Miracle-dz/UniFAR-FTUs huggingface dataset:
Developmental and Hormonal Regulation of Transforming Growth Factor-β1 (TGFβ1), -2, and -3 Gene Expression in Isolated Prostatic Epithelial and Stromal Cells: Epidermal Growth Factor and TGFβ Interactions.

Growth factors are postulated to mediate stromal-epithelial interactions in the prostate to maintain normal tissue physiology. Transforming growth factor-beta (TGFbeta) has been shown to influence the prostate and probably mediate stromal-epithelial interactions. TGFbeta1 messenger RNA (mRNA) expression is stimulated after castration and can be suppressed by in vivo treatment with androgens. The hypothesis tested is that TGFbeta is regulated not only by androgen, but also by a network of locally produced growth factors that influence prostatic growth and differentiation. Epithelial and stromal cells from 20-day-old rat ventral prostate were isolated and used to test this hypothesis. The expression of mRNA for TGFbeta1, -2, and -3 was analyzed by a quantitative RT-PCR procedure. Observations from this assay demonstrate that both epithelial and stromal cells express the mRNA for TGFbeta1, -2, and -3. TGFbeta1 mRNA expression was constant during development of the prostate. TGFbeta2 mRNA expression was elevated at birth, then declined and elevated again at 100 days of age. TGFbeta3 mRNA expression was high during puberty and young adult ages then declined at 100 days of age. TGFbeta2 and TGFbeta3 expression are inversely related during prostate development. After castration of 60-day-old rats, both TGFbeta1 and TGFbeta2 mRNA were enhanced. Interestingly, TGFbeta3 mRNA was significantly suppressed after castration. Epidermal growth factor (EGF) stimulated TGFbeta1 mRNA expression in stromal cells (6-fold increase), whereas keratinocyte growth factor stimulated TGFbeta2 mRNA in epithelial cells. TGFbeta inhibited both testosterone- and EGF-stimulated prostatic stromal and epithelial cell growth. EGF and TGFbeta also inhibited prostatic ductal morphogenesis and growth in organ culture. Immunocytochemical localization of TGFbeta in 20-day-old prostate demonstrated predominately stromal localization of the protein. These results indicate that the isoforms of TGFbeta2 and TGFbeta3 are differentially regulated during prostate development, suggesting distinct regulatory mechanisms. Testosterone did not affect TGFbeta expression in cultured prostatic cells. These observations suggest that the in vivo effects of castration on TGFbetas are regulated indirectly through a complex network of growth factors, not simply by direct androgen depletion. The ability of EGF to inhibit prostatic ductal morphogenesis and growth in organ culture is postulated to be in part mediated by the increase in TGFbeta1 expression. In summary, a network of growth factor-mediated stromal-epithelial interactions is needed to maintain prostate growth and development. TGFbeta is postulated to have an important role in this process.
The Impact of FTAs on FDI in Korea

This study sheds light on the effects of FTAs on outward and inward FDI in Korea. It finds that there has been an upsurge in overseas investments made by Korea through the FTAs. The FTAs have encouraged vertical investments in developing countries as cheap manufacturing bases and horizontal investments in the services sectors of developed countries. This study also shows that the FTAs have stimulated inward FDI to Korea, mainly from high-income partners.
Successful treatment of post-transplant Kaposi's sarcoma by reduction of immunosuppression.

BACKGROUND The aim of this study was to investigate retrospectively the clinical presentation, the efficacy of reducing immunosuppression and the consequences of this therapeutic approach in Kaposi's sarcoma (KS) developing after renal transplantation. METHODS We reviewed the records of 502 patients who had been followed up at our transplantation unit between October 1, 1987 and December 30, 1998. Twelve patients (2.4%) with KS were included in the study. RESULTS The mean age of KS patients was 38+/-11 years (one female, 11 males). All were on prednisone, azathioprine (AZT) and cylcosporin treatment. KS was encountered at a mean of 18+/-10 months post-renal transplantation. Typical Kaposi's lesions were present in the skin of 11 out of l2 patients. In the only patient without skin involvement, who died from haemophagocytic histiocytic syndrome caused by septicaemia, KS was diagnosed post-mortem in a lymph node. In five patients only skin involvement was present, while the others also had visceral involvement (oropharynx in two patients, trachea and lung in three, lymph node in two, stomach and duodenum in two). Cyclosporin was stopped within 1 month after KS diagnosis, and AZT was stopped in three patients. Both cutaneous and visceral KS manifestations disappeared and no patient was lost due to KS. During a follow-up period 46+/-19 months, KS recurred in the lungs in one patient together with lung tuberculosis, while he was on prednisone and AZT. Two patients lost their graft due to chronic rejection. The remaining eight patients currently have a functioning graft with a mean creatinine level of 1.4+/-0.5 mg/dl. CONCLUSION KS is the most frequent post-transplant neoplasia (80%) in our country. In the present study cohort, half of the patients had visceral involvement. Reduction or discontinuation of immunosuppression caused complete remission in all patients without surgical intervention, chemotherapy or radiotherapy.
Detection and identification of Candida species in experimentally infected tissue and human blood by rRNA-specific fluorescent in situ hybridization

Two 18S rRNA-targeted oligonucleotide probes specific for Candida albicans and Candida parapsilosis were used to detect and identify by fluorescent in situ hybridization these medically important Candida species in deep organs of mice after experimental systemic infection. The C. albicans-specific probe detected fungal cells in kidney, spleen, and brain sections of a mouse infected with C. albicans but not in a mouse infected with the closely related species C. parapsilosis. Conversely, the C. parapsilosis-specific probe detected fungal cells in the deep organs of a mouse infected with C. parapsilosis but not in the deep organs of a C. albicans-infected mouse. In addition, the C. albicans-specific probe was used to detect this species in human blood spiked with yeast cells by a lysis-filtration assay and subsequent fluorescent in situ hybridization. By this assay, as few as three yeast cells per 0.5 ml of blood were consistently detected. Our results demonstrate that fluorescent in situ hybridization with species-specific rRNA-targeted oligonucleotide probes provides a novel, culture-independent method for the sensitive detection and identification of Candida species in clinically relevant material.
A critical appraisal of coverage and resource allocation decisions through the use of health technology assessment: evidence on orphan drugs from four countries

Health Technology Assessment (HTA) relies on evidence-based medicine to inform drug coverage recommendations about the most efficient use of resources. Despite appraising the same evidence based on similar methodological approaches, HTA recommendations for the same drug differ across countries. This thesis aimed to understand the reasons for these differences, and based on cross-national comparisons, whether they are a consequence of methodological challenges in HTA. A mixed methods research design was used to develop a methodological framework that allows to breakdown these complex processes in a comparable and understandable manner, by considering: (a) the evidence appraised, (b) its interpretation, and (c) how this influenced the final decision. Ten orphan drug-indication pairs appraised in four countries (England, Scotland, Sweden and France (N=35)) were systematically analysed and compared on this basis. Results present the criteria accounted for at each stage of the process in the decisions, the reasons for differences across countries, and how HTA bodies are dealing with issues relating to orphan drugs. Quantitative analysis of these provided information about agency-specific risk and value preferences, and measured agreement in interpreting the same evidence. There was heterogeneity within and across countries in the criteria accounted for and reasons for cross-country differences. Interviews to competent authorities provided insights about these differences and implications for HTA. Although agreement was seen in the evidentiary requirements or preferences, there were subtle differences in the circumstances where uncertain evidence may be considered acceptable, partly explaining diverging HTA recommendations. The three main contributions of this thesis are: (1) the development of a methodological framework to understand what criteria feed into HTAs, which can be applied to other drugs and countries; (2) through its application, the identification of a full taxonomy of criteria considered in decisionmaking; and (3) the ability to understand the differences in HTA recommendations across countries. A better understanding of HTA in different settings may help advance these processes, and, ultimately, improve access to treatments.
Costs of Capital under Credit Risk

Credit risk analysis represents a growing field in financial research since decades. However, in company valuation – to be more precise, in cost of capital computations – credit risk is merely taken into consideration at the level of the debt beta approach. Our paper proves that applications of the debt beta approach suffer from unrealistic assumptions. As an advantageous approach, we develop an alternative framework to determine costs of capital based on Merton’s model. We present (quasi-) analytic formulas for costs of equity and debt which are consistent with Modigliani-Miller theory in continuous-time and discrete-time settings without taxes. Our framework is superior to the debt beta approach regarding the quantity and quality of required data in peer group analysis. Since equity and debt are represented by options in Merton’s model, we compute expected option rates of return without resorting to betas. Thereby, our paper also contributes to the option pricing literature.
The cognitive neuropsychology of depression in the elderly

ABSTRACT Background The cognitive impairment of older depressed patients with late- as opposed to early-onset illness may show important differences, in that patients with early onset may suffer predominantly from impaired episodic memory, and those with late onset mainly from reductions of executive function and processing speed. Method We searched Medline and EMBASE as well as individual papers' reference lists for relevant publications, recording comparisons in neuropsychological test results between early-onset depression (EOD), late-onset depression (LOD) and healthy volunteers. Effect sizes are presented for cognitive domains, such as executive function, processing speed, episodic memory, semantic memory and mental state examination. Results Patients with LOD showed greater reductions in processing speed and executive function than patients with EOD and controls. Both patient groups showed reduced function in all domains, except mental state, compared with controls. Conclusion Pronounced executive deficits are typical of the late-onset patients described in published studies, while episodic memory impairment is not specific to early-onset illness. Possible reasons and confounders are discussed.
Effects of SOX 404(b) Implementation on Audit Fees by SEC Filer Size Category

Abstract This study provides novel information about the consequences of the Sarbanes-Oxley Act (SOX) by documenting differential audit fee shocks accompanying implementation of SOX 404(b) internal control tests and reports for clients in three size categories: large accelerated filers (LAFs), small accelerated filers (SAFs), and non-accelerated filers (NAFs). First, we find that although both LAFs and SAFs experience audit fee shocks attributable to 404(b), SAFs on average experience relatively greater fee shocks than LAFs (107.8% versus 84.6%; Table 6 ). Second, even though NAFs are not subject to 404(b) procedures, we document a 42.7% fee shock for NAFs. Our interpretation is that 404(b) generated an immediate increase in demand for audit services with no corresponding sudden increase in supply of experienced audit personnel, enabling audit firms to charge higher prices for all filers including NAFs. We find that audit fee shocks attributable to 404(b) are positively associated with audit offices’ bargaining power relative to clients, and that the effect of offices’ bargaining power is strongest for SAFs and weakest for NAFs. Although higher audit fees (with client characteristics held constant) are often considered an indicator of better audit quality, we find virtually no evidence that the massive fee increases in 2004 are accompanied by improvements in same-year or next-year audit quality, measured as decreases in discretionary accruals and a lower likelihood of subsequent restatements of audited financial reports.
Serological and molecular evidence of Coxiella burnetii in samples from humans and animals in China.

INTRODUCTION Coxiella burnetii is the agent of Q fever, a worldwide zoonosis. To add to the available knowledge of the disease in China, C. burnetti infections were investigated in convenience samples from five animal species and humans from Yangzhou, Jiangsu province, eastern China. MATERIALS AND METHODS Commercial ELISA kits were used to detect antibodies to phase I and II C. burnetii. A FRET-qPCR targeting the outer membrane protein com1 gene was also developed to detect C. burnetii DNA in blood samples from animals and humans, and bovine milk samples. RESULTS Seropositive cattle (44/150; 29%), goats (33/150; 22%), humans (45/180; 25%) and pigs (4/130; 3%) were found, while dogs (0/136; 0%) and cats (0/140; 0%) were seronegative. Seropositivity in humans was associated with increasing age, but there was no gender difference. DNA was amplified from two milk samples (2/150, 1.3%), while none of the blood samples were positive. The sequences of the obtained amplicons were identical to those of the com1 gene of the universal C. burnetii RSA 493 strain and other stains from China. CONCLUSIONS The findings indicaten that C. burnetii is endemic in Yangzhou, China, and therefore human and animal health workers should be aware of the possibility of infections and the occurrence of outbreaks of Q fever.
Bone induction by recombinant human osteogenic protein‐1 (hOP‐1, BMP‐7) in the primate Papio ursinus with expression of mRNA of gene products of the TGF‐β superfamily

Predictable bone induction in clinical contexts requires information on the expression and cross regulation of gene products of the transforming growth factor‐β (TGF‐β) superfamily elicited by single applications of each recombinant human bone morphogenetic/ostegenic proteins (BMPs/OPs). Using the calvarium and the rectus abdominis muscle of adult baboons Papio ursinus as a model for tissue induction and morphogenesis, this study investigated the induction of bone morphogenesis by γ‐irradiated hOP‐1 delivered by γ‐irradiated bovine insoluble collagenous bone matrix, the hOP‐1 osteogenic device, for bone induction in heterotopic and orthotopic sites of the primate Papio ursinus and the expression patterns of OP‐1, collagen type IV, BMP‐3 and TGFβ1mRNAs elicited by increasing single applications of doses of the hOP‐1 osteogenic devices (0.1, 0.5 and 2.5 mg hOP‐1/g of matrix) applied heterotopically in the rectus abdominis muscle and orthotopically in 48 calvarial defects of 12 adult baboons. Histology and histomorphometry on serial undecalcified sections prepared from the specimens harvested on day 15, 30 and 90 showed that all the doses of the hOP‐1 osteogenic device induced bone formation culminating in complete calvarial regeneration by day 90. Type IV collagen mRNA expression, a marker of angiogenesis, was strongly expressed in both heterotopic and orthotopic tissues. High levels of expression of OP‐1 mRNA demonstrated autoinduction of OP‐1 mRNAs. Expression levels of BMP‐3 mRNA varied from tissues induced in heterotopic vs. orthotopic sites with high expression in rapidly forming heterotopic ossicles together with high expression of type IV collagen mRNA. The temporal and spatial expressions of TGF‐β1 mRNA indicate a specific temporal transcriptional window during which expression of TGF‐β1 is mandatory for successful and optimal osteogenesis. The induction of bone by hOP‐1 in Papio ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF‐β superfamily that singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis.
Neuropathy in rheumatoid arthritis.

BACKGROUND Paucity of Indian literature on rheumatoid neuropathy creates a lacuna in the critical evaluation and discussion of the subject. We did this study to find out the incidence and pattern of neuropathy and to correlate it with disease parameters and other extra-articular involvement. MATERIAL AND METHODS We studied 31 patients of rheumatoid arthritis (RA) classified by ACR criteria. Electromyography and nerve conduction studies (EMG/NCV) were done in all the patients apart from routine laboratory and radiological investigations. Electrocardiograph (ECG), pulmonary function tests (PFT) and ophthalmological examination were also carried out to ascertain extra-articular involvement. RESULTS Ten out of 31 RA patients had neuropathy of which five each were overt and subclinical respectively. Only one patient had entrapment neuropathy. Four of the ten patients had pure motor neuropathy whereas the other six were sensori-motor neuropathies. Four patients had mononeuritis multiplex and five had symmetrical peripheral neuropathy. Nine of the ten neuropathic patients had RA for more than 2 years. Seven patients had other extra-articular features along with neuropathy. CONCLUSIONS One-third of patients with RA have evidence of neuropathy. Disease parameters such as activity, rheumatoid factor and functional and radiological grade do not correlate with neuropathy. Non-entrapment sensori-motor type of neuropathy is the most common type.
Complexity of parental prenatal attachment during pregnancy at risk for preterm delivery

Abstract Objective: To clarify the links between parents’ prenatal attachment and psychosocial perinatal factors such as maternal depression, anxiety and social support. Methods: Cross-sectional study including 43 couples with high-risk pregnancy (RP) and 37 with physiologic pregnancy (PP). Self-report measures (depression, anxiety, social support and prenatal attachment) are completed by mothers, prenatal attachment questionnaire by fathers. Results: Depression (p < 0.001) and state anxiety (p < 0.001) are higher in RP. Both, maternal and paternal antenatal attachment is significantly lower in RP (p < 0.001; p < 0.005) but not related to depression or anxiety. Paternal antenatal attachment is strictly related to the maternal attachment scale in both groups (PP: r < 0.034; RP: r < 0.004) and paternal antenatal scores in RP have a negative significant correlation with mothers’ depression (r < 0.095). Conclusion: Hospitalized expecting parents at risk of preterm delivery develop less attachment to the fetus and higher levels of anxiety and depression compared to the physiologic pregnancy group. Maternal antenatal attachment is an independent variable related to the diagnosis of a possible preterm delivery. The promotion of prenatal psychological well-being and attachment for future mothers and fathers may serve to improve maternal health practices, perinatal health and neonatal outcome.
Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes*

Titin, the largest myofilament protein, serves as a template for sarcomere assembly and acts as a molecular spring to contribute to diastolic function. Titin is known to be extremely susceptible to calcium-dependent protease degradation in vitro. We hypothesized that titin degradation is an early event in doxorubicin-induced cardiac injury and that titin degradation occurs by activation of the calcium-dependent proteases, the calpains. Treatment of cultured adult rat cardiomyocytes with 1 or 3 μmol/liter doxorubicin for 24 h resulted in degradation of titin in myocyte lysates, which was confirmed by a reduction in immunostaining of an antibody to the spring-like (PEVK) domain of titin at the I-band of the sarcomere. The elastic domain of titin appears to be most susceptible to proteolysis because co-immunostaining with an antibody to titin at the M-line was preserved, suggesting targeted proteolysis of the spring-like domain of titin. Doxorubicin treatment for 1 h resulted in ∼3-fold increase in calpain activity, which remained elevated at 48 h. Co-treatment with calpain inhibitors resulted in preservation of titin, reduction in myofibrillar disarray, and attenuation of cardiomyocyte necrosis but not apoptosis. Co-treatment with a caspase inhibitor did not prevent the degradation of titin, which precludes caspase-3 as an early mechanism of titin proteolysis. We conclude that calpain activation is an early event after doxorubicin treatment in cardiomyocytes and appears to target the degradation of titin. Proteolysis of the spring-like domain of titin may predispose cardiomyocytes to diastolic dysfunction, myofilament instability, and cell death by necrosis.
Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-Class II restricted T cell receptors: implications for clinical medicine

In humans, increased susceptibility to specific autoimmune diseases is closely associated with specific HLA-class II alleles. CD4+ T cells that recognize short self-peptides in the context of HLA-class II molecules via their T cell receptor (TCR) are considered to mediate the central role of pathogenesis in autoimmunity. Although both self- and nonself-peptides are presented on HLA-class II molecules under physiological conditions, several mechanisms exist to avoid the T cell response to the self-peptide/HLA-class II complex. One of the mechanisms that account for the breakdown in immune tolerance is cross-recognition by TCR between a pathogen-derived antigen and a host antigen (molecular mimicry theory). Epidemiological studies have indicated that a number of autoimmune diseases are developed or exacerbated after infections. Therefore, elucidating the recognition nature of HLA-class II restricted TCR in detail is necessary in order to understand disease processes. A large body of evidence indicates that T cell recognition is highly degenerate, and many different peptides can activate an individual T cell. Degeneracy of TCR recognition also can appear in various physiological outcomes, ranging from full activation to strong antagonism. Here, we review the clinical implications of our findings on T cell recognition, as well as a new direction of future applications for analyses in molecular mimicry. We also describe the latest developments in methods of mapping TCR epitopes for CD4+ T cells using a peptide epitope expression library generated in the class II-associated invariant chain peptide substituted invariant chain gene format.