bluuebunny/crossref_metadata_2025 huggingface dataset:
A Complete Extracorporeal Circulation-Free Approach to Patients With Functionally Univentricular Hearts Provides Superior Early Outcomes
Authors: Talwar Sachin , Muthukkumaran Subramanian , Choudhary Shiv Kumar , Makhija Neeti , Sreenivas Vishnubhatla , Saxena Anita , Juneja Rajnish , Kothari Shyam Sunder , Airan Balram
Published: January 2014

Objective:

We compared the early outcomes of patients undergoing extracardiac total cavopulmonary connection (TCPC) with or without cardiopulmonary bypass (CPB).

Methods:

Between February 2012 and February 2013, 27 patients undergoing TCPC without CPB (off-pump group) were compared with matched 27 patients undergoing TCPC on CPB (on-pump group). Outcome parameters studied were inotropic score, time to extubation, intensive care unit (ICU) stay, first 12 hours mediastinal drainage in ICU, average pleural drainage, time to removal of chest tubes, total hospital stay, and saturation at discharge.

Results:

There was one early death in each group. No patient required conversion from off CPB to CPB. The inotropic score (6.1 ± 5.91 vs 10.1 ± 6.80, P = .03), time to extubation (8.7 ± 6.95 vs 10.31 ± 8.69 hours, P = .03), first 12 hours mediastinal drainage in ICU (611.9 ± 341.4 vs 922.2 ± 145.6 mL, P = .03), and ICU stay (1.6 ± 0.58 vs 2.9 ± 1.37 days, P = .001) were significantly less in the off-pump group when compared to the on-pump group, and saturation at discharge (99.7 ± 0.60 vs 98.6 ± 2.13, P = .026) was higher in the off-pump group. However, the average daily pleural drainage (125 ± 61.72 vs 150 ± 103.4 mL, P = .7), time to removal of chest tubes (12.69 ± 7.1 vs 15.44 ± 19.26 days, P = .45), and the total hospital stay (14.23 ± 7.4 vs 18.89 ± 19.9 days, P = .22) were no different. There were substantial savings in costs in patients undergoing off-pump TCPC ( P = .016).

Conclusions:

The TCPC without CPB is easy to perform, is cost-effective, and is associated with superior early postoperative outcomes as compared to TCPC on CPB. With appropriate modifications, this operation can be performed in almost all morphological subsets of patients who do not need an associated intracardiac procedure.
Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors
Authors: Marty Caroline , Saint-Martin Cécile , Pecquet Christian , Grosjean Sarah , Saliba Joseph , Mouton Céline , Leroy Emilie , Harutyunyan Ashot S. , Abgrall Jean-François , Favier Rémi , Toussaint Aurélie , Solary Eric , Kralovics Robert , Constantinescu Stefan N. , Najman Albert , Vainchenker William , Plo Isabelle , Bellanné-Chantelot Christine
Published: January 2014

Key Points

New germ-line mutations of JAK2 in the kinase domain were identified. Specificity for MPL and resistance to JAK2 and HSP90 inhibitors was determined.
A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma
Authors: Salaverria Itziar , Martin-Guerrero Idoia , Wagener Rabea , Kreuz Markus , Kohler Christian W. , Richter Julia , Pienkowska-Grela Barbara , Adam Patrick , Burkhardt Birgit , Claviez Alexander , Damm-Welk Christine , Drexler Hans G. , Hummel Michael , Jaffe Elaine S. , Küppers Ralf , Lefebvre Christine , Lisfeld Jasmin , Löffler Markus , Macleod Roderick A. F. , Nagel Inga , Oschlies Ilske , Rosolowski Maciej , Russell Robert B. , Rymkiewicz Grzegorz , Schindler Detlev , Schlesner Matthias , Scholtysik René , Schwaenen Carsten , Spang Rainer , Szczepanowski Monika , Trümper Lorenz , Vater Inga , Wessendorf Swen , Klapper Wolfram , Siebert Reiner
Published: January 2014

Key Points

A subset of lymphomas with gene expression and pathological characteristics of Burkitt lymphomas but absence of MYC translocation does exist. These lymphomas carry chr 11q proximal gains and telomeric losses, suggesting co-deregulation of oncogenes and tumor suppressor genes.
Epidemiology of extrapulmonary tuberculosis in Brazil: a hierarchical model
Authors: Gomes Teresa , Reis-Santos Bárbara , Bertolde Adelmo , Johnson John L , Riley Lee W , Maciel Ethel Leonor
Published: January 2014

Background

Although extrapulmonary tuberculosis (EPTB) is less frequent than Pulmonary Tuberculosis (PTB) and is a secondary target for national TB control programs, its significance has increased worldwide during the HIV epidemic. The objective of this study was to examine the epidemiology of EPTB in Brazil between 2007 and 2011.

Methods

Cross-sectional study involving all cases of TB reported to the Brazilian Notifiable Diseases Surveillance System (Sistema de Informações de Agravo de Notificação - SINAN) in Brazil between 2007 and 2011. Sociodemographic and clinical characteristics of patients with exclusively PTB and exclusively EPTB were compared. Following analysis with Pearson’s chi-square test, variables with p < 0.05 were included in a hierarchical regression model. Variables with p < 0.05 in the corresponding level were kept in the model.

Results

A total of 427,548 cases of TB were included. Of these, 356,342 cases (83.35%; 95% confidence interval (CI) 83.23% - 83.45%) were PTB, 57,217 (13.37%; 95% CI 13.28% - 13.48%) were EPTB, 13,989 (3.27%; 95% CI 3.21% - 3.32%) were concurrent pulmonary and extrapulmonary TB. Patients with EPTB were mainly white (16.7%), and most (29.1%) patients had five to eight years of education. Among comorbidities, HIV infection was prominent (OR 2.15; 95% CI 2.09 – 2.21), although the proportion of cases awaiting test results or untested was high (39%). Ethanol use (OR 0.45; 95% CI 0.43 – 0.46), diabetes mellitus (OR 0.54; 95% CI 0.51 – 0.57) and mental illness (OR 0.88; 95% CI 0.82 – 0.95) were associated with PTB.

Conclusions

Thirteen percent of patients diagnosed with TB in Brazil have only EPTB. More effective diagnostic strategies and control measures are needed to reduce the number of cases of extrapulmonary TB in Brazil.
Differences in serum SP-D levels between German and Japanese subjects are associated with SFTPDgene polymorphisms
Authors: Horimasu Yasushi , Hattori Noboru , Ishikawa Nobuhisa , Tanaka Sonosuke , Bonella Francesco , Ohshimo Shinichiro , Guzman Josune , Costabel Ulrich , Kohno Nobuoki
Published: January 2014

Background

Surfactant protein A (SP-A) and SP-D are clinically established in Japan as serum biomarkers for diagnosing interstitial lung diseases (ILDs). Serum SP-D levels are affected by genetic variants. We conducted the present study to examine whether serum SP-A and/or SP-D levels in healthy subjects (HS) and patients with ILDs differ between populations with different genetic backgrounds.

Methods

German subjects (n = 303; 138 patients with idiopathic interstitial pneumonias [IIPs] and 165 HS) and Japanese subjects (n = 369; 94 patients with IIPs and 275 HS) were enrolled. Serum SP-A and SP-D levels were measured using an enzyme-linked immunosorbent assay, and four single-nucleotide polymorphisms (SNPs) in the SFTPD gene were genotyped using genomic DNA extracted from blood samples.

Results

In both the German and Japanese cohorts, serum SP-A and SP-D levels were significantly higher in patients with IIPs than in HS. There were no significant differences in SP-A levels between the German and Japanese cohorts; however, we found that serum SP-D levels were significantly higher in the German cohort, both in patients with IIPs and in HS (p < 0.001 and p = 0.005, respectively). Furthermore, the genotype distributions of the four SNPs in the SFTPD gene (rs721917, rs1998374, rs2243639, and rs3088308) were significantly different between German and Japanese cohorts (p < 0.001, p < 0.001, p = 0.022, and p < 0.001, respectively), and univariate linear regression analyses revealed that the genotypes of rs721917, rs1998374, and rs2243639 significantly correlated with serum SP-D levels (p < 0.001, p < 0.001, and p = 0.011, respectively). Furthermore, multivariate analyses revealed that the genotypes of these three SNPs correlated independently with serum SP-D levels (p < 0.001, p = 0.001, and p = 0.038, respectively), whereas ethnicity did not significantly correlate with serum SP-D levels.

Conclusions

In patients with IIPs and HS, serum SP-D, but not SP-A, levels were significantly higher in the German than in the Japanese cohort, in part, because of the different frequencies of SFTPD gene polymorphisms.
Utility of self-reported mental health measures for preventing unintentional injury: results from a cross-sectional study among French schoolchildren
Authors: Constant Aymery , Dulioust Judith , Wazana Ashley , Shojaei Taraneh , Pitrou Isabelle , Kovess-Masfety Viviane
Published: January 2014

Background

Identify children at-risk of having mental health problems is of value to prevent injury. But the limited agreement between informants might jeopardize prevention initiatives. The aims of the present study were 1) to test the concordance between parents and children reports, and 2) to investigate their relationships with parental reports of children’ unintentional injuries.

Methods

In a population-based sample of 1258 children aged 6 to 11, the associations between child psychopathology (using the Dominic Interactive and the Strengths and Difficulties Questionnaire) and unintentional injuries in the past 12 months were examined in univariate and multivariate models.

Results

As compared to children, parents tended to overestimate behavior problems and hyperactivity/inattention, and underestimate emotional symptoms. Unintentional injury in the last 12-month period was reported in 184 out of 1258 children (14.6%) and multivariate analyses showed that the risk of injury was twice as high in children self-reporting hyperactivity/inattention as compared to others. However this association was not retrieved with the parent-reported instrument.

Conclusion

Our findings support evidence that child-reported measures of psychopathology might provide relevant information for screening and injury prevention purposes, even at a young age. It could be used routinely in combination with others validated tools.
Collision tumor with inflammatory breast carcinoma and malignant phyllodes tumor: a case report and literature review
Authors: Shin Young Duck , Lee Seul Kee , Kim Kyu Sun , Park Mi Ja , Kim Joo Heon , Yim Hyun Sun , Choi Young Jin
Published: January 2014

There have been some reports of coincidental presentation of breast carcinoma and phyllodes tumor in the same breast. Most of the cases were carcinoma that arose from a phyllodes tumor with a histologically identified transitional area, and they behaved less aggressively than the usually encountered carcinoma. Collision tumors are rare clinical entities in which two histologically distinct tumor types show involvement at the same site. The occurrence of these tumors in the breast is extremely rare. Here, we report a case of 45-year-old woman who had both invasive ductal carcinoma as the finding of inflammatory carcinoma and a malignant phyllodes tumor in the same breast. There was no evidence of a transitional area between the phyllodes tumor and the invasive ductal carcinoma. To our knowledge, this is the first report of a collision tumor of inflammatory breast carcinoma coincident with a malignant phyllodes tumor in same breast.
Inference of the Xenopus tropicalis embryonic regulatory network and spatial gene expression patterns
Authors: Zheng Zhenzhen , Christley Scott , Chiu William T , Blitz Ira L , Xie Xiaohui , Cho Ken WY , Nie Qing
Published: January 2014

Background

During embryogenesis, signaling molecules produced by one cell population direct gene regulatory changes in neighboring cells and influence their developmental fates and spatial organization. One of the earliest events in the development of the vertebrate embryo is the establishment of three germ layers, consisting of the ectoderm, mesoderm and endoderm. Attempts to measure gene expressionin vivoin different germ layers and cell types are typically complicated by the heterogeneity of cell types within biological samples (i.e., embryos), as the responses of individual cell types are intermingled into an aggregate observation of heterogeneous cell types. Here, we propose a novel method to elucidate gene regulatory circuits from these aggregate measurements in embryos of the frogXenopus tropicalisusing gene network inference algorithms and then test the ability of the inferred networks to predict spatial gene expression patterns.

Results

We use two inference models with different underlying assumptions that incorporate existing network information, an ODE model for steady-state data and a Markov model for time series data, and contrast the performance of the two models. We apply our method to both control and knockdown embryos at multiple time points to reconstruct the core mesoderm and endoderm regulatory circuits. Those inferred networks are then used in combination with known dorsal-ventral spatial expression patterns of a subset of genes to predict spatial expression patterns for other genes. Both models are able to predict spatial expression patterns for some of the core mesoderm and endoderm genes, but interestingly of different gene subsets, suggesting that neither model is sufficient to recapitulate all of the spatial patterns, yet they are complementary for the patterns that they do capture.

Conclusion

The presented methodology of gene network inference combined with spatial pattern prediction provides an additional layer of validation to elucidate the regulatory circuits controlling the spatial-temporal dynamics in embryonic development.
Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance
Authors: Mottaghi-Dastjerdi Negar , Soltany-Rezaee-Rad Mohammad , Sepehrizadeh Zargham , Roshandel Gholamreza , Ebrahimifard Farzaneh , Setayesh Neda
Published: January 2014

Background

In cancer cells, apoptosis is an important mechanism that influences the outcome of chemotherapy and the development of chemoresistance. To find the genes involved in chemoresistance and the development of gastric cancer, we used the suppression subtractive hybridization method to identify the genes that are overexpressed in gastric cancer tissues compared to normal gastric tissues.

Results

In the suppression subtractive hybridization library we constructed, the most highly overexpressed genes were humanin isoforms. Humanin is a recently identified endogenous peptide that has anti-apoptotic activity and has been selected for further study due to its potential role in the chemoresistance of gastric cancer. Upregulation of humanin isoforms was also observed in clinical samples by using quantitative real-time PCR. Among the studied isoforms, humanin isoform 3, with an expression level of 4.166 ± 1.44 fold, was the most overexpressed isoform in GC.

Conclusions

The overexpression of humanin in gastric cancer suggests a role for chemoresistance and provides new insight into the biology of gastric cancer. We propose that humanin isoforms are novel targets for combating chemoresistance in gastric cancer.
Sudden hearing loss subsequent to diarrhea: what is the missing link?
Authors: Jafari Gholamali , Hosseini Seyed Mohammadreza , Akhondzadeh Shahin
Published: January 2014

Sudden sensorineural hearing loss (SSNHL) is a debilitating condition with an incidence of nearly 20 per 100,000 in populations. Metronidazole-induced ototoxicity is an extremely rare etiology of SSNHL. In this report, we describe a young female with bilateral SSNHL due to oral use of metronidazole. A 23 years old female presented to the emergency department with acute bilateral hearing loss. We found out that her hearing loss had started 4 days after initiation of metronidazole which was administered for treatment of diarrhea. This case report shows that physicians should be aware of the uncommon side effects while prescribing metronidazole to patients in order to manage the possible adverse events on time.
Transformation efficiency and formation of transformation products during photochemical degradation of TCE and PCE at micromolar concentrations
Authors: Dobaradaran Sina , Lutze Holger , Mahvi Amir Hossein , Schmidt Torsten C
Published: January 2014

Background

Trichloroethene and tetrachloroethene are the most common pollutants in groundwater and two of the priority pollutants listed by the U.S. Environmental Protection Agency. In previous studies on TCE and PCE photolysis and photochemical degradation, concentration ranges exceeding environmental levels by far with millimolar concentrations of TCE and PCE have been used, and it is not clear if the obtained results can be used to explain the degradation of these contaminants at more realistic environmental concentration levels.

Methods

Experiments with micromolar concentrations of TCE and PCE in aqueous solution using direct photolysis and UV/H2O2 have been conducted and product formation as well as transformation efficiency have been investigated. SPME/GC/MS, HPLC/UV and ion chromatography with conductivity detection have been used to determine intermediates of degradation.

Results

The results showed that chloride was a major end product in both TCE and PCE photodegradation. Several intermediates such as formic acid, dichloroacetic acid, dichloroacetaldehyede, chloroform, formaldehyde and glyoxylic acid were formed during both, UV and UV/H2O2 treatment of TCE. However chloroacetaldehyde and chloroacetic acid were only detected during direct UV photolysis of TCE and oxalic acid was only formed during the UV/H2O2 process. For PCE photodegradation, formic acid, di- and trichloroacetic acids were detected in both UV and UV/H2O2 systems, but formaldehyde and glyoxylic acid were only detected during direct UV photolysis.

Conclusions

For water treatment UV/H2O2 seems to be favorable over direct UV photolysis because of its higher degradation efficiency and lower risk for the formation of harmful intermediates.
Effect of fibrate treatment on liver function tests in patients with the metabolic syndrome
Authors: Gandhi Nirav , Lenton Richard , Bhartia Mithun , Abbas Ahmed , Raju Jessie , Ramachandran Sudarshan
Published: January 2014

Background

Fibrates are used especially in patients with hypertriglyceridaemia, a feature of the metabolic syndrome. Elevated LFTs are often observed in these patients perhaps related to fatty infiltration.

Aim

We wished to study changes seen in LFTs (GGT, ALT and ALP) following fibrate therapy and then determine associated factors.

Methods

This was a retrospective observational study in which data was collected from case notes of patients started on fibrates (n = 118, 2002–2008) in the lipid clinic at Good Hope Hospital and pre/post-fibrate lipid and LFT values were obtained. All biochemistry was performed on the Roche P-Unit using supplied reagents. Statistical analyses included t tests and regression analyses (factorised when quartiles were compared).

Results

Of the study population 106 patients were on fenofibrate; the remaining on bezafibrate. Significant lowering of GGT (p < 0.0001), ALT (p = 0.0014) and ALP (p < 0.0001) levels were observed following fibrate treatment. Baseline lipid (cholesterol, triglycerides and HDL) concentrations, alcohol intake, length of treatment, gender, concurrent statin treatment and diabetes did not correlate with these changes in LFT in a multiple regression analysis. Higher pre-fibrate GGT (p < 0.0001), ALT (p < 0.0001) and ALP (p < 0.0001) concentrations were associated with larger decreases in each of these tests respectively with the highest 2 quartiles (GGT > 57 IU/l, ALT > 34 IU/l and ALP > 94 IU/l) significantly different to the lowest quartile. The above associations remained significant even when the regression analyses were corrected for changes in lipid values (which did not show an association).

Conclusions

Fibrate treatment led to improvements in LFT, the greatest benefit seen in patients with higher baseline LFT values. It appears that baseline and changes in lipid values post fibrate treatment were not associated with change in LFT.
Estrogen treatment predisposes to severe and persistent vaginal candidiasis in diabetic mice
Authors: Hamad Mawieh
Published: January 2014

Background

Increased levels of estrogen and diabetes mellitus separately predispose to vaginal candidiasis (VC). However, the compounding effect of estrogen on the severity and persistence of VC in diabetic females is not clear.

Methods

To address this issue, a diabetic mouse model with estrogen-maintained VC was developed and evaluated for vaginal fungal burden (VFB) and immune competence at different time points throughout the study period.

Results

Blood glucose levels in estrogen-treated diabetic mice were consistently lower than that in untreated counterparts. Estrogen-treated C. albicans-infected non-diabetic mice experienced persistent episodes of VC as compared with naïve controls (P < 0.01). However, severity and persistence of VC in estrogen-treated C. albicans-infected diabetic mice was significantly greater than that in non-diabetic counterparts (P < 0.05). Mortality rates among estrogen-treated C. albicans-infected diabetic mice were significantly higher (P < 0.05) than that in non-diabetic counterparts. Statistically significant (P < 0.05) and persistent suppression of the delayed hypersensitivity response (DTH) was evident in estrogen-treated C. albicans-infected diabetic and non-diabetic mice as compared with controls. Levels of expression of the inhibitory molecule CD152 on vaginal and splenic T cells isolated from estrogen-treated C. albicans infected mice was significantly higher than that in naive untreated controls (P < 0.01).

Conclusions

These findings suggest that estrogen treatment in diabetic females may protect against the progression of DM on the one hand and predispose to severe and persistent VC on the other. The later outcome could be related to the immunosuppressed status of the host.
Metals in the pathogenesis of type 2 diabetes
Authors: Khan Abdul Rehman , Awan Fazli Rabbi
Published: January 2014

Minerals are one of the components of food, though they are not synthesized in the body but they are essential for optimal health. Several essential metals are required for the proper functioning of many enzymes, transcriptional factors and proteins important in various biochemical pathways. For example Zn, Mg and Mn are cofactors of hundreds of enzymes, and Zn is involved in the synthesis and secretion of insulin from the pancreatic beta-cells. Similarly, Cr enhances the insulin receptor activity on target tissues, especially in muscle cells. Insulin is the key hormone required to maintain the blood glucose level in normal range. In case of insulin deficiency or resistance, blood glucose concentration exceeds the upper limit of the normal range of 126 mg/dl. Persistent increase of blood serum glucose level leads to overt chronic hyperglycemia, which is a major clinical symptom of diabetes mellitus. Poor glycemic control and diabetes alters the levels of essential trace elements such as Zn, Mg, Mn, Cr, Fe etc. by increasing urinary excretion and their concomitant decrease in the blood. Hence, the main purpose of this review is to discuss the important roles of essential trace elements in normal homeostasis and physiological functioning. Moreover, perturbation of essential trace elements is also discussed in perspective of type 2 diabetes pathobiology.
The Molecular and Genetic Basis of Fibroblast Growth Factor Receptor 3 Disorders: The Achondroplasia Family of Skeletal Dysplasias, Muenke Craniosynostosis, and Crouzon Syndrome with Acanthosis Nigricans*
Authors: Vajo Zoltan , Francomano Clair A. , Wilkin Douglas J.
Published: January 2014

Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time of conception of affected individuals. More then 97% of persons with achondroplasia have a Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active.

Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. These specific genotype-phenotype correlations in the FGFR disorders seem to be unprecedented in the study of human disease. The explanation for this high degree of mutability at specific bases remains an intriguing question.
Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency*
Authors: White Perrin C. , Speiser Phyllis W.
Published: January 2014

More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal “salt wasting” crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions—transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.
Endocrine and Paracrine Regulation of Birth at Term and Preterm*
Authors: Challis John R.G. , Matthews Stephen G. , Gibb William , Lye Stephen J.
Published: January 2014

We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.
Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting
Authors: Weinstein Lee S. , Yu Shuhua , Warner Dennis R. , Liu Jie
Published: January 2014

The heterotrimeric G protein Gs couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate Gs by promoting exchange of GTP for GDP on the Gs α-subunit (Gsα) while an intrinsic GTPase activity of Gsα that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific Gsα residues (Arg201 or Gln227) that are critical for the GTPase reaction lead to constitutive activation of Gs-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate Gs in their target tissues (pseudohypoparathyroidism type IA). Studies in Gsα knockout mice demonstrate that Gsα is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of Gsα expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on Gsα expression or PTH action. Gsα has recently been shown to be also imprinted in human pituitary glands. The Gsα gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gsα, XLαs (a novel Gsα isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the Gsα promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of Gsα. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease Gsα expression in renal proximal tubules. Studies in Gsα knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.
Postpartum Thyroiditis and Autoimmune Thyroiditis in Women of Childbearing Age: Recent Insights and Consequences for Antenatal and Postnatal Care
Authors: Muller Alex F. , Drexhage Hemmo A. , Berghout Arie
Published: January 2014

Postpartum thyroiditis is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery and based on an autoimmune inflammation of the thyroid. The prevalence ranges from 5–7%. We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis. Postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. From pregnancy an enhanced state of immune tolerance ensues. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis. Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem. 1) Thyroid autoimmunity increases the probability of spontaneous fetal loss. 2) Thyroid failure due to autoimmune thyroiditis—often mild and subclinical—can lead to permanent and significant impairment in neuropsychological performance of the offspring. 3) Evidence is emerging that as women age subclinical hypothyroidism—as a sequel of postpartum thyroiditis—predisposes them to cardiovascular disease. Hence, postpartum thyroiditis is no longer considered a mild and transient disorder. Screening is considered.
Hepatic Nuclear Factor 3 and High Mobility Group I/Y Proteins Bind the Insulin Response Element of the Insulin-Like Growth Factor-Binding Protein-1 Promoter*
Authors: Allander Susanne V. , Durham Susan K. , Scheimann Ann O. , Wasserman Richard M. , Suwanichkul Adisak , Powell David R.
Published: January 2014

The insulin response element (IRE) of the human insulin-like growth factor-binding protein-1 (IGFBP-1) promoter contains a palindrome of the T(A/G)TTT sequence crucial to hormonal regulation of many genes. In initial studies of how this IRE participates in hormonal regulation, the electromobility shift assay was used under a variety of conditions to identify IRE-binding proteins. An exhaustive search identified five proteins that specifically bind this IRE; purified proteins were used to show that all five are related to either the high mobility group I/Y (HMGI/Y) or hepatic nuclear factor 3 (HNF3) protein families. Further studies used purified HNF3 and HMGI proteins to show: 1) each protects the IGFBP-1 IRE from deoxyribonuclease I (DNaseI) digestion; and 2) HNF3 but not HMGI/Y binds to the related phosphoenolpyruvate carboxykinase and Apo CIII IREs. A series of IRE mutants with variable responsiveness to insulin were used to show that the presence of a TGTTT sequence in the mutants did parallel, but HMGI/Y and HNF3 binding to the mutants did not parallel, the ability of the mutants to confer the inhibitory effect of insulin. In contrast, HNF3 binding to these IRE mutants roughly correlates with response of the mutants to glucocorticoids. The way by which HNF3 and/or other as yet unidentified IRE-binding proteins confer insulin inhibition to IGFBP-1 transcription and the role of HMGI/Y in IRE function have yet to be established.
Low Density Lipoprotein Binding and Uptake by Human and Rat Isletβ Cells*
Authors: Grupping A. Y. , Cnop M. , Van Schravendijk C. F. H. , Hannaert J. C. , Van Berkel Th. J. C. , Pipeleers D. G.
Published: January 2014

Abnormalities in lipoprotein metabolism are common in diabetes. It is unknown whether variations in form or concentration of lipoproteins influence the function of pancreatic β cells. This study investigates whether low density lipoproteins (LDL) exhibit specific interactions with islet β cells. Radioactively labeled LDL (125I-LDL) and fluorescently labeled LDL (DiI-LDL) were used as tracers. Rat islet cells express high affinity LDL binding sites (Kd = 9 nm), which are also recognized by very low density lipoproteins and which are down-regulated by LDL. Binding of LDL appears restricted to the β cells, as it was not detected on islet endocrine non-β cells. At 37 C, LDL is taken up and lysosomally degraded by islet β cells but not by islet non-β cells. Human islet cells were also found to present LDL binding, uptake, and degradation. Compared with rat islet cells, human islet cells exhibit 10-fold less binding sites (2.107vs. 2.108 per 103 cells) with a 2-fold lower Kd value (5 nm) and an equal sensitivity to LDL-induced down-regulation. In conclusion, human and rat islet β cells express LDL receptors that can internalize the lipoprotein. This pathway should be examined for its potential role in (dys)regulating pancreatic β cell functions.
Characterization of Germ Cell-Specific Expression of the Orphan Nuclear Receptor, Germ Cell Nuclear Factor*
Authors: Katz Deborah , Niederberger Craig , Slaughter Gayle R. , Cooney Austin J.
Published: January 2014

Nuclear receptors, such as those for androgens, estrogens, and progesterones, control many reproductive processes. Proteins with structures similar to these receptors, but for which ligands have not yet been identified, have been termed orphan nuclear receptors. One of these orphans, germ cell nuclear factor (GCNF), has been shown to be germ cell specific in the adult and, therefore, may also participate in the regulation of reproductive functions. In this paper, we examine more closely the expression patterns of GCNF in germ cells to begin to define spatio-temporal domains of its activity. In situ hybridization showed that GCNF messenger RNA (mRNA) is lacking in the testis of hypogonadal mutant mice, which lack developed spermatids, but is present in the wild-type testis. Thus, GCNF is, indeed, germ cell specific in the adult male. Quantitation of the specific in situ hybridization signal in wild-type testis reveals that GCNF mRNA is most abundant in stage VII round spermatids. Similarly, Northern analysis and specific in situ hybridization show that GCNF expression first occurs in testis of 20-day-old mice, when round spermatids first emerge. Therefore, in the male, GCNF expression occurs postmeiotically and may participate in the morphological changes of the maturing spermatids. In contrast, female expression of GCNF is shown in growing oocytes that have not completed the first meiotic division. Thus, GCNF in the female is expressed before the completion of meiosis. Finally, the nature of the two different mRNAs that hybridize to the GCNF complementary DNA was studied. Although both messages contain the DNA binding domain, only the larger message is recognized by a probe from the extreme 3′ untranslated region. In situ hybridization with these differential probes demonstrates that both messages are present in growing oocytes. In addition, the coding region and portions of the 3′ untranslated region of the GCNF complementary DNA are conserved in the rat.
Examination of Guinea Pig Luteinizing Hormone-Releasing Hormone Gene Reveals a Unique Decapeptide and Existence of Two Transcripts in the Brain*
Authors: Jimenez-Liñan Mercedes , Rubin Beverly S. , King Joan C.
Published: January 2014

We sequenced the complementary DNA (cDNA) encoding guinea pig LHRH from an expression library derived from the preoptic area-anterior hypothalamus. Data from in situ hybridization and RNase protection assays verified that the cloned cDNA was complementary to guinea pig LHRH messenger RNA. The architecture of the deduced precursor resembles that of LHRH precursors identified in other species. In contrast, the predicted sequence of the decapeptide differs from mammalian LHRH by two amino acid substitutions in positions 2 and 7. This is a novel finding, because the amino acid sequence that comprises LHRH decapeptide is identical in all mammals studied to date. Moreover, the predicted substitution in amino acid position 2 is unique among vertebrates. A second observation of potential significance is the existence of two subspecies of LHRH messenger RNA differing only in the length of their 3′ untranslated regions. These two transcripts were verified by sequence analysis of positive clones from the cDNA library and by RNase protection analysis of preoptic area-anterior hypothalamus extracts, and their presence is consistent with the two polyadenylation signals identified in the untranslated regions of the LHRH gene. Future studies will examine LHRH gene expression in guinea pigs, which like primates but unlike rats, have a true luteal phase as a component of their reproductive cycle.
Expression and Subcellular Distribution of the β-Isoform of the Human Glucocorticoid Receptor*
Authors: Oakley Robert H. , Webster Jeffrey C. , Sar Madhabananda , Parker C. Richard , Cidlowski John A.
Published: January 2014

Alternative splicing of the human glucocorticoid receptor (hGR) primary transcript produces two highly homologous protein isoforms, termed hGRα and hGRβ, that differ at their carboxy-termini. In contrast to the well characterized hGRα isoform, which modulates gene expression in a hormone-dependent fashion, the biological significance of hGRβ has only recently begun to emerge. We and others have shown that the hGRβ messenger RNA transcript is widely expressed in human tissues and that the hGRβ protein functions as a dominant negative inhibitor of hGRα in transfected cells. Unfortunately, these initial studies did not determine whether the hGRβ protein was made in vivo. Such analyses are hindered because available anti-hGR antibodies cannot discriminate between the similarly sized hGRα and hGRβ proteins. Therefore, to investigate the expression of the hGRβ protein, we have produced an antipeptide, hGRβ-specific antibody termed BShGR. This antibody was made against the unique 15-amino acid peptide at the carboxy-terminus of hGRβ and recognizes both the native and denatured conformations of hGRβ, but does not cross-react with hGRα. Using BShGR on Western blots and in immunoprecipitation experiments, we detected the hGRβ protein in a variety of human cell lines and tissues. Immunocytochemistry was then performed with BShGR on HeLa S3 and CEM-C7 cells and on tissue sections prepared from lung, thymus, and liver to assess the cellular and subcellular distribution of hGRβ. In all immunopositive cells, hGRβ was found in the nucleus independent of glucocorticoid treatment. Within tissues, the hGRβ protein was expressed most abundantly in the epithelial cells lining the terminal bronchiole of the lung, forming the outer layer of Hassall’s corpuscle in the thymus, and lining the bile duct in the liver. As a potential in vivo inhibitor of hGRα activity, expression of hGRβ may be an important factor regulating target cell responsiveness to glucocorticoids.
Regulation of Hypothalamic Proopiomelanocortin mRNA by Leptin in ob/ob Mice
Authors: Thornton Janice E. , Cheung Clement C. , Clifton Donald K. , Steiner Robert A.
Published: January 2014

The hormone leptin acts on the brain to regulate feeding, metabolism, and reproduction; however, its cellular targets and molecular mechanisms of action remain to be fully elucidated. The melanocortins, which are derived from the precursor proopiomelanocortin (POMC), are also implicated in the physiological regulation of body weight. POMC-containing neurons express the leptin receptor, and thus it is conceivable that the POMC gene itself may be part of the signaling pathway involved in leptin’s action on the brain. Using in situ hybridization and computerized image analysis, we tested the hypothesis that the POMC gene is a target for regulation by leptin by comparing cellular levels of POMC mRNA in the hypothalamus among groups of leptin-deficient (ob/ob) mice, leptin-treated ob/ob mice, and wild-type controls. POMC mRNA levels were significantly reduced throughout the arcuate nucleus in vehicle-treated ob/ob mice relative to wild-type controls, whereas POMC mRNA levels in leptin-treated ob/ob mice were indistinguishable from wild-type controls. These observations suggest that one or more products of POMC serve as an integrative link between leptin and the central mechanisms governing body weight regulation and reproduction.
Breed Differences in Expression of Inhibin/Activin Subunits in Porcine Anterior Pituitary Glands*
Authors: Li M. D. , MacDonald G. J. , Ford J. J.
Published: January 2014

Chinese Meishan (MS) boars have greater plasma FSH concentrations than European White Composite boars, but this difference does not occur in females of these breeds. To understand this disparity, we studied expression of the follistatin gene and of genes for the inhibin/activinα -, βA-, and βB-subunits in porcine anterior pituitary glands using quantitative reverse transcription-PCR and ribonuclease protection techniques. We found that 1) the inhibin/activin βA- and βB-subunits and follistatin were expressed in porcine pituitary; 2) the α-subunit was not detected in the porcine pituitary, but was highly expressed in porcine follicles; and 3) the βB-subunit gene is more abundantly expressed (2-fold greater) in MS boar pituitaries than in pituitaries of White Composite boars. We conclude that this is not due to a breed difference, because the expression levels of this gene were similar in pituitaries of females of these breeds. No breed differences were detected for other genes screened in this study. From these observations, we propose that activin B, a dimer ofβ B-subunits and a stimulator of FSH secretion, may be partially responsible for the elevated plasma FSH concentrations in MS boars, and intrapituitary inhibin plays no or a very minimal role.
Only the Substitution of Methionine 918 with a Threonine and Not with Other Residues Activates RET Transforming Potential*
Authors: Cirafici Anna Maria , Salvatore Giuliana , De Vita Gabriella , Carlomagno Francesca , Dathan Nina A. , Visconti Roberta , Melillo Rosa Marina , Fusco Alfredo , Santoro Massimo
Published: January 2014

Specific point-mutations of the RET receptor tyrosine kinase protooncogene are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). MEN2B is caused by the substitution of methionine 918 by a threonine in the tyrosine kinase (TK) domain of RET. This mutation converts RET into a dominant transforming oncogene. We have substituted Met918 with four different residues and found that RET acquired transforming activity only when Met918 was substituted with a threonine. However, also when serine and valine, but not leucine or phenylalanine, were inserted in position 918, the RET TK function was activated and induced, especially in the case of the RET(918Ser), immmediate-early response genes. We conclude that the preservation of Met918 is critical for the control of RET kinase. However, only when a threonine residue is present in position 918, does RET efficiently couple with a transforming pathway.
Nuclear Transport of Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3 in Opossum Kidney Cells
Authors: Li Wenlu , Fawcett Janet , Widmer H. Ramon , Fielder Paul J. , Rabkin Ralph , Keller Gilbert-André
Published: January 2014

When added to cultured opossum kidney cells, IGF-I is internalized and transported to distinct intracellular compartments that depend on the cell location within the monolayer. In resting cells away from the periphery of the monolayer, IGF-I is internalized by a clathrin coated pit pathway and delivered to the endosomal compartment. In contrast, cells growing at the edges of a monolayer or an experimental wound internalize IGF-I by an alternative route which rapidly delivers IGF-I to the nucleus. Similarly to IGF-I, IGFBP-3 is also internalized and accumulates in the endosomal compartment in resting cells whereas it is targeted to the nucleus in proliferating cells. IGFBP-3, which contains a putative nuclear targeting signal, may act as a carrier for IGF-I nuclear transport. The transport of IGF-I and IGFBP-3 to two different compartments may influence their biological activity.