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PubMed1988

Success of fertilization in golden hamsters is a function of the relative gamete ratio.

Gamete concentrations can be expressed as either absolute gamete ratios (sperm/egg), the concentration of the motile sperm (sperm/ml), or as a relative gamete ratio (sperm/egg x ml). We demonstrate that the success of hamster fertilization in vitro is a function of the relative gamete ratio and that any effect of the insemination medium geometry is minimal. Consistent fertilization occurs when the relative gamete ratio is above 10(3.5) sperm/egg x ml, but becomes variable above 10(5.0) sperm/egg x ml. At suboptimal relative gamete ratios, there is a strong sperm concentration effect on both the consistency and level of fertilization, whereas the absolute gamete ratio only affects the overall level of fertilization. These effects are seen when the sperm concentration is below 10(3.5) sperm/ml and when the absolute gamete ratio is below 10(2.3) sperm/egg. These influences are probably due to reduced sperm survival at low sperm concentrations and due to a sampling error that occurs when small numbers of sperm are transferred. When the absolute gamete ratios found in vivo in the hamster [Cummins and Yanagimachi, 1982, Gamete Res 5, 239-256] are converted to relative gamete ratios, they are similar to our in vitro results. Thus relative gamete ratios allow, for the first time, comparison between in vitro and in vivo data in the hamster, and between other rodents.

Animals↗
PubMed1996

Enhanced resolution of proton NMR spectra of malignant lymph nodes using magic-angle spinning.

Proton NMR spectroscopy has proven useful in the detection of cancer in lymph node tissue. However, due to the high fat content of this type of tissue, 2D 1H COSY measurements (requiring acquisition times of 4-5 h or longer) are necessary to obtain the spectral information necessary for diagnosis. T2-filtered proton magic-angle spinning (MAS) NMR spectroscopy provides 1D spectra of lymph nodes in approximately 20 min with sufficient spectral resolution allowing for identification of changes in cellular chemistry due to the presence of malignant cells. MAS data from lymph nodes of five control and six rats with mammary adenocarcinoma (R13762) demonstrated increases in the signal intensity of resonances associated primarily with lactate (delta = 4.12 ppm) P < 0.0004, creatines/lysine (delta = 3.04 ppm) P < 0.0032, and glutamate/ glutamine (delta = 2.36 ppm) P < 0.0002 in metastatic compared with normal lymph nodes. The infiltration of lymph nodes by malignant cells is an important prognostic factor for many cancers. The rapid assessment of node tissue without the introduction of sampling errors (inherent in currently employed histological procedures) would allow postoperative therapy decisions to be made more efficiently.

Adenocarcinoma↗
PubMed2005

An introduction to medical statistics for health care professionals: Hypothesis tests and estimation.

This article is the second in a series of three that will give health care professionals (HCPs) a sound introduction to medical statistics (Thomas, 2004). The objective of research is to find out about the population at large. However, it is generally not possible to study the whole of the population and research questions are addressed in an appropriate study sample. The next crucial step is then to use the information from the sample of individuals to make statements about the wider population of like individuals. This procedure of drawing conclusions about the population, based on study data, is known as inferential statistics. The findings from the study give us the best estimate of what is true for the relevant population, given the sample is representative of the population. It is important to consider how accurate this best estimate is, based on a single sample, when compared to the unknown population figure. Any difference between the observed sample result and the population characteristic is termed the sampling error. This article will cover the two main forms of statistical inference (hypothesis tests and estimation) along with issues that need to be addressed when considering the implications of the study results.

Journal Article↗
PubMed1993

Co-amplification of the cystic fibrosis delta F508 mutation with the HLA DQA1 sequence in single cell PCR: implications for improved assessment of polar bodies and blastomeres in preimplantation diagnosis.

We have developed a heminested PCR (polymerase chain reaction) method, performed on single cells, for the analysis of the most common cystic fibrosis (CF) mutation (delta F508). As a quality control, the polymorphic exon 2 of the HLA DQA1 locus was co-amplified from the same cell. With a non-radioactive reverse dot-blot assay, the genotype of these two loci could be determined. Experiments on 98 single fibroblasts, heterozygous for the CFTR and the DQA1 locus, showed that amplification of either locus could be obtained in 97 per cent of the cases, but only 90 per cent showed heterozygosity for CF, 75 per cent showed heterozygosity for DQA1, and 74 per cent showed heterozygosity for both CF and DQA1. Contaminations detected only after DQA1 typing occurred in 3 per cent of our samples. Error rate calculations based on our experimental PCR data indicate that single blastomere diagnosis would lead to unacceptable errors, i.e., an affected fetus, in less than 1 per cent of the cases. The risk of undetected crossing-over or the dubious results that crossing-over could generate, would make isolated polar body diagnosis at the present time very difficult. The combined approach of PCR on polar bodies followed by confirmation of the diagnosis on blastomeres, however, should give a solid base for preimplantation diagnosis of monogenic disorders.

Base Sequence↗
PubMed1984

Incidental adenocarcinoma of the prostate: the role of repeat transurethral resection in staging.

Accurate staging of patients with incidental prostatic adenocarcinoma (A1 vs A2) is crucial to the selection of appropriate treatment. To evaluate the potential sampling error in specimens obtained by transurethral resection, repeat resection was performed on 31 patients pathologically staged as A1 (five or less chips with tumor). Second specimens showed no tumor in 22 (71%), stage A1 in six (20%), and stage A2 in three (9%). The weight of tissue removed at reresection was greater in patients found to have more extensive involvement (P less than 0.005). No patient with initial Gleason score 2, 3, or 4 had stage A2 at reresection. Repeat resection is not routinely necessary, but may be helpful when the tumor is high grade but of minimal extent, in an anxious younger patient who may wish therapy if disease persists, or where some suspicion of an incomplete resection exists.

Adenocarcinoma↗
PubMed1989

A molecular dynamics analysis of protein structural elements.

The relation between protein secondary structure and internal motions was examined by using molecular dynamics to calculate positional fluctuations of individual helix, beta-sheet, and loop structural elements in free and substrate-bound hen egg-white lysozyme. The time development of the fluctuations revealed a general correspondence between structure and dynamics; the fluctuations of the helices and beta-sheets converged within the 101 psec period of the simulation and were lower than average in magnitude, while the fluctuations of the loop regions were not converged and were mostly larger than average in magnitude. Notable exceptions to this pattern occurred in the substrate-bound simulation. A loop region (residues 101-107) of the active site cleft had significantly reduced motion due to interactions with the substrate. Moreover, part of a loop and a 3(10) helix (residues of 67-88) not in contact with the substrate showed a marked increase in fluctuations. That these differences in dynamics of free and substrate-bound lysozyme did not result simply from sampling errors was established by an analysis of the variations in the fluctuations of the two halves of the 101 psec simulation of free lysozyme. Concerted transitions of four to five mainchain phi and psi angles between dihedral wells were shown to be responsible for large coordinate shifts in the loops. These transitions displaced six or fewer residues and took place either abruptly, in 1 psec or less, or with a diffusive character over 5-10 psec. Displacements of rigid secondary structures involved longer timescale motions in bound lysozyme; a 0.5 A rms change in the position of a helix occurred over the 55 psec simulation period. This helix reorientation within the protein appears to be a response to substrate binding. There was little correlation between the solvent accessible surface area and the dynamics of the different structural elements.

Binding Sites↗
PubMed1993

Accuracy of frozen section for lymph node metastasis in patients undergoing radical hysterectomy for carcinoma of the cervix.

The efficacy of frozen section in detecting metastases in pelvic and or periaortic lymph nodes during radical hysterectomy is unknown. The finding of positive nodes may result in termination of the operative procedure. In this study, we attempted to determine the accuracy of frozen sections in this situation. Intraoperative pathology consultation records were examined for 127 patients undergoing surgical exploration for radical hysterectomy between 1977 and 1992. Microscopic slides of lymph nodes were reviewed for accuracy. Metastasis diameters were measured and blocks cut five close microtome levels deeper. In 19 cases (15%) positive nodes were documented on permanent section, with metastases ranging in size from less than 1 to 19 mm. Thirteen cases of node metastasis were diagnosed at frozen section. All were suspicious to the pathologist on palpation and gross inspection after bisection. Six cases were missed by sampling error on frozen section; in 4, metastases were smaller than 1 mm; in 1, between 2 and 3 mm; and in 1, 19 mm. The sensitivity was 68%, the false-negative rate was 32%, and the specificity was 100%. No cases were false positive at frozen section. The frequency of nodal metastasis and detection rate by frozen section did not differ significantly between carcinoma types. No micrometastases (< 2 mm) were detected by frozen section. All micrometastases were no longer present within five microtome levels. Frozen section diagnosis of pelvic node metastasis is a highly specific procedure which should alter intraoperative management of early-stage cervical cancer.

Carcinoma↗
PubMed2000

Key Concepts in Model Selection: Performance and Generalizability.

What is model selection? What are the goals of model selection? What are the methods of model selection and how do they work? Which methods perform better than others and in what circumstances? These questions rest on a number of key concepts in a relatively underdeveloped field. The aim of this paper is to explain some background concepts, to highlight some of the results in this special issue, and to add my own. The standard methods of model selection include classical hypothesis testing, maximum likelihood, Bayes method, minimum description length, cross-validation, and Akaike's information criterion. They all provide an implementation of Occam's razor, in which parsimony or simplicity is balanced against goodness-of-fit. These methods primarily take account of the sampling errors in parameter estimation, although their relative success at this task depends on the circumstances. However, the aim of model selection should also include the ability of a model to generalize to predictions in a different domain. Errors of extrapolation, or generalization, are different from errors of parameter estimation. So, it seems that simplicity and parsimony may be an additional factor in managing these errors, in which case the standard methods of model selection are incomplete implementations of Occam's razor. Copyright 2000 Academic Press.

Journal Article↗
PubMed1998

Evaluating human breast ductal carcinomas with high-resolution magic-angle spinning proton magnetic resonance spectroscopy.

We report the results of a study of human breast ductal carcinomas, conducted by using high resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS 1HMRS). This recently developed spectroscopic technique can measure tissue metabolism from intact pathological specimens and identify tissue biochemical changes, which closely correspond to tumor in vivo state. This procedure objectively indicates diagnostic parameters, independent of the skill and experience of the investigator, and has the potential to reduce the sampling errors inherently associated with procedures of conventional histopathology. In this study, we measured 19 cases of female ductal carcinomas. Our results demonstrate that: (1) highly resolved spectra of intact specimens of human breast ductal carcinomas can be obtained; (2) carcinoma-free tissues and carcinomas are distinguishable by alterations in the intensities and the spin-spin relaxation time T2 of cellular metabolites; and (3) tumor metabolic markers, such as phosphocholine, lactate, and lipids, may correlate with the histopathological grade determined from evaluation of the adjacent specimen. Our results suggest that biochemical markers thus measured may function as a valuable adjunct to histopathology to improve the accuracy of and reduce the time frame required for the diagnosis of human breast cancer.

Adult↗
PubMed1994

Why one-kilobase sequences from mitochondrial DNA fail to solve the Hoatzin phylogenetic enigma.

To address the suitability of mitochondrial DNA sequence data for higher avian systematics, cytochrome b sequences for nine species of Cuculiformes and Galliformes were gathered and compared to those of the Hoatzin, a specialized bird whose phylogenetic affinities have long puzzled ornithologists. Additional avian cytochrome b sequences from GenBank also were incorporated into the comparisons. Various phenetic and parsimony analyses applied to the molecular data coded in four formats (nucleotide sequences, purines versus pyrimidines, first and second positions of codons, and translated amino acid sequences) yielded several consistent phylogenetic arrangements, including the distinction of Galliformes from Cuculiformes, a clade composed of the Guira Cuckoo and Groove-billed Ani (Crotophagidae) to the exclusion of the other assayed cuculiforms (Cuculidae and Coccyzidae), and a clade composed of the New World quail (Odontophoridae, in the Sibley-Ahlquist classification) as a sister group to most or all Old World galliforms assayed (Phasianidae and Numididae). The latter result is of particular interest because it supports a controversial systematic realignment of the Galliformes based on DNA-DNA hybridization data. With regard to the phylogenetic position of the Hoatzin, the analysis differed in face-value outcome, although alternative clades were in all cases poorly supported by bootstrapping, and internodal distances were small relative to the range of genetic separations within either Cuculiformes or Galliformes. These uncertainties in phylogenetic resolution of the Hoatzin appear to be attributable to shallow slopes in the regressions relating cytochrome b sequence differences to evolutionary time, in conjunction with homoplasy in the data, sampling error in the estimation of genetic differences, and the relatively close temporal placements of relevant evolutionary nodes.

Animals↗
PubMed1995

Systematics of cetaceans using restriction site mapping of mitochondrial DNA.

Phylogenetic analysis of 14 cetacean species, including members from two baleen whale families and three toothed whale families, was undertaken using restriction site mapping of mitochondrial DNA and using cladistic and distance measures to infer phylogenies. The amount of between-taxa sequence divergence inferred from the data was lower than expected from the standard interpretation of the fossil record, but more consistent with some recent estimates of sequence divergence in cetacean mitochondrial DNA or nuclear DNA. This implies either that the rate of molecular evolution of cetacean DNA is much lower than that of other mammalian orders or that the fossil record of cetaceans requires reinterpretation. The incompleteness of the cetacean fossil record precludes resolution of the paradox at the present time. However, this discrepancy could in part be attributed to the sampling error inherent in the restriction site mapping technique, as comparative studies using the complete mtDNA genome and restriction site data of the blue and fin whales (genus Balaenoptera) indicate that the restriction site maps underestimate sequence divergence by about 40%. In contrast to a recent study suggesting that toothed whales were paraphyletic, with the sperm whales being more closely related to the rorquals than to the other toothed whales, the restriction data tend to support the monophyly of the baleen and the toothed whales, a finding which is consistent with a recent molecular-based study and with morphological and paleontological data. Topologies of the subfamily and generic levels are generally consistent with morphologically based schemes.

Animals↗
PubMed2006

Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management.

Polyomavirus-associated nephropathy (PVAN) is an emerging disease in renal transplant patients with variable prevalence of 1-10% and graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases. Intense immunosuppression is viewed as the most important risk factor. However, the preferential manifestation in renal transplants as compared to other allografts or to autologous kidneys of other organ transplants suggests that organ determinants and immunologic factors synergize: Renal tubular epithelial cells and their compensatory proliferation to restore tubular integrity after immunologic, ischemic or toxic injury may provide the critical cellular milieu supporting polyomavirus replication while immune control is impaired due to maintenance immunosuppression, anti-rejection treatment and HLA-mismatches. Patient determinants (older age, male gender, seronegative recipient), and viral factors (genotype, serotype) may have a contributory role. The definitive diagnosis of PVAN requires allograft biopsy which is, however, challenged by (i) limited sensitivity due to (multi-)focal involvement (sampling errors); (ii) varying presentations with cytopathic-inflammatory and/or fibrotic/scarring patterns; (iii) coexisting acute rejection which is difficult to differentiate, but impacts on intervention strategies. Screening for polyomavirus replication in the urine and in the plasma complements allograft biopsy by high sensitivity and allows for noninvasive monitoring. Thus, we suggest a terminology similar to invasive fungal diseases where viruria ("decoy cells") defines patients at risk ("possible PVAN") who should be evaluated for plasma viral load. Increasing BK viremia (>10,000 copies/mL) or urine VP-1 mRNA (>6.5x10(5) copies/ng total RNA) load defines "presumptive PVAN" for which an intervention of reducing immunosuppression should be considered even if the diagnosis could not be confirmed by allograft biopsy ("definitive PVAN"). The response to intervention should be monitored using plasma DNA or urine mRNA load.

Humans↗
PubMed1994

Oncogene expression in cervical cancer.

Significant advances have been made toward the understanding of the initiation and progression of cervical dysplasia and neoplasia at the molecular level. To date, this has not translated into improvements in diagnosis or treatment although it is a realistic expectation that this will occur. Significant variation in the proportion of tissue specimens that exhibit genetic alterations is striking. This may be attributed to different methods of analysis, different methods of tissue fixation, which influence antigen preservation, and the analysis of small numbers of samples per report, which introduces the possibility of sampling error. In spite of the variation among published reports, it is clear that several genetic alterations occur in preneoplastic and early-stage invasive cervical neoplasms. It remains to be determined which alterations of genetic structure or expression contribute to tumor initiation. The prognostic applicability of oncogene mutations is a particularly interesting area of investigation that is the closest to clinical application, although additional research involving larger numbers of patients is critical. The development of convenient methods of tissue fixation that preserve the myc oncoprotein, the synthesis of specific antibodies that provide consistent results, and the application of computer-assisted image analysis to quantitate results will be particularly important in this regard.

Female↗
PubMed2000

Malignant progression in Barrett's esophagus: pathology and molecular biology.

Due to its increasing incidence, esophageal adenocarcinoma and its precursor lesions have received increasing attention in recent years. The histopathologic steps in the process of malignant progression in Barrett's esophagus are well described and include the following: (a) metaplasia of the normal esophageal squamous epithelium to a specialized intestinal glandular epithelium, (b) development of dysplasia (classified histologically as low and high grade), and (c) development of adenocarcinoma characterized by invasive and metastatic potential. Intestinal metaplasia can be identified by the presence of goblet cells, the detection of which can be aided by finding mucin stained by Alcian blue at low pH. Despite this well-characterized sequence, the timing of the development of dysplasia and the subsequent transition to carcinoma and the risk of development of carcinoma in low- and high-grade dysplasia are not precisely known. In addition, there are problems in the identification of dysplasia, including sampling error and interobserver discrepancies among pathologists. A better understanding of the mechanisms of these events would allow early identification and elimination of high-risk lesions before adenocarcinoma with its attendant poor prognosis were able to develop. In order to better understand this process and to potentially identify early markers of malignant transformation, a variety of molecular studies have been carried out in recent years on adenocarcinoma and its precursor lesions in Barrett's esophagus. On the phenotypic level, increased expression and changes in pattern of expression of proliferation marker (Mib-1) Ki-67 antigen, overexpression of p53 protein, overexpression of growth factors such as epidermal growth factor (EGF), c-erbB2, and transforming growth factor (TGF)-a, decreased and abnormal expression of the cell adhesion molecule E-cadherin, and, in carcinomas, increased expression of serine proteases have all been described. A new area of interest is the family of rab proteins, which play an important role in maintaining cell polarity in the gastrointestinal tract. Increased expression of one of these proteins, rab11, has been described in low-grade, but not high-grade dysplasia. In cytogenetic studies, an increased S-phase fraction, followed by an increased tetraploid (4N) fraction and then aneuploidy, has been described. So far, the specific genes which have been most thoroughly investigated have been p53, APC, p16, and the sites of probable tumor suppressor genes, including 3p (FHIT), 13q, and 18q. With only a few exceptions (i.e., rab11 expression, and possibly mutations of FHIT), the numerous molecular abnormalities which have been described occur late in malignant progression, which means that the best marker which presently exists to identify high-risk lesions in Barrett's esophagus is the histologic identification of dysplasia in endoscopic biopsies, especially high-grade dysplasia. We are presently beginning studies using laser microdissection and competitive genomic hybridization (CGH), which could help to identify new chromosomal areas that might contain genes that are crucial in the early phases of malignant progression in Barrett's esophagus. In the future, identification of such early molecular events which predispose to carcinoma development will allow more precise and earlier risk assessment for individual patients, therefore, enabling more effective therapy.

Barrett Esophagus↗
PubMed1996

Molecular staging of head and neck squamous carcinoma.

The staging system of head and neck cancer is a Tumor-Node-Metastases system that was developed by the American Joint Committee on Cancer. The stage of the head and neck cancer defines the extent of the lesion and is determined by physical examination, radiologic studies, and pathologic examination. Accurate staging of head and neck cancer is critical since it will determine the treatment modalities used to cure the disease. Recent advances in the field of molecular genetics have allowed clinicians to detect occult cancer cells previously missed by physical examination and standard histopathologic techniques. Molecular assays are 500 times more sensitive in identifying cancer cells than standard techniques and provide more objective analyses with fewer sampling errors. Consequently, these techniques are currently being used to perform molecular staging of head and neck cancer patients. Preliminary results show that molecular staging will accurately identify those patients at significantly increased risk for recurrence of their head and neck cancer.

Adult↗
PubMed1994

Unusual neoplasms detected in testicular cancer patients undergoing postchemotherapy retroperitoneal lymphadenectomy.

Approximately 30% of patients with disseminated testicular cancer who receive platinum-based chemotherapy will experience normalization of tumor markers but have persistent, radiographically evident disease in the retroperitoneum. These patients are usually subjected to retroperitoneal lymph-node dissection (RPLND). In all, 45 of 557 patients (8.1%) undergoing postchemotherapy RPLND at Indiana University Medical Center (IUMC) were found to have neoplastic elements distinct from the classic germ-cell tumor types within their resected specimens. Examples included various sarcomas in 14 patients (3.7%), other nonsarcomatous non-germ-cell cancers in 18 patients (3.2%), and cystic atypical choriocarcinoma in 8 patients (1.4%). No distinct patient characteristic or histologic pattern in the primary tumor was predictive of these unusual findings in the RPLND specimen, although sampling error in the orchiectomy specimen could be the reason for this lack of correlation. Surgical resection of these chemoresistant tumors is potentially curative, with disease-free survival being obtained in 13 of 19 patients (68.4%) with sarcoma, 10 of 18 patients (55.6%) with nonsarcomatous cancers, and 7 of 8 patients (87.5%) with cystic atypical choriocarcinoma at mean follow-up intervals of 30.6, 42.5, and 24.7 months, respectively.

Adult↗
PubMed1992

Contribution of thallium-201-SPECT to the grading of tumorous alterations of the brain.

Single photon emission computed tomography (SPECT) with thallium-201-chloride (201Tl) was used in 22 patients to assess the grade of malignancy of brain tumors. Low- and high-grade malignant gliomas could be well differentiated by calculating the Grade Index (GI), i.e., 201Tl uptake in the tumor area relative to a contralateral brain region. Low-grade gliomas (WHO-grade I-II) usually showed a GI of < 1.5. Tumors classified histologically as high-grade malignant (WHO-grade III-IV) had GI values greater than 1.42 and a mean value of 1.89. Until labelled amino-acid tracers for gamma-cameras become commercially available, thallium-201 brain-SPECT can provide an independent and complementary method to CT/MRI for the differential diagnosis of grading of brain tumors. This simple technique can help to reduce sampling errors during needle biopsies of brain tumors, particularly of high-grade lesions incorrectly graded as low-grade tumors due to inadequate biopsy material. In addition, pre- and post-therapy studies can influence the strategy of therapy itself and allow an early detection of recurrences.

Adenoma↗
PubMed1987

Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria.

Eight polymorphic restriction enzyme sites at the phenylalanine hydroxylase (PAH) locus were analyzed from the parental chromosomes in 33 Danish nuclear families with at least one phenylketonuric (PKU) child. Determination of haplotypes of 66 normal chromosomes and 66 chromosomes bearing mutant allele(s) demonstrated that there are at least two haplotypes which occur predominantly on PKU chromosomes and rarely otherwise. Overall, the relative frequencies of the various haplotypes are significantly different on PKU- and normal-allele bearing chromosomes, even though there is no predominantly occurring unique haplotype which can characterize the PKU chromosomes. In addition, no significant association (linkage disequilibrium) between any single polymorphic site and the mutant allele(s) was observed. The results suggest that either the phenylketonuric mutation was very ancient so that the polymorphic sites and the mutation have reached linkage equilibrium or the mutant allele(s) are the results of multiple mutations in the phenylalanine hydroxylase gene in man. Furthermore, a crude relationship between standardized linkage disequilibria and physical map distances of the polymorphic sites indicates that there is no apparent recombination hot-spot in the human phenylalanine hydroxylase gene, since the recombination rate within the locus appears to be uniform and likely to be occurring at a rate similar to that within the HLA gene cluster. The limitations of this later analysis are discussed in view of the sampling errors of disequilibrium measure used, and the potential utility of the PAH haplotypes for prenatal diagnosis and detection of PKU carriers is established.

Alleles↗