exclusively peroxisomal localization of human ALDRP, the full length cDNA, the transcriptional start, and 2.4 kb of the putative promoter region DNA sequence. The human ALDR gene extends over 33 kb on chromosome 12q12 and consists of 10 exons. The gene structure is highly similar to the ALD gene, indicating a recent divergence from a common ancestor. The putative human promoter sequence contains a novel motif conserved in peroxisomal ABC transporters in the mouse. Our data will enable sequence analysis in X-ALD patients to determine a possible role of ALDRP as a modifier and provide tools for the study of therapeutic ALDRP induction.

ATP Binding Cassette Transporter, Subfamily D↗
PubMed1999

L-764406 is a partial agonist of human peroxisome proliferator-activated receptor gamma. The role of Cys313 in ligand binding.

Insulin-sensitizing thiazolidinedione (TZD) compounds are high affinity ligands for a member of the nuclear receptor family, peroxisome proliferator-activated receptor (PPAR) gamma. A scintillation proximity assay for measurement of 3H-radiolabeled TZD binding to human PPARgamma under homogeneous conditions was developed. Using this approach, a novel non-TZD compound (L-764406) was shown to be a potent (apparent binding IC50 of 70 nM) PPARgamma ligand. Preincubation of PPARgamma with L-764406 prevented binding of the [3H]TZD, suggesting a covalent interaction with the receptor; in addition, structurally related analogues of L-764406, which would be predicted not to interact with PPARgamma in a covalent fashion, did not displace [3H]TZD binding to PPARgamma. Covalent binding of L-764406 was proven by an observed molecular weight shift of a tryptic PPARgamma ligand binding domain (LBD) peptide by mass spectrometric analysis. A specific cysteine residue (Cys313 in helix 3 of hPPARgamma2) was identified as the attachment site for this compound. In protease protection experiments, the liganded receptor adopted a typical agonist conformation. L-764406 exhibited partial agonist activity in cells expressing a chimeric receptor containing the PPARgamma LBD and a cognate reporter gene and also induced the expression of the adipocyte-specific gene aP2 in 3T3-L1 cells. In contrast, L-764406 did not exhibit activity in cells transfected with chimeric receptors containing PPARalpha or PPARdelta LBDs. The partial agonist properties of L-764406 were also evident in a co-activator association assay, indicating that the increased transcription in cells was co-activator mediated. Thus, L-764406 is a novel non-TZD ligand for PPARgamma and is also the first known partial agonist for this receptor. The results suggest a critical functional role for Cys313, and helix 3, in contributing to ligand binding and subsequent agonist-induced conformational changes.

Amino Acid Sequence↗
PubMed1999

Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects.

The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by separate genes: PPARalpha, PPARdelta, and PPARgamma. PPARgamma has been implicated as a mediator of adipocyte differentiation and the mechanism by which thiazolidinedione drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPARgamma and PPARdelta that were identified by radioligand binding assays. In transient transactivation assays these ligands were agonists of the receptors to which they bind. Protease protection studies showed that ligand binding produced specific alterations in receptor conformation. Both PPARgamma and PPARdelta directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner. Only the PPARgamma agonists were able to promote differentiation of 3T3-L1 preadipocytes. In diabetic db/db mice all PPARgamma agonists were orally active insulin-sensitizing agents producing reductions of elevated plasma glucose and triglyceride concentrations. In contrast, selective in vivo activation of PPARdelta did not significantly affect these parameters. In vivo PPARalpha activation with WY-14653 resulted in reductions in elevated triglyceride levels with minimal effect on hyperglycemia. We conclude that: 1) synthetic non-thiazolidinediones can serve as ligands of PPARgamma and PPARdelta; 2) ligand-dependent activation of PPARdelta involves an apparent conformational change and association of the receptor ligand binding domain with CREB-binding protein; 3) PPARgamma activation (but not PPARdelta or PPARalpha activation) is sufficient to potentiate preadipocyte differentiation; 4) non-thiazolidinedione PPARgamma agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5) although PPARalpha activation is sufficient to affect triglyceride metabolism, PPARdelta activation does not appear to modulate glucose or triglyceride levels.

Adipocytes↗
PubMed1999

Scanning E-field sensor device for online measurements in annular phased-array systems.

PURPOSE: A measurement device for noninvasive and simultaneous control of antennas during regional radiofrequency (rf) hyperthermia and, subsequently, the estimation of the power distribution in the interior of patients are essential preconditions for further technological progress. Aiming at this, the feasibility of an electro-optical electric field sensor was investigated during clinical rf hyperthermia. MATERIAL AND METHODS: The electro-optical electric field (E-field) sensor is based on lithiumniobate crystals and the Mach-Zehnder interferometer structure, and was tested in an earlier phantom study. For this study, a mechanical scanning device was developed allowing the registration of the E-field during clinical application. Data were recorded along a curve in the water bolus of the SIGMA 60 applicator of the annular phased-array system BSD-2000 (BSD Medical Corp., Salt Lake City, UT) close to the base points of the flat biconical dipole antennas. The results were compared with modeling calculations using the finite-difference time-domain (FDTD) method. For the latter, different antenna models were assumed. For systematic registration of the E-field curves in amplitude and phase, we employed an elliptical lamp phantom with fat-equivalent ring (filled with saline solution) and an elliptical polyacrylamide phantom with acrylic glass wall. Further measurements were carried out during the treatment of 5 patients with 20 hyperthermia treatments. RESULTS: Data of both phantom and patient measurements can be satisfactorily described by the FDTD method, if the antenna model is refined by taking into account the conical form of the dipoles and the special dielectric environment of the feeding point. Phase deviations can be entered ex posteriori for correction in the calculation algorithm. A comparison of amplifier power measurement (forward and backward power) and bolus E-field scans near the antenna base points demonstrates that E-field measurements between antennas and patient are a necessity for the appropriate characterization of antenna radiation properties. These measurements are sensitive to variations of the lossy medium in position and shape, and can be correctly predicted with current models. However, the differences between different patients are moderate and unspecific in both calculations and measurements, with fluctuations at maximum of 30 degrees in phases and 40% in amplitudes. CONCLUSIONS: The measurement method presented here turned out to be a practical tool for online registration of E-fields in phases and amplitudes along arbitrary curves in a water bolus or phantom. It can be utilized to evaluate antenna design and modeling calculations and leads, thus, to a better understanding of complicated multiantenna systems. In clinical routine, it can be employed as input for patient-specific hyperthermia planning and, finally, for the realization of online control with subsequent optimization of the power distribution in the patient.

Algorithms↗
PubMed1999

Coincidence of two novel arylsulfatase A alleles and mutation 459+1G>A within a family with metachromatic leukodystrophy: molecular basis of phenotypic heterogeneity.

In a family with three siblings, one developed classical late infantile metachromatic leukodystrophy (MLD), fatal at age 5 years, with deficient arylsulfatase A (ARSA) activity and increased galactosylsulfatide (GS) excretion. The two other siblings, apparently healthy at 12(1/2) and 15 years, respectively, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients. Mutation screening and sequence analysis disclosed the involvement of three different ARSA mutations being the molecular basis of intrafamilial phenotypic heterogeneity. The late infantile patient inherited from his mother the frequent 0-type mutation 459+1G>A, and from his father a novel, single basepair microdeletion of guanine at nucleotide 7 in exon 1 (7delG). The two clinically unaffected siblings carried the maternal mutation 459+1G>A and, on their paternal allele, a novel cytosine to thymidine transition at nucleotide 2435 in exon 8, resulting in substitution of alanine 464 by valine (A464V). The fathers genotype thus was 7delG/A464V. Mutation A464V was not found in 18 unrelated MLD patients and 50 controls. A464V, although clearly modifying ARSA and GS levels, apparently bears little significance for clinical manifestation of MLD, mimicking the frequent ARSA pseudodeficiency allele. Our results demonstrate that in certain genetic conditions MLD-like ARSA and GS values need not be paralleled by clinical disease, a finding with serious diagnostic and prognostic implications. Moreover, further ARSA alleles functionally similar to A464V might exist which, together with 0-type mutations, may cause pathological ARSA and GS levels, but not clinical outbreak of the disease.

Adolescent↗
PubMed1999

Ultrasound detection of pneumothorax.

OBJECTIVE: To determine the accuracy of ultrasound in the detection of pneumothorax. METHODS: Prospective blinded study comparing ultrasound, CT and radiographic findings in 29 patients following 41 CT-guided lung biopsies. Ultrasound examination of the chest was limited to the biopsy needle entry site. RESULTS: Thirteen patients developed a post-biopsy pneumothorax demonstrated by CT. Seven of these were detected by ultrasound and six were visible on erect chest radiographs. Six of the 13 pneumothoraces were not detected by ultrasound, but five of these were loculated away from the biopsy needle entry site and were therefore in areas not examined during the limited ultrasound examination. There were no false-positive diagnoses of pneumothorax using ultrasound. The positive predictive value for ultrasound was 100% and the negative predictive value was 82%. CONCLUSION: In this patient group, ultrasound was more sensitive than erect chest radiography in the detection of pneumothorax. Both have a specificity of 100%. This study suggests that ultrasound may prove valuable in pneumothorax detection when rapid conventional radiography is not possible or practical, and in circumstances where ultrasound is readily available, such as during ultrasound-guided interventional procedures.

Biopsy, Needle↗
PubMed1999

Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro.

Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the retinoic acid receptor gamma (RAR-gamma) selective agonists CD2325 and CD437 (1 microM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptor-dependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.

Alitretinoin↗