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PubMed2007

Understanding binding selectivity toward trypsin and factor Xa: the role of aromatic interactions.

A congeneric series of four bis-benzamidine inhibitors sharing a dianhydrosugar isosorbide scaffold in common has been studied by crystal structure analysis and enzyme kinetics with respect to their binding to trypsin and factor Xa. Within the series, aromatic interactions are an important determinant for selectivity discrimination among both serine proteases. To study the selectivity-determining features in detail, we used trypsin mutants in which the original binding site is gradually substituted to finally resemble the factor Xa binding pocket. The influence of these mutations has been analyzed on the binding of the closely related inhibitors. We present the crystal structures of the inhibitor complexes obtained by co-crystallizing an "intermediate" trypsin mutant. They could be determined to a resolution of up to 1.2 A, and we measured the inhibitory activity (K(i)) of each ligand against factor Xa, trypsin, and the various mutants. From these data we were able to derive a detailed structure-activity relationship which demonstrates the importance of aromatic interactions in protein-ligand recognition and their role in modulating enzyme selectivity. Pronounced preference is experienced to accommodate the benzamidine anchor with meta topology in the S(1) specificity pocket. One ligand possessing only para topology deviates strongly from the other members of the series and adopts a distinct binding mode addressing the S(1)' site instead of the distal S(3)/S(4) binding pocket.

Benzamidines↗
PubMed2000

Quantitative cytological assessment of Ki67 and AgNORs using computer-digitized image analysis of four clinicopathological breast lesions.

Analysis of silver-stained proteins associated with nucleolar organiser regions (AgNORs) is proposed as a marker of cellular proliferation. This study describes the application of AgNORs and Ki67 in breast lesions. Sixty-one cases including fibroadenoma (FA), fibrocystic disease (FCD), ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) were studied by image analysis to evaluate quantitative changes in AgNORs in both Ki67-positive, and Ki67-negative smears. The Ki67 index was assessed. Morphometric features of cell nuclei and AgNORs were determined by digitized computer image analysis (Prodit 5.2). The growth fraction was 5.08 for FA, 5.71 for FCD, 16.75 for DCIS and 23.26 for IC. The mean nuclear area was significantly higher in malignant cells than those of fibroadenoma and fibrocystic disease. In Ki67-positive cells the total area, long axis and number of AgNORs increased progressively across disease groups. Eccentricity of AgNORs and AgNORs: nuclear area ratios were significantly increased in malignant breast lesion in comparison with benign lesion in Ki67 positive cells. In Ki67 negative cells, the highest value of AgNORs was observed in DCIS. The AgNORs: nuclear area ratio demonstrated a statistically significant trend across the disease groups. This study demonstrates that the growth fraction, mean nuclear area and selected AgNORs features have potential for differentiating benign from malignant breast tumours.

Breast Neoplasms↗
PubMed1984

Structure, distribution, and origin of M cells in Peyer's patches of mouse ileum.

The derivation of membranous epithelial (M) cells, which are specialized antigen sampling cells overlying the lymphoid follicles of Peyer's patches, is unknown; it has been suggested recently, however, that M cells differentiate from absorptive cells on the follicular epithelium. To examine whether M cells, like other intestinal epithelial cells, derive directly from undifferentiated crypt cells, we studied the structure, selected functional features, proliferation, and distribution of Peyer's patch M cells in the ileum of adult mice. We observed a spectrum of M-cell structure ranging from mature to immature-appearing M cells. Most immature-appearing M cells lacked the central cytoplasmic hollow found in those mature M cells that contained lymphoid cells. The microvilli of immature-appearing M cells were more numerous and regular appearing than those of mature M cells, but they were sparser and shorter, and some were wider than those of absorptive cells. Many immature-appearing M cells contained more free ribosomes than did mature M cells. Both mature and immature-appearing M cells were observed on all regions of follicular domes, including the base near the mouths of surrounding crypts. Type 1 reovirions adhered with considerable selectivity to the apical membrane of mature and immature-appearing M cells but were observed in endocytic vesicles only in mature M cells. Neither mature nor immature-appearing M cells showed evidence of lipid absorption, in contrast to adjacent absorptive cells. Both mature and immature-appearing M cells internalized more bound cationized ferritin than did absorptive cells. Only mature M cells transported cationized ferritin to the intercellular spaces. Nuclei of a few immature-appearing M cells were labeled 24 h after injection of [3H]thymidine in concert with the appearance of labeled absorptive cell nuclei. These observations strongly suggest that many, if not all, M cells derive directly from undifferentiated crypt cells.

Animals↗
PubMed2002

Primary structure of selected archaeal mesophilic and extremely thermophilic outer surface layer proteins.

The archaea are recognized as a separate third domain of life together with the bacteria and eucarya. The archaea include the methanogens, extreme halophiles, thermoplasmas, sulfate reducers and sulfur metabolizing thermophiles, which thrive in different habitats such as anaerobic niches, salt lakes, and marine hydrothermals systems and continental solfataras. Many of these habitats represent extreme environments in respect to temperature, osmotic pressure and pH-values and remind on the conditions of the early earth. The cell envelope structures were one of the first biochemical characteristics of archaea studied in detail. The most common archaeal cell envelope is composed of a single crystalline protein or glycoprotein surface layer (S-layer), which is associated with the outside of the cytoplasmic membrane. The S-layers are directly exposed to the extreme environment and can not be stabilized by cellular components. Therefore, from comparative studies of mesophilic and extremely thermophilic S-layer proteins hints can be obtained about the molecular mechanisms of protein stabilization at high temperatures. First crystallization experiments of surface layer proteins under microgravity conditions were successful. Here, we report on the biochemical features of selected mesophilic and extremely archaeal S-layer (glyco-) proteins.

Amino Acid Sequence↗
PubMed2003

Clinical features that discriminate inhalational anthrax from other acute respiratory illnesses.

Inhalational anthrax (IA) is a rapidly progressive disease that frequently results in sepsis and death, and prompt recognition is critical. To distinguish IA from other causes of acute respiratory illness, patients who had IA were compared with patients in an ambulatory clinic who had influenza-like illness (ILI) and with hospitalized patients who had community-acquired pneumonia (CAP) at the initial health care visit. Compared with patients who had ILI, patients who had IA were more likely to have tachycardia, high hematocrit, and low albumin and sodium levels and were less likely to have myalgias, headache, and nasal symptoms. Scoring systems were devised to compare IA with ILI or CAP on the basis of strength of association. For ILI, a score of > or =4 captured all 11 patients with IA and excluded 664 (96.1%) of 691 patients with ILI. Compared with patients who had CAP, patients with IA were more likely to have nausea or vomiting, tachycardia, high transaminase levels, low sodium levels, and normal white blood cell counts. For CAP, a score of > or =3 captured 9 (81.8%) of 11 patients with IA and excluded 528 (81.2%) of 650 patients with CAP. In conclusion, selected clinical features of patients with IA differ from those of patients with ILI and are more similar to those of patients with CAP.

Acute Disease↗
PubMed2005

From projection pursuit and CART to adaptive discriminant analysis?

While many efforts have been put into the development of nonlinear approximation theory and its applications to signal and image compression, encoding and denoising, there seems to be very few theoretical developments of adaptive discriminant representations in the area of feature extraction, selection and signal classification. In this paper, we try to advocate the idea that such developments and efforts are worthwhile, based on the theorerical study of a data-driven discriminant analysis method on a simple--yet instructive--example. We consider the problem of classifying a signal drawn from a mixture of two classes, using its projections onto low-dimensional subspaces. Unlike the linear discriminant analysis (LDA) strategy, which selects subspaces that do not depend on the observed signal, we consider an adaptive sequential selection of projections, in the spirit of nonlinear approximation and classification and regression trees (CART): at each step, the subspace is enlarged in a direction that maximizes the mutual information with the unknown class. We derive explicit characterizations of this adaptive discriminant analysis (ADA) strategy in two situations. When the two classes are Gaussian with the same covariance matrix but different means, the adaptive subspaces are actually nonadaptive and can be computed with an algorithm similar to orthonormal matching pursuit. When the classes are centered Gaussians with different covariances, the adaptive subspaces are spanned by eigen-vectors of an operator given by the covariance matrices (just as could be predicted by regular LDA), however we prove that the order of observation of the components along these eigen-vectors actually depends on the observed signal. Numerical experiments on synthetic data illustrate how data-dependent features can be used to outperform LDA on a classification task, and we discuss how our results could be applied in practice.

Algorithms↗
PubMed2000

Social aspects of epilepsy in the adult in seven European countries. The RESt-1 Group.

PURPOSE: The social implications of epilepsy are ill-defined, and there are no comparative findings from different countries. A multicenter cohort study has recently been completed on the risk of morbidity and accidents. The main social issues in the study population (patients with epilepsy and control subjects) are investigated and correlated to the clinical features of the disease. METHODS: Seven hundred six adult patients with idiopathic or remote symptomatic epilepsy and 662 matched controls without epilepsy were enrolled by secondary and tertiary centers in seven European countries (Italy, Germany, Spain, the Netherlands, England, Portugal, and Russia). At entry, patients and controls were interviewed, and data were collected on social variables (education, current occupation, marital status, driving, involvement in sports, and insurance). The main clinical features of epilepsy (seizure types, frequency and timing, disease duration, and syndrome) were also recorded. RESULTS: The sample included 690 men and 678 women aged 18 to 86 years. The level of education (mostly basic or high school) was slightly higher among patients with epilepsy. More patients than controls were single (56% versus 50%) or unemployed (18% versus 13%). Fewer patients than controls held a driver's license (44% versus 67%) or practiced sports (30% versus 41%). The distribution of each social variable varied significantly across countries, but with few exceptions, the differences between patients and controls were fairly similar. Based on multivariate analysis, for patients with epilepsy the odds ratio for driving was 0.27, and the corresponding odds ratios for sports involvement, better education, better occupation, and insurance were 0.59, 1.30, 0.60, and 1.49. Among patients with epilepsy, social variables were correlated to seizure remission and selected clinical features. CONCLUSIONS: Comparative findings from different European countries support the concept that epilepsy has a considerable impact on driving and-to a lesser extent-on education, occupation, leisure activities, and insurance. The social implications of epilepsy in this sample are partly related to its severity and clinical features.

Adolescent↗
PubMed2025

High MGMT expression identifies aggressive colorectal cancer with distinct genomic features and immune evasion properties.

INTRODUCTION: The epigenetic silencing of O6-methylguanine DNA methyltransferase (MGMT) is associated with reduced DNA repair capacity, carcinogenesis and increased sensitivity to alkylating chemotherapy. However, the biological role and clinical significance of MGMT overexpression in cancer remains poorly understood. METHODS: Using multiplexed quantitative immunofluorescence we measured the localized levels of MGMT protein, γH2AX and CD8+ T cells in multiple retrospective colorectal cancer (CRC) cohorts. Genomic and transcriptomic features of selected cases were also studied with whole exome DNA sequencing and genome-wide methylation analysis. MGMT-methylated human CRC cells SW620 were transfected with an MGMT-containing plasmid and co-cultured with allogeneic peripheral blood mononuclear cells. RESULTS: A subset of CRCs showed MGMT protein upregulation associated with lower γH2AX, reduced CD8+ tumor infiltrating lymphocytes (TILs), mismatch repair proficient (pMMR) status and shorter survival. CD8+ TILs were more distant from MGMT-expressing cells than MGMT-negative cells and the MGMT promoter methylation status did not highly correlate with MGMT protein levels in CRC. In genomic/transcriptomic analysis, high MGMT expression was associated with a lower nonsynonymous somatic mutational burden, higher transition-to-transversion mutation ratio, increased deleterious TP53 variants and distinct transcriptomic profiles. The exogenous expression of MGMT in SW620 CRC cells reduced the number of spontaneous nonsynonymous mutations, reproduced mutational features of MGMT-high CRC and limited the in vitro T-cell-mediated killing of malignant cells induced by proinflammatory cytokines in tumor/immune cell co-cultures. CONCLUSIONS: MGMT overexpression identifies a previously undescribed subset of CRCs with distinct biological and clinical properties including reduced mutagenesis, adaptive immune evasion, predominantly pMMR phenotype and aggressive clinical course. Direct, quantitative assessment of MGMT protein expression using spatially resolved analysis is more reliable than inference of MGMT expression by promoter methylation status in CRC.

Humans↗
PubMedDate not supplied

Operationalizing DSM-IV criteria for PMDD: selecting symptomatic and asymptomatic cycles for research.

While diagnostic criteria for premenstrual syndromes (PMS) exist, studies rarely state how these criteria are operationally applied. We examined the consequences of application of different operational methods for DSM-IV criteria for premenstrual dysphoric disorder (PMDD) to individual cycles in women with PMS and controls. PMDD criteria require the presence of both certain types or numbers of symptoms (5/11 symptoms present premenstrually, at least one being one of four mood symptoms) and certain phenomenal characteristics (present premenstrually, absent postmenstrually, causing interference premenstrually). We identified individual cycles as symptomatic or asymptomatic by applying criteria that operationalized the required phenomenal elements of PMDD according to four severity thresholds: literal (i.e. present or absent), 30%, 50%, 70%. Data examined were Daily Rating Form symptom scores from two symptomatic menstrual cycles both in 25 women with PMS and 25 controls. Literal thresholds correctly identified 28% of symptomatic and 4% of asymptomatic cycles, compared with 86 and 70% identification with a 30% threshold, 60 and 86% with a 50% threshold, and 0 and 100% with a 70% threshold. An "optimal" combination of 30% thresholds for premenstrual symptomatology and premenstrual interference and a 50% threshold for postmenstrual symptomatology correctly identified 92% of symptomatic cycles in women with PMS and 72% of asymptomatic cycles in controls. Different criteria for cycle inclusion yield markedly different sample compositions. No single operational threshold of the phenomenal features maximizes selection of both symptomatic and asymptomatic cycles, largely consequent to the ubiquity of postmenstrual symptoms and premenstrual "interference" even in women without PMS. At the very least, the method for operationalizing DSM-IV criteria should be described in studies of PMDD.

Adult↗
PubMedDate not supplied

Dilated coronary sinus in a dog with persistent left cranial vena cava.

This paper describes the electrocardiographic, echocardiographic (two-dimensional, M-mode, contrast and Doppler) and non-selective angiocardiographic features in a 3 year old female Beagle with dilated coronary sinus due to persistent left cranial vena cava. Negative P waves in leads III and aVR and a positive P wave in lead aVL were seen. Echocardiographically, a hypoechoic circular structure was seen between the left atrium and the pericardium in the area where the coronary sinus is located. A velocity pattern with two peaks was obtained, one systolic with velocity = 0.44 +/- 0.05 m/sec and the other diastolic with velocity = 0.27 +/- 0.01 m/sec. By M-mode echocardiography, at level of the aorta and the left atrium, a linear structure was identified between the left atrium and the pericardium; this structure was characterized by phasic movements of the anterior wall during the cardiac cycle. Following a left cephalic vein injection of saline, bubbles were seen within the coronary sinus; when saline was injected into the right cephalic vein, bubbles were also seen within the coronary sinus and right atrium and ventricle. Non-selective angiocardiography confirmed a dilated coronary sinus with persistent left cranial vena cava. The right cranial vena cava was absent. The dog was clinically normal and the unusual vessel was an incidental finding.

Angiocardiography↗
PubMed2000

Noninvasive and minimally invasive papillary carcinomas of the extrahepatic bile ducts.

BACKGROUND: Adenocarcinomas of the extrahepatic bile ducts (EBD) are uncommon neoplasms that are morphologically heterogenous and associated with a poor prognosis. Papillary carcinomas of the EBD, however, appear to follow a much less aggressive clinical course. METHODS: The authors reviewed the clinical records of nine patients with papillary carcinoma of the EBD, analyzed the microscopic features, and selected immunohistochemical reactivity (p53 and MIB-1) that might correlate with patient survival. RESULTS: Six patients were male and three were female, with a mean age of 65 years (range, 48-83 years). The clinical presentation of disease in these patients was similar to that reported for conventional adenocarcinoma of EBD. According to their cell phenotypes, these papillary carcinomas were classified as biliary type (7 cases) and intestinal type (2 cases). Most were located in the common bile duct and were well differentiated (7 cases). Five showed minimal expansile invasion into the ductal wall and four were noninvasive. Five patients were treated with a Whipple operation, three underwent segmental resections, and one underwent a left hepatic lobectomy. One patient died of unrelated causes 16 years after a Whipple operation, and another died of postoperative complications. The remaining 7 patients are alive and disease free 1-13 years after surgery. CONCLUSIONS: Noninvasive and minimally invasive papillary carcinomas of the EBD are associated with excellent long term prognosis regardless of their cytologic features or their immunohistochemical reactivity to p53 and MIB-1. These tumors should be distinguished from biliary papillomatosis, intraductal papillary mucinous carcinomas of the pancreas extending into the bile ducts, papillary adenomas, and papillary hyperplasia.

Aged↗
PubMed2005

Human pol II promoter prediction: time series descriptors and machine learning.

Although several in silico promoter prediction methods have been developed to date, they are still limited in predictive performance. The limitations are due to the challenge of selecting appropriate features of promoters that distinguish them from non-promoters and the generalization or predictive ability of the machine-learning algorithms. In this paper we attempt to define a novel approach by using unique descriptors and machine-learning methods for the recognition of eukaryotic polymerase II promoters. In this study, non-linear time series descriptors along with non-linear machine-learning algorithms, such as support vector machine (SVM), are used to discriminate between promoter and non-promoter regions. The basic idea here is to use descriptors that do not depend on the primary DNA sequence and provide a clear distinction between promoter and non-promoter regions. The classification model built on a set of 1000 promoter and 1500 non-promoter sequences, showed a 10-fold cross-validation accuracy of 87% and an independent test set had an accuracy >85% in both promoter and non-promoter identification. This approach correctly identified all 20 experimentally verified promoters of human chromosome 22. The high sensitivity and selectivity indicates that n-mer frequencies along with non-linear time series descriptors, such as Lyapunov component stability and Tsallis entropy, and supervised machine-learning methods, such as SVMs, can be useful in the identification of pol II promoters.

Algorithms↗
PubMed2004

Citation patterns in tropical medicine journals.

Selections of most important journals in the field of tropical medicine have previously been identified with the help of resources such as bibliographical and citation databases. This article uses ISI's Journal Citation Reports (JSR) for 2002 to analyse the citation characteristics of the Tropical Medicine category. According to these data, this small but diverse group of 12 journals bestows some 40% more citations than it receives. Its six typical core journals tend to cite one another heavily, but they also refer a lot to multidisciplinary science and general medicine journals, and to infectious diseases and parasitology journals. Looking at the sources from which JCR's tropical medicine journals derive their citations, it is clear that in this reverse direction, the specialty's literature is still more concentrated. Apart from the typical core, this JCR category also contains a number of journals with more idiosyncratic citing patterns, focused on specialties such as paediatrics, a single disease (leprosy) and a representative of Latin American and Francophone biomedical science each. Implications of concentrated citedness and language biases are discussed briefly. This paper features a selection of bibliometric parameters relating to the tropical medicine journals and lists of the 80 journals most citing and cited by them.

Bibliometrics↗
PubMed2000

Solitary tract nuclei in acute heart failure.

BACKGROUND AND PURPOSE: Symmetrical necrosis of the brain stem nuclei has been described as a consequence of severe transitory cerebral hypoxia mainly in neonates or young adults who experienced an episode of acute ischemia due to transitory acute heart failure. We report selective bilateral lesions of the solitary tract nuclei in 5 adults with short survival intervals after acute heart failure. METHODS: In 5 patients who died due to cardiovascular pathology, histological examination was performed on multiple samples of cerebral hemispheres, on transverse sections of the midbrain and pons, and on transverse serial sections of the medulla stained with hematoxylin-eosin, Klüver-Barrera, and Luxol fast blue. The 3-dimensional reconstruction of the extension and topography of the medullary lesions was obtained with computed image analysis. RESULTS: In 4 subjects who died soon after an episode of acute heart failure (range of survival 10 hours to 2 days), the dorsal portion of the solitary tract nuclei showed an eosinophilic roundish aspect bilaterally. In their context, the neurons showed changes characteristic of ischemic coagulation necrosis. In a fifth patient, a 32-year-old man who died 15 days after an episode of cardiac arrest, 2 circumscribed symmetrical infarcts with macrophagic and astrocytic reactions were found at the same level. The topography of the lesions and the inflammatory reaction and gliosis of patient 5 suggest that the findings in the other 4 patients correspond to initial features of selective lesions of the solitary tract nuclei after acute heart failure: the short interval of survival prevented the evolution of the reactive process. The nucleus is localized at the watershed zone between the terminal branches of the medullary collateral vessels of the vertebral arteries, thus representing the last meadow in the case of sudden fall of the systemic blood flow due to acute heart failure. The absence of lesions of other medullary and pontine nuclei accounts for a selective vulnerability of the neurons of the solitary tract nuclei, and the selective dendritic lesions suggest an excitotoxic component to ischemic cell death. CONCLUSIONS: The commonly accepted resistance of the medullary centers to ischemic hypoxia in adults apparently could be due to the rapidity of death, which prevents the evolution of lesions that can be diagnosed. In addition, minor lesions in the medullary tegmentum after acute heart failure could play a role in the prevention of the resumption of autonomous cardiac and respiratory functions despite life-saving procedures.

Adult↗
PubMed2002

Expert system support using a Bayesian belief network for the classification of endometrial hyperplasia.

Accurate morphological classification of endometrial hyperplasia is crucial as treatments vary widely between the different categories of hyperplasia and are dependent, in part, on the histological diagnosis. However, previous studies have shown considerable inter-observer variation in the classification of endometrial hyperplasias. The aim of this study was to develop a decision support system (DSS) for the classification of endometrial hyperplasias. The system used a Bayesian belief network to distinguish proliferative endometrium, simple hyperplasia, complex hyperplasia, atypical hyperplasia and grade 1 endometrioid adenocarcinoma. These diagnostic outcomes were held in the decision node. Four morphological features were selected as diagnostic clues used routinely in the discrimination of endometrial hyperplasias. These represented the evidence nodes and were linked to the decision node by conditional probability matrices. The system was designed with a computer user interface (CytoInform) where reference images for a given clue were displayed to assist the pathologist in entering evidence into the network. Reproducibility of diagnostic classification was tested on 50 cases chosen by a gynaecological pathologist. These comprised ten cases each of proliferative endometrium, simple hyperplasia, complex hyperplasia, atypical hyperplasia and grade 1 endometrioid adenocarcinoma. The DSS was tested by two consultant pathologists, two junior pathologists and two medical students. Intra- and inter-observer agreement was calculated following conventional histological examination of the slides on two occasions by the consultants and junior pathologists without the use of the DSS. All six participants then assessed the slides using the expert system on two occasions, enabling inter- and intra-observer agreement to be calculated. Using unaided conventional diagnosis, weighted kappa values for intra-observer agreement ranged from 0.645 to 0.901. Using the DSS, the results for the four pathologists ranged from 0.650 to 0.845. Both consultant pathologists had slightly worse weighted kappa values using the DSS, while both junior pathologists achieved slightly better values using the system. The grading of morphological features and the cumulative probability curve provided a quantitative record of the decision route for each case. This allowed a more precise comparison of individuals and identified why discordant diagnoses were made. Taking the original diagnoses of the consultant gynaecological pathologist as the 'gold standard', there was excellent or moderate to good inter-observer agreement between the 'gold standard' and the results obtained by the four pathologists using the expert system, with weighted kappa values of 0.586-0.872. The two medical students using the expert system achieved weighted kappa values of 0.771 (excellent) and 0.560 (moderate to good) compared to the 'gold standard'. This study illustrates the potential of expert systems in the classification of endometrial hyperplasias.

Bayes Theorem↗
PubMed2005

Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues.

Gonadal germ cell tumors continue to be the cause of diverse, diagnostically challenging issues for the pathologist, and their correct resolution often has major important therapeutic and prognostic implications. They are academically interesting because of the biological diversity exhibited in the two gonads and variation in frequency of certain neoplasms. The most dramatic examples of the latter are the frequency of dermoid cyst in the ovary compared to the testis and the reverse pertaining to embryonal carcinoma. Within the teratoma group, there is strong evidence that ovarian and prepubertal testicular teratomas are derived from benign germ cells, a pathogenesis that likely applies also to the rare dermoid cysts and uncommon epidermoid cysts of the testis. In contrast, postpubertal testicular teratomas derive from malignant germ cells, specifically representing differentiation within a preexistent nonteratomatous cancer. As expected, given the foregoing, teratomas in boys are clinically benign, whereas in postpubertal males they are malignant, independent of their degree of immaturity. On the other hand, immaturity is an important finding in ovarian teratomas, irrespective of age, although its significance in children has recently been challenged. It is usually recognized on the basis of embryonic-appearing neuroepithelium, which shows mitotic activity and apoptosis in contrast to differentiated neuroepithelial tissues, which may occur in mature ovarian teratomas. Rarely it is based on the presence of cellular, mitotically active glial tissue. Fetal-type tissues alone are not sufficient for a diagnosis of immature teratoma. Further differences between the teratomatous tumors in the two gonads are the relative frequency of monodermal teratomas in the ovary in contrast to the testis, where only one subset, carcinoids, is seen with any frequency. When uncommon somatic-type malignancies (usually squamous cell carcinoma) occur in mature cystic teratomas of the ovary, this is a de novo form of malignant transformation; similar tumors in the testis, a very rare event, represent overgrowth of teratomatous elements that originated from malignant, nonteratomatous germ cell tumors and, therefore, had previously undergone malignant transformation. Germinomas may have several unusual features in each gonad; these include microcystic arrangements that suggest yolk sac tumor, tubular patterns that mimic Sertoli cell tumor, apparent increased cytological atypia that causes concern for embryonal carcinoma, and prominent syncytiotrophoblast giant cells that suggest choriocarcinoma. Awareness of these variants, good technical preparations, the retained typical cytological features of germinoma cells, and the judicious use of tailored panels of immunohistochemical stains resolve these dilemmas in virtually all instances. Two aspects of germinomas are unique to the testis. Firstly, intertubular growth of small seminomas may cause them to be overlooked. Secondly, the distinctive spermatocytic seminoma occurs only in the testis. A newly recognized aspect of this tumor is the propensity for some to be relatively monomorphic, making them apt to be mistaken for usual seminoma or embryonal carcinoma, although the characteristic polymorphic appearance in some foci, absence of intratubular germ cell neoplasia, unclassified type, and immunohistochemical stains should prevent this error. Cytoplasmic membrane immunoreactivity for placental alkaline phosphatase and CD117, with usual negativity for AE1/AE3 cytokeratins, is helpful in the diagnosis of germinoma. The recently described marker, OCT3/4, a nuclear transcription factor, is especially helpful in the differential of germinoma and embryonal carcinoma with other neoplasms. Yolk sac tumor continues to be confused occasionally with clear cell carcinoma of the ovary. Glandular ('endometrioid-like') yolk sac tumors mimic endometrioid carcinomas; predominant or pure hepatoid yolk sac tumors cause concern for metastatic hepatocellular carcinoma or, in the ovary, primary hepatoid carcinoma, and solid patterns, especially in limited samplings, may be misinterpreted as germinoma. The usually younger age of patients with yolk sac tumors helps with the differential considerations with the nongerm cell tumors, as do other clinical and microscopic features and selected immunohistochemical stains. Choriocarcinoma is rare in both gonads, and those in the ovary must be distinguished from metastatic tumors of placental origin. Syncytiotrophoblast cells alone, admixed with other forms of germ cell tumor, still are confused with choriocarcinoma, but this phenomenon, which is much more frequent than choriocarcinoma, lacks the plexiform arrangement of different trophoblast cell types that typifies the latter. Mixed germ cell tumors (which may show almost any combination of components) are common in the testis but rare in the ovary. A separately categorized, rare form of mixed germ cell tumor seen in both gonads is the polyembryoma. It is perhaps the most photogenic of all gonadal germ cell tumors and is also intriguing because of its distinctive, organized arrangement of yolk sac tumor and embryonal carcinoma elements and recapitulation of very early embryonic development, even to the extent of having in its fundamental unit, the embryoid body, a miniature yolk sac, and amniotic cavity. These tumors, which are constituted by innumerable embryoid bodies, almost always contain teratomatous glands in minor amounts, and one way of viewing the polyembryoma is to consider it the most immature form of teratoma. Embryoid bodies are also common as a minor component of many mixed germ cell tumors, particularly in the testis, and the diffuse embryoma is another variant that has a particular arrangement of yolk sac tumor and embryonal carcinoma elements. Regression of gonadal germ cell tumors is a phenomenon restricted to the testis, for unknown reasons. These so-called 'burnt-out' germ cell tumors can be recognized by a distinctive constellation of findings, including sometimes minor foci of residual recognizable germ cell neoplasia, a well-defined zone of scarring (often having residual ghost tubules), associated lymphoplasmacytic infiltrate, intratubular calcification and, in about 50%, of in situ germ cell neoplasia.

Diagnosis, Differential↗
PubMed2001

Bone marrow aspiration, biopsy, and culture in the evaluation of HIV-infected patients for invasive mycobacteria and histoplasma infections.

Bone marrow (BM) aspiration and biopsy are used commonly in clinical practice to diagnose invasive tissue infections caused by Mycobacterium avium intracellulare (MAC), Mycobacterium tuberculosis (TB), and Histoplasma capsulatum (HC) in patients with human immunodeficiency virus-1 (HIV) infection. However, the value of these invasive procedures relative to other diagnostic approaches has not been clearly defined. To determine the value of BM culture and BM histology in the diagnosis of opportunistic MAC/TB and HC infections in immunosuppressed patients with HIV, we retrospectively reviewed the records of 56 adult patients with HIV who underwent a single BM aspiration, biopsy, and culture because of unexplained fever and/or other clinical features suggestive of MAC/TB or HC infection. Thirty-two patients (57%) were ultimately diagnosed with MAC/TB or HC infection by positive cultures of BM, blood, sputum, or bronchoalveolar lavage fluid or by the histologic detection of organisms in biopsies of BM or other tissues. The diagnostic sensitivity of BM cultures was equal to that of blood cultures (20/32, or 63%). Granuloma and/or histologically apparent organisms were seen in BM biopsy specimens in 11 of 32 individuals (34%) ultimately diagnosed with MAC/TB or HC infections. Among these 11 cases, both granuloma and acid-fast staining organisms were found in the BM biopsy specimens of 2 individuals for whom both BM and blood cultures were negative. Certain clinical symptoms and signs at the time of BM examination were found by logistic regression analysis to be significantly associated with a subsequent diagnosis of MAC/TB or HC infections; these included high fever, long duration of febrile days prior to BM examination, and elevated direct bilirubin. In conclusion, while the diagnostic sensitivity of BM cultures was found to be no greater than that of blood cultures in detecting MAC/TB or HC infections in immunosuppressed HIV+ patients, histopathologic examination of BM specimens resulted in the relatively rapid identification of nearly one third of infected patients who underwent BM examination, and also identified infections in some patients who were culture negative. These findings support the continued use of BM aspiration, biopsy, and culture for the diagnosis of opportunistic MAC/TB or HC infections in immunosuppressed HIV+ patients, particularly when selected clinical features are present.

AIDS-Related Opportunistic Infections↗
PubMed2002

[Nationwide survey of intractable disease patients. Analyses of patients receiving public financial aid for treatment in fiscal year 1997].

OBJECTIVE: In order to clarify epidemiologic features of selected intractable diseases, an investigation of the fourth nationwide survey, in 1998, was performed. METHODS: We asked 47 prefectural governments to provide data concerning every patient receiving financial aid for treatment of 39 selected intractable diseases from April 1997 to March 1998. The items for each patient required were the beginning year of the financial aid, the disease code, sex, date of birth, residence, type of insurance, whether an in-patient or outpatient, medical institution and the clinical division where the patient was treated. We performed a detailed analysis regarding the age distribution, the prefecture, in-patient or outpatient, the clinical division, the insurance, and the disease, for both males and females. RESULTS: 1. The total number of patients who received financial aid for treatment was 399, 719 with a sex ratio of 0.66 (males 158, 766, or female 240, 953), 60.7% being between 45 and 74 years of age. Of 214, 173 patients whose status could be confirmed regarding outpatient or inpatient. 14.7% were the latter. Of 129, 685 cases, 56, 471 (43.6%) were treated in departments of internal medicine. Of 396, 187 patients, 65, 841 (16.6%) were covered by the health and medical services law for the aged. The greatest number of patients resided in Tokyo, and the least was in Yamanashi Prefecture. 2. With regard to specific intractable diseases, the largest number of patients receiving aid for treatment were suffering from ulcerative colitis at 52, 261, while the least number was for primary pulmonary hypertension at 96. The numbers for each group had increased within the 13 years from 1984 to 1997, except for SMON. As the patients' age increased, the percentage of those receiving treatment also increased and the numbers of aged individuals were especially elevated. 3. The proportion of in-patients for the Creutzfelde-Jakob disease was 76.4 percent, which was remarkably higher than for other diseases. CONCLUSION: By the present analysis of the nationwide survey in fiscal year 1997, we could clarify changes in epidemiologic features of patients receiving financial aid for treatment. This kind of analysis should be continued to obtain important information on the epidemiology of intractable diseases.

Adolescent↗