Soil nematode abundance and functional group composition at a global scale.

Soil organisms are a crucial part of the terrestrial biosphere. Despite their importance for ecosystem functioning, few quantitative, spatially explicit models of the active belowground community currently exist. In particular, nematodes are the most abundant animals on Earth, filling all trophic levels in the soil food web. Here we use 6,759 georeferenced samples to generate a mechanistic understanding of the patterns of the global abundance of nematodes in the soil and the composition of their functional groups. The resulting maps show that 4.4 ± 0.64 × 1020 nematodes (with a total biomass of approximately 0.3 gigatonnes) inhabit surface soils across the world, with higher abundances in sub-Arctic regions (38% of total) than in temperate (24%) or tropical (21%) regions. Regional variations in these global trends also provide insights into local patterns of soil fertility and functioning. These high-resolution models provide the first steps towards representing soil ecological processes in global biogeochemical models and will enable the prediction of elemental cycling under current and future climate scenarios.

Percutaneous left stellate ganglion block for refractory ventricular tachycardia in structural heart disease: our single-centre experience.

INTRODUCTION: When electrical storm (ES) is amenable to neither antiarrhythmic drugs, nor deep sedation or catheter ablation, autonomic modulation may be considered. We report our experience with percutaneous left stellate ganglion block (PSGB) to temporarily suppress refractory ventricular arrhythmia (VA) in patients with structural heart disease. METHODS: A retrospective analysis was performed at our institution of patients with structural heart disease and an implantable cardioverter defibrillator (ICD) who had undergone PSGB for refractory VA between January 2018 and October 2021. The number of times antitachycardia pacing (ATP) was delivered and the number of ICD shocks/external cardioversions performed in the week before and after PSGB were evaluated. Charts were checked for potential complications. RESULTS: Twelve patients were identified who underwent a combined total of 15 PSGB and 5 surgical left cardiac sympathetic denervation procedures. Mean age was 73 ± 5.8 years and all patients were male. Nine of 12 (75%) had ischaemic cardiomyopathy, with the remainder having non-ischaemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 35% (±â€¯12.2%). Eight of 12 (66.7%) patients were already being treated with both amiodarone and beta-blockers. The reduction in ATP did not reach statistical significance (p = 0.066); however, ICD shocks (p = 0.028) and ATP/shocks combined were significantly reduced (p = 0.04). At our follow-up electrophysiology meetings PSGB was deemed ineffective in 4 of 12 patients (33%). Temporary anisocoria was seen in 2 of 12 (17%) patients, and temporary hypotension and hoarseness were reported in a single patient. DISCUSSION: In this limited series, PSGB showed promise as a method for temporarily stabilising refractory VA and ES in a cohort of male patients with structural heart disease. The side effects observed were mild and temporary.

Removal of redox-sensitive Rubisco Activase does not alter Rubisco regulation in soybean.

Rubisco activase (Rca) facilitates the catalytic repair of Rubisco, the CO2-fixing enzyme of photosynthesis, following periods of darkness, low to high light transitions or stress. Removal of the redox-regulated isoform of Rubisco activase, Rca-α, enhances photosynthetic induction in Arabidopsis and has been suggested as a strategy for the improvement of crops, which may experience frequent light transitions in the field; however, this has never been tested in a crop species. Therefore, we used RNAi to reduce the Rca-α content of soybean (Glycine max cv. Williams 82) below detectable levels and then characterized the growth, photosynthesis, and Rubisco activity of the resulting transgenics, in both growth chamber and field conditions. Under a 16 h sine wave photoperiod, the reduction of Rca-α contents had no impact on morphological characteristics, leaf expansion rate, or total biomass. Photosynthetic induction rates were unaltered in both chamber-grown and field-grown plants. Plants with reduced Rca-α content maintained the ability to regulate Rubisco activity in low light just as in control plants. This result suggests that in soybean, Rca-α is not as centrally involved in the regulation of Rca oligomer activity as it is in Arabidopsis. The isoform stoichiometry supports this conclusion, as Rca-α comprises only ~ 10% of the Rubisco activase content of soybean, compared to ~ 50% in Arabidopsis. This is likely to hold true in other species that contain a low ratio of Rca-α to Rca-ß isoforms.

Genetic causes of growth hormone insensitivity beyond GHR.

Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.

Perfusion Assessment in Left-Sided/Low Anterior Resection (PILLAR III): A Randomized, Controlled, Parallel, Multicenter Study Assessing Perfusion Outcomes With PINPOINT Near-Infrared Fluorescence Imaging in Low Anterior Resection.

BACKGROUND: Indocyanine green fluoroscopy has been shown to improve anastomotic leak rates in early phase trials. OBJECTIVE: We hypothesized that the use of fluoroscopy to ensure anastomotic perfusion may decrease anastomotic leak after low anterior resection. DESIGN: We performed a 1:1 randomized controlled parallel study. Recruitment of 450 to 1000 patients was planned over 2 years. SETTINGS: This was a multicenter trial. PATIENTS: Included patients were those undergoing resection defined as anastomosis within 10 cm of the anal verge. INTERVENTION: Patients underwent standard evaluation of tissue perfusion versus standard in conjunction with perfusion evaluation using indocyanine green fluoroscopy. MAIN OUTCOME MEASURES: Primary outcome was anastomotic leak, with secondary outcomes of perfusion assessment and the rate of postoperative abscess requiring intervention. RESULTS: This study was concluded early because of decreasing accrual rates. A total of 25 centers recruited 347 patients, of whom 178 were randomly assigned to perfusion and 169 to standard. The groups had comparable tumor-specific and patient-specific demographics. Neoadjuvant chemoradiation was performed in 63.5% of perfusion and 65.7% of standard (p > 0.05). Mean level of anastomosis was 5.2 ± 3.1 cm in perfusion compared with 5.2 ± 3.3 cm in standard (p > 0.05). Sufficient visualization of perfusion was reported in 95.4% of patients in the perfusion group. Postoperative abscess requiring surgical management was reported in 5.7% of perfusion and 4.2% of standard (p = 0.75). Anastomotic leak was reported in 9.0% of perfusion compared with 9.6% of standard (p = 0.37). On multivariate regression analysis, there was no difference in anastomotic leak rates between perfusion and standard (OR = 0.845 (95% CI, 0.375-1.905); p = 0.34). LIMITATIONS: The predetermined sample size to adequately reduce the risk of type II error was not achieved. CONCLUSIONS: Successful visualization of perfusion can be achieved with indocyanine green fluoroscopy. However, no difference in anastomotic leak rates was observed between patients who underwent perfusion assessment versus standard surgical technique. In experienced hands, the addition of routine indocyanine green fluoroscopy to standard practice adds no evident clinical benefit. See Video Abstract at http://links.lww.com/DCR/B560. VALORACIN DE LA IRRIGACIN DE LADO IZQUIERDO/RESECCIN ANTERIOR BAJA PILAR III UN ESTUDIO ALEATORIZADO, CONTROLADO, PARALELO Y MULTICNTRICO QUE EVALA LOS RESULTADOS DE LA IRRIGACIN CON PINPOINT IMGENES DE FLUORESCENCIA CERCANA AL INFRARROJO EN LA RESECCIN ANTERIOR BAJA: ANTECEDENTES:Se ha demostrado que la fluoroscopia con verde de indocianina mejora las tasas de fuga anastomótica en ensayos en fases iniciales.OBJETIVO:Nuestra hipótesis es que la utilización de fluoroscopia para asegurar la irrigación anastomótica puede disminuir la fuga anastomótica luego de una resección anterior baja.DISEÑO:Realizamos un estudio paralelo, controlado, aleatorizado 1:1. Se planificó el reclutamiento de 450-1000 pacientes durante 2 años.AMBITO:Multicéntrico.PACIENTES:Pacientes sometidos a resección definida como una anastomosis dentro de los 10cm del margen anal.INTERVENCIÓN:Pacientes que se sometieron a la evaluación estándar de la irrigación tisular contra la estándar en conjunto con la valoración de la irrigación mediante fluoroscopia con verde indocianina.PRINCIPALES VARIABLES EVALUADAS:El principal resultado fue la fuga anastomótica, y los resultados secundarios fueron la evaluación de la perfusión y la tasa de absceso posoperatorio que requirió intervención.RESULTADOS:Este estudio se cerró anticipadamente debido a la disminución de las tasas de acumulación. Un total de 25 centros reclutaron a 347 pacientes, de los cuales 178 fueron, de manera aleatoria, asignados a perfusión y 169 a estándar. Los grupos tenían datos demográficos específicos del tumor y del paciente similares. Recibieron quimio-radioterapia neoadyuvante el 63,5% de la perfusión y el 65,7% del estándar (p> 0,05). La anastomosis estuvo en un nivel promedio de 5,2 + 3,1 cm en perfusión en comparación con 5,2 + 3,3 cm en estándar (p> 0,05). Se reportó una visualización suficiente de la perfusión en el 95,4% de los pacientes del grupo de perfusión. El absceso posoperatorio que requirió tratamiento quirúrgico fue de 5,7% de los perfusion y en el 4,2% del estándar (p = 0,75). Se informó fuga anastomótica en el 9,0% de la perfusión en comparación con el 9,6% del estándar (p = 0,37). En el análisis de regresión multivariante, no hubo diferencias en las tasas de fuga anastomótica entre la perfusión y el estándar (OR 0,845; IC del 95% (0,375; 1,905); p = 0,34).LIMITACIONES:No se logró el tamaño de muestra predeterminado para reducir satisfactoriamente el riesgo de error tipo II.CONCLUSIÓN:Se puede obtener una visualización adecuada de la perfusión con ICG-F. Sin embargo, no se observaron diferencias en las tasas de fuga anastomótica entre los pacientes que se sometieron a evaluación de la perfusión versus la técnica quirúrgica estándar. En manos expertas, agregar ICG-F a la rutina de la práctica estándar no agrega ningún beneficio clínico evidente. Consulte Video Resumen en http://links.lww.com/DCR/B560. (Traducción-Dr Juan Antonio Villanueva-Herrero).

Global characterization of copy number variants in epilepsy patients from whole genome sequencing.

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. For both large and small variants, we found an enrichment of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive sequence-based profiling of CNVs could help explain a larger fraction of epilepsy cases.

Incidence, associated risk factors, and impact of conversion to laparotomy in elective minimally invasive sigmoidectomy for diverticular disease.

BACKGROUND: Benefits of minimally invasive surgical approaches to diverticular disease are limited by conversion to open surgery. A comprehensive analysis that includes risk factors for conversion may improve patient outcomes. METHODS: The US Premier Healthcare Database was used to identify patients undergoing primary elective sigmoidectomy for diverticular disease between 2013 and September 2015. Propensity-score matching was used to compare conversion rates for laparoscopic and robotic-assisted sigmoidectomy. Patient, clinical, hospital, and surgeon characteristics associated with conversion were analyzed using multivariable logistic regression, providing odds ratios for comparative risks. Clinical and economic impacts were assessed comparing surgical outcomes in minimally invasive converted, completed, and open cases. RESULTS: The study population included 13,240 sigmoidectomy patients (8076 laparoscopic, 1301 robotic-assisted, 3863 open). Analysis of propensity-score-matched patients showed higher conversion rates in laparoscopic (13.6%) versus robotic-assisted (8.3%) surgeries (p < 0.001). Greater risk of conversion was associated with patients who were Black compared with Caucasian, were Medicaid-insured versus Commercially insured, had a Charlson Comorbidity Index ≥ 2 versus 0, were obese, had concomitant colon resection, had peritoneal abscess or fistula, or had lysis of adhesions. Significantly lower risk of conversion was associated with robotic-assisted sigmoidectomy (versus laparoscopic, OR 0.58), hand-assisted surgery, higher surgeon volume, and surgeons who were colorectal specialties. Converted cases had longer operating room time, length of stay, and more postoperative complications compared with minimally invasive completed and open cases. Readmission and blood transfusion rates were higher in converted compared with minimally invasive completed cases, and similar to open surgeries. Differences in inflation-adjusted total ($4971), direct ($2760), and overhead ($2212) costs were significantly higher for converted compared with minimally invasive completed cases. CONCLUSIONS: Conversion from minimally invasive to open sigmoidectomy for diverticular disease results in additional morbidity and healthcare costs. Consideration of modifiable risk factors for conversion may attenuate adverse associated outcomes.

Growth and growth hormone in Turner syndrome: Looking back, looking ahead.

Short stature is the most ubiquitous feature of Turner syndrome (TS). Today, many girls with TS are treated with recombinant human growth hormone (GH) to accelerate growth in childhood and to improve adult height. Here, we will review the history of our understanding of growth in TS, reflect on the path of clinical trials ultimately leading to regulatory approval for clinical use of GH, discuss factors associated with growth outcomes and survey the current unanswered questions about growth and GH in TS.

Reduced tillage, but not organic matter input, increased nematode diversity and food web stability in European long-term field experiments.

Soil nematode communities and food web indices can inform about the complexity, nutrient flows and decomposition pathways of soil food webs, reflecting soil quality. Relative abundance of nematode feeding and life-history groups are used for calculating food web indices, i.e., maturity index (MI), enrichment index (EI), structure index (SI) and channel index (CI). Molecular methods to study nematode communities potentially offer advantages compared to traditional methods in terms of resolution, throughput, cost and time. In spite of such advantages, molecular data have not often been adopted so far to assess the effects of soil management on nematode communities and to calculate these food web indices. Here, we used high-throughput amplicon sequencing to investigate the effects of tillage (conventional vs. reduced) and organic matter addition (low vs. high) on nematode communities and food web indices in 10 European long-term field experiments and we assessed the relationship between nematode communities and soil parameters. We found that nematode communities were more strongly affected by tillage than by organic matter addition. Compared to conventional tillage, reduced tillage increased nematode diversity (23% higher Shannon diversity index), nematode community stability (12% higher MI), structure (24% higher SI), and the fungal decomposition channel (59% higher CI), and also the number of herbivorous nematodes (70% higher). Total and labile organic carbon, available K and microbial parameters explained nematode community structure. Our findings show that nematode communities are sensitive indicators of soil quality and that molecular profiling of nematode communities has the potential to reveal the effects of soil management on soil quality.

Imaging Recoil Ions from Optical Collisions between Ultracold, Metastable Neon Isotopes.

We present an experimental scheme that combines the well-established method of velocity-map imaging with a cold trapped metastable neon target. The device is used for obtaining the branching ratios and recoil-ion energy distributions for the penning ionization process in optical collisions of ultracold metastable neon. The potential depth of the highly excited dimer potential is extracted and compared with theoretical calculations. The simplicity to construct, characterize, and apply such a device makes it a unique tool for the low-energy nuclear physics community, enabling opportunities for precision measurements in nuclear decays of cold, trapped, short-lived radioactive isotopes.

Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII).

We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off-target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac γ/δ vs. neuronal α/ß). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat F = 73%) and IV pharmacological studies.

Monitoring rhGH Safety: rhGH Registries, SAGhE and Future Needs.

The safety of growth hormone (GH) therapy in children has been studied extensively. The identification of Creutzfeldt-Jacob disease in individuals who received pituitary-derived GH led to heightened surveillance for safety issues related to recombinant human GH (rhGH). An excellent safety profile of rhGH has been demonstrated in large Phase IV registries comprising > 600,000 patient-years of rhGH exposure and long-term safety cohorts of adults treated with GH as children. Increased mortality risk has been reported but eliminated when corrected for small size at birth. Increased risk of mortality from cerebrovascular disease has been reported but interpretation of these events remains difficult due to the lack of appropriate control groups and a lack of replication of these findings in other studies. The advent of new long-acting growth hormone (LAGH) products provides an opportunity for the development of cohorts of individuals receiving LAGH replacement therapy for continued long-term safety studies.

Macrocephaly associated with the DICER1 syndrome.

PURPOSE: Germ-line mutations in DICER1 increase the risk of various tumors, including pleuropulmonary blastoma. Macrocephaly and symmetric overgrowth have been reported in some, but not all, patients with mosaic DICER1 RNase IIIb mutations. The prevalence of these features in individuals with constitutional germ-line DICER1 mutations is unknown. METHODS: We analyzed prospectively collected auxology data from 67 DICER1 mutation carriers and 43 family controls. We assessed differences between groups using an exact test for proportions and generalized estimating equations for continuous dependent variables. RESULTS: Twenty-eight DICER1 mutation carriers (42%) were macrocephalic, and none had an occipitofrontal circumference (OFC) below the third centile, which significantly differed from family controls, of whom five were macrocephalic (12%) and two had OFC below the third centile (5%) (P < 0.001). DICER1 mutation carriers were taller than familial controls after controlling for gender (P = 0.048), but similar proportions of both groups were above the 97th centile of population norms. Head circumference remained increased after adjusting for differences in height. CONCLUSION: For the first time, we establish macrocephaly as a common finding in the DICER1 syndrome. Like some other tumor-predisposition disorders, macrocephaly may be a useful, albeit a subtle, clinical clue to the DICER1 syndrome diagnosis.Genet Med 19 2, 244-248.

In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone.

MOD-4023 is a novel long-acting version of human growth hormone (hGH), containing the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG). MOD-4023 is being developed as a treatment for adults and children with growth hormone deficiency (GHD), which would require fewer injections than currently available GH formulations and thus reduce patient discomfort and increase compliance. This study characterizes MOD-4023's binding affinities for the growth hormone receptor, as well as the pharmacokinetic and pharmacodynamics, toxicology, and safety profiles of repeated dosing of MOD-4023 in Sprague-Dawley rats and Rhesus monkeys. Although MOD-4023 exhibited reduced in vitro potency and lower affinity to the GH receptor than recombinant hGH (rhGH), administration of MOD-4023 every 5 days in rats and monkeys resulted in exposure comparable to daily rhGH, and the serum half-life of MOD-4023 was significantly longer. Repeated administration of MOD-4023 led to elevated levels of insulin-like growth factor 1 (IGF-1), and twice-weekly injections of MOD-4023 resulted in larger increase in weight gain with fewer injections and a lower accumulative hGH dose. Thus, the increased half-life of MOD-4023 in comparison to hGH may increase the frequency of protein-receptor interactions and compensate for its decreased in vitro potency. MOD-4023 was found to be well-tolerated in rats and monkeys, with minimal adverse events, suggesting an acceptable safety profile. These results provide a basis for the continued clinical development of MOD-4023 as a novel treatment of GHD in children and adults.

[ASSOCIATION OF POLYMORPHIC MARKERS IN GENES OF INNATE IMMUNITY IN PATIENTS WITH PERIODONTITIS AND INFLAMMATORY DISEASES OF UPPER RESPIRATORY TRACT].

AIM: Search of association of polymorphisms in DEFB1, IL-10, TNF-α and TLR2 genes with development of chronic generalized periodontitis in representatives of Ural region (Caucasian race). MATERIALS AND METHODS: 142 patients, that were split into 3 groups, took part in the study: a group of patients with periodontitis, a group with frequent inflammatory disease of upper respiratory tract and a comparison group--healthy donors. A study of polymorphic markers was carried out: DEFB1 (-44G/C), DEFB1 (-20A/G), IL-10 (-1082.A/G), TNF-α (-308 G/A), Arg753Gln and Arg677Trp using PCR in real time mode. RESULTS: Association of infectious pathology ofupper respiratory tract and development of periodontitis diseases with markers in DEFB1 (-44G/C) and Arg753Gln and Arg677Trp genes was determined. Significant differences in distribution of genotypes and alleles of genes IL-10 and TNF-α in the group of patients with periodontitis and comparison group were not detected. CONCLUSION: DEFB1 (-44G/C) polymorphism can be examined as a marker of periodontitis development risk.

Choice of resolution by functional trait or taxonomy affects allometric scaling in soil food webs.

Belowground organisms often display a shift in their mass-abundance scaling relationships due to environmental factors such as soil chemistry and atmospheric deposition. Here we present new empirical data that show strong differences in allometric scaling according to whether the resolution at the local scale is based on a taxonomic or a functional classification, while only slight differences arise according to soil environmental conditions. For the first time, isometry (an inverse 1:1 proportion) is recognized in mass-abundance relationships, providing a functional signal for constant biomass distribution in soil biota regardless of discrete trophic levels. Our findings are in contrast to those from aquatic ecosystems, in that higher trophic levels in soil biota are not a direct function of increasing body mass.

[Evaluation of the clinical efficacy of a new composition of tizol with triamcinolon in complex treatment of patients with erosive ulcerous form of lichen planus of the oral mucosa].

The most significant of the primary stages of complex therapy of oral lichen planus (OLP), among causal and pathogenetic therapy is a local conservative treatment. The aim of the study was to evaluate the clinical efficacy of the local use of the new compositions TIZOL with triamcinolon in complex therapy of erosive-ulcerous forms OLP oral mucosa. The study was performed with 47 patients with lichen planus in age from 24 to 70 years with erosive-ulcerous form OLP whose diagnosis was confirmed histologically. The first group included 25 patients in the complex treatment of locally applied composition TIZOL with triamcinolon. The second group of 22 people, who in the complex treatment applied locally 0.5% prednisone ointment. The high efficiency of topical TIZOL with a highly topical steroid in the complex therapy of erosive-ulcerous forms OLP, which was confirmed by the positive clinical dynamics in all patients (100%) and high self-esteem of patients (84% positive ratings), reduced life complete epithelialization of erosions.

Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations.

CONTEXT AND OBJECTIVE: Titrating the dosage of growth hormone (GH) to serum levels of insulin-like growth factor-I (IGF-I) is a feasible treatment strategy in children with GH deficiency (GHD) and idiopathic short stature (ISS). The objective was to assess the dose-sparing effect and theoretical safety of IGF-I-based GH therapy. DESIGN, SETTING AND PATIENTS: This was a post hoc analysis of a previously described 2-year, multicenter, open-label, randomized, outpatient, controlled clinical trial in 172 prepubertal short children [age 7·5 ± 2·4 years; height standard deviation score (HSDS) -2·64 ± 0·61] classified by baseline peak GH levels as GHD (<7 ng/ml) or ISS (≥7 ng/ml). INTERVENTION: Conventional weight-based dosing of GH (0·04 mg/kg/day) (n = 34) or GH dosing titrated to an IGF-I target of 0 SDS (IGF0T; n = 70) or an IGF-I target of +2 SDS (IGF2T; n = 68). MAIN OUTCOME MEASURES: Change in HSDS per GH mg/kg/day dose (∆HSDS/GH dose ratio) and proportion of IGF-I levels above +2 SDS at the end of 2 years. RESULTS: GH dosing titrated to an IGF-I target of 0 SDS was the most dose-sparing treatment regimen for GHD or ISS children (mean±SE ∆HSDS/GH dose ratios 48·1 ± 4·4 and 32·5 ± 2·8, respectively) compared with conventional dosing (30·3 ± 6·6 and 21·3 ± 3·5, respectively; P = 0·02, P = 0·005) and IGF2T (32·7 ± 4·8 and 16·3 ± 2·8, respectively; P = 0·02, P < 0·0001). IGF0T also resulted in the fewest IGF-I excursions above +2 SDS (6·8% vs 30·0% for conventional dosing; P < 0·01). CONCLUSIONS: IGF-I-based GH dosing, targeted to age- and gender-adjusted means, may offer a more dose-sparing and potentially safer mode of therapy than traditional weight-based dosing.

Search at the Mainz Microtron for light massive gauge bosons relevant for the muon g-2 anomaly.

A massive, but light, Abelian U(1) gauge boson is a well-motivated possible signature of physics beyond the standard model of particle physics. In this Letter, the search for the signal of such a U(1) gauge boson in electron-positron pair production at the spectrometer setup of the A1 Collaboration at the Mainz Microtron is described. Exclusion limits in the mass range of 40 MeV/c^{2} to 300 MeV/c^{2}, with a sensitivity in the squared mixing parameter of as little as ε^{2}=8×10^{-7} are presented. A large fraction of the parameter space has been excluded where the discrepancy of the measured anomalous magnetic moment of the muon with theory might be explained by an additional U(1) gauge boson.

The E180splice mutation in the GHR gene causing Laron syndrome: witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?

Laron syndrome (LS) is a genetic disorder caused by mutations in the growth hormone receptor (GHR) gene. The most frequent GHR mutation is E180splice (rs121909360), which was initially found in an inbred population of Spanish descent in Ecuador and subsequently in Israel, Brazil, Chile, and the United States. The aim of the present study is to determine if the E180splice mutation arose from a common origin. We studied 22 patients with LS from Ecuador, Israel (of Moroccan origin), Brazil, Chile, and the United States (of Mexican origin) who were homozygous for the E180splice mutation and compared them to control individuals for markers surrounding the GHR, intragenic polymorphisms, and Y-chromosome STR. An identical haplotype was found in all but one of the subjects carrying the E180splice mutation: D5S665: 150/150; D5S2082: 192/192; D5S2087: 246/246; rs6179 G/G; and rs6180 C/C. One patient differed from the others only at D5S2082 (168/192). This haplotype is rare (~1%) in control individuals and confirmed that the E180splice-associated haplotype was not derived from independent origins but represented recombination from a common ancestor. The analysis of paternal lineage markers showed that 50% belong to haplogroup R1b (found in Portugal and Spain) and 40% to haplogroups J and E (typical in the Middle East and in Eastern European Jews). The germline E180Splice mutation appears to have originated from a single common ancestor. The presence of Y-chromosome markers associated with Sephardic populations in persons harboring the E180splice mutation provides genetic evidence in support of the historical tracking of the exodus of this specific population.