Outcome of pregnancies in a large cohort of women with acromegaly.

OBJECTIVE: To assess the outcome of pregnancies in a large cohort of women with acromegaly. DESIGN AND METHODS: This is a retrospective analysis of 31 pregnancies in 20 patients with acromegaly. RESULTS: Twenty-seven pregnancies resulted in healthy offspring, and 4 resulted in abortion. Three patients underwent transsphenoidal surgery during pregnancy. IGF-1 levels remained elevated during pregnancy in 4 pregnancies and normalized in 23 cases. Fifteen cases were followed during pregnancy without any medical or surgical treatment, and 13 of these exhibited normal IGF-1 levels. Before or during pregnancy, somatostatin receptor ligands usage was not associated with higher risk for adverse outcomes. Arterial hypertension worsening (45%) and impairment of glucose levels (32%) were the most common complications during pregnancies. There were no maternal or neonatal deaths. One woman delivered twins. Two cases of congenital malformations and one with foetal macrosomia were observed. Caesarean delivery was performed in sixteen cases. CONCLUSION: Our study confirms the impact of gestation on IGF-1 levels. However, it also indicates that acromegaly still holds an increased risk for worsening of comorbidities, especially in uncontrolled patients.

Is the association between hip fractures and seasonality modified by influenza vaccination? An ecological study.

Osteoporotic hip fractures in 4344 patients were more common during winter. Lower temperatures were associated with higher rates of fracture only in those not vaccinated for influenza. Influenza outbreaks increased the risk of hip fractures. Further studies are needed to assess whether influenza vaccination can prevent hip fractures. INTRODUCTION: Winter seasonality of osteoporotic hip fracture incidence has been demonstrated, yet the explanation for the association is lacking. We hypothesize that the seasonality of osteoporotic hip fracture can be explained by an association between hip fractures and seasonal influenza outbreaks. METHODS: This retrospective cohort study included all patients admitted to Soroka University Medical Center with a diagnosis of osteoporotic hip fracture (ICD-9 code 820) between the years 2001 and 2013. Patients with malignancies, trauma, and age under 50 were excluded. In a time series analysis, we examined the association between hip fracture incidence and seasonality adjusted for meteorological factors, and population rates of influenza infection and vaccination using Poisson models. RESULTS: Four thousand three hundred forty-four patients with a hip fracture were included (69% females, mean age 78). Daily fracture rates were significantly higher in winter (1.1 fractures/day) compared to summer, fall, and spring (0.79, 0.90, and 0.91; p < 0.001). In analysis adjusted for seasons and spline function of time, temperatures were associated with hip fractures risk only in those not vaccinated for influenza (n = 2939, for every decrease of 5 °C, RR 1.08, CI 1.02-1.16; p < 0.05). In subgroup analysis during the years with weekly data on national influenza rates (2010-2013), the risk for hip fracture, adjusted for seasons and temperature, was 1.26 2 weeks following a week with high infection burden (CI 1.05;1.51 p = 0.01), while the temperature was not significantly associated with the fracture risk. CONCLUSIONS: Under dry and warm desert climate, winter hip fracture incidence increase might be associated with influenza infection, and this effect can be negated by influenza vaccination.

Maternal First Trimester TSH Concentrations: Do They Affect Perinatal and Endocrine Outcomes?

We aimed to examine the distribution of 1(st) trimester TSH and evaluate its association with perinatal outcomes and future development of maternal thyrotoxicosis. This retrospective cohort study included data of all women without prior thyroid disease who delivered a singleton at our medical center from 1/2001 to 12/2011 and had a 1(st) trimester TSH<4.0 mU/l. Women were divided according to 1(st) trimester TSH concentrations into quartiles and by predefined TSH values (mU/l): 1) TSH<0.1; 2) TSH 0.11-0.2; 3) TSH 0.21-0.4; and 4) TSH 0.4-4. Obstetrical outcomes, hCG concentrations, and future thyroid status were collected from electronic medical records. A total of 13 841 women fulfilled the inclusion criteria. Mean maternal TSH concentration at 5 weeks of gestation was 2.09±0.83 mU/l and decreased to 1.29±0.87 mU/l in weeks 8-9 with an increase towards the end of the 1(st) trimester. Odds ratio for future thyrotoxicosis was 3.64 in the lowest compared to the highest TSH quartile and 10.03 in those with TSH<0.1 compared to TSH 0.41-4 mU/l. Rates of female fetuses were higher in the low TSH quartiles and in the lower TSH groups, however baby gender was not associated with increased risk of future thyrotoxicosis. Low maternal 1(st) trimester TSH quartiles or concentrations were not associated with adverse pregnancy outcome. Only a minor fraction of pregnant women with a low first tirmester TSH subsequently developed future thyrotoxicosis.

Androgen Receptor CAG Repeat Length in Relation to Phenotype Among Females with Nonclassical 21-Hydroxylase Deficiency.

Nonclassical 21-hydroxylase deficiency (NC21OHD) manifests with various degrees of post natal virilization. The length of CAG repeats of the androgen receptor gene (AR) is inversely correlated to activity of the human androgen receptor (AR) and affects phenotype of several androgen-dependent disorders. The aim of the study was to investigate the associations between CAG repeat length and the phenotype of females with NC21OHD. CAG repeat length and AR inactivation were assessed in females with NC21OHD, and related to their clinical presentation. CAG repeat length and AR inactivation were assessed in 119 females with NC21OHD. Biallelic mean (BAM) of the CAG repeat length and the weighted BAM (WBAM) were related to various clinical parameters. Age at diagnosis and age of menarche positively correlated with BAM (r=0.22, p=0.02, and r=0.23, p=0.01, respectively). A shorter (<25) BAM was associated with younger age at diagnosis (14.8 vs. 21.4 years, p<0.01), at adrenarche (8.1 vs. 10.2 years, p<0.01) and gonadarche (9.9 vs. 11.2 years, p<0.01), and higher corrected height standard deviation score at diagnosis (0.77 vs. 0.15, p=0.01). Precocious pubarche and precocious puberty were more frequent in these with the shorter BAM. Results of WBAM were similar. The CAG repeat length of the AR gene contributes to the clinical diversity of the phenotype in females with NC21OHD.

Calibration of image plate and back illuminated charge coupled device detectors at the thermal emission band of high Z target laser produced plasmas (80-800 eV).

We present a systematic method to absolutely calibrate detector efficiency vs photon energy using a laser produced plasma broadband x-ray source, a gold standard calibrated detector, and transmission gratings (TGs) as dispersive elements. Calibration uses one calibrated TG and a calibrated gold standard detector on one channel and a second calibrated TG and a detector to be calibrated on the other channel. Both channels simultaneously view the laser-produced plasma x-ray source from the same angle with respect to the laser beam and the planar target normal. Image plate detectors are calibrated for the first time at photon energies below 700 eV. Single shot simultaneous calibration of several detectors is possible, making this method an efficient and practical way to periodically calibrate detectors, using in-house capabilities of laser laboratories.

Laser produced soft x-ray source diagnostics with temporal, spectral, and spatial resolution.

We demonstrate the use of three diagnostic tools which simultaneously view the target from nearly the same direction, and their results are combined to provide temporally, spectrally, and spatially resolved absolutely calibrated target emission information. To demonstrate this capability, Au targets were irradiated by 1.8 kJ, 3 ns laser pulses to produce broadband soft x-ray emission in the 0.1-3.5 keV spectral range. Target diagnostics included a time-resolved x-ray diode array, each measured a partial spectral band, time-integrated spectrally resolved absolutely calibrated transmission grating spectrometer, and static and time-resolved soft x-ray imagers coupled to a charge-coupled device camera and to a streak camera, respectively, measuring spatially and temporally resolved radiation at the main Au target emission bands. The combined temporally, spectrally, and spatially resolved absolutely calibrated target emission result can be compared to simulations and be used to design and analyze experiments in which the source emission is used as a drive for various physical processes.

Measurement of L-shell emission from mid-Z targets under non-LTE conditions using Transmission Grating Spectrometer and DANTE power diagnostics.

In this work, we present the measurement of L-band emission from buried Sc/V targets in experiments performed at the OMEGA laser facility. The goal of these experiments was to study non-local thermodynamic equilibrium plasmas and benchmark atomic physics codes. The L-band emission was measured simultaneously by the time resolved DANTE power diagnostic and the recently fielded time integrated Soreq-Transmission Grating Spectrometer (TGS) diagnostic. The TGS measurement was used to support the spectral reconstruction process needed for the unfolding of the DANTE data. The Soreq-TGS diagnostic allows for broadband spectral measurement in the 120 eV-2000 eV spectral band, covering L- and M-shell emission of mid- and high-Z elements, with spectral resolution λ/Δλ = 8-30 and accuracy better than 25%. The Soreq-TGS diagnostic is compatible with ten-inch-manipulator platforms and can be used for a wide variety of high energy density physics, laboratory astrophysics, and inertial confinement fusion experiments.

Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001).

Phaeochromocytoma and paraganglioma are rare neuroendocrine tumours (NETS). They may be benign or malignant but the pathological distinction is mainly made when metastases are present. Available treatments in the form of surgery, chemotherapy, and radionuclide therapy may improve symptoms and biochemical markers, but the results for the control of tumour bulk are less favourable. Furthermore, responses to treatment are frequently short-lived. This short review outlines the main molecular and histological features of malignant phaeochromocytoma and the difficulties in differentiating between benign and malignant disease. We list current therapies used for malignant pheochromocytoma; however, these generally achieve relatively low success rates. Hence, there is a need for new and more effective therapies. In vitro studies have implicated the PI3/Akt/mTOR pathway in the pathogenesis of malignant NETS, including phaeochromocytoma. Everolimus (RAD001, Novartis UK) is a compound that inhibits mTOR (mammalian Target Of Rapamycin) signalling. We have used RAD001 in four patients with progressive malignant paraganglioma/phaeochromocytoma in addition to other therapies (with institutional approval for compassionate use), and evaluated the effects of this treatment. We outline these four cases and review the theoretical background for this therapy, although the outcomes were relatively disappointing.

Hypothesis: Persistently normal TSH levels may be used to recognize patients with transient forms of hypothyroidism and to suggest treatment withdrawal.

There are no text-book recommendations on when or if treatment should or could be stopped in patients with a diagnosis of hypothyroidism, and these patients usually receive lifelong thyroxine therapy (despite the fact that some of them may have forms of transient hypothyroidism that will later recover function). Since TSH fluctuations during thyroxine treatment are common and a lack of this fluctuation might be used to identify patients who no longer need thyroxine treatment, we hypothesize that by offering patients with persistently controlled TSH levels a withdrawal trial of thyroxine treatment we may identify those who no longer need life-long treatment.

Fish oil for kidney transplant recipients.

BACKGROUND: Calcineurin inhibitors used in kidney transplantation for immunosuppression have adverse effects that may contribute to nephrotoxicity and increased cardiovascular risk profile. Fish oils are rich in very long chain omega-3 fatty acids, which may reduce nephrotoxicity by improving endothelial function and reduce rejection rates through their immuno-modulatory effects. They may also modify the cardiovascular risk profile. Hence, fish oils may potentially prolong graft survival and reduce cardiovascular mortality. OBJECTIVES: To assess the benefits and harms of fish oil supplementation on kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library, issue 2 2005), MEDLINE (1966-April 2005) and EMBASE (1980-April 2005). SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs of fish oils in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. RCTs of fish oil versus statins were included. DATA COLLECTION AND ANALYSIS: Data was extracted and the quality of studies assessed by two authors, with differences resolved by discussion with a third independent author. Dichotomous outcomes were reported as relative risk (RR) and continuous outcome measures were reported as the mean difference (MD) with 95% confidence intervals using the random effects model. Heterogeneity was assessed using a Chi(2) test on n-1 degrees of freedom and the I(2) statistic. Data not suitable for pooling were tabulated and described. MAIN RESULTS: Sixteen studies (733 patients) were suitable for analysis. Fish oil did not significantly affect patient or graft survival, acute rejection rates, calcineurin inhibitor toxicity or renal function, when compared to placebo. Fish oil treatment was associated with a lower diastolic blood pressure (MD 4.5 mmHg; P = 0.004) compared to placebo. Patients receiving fish oil for more than six months had a modest increase in HDL (MD 0.12 mmol/L; P = 0.01) compared to placebo. Fish oil effects on lipids were not significantly different from low-dose statins. There was insufficient data to analyse cardiovascular outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant patient drop-out. AUTHORS' CONCLUSIONS: There is insufficient evidence from currently available RCTs to recommend fish oil therapy to improve renal function, rejection rates, patient survival or graft survival. The improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use. To determine a benefit in clinical outcomes, future RCTs will need to be adequately powered with these outcomes in mind.

Enhanced accuracy of x-ray spectra reconstruction from filtered diode array measurements by adding a time integrated spectrometer.

A new approach for the spectral reconstruction of time-dependent emission of soft x-ray sources based on the measurement of filtered x-ray diode array systems is suggested. Two reconstruction methods, based on this approach, are demonstrated using both simulated and measured data. The methods use the filtered x-ray diode measurement together with a co-aligned, time-integrated, spectrally resolved measurement, such as transmission grating spectroscopy. The additional experimental information allows for high accuracy spectral reconstruction, even for plasmas far from local thermodynamic equilibrium where the traditional reconstruction methods may miss some important source spectral features. For the demonstrated cases, the accuracy of the new reconstruction methods is better than 10% for the energy dependent flux and 1% of the total flux, which is higher than the accuracy of previous methods and better than the accuracy of the measurement itself.

Sex-steroid milieu determines diabetes rescue in pttg-null mice.

Male mice that are pttg-null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced postnatal-cell proliferation and an inability to expand islet cell mass with aging. We therefore examined the effects of sex-steroid manipulation on diabetes development in pttg-/- male mice. Surgical gonadectomy was followed by implantation of 90-day slow-release pellets releasing 17beta-estradiol (0.36 mg/pellet), placebo or dihydrotestosterone (DHT; 12.5 mg/pellet). Mean fasting blood sugars at the end of the study were 414 +/- 54 mg/dl for pttg-/- controls and 371 +/- 14 mg/dl for pttg-/- mice gonadectomized and treated with DHT compared with 124 +/- 40 and 85 +/- 12 mg/dl in gonadectomized pttg-/- males treated with placebo or estradiol, respectively (P < 0.01 compared with control pttg-/-). Gonadectomy with and without estradiol treatment did not increase the very low circulating insulin levels in pttg-null males (fasting insulin 0.44 +/- 0.04 ng/ml in pttg-/- controls, 0.47 +/- 0.07 and 0.4 ng/ml in pttg-/- gonadectomized males treated with placebo or estradiol, respectively). Gonadectomy increased serum adiponectin levels (4.9 +/- 008 microg/ml in pttg-/- controls versus 13 +/- 0.08 and 7.5 +/- 0.6 microg/ml in pttg-/- gonadectomized males treated with placebo or estradiol, respectively; P < 0.001 and P < 0.05), accompanied by increased insulin sensitivity. The results show that gonadectomy delayed, and gonadectomy with additional estradiol treatment prevented, diabetes development in pttg-/- males, possibly through increased insulin sensitivity mediated by elevated serum adiponectin levels. Male-selective effects of disrupted beta-cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.

Measurements of laser generated soft X-ray emission from irradiated gold foils.

Soft x-ray emission from laser irradiated gold foils was measured at the Omega-60 laser system using the Dante photodiode array. The foils were heated with 2 kJ, 6 ns laser pulses and foil thicknesses were varied between 0.5, 1.0, and 2.0 µm. Initial Dante analysis indicates peak emission temperatures of roughly 100 eV and 80 eV for the 0.5 µm and 1.0 µm thick foils, respectively, with little measurable emission from the 2.0 µm foils.

Interband and intraband (Drude) contributions to femtosecond laser absorption in aluminum.

Theoretical and experimental investigations of the absorption in metallic aluminum of femtosecond-laser radiation pulses with peak intensity I0 less similar 10(15) W/cm(2) are reported. Energy balance equations are solved for electron and phonon subsystems, together with Helmholtz equation for the laser radiation. Expressions for the relaxation times as functions of electron and phonon temperatures are obtained, with no free parameters. Contrary to the assumption made in published studies, we find that the interband rather than the intraband (Drude) absorption plays the dominant role in the near infrared and throughout the visible region at low and moderate intensities. For 50 fs, 800 nm laser pulses the absorption in interband transitions dominates for intensities up to few times 10(13) W/cm(2). For such pulses, broadening of the parallel-band interband absorption line with the increase in electron and phonon temperatures results, for I0 < or =5 x 10(13) W/cm(2), in the decrease of the absorption coefficient compared to the room-temperature value. In this paper, we present both the first theoretical prediction and the first experimental observation of this phenomenon. Dielectric permittivity gradients within the skin layer also contribute to the decrease in absorption. The mechanisms of the lattice disordering are considered quantitatively, and it is shown that for I0 < 10(14) W/cm(2) melting does not occur in the laser-pulse duration. Experimental results are presented for 800 and 400 nm wavelengths. The agreement between the theory and the experiment is very good.

Effect of four treatment variants on the functional and cosmetic state of mature scars.

A randomised, intra-individual, comparative study demonstrated that both qualitative improvements and significant changes in skin functional condition can be achieved in the tissue of older, mature scars. Four treatment modalities were studied in an intra-individual comparison involving 12 volunteers with 2.5 to 4-year-old scars. The treatments were: a self-adherent, hydroactive, polyurethane dressing alone; polyurethane plus compression; silicone sheeting plus compression; and compression alone. Evaluation criteria were changes in the microcirculation, roughness and the skin temperature of the scar tissue. All treatment modalities were found to have significant effects both on tissue function and scar tissue surface structure. The most pronounced effects were achieved with the combination of polyurethane dressing plus compression or silicone sheeting plus compression. The positive effect of the polyurethane dressing alone on scar tissue was even slightly superior to that of compression therapy alone.

Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature.

Based on the current medical literature, the worldwide incidence of neuroendocrine tumours (NETs) seems to have increased; however, a systematic literature overview is lacking. This study aimed to collect all available data on the incidence of gastroenteropancreatic (GEP)-NETs and characteristics of population to establish their epidemiology. A sensitive MEDLINE search was carried out. The papers were selected via a cascade process that restricted the initial pool of 7991 articles to 33, using predefined inclusion and exclusion criteria. Original articles evaluating the incidence of sporadic GEP-NETs in regional, institutional and national registries were considered. The majority of data originated from the US National Cancer Institute Surveillance, Epidemiology and End Results database and from national cancer registries in Western Europe. Generally, because of the retrospective nature of existing databases the outcomes of studies might be biased, which hinders the drawing of firm conclusions. The age-adjusted incidence of GEP-NETs has increased steadily over the past four decades (1973-2007), increasing 3.65-fold in the USA and 3.8- to 4.8-fold in the UK. Incidence has changed variably from one anatomical site to another. The greatest increase in incidence occurred for gastric and rectal NETs, while the smallest increase occurred for small intestine NETs. There were gender and racial differences, which differed site by site and, in some cases, changed over time. The incidence rates (IRs) of GEP-NETs have increased significantly in the last 40 years. Data are only available from North America, Western Europe and Japan. A site-by-site analysis revealed that the IRs of some NETs increased more than those of others.

Everolimus therapy for progressive adrenocortical cancer.

Patients with advanced adrenocortical carcinoma (ACC) have limited treatment options after failure of chemotherapy. Tumor IGF2 expression has been shown to be amplified in the majority of cases of ACC and autocrine/paracrine activation of the IGF receptor (IGF-R) is thought to play a major role in the pathogenesis of ACC. It has been shown in vitro that inhibition of the IGF-R inhibits ACC cell proliferation. mTOR is a downstream effector of the IGFR signaling pathway; therefore, the rapamycin analog everolimus could prove to be useful for treatment of patients with ACC. Four women with ACC (ages 25-60 years) developed stage IV disease after surgery. All had progressive disease (PD) despite treatment with mitotane and other treatment modalities (etoposide, doxorubicin, cis-platinum in 3/4 patients, further streptozotocin + 5-FU in 1/4 patients, further thalidomide therapy in 2/4 patients; 1 patient progressed on an IGF-R antagonist). The patients were started on everolimus 10 mg/day orally and 2/4 patients also continued mitotane. Disease progression was monitored monthly by CT in 3/4 and after 3 months in 1/4. In all patients everolimus was well tolerated. In the three patients monitored monthly, PD was evident after 1, 3, and 4 months; in the patient evaluated after 3 months PD was also evident. In this small exploratory study, no clinically meaningful response was observed with everolimus in four patients with advanced ACC. The failure of efficacy could be related to an interaction with mitotane, multiple signaling pathways, and/or other downstream IGF-R effectors operative in the pathogenesis of ACC.

Epidemiology of gastroenteropancreatic neuroendocrine tumours.

Gastroenteropancreatic neuroendocrine tumours are a heterogeneous group of tumours arising from diffuse endocrine cells, causing unique clinical syndromes. These tumours, formerly named carcinoid, can involve any part of the gastrointestinal tract and the endocrine pancreas and have a wide range of malignant potential: from benign to poorly differentiated tumours. In this review we will summarize the data available on the epidemiology of gastroenteropancreatic tumours as it is reported from around the world. This includes annual incidence rates at the various anatomic sites, and trends in incidence rates with time. In addition age and stage at presentation, gender and racial differences and finally prognosis and survival were collected when reported.