bluuebunny/crossref_metadata_2025 huggingface dataset:
College campus smoking policies and programs and students' smoking behaviors
Authors: Borders Tyrone F , Xu K Tom , Bacchi Donna , Cohen Lee , SoRelle-Miner Danielle
Published: July 2005

Background

Although tobacco use in the United States has declined over the past 20 years, cigarette use among college students remains high. Additional research is thus needed to determine how university tobacco control policies and preventive education programs affect college students' smoking behaviors.

Methods

Approximately 13,000 undergraduate students at 12 universities or colleges in the state of Texas completed a web-based survey. College smoking policies were obtained from a survey of college administrators and from college websites. Logistic regression analyses were conducted to estimate the effects of individual smoking policies and programs on the odds of cigarette smoking.

Results

Of the individual programs, only having a preventive education program on campus was associated with lower odds of smoking. The existence of smoking cessation programs and designated smoking areas were associated with higher odds of smoking. Policies governing the sale and distribution of cigarettes were insignificantly associated with smoking.

Conclusion

Rather than focusing on policies restricting cigarette sales and use, college administrators should consider implementing or expanding tobacco prevention and education programs to further reduce student smoking rates.
Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids
Authors: Valeria Ponce de León , Raúl Barrera-Rodríguez
Published: July 2005

Background

Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, can lead to multidrug resistance in tumours. However, the physiological role of P-gp in tumours growing as multicellular spheroids is not well understood. Recent evidence suggests that P-gp activity may be modulated by cellular components such as membrane proteins, membrane-anchoring proteins or membrane-lipid composition. Since, multicellular spheroids studies have evidenced alterations in numerous cellular components, including those related to the plasma membrane function, result plausible that some of these changes might modulate P-gp function and be responsible for the acquisition of multicellular drug resistance. In the present study, we asked if a human lung cancer cell line (INER-51) grown as multicellular spheroids can modify the P-gp activity to decrease the levels of doxorubicin (DXR) retained and increase their drug resistance.

Results

Our results showed that INER-51 spheroids retain 3-folds lower doxorubicin than the same cells as monolayers however; differences in retention were not observed when the P-gp substrate Rho-123 was used. Interestingly, neither the use of the P-gp-modulating agent cyclosporin-A (Cs-A) nor a decrease in ATP-pools were able to increase DXR retention in the multicellular spheroids. Only the lack of P-gp expression throughout the pharmacological selection of a P-gp negative (P-gpneg) mutant clone (PSC-1) derived from INER-51 cells, allow increase of DXR retention in spheroids.

Conclusion

Thus, multicellular arrangement appears to alter the P-gp activity to maintain lower levels of DXR. However, the non expression of P-gp by cells forming multicellular spheroids has only a minor impact in the resistance to chemotherapeutic agents.
Se-methylselenocysteine inhibits phosphatidylinositol 3-kinase activity of mouse mammary epithelial tumor cells in vitro
Authors: Unni Emmanual , Koul Dimpy , Yung Wai-Kwan Alfred , Sinha Raghu
Published: July 2005

Introduction

Se-methylselenocysteine (MSC), a naturally occurring selenium compound, is a promising chemopreventive agent against in vivo and in vitro models of carcinogen-induced mouse and rat mammary tumorigenesis. We have demonstrated previously that MSC induces apoptosis after a cell growth arrest in S phase in a mouse mammary epithelial tumor cell model (TM6 cells) in vitro. The present study was designed to examine the involvement of the phosphatidylinositol 3-kinase (PI3-K) pathway in TM6 tumor model in vitro after treatment with MSC.

Methods

Synchronized TM6 cells treated with MSC and collected at different time points were examined for PI3-K activity and Akt phosphorylation along with phosphorylations of Raf, MAP kinase/ERK kinase (MEK), extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). The growth inhibition was determined with a [3H]thymidine incorporation assay. Immunoblotting and a kinase assay were used to examine the molecules of the survival pathway.

Results

PI3-K activity was inhibited by MSC followed by dephosphorylation of Akt. The phosphorylation of p38 MAPK was also downregulated after these cells were treated with MSC. In parallel experiments MSC inhibited the Raf–MEK–ERK signaling pathway.

Conclusion

These studies suggest that MSC blocks multiple signaling pathways in mouse mammary tumor cells. MSC inhibits cell growth by inhibiting the activity of PI3-K and its downstream effector molecules in mouse mammary tumor cells in vitro.
Functional interaction between mouse erbB3 and wild-type rat c-neu in transgenic mouse mammary tumor cells
Authors: Kim Aeree , Liu Bolin , Ordonez-Ercan Dalia , Alvarez Kathy M , Jones Lynn D , McKimmey Christine , Edgerton Susan M , Yang XiaoHe , Thor Ann D
Published: July 2005

Introduction

Co-expression of several receptor tyrosine kinases (RTKs), including erbB2 and erbB3, is frequently identified in breast cancers. A member of the RTK family, the kinase-deficient erbB3 can activate downstream signaling via heterodimer formation with erbB2. We studied the expression of RTK receptors in mammary tumors from the wild-type (wt) rat c-neu transgenic model. We hypothesized that physical and functional interactions between the wt rat neu/ErbB2 transgene and mouse ErbB3-encoded proteins could occur, activating downstream signaling and promoting mammary oncogenesis.

Methods

Immunohistochemical and Western blot analyses were performed to study the expression of rat c-neu/ErbB2 and mouse erbB3 in mammary tumors and tumor-derived cell lines from the wt rat c-neu transgenic mice. Co-immunoprecipitation methods were employed to quantitate heterodimerization between the transgene-encoded protein erbB2 and the endogenous mouse erbB3. Tumor cell growth in response to growth factors, such as Heregulin (HRG), epidermal growth factor (EGF), or insulin-like growth factor-1 (IGF-1), was also studied. Post-HRG stimulation, activation of the RTK downstream signaling was determined by Western blot analyses using antibodies against phosphorylated Akt and mitogen-activated protein kinase (MAPK), respectively. Specific inhibitors were then used with cell proliferation assays to study the phosphoinositide-3 kinase (PI-3K)/Akt and MAPK kinase (MEK)/MAPK pathways as possible mechanisms of HRG-induced tumor cell proliferation.

Results

Mammary tumors and tumor-derived cell lines frequently exhibited elevated co-expression of erbB2 and erbB3. The transgene-encoded protein erbB2 formed a stable heterodimer complex with endogenous mouse erbB3. HRG stimulation promoted physical and functional erbB2/erbB3 interactions and tumor cell growth, whereas no response to EGF or IGF-1 was observed. HRG treatment activated both the Akt and MAPK pathways in a dose- and time-dependent manner. Both the PI-3K inhibitor LY 294002 and MEK inhibitor PD 98059 significantly decreased the stimulatory effect of HRG on tumor cell proliferation.

Conclusion

The co-expression of wt rat neu/ErbB2 transgene and mouse ErbB3, with physical and functional interactions between these two species of RTK receptors, was demonstrated. These data strongly suggest a role for erbB3 in c-neu (ErbB2)-associated mammary tumorigenesis, as has been reported in human breast cancers.
Intra-abdominal hypertension in patients with severe acute pancreatitis
Authors: De Waele Jan J , Hoste Eric , Blot Stijn I , Decruyenaere Johan , Colardyn Francis
Published: July 2005

Introduction

Abdominal compartment syndrome has been described in patients with severe acute pancreatitis, but its clinical impact remains unclear. We therefore studied patient factors associated with the development of intra-abdominal hypertension (IAH), the incidence of organ failure associated with IAH, and the effect on outcome in patients with severe acute pancreatitis (SAP).

Methods

We studied all patients admitted to the intensive care unit (ICU) because of SAP in a 4 year period. The incidence of IAH (defined as intra-abdominal pressure ≥ 15 mmHg) was recorded. The occurrence of organ dysfunction during ICU stay was recorded, as was the length of stay in the ICU and outcome.

Results

The analysis included 44 patients, and IAP measurements were obtained from 27 patients. IAH was found in 21 patients (78%). The maximum IAP in these patients averaged 27 mmHg. APACHE II and Ranson scores on admission were higher in patients who developed IAH. The incidence of organ dysfunction was high in patients with IAH: respiratory failure 95%, cardiovascular failure 91%, and renal failure 86%. Mortality in the patients with IAH was not significantly higher compared to patients without IAH (38% versus 16%, p = 0.63), but patients with IAH stayed significantly longer in the ICU and in the hospital. Four patients underwent abdominal decompression because of abdominal compartment syndrome, three of whom died in the early postoperative course.

Conclusion

IAH is a frequent finding in patients admitted to the ICU because of SAP, and is associated with a high occurrence rate of organ dysfunction. Mortality is high in patients with IAH, and because the direct causal relationship between IAH and organ dysfunction is not proven in patients with SAP, surgical decompression should not routinely be performed.
CD8+ T cells produce IL-2, which is required for CD4+CD25+ T cell regulation of effector CD8+ T cell development for contact hypersensitivity responses
Authors: Kish Danielle D , Gorbachev Anton V , Fairchild Robert L
Published: July 2005

Interleukin (IL)-2 functions to promote, as well as down-regulate, expansion of antigen-reactive CD4+ and CD8+ T cells, but the role of IL-2 in hapten-specific CD8+ T cell priming for contact hypersensitivity (CHS) responses remains untested. Using enzyme-linked immunospot to enumerate numbers of hapten-specific CD4+ and CD8+ T cells producing IL-2 in hapten-sensitized mice, the number of IL-2-producing CD8+ T cells was tenfold that of CD4+ T cells. Hapten-primed D4+ T cells produced low amounts of IL-2 during culture with hapten-presenting Langerhans cells, whereas production by hapten-primed CD8+ T cells was fivefold greater. CD8+ T cells did not express CD25 during hapten priming, but treatment with anti-IL-2 or anti-CD25 monoclonal antibodies during hapten sensitization increased hapten-specific effector CD8+ T cells as well as the magnitude and duration of the CHS response. These results indicate that CD8+ T cells are the primary source of IL-2 and that this IL-2 is required for the function of a population of CD4+CD25+ T cells to restrict the development of the hapten-reactive effector CD8+ T cells that mediate CHS responses.
Recombinant dimeric MHC antigens protect cardiac allografts from rejection and visualize alloreactive T cells
Authors: Fried Ari , Berg Martina , Sharma Bhavna , Bonde Sabrina , Zavazava Nicholas
Published: July 2005

Monomeric and dimeric soluble major histocompatibility complex (MHC) molecules down-regulate activated T cells in an antigen-specific manner in vitro. This property could be exploited to modulate alloresponses in vivo but has remained difficult to demonstrate. Here, intraperitoneal infusion of a Lewis-derived rat MHC class I molecule, RT1.Al-Fc, in Dark Agouti (RT1.Aa) recipient rats prolonged cardiac graft survival, which led to permanent engraftment. This effect was mediated by T cell impairment of target cell lysis by CD8+ T cells and down-regulation of interferon-γ production by CD4+ T cells. The binding of the dimeric MHC allowed ex vivo visualization of alloreactive T cells in peripheral blood, splenocytes, and allografts, revealing low frequency of alloreactive CD8+ T cells after establishment of permanent engraftment of cardiac allografts. Thus, these data show the potential of dimeric MHC molecules to promote graft survival and allow visualization of alloreactive T cells.
Cytokine induction of interleukin-24 in human peripheral blood mononuclear cells
Authors: Poindexter Nancy J , Walch Eugene T , Chada Sunil , Grimm Elizabeth A
Published: July 2005

Interleukin-24 (IL-24) is a recently identified member of the IL-10 family of cytokines. It was originally identified as a tumor suppressor molecule, melanoma differentiation-associated gene 7, and then renamed IL-24 and classified as a cytokine, based on its chromosomal location in the IL-10 locus, its mRNA expression in leukocytes, and its secretory sequence elements. Here, we correlate the kinetics of IL-24 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) stimulated by polyclonal activators phytohemagglutinin (PHA) and lipopolysaccharide (LPS) or by allogeneic major histocompatbility complex. PHA-stimulated PBMC express IL-24 mRNA, reaching peak levels at 8–12 h after stimulation. Protein expression, as measured by intracellular flow cytometry, followed the message, reaching maximum expression at 24 h. Subset analysis of mitogen-stimulated PBMC showed that IL-24 was expressed primarily in T cells and macrophages. Expression of IL-24 in mitogen-stimulated PBMC is the result of cytokine stimulation. Individual cytokines including IL-2, IL-7, IL-15, tumor necrosis factor α, granulocyte macrophage-colony stimulating factor, and IL-1β stimulate the expression of IL-24 mRNA and protein, whereas interferons and T helper cell type 2 cytokines fail to induce substantial IL-24. When LPS- or PHA-stimulated cells were treated with Actinomycin D, IL-24 mRNA persisted at high levels over the 4-h course of treatment. These data strongly suggest that the expression of IL-24 in human PBMC results from cytokine stimulation and is regulated at the post-transcriptional level through stabilization of IL-24 mRNA.
Morphine inhibits CD8+ T cell-mediated, noncytolytic, anti-HIV activity in latently infected immune cells
Authors: Wang Xu , Tan Ning , Douglas Steven D , Zhang Ting , Wang Yan-Jian , Ho Wen-Zhe
Published: July 2005

Opiates have profound effects on the function of human immune cells and are a possible cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) disease. We investigated the impact of morphine on CD8+ T cell-mediated, noncytotoxic, anti-HIV activity in latently infected human immune cells. Morphine inhibited the noncytotoxic, anti-HIV activity of CD8+ T cells in HIV latently infected cells (U1 and J1.1). Naltrexone abrogated the morphine-mediated, inhibitory effect on the noncytotoxic, anti-HIV activity of CD8+ T cells. Interferon-γ (IFN-γ), a potent antiviral cytokine produced by CD8+ T cells, was partially responsible for CD8+ T cell-mediated, noncytotoxic, anti-HIV activity. The anti-HIV activity of IFN-γ was also compromised by morphine treatment. Further, morphine attenuated CD8+ T cell-mediated suppression of the HIV long-terminal repeat promoter activation. Morphine also inhibited CD8+ T cell-induced expression of the signal transducer and activator of transcription-1, an important transcriptional factor in the IFN signaling pathway. These data provide additional evidence to support the notion that opioids play a role in impairing the anti-HIV function of the immune system.
Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages
Authors: Pritchard Michele T , Li Zihai , Repasky Elizabeth A
Published: July 2005

As macrophages are often called to function at times of elevated ambient temperature (e.g., during local inflammation or systemic fever), it is possible that their production of critical effector molecules, such as nitric oxide (NO) or inducible NO synthase (iNOS), is sensitive to physiological changes in temperature. To test this possibility, the threshold requirements for production of NO and iNOS in murine peritoneal macrophages maintained under normothermic conditions (37°C) or following mild (fever-range) hyperthermia (39.5°C) were compared. We found that hyperthermia alone had no observable effect on basal NO production or iNOS protein or message. However, although interferon (IFN)-γ and lipopolysaccharide (LPS) were needed to induce NO at 37°C we observed that addition of only LPS was sufficient for production of NO if there were a pretreatment at 39.5°C. Further, if IFN-γ and LPS were given after thermal exposure, a substantial increase in NO and iNOS was observed over that seen using cells kept at normothermic conditions. Macrophages isolated from mice lacking heat shock factor-1 did not attenuate the ability of mild thermal stress to modulate NO production. Reverse transcriptase-polymerase chain reaction data revealed that thermal regulation of iNOS expression is not entirely at the transcriptional level, suggesting possible points of post-transcriptional thermal sensitivity. These data support the concept that altering the thermal microenvironment is an important means by which the host can manipulate macrophage responses. Increases in temperature (e.g., during fever) may function to lower the activation threshold needed for production of effector molecules in times of infection.
Annexin 1-deficient neutrophils exhibit enhanced transmigration in vivo and increased responsiveness in vitro
Authors: Chatterjee Bristi E , Yona Simon , Rosignoli Guglielmo , Young Rebecca E , Nourshargh Sussan , Flower Roderick J , Perretti Mauro
Published: July 2005

The role of the endogenous anti-inflammatory mediator annexin 1 (AnxA1) in controlling polymorphonuclear leukocyte (PMN) trafficking and activation was addressed using the recently generated AnxA1 null mouse. In the zymosan peritonitis model, AnxA1 null mice displayed a higher degree (50–70%) of PMN recruitment compared with wild-type littermate mice, and this was associated with reduced numbers of F4/80+ cells. Intravital microscopy analysis of the cremaster microcirculation inflamed by zymosan (6 h time-point) indicated a greater extent of leukocyte emigration, but not rolling or adhesion, in AnxA1 null mice. Real-time analysis of the cremaster microcirculation did not show spontaneous activation in the absence of AnxA1; however, superfusion with a direct-acting PMN activator (1 nM platelet-activating factor) revealed a subtle yet significant increase in leukocyte emigration, but not rolling or adhesion, in this genotype. Changes in the microcirculation were not secondary to alterations in hemodynamic parameters. The phenotype of the AnxA1 null PMN was investigated in two in vitro assays of cell activation (CD11b membrane expression and chemotaxis): the data obtained indicated a higher degree of cellular responses irrespective of the stimulus used. In conclusion, we have used a combination of inflammatory protocols and in vitro assays to address the specific counter-regulatory role of endogenous AnxA1, demonstrating its inhibitory control on PMN activation and the consequent impact on the inflamed microcirculation.
Systemic Therapy for Metastatic Colorectal Cancer: Current Options, Current Evidence
Authors: Kelly Hanna , Goldberg Richard M.
Published: July 2005

Combination chemotherapy regimens including irinotecan and oxaliplatin markedly improve response rate and prolong median survival over fluorouracil with leucovorin (FU/LV), and have supplanted FU/LV as the standard systemic approach for metastatic colorectal cancer. The recent availability of five active chemotherapeutic agents has doubled the median overall survival for metastatic colorectal cancer from 10 to 20 months, and though the optimal strategy for incorporation of all drugs is still unclear, current data support the use of chemotherapy doublets in first-line rather than sequential single-agent therapy. Multidrug regimens increase both response rate and the proportion of patients able to undergo potentially curative resection. In addition, as many as 20% to 30% of patients never receive second-line chemotherapy. When used as single agents, bolus and infusional FU/LV and capecitabine are similarly effective but have differing toxicity. Chemotherapy combinations that incorporate infusion of FU are less toxic and more effective than those using bolus FU dosing. Capecitabine is under study as an alternative dosing method for use in combination regimens; however, the optimal dose has not been defined and final safety and efficacy outcomes are being addressed in ongoing phase II and III investigations. Three combinations have shown excellent first-line efficacy in phase III trials—IFL with bevacizumab, FOLFOX, and FOLFIRI—but neither of these combinations is clearly superior. Sound clinical judgment must continue to guide treatment decisions while we await data regarding the optimal combination and sequence of fluorouracil, irinotecan, oxaliplatin, bevacizumab, and cetuximab.
Does Screening for Barrett's Esophagus and Adenocarcinoma of the Esophagus Prolong Survival?
Authors: Dellon Evan S. , Shaheen Nicholas J.
Published: July 2005

Despite the paucity of data supporting its use, screening upper endoscopy for patients with chronic gastroesophageal reflux disease symptoms to assess for Barrett's esophagus and esophageal adenocarcinoma has become a widely accepted practice. We apply the principles of screening to Barrett's esophagus and esophageal adenocarcinoma. Critical application of the key criteria of screening to this situation demonstrates that several criteria are unfulfilled. Key data are not available with which to judge other criteria. The major fault with screening for Barrett's esophagus is that the at-risk population is too broadly characterized and that too many cancers occur outside of this risk pool. Thus, recommendations for screening cannot be endorsed. Efforts may be better directed at further research identifying groups at risk for esophageal adenocarcinoma, developing more accurate and less-invasive methods of diagnosis, and discovering the underlying factors which continue to drive the increased incidence of this disease.
Endoscopic Mucosal Resection for Early Cancers of the Upper Gastrointestinal Tract
Authors: Soetikno Roy , Kaltenbach Tonya , Yeh Ronald , Gotoda Takuji
Published: July 2005

The purpose of this literature review is to examine recent advances in technique and technology of endoscopic mucosal resection of superficial early cancers of the upper gastrointestinal tract. Endoscopic mucosal resection (EMR) of superficial early cancers of the upper gastrointestinal tract is standard technique in Japan and is increasingly used in Western countries. Newer techniques of EMR allow removal of larger lesions en-bloc. These minimally invasive techniques, when applied correctly, allow safe and efficacious treatment in situations that would otherwise require major surgery. Through the establishment of long-term outcomes data, standardization of endoscopic and pathologic reporting, and newer EMR technology and techniques, the future treatment of early cancers in the upper gastrointestinal tract may be achieved primarily through the endoscope.
Intraductal Papillary Mucinous Tumors of the Pancreas
Authors: Conlon Kevin C.
Published: July 2005

Intraductal papillary mucinous neoplasms of the pancreas (IPMNs) are increasingly recognized in clinical practice. They are a unique clinicopathologic entity that is characterized by mucin production, cystic dilation of the pancreatic ducts, and intraductal papillary growth. Histologically, they may demonstrate a spectrum of cellular atypia ranging from minimal mucinous hyperplasia to frank invasive carcinoma. Similar to invasive ductal adenocarcinoma of the pancreas, patients with IPMN generally present in the seventh or eighth decade of life with the head of the gland being the predominant disease site. The majority of patients are symptomatic at presentation with abdominal pain, weight loss, and diarrhea being the predominant symptoms. Traditionally, the diagnosis was made following an endoscopic retrograde cholangiopancreatography. However, a cross-sectional imaging study such as a computed tomography or magnetic resonance imaging is now the radiological imaging studies of choice. Current thinking suggests that at best IPMN represents a premalignant condition and, as such, surgical intervention should be recommended. The aim should be to resect all gross disease while attempting to achieve a negative surgical margin, which in the majority of cases can be achieved by a partial pancreatectomy. The disease seems to be somewhat indolent with resection of noninvasive disease being curative in the majority of patients with 5- and 10-year actuarial survival rates of 75% and 60% reported. However, up to 50% of cases will have invasive cancer, and for this cohort the prognosis is more guarded. The role of adjuvant therapies is unclear, and further studies are required in this area.
Locally Advanced Pancreatic Cancer
Authors: Willett Christopher G. , Czito Brian G. , Bendell Johanna C. , Ryan David P.
Published: July 2005

Of the 32,180 patients diagnosed with pancreatic carcinoma in the United States this year, approximately 40% will present with locally advanced disease. Radiotherapeutic approaches are often employed because these patients have unresectable tumors by virtue of local invasion into the retroperitoneal vessels in the absence of clinically detectable metastases. These treatments include external-beam irradiation with and without fluorouracil-based chemotherapy, intraoperative irradiation, and, more recently, external-beam irradiation with new systemic targeted agents.
Circulating Leptin Correlates with Left Ventricular Mass in Morbid (Grade III) Obesity before and after Weight Loss Induced by Bariatric Surgery: A Potential Role for Leptin in Mediating Human Left Ventricular Hypertrophy
Authors: Perego Lucia , Pizzocri Pierluigi , Corradi Domenico , Maisano Francesco , Paganelli Michele , Fiorina Paolo , Barbieri Michelangela , Morabito Alberto , Paolisso Giuseppe , Folli Franco , Pontiroli Antonio E.
Published: July 2005

Context: Obesity is frequently associated with left ventricular hypertrophy, even when uncomplicated by hypertension or diabetes mellitus. Left ventricular hypertrophy is an important risk factor for congestive heart failure.

Objective: The objective of this study was to evaluate the relationship between leptin and left ventricular mass in uncomplicated, morbid (grade 3) obesity and the existence of leptin receptors and intracellular signaling proteins in the human heart.

Design: Left ventricular mass (LVM) was calculated through electrocardiogram reading in normotensive grade III obese patients (World Health Organization classification) undergoing bariatric surgery [laparoscopic adjustable gastric banding (LAGB)] at baseline and 1 yr later. The control group was composed of healthy lean normotensive subjects. Leptin receptors were detected by PCR and immunocytochemistry in human heart biopsies.

Setting: This study was performed at university hospitals.

Patients: Thirty-one grade 3 obese patients and 30 healthy nonobese normotensive, age- and sex-matched control subjects were studied.

Intervention: Obese subjects underwent LAGB to induce weight loss and were evaluated at baseline and after 1 yr.

Results: LVM, plasma leptin, glucose, insulin levels, and homeostasis model assessment index were higher in obese than in lean controls (P < 0.01); at univariate regression analysis, LVM correlated with body mass index, leptin, and homeostasis model assessment index; at multiple regression analysis, LVM only correlated with leptin levels (P = 0.001). Obese subjects were reevaluated 1 yr after LAGB, when their body mass index changed from 46.2 ± 1.24 to 36.6 ± 1.05 kg/m2 (P < 0.01); the decrease in LVM correlated only with the decrease in leptin levels (P < 0.01). We demonstrated that long and short isoforms of the leptin receptor and intracellular proteins mediating leptin signaling were expressed in human heart by RT-PCR, immunocytochemistry, or both methods.

Conclusions: These data suggest that leptin could contribute to the left ventricular hypertrophy in humans.
Cutoff Levels of 17-α-Hydroxyprogesterone in Neonatal Screening for Congenital Adrenal Hyperplasia Should Be Based on Gestational Age Rather Than on Birth Weight
Authors: van der Kamp Hetty J. , Oudshoorn Caren G. M. , Elvers Bert H. , van Baarle Maja , Otten Barto J. , Wit Jan M. , Verkerk Paul H.
Published: July 2005

Objective: In newborn screening programs for congenital adrenal hyperplasia, 17-α-hydroxyprogesterone (17OHP) cutoff levels are based on birth weight (BW) or on gestational age (GA). We investigated which approach would result in the greatest specificity and sensitivity.

Study design: For the determination of 17OHP, a neonatal 17OHP assay was used in filter paper blood of 9492 newborns. The relationships between 17OHP and BW and between 17OHP and GA were studied by regression analysis. Reference curves with a specificity of 99.95% were constructed with the method that summarizes the distribution by three smoothed curves representing the skewness (L curve), the median (M curve), and the coefficient of variation (S curve). Median cutoff levels for BW and for GA according to the 99.95% reference curves were calculated.

Results: Regression analysis showed that GA is a better predictor of 17OHP than BW (R2 was 50.6 vs. 35.8%, respectively). At a specificity of 99.95%, the calculated median 17OHP cutoff level was lower for GA [12.6 μg/liter (38 nmol/liter)] than for BW [17.6 μg/liter (54 nmol/liter)], thus leading to a greater sensitivity.

Conclusion: This study demonstrates that GA is a better predictor of 17OHP in newborns and will result in greater specificity than BW despite the fact that the determination of GA might be less reliable than BW.
Obesity and Type 2 Diabetes Do Not Alter Splanchnic Cortisol Production in Humans
Authors: Basu Rita , Singh Ravinder J. , Basu Ananda , Chittilapilly Elizabeth G. , Johnson Michael C. , Toffolo Gianna , Cobelli Claudio , Rizza Robert A.
Published: July 2005

Context: Cortisol is a potent regulator of carbohydrate, fat, and protein metabolism.

Objective: The objective of the study was to determine whether obesity alone or in combination with type 2 diabetes increases splanchnic and/or leg cortisol production.

Design: Splanchnic and leg cortisol production were measured using the hepatic and leg catheterization technique combined with infusion of D4-cortisol.

Setting: The study was conducted in a General Clinical Research Center.

Participants: Nine lean nondiabetic, 10 obese nondiabetic, and 11 obese diabetic subjects were studied.

Interventions: Diabetic volunteers were withdrawn from their glucose-lowering medications before study.

Main Outcome Measures: Rates of total body, splanchnic and leg cortisol, and D3-cortisol production were measured.

Results: Rates of splanchnic cortisol production equaled or exceeded those occurring in extrasplanchnic tissues (e.g. the adrenals) in all three groups. However, because concurrent splanchnic cortisol uptake also occurred, net splanchnic cortisol release was minimal. Splanchnic cortisol production and splanchnic D3-cortisol production (an index of splanchnic 11β-hydroxysteroid dehydrogenase type 1 activity) did not differ among the three groups. In addition, splanchnic cortisol production did not correlate with either visceral fat or endogenous glucose production. On the other hand, splanchnic cortisol uptake was greater in the obese diabetic than lean nondiabetic subjects (25 ± 2.9 vs. 15.3 ± 2.5 μg/min; P < 0.05). Splanchnic, but not leg, D3-cortisol production was correlated with total body D3-cortisol production (r = 0.70; P < 0.001).

Conclusions: Although large amounts of cortisol are produced within the splanchnic bed, implying high intrahepatic glucocorticoid concentrations, rates do not differ in lean and obese nondiabetic humans and are not influenced by the presence of type 2 diabetes mellitus. On the other hand, obesity but not diabetes increases splanchnic cortisol uptake.
A Critical Analysis of Pituitary Tumor Shrinkage during Primary Medical Therapy in Acromegaly
Authors: Melmed Shlomo , Sternberg Richard , Cook David , Klibanski Anne , Chanson Philippe , Bonert Vivien , Vance Mary Lee , Rhew David , Kleinberg David , Barkan Ariel
Published: July 2005

Context: Somatostatin analogs have been successfully used to treat patients with GH-secreting pituitary adenomas because they are safe, effective, and usually well tolerated. The results of studies evaluating acromegaly treatment with the somatostatin receptor ligands (SRLs), octreotide and lanreotide, have supported the use of these agents for primary medical therapy before or as an alternative to traditional interventions of surgery and radiotherapy in selected cases.

Evidence Acquisition: We therefore undertook a systematic literature overview to characterize the results of studies involving primary therapy with somatostatin analogs and their effects on pituitary tumor size. Because most studies in which pituitary tumor shrinkage has been assessed involve uncontrolled, open-label, prospective trials or retrospective case series, the lack of a control arm does not permit pooling of data in a metaanalytic fashion to determine tumor size reduction. Therefore, this systematic review was designed to document and stratify data by study design, summarize therapeutic regimens and patient characteristics, assess the percentage of patients showing changes in tumor size, and calculate the weighted average effect on size reduction.

Evidence Synthesis: Overall, for patients who experience significant shrinkage, an approximately 50% decrease in pituitary mass is achieved when a somatostatin analog is used exclusively or before surgery or radiotherapy. Fourteen studies (n = 424) provided a definition of significant tumor shrinkage, and the results showed that 36.6% (weighted mean percentage) of patients receiving primary SRL therapy for acromegaly experienced a significant reduction in tumor size. The weighted mean percent reduction in tumor size was 19.4% for those studies in which all patients received SRLs and change in tumor size was reported for all patients.

Conclusions: Clinical implications are discussed for patients in whom tumor size control with SRLs is an important objective, typically those who have failed surgery or are being treated with primary medical therapy with large tumors.
Efficacy of Octreotide-LAR in Dieting Women with Abdominal Obesity and Polycystic Ovary Syndrome
Authors: Gambineri Alessandra , Patton Laura , De Iasio Rosaria , Cantelli Barbara , Cognini Graciela Estela , Filicori Marco , Barreca Antonina , Diamanti-Kandarakis Evanthia , Pagotto Uberto , Pasquali Renato
Published: July 2005

Context: Somatostatin reduces LH, GH, and insulin, and somatostatin receptors are present at the ovarian level; somatostatin analogs are thus potential candidates for treatment of the polycystic ovary syndrome (PCOS).

Objective: The purpose of this study was to evaluate the effect of octreotide-LAR, a long-acting somatostatin analog, in anovulatory abdominal obese women with PCOS.

Design: A single-blind, placebo-controlled study was performed, lasting for 7 months.

Setting: The patients were ambulatory throughout the study.

Patients: Twenty PCOS subjects were enrolled. Eighteen completed the study.

Interventions: A low-calorie diet was given during the first month, a low-calorie diet plus octreotide-LAR (10 mg; n = 10 subjects) or placebo (n = 10 subjects) was then given, with one im injection every 28 d (for 6 months).

Main Outcome Measures: The main outcome measures were clinical features, computerized tomography measurement of fat distribution, androgens, GH, IGF-I, IGF-binding proteins (IGFBPs), fasting and glucose-stimulated insulin, and ovulation.

Results: Octreotide had no additional effect in reducing body fat or improving fat distribution than placebo. Conversely, octreotide produced an additional decrease in fasting (P = 0.018) and glucose-stimulated (P = 0.038) insulin levels, an increase in IGFBP-2 (P = 0.042) and IGFBP-3 (P = 0.047), and an improvement in hirsutism (P = 0.004). Moreover, a trend toward greater reductions in testosterone (P = 0.061) and androstenedione (P = 0.069) was observed in women treated with octreotide-LAR compared with those given placebo. All women treated with octreotide ovulated at the end of the study compared with only one of those receiving placebo (P < 0.001).

Conclusions: Octreotide-LAR may be usefully applied to hypocalorically dieting, abdominal obese PCOS women to improve hyperandrogenism and the insulin-IGF-I system. Restoration of ovulatory menstrual cycles appears to be another advantage of this treatment.
Identification of 9α,11β-Prostaglandin F2 in Human Amniotic Fluid and Characterization of Its Production by Human Gestational Tissues
Authors: Mitchell Murray D. , Chang Maxwell C. , Chaiworapongsa Tinnakorn , Lan Hao-Yi , Helliwell Rachel J. A. , Romero Roberto , Sato Timothy A.
Published: July 2005

Context: 9α,11β-Prostaglandin F2 (9α,11β-PGF2) can contract uterine smooth muscle with a potency equal to PGF2α. Its presence in the human uterus and production by human gestational tissues is unknown.

Objective: These studies were performed to determine whether the PGD2-derived 9α,11β-PGF2 is both present in human amniotic fluid and synthesized by human gestational tissues and if so, whether labor-related substances could regulate its production.

Results: Detectable concentrations of 9α,11β-PGF2 were found in amniotic fluid samples and appeared to increase in late gestation. All gestational tissues studied synthesized 9α,11β-PGF2, with the placenta having the highest basal production rate, followed by the amnion and then the choriodecidua. IL-1β and TNFα caused concentration-dependent increases in 9α,11β-PGF2 production in human amnion and choriodecidual explants. Moreover, treatment of choriodecidual and placental explants with lipopolysaccharide resulted in a significant increase in 9α,11β-PGF2 production rates, reaching a maximum of 13-fold in the choriodecidua. Studies examining the effects of the addition of exogenous PGD2 strongly indicated that the choriodecidua has significant ability to convert PGD2 to 9α,11β-PGF2, whereas the amnion has little.

Conclusions: These results demonstrate for the first time that 9α,11β-PGF2 is present in human amniotic fluid and that it is produced by human gestational tissues and up-regulated by bacterial cell wall components and proinflammatory cytokines. We suggest that this prostaglandin may play a part in the mechanisms of human labor at term and preterm.
Fibroblast Growth Factor-23 in Patients with Graves’ Disease before and after Antithyroid Therapy: Its Important Role in Serum Phosphate Regulation
Authors: Yamashita Hiroyuki , Yamazaki Yuji , Hasegawa Hisashi , Yamashita Takeyoshi , Fukumoto Seiji , Shigematsu Takashi , Kazama Junichiro James , Fukagawa Masafumi , Noguchi Shiro
Published: July 2005

Objective: Hyperthyroidism is a well-described cause of hyperphosphatemia. We aimed to clarify the physiological role of fibroblast growth factor (FGF)-23 in serum phosphate homeostasis in patients with Graves’ disease during the course of treatment for hyperthyroidism.

Context: The study group comprised 56 patients (45 for a cross-sectional study and 11 for a longitudinal study) with Graves’ disease. For the cross-sectional study, patients were assigned, on the basis of their serum phosphate level, to a hypophosphatemia group (n = 14), a normophosphatemia group (n = 16), or a hyperphosphatemia group (n = 15). Serum FGF-23, calcium, phosphate, PTH, and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were compared between the three groups. For the longitudinal study, we assessed changes in these biochemical indices before and after antithyroid treatment.

Results: In the cross-sectional study, the serum FGF-23 level was significantly higher (P < 0.05) in the hyperphosphatemia group than in the other groups (61 ± 36 ng/liter vs. 31 ± 22 ng/liter and 30 ± 9 ng/liter). In the longitudinal study, serum levels of FGF-23 decreased significantly (P < 0.05) from a high of 54 ± 12 ng/liter before treatment to 29 ± 14 ng/liter after treatment. In contrast, the serum 1,25(OH)2D level increased significantly (P < 0.005) from 55 ± 22 pmol/liter before treatment to 185 ± 76 pmol/liter 3 months after treatment. Serum FGF-23 levels were positively correlated with serum phosphate levels (P < 0.0001) and negatively correlated with serum 1,25(OH)2D levels (P < 0.0001).

Conclusions: The significant positive correlation between serum levels of phosphate and FGF-23 indicates that FGF-23 may play an important role in serum phosphate homeostasis by its up-regulation in the hyperphosphatemic condition.
Limited Efficacy of Growth Hormone (GH) during Transition of GH-Deficient Patients from Adolescence to Adulthood: A Phase III Multicenter, Double-Blind, Randomized Two-Year Trial
Authors: Mauras Nelly , Pescovitz Ora Hirsch , Allada Vivek , Messig Michael , Wajnrajch Michael P. , Lippe Barbara
Published: July 2005

Context: Treatment of GH-deficient adolescents in transition to adulthood remains challenging.

Objective: The objective was to assess the safety and efficacy of GH in GH-deficient adolescents in transition.

Patients: Fifty-eight GH-deficient adolescents (mean age, 15.8 ± 1.8 yr; 33 males) at near completion of their linear growth participated in the study.

Intervention: Baseline studies were done while subjects were on GH. Subjects were retested (insulin-induced hypoglycemia) 4 wk after GH discontinuation and reclassified as persistently GH-deficient or controls (n = 18). GH-deficient subjects were randomized to GH (n = 25, ∼20 μg/kg·d) or placebo (n = 15).

Setting: The multicenter study was conducted over a 2-yr period.

Main Outcomes: Changes in body composition, bone mineral density (BMD), quality of life (QOL), cardiovascular and metabolic markers were measured.

Results: All groups had normal measures of lipid and carbohydrate metabolism, body composition, BMD, cardiac function, muscle strength, and QOL at baseline and after 2 yr. IGF-I concentrations decreased in all, but less so in the GH-group (P = 0.013). There was a greater increase in lean body mass (lesser adiposity) in the GH group than placebo at 12 months, but not at 24 months.

Conclusions: 1) GH-deficient patients properly treated in childhood can have normal BMD, body composition, cardiac function, muscle strength, carbohydrate and lipid metabolism, and QOL when reaching adult height; and 2) continuation of GH therapy for 2 yr did not change these measures as compared to placebo-treated or control subjects. GH-deficient adolescents in good metabolic status at the time of epiphyseal fusion may safely discontinue GH for at least 2 yr. Follow-up is needed to determine whether GH therapy is eventually warranted in subjects treated with GH during childhood.
Androgen Levels in Adult Females: Changes with Age, Menopause, and Oophorectomy
Authors: Davison S. L. , Bell R. , Donath S. , Montalto J. G. , Davis S. R.
Published: July 2005

Context: Changes in androgen levels across the adult female life span and the effects of natural menopause and oophorectomy have not been clearly established.

Objective: The objective of this study was to document the effects of age on androgen levels in healthy women and to explore the effects of natural and surgical menopause.

Design, Setting, and Participants: A cross-sectional study was conducted of 1423 non-healthcare-seeking women, aged 18–75 yr, randomly recruited from the community over 15 months.

Main Outcome Measures: Serum levels by age of total testosterone (T), calculated free T, dehydroepiandrosterone sulfate, and androstenedione in a reference group of women free of confounding factors. Women in the reference group had no usage of exogenous steroid therapy; no history of tubal ligation, hysterectomy, or bilateral oophorectomy; and no hyperprolactinemia or polycystic ovarian syndrome. The effects of natural and surgical menopause on sex steroid levels were also examined.

Results: In the reference population (n = 595), total T, calculated free T, dehydroepiandrosterone sulfate, and androstenedione declined steeply with age (P < 0.001), with the decline of each being greater in the earlier than the later decades. Examination of serum androgen levels by year in women aged 45–54 yr showed no independent effect of menopausal status on androgen levels. In women aged 55 yr or older, those who reported bilateral oophorectomy and were not on exogenous steroids had significantly lower total T and free T levels than women 55 yr or older in the reference group.

Conclusions: We report that serum androgen levels decline steeply in the early reproductive years and do not vary because a consequence of natural menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production. These significant variations in androgens with age must be taken into account when normal ranges are reported and in studies of the role of androgens in women.
Requirement for JAK/STAT signaling throughout border cell migration inDrosophila
Authors: Silver Debra L. , Geisbrecht Erika R. , Montell Denise J.
Published: July 2005

The evolutionarily conserved JAK/STAT signaling pathway is essential for the proliferation, survival and differentiation of many cells including cancer cells. Recent studies have implicated this transcriptional pathway in the process of cell migration in humans, mice, Drosophila and Dictyostelium. In the Drosophila ovary, JAK/STAT signaling is necessary and sufficient for the specification and migration of a group of cells called the border cells; however, it is not clear to what extent the requirement for cell fate is distinct from that for cell migration. We found that STAT protein is enriched in the migrating border cells throughout their migration and is an indicator of cells with highest JAK/STAT activity. In addition, statts mutants exhibited border cell migration defects after just 30 minutes at the non-permissive temperature, prior to any detectable change in the expression of cell fate markers. At later times, cell fate changes became evident, indicating that border cell fate is labile. JAK/STAT signaling was also required for organization of the border cell cluster. Finally, we show that both the accumulation of STAT protein and nuclear accumulation are positively regulated by JAK/STAT activity. The activity of the pathway is negatively regulated by overexpression of a SOCS protein and by blocking endocytosis. Together, our findings suggest that the requirement for STAT in border cells extends beyond the initial specification and delamination of cells from the epithelium.