Miracle-dz/UniFAR-FTUs huggingface dataset:
Gelatinase A-immunoreactive protein in ovarian lesions- prognostic value in epithelial ovarian cancer.

OBJECTIVE Gelatinase A (MMP-2) is a member of the matrix metalloproteinase family and it degrades the major component of the basement membrane, type IV collagen. MMP-2 has been linked to invasion in different types of cancer. METHOD We have studied the localization of MMP-2 in 18 benign, 3 borderline, and 33 malignant ovarian lesions by immunohistochemical stainings using a monoclonal antibody against MMP-2. RESULTS MMP-2-immunoreactive protein was localized in epithelial cells and in fibroblasts. Two types of cytoplasmic staining were observed, a diffuse and a granular pattern. The diffuse staining model was found more often. In 19% of the cases, both staining patterns were present in epithelial cells. Granular staining was found in epithelial cells in cystadenomas and in ovarian cancer cells. The pattern of MMP-2 positivity in fibroblasts was diffuse. MMP-2 positivity in cancer cells was associated with recurrent disease (P < 0.05) in ovarian cancers. MMP-2 negativity in fibroblasts correlated to Grade 3 (P < 0.01), Stage III-IV (P < 0.001), recurrency (P < 0.05), and refractory disease (P < 0.05) in ovarian cancer. The relative survival rate was 32% in patients with an MMP-2-positive ovarian cancer, 57% in patients with an MMP-2-negative ovarian cancer, and 19% in patients with MMP-2 positivity in cancer cells and concomitant negativity in stromal fibroblasts. The disease-free 5-year survival rates were 25, 57, and 12.5%, respectively. CONCLUSIONS These data suggest that MMP-2 may contribute to poor prognosis of ovarian cancer.
Cardiac stem cells: biology and clinical applications.

SIGNIFICANCE Heart disease is the primary cause of death in the industrialized world. Cardiac failure is dictated by an uncompensated reduction in the number of viable and fully functional cardiomyocytes. While current pharmacological therapies alleviate the symptoms associated with cardiac deterioration, heart transplantation remains the only therapy for advanced heart failure. Therefore, there is a pressing need for novel therapeutic modalities. Cell-based therapies involving cardiac stem cells (CSCs) constitute a promising emerging approach for the replenishment of the lost tissue and the restoration of cardiac contractility. RECENT ADVANCES CSCs reside in the adult heart and govern myocardial homeostasis and repair after injury by producing new cardiomyocytes and vascular structures. In the last decade, different classes of immature cells expressing distinct stem cell markers have been identified and characterized in terms of their growth properties, differentiation potential, and regenerative ability. Phase I clinical trials, employing autologous CSCs in patients with ischemic cardiomyopathy, are being completed with encouraging results. CRITICAL ISSUES Accumulating evidence concerning the role of CSCs in heart regeneration imposes a reconsideration of the mechanisms of cardiac aging and the etiology of heart failure. Deciphering the molecular pathways that prevent activation of CSCs in their environment and understanding the processes that affect CSC survival and regenerative function with cardiac pathologies, commonly accompanied by alterations in redox conditions, are of great clinical importance. FUTURE DIRECTIONS Further investigations of CSC biology may be translated into highly effective and novel therapeutic strategies aiming at the enhancement of the endogenous healing capacity of the diseased heart.
Molecular analysis of the rat MHC. I. Delineation of the major regions in the MHC and in the grc.

Southern blot analysis with liver DNA from a unique series of recombinant (R10, R11, R16, R18, R21, and R22), congenic (Y0.1U.grc+, Y0.1U.grc+/Y0.1L.grc, and Y0.1L.grc) and inbred rats has been performed to examine the restriction fragment length polymorphisms of class I genes. After digestion with Xba I or Eco RI, the genomic DNA was resolved on agarose gels, was transferred to nitrocellulose membranes, and was hybridized with murine H-2 cDNA probes. Eighteen to 25 bands of varying intensities could be clearly resolved in any given strain. Analysis of these hybridization patterns detected restriction fragment length polymorphisms that permitted the assignment of 17 specific fragments to regions within the major histocompatibility complex: RT1.A, RT1.B/D, and the RT1.E-grc-T1 alpha region. Fragments have been identified that are specific for grc, grc+, and RT1.E, and mark the junction sites between these loci. In addition, several markers identify the region around the sites of recombination in some strains. The hybridization pattern of the R18 recombinant had a unique band that specified a point of recombination within the grc. The recombinant R11 presented a unique restriction pattern unrelated to either of the parental strains or other related strains. This result suggests that R11 arose from a recombination event(s) undetected by conventional serologic methods.
Complexity of mechanisms among human proprotein convertase subtilisin–kexin type 9 variants

Purpose of review There are many reports of human variants in proprotein convertase subtilisin–kexin type 9 (PCSK9) that are either gain-of-function (GOF) or loss-of-function (LOF), with downstream effects on LDL cholesterol and cardiovascular disease (CVD) risk. However, data on particular mechanisms have only been minimally curated. Recent findings GOF variants are individually ultrarare, affect all domains of the protein, act to reduce LDL receptor expression through several mechanisms, are a minor cause of familial hypercholesterolemia, have been reported mainly within families, have variable LDL cholesterol–raising effects, and are associated with increased CVD risk mainly through observational studies in families and small cohorts. In contrast, LOF variants can be either ultrarare mutations or relatively more common polymorphisms seen in populations, affect all domains of the protein, act to increase LDL receptor expression through several mechanisms, have variable LDL cholesterol–lowering effects, and have been associated with decreased CVD risk mainly through Mendelian randomization studies in epidemiologic populations. Summary There is considerable complexity underlying the clinical concept of both LOF and GOF variants of PCSK9. But despite the underlying mechanistic heterogeneity, altered PCSK9 secretion or function is ultimately correlated with plasma LDL cholesterol level, which is also the driver of CVD outcomes.
Genetic Theorizing and Schizophrenia

Schizophrenia research embodies a microcosm of the vexing problems that confront the behavioural sciences, but particularly those disciplines concerned with psychopathology. We are ignorant of the means to prevent schizophrenia because we continue to be ignorant about its aetiology. Despite recognizable descriptions of the syndrome in ancient Hindu treatises (c. 1400 b.c.) and 76 years after its designation as dementia praecox by Kraepelin (1896), we are still grappling with such basic issues as when and how to diagnose Eugen Bleuler's (1911) ‘group of schizophrenias' (cf. Katz, Cole, and Barton, 1968). Despite brilliant advances in molecular biology, neurochemistry, and brain-behaviour phenomena generally, we cannot pinpoint any necessary biological defect in all or most schizophrenics. Despite selfless expenditures of time and energy by gifted psychotherapists and sophisticated social science efforts, we cannot specify any necessary life experience, either at the level of the family or of a culture, common to all or most schizophrenics. While there is obvious merit in casting the problem in an interactionist framework, aetiology still defies an easy solution because we must then isolate what element(s) in the genotype interact with what element(s) in the internal and/or external environment (as well as when and how) to produce the phenotype we recognize as a schizophrenic one.
Assessing Disease Risk in Genome-wide Association Studies Using Family History

We show how to use reports of cancer in family members to discover additional genetic associations or confirm previous findings in genome-wide association (GWA) studies conducted in case-control, cohort, or cross-sectional studies. Our novel family history–based approach allows economical association studies for multiple cancers, without genotyping of relatives (as required in family studies), follow-up of participants (as required in cohort studies), or oversampling of specific cancer cases (as required in case-control studies). We empirically evaluate the performance of the proposed family history–based approach in studying associations with prostate and ovarian cancers, using data from GWA studies previously conducted within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The family history–based method may be particularly useful for investigating genetic susceptibility to rare diseases for which accruing cases may be very difficult, by using disease information from nongenotyped relatives of participants in multiple case-control and cohort studies designed primarily for other purposes.
Proteomic Analysis of the Drosophila Larval Hemolymph Clot*

Components of the insect clot, an extremely rapid forming and critical part of insect immunity, are just beginning to be identified (1). Here we present a proteomic comparison of larval hemolymph before and after clotting to learn more about this process. This approach was supplemented by the identification of substrates for the enzyme transglutaminase, which plays a role in both vertebrate blood clotting (as factor XIIIa) and hemolymph coagulation in arthropods. Hemolymph proteins present in lower amounts after clotting include CG8502 (a protein with a mucin-type domain and a domain with similarity to cuticular components), CG11313 (a protein with similarity to prophenoloxidase-activating proteases), and two phenoloxidases, lipophorin, a secreted gelsolin, and CG15825, which had previously been isolated from clots (2). Proteins whose levels increase after clotting include a ferritin-subunit and two members of the immunoglobulin family with a high similarity to the small immunoglobulin-like molecules involved in mammalian innate immunity. Our results correlate with findings from another study of coagulation (2) that involved a different experimental approach. Proteomics allows the isolation of novel candidate clotting factors, leading to a more complete picture of clotting. In addition, our two-dimensional protein map of cell-free Drosophila hemolymph includes many additional proteins that were not found in studies performed on whole hemolymph.
Reassessment of the predictive value of the postural stimulation test in primary aldosteronism.

Postural stimulation tests (PST) from 146 patients with primary aldosteronism were reviewed: 83 had an aldosterone-producing adenoma (APA), 48 idiopathic hyperaldosteronism (IHA), nine primary adrenal hyperplasia (PAH), and six aldosterone-producing renin-responsive adenoma (AP-RA). Plasma aldosterone and cortisol levels were measured after overnight recumbency and in response to upright posture for 2 to 4 h. The test was considered invalid in 32% of the patients because cortisol levels increased during the maneuver. As both cortisol and aldosterone are responsive to ACTH in subjects with primary aldosteronism, as well as in normal subjects, we examined their percent variation instead of the absolute values. In order to validate those tests in which cortisol increased, we subtracted the percent cortisol change from the percent aldosterone response. An aldosterone increase of less than 30% (considered a positive response for the presence of an adenoma) identified 76 of the 89 patients with an adenoma (APA and AP-RA) (sensitivity of 85%). Among the 13 false-negative tests, six were proven cases of AP-RA. In each and every case an adenoma was detected by CT/MRI scanning (or bilateral adrenal vein catheterization). Hypertension was ameliorated or cured by surgery. A postural response of less than 30% was also present in 11 of the 57 patients who did not have a discrete adenoma confirmed by imaging techniques (specificity of 81%). Among these false-positive results there were the nine cases of PAH where the hypertension could be ameliorated or cured by partial removal of hyperplastic adrenal tissue. (ABSTRACT TRUNCATED AT 250 WORDS)
Putting the behavior into animal movement modeling: Improved activity budgets from use of ancillary tag information

Abstract Animal movement research relies on biotelemetry, and telemetry‐based locations are increasingly augmented with ancillary information. This presents an underutilized opportunity to enhance movement process models. Given tags designed to record specific behaviors, efforts are increasing to update movement models beyond reliance solely upon horizontal movement information to improve inference of space use and activity budgets. We present two state‐space models adapted to incorporate ancillary data to inform three discrete movement states: directed, resident, and an activity state. These were developed for two case studies: (1) a “haulout” model for Weddell seals, and (2) an “activity” model for Antarctic fur seals which intersperse periods of diving activity and inactivity. The methodology is easily implementable with any ancillary data that can be expressed as a proportion (or binary) indicator. A comparison of the models augmented with ancillary information and unaugmented models confirmed that many behavioral states appeared mischaracterized in the latter. Important changes in subsequent activity budgets occurred. Haulout accounted for 0.17 of the overall Weddell seal time budget, with the estimated proportion of time spent in a resident state reduced from a posterior median of 0.69 (0.65–0.73; 95% HPDI) to 0.54 (0.50–0.58 HPDI). The drop was more dramatic in the Antarctic fur seal case, from 0.57 (0.52–0.63 HPDI) to 0.22 (0.20–0.25 HPDI), with 0.35 (0.31–0.39 HPDI) of time spent in the inactive (nondiving) state. These findings reinforce previously raised contentions about the drawbacks of behavioral states inferred solely from horizontal movements. Our findings have implications for assessing habitat requirements; estimating energetics and consumption; and management efforts such as mitigating fisheries interactions. Combining multiple sources of information within integrated frameworks should improve inference of relationships between movement decisions and fitness, the interplay between resource and habitat dependencies, and their changes at the population and landscape level.
Falsely normal C4 in a case of acquired C1 esterase inhibitor deficiency

A 59-year-old lady presented with recurrent angioedema without urticaria. The clinical history and examination were consistent with an acquired C1 esterase deficiency secondary to lymphoproliferative disease. Despite a low C1 esterase level, the C4 level assayed by nephelometry on our automated analyser was normal. Analysis using different nephelometric analysers revealed consistently low C4, despite consistent normal readings in our analyser. Further investigation revealed an IgM-κ paraprotein that seemed to interfere with both this and haematology coagulation assays. Splenic marginal zone lymphoma was confirmed on bone marrow biopsy. Monoclonal paraproteins may interfere with nephelometric, turbidimetric and immunological assays in a non-antibody-specific manner and should be considered when there are unusual or unexpected results, particularly in a patient with lymphoproliferative disease.
Blockade of the NMDA receptor increases developmental apoptotic elimination of granule neurons and activates caspases in the rat cerebellum

Elimination of neurons produced in excess naturally occurs during brain development through programmed cell death. Among the many survival factors affecting this process, a role for neurotransmitters acting on specific receptors has been suggested. We have performed an in vivo pharmacological blockade of the N‐methyl‐ d‐aspartate (NMDA) subtype of glutamate receptors, using the competitive NMDA receptor antagonist CGP 39551 at developmental stages corresponding to those at which a survival dependence on the stimulation of this receptor has been demonstrated for cerebellar granule neurons explanted in culture (typically from postnatal day 7 to postnatal day 11 or 13). We were able to demonstrate an increased level of DNA fragmentation in the cerebellum of the treated rats. At the P11 stage, in particular, the fragmented DNA extracted from the cerebellum of CGP 39551‐treated pups showed a clear laddering of nucleosomal fragments after agarose‐gel electrophoresis. Accordingly, in situ TUNEL technique showed a remarkable increase of cells positive for nucleosomal DNA fragmentation, particularly in the inner granular layer of the cerebellum of treated rats at P11 stage. Therefore, the natural rate of apoptotic elimination of cerebellar granule neurons is considerably enhanced under conditions of pharmacological blockade of the NMDA receptor, thus demonstrating, for the first time in vivo, a clear survival dependence of these neurons upon the stimulation of the NMDA receptor. Concomitantly with the increased rate of apoptotic elimination of granule neurons, the activity of two death proteases of the caspase family, in particular of caspase 3 and caspase 1 at a lower extent, was remarkably increased in the cerebellum of the treated rats. On the contrary, a marker related to the normal differentiation process of granule neurons, the enzyme ornithine decarboxylase, was strongly decreased in its activity in the cerebellum of treated rat pups.
A prospective analysis of intrathecal granuloma in chronic pain patients: a review of the literature and report of a surveillance study.

BACKGROUND Over the past decade granulomas have been noted to occur at or near the tip of intrathecal catheters used for spinal infusions. The majority of cases involved morphine infusions, although other drugs have been implicated. Granulomas may be asymptomatic or cause significant neurological deficits. METHODS Consecutive patients with intrathecal infusions were examined for the presence of intrathecal granulomas. MRI or CT was used to make the diagnosis. RESULTS A total of 208 patients underwent imaging over a period of 34 weeks. Six patients (3%) were found to have a significant lesion. Five of the six patients were asymptomatic and one patient complained of radicular pain in the distribution of the catheter tip. The average catheter infusion time for patients with granulomas was 27 months, not significantly different from patients without granulomas. No specific characteristics, such as drugs or concentrations were identified. All six patients had percutaneous catheter revisions without complication. CONCLUSION Intrathecal granulomas were identified in 3% of patients imaged in this series. Eighty percent of the patients were asymptomatic. MRI imaging remains the diagnostic method of choice for most patients, and can be done safely when scans are taken at the level of the catheter tip. Given the low incidence of granulomas with intrathecal catheters, routine imaging to identify granulomas is not warranted.
Absolute requirement of macrophages for the development and activation of beta-cell cytotoxic CD8+ T-cells in T-cell receptor transgenic NOD mice.

The development of autoimmune diabetes in NOD mice results from selective destruction of beta-cells by a T-cell-dependent autoimmune process. However, the mechanisms that control the generation of beta-cell cytotoxic T-cells in vivo are poorly understood. We recently established 8.3-T-cell receptor (TCR)-beta transgenic NOD mice that show a selective acceleration of the recruitment of CD8+ T-cells into the islets of prediabetic animals, resulting in rapid beta-cell destruction and early onset of diabetes. This study was initiated to determine the role of macrophages in the development and activation of diabetogenic CD8+ T-cells in 8.3-TCR-beta transgenic NOD mice. Inactivation of macrophages in these transgenic mice resulted in the complete prevention of diabetes. When splenic T-cells from macrophage-depleted 8.3-TCR-beta transgenic NOD mice were transfused into severe combined immunodeficiency disease (NOD.scid) mice, none of the recipients developed diabetes up to 10 weeks after transfer, while most of the recipients of T-cells from age-matched control 8.3-TCR-beta transgenic NOD mice became diabetic. When intact NOD islets were transplanted under the renal capsule of macrophage-depleted 8.3-TCR-beta transgenic NOD mice, the majority of the grafted islets remained intact, while most of the islets grafted into age-matched, control 8.3-TCR-beta transgenic NOD mice were destroyed within 3 weeks after transplantation. The depletion of macrophages in these mice resulted in a decrease in the Th1 immune response along with an increase in the Th2 immune response because of significant decreases in the expression of macrophage-derived cytokines, particularly interleukin-12, and a decrease in beta-cell-specific T-cell activation, as shown by significant decreases in the expression of Fas ligand (FasL), CD40 ligand (CD40L), and perforin, as compared with control mice. We conclude that macrophages are absolutely required for the development and activation of beta-cell cytotoxic CD8+ T-cells in 8.3-TCR-beta transgenic NOD mice.
Sensibility analysis of the Arruda localization method

This paper presents an analysis of the Arruda accessory pathway localization method (for patients suffering from Wolff-Parkinson-White syndrome) with suggestions to increase the overall performance. The Arruda method was tested on a total of 121 patients, and a 90% localization performance was reached. This was considered almost as performing result as the highest published (90%) by L. Boersma in 2002. After a deeper analysis of each decision point of Arruda localization method we considered that the lead AVF is not as relevant as other used leads (I, II, III, VI). The overall performance (90%) was slightly lower then the correct decision rate (91.67%) at the weakest decision element (AVF+) of the method. The vectorial space constructed from the most used leads (II, VI, AVF) is not orthogonal which can be a reason for weaker rate in case of AVF
Validity of a tracer-injection method for studying glucose turnover in normal dogs.

F M M M M F F F M M M M In the measurement of glucose turnover one methodâ€”that of successive measured injections of tracer (SMIT) (1 )â€”has been partially validated. Although an absolute validation of SMIT has been carried out in eviscerated dogs (2,3), it has not previously been done in normal animals because normal production of glucose makes matching of infused rate with tracer-determined rate impossible. What might be called a nonabso! ute validation has also been reported (4) in which the injection method is compared to the equally unvalidated infusion method of Steele (5) under near dynamic steady state conditions. However, if labeled glucose will trace the entry of any unlabeled glucose into the intermixing region, it should also measure the entry of any differently labeled glucose into the same region. Therefore an absolute validation of any tracer for glucose can be made if the measured appearance rate is the rate for a type of glucose which is not confused with glucose produced by the liver, and yet is chemically indis tinguishable from it. With this in mind, we have undertaken a validation by measuring the rate of appearance of 1-'4C-glucose by the SMIT method using injections of 6-'4C-glucose.