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PubMed1994

Analysis of the bimolecular reduction of ferricytochrome c by ferrocytochrome b5 through mutagenesis and molecular modelling.

Site-directed mutagenesis has been used to produce variants of cytochrome c in which selected structural or functional properties of this protein are altered that have been implicated previously in contributing to the rate at which ferricytochrome c is reduced by ferrocytochrome b5. In total, 18 variants have been studied by kinetics and electrochemical methods to assess the contributions of thermodynamic driving force, surface charge and hydrophobic interactions, and redox-linked structural reorganization of the protein to the rate of electron transfer between these two proteins under conditions where the reaction is bimolecular. While some variants (those at position-38) appear to affect primarily the driving force of the reaction, others appear to influence the rearrangement barrier to electron transfer (those at positions-67 and -52) while the interface between electron donor and acceptor centers is the principal effect of substitutions for a conserved aromatic heme contact residue at the surface of the protein (position-82). Interpretation of these results has been facilitated through the use of energy minimization calculations to refine the hypothetical models previously suggested for the cytochrome c- cytochrome b5 precursor complex on the basis of Brownian dynamics simulations of the bimolecular encounter event.

Amino Acid Sequence↗
PubMed1997

Polymorphisms of CYP1A1 and GSTM1 influence the in vivo function of CYP1A2.

Differences in human cancer susceptibility have been attributed to polymorphisms of carcinogen metabolizing enzymes. Our efforts have focused on the systems responsible for metabolism of aromatic and heterocyclic amines found in cigarette smoke and in cooked foods. Cytochrome P4501A2 (CYP1A2), which catalyzes aromatic and heterocyclic amine N-oxidation, has been implicated as a risk factor in both urinary bladder and colorectal cancer. In the present study we used the results of caffeine phenotyping experiments to measure the effects of cigarette smoke and compounds present in meat cooked at high temperature on CYP1A2 activity. Subjects in the smoking cessation study had mean CYP1A2 activity of 17.8 (expressed as the urinary molar ratio of [17X + 17U]/137X) while smoking: however, this activity decreased to 10.9 three weeks after cessation of smoking. Subjects in the cooked meat feeding study had mean CYP1A2 activity of 9.01 after 1 week of consuming meat cooked at low temperature, but this value increased to 12.7 after 1 week of consuming meat cooked at high temperature. Because no association has been identified between differences in CYP1A2 activity and variations in the CYP1A2 structural gene, we sought to determine whether the activities of other carcinogen metabolizing enzymes are involved in the regulation of CYP1A2 activity. CYP1A2 activity was higher in individuals who express the GSTM1 null allele compared to those expressing the GSTM1*A,B allele, 10.2 vs. 8.5 for unexposed conditions and 15.0 vs. 12.3 for exposed conditions. CYP1A1 genotyping demonstrated that individuals possessing the Ile/Ile CYP1A1 genotype had greater mean CYP1A2 activity than those who had the heterozygous Ile/Val allelic variant of the CYP1A1 gene. However, upon exposure to cigarette smoke or high-temperature cooked meat, individuals possessing the heterozygous form of the CYP1A1 gene had significantly increased CYP1A2 activity (18.1) compared to those with the more common Ile/Ile CYP1A1 genotype (13.3). These results indicate that CYP1A2, CYP1A1, and GSTM1 gene-gene interactions could be important confounders in the interpretation of molecular epidemiology studies.

Arylamine N-Acetyltransferase↗
PubMed1998

Utility of ethological analysis to overcome locomotor confounds in elevated maze models of anxiety.

The elevated plus-maze is a commonly used model to identify putative anxiolytic and anxiogenic drugs. However, the validity of elevated plus-maze and other recently developed variants such as the elevated zero-maze has recently been questioned on the grounds that both the reference anxiolytic drug chlordiazepoxide and the psychostimulant d-amphetamine increase open arm exploration and stimulate locomotor activity. These findings suggest that measures of "anxiety" in the elevated maze cannot be adequately dissociated from simple changes in locomotor activity, which may confound the interpretation of results obtained using these models. A variety of approaches to assess drug effects on locomotor activity in the elevated maze have been suggested, including the use of total and closed arm entries, as well as supplementary tests such as exploration of the holeboard apparatus. However, all these approaches utilise the measurement of exploration in a novel environment, and as such, could potentially be influenced by either changes in anxiety or locomotor activity. Recently, it has been shown that ethological measures of "risk assessment", such as stretched-attend postures and head-dipping, are sensitive indicators of drug-effects in the elevated maze. The present study assessed the utility of ethological analysis in dissociating locomotor activity from "anxiety" by comparing the effects of d-amphetamine to those of chlordiazepoxide in the rat elevated zero-maze. The results showed that both chlordiazepoxide and d-amphetamine increase the amount of time spent in the open arms and reduce "risk assessment" without increasing line crossing or rearing. These results confirm that under certain test conditions, psychostimulants are capable of producing "false-positives" in elevated maze models, and that both traditional methods and the ethological measures used in this study fail to unequivocally dissociate drug effects on anxiety from effects on locomotor activity. Further studies using other species and different classes of psychostimulants are warranted to determine the generality of these findings.

Animals↗
PubMed2003

Psychosocial development in racially and ethnically diverse youth: conceptual and methodological challenges in the 21st century.

As the US population becomes more diverse in the 21st century, researchers face many conceptual and methodological challenges in working with diverse populations. We discuss these issues for racially and ethnically diverse youth, using Spencer's phenomenological variant of ecological systems theory (PVEST) as a guiding framework. We present a brief historical background and discuss recurring conceptual flaws in research on diverse youth, presenting PVEST as a corrective to these flaws. We highlight the interaction of race, culture, socioeconomic status, and various contexts of development with identity formation and other salient developmental processes. Challenges in research design and interpretation of data are also covered with regard to both assessment of contexts and developmental processes. We draw upon examples from neighborhood assessments, ethnic identity development, and attachment research to illustrate conceptual and methodological challenges, and we discuss strategies to address these challenges. The policy implications of our analysis are also considered.

Adolescent↗
PubMed1997

Mutations of the HIV type 1 V3 loop under selection pressure with neutralizing monoclonal antibody NM-01.

Variants of human immunodeficiency virus type 1 (HIV-1) were selected for resistance to the neutralizing monoclonal antibody (MAb) NM-01. MAb NM-01 recognizes the center of the third hypervariable domain (V3 loop) of the envelope gp120, and neutralizes diverse HIV-1 strains. In the continuous presence of MAb NM-01, transmission and propagation of molecularly cloned HIV-1 were performed in vitro to isolate escape variants. The polymerase chain reaction-single-strand conformation polymorphism and sequence analyses of these variants indicated that the antigenic change against MAb NM-01 is due to a single base substitution resulting in one amino acid interchange within the recognition site of MAb NM-01 in the V3 loop. Mutational analyses also demonstrated a nonrandom event of variability and the existence of mutational hot spots in the V3 loop. The bias of variability could be interpreted by the specificity of error-prone replication by HIV-1 reverse transcriptase. Furthermore, the results suggest that distribution of mutability might correlate closely with the stability of the secondary structure of RNA encoding the V3 loop region.

Antibodies, Monoclonal↗
PubMed1996

Florid cystitis glandularis of intestinal type with mucin extravasation: a mimic of adenocarcinoma.

Six florid examples of cystitis glandularis of intestinal type associated with focal mucin extravasation into the stroma are reported. Several of the cases caused major diagnostic difficulty with regard to their distinction from adenocarcinoma. Five patients had masses that simulated a bladder neoplasm. Patients ranged from 27 to 65 (average 46) years of age and complained of hematuria or irritative symptoms. Four patients were treated only by transurethral resection. One patient underwent partial cystectomy because of an erroneous diagnosis of adenocarcinoma and another total cystectomy because of a neurogenic bladder. Microscopic examination showed numerous glands lined by intestinal type epithelium, conforming to the appearance of the intestinal variant of cystitis glandularis. All cases had at least a minor component of typical cystitis glandularis, and it was prominent in four cases. All six cases had foci of basophilic mucin in the stroma, and this was prominent in four cases. Rounded aggregates of mucin were occasionally surrounded by compressed connective tissue cells, simulating mucinous cysts. In favour of a benign interpretation were the absence of epithelial cells in the extravasated mucin, the lack of atypicality of the cells lining the intestinal type glands in all but one case, a generally orderly distribution of the glands, and their lack of infiltration of the muscularis propria, although they abutted the latter in several cases. Follow-up from 2 to 14 years is available for three of the cases and has been uneventful, the longest follow-up being in the case diagnosed as adenocarcinoma. These cases illustrate the extent to which cystitis glandularis may mimic a neoplasm on gross evaluation and the propensity of mucin extravasation to cause diagnostic difficulty, a finding documented only rarely previously.

Adenocarcinoma↗
PubMed1997

Intravascularly disseminated angiosarcoma: true neoplastic angioendotheliomatosis? Report of two cases.

Although vascular invasion is common in many malignant tumors, disseminated intravascular anaplastic neoplasms with occult primary tumor are rare occurrences. Intravascular malignant lymphoma, also called angiotropic lymphoma, is a rare variant of large cell lymphoma predominantly involving vessels in multiple organs, and usually without significant nodal involvement. Although initially misinterpreted as an endothelial neoplasm-angioendotheliomatosis-immunohistochemical studies subsequently proved it to represent a peculiar form of malignant lymphoma. In this report, we describe two patients with extensive intravascular dissemination of angiosarcoma initially without clinically obvious primary tumor. These may be interpreted as examples of true angioendotheliomatosis. In each case the immunohistochemical studies ruled out the most common intravascular malignant neoplasms. The diagnosis of intravascular angiosarcoma was confirmed by the immunoreactivity of the tumor cells to several markers of endothelial lineage in both cases. Thus, angiosarcoma may present with intravascular dissemination and occult primary tumor and closely resemble metastatic carcinoma, melanoma, or angiotropic lymphoma. Immunohistochemical studies are crucial in ruling out these possibilities and in confirming the endothelial origin of the neoplastic cells.

Adult↗
PubMed2004

Poincare Husimi representation of eigenstates in quantum billiards.

For the representation of eigenstates on a Poincare section at the boundary of a billiard different variants have been proposed. We compare these Poincare Husimi functions, discuss their properties, and based on this select one particularly suited definition. For the mean behavior of these Poincare Husimi functions an asymptotic expression is derived, including a uniform approximation. We establish the relation between the Poincare Husimi functions and the Husimi function in phase space from which a direct physical interpretation follows. Using this, a quantum ergodicity theorem for the Poincare Husimi functions in the case of ergodic systems is shown.

Journal Article↗
PubMed2003

The iceman: discovery and imaging.

The anatomic features of a 5,300-year-old mummy, the iceman, were documented with conventional radiographic, portable computed radiographic, and conventional and spiral computed tomographic images obtained between September 1991 and June 2001. A team of scientists and radiologists from Austria, Italy, and the United States supervised the examinations and interpreted the images. The images demonstrated excellent preservation of the mineralized skeleton with profound dehydration of the soft tissues. The skeleton exhibited several types of trauma, including (a) healed rib fractures, (b) hairline skull fractures and a compression deformity of the thorax, probably acquired while encased in the glacier, and (c) damage acquired during the effort to recover the corpse. Skeletal variants were present, as was evidence of degenerative arthritis, frostbite, vascular calcification, and adaptation to cultural and geographic influences. In terms of anatomy and apparent health-related conditions, the iceman was very similar to modern humans. An arrowhead lodged between the rib cage and the left scapula was the probable cause of the iceman's death. Study of the images also provided insight regarding postmortem processes that led to the iceman's mummification.

Animals↗
PubMed1994

Genetic contamination of Dahl SS/Jr rats. Impact on studies of salt-sensitive hypertension.

The Dahl salt-sensitive rat (SS/Jr) is a widely used animal model of salt-sensitive hypertension. SS/Jr rats are believed to be highly inbred and uniformly sensitive to the hypertensinogenic effects of sodium chloride, but we have recently observed that SS/Jr rats from Harlan Sprague Dawley, Inc, exhibit considerable variability in their blood pressure response to supplemental dietary salt. To test the possibility that commercially available SS/Jr rats are genetically contaminated and therefore no longer fully inbred, we performed molecular genetic studies and blood pressure measurements in several groups of SS/Jr rats purchased from Harlan Sprague Dawley. We found molecular evidence of heterozygosity and/or atypical allelic variants involving loci on at least five different chromosomes. Many of the rats also failed to exhibit a salt-sensitive blood pressure phenotype. We conclude that SS/Jr rats being sold by the only commercial vendor of Dahl rats in the United States are genetically contaminated and resistant to the hypertensinogenic effects of salt. These findings raise serious questions about the interpretation of research conducted with SS/Jr rats obtained from Harlan Sprague Dawley.

Animals↗
PubMed1996

Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene.

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5-10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C-peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed.

Adult↗
PubMed2001

Seroepidemiology of influenza in Pune, India.

BACKGROUND & OBJECTIVES: Influenza viruses cause frequent epidemics and periodic pandemics throughout the world due to antigenic variations. Serological data can be useful to determine the disease burden and population immunity and for predicting the likelihood of occurrence and potential severity of subsequent epidemics. We undertook a serological analysis of antibodies against ten influenza virus strains in Pune, India. METHODS: Haemagglutination inhibition (HI) test was done on 619 sera collected between 1997-99 during an age-stratified serosurvey in Pune, India against 10 strains of influenza virus. Overall prevalence and spectrum of HI antibodies against these strains was determined. RESULTS: Antibodies to at least one influenza virus strain was seen in 62 per cent (116/188) of the sera from individuals in the age group 5-15 yr, 77 per cent (85/111) in sera from 16-25 yr, 78 per cent (93/119) from 26-35 yr, 84 per cent (77/92) from 36-45 yr and 93 per cent (101/109) in sera from individuals aged > 45 yr. The antibody spectrum progressively increased with age. Antibodies to the pandemic strain A(H2N2) were absent in the age groups < 25 yr. INTERPRETATION & CONCLUSION: The results indicate that influenza virus infection occurs in a large proportion of individuals in our community and may be responsible for a considerable amount of morbidity and mortality. The study also demonstrates the absence of antibody to A/Singapore/1/57 (H2N2) strain in younger persons < 25 yr of age. The potential of its reintroduction cannot be ruled out as H2 variants are circulating in wild birds and population immunity in humans is decreasing.

Adolescent↗
PubMed1989

Aberrant course of the anterior interventricular part of the great cardiac vein in the human heart.

A rarely encountered aberrant course of the great cardiac vein was found during exploration of 250 human heart specimens in 1984 to 1987. Originating in the distal anterior interventricular groove, it leaves the sulcus to the right, passes the arterial conus, and crosses the right atrioventricular groove, and empties, together with the anterior cardiac veins, into the right atrium. So the great cardiac vein is not a tributary of the coronary sinus. This atypical variant can be explained phylogenetically as the result of an unusual development of the anterior cardiac vein system. Comparative anatomy demonstrates some birds and some mammalia showing large anterior cardiac veins and anterior conus veins, which drain the right lateral and anterior wall of the heart and empty into the right atrium or the superior vena cava. Our specimen may be interpreted as a remnant and as an enlarged conus vein. There is no known previous description of such a variation.

Aged↗
PubMed1978

[Effect of plant residues on the parasitic activity of soilborne pathogens and the saprophytic microflora of the soil. III. Influence of rye and rape grown as winter catch crop on the incidence of Cercosporella herpotrichoides Fron (author's transl)].

In a five-years field trial, the influence of two winter catchcrops, rye and rape, upon the incidence of Cercosporella herpotrichoides has been studied. The winter catch-crops had been repeated three times, followed either by stubble-crop or without in fall of the fourth year. The variants (blocks) had been completed by two variants without catch-crop, either carefully cultivated or overgrown with weeds. Each of the four blocks had been divided three times to be grown with three different crop sequences containing 80%, 60% (with the insusceptible corn), or 40% haulm fruit, respectively. Each of the 12 variants had been divided into two parts by continuous fallow stripe, one part being artificially infested with the pathogen in the beginning (1st winter wheat). In the 2nd, 3rd, and 4th year, only spring crops were grown, followed by winter wheat in the 5th year. The final exploration resulted in a medium to heavy degree of infection, being significantly higher in the 80% cereal crop sequence than in the 60% and 40% sequences. Concerning the catch-crops, infection in the rye variants was equal or significantly lower than in the carefully cultivated variants without catch-crop. On the other hand, infection of the rape variants had become significantly higher than that of the catch-crop-free ones, about as heavily as in the weed-infested variants. From fall 1966 to summer 1969, the development of the saprophytic soil microflora and several other edaphic parameters had been investigated. Remarkable differences in intensity of disintegration have been observed under the influence of the main crops, cereals or potatoes, respectively, but no differences could be stated resulting from the matter of disintegration--residues of rye or rape--, which might interpret the contrasting effects on the pathogen. Too, no indication for antagonistic activity of bacteria or actinomycetes has been noted. The results are compared with known facts of Cercosporella and of other soil borne pathogens. The difference in biology of Cercosporella on the one hand, and of root infecting fungi on the other hand seems to be most important to explain the results obtained.

Actinomycetales↗
PubMed1995

Malignancies in the lung and pleura mimicking benign processes.

As pathologists, we are most concerned about overcalling reactive changes in the lung as carcinoma and the fact that malignant processes may be misinterpreted as benign processes in the lung is less well recognized. This review covers five such lesions. Well-differentiated adenocarcinomas, especially bronchioloalveolar carcinomas, are frequently undercalled, particularly in small biopsy and cytology specimens. In such cases, one must pay particular attention to the uniformity and monotony of the epithelium even though it may be extremely well differentiated. Spindle cell carcinomas may have necrosis and cavitation, interstitial growth, and a reactive fibroblastic reaction, and thus be mistaken as organizing inflammatory processes. Careful attention to the atypical cytological features, prominent vascular invasion, and getting immunohistochemical supports helps in recognizing them. Lymphoid lesions of the lung present a number of problems; small lymphocytic lymphomas and Hodgkin's disease are often misinterpreted as inflammatory processes. Intravascular lymphomatosis in the lung may be misinterpreted as an interstitial pneumonia if one does not appreciate the atypical lymphoid cells within the capillaries. The desmoplastic variant of sarcomatous mesothelioma may be extremely difficult to diagnose, because large portions of the tumors are composed of bland-appearing fibrous tissue. A case of desmoplastic mesothelioma presenting predominantly as a mediastinal mass is discussed, and problems in differential diagnosis are outlined. Angiosarcomas are rare tumors, but an appreciable percentage of them present as pulmonary metastases which may be interpreted as pulmonary hemorrhage or organizing infarction. The clinical and radiographic pattern, usually mimicking metastatic disease, and the fact that atypical spindle cells occlude small pulmonary arteries with surrounding alveolar hemorrhage are clues to the recognition of these lesions.

Adenocarcinoma↗
PubMed1997

Genetic polymorphisms of orosomucoid ORM1 and ORM2 in Egyptians, Sudanese, and Qataris: occurrence of two new alleles.

Isoelectric focusing was used to investigate the genetic variants of the human plasma orosomucoid ORM1 and ORM2 gene loci in samples of Egyptians, Sudanese, and Qataris. The study populations were classified into 28 ORM phenotypes determined by 10 ORM1 and 9 ORM2 alleles that included 2 new alleles, designated ORM1*B13 and ORM2*H21. Family studies of these new alleles are in accordance with codominant autosomal inheritance. A new interpretation for two previously reported alleles, ORM1*C6 and ORM2*H17, is also presented.

Alleles↗
PubMed1992

A bootstrap resampling procedure for model building: application to the Cox regression model.

A common problem in the statistical analysis of clinical studies is the selection of those variables in the framework of a regression model which might influence the outcome variable. Stepwise methods have been available for a long time, but as with many other possible strategies, there is a lot of criticism of their use. Investigations of the stability of a selected model are often called for, but usually are not carried out in a systematic way. Since analytical approaches are extremely difficult, data-dependent methods might be an useful alternative. Based on a bootstrap resampling procedure, Chen and George investigated the stability of a stepwise selection procedure in the framework of the Cox proportional hazard regression model. We extend their proposal and develop a bootstrap-model selection procedure, combining the bootstrap method with existing selection techniques such as stepwise methods. We illustrate the proposed strategy in the process of model building by using data from two cancer clinical trials featuring two different situations commonly arising in clinical research. In a brain tumour study the adjustment for covariates in an overall treatment comparison is of primary interest calling for the selection of even 'mild' effects. In a prostate cancer study we concentrate on the analysis of treatment-covariate interactions demanding that only 'strong' effects should be selected. Both variants of the strategy will be demonstrated analysing the clinical trials with a Cox model, but they can be applied in other types of regression with obvious and straightforward modifications.

Brain Neoplasms↗
PubMed2006

A Markov model for blind image separation by a mean-field EM algorithm.

This paper deals with blind separation of images from noisy linear mixtures with unknown coefficients, formulated as a Bayesian estimation problem. This is a flexible framework, where any kind of prior knowledge about the source images and the mixing matrix can be accounted for. In particular, we describe local correlation within the individual images through the use of Markov random field (MRF) image models. These are naturally suited to express the joint pdf of the sources in a factorized form, so that the statistical independence requirements of most independent component analysis approaches to blind source separation are retained. Our model also includes edge variables to preserve intensity discontinuities. MRF models have been proved to be very efficient in many visual reconstruction problems, such as blind image restoration, and allow separation and edge detection to be performed simultaneously. We propose an expectation-maximization algorithm with the mean field approximation to derive a procedure for estimating the mixing matrix, the sources, and their edge maps. We tested this procedure on both synthetic and real images, in the fully blind case (i.e., no prior information on mixing is exploited) and found that a source model accounting for local autocorrelation is able to increase robustness against noise, even space variant. Furthermore, when the model closely fits the source characteristics, independence is no longer a strict requirement, and cross-correlated sources can be separated, as well.

Algorithms↗