Assessment and referral of patients with short stature by primary care physicians in the Arabian gulf region: Current perspectives from a regional survey.

Children with short stature are frequently referred late to pediatric endocrinologists in the Arabian Gulf region. This is likely a contributing factor to late initiation of treatment despite current evidence suggesting that children with short stature have better outcomes with earlier treatment. This delay in referral could be due to a lack of identification or proper assessment of short stature by front-line physicians. To analyze the assessment and perception of short stature in this group of physicians, an expert group of pediatric endocrinologists developed and disseminated an anonymous online survey of 22 multiple choice questions amongst general pediatricians, pediatric subspecialists, and family medicine physicians in the Arabian Gulf region. Of the 640 respondents, 450 completed the survey (70.3% completion rate). While most surveyed physicians use the correct definition for short stature in children, only 24% reported a consistent use of a wall-mounted stadiometer. Of the respondents, 50% or less would consider referring clinical conditions other than growth hormone (GH) deficiency or idiopathic short stature, 41% would refer a child with short stature as soon as height dropped below the 5th percentile, 57% considered GH a treatment option for short stature, and only 60% consider GH treatment safe. The results of this survey demonstrate knowledge gaps in short stature assessment and referral that need to be addressed through education on short stature amongst target physicians, and lay groundwork for future recommendations to address those gaps in the Arabian Gulf region.

A perspective on global access to insulin: a descriptive study of the market, trade flows and prices.

AIM: To describe the global insulin market. METHODS: Market intelligence data, United Nations Commodity Trade Statistics for insulin trade, the International Medical Products Price Guide for prices of human insulin and additional web searches were used as data sources. These sources were combined to gain further insight into possible links among market, trade flows and prices. Descriptive statistics and Spearman's rank order correlation were used for the analysis. RESULTS: A total of 34 insulin manufacturers were identified. Most countries and territories are reliant on a limited number of supplying countries. The overall median (interquartile range) government procurement price for a 10-ml, 100-IU/ml vial during the period 1996-2013 equivalent was US$4.3 (US$ 3.8-4.8), with median prices in Africa (US$ 4.7) and low- (US$ 6.9) and low- to middle- (US$ 4.7) income countries being higher over this period. The relationships between price and quantity of insulin (Spearman's r=0.046; P>0.1) and number of import links (Spearman's r=0.032; P>0.1) were weak. The links between price and percentage of total insulin from a country where a 'big three' manufacturer produces insulin (Spearman's r=0.294; P<0.05) and total insulin from the main import link (Spearman's r=-0.392; P<0.05) were stronger. CONCLUSIONS: This research shows the high variability of insulin prices and the reliance on a few sources, both companies and countries, for global supply. In addressing access to insulin, countries need to use existing price data to negotiate prices, and mechanisms need to be developed to foster competition and security of supply of insulin, given the limited number of truly global producers.

Optical control of capacitance in a metal-insulator-semiconductor diode with embedded metal nanoparticles.

This paper describes a metal-insulator-semiconductor (MIS) capacitor with flat capacitance voltage characteristics and a small quadratic voltage capacitance coefficient. The device characteristics resemble a metal-insulator-metal diode except that here the capacitance depends on illumination and exhibits a strong frequency dispersion. The device incorporates Fe nanoparticles (NPs), mixed with SrF2, which are embedded in an insulator stack of SiO2 and HfO2. Positively charged Fe ions induce dipole type traps with an electronic polarization that is enhanced by photogenerated carriers injected from the substrate and/or by inter nanoparticle exchange of carriers. The obtained characteristics are compared with those of five other MIS structures: two based on Fe NPs, one with and the other without SrF2 sublayers. Additionally, devices contain Co NPs embedded in SrF2 sublayers, and finally, two structures have no NPs, with one based on a stack of SiO2 and HfO2 and the other which also includes SrF2. Only structures containing Fe NPs, which are incorporated into SrF2, yield a voltage independent capacitance, the level of which can be changed by illumination. These properties are essential in radio frequency/analog mixed signal applications.

Correlation between pre-ramadan glycemic control and subsequent glucose fluctuation during fasting in adolescents with Type 1 diabetes.

BACKGROUND: Even though patients with type 1 diabetes mellitus (T1DM) are exempted from fasting, the vast majority elect to fast against the advice of their healthcare providers. We have previously reported the incidence of wide fluctuations in blood glucose (BG) along with "unrecognized" severe hypoglycemia during Ramadan fasting in adolescents with T1DM. This report compares the continuous glucose monitoring (CGM) data during fasting in adolescents with T1DM according to their Pre-Ramadan diabetes control. METHODS: Children and adolescents with T1DM who intended to fast the month of Ramadan were asked to wear the CGM during fasting for a minimum of 3 days. Hypoglycemia, hyperglycemia, and severe hyperglycemia were identified as BG <70 mg/dL (3.9 mmol/L), BG 201-300 mg/dL (11.2-16.7 mmol/L), or BG >300 mg/dL (16.7 mmol/L) respectively, while normoglycemia was identified as BG 70-200 mg/dL (3.9-11.1 mmol/L). Patients were categorized as well-controlled (Group 1) and poorly controlled (Group 2) if the pre-fasting HbA1C was ≤8% (64 mmol/mol) and >8%, respectively. We compared the mean BG and the percentages of time spent in hypoglycemia, hyperglycemia, and severe hyperglycemia between the two groups using Chi-square (significant difference when P value was <0.05). RESULTS: A total of 21 patients were enrolled (15 females), age 15 ± 4 years, duration of diabetes 6 ± 3 years, and HbA1C 8.5 ± 1.0% (70 mmol/mol). There were 7 subjects in Group 1, mean HbA1C 7.5 ± 0.4, and 14 subjects in Group 2, mean HbA1C 9.1 ± 0.9. The mean ± SD BG was 174 ± 76 mg/dL versus 199 ± 98, (P < 0.05) in Group 1 and Group 2, respectively. The percentages of hypoglycemia, hyperglycemia, and severe hyperglycemia were significantly higher in Group 2, while there was a higher percentage of normoglycemia in Group 1. The overall durations of hypoglycemia, hyperglycemia, and severe hyperglycemia in Group 2 were longer by 30, 14, and 135%, respectively, than those in Group 1. CONCLUSIONS: Glycemic control before Ramadan in adolescents with T1 DM appears to correlate with blood glucose profile during Ramadan fasting. Our data suggest that optimal glycemic control before Ramadan may reduce the potential risks associated with fasting and minimize glucose fluctuation.

Prices and availability of locally produced and imported medicines in Ethiopia and Tanzania.

BACKGROUND: To assess the effect of policies supporting local medicine production to improve access to medicines. METHODS: We adapted the WHO/HAI instruments measuring medicines availability and prices to differentiate local from imported products, then pilot tested in Ethiopia and Tanzania. In each outlet, prices were recorded for all products in stock for medicines on a country-specific list. Government procurement prices were also collected. Prices were compared to an international reference and expressed as median price ratios (MPR). RESULTS: The Ethiopian government paid more for local products (median MPR = 1.20) than for imports (median MPR = 0.84). Eight of nine medicines procured as both local and imported products were cheaper when imported. Availability was better for local products compared to imports, in the public (48% vs. 19%, respectively) and private (54% vs. 35%, respectively) sectors. Patient prices were lower for imports in the public sector (median MPR = 1.18[imported] vs. 1.44[local]) and higher in the private sector (median MPR = 5.42[imported] vs. 1.85[local]). In the public sector, patients paid 17% and 53% more than the government procurement price for local and imported products, respectively. The Tanzanian government paid less for local products (median MPR = 0.69) than imports (median MPR = 1.34). In the public sector, availability of local and imported products was 21% and 32% respectively, with patients paying slightly more for local products (median MPR = 1.35[imported] vs. 1.44[local]). In the private sector, local products were less available (21%) than imports (70%) but prices were similar (median MPR = 2.29[imported] vs. 2.27[local]). In the public sector, patients paid 135% and 65% more than the government procurement price for local and imported products, respectively. CONCLUSIONS: Our results show how local production can affect availability and prices, and how it can be influenced by preferential purchasing and mark-ups in the public sector. Governments need to evaluate the impact of local production policies, and adjust policies to protect patients from paying more for local products.

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer.

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.

The effect of Fe-coverage on the structure, morphology and magnetic properties of α-FeSi2 nanoislands.

Self-assembled α-FeSi(2) nanoislands were formed using solid-phase epitaxy of low (~1.2 ML) and high (~21 ML) Fe coverages onto vicinal Si(111) surfaces followed by thermal annealing. At a resulting low Fe-covered Si(111) surface, we observed in situ, by real-time scanning tunneling microscopy and surface electron diffraction, the entire sequence of Fe-silicide formation and transformation from the initially two-dimensional (2 × 2)-reconstructed layer at 300 °C into (2 × 2)-reconstructed nanoislands decorating the vicinal step-bunch edges in a self-ordered fashion at higher temperatures. In contrast, the silicide nanoislands at a high Fe-covered surface were noticeably larger, more three-dimensional, and randomly distributed all over the surface. Ex situ x-ray photoelectron spectroscopy and high-resolution transmission electron microscopy indicated the formation of an α-FeSi(2) island phase, in an α-FeSi(2){112} // Si{111} orientation. Superconducting quantum interference device magnetometry showed considerable superparamagnetism, with ~1.9 µ(B)/Fe atom at 4 K for the low Fe-coverage, indicating stronger ferromagnetic coupling of individual magnetic moments, as compared to high Fe-coverage, where the calculated moments were only ~0.8 µ(B)/Fe atom. Such anomalous magnetic behavior, particularly for the low Fe-coverage case, is radically different from the non-magnetic bulk α-FeSi(2) phase, and may open new pathways to high-density magnetic memory storage devices.

Shape-controlled nanopores in single crystals.

Nanometer length-scale holes (nanopores) are often formed in amorphous materials for fundamental studies of molecular mass transport. In the current study, electron beam irradiation in the transmission electron microscope was used to form nanopores in a crystalline material (Si). Analysis of the nanopores showed that they are formed by knock-on of atoms by the high energy incident electron beam, and surface diffusion is partially responsible for the hour-glass shapes that are found for some nanopores. Energetically favorable three-dimensional shapes of nanopores were simulated, and the nanopores simulated in the model crystalline material were found to be more stable than the nanopores simulated in the amorphous material. The nanopore shape was also found to depend on the nanopore diameter-to-length ratio. Based on the above, we demonstrate the advantage in using a crystalline material for nanopore formation and show that control of the three-dimensional shape of nanopores formed by electron beam irradiation is possible.

The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5.

Prolactin and progesterone act together to regulate mammary alveolar development, and both hormones have been implicated in breast cancer initiation and progression. Here we show that Elf5, a prolactin-induced ETS transcription factor that specifies the mammary secretory cell lineage, is also induced by progestins in breast cancer cells via a direct mechanism. To define the transcriptional response to progestin elicited via Elf5, we made an inducible Elf5 short hairpin-RNA knock-down model in T47D breast cancer cells and used it to prevent the progestin-induction of Elf5. Functional analysis of Affymetrix gene expression data using Gene Ontologies and Gene Set Enrichment Analysis showed enhancement of the progestin effects on cell cycle gene expression. Cell proliferation assays showed a more efficacious progestin-induced growth arrest when Elf5 was kept at baseline levels. These results showed that progestin induction of Elf5 expression tempered the antiproliferative effects of progestins in T47D cells, providing a further mechanistic link between prolactin and progestin in the regulation of mammary cell phenotype.

An experimental method for calibration of the plasmon mean free path.

Transmission electron microscopy specimens in the form of elongated, conical needles were made using a dual-beam focused ion beam system, allowing the specimen thickness to be geometrically determined for a range of thickness values. From the same samples electron energy loss maps were acquired and the plasmon mean free path (lambda) for inelastic scattering was determined experimentally from the measured values of specimen thickness. To test the method lambda was determined for Ni (174 +/- 17 nm), alpha-Al(2)O(3) (143 +/- 14 nm), Si (199 +/- 20 nm) and amorphous SiO(2) (238 +/- 12 nm), and compared both to experimental values of lambda taken from the literature and to calculated values. The calculated values of lambda significantly underestimate the true sample thickness for high accelerating voltages (300 kV) and large collection angles. A linear dependence of lambda on thickness was confirmed for t/lambda < 0.5-0.6, but this method also provides an approach for calibrating lambda at sample thicknesses for which multiple scattering occurs, thus expanding the thickness range over which electron energy loss spectroscopy can be used to determine the absolute sample thickness (t/lambda > 0.6). The experimental method proposed in this contribution offers a means to calibrate lambda for any type of material or phase that can be milled using a focused ion beam system.

Quantitative HRTEM analysis of FIB prepared specimens.

The preparation of good transmission electron microscopy specimens with minimum milling damage can be very complicated, especially from a specific area in a sample. Therefore, a novel approach for transmission electron microscopy specimen preparation using a focused ion beam system is proposed, based on the use of low energy (5 kV)Ga ions and a low incident ion angle (approximately 1 degree ) from a thickness of approximately 500 nm until the sample is electron transparent. Transmission electron microscopy specimens prepared by this method have significantly less irradiation damage, demonstrated by successful quantitative high-resolution transmission electron microscopy conducted on sapphire from data acquired using an aberration-corrected field emission gun transmission electron microscopy. Quantitative analysis was conducted by iterative digital image matching. The accuracy and sensitivity of the matching process is discussed.

Ordered liquid aluminum at the interface with sapphire.

Understanding the nature of solid-liquid interfaces is important for many processes of technological interest, such as solidification, liquid-phase epitaxial growth, wetting, liquid-phase joining, crystal growth, and lubrication. Recent studies have reported on indirect evidence of density fluctuations at solid-liquid interfaces on the basis of x-ray scattering methods that have been complemented by atomistic simulations. We provide evidence for ordering of liquid atoms adjacent to an interface with a crystal, based on real-time high-temperature observations of alumina-aluminum solid-liquid interfaces at the atomic-length scale. In addition, crystal growth of alumina into liquid aluminum, facilitated by interfacial transport of oxygen from the microscope column, was observed in situ with the use of high-resolution transmission electron microscopy.

Ureterocystoplasty: indications for a successful augmentation.

PURPOSE: We evaluate the outcome of ureterocystoplasty based on preoperative evaluations. MATERIALS AND METHODS: We reviewed preoperative ultrasound, voiding cystourethrography and preoperative/postoperative urodynamic studies (UDS) in 64 patients undergoing ureterocystoplasty. RESULTS: Augmentation was performed with the distal 5 to 8 cm of a single megaureter in 8 patients without and 16 with grade 4 to 5/5 reflux. Median gain or loss in capacity and compliance was +0.14-fold and -0.11-fold, respectively. Re-augmentation has occurred or is pending in 23 cases (92%). Augmentation was performed in 40 patients with either a complete single or double collecting system. In 9 patients without reflux the diameter of the augmenting system was directly related to success. None of 6 with a ureteral diameter of greater than 1.5 cm required re-augmentation (median increase in bladder capacity and compliance 6 and 50-fold, respectively). Ureterocystoplasty was inadequate in 3 patients with a ureteral diameter of less than 1.5 cm and re-augmentation was required. In 31 patients with reflux, preoperative UDS of the entire system was beneficial. If the system had either normal or mild noncompliance (greater than 20 ml/cm H2O) ureterocystoplasty improved compliance 1-fold (6 cases) and re-augmentation not required. If UDS showed moderately or severely noncompliant system (less than 20 ml/cm H2O, 26 cases) ureterocystoplasty increased capacity and compliance by 0.4-fold (40%) and 0.25-fold (25%), respectively. Re-augmentation has occurred or is pending in 21 of 26 cases (81%). CONCLUSIONS: Ureterocystoplasty with any single or double collecting system is warranted in patients without reflux and a ureteral width greater than 1.5 cm, and in patients with reflux and mild noncompliance (greater than 20 ml/cm H2O) on UDS.

Prognostic significance of the number of bone scan abnormalities at the time of initial bone metastatic recurrence in breast carcinoma.

BACKGROUND: To gain insight into the factors that contribute to the more favorable prognosis associated with recurrence limited to bone in patients with breast carcinoma, the authors analyzed the number of sites of initial involvement identified on radionuclide bone scans in relation to long term outcome. METHODS: Records of 641 patients with clinical Stage I-III breast carcinoma that originally was diagnosed in 1974-1985 were reviewed. During follow-up, 295 patients (46%) experienced distant recurrence, including 116 with bone as the sole initial site of metastatic disease. Radionuclide bone scans identified the initial site(s) of recurrence in 113 of these latter 116 patients, and these studies were categorized by the number of skeletal lesions subsequently confirmed as metastases (1, 2, or > or = 3). Survival from time of recurrence and time of original diagnosis was analyzed using Kaplan-Meier methods, and factors associated with recurrence and mortality were examined using logistic and Cox regression. RESULTS: Median survival from time of recurrence was 35 months in the patients with bone-only metastases, compared with 11-26 months for all other sites of visceral recurrence exclusive of bone. Number of positive lymph nodes and estrogen receptor status were the only predictive variables for recurrence. Median survival from time of recurrence and time of original diagnosis for the 3 bone scan categories was: 1 lesion (n = 47), 53 and 86 months; 2 lesions (n = 22), 38 and 68 months; and > or = 3 lesions (n = 44), 22 and 58 months (P < 0.0001 and P < 0.005 for 1 and 2 lesions vs. > or = 3). In the "bone-only" group, the number of scan lesions was the strongest predictor of length of survival. CONCLUSIONS: Patients with breast carcinoma who experience a recurrence in bone at only one or two sites initially have a survival advantage over those with more extensive (> or = 3 sites) skeletal metastases and those with metastatic disease involving other visceral organs.

Injectable small intestinal submucosa: preliminary evaluation for use in endoscopic urological surgery.

PURPOSE: We evaluated the possible use of small intestinal submucosa in endoscopic urological surgery by assessing the smooth muscle regenerative capabilities and physical response of various forms of injectable small intestinal submucosa in the canine model. MATERIALS AND METHODS: In blinded fashion we injected small intestinal submucosa in 12 dogs submucosally under direct vision using a 20 gauge endoscopic needle. The 4 small intestinal submucosa formulations varied in harvesting method and sterilization technique. Animals were divided into groups of 3 and sacrificed 2 weeks, 6 weeks, 3 months and 6 months after surgery. Each injection site was analyzed grossly and histologically. Smooth muscle regeneration was identified by alpha-smooth muscle actin immunohistochemical staining. RESULTS: We identified 2 injectable small intestinal submucosa formulations that induced progressive smooth muscle regeneration at the site of submucosal injection compared with controls. De novo smooth muscle cells appeared in single cell aggregates as early as 6 weeks and in globular aggregates at 3 months. By 6 months early muscle bundle formation was noted. These 2 injectable small intestinal submucosa formulations also had the best submucosal volume preservation of about 25% of injected material during the study period. CONCLUSIONS: Injectable small intestinal submucosa promotes progressive submucosal smooth muscle regeneration in the canine bladder. The combined regenerative and bulking abilities of injectable small intestinal submucosa make this compound unique and novel. The clinical usefulness of injectable small intestinal submucosa for endoscopic correction of reflux and incontinence deserves further investigation.

Equilibrium folding of dimeric class mu glutathione transferases involves a stable monomeric intermediate.

The conformational stabilities of two homodimeric class mu glutathione transferases (GSTM1-1 and GSTM2-2) were studied by urea- and guanidinium chloride-induced denaturation. Unfolding is reversible and structural changes were followed with far-ultraviolet circular dichroism, tryptophan fluorescence, enzyme activity, chemical cross-linking, and size-exclusion chromatography. Disruption of secondary structure occurs as a monophasic transition and is independent of protein concentration. Changes in tertiary structure occur as two transitions; the first is protein concentration dependent, while the second is weakly dependent (GSTM1-1) or independent (GSTM2-2). The second transition corresponds with the secondary structure transition. Loss in catalytic activity occurs as two transitions for GSTM1-1 and as one transition for GSTM2-2. These transitions are dependent upon protein concentration. The first deactivation transition coincides with the first tertiary structure transition. Dimer dissociation occurs prior to disruption of secondary structure. The data suggest that the equilibrium unfolding/refolding of the class mu glutathione transferases M1-1 and M2-2 proceed via a three-state process: N(2) <--> 2I <--> 2U. Although GSTM1-1 and GSTM2-2 are homologous (78% identity/94% homology), their N(2) tertiary structures are not identical. Dissociation of the GSTM1-1 dimer to structured monomers (I) occurs at lower denaturant concentrations than for GSTM2-2. The monomeric intermediate for GSTM1-1 is, however, more stable than the intermediate for GSTM2-2. The intermediates are catalytically inactive and display nativelike secondary structure. Guanidinium chloride-induced denaturation yields monomeric intermediates, which have a more loosely packed tertiary structure displaying enhanced solvent exposure of its tryptophans and enhanced ANS binding. The three-state model for the class mu enzymes is in contrast to the equilibrium two-state models previously proposed for representatives of classes alpha/pi/Sj26 GSTs. Class mu subunits appear to be intrinsically more stable than those of the other GST classes.

Erectile dysfunction in patients with spina bifida is a treatable condition.

PURPOSE: Now that individuals with spina bifida live well into adulthood erectile dysfunction has become a recognized associated medical disorder. To our knowledge no study has dealt specifically with treatment of erectile dysfunction in men with spina bifida. Therefore, we conducted a prospective, blinded, randomized, placebo controlled, dose escalation, crossover study to determine the ability to treat erectile dysfunction in men with spina bifida with sildenafil citrate. MATERIALS AND METHODS: Erectile dysfunction was diagnosed in 15 men 19 to 35 years old with spina bifida who were assigned to take 4 sets of tablets, 5 tablets per set, in a random order. All patients took 25 and 50 mg. sildenafil and 2 identical looking sets of corresponding placebos 1 hour before planned sexual activity. Efficacy was assessed by the effect of treatment compared to baseline, that is before treatment, on rating of erections (scored from 0 to 10), duration of erections, frequency of erections based on response to question 1 (scored from 0 to 5) of the International Index of Erectile Function and confidence to obtain an erection based on response to question 15 (scored from 1 to 5) of the International Index of Erectile Function. RESULTS: Improved erectile function was reported while on sildenafil by 12 (80%) men compared to baseline and placebos. There was a significant dose dependent improvement of erectile function with both 25 and 50 mg. sildenafil compared to baseline (p <0.05), as mean erectile score increased by 50% and 88%, mean duration of erections increased by 192% and 266%, mean frequency of erections increased by 61% and 96%, and mean level of confidence increased by 33% and 63%, respectively. Furthermore, 50 mg. sildenafil provided greater improvement in all 4 parameters compared to 25 mg. The placebo results were not significantly different compared to baseline for any of the parameters. CONCLUSIONS: Erectile dysfunction in patients with spina bifida is a medically treatable condition. Sildenafil is effective in this patient population and improves level of sexual confidence.