Performance and environmental impact of egg production in response to dietary supplementation of mannan oligosaccharide in laying hens: a meta-analysis.

A meta-analysis was conducted to examine the effect of supplementing mannan oligosaccharide (MOS; Bio-Mos, Alltech Inc., Nicholasville, KY) in the diets of laying hens on the performance and environmental impact of egg production. Data on production performance (feed intake, hen-day production [HDP], feed conversion ratio [FCR], and mortality) and egg quality attributes (egg weight, egg mass, and eggshell thickness) were extracted from 18 studies to build a database of comparisons between nonsupplemented diets (control) and diets supplemented with MOS. A total of 4,664 laying hens were involved in the comparisons and the average MOS dosage and age of hens were 0.97 kg/ton and 44 wk, respectively. The dataset was analyzed using the random-effects model to estimate the effect size of MOS supplementation on production performance and egg quality attributes. The impact of feeding MOS on the carbon footprint (feed and total emission intensities) of egg production was evaluated by using the meta-analysis results of production performance to develop a scenario simulation that was analyzed by a life cycle assessment (LCA) model. Overall pooled effect size (raw mean difference) indicated that MOS supplementation did not affect feed intake. In contrast, HDP increased by +1.76% and, FCR and mortality reduced by -26.64 g feed/kg egg and -2.39%, respectively. Dietary MOS did not influence egg weight while egg mass increased (P < 0.01) by +0.95 g/day/hen and eggshell thickness tended to increase (P = 0.07) by +0.05 mm. Subgroup analysis indicated that dietary MOS exhibited consistent improvement on HDP and FCR under several study factors (age of hens, number of hens, production challenges, MOS dosage, and study duration). Additionally, the simulated LCA revealed that supplementing MOS decreased feed and total emission intensities of egg production by -1.3 and -1.5%, respectively. Overall, dietary supplementation of MOS at 1.0 kg/ton improved the production performance of laying hens and reduced the carbon footprint and, therefore, can enhance the sustainability credentials of egg production.

Effect of neck flexor muscle activation on impact velocity of the head during backward falls in young adults.

Falls are a common cause of traumatic brain injuries (TBI) across the lifespan. A proposed but untested hypothesis is that neck muscle activation influences impact severity and risk for TBI during a fall. We conducted backward falling experiments to test whether activation of the neck flexor muscles facilitates the avoidance of head impact, and reduces impact velocity if the head contacts the ground. Young adults (n=8) fell from standing onto a 30cm thick gymnastics mat while wearing a helmet. Participants were instructed to fall backward and (a) prevent their head from impacting the mat ("no head impact" trials); (b) allow their head to impact the mat, but with minimal impact severity ("soft impact" trials); and (c) allow their head to impact the mat, while inhibiting efforts to reduce impact severity ("hard impact" trials). Trial type associated with peak magnitude of electromyographic activity of the sternocleidomastoid (SCM) muscles (p<0.017), and with the vertical and horizontal velocity of the head at impact (p<0.001). Peak SCM activations, expressed as percent maximal voluntary isometric contraction (%MVIC), averaged 75.3, 67.5, and 44.5%MVIC in "no head impact", "soft impact", and "hard impact" trials, respectively. When compared to "soft impact" trials, vertical impact velocities in "hard impact" trials averaged 87% greater (3.23 versus 1.73m/s) and horizontal velocities averaged 83% greater (2.74 versus 1.50m/s). For every 10% increase in SCM %MVIC, vertical impact velocity decreased 0.24m/s and horizontal velocity decreased 0.22m/s. We conclude that SCM activation contributes to the prevention and modulation of head impact severity during backward falls.

Relative emissions intensity of dairy production systems: employing different functional units in life-cycle assessment.

This study aimed to assess the merit and suitability of individual functional units (FU) in expressing greenhouse gas emissions intensity in different dairy production systems. An FU provides a clearly defined and measurable reference to which input and output data are normalised. This enables the results from life-cycle assessment (LCA) of different systems to be treated as functionally equivalent. Although the methodological framework of LCA has been standardised, selection of an appropriate FU remains ultimately at the discretion of the individual study. The aim of the present analysis was to examine the effect of different FU on the emissions intensities of different dairy production systems. Analysis was based on 7 years of data (2004 to 2010) from four Holstein-Friesian dairy systems at Scotland's Rural College's long-term genetic and management systems project, the Langhill herd. Implementation of LCA accounted for the environmental impacts of the whole-farm systems and their production of milk from 'cradle to farm gate'. Emissions intensity was determined as kilograms of carbon dioxide equivalents referenced to six FU: UK livestock units, energy-corrected milk yield, total combined milk solids yield, on-farm land used for production, total combined on- and off-farm land used for production, and the proposed new FU-energy-corrected milk yield per hectare of total land used. Energy-corrected milk was the FU most effective for reflecting differences between the systems. Functional unit that incorporated a land-related aspect did not find difference between systems which were managed under the same forage regime, despite their comprising different genetic lines. Employing on-farm land as the FU favoured grazing systems. The proposed dual FU combining both productivity and land use did not differentiate between emissions intensity of systems as effectively as the productivity-based units. However, this dual unit displayed potential to quantify in a simple way the positive or negative outcome of trade-offs between land and production efficiencies, in which improvement in emissions intensity using one FU may be accompanied by deterioration using another FU. The perceived environmental efficiencies of different dairy production systems in terms of their emissions intensities were susceptible to change based upon the FU employed, and hence the FU used in any study needs to be taken into account in the interpretation of results.

Engineering and manufacturing of pharmaceutical co-crystals: a review of solvent-free manufacturing technologies.

Design and synthesis of pharmaceutical cocrystals have received great interest in recent years. Cocrystallization of drug substances offers a tremendous opportunity for the development of new drug products with superior physical and pharmacological properties such as solubility, stability, hydroscopicity, dissolution rates and bioavailability. It is now possible to engineer and develop cocrystals via 'green chemistry' and environmentally friendly approaches such as solid-state synthesis in the absence of organic solvents. In addition, significant efforts have been directed towards computational screening, cocrystal manufacturing in a continuous manner and real-time monitoring for quality purposes by using various analytical tools. Pharmaceutical cocrystals are not fully exploited yet and there is a lot of ground to cover before they can be successfully utilized as medical products.

Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial.

AIMS: To evaluate glucose-lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted. METHODS: A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5-12.0%, were randomized 1:1 to double-blind, free-combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245). RESULTS: The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by -2.8 ± 0.1% with linagliptin/metformin and -2.0 ± 0.1% with linagliptin; a treatment difference of -0.8% (95% confidence interval -1.1 to -0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean ± s.e. changes in HbA1c of -2.7 ± 0.1% and -1.8 ± 0.1%, respectively; treatment difference of -0.9% (95% CI -1.3 to -0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (-1.3 kg between-group difference; p =0.0033). CONCLUSIONS: Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy.

Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.

The safety and efficacy of adding once-daily insulin detemir to oral hypoglycaemic agents in patients with type 2 diabetes in a clinical practice setting in 10 countries.

AIMS: Evaluate the safety and efficacy of once-daily insulin detemir initiated in routine clinical practice in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycaemic agents (OHAs). METHODS: This large observational study was conducted in 10 countries. Adverse event data (including hypoglycaemia) and glycaemic control were recorded before and 24 weeks following insulin initiation while patients continued routine clinical management. RESULTS: In this study, 17 374 patients (53% male) were included. Mean pre-insulin values (±s.d.) were: age 62 ± 12 years; body mass index (BMI) 29.3 ± 5.4 kg/m(2); diabetes duration 10 ± 7 years; haemoglobin A1c (HbA1c) 8.9 ± 1.6%. During the study, 27 patients experienced serious adverse drug reaction, severe hypoglycaemic events or both; and there were 31 episodes of severe hypoglycaemia in 21 patients. After 24 weeks, HbA1c was 7.5 ± 1.2% (change of -1.3%; p < 0.001) and mean weight change was -0.6 kg (confidence interval -0.7, -0.5 kg, p < 0.001). Daily insulin dose increased from 13 ± 6 U (0.16 ± 0.09 U/kg) to 22 ± 16 U (0.27 ± 0.17U/kg) by 24 weeks. Multivariate regression analysis identified several independent demographic and treatment predictors of end of study HbA1c. CONCLUSIONS: Addition of once-daily insulin detemir to patients with type 2 diabetes mellitus on OHA therapy resulted in few adverse events, significant improvements in glycaemic control, small reductions in weight and low rates of hypoglycaemia. On the basis of this study, concerns about hypoglycaemia or weight gain should not preclude initiation of basal insulin analogues in patients with poor glycaemic control on OHAs.

Randomized controlled trial assessing participation and quality of life in a supported speed treadmill training exercise program vs. a strengthening program for children with cerebral palsy.

OBJECTIVE: A multi-site Randomized-Controlled Trial compared a home-based Supported Speed Treadmill Training Exercise Program (SSTTEP) with a strengthening exercise program in children with cerebral palsy (CP) on the following categories; Participation, quality of life (QOL), self-concept, goal attainment, and satisfaction. DESIGN: Twenty-six children with spastic cerebral palsy were assigned by site-based block randomization to the SSTTEP (n=14) or strengthening exercise (n=12) group. Both groups participated in a two week clinic-based induction period and continued the intervention at home for ten weeks. Data were collected at baseline, post-intervention (12 weeks), and follow-up (16 weeks). Assessments included the Canadian Occupational Performance Measure, Children's Assessment of Participation and Enjoyment Scale, Pediatric Quality of Life Cerebral Palsy Module, and Piers-Harris Children's Self-Concept Scale. Evaluators were blinded to group assignment at two sites. RESULTS: Satisfaction and performance on individual goals, participation, and parent-reported QOL improved in both groups with improvement maintained for four weeks post intervention. CONCLUSION: The hypothesis that the SSTTEP group would have better outcomes than the exercise group was not supported. However, both groups showed that children with CP can make gains in participation, individual goals, and satisfaction following a 12-week intensive exercise intervention, and these findings persisted for four weeks post intervention.

Weight beneficial treatments for type 2 diabetes.

CONTEXT: The close link between type 2 diabetes and excess body weight highlights the need to consider the weight effects of different treatment regimens. We examine the impact of "weight-friendly" type 2 diabetes pharmacotherapies and suggest treatment strategies that mitigate weight gain. EVIDENCE ACQUISITION: Evidence was identified via PubMed search by class and agent and in bibliographies of review articles, with final articles for inclusion selected by author consensus. EVIDENCE SYNTHESIS: Substantial evidence confirms the weight benefits of metformin and shows that, of the newer available agents, glucagon-like peptide-1 (GLP-1) agonists and amylin analogs promote weight loss. Dipeptidyl peptidase-4 (DPP-4) inhibitors and bile acid sequestrants are weight-neutral. Liraglutide and exenatide appear to have similar effects on weight; however, recent research suggests a potentially greater effect of liraglutide on glycemic control compared to exenatide, when used as a second-line therapy. Mounting evidence suggests that insulin detemir may provide the most favorable weight benefits of available insulins. CONCLUSIONS: Weight-beneficial agents should be considered in patients, particularly obese patients, who fail to reach glycemic targets on metformin therapy. We propose the following treatment choices based on potential weight benefit and blood glucose increment: long-acting GLP-1 agonists (liraglutide), DPP-4 inhibitors, bile acid sequestrants, amylin analogs, and basal insulin for patients with elevated fasting plasma glucose; and short-acting (exenatide) or long-acting GLP-1 agonists, amylin analogs, DPP-4 inhibitors, acarbose, and bile acid sequestrants for patients with elevated postprandial glucose. The weight-sparing effects of insulin detemir, notably in patients with high body mass index, should also be considered when initiating insulin therapy.

Overview of the diagnosis of cytomegalovirus infection.

Cytomegalovirus (CMV) is recognized as the most common congenital viral infection in humans and an important cause of morbidity and mortality in immunocompromised hosts. This recognition of the clinical importance of invasive CMV disease in the setting of immunodeficiency and in children with congenital CMV infection has led to the development of new diagnostic procedures for the rapid identification of CMV. Diagnosis of acute maternal CMV infection by the presence of immunoglobulin (Ig)M and low-avidity IgG requires confirmation of fetal infection, which is typically performed using polymerase chain reaction (PCR) assays for CMV on amniotic fluid. Viral culture of the urine and saliva obtained within the first two weeks of life continues to be the gold standard for diagnosis of congenitally-infected infants. PCR assays of dried blood spots from newborns have been shown to lack sufficient sensitivity for the identification of most neonates with congenital CMV infection for universal screening purposes. However, saliva PCR assays are currently being assessed as a useful screening method for congenital CMV infection. In the immunocompromised host, newer rapid diagnostic assays, such as phosphoprotein 65 antigenemia and CMV real-time PCR of blood or plasma have allowed for preemptive treatment, reducing morbidity and mortality. However, lack of standardized real-time PCR protocols hinders the comparison of data from different centers and the development of uniform guidelines for the management of invasive CMV infections in immunocompromised individuals.

Evidence for the relationship between diet and cancer.

The relationship between diet and cancer has advanced in recent years, but much remains to be understood with respect to diet and dietary components in cancer risk and prevention. Evidence from clinical trial outcomes, epidemiological observations, preclinical models and cell culture systems have all provided clues about the biology of cancer prevention. Sequencing of the human genome has opened the door to an exciting new phase for nutritional science. There are also many advances in our understanding of the control of gene expression in eukaryotic cells that might impact cancer development, including mechanisms regulating chromatin structure and dynamics, epigenetic processes (DNA methylation, histone posttranslational modification), transcription factors, and noncoding RNA and evidence suggests that environmental factors such as diet influence these processes. Unraveling the effects of bioactive food components on genes and their encoded proteins as well as identifying genetic influences on dietary factors is essential for identifying those who will and will not benefit from intervention strategies for cancer prevention. Additional research needs concerning diet and cancer prevention include: identification and validation of cancer biomarkers and markers of dietary exposure; investigation of the exposure/temporal relationship between food component intakes and cancer prevention; examination of possible tissue specificity in response to dietary factors; and examination of interactions among bioactive food components as determinants of response. Other emerging areas that require greater attention include understanding the link between obesity, diet and cancer, the interaction between diet and the microbiome, as well as how bioactive food components modulate inflammatory processes. Importantly, for the future of nutrigenomics, the "omics" (e.g., genomics, epigenomics, transcriptomics, proteomics, metabolomics) approach may provide useful biomarkers of cancer prevention, early disease, or nutritional status, as well as identify potential molecular targets in cancer processes that are modulated by dietary constituents and/or dietary patterns.

Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model.

BACKGROUND AND PURPOSE: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. EXPERIMENTAL APPROACH: Sixteen marketed drugs from various pharmacological classes with a known incidence -- or lack thereof -- of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. KEY RESULTS: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. CONCLUSIONS AND IMPLICATIONS: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization.

Nutritional genomic approaches to cancer prevention research.

A wealth of evidence points to the diet as one of the most important modifiable determinants of the risk of developing cancer, but a greater understanding of the interaction between diet and genes may help distinguish who will and will not respond to dietary interventions. The term nutrigenomics or nutritional genomics refers to the bidirectional interactions between genes and diet. Nutritional genomics encompasses an understanding about how the response to bioactive food components depends on an individual's genetic background (nutrigenetics), nutrient induced changes in DNA methylation, histone posttranslational modifications, and other chromatin alterations (nutritional epigenetics), and nutrient induced changes in gene expression (nutritional transcriptomics). These approaches to the study of nutrition will assist in understanding how genetic variation, epigenetic events, and regulation of gene expression alter requirements for, and responses to, nutrients. Recognition of the interplay between genes and diet could ultimately help identify modifiable molecular targets for preventing, delaying, or reducing the symptoms of cancer and other chronic diseases.

Identification and enrichment of colony-forming cells from the adult murine pituitary.

Stem and progenitor cells have been identified in many adult tissues including bone marrow, the central nervous system, and skin. While there is direct evidence to indicate the activity of a progenitor cell population in the pituitary gland, this putative subpopulation has not yet been identified. Herein we describe the isolation and characterization of a novel clonogenic cell type in the adult murine pituitary, which we have termed Pituitary Colony-Forming Cells (PCFCs). PCFCs constitute 0.2% of pituitary cells, and generate heterogeneous colonies from single cells. PCFCs exhibit variable proliferative potential, and may exceed 11 population doublings in 14 days. Enrichment of PCFCs to 61.5-fold with 100% recovery can be obtained through the active uptake of the fluorescent dipeptide, beta-Ala-Lys-Nepsilon-AMCA. PCFCs are mostly contained within the large, agranular subpopulation of AMCA+ cells, and constitute 28% of this fraction, corresponding to 140.5-fold enrichment. Interestingly, the AMCA+ population contains rare cells that are GH+ or PRL+. GH+ cells were also identified in PCFC single cell colonies, suggesting that PCFCs have the potential to differentiate into GH+ cells. Together, these data show that the pituitary contains a rare clonogenic population which may correspond to the somatotrope/lactotrope progenitors suggested by previous experiments.

Developmentally regulated expression of the regulator of G-protein signaling gene 2 (Rgs2) in the embryonic mouse pituitary.

During the development of the anterior pituitary gland, five distinct hormone-producing cell types emerge in a spatially and temporally regulated pattern from an invagination of oral ectoderm termed Rathke's Pouch. Evidence from mouse knockout and ectopic expression studies indicates that 12.5 days post coitum (dpc) to 14.5 dpc is a critical period for the expansion of the progenitor cell pool and the determination of most hormone-secreting cell types. While signaling proteins and transcription factors have been identified as having key roles in pituitary cell differentiation, little is known about the identity and function of proteins that mediate signal transduction in progenitor cells. To identify genes that are enriched in the embryonic pituitary gland, we compared gene expression in 14.5 dpc pituitary and 14.5 dpc embryo minus pituitary tissues using the NIA 15K microarray. Analysis of the data using the R program revealed that the Regulator of G Protein Signaling 2 (Rgs2) gene was 3.9-fold more abundant in the 14.5 dpc pituitary. In situ hybridisation confirmed this finding, and showed that Rgs2 expression in midline tissues was restricted to the pituitary and discrete regions of the nervous system. Within the pituitary, Rgs2 was expressed in undifferentiated cells, and was downregulated at the completion of the hormone cell differentiation. To investigate Rgs2 function in the pituitary, we examined hormone cell differentiation in Rgs2 null neonate mice. Pituitary cell differentiation and morphology appeared normal in the Rgs2 mutant animals, suggesting that other Rgs family members with similar activities may be present in the developing pituitary.

Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3.

INTRODUCTION: Array comparative genomic hybridisation (array CGH) is a powerful method that detects alteration of gene copy number with greater resolution and efficiency than traditional methods. However, its ability to detect disease causing duplications in constitutional genomic DNA has not been shown. We developed an array CGH assay for X linked hypopituitarism, which is associated with duplication of Xq26-q27. METHODS: We generated custom BAC/PAC arrays that spanned the 7.3 Mb critical region at Xq26.1-q27.3, and used them to search for duplications in three previously uncharacterised families with X linked hypopituitarism. RESULTS: Validation experiments clearly identified Xq26-q27 duplications that we had previously mapped by fluorescence in situ hybridisation. Array CGH analysis of novel XH families identified three different Xq26-q27 duplications, which together refine the critical region to a 3.9 Mb interval at Xq27.2-q27.3. Expression analysis of six orthologous mouse genes from this region revealed that the transcription factor Sox3 is expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus. DISCUSSION: Array CGH is a robust and sensitive method for identifying X chromosome duplications. The existence of different, overlapping Xq duplications in five kindreds indicates that X linked hypopituitarism is caused by increased gene dosage. Interestingly, all X linked hypopituitarism duplications contain SOX3. As mutation of this gene in human beings and mice results in hypopituitarism, we hypothesise that increased dosage of Sox3 causes perturbation of pituitary and hypothalamic development and may be the causative mechanism for X linked hypopituitarism.

Developmental regulation of Notch signaling genes in the embryonic pituitary: Prop1 deficiency affects Notch2 expression.

Normal development of the pituitary gland requires coordination between the maintenance of a progenitor cell pool and the selection of progenitor cells for differentiation. As Notch signaling controls progenitor cell differentiation in many embryonic tissues, we investigated the involvement of this important developmental pathway in the embryonic pituitary. We report that expression of Notch signaling genes is spatially and temporally regulated in pituitary embryogenesis and implicate Notch2 in the differentiation of several cell lineages. Notch2, Notch3, and Dll1 are initially expressed by most cells within the pituitary primordium and become restricted to a subset of the progenitor cell pool as differentiated pituitary cells begin to appear. Mutations in the transcription factor Prop1 interfere with pituitary growth and cell specification, although the mechanism is unknown. Notch2 expression is nearly absent in the developing pituitaries of Prop1 mutant mice, but unaltered in some other panhypopituitary mutants, revealing that Prop1 is directly or indirectly required for normal Notch2 expression. Transgenic overexpression of Prop1 is not sufficient for enhancement of endogenous Notch2 expression, indicating that there are multiple inputs into this pathway. Dll3 is expressed only in the presumptive corticotrope and melanotrope cells. Analysis of Dll3 null mutants indicates that Dll3 is not required for specification of these two cell types, although there may be functional overlap with Dll1. The spatial and temporal expression patterns of Notch signaling genes in the pituitary suggest overlapping roles in pituitary growth and cell specification.

Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice.

Neuronal nicotinic acetylcholine receptors are ligand-gated ion channels that subserve a range of functions in the brain and peripheral nervous system. They are pentamers variously composed of alpha (alpha2-alpha10) and beta subunits (beta2-beta4). Pharmacological and ligand-binding studies have shown that the different subunits vary in their distribution and channel properties, but precise delineation of the in vivo function of individual subunits has been hampered by lack of subunit-specific antagonists. The development of transgenic mice with targeted deletions of specific subunits (knockout mice) or mutations in critical receptor domains (knockin mice) has extended understanding of nicotinic receptors, revealing that some subunits are necessary for viability, whereas others mediate modulatory effects on learning and memory, locomotion, anxiety, nociception, dopaminergic neurotransmission, seizure threshold, development of the visual system and autonomic function. In some cases, studies of transgenic mice have confirmed expectations derived from pharmacological and expression studies, but in other cases, compensation by related subunits has revealed a degree of functional redundancy not predicted by previous approaches.

Spasticity, strength, and gait changes after surgery for cervical spondylotic myelopathy: a case report.

STUDY DESIGN: A case report with repeated measures is presented. OBJECTIVE: To describe an objective method for evaluating changes in upper- and lower-extremity spasticity and strength, as well as temporal and kinematic gait variables, after surgical intervention for cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: Degenerative cervical spinal disease is a common disorder, with some form of spondylosis demonstrated radiographically in more than 80% of those older than 55 years. Normative pre- and postoperative objective data quantifying spasticity, strength, and gait do not exist. METHODS: A 65-year-old woman underwent C2-C3 anterior cervical discectomy and fusion for progressive myelopathy secondary to a spondylosis and disc herniation. The measure for spasticity and strength at the ankles and elbows and a gait analysis were collected before surgery and at 11 days, 3 and 6 months after surgery. Spasticity and strength were assessed using a dynamometer, and a six-camera video system was used to record the gait. RESULTS: Preoperative left elbow flexor spasticity was more than 10 times greater than the values for the able bodies. It was reduced to normal levels after surgery. Substantial presurgery weakness was present in the elbow flexors and extensors bilaterally. Elbow extensor strength was at able-body levels after surgery. Gait speed was 57% of the able-body level before surgery and 78% of the able-body level 6 months after surgery. CONCLUSIONS: This case study demonstrated the role of biomechanics in characterizing impairments associated with cervical spondylosis and its surgical intervention. Measures for spasticity, strength, and gait taken before and after surgery indicated a favorable outcome. This report provides a foundation for the continued use of biomechanical methods to measure changes in function and impairments associated with surgical intervention of cervical spine disorders.

Acarbose in the treatment of elderly patients with type 2 diabetes.

AIMS: To study the effect of acarbose, an alpha-glucosidase inhibitor, on glycemic control in elderly patients with type 2 diabetes. METHODS: Elderly patients with type 2 diabetes treated with diet alone were randomly treated in a double-blind fashion with placebo (n=99) or acarbose (n=93) for 12 months. RESULTS: After 12 months of therapy, there was a statistically significant difference in the change in glycated haemoglobin (HbA(1c)) (-0.6%) in the acarbose group versus placebo, as well as in the incremental post-prandial glucose values (-2.1 mmol h/l) and mean fasting plasma glucose (-0.7 mmol/l). Although there was no effect of acarbose on insulin release, there was a clear effect of acarbose to decrease relative insulin resistance (-0.8) (HOMA method). In addition, acarbose was generally well tolerated and safe in the elderly; most discontinuations were due to gastrointestinal side effects such as flatulence and diarrhea. There were no cases of hypoglycemia reported, and no clinically relevant changes in laboratory abnormalities or vital signs during the study. CONCLUSIONS: Acarbose improves the glycemic profile and insulin sensitivity in elderly patients with type 2 diabetes who are inadequately controlled on diet alone.