Management of the child born small for gestational age through to adulthood: A consensus statement of the international societies of pediatric endocrinology and the Growth Hormone Research Society

Objective: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies. Participants: There were 42 participants chosen for their expertise in obstetrics, peri- and neonatal medicine, pediatrics, pediatric and adult endocrinology, epidemiology, and pharmacology. Evidence: Written materials were exchanged, reviewed, revised, and then made available to all. This formed the basis for discussions at the meeting. Where published data were not available or adequate, discussion was based on expert clinical opinions. Consensus Process: Each set of questions was considered by all and then discussed in plenary sessions with consensus and unresolved issues identified. The consensus statement was prepared in plenary sessions and then edited by the group chairs and shared with all participants. Conclusions: The diagnosis of SGA should be based on accurate anthropometry at birth including weight, length, and head circumference. We recommend early surveillance in a growth clinic for those without catch-up. Early neurodevelopment evaluation and interventions are warranted in at-risk children. Endocrine and metabolic disturbances in the SGA child are recognized but infrequent. For the 10% who lack catch-up, GH treatment can increase linear growth. Early intervention with GH for those with severe growth retardation (height SD score, < -2.5; age, 2-4 yr) should be considered at a dose of 35-70 mu g/kg center dot d. Long-term surveillance of treated patients is essential. The associations at a population level between low birth weight, including SGA, and coronary heart disease and stroke in later life are recognized, but there is inadequate evidence to recommend routine health surveillance of all adults born SGA outside of normal clinical practice

Allelic loss at chromosome 13q12-q13 is associated with poor prognosis in familial and sporadic breast cancer.

Loss of heterozygosity (LOH) was analysed in 84 primary tumours from sporadic, familial and hereditary breast cancer using five microsatellite markers spanning the chromosomal region 13q12-q13 which harbours the BRCA2 breast cancer susceptibility gene, and using one other marker located within the RBI tumour-suppressor gene at 13q14. LOH at the BRCA2 region was found in 34% and at RBI in 27% of the tumours. Selective LOH at BRCA2 occurred in 7% of the tumours, whereas selective LOH at RBI was observed in another 7%. Moreover, a few tumours demonstrated a restricted deletion pattern, suggesting the presence of additional tumour-suppressor genes both proximal and distal of BRCA2. LOH at BRCA2 was significantly correlated to high S-phase values, low oestrogen and progesterone receptor content and DNA non-diploidy. LOH at BRCA2 was also associated, albeit non-significantly, with large tumour size and the ductal and medullar histological types. No correlation was found with lymph node status, patient age or a family history of breast cancer. A highly significant and independent correlation existed between LOH at BRCA2 and early recurrence and death. LOH at RBI was not associated with the above mentioned factors or prognosis. The present study does not provide conclusive evidence that BRCA2 is the sole target for deletions at 13q12-q13 in breast tumours. However, the results suggest that inactivation of one or several tumour-suppressor genes in the 13q12-q13 region confer a strong tumour growth potential and poor prognosis in both familial and sporadic breast cancer

Lake Erie 1993, Western, West Central and Eastern Basins: Change in Trophic Status, and Assessment of the Abundance, Biomass and Production of the Lower Trophic Levels

The western and west central basins were mesotrophic and the eastern basin was oligotrophic, based on many biological and chemical parameters measured in 1993. Gradients were observed for most parameters, with chlorophyll a, nitrogen, phosphorus, silica, and light extinction decreasing from west to east. In the western basin, phytoplankton biomass declined by 51% from 1983-85. Phytoplankton photosynthesis (g C·m-2), predicted from total phosphorus (TP) using a relationship developed in other offshore productivity studies in Lake Ontario, declined by 35% in 1993, without a corresponding decline in phosphorus (P) loading or TP. Diatoms decreased and there was a shift towards smaller phytoplankton species. These changes were attributed to zebra mussel filtration, but were not of sufficient magnitude to reduce zooplankton biomass. In the west central basin, the reductions in phytoplankton biomass were modest. Photosynthesis (g C·m-2) in 1993, was in line with that predicted by TP and the empirical relationship developed in other offshore studies. Limited mussel populations in the west central basin, resulting from low hypolimnetic oxygen concentrations, caused little change in the phytoplankton. There also were no reductions in mean biomass of zooplankton from 1984-87. In the eastern basin, phytoplankton biomass declined by 49% from 1983-85. Photosynthesis (g C·m-2) declined by 50% from the value predicted, from TP and the empirical relationship developed for other studies, for 1983-85, without a decline in P-leading. TP was lower in 1993 and was attributed to filtering by Dreissena and subsequent redirection of pelagic material to the sediments. Phytoplankton species indicative of eutrophy were reduced and there was an overall shift towards smaller species. Zooplankton biomass was also reduced. Mean zooplankton community size and the loss of Daphnia sp. suggest that predation by planktivores as well as a reduced food supply, affected zooplankton biomass in 1993. The Dreissena population also affected the benthic community structure as Diporeia were virtually eliminated from the eastern basin and Gammarus increased in all basins. Benthic biomass was 40% higher on average than in 1979. Dreissena dominated benthic production at all stations except offshore in the west-central basin

Assessment of Abundance, Biomass and Production of the Lower Trophic Levels in the Eastern Basin of Lake Erie, 1994

The Lake Erie Biomonitoring (LEB) program conducted in 1994, focused on the eastern basin of the lake, resampling the same sites as in 1993. Nutrient conditions were similar in the two years. Responses differed between the stratified offshore and unstratified nearshore. At the offshore station, seasonal phytoplankton biomass was 56% higher in 1994 than in 1993 and apparently resulted from a reduction in grazing pressure by Dreissena. Dreissena biomass and their potential clearance rates at the offshore station were much lower in the spring of 1994 than in the spring of 1993 (2.5 vs. 14.9 m3·m·2·d·\u27), respectively. Despite this increase in phytoplankton biomass, chlorophyll (Chi) and phytoplankton photosynthesis (PP) were not significantly higher in 1994. Dinoflagellates, which have lower Chl:C and lower photosynthesis:Chl ratios than other groups of phytoplankton, accounted for much of the increase in biomass. Rotifer biomass decreased by 50% and zooplankton biomass by 40% between the two years. Calanoids were responsible for much of the decrease in zooplankton biomass. Composition also shifted towards larger bodied cladocerans, such as Daphnia and Bythotrephes, and away from Bosmina. This shift coincided with changes in predation pressure. Age-one smelt abundance was extremely high in 1993 and low in 1994, while the reverse was true of the YOY smelt. Age-one smelt consume mainly cladocerans and the YOY, copepods (REF). At the nearshore stations, seasonal PP and Chi were well below that expected given the total phosphorus (TP) concentration, indicating that Dreissena had an important impact on phytoplankton photosynthesis in this region. Low transparency due to suspended sediments also contributed to the low PP at station El. Zooplankton biomass was lower in 1994 than in 1993, and species composition and size shifted. Daphnia increased and calanoids and Bosmina decreased in the nearshore as in the offshore, presumably in response to changes in the smelt population. However, Bythotrephes decreased and rotifer biomass increased unlike in the offshore

Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Inherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease. METHODS: Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy. RESULTS: Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis. CONCLUSIONS: The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.Eimskipafelag University Minningarsjodur Bergthoru Magnusdottur and Jakobs J Bjarnasonar Gongum Saman Icelandic Cancer Research Fund SKI Icelandic Centre for Research RANNIS The University of Icelan

Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial

OBJECTIVE: Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin. Local tolerability and treatment satisfaction were also assessed. DESIGN: 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). METHODS: Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan ( = 61) or once-daily Norditropin ( = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). RESULTS: Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin ( = 0.0171). CONCLUSIONS: In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin

Model-based evaluation of the genetic impacts of farm-escaped Atlantic salmon on wild populations

Acknowledgements. The authors thank R. Gregory and T. Kess for comments on this manuscript. Funding was provided through the Fisheries and Oceans Program for Aquaculture Regulatory Research. This work has benefited greatly from a 3 year Canada-EU Galway Statement for the Transatlantic Ocean Research Alliance Working Group on modelling genetic interactions among wild and farm escaped Atlantic Salmon in the North Atlantic, involving participants from 7 countries. The models applied here were evaluated and discussed as part of this working group.Peer reviewedPublisher PD

Deaths Among Adult Patients with Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality.

Context:Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified.Objective:To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up.Design and Methods:All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed.Main Outcome Measures:Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up.Results:An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy.Conclusion:Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease