Maturation of the Human Cerebral Cortex During Adolescence: Myelin or Dendritic Arbor?

Previous in vivo studies revealed robust age-related variations in structural properties of the human cerebral cortex during adolescence. Neurobiology underlying these maturational phenomena is largely unknown. Here we employ a virtual-histology approach to gain insights into processes associated with inter-regional variations in cortical microstructure and its maturation, as indexed by magnetization transfer ratio (MTR). Inter-regional variations in MTR correlate with inter-regional variations in expression of genes specific to pyramidal cells (CA1) and ependymal cells; enrichment analyses indicate involvement of these genes in dendritic growth. On the other hand, inter-regional variations in the change of MTR during adolescence correlate with inter-regional profiles of oligodendrocyte-specific gene expression. Complemented by a quantitative hypothetical model of the contribution of surfaces associated with dendritic arbor (1631 m2) and myelin (48 m2), these findings suggest that MTR signals are driven mainly by macromolecules associated with dendritic arbor while maturational changes in the MTR signal are associated with myelination.

A Systematic Review and Meta-Analysis of Baseline Ohip-Edent Scores.

BACKGROUND: OHIP-EDENT is widely used in the literature to assess Oral-Health-Related-Quality-of-Life (OHRQoL) for edentulous patients. However the normal variance and mean of the baseline OHIP scores has not been reported. It would facilitate critical appraisal of studies if we had knowledge of the normal variation and mean of baseline OHIP-EDENT scores. An established figure for baseline OHIP-EDENT, obtained from a meta-analysis, would simplify comparisons of studies and quantify variations in initial OHRQoL of the trial participants. OBJECTIVES: The aim of this study is to quantify a normal baseline value for pre-operative OHIP-EDENT scores by a systematic review and meta-analysis of the available literature. METHODS: A systematic literature review was carried. 83 papers were identified that included OHIP-EDENT values. After screening and eligibility assessment, 7 papers were selected and included in the meta-analysis. RESULTS: A meta-analysis for the 7 papers by a random-effect model yielded a mean baseline OHIP-EDENT score of 28.63 with a 95% Confidence intervals from 21.93 to 35.34. CONCLUSION: A pre-operative baseline OHIP-EDENT has been established by meta-analysis of published papers. This will facilitate the comparison of the initial OHRQoL of one study population to that found elsewhere in the published literature.

Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis.

OBJECTIVE: Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with ß-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca2+]I activity and insulin secretion. METHODS: Metabolic profiling was conducted on Gcgrß-cell-/- and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for ß-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in ß-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. RESULTS: Gcgrß-cell-/- mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgrß-cell-/- 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgrß-cell-/- islets showed profound loss of pan-islet [Ca2+]I waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n = 8). CONCLUSION: These data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised [Ca2+]I waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D.

Effect of acarbose to delay progression of carotid intima-media thickness in early diabetes.

BACKGROUND: The anti-diabetic agent acarbose reduces postprandial glucose excursions. We have evaluated the effect of randomized treatment with acarbose on the progression of carotid intima-media thickness (IMT) in early diabetes. METHODS: The Early Diabetes Intervention Program was a randomized trial of acarbose versus placebo in 219 participants with early diabetes characterized by glucose values over 11.1 mmol/L 2 h after a 75 g oral glucose load and a mean HbA1c of 6.3%. IMT was measured at baseline and yearly. Follow-up was discontinued if participants progressed to the study glucose endpoints; IMT readings were available for a median of 2 years, with 72 subjects followed for 5 years. RESULTS: Progressive increases in IMT were seen in both treatment groups, but progression was reduced in participants randomized to acarbose (p = 0.047). In age, sex and smoking-adjusted analyses, IMT progression was associated with greater fasting and oral glucose tolerance test-excursion glucose, fasting insulin, cholesterol and glycated low-density lipoprotein concentrations. IMT progression was reduced with study-related changes in weight, insulin and non-esterified fatty acids; these features were more strongly associated with reduced IMT progression than acarbose treatment. Despite strong associations of baseline glycemia with IMT progression, study-related changes in glucose were not important determinants of IMT progression. CONCLUSIONS: Acarbose can delay progression of carotid intima-media thickness in early diabetes defined by an oral glucose tolerance test. Glucose, weight, insulin and lipids contributed to risk of progression but reductions in glycemia were not major determinants of reduced rate of IMT progression. Vascular benefits of acarbose may be independent of its glycemic effects.

An innovative analysis of nasolabial dynamics of surgically managed adult patients with unilateral cleft lip and palate using 3D facial motion capture.

AIM: To compare dynamic nasolabial movement between end-of-treatment cleft and a matched non-cleft group in adult patients. MATERIALS AND METHODS: Thirteen treated adult participants with unilateral cleft lip and palate had images taken using a facial motion capture system performing a maximum smile. Seventeen landmarks were automatically tracked. For each landmark pair, on either side of the midline, changes in the x, y, and z directions were used to analyze the magnitude of displacement and path of motion. An asymmetry score was developed at rest, mid-smile, and maximum smile to assess the shape of the mouth and/or nose. RESULTS: At maximum smile, displacement of right and left cheilion was clinically and statistically (p < 0.05) less in the cleft group. The lip asymmetry score was greater (p < 0.05) at each time point in the cleft group using the clinical midline. Using Procrustes superimposition, the differences were significant (p < 0.05) only at rest and mid-smile. The alar bases were displaced significantly less (p < 0.05) in the z direction in the cleft group. The asymmetry score of the alar base was significantly higher using the clinical midline than using Procrustes superimposition in patients with cleft conditions (p < 0.001). In the cleft group, at maximum smile, the right and left cristae philter moved significantly less (p < 0.05) in the x and z directions. CONCLUSIONS: There was an increase in asymmetry score of the corners of the mouth and alar bases from rest to maximum smile. The lips were similar in shape but oriented differently in the faces of patients with cleft conditions than in individuals without those conditions.

Incidence of Deep Venous Thrombosis and Sickle Cell Disease in Patients Undergoing Spinal Surgery in South Gujarat, India: A Prospective Observational Study.

Introduction: Our objective of this study was to assess the incidence of Deep Venous Thrombosis in patients including those with sickle cell disease who underwent spine surgery, and also to determine the association of Sickle Cell Disease as a clinical predictor for Deep Venous Thrombosis in spinal surgery patients. Materials and methods: All patients who underwent spinal surgery from January 2016 to October 2016 were included in this study. Detailed history, demographic data, physical findings, pre-operative haematological and radiological investigations were documented. All the patients underwent daily clinical evaluation for clinical signs of Deep Venous Thrombosis and also underwent a post-operative venous Doppler and D-dimer test. Results: Seventy-nine consecutive patients were included in the study with the mean age of 41 years. All patients had normal venous Doppler pre-operatively. A total of 2.5% patients had deep vein thrombosis in bilateral lower limbs while 2 patients (2.5%) had evidence of venous stasis but no thrombosis on Doppler ultrasound done post-operatively. Nine patients (11.4%) were sickle cell positive from which 4 patients showed evidence of Deep Venous Thrombosis or Venous Stasis. D-dimer was positive in 5 (8.3%) patients which included 4 patients with Sickle Cell Disease. Conclusion: This study concludes that Sickle Cell Disease is a risk factor for developing Deep Venous Thrombosis in patients undergoing spinal surgery. The study also concludes the effectiveness of mechanical prophylaxis in preventing Deep Venous Thrombosis and recommends pharmacological prophylaxis after assessing the risk profile or positive D-dimer test.

Contributions of dysglycaemia, obesity, and insulin resistance to impaired endothelium-dependent vasodilation in humans.

BACKGROUND: Individual effects of hyperglycaemia and obesity to impair vascular health are recognized. However, the relative contributions of dysglycaemia versus other obesity-related traits to vascular dysfunction have not been systematically evaluated. METHODS: We undertook a cross-sectional evaluation of factors contributing to vascular function in 271 consecutive subjects, categorized as non-obese normal glucose tolerant (n = 115), non-obese dysglycaemic (n = 32), obese normal glucose tolerant (n = 57), obese dysglycaemic (n = 38), or type 2 diabetic (n = 29). Vascular function was measured invasively as leg blood flow responses to methacholine chloride, an endothelium-dependent vasodilator. Categorical and continuous analyses were carried out to assess the contributions of hyperglycaemia to vascular dysfunction. RESULTS: Even among normoglycaemic subjects, obese subjects had impaired vascular function compared to non-obese subjects (p = 0.004). Vascular function was also impaired in non-obese dysglycaemic subjects (p = 0.04 versus non-obese normoglycaemic subjects), to a level comparable to normoglycaemic obese subjects. Within obese subject groups, gradations of dysglycaemia including the presence of diabetes were not associated with further worsening of these vascular responses beyond the effect of obesity alone (p = not significant comparing all obese groups, p < 0.001 versus lean normoglycaemic subjects). After univariate and multivariable modelling analyses we found that effects of glycaemia were less powerful than effects of insulin resistance and obesity on vascular dysfunction. CONCLUSIONS: Dysglycaemia contributes to impaired vascular function in non-obese subjects, but obesity and insulin resistance are more important determinants of vascular function in obese and diabetic subjects.

A cross-sectional evaluation of seasonality as a determinant of endothelial function.

Endothelium-dependent vasodilation is impaired in obese versus lean humans. We set out to evaluate whether agonist-mediated endothelium-dependent vasodilation varies by season in a cross-sectional dataset of lean and obese humans, and whether this effect differed by obesity status. All vascular studies performed in our laboratory over a 12 year period from 1997 to 2009 were evaluated. Endothelium-dependent vasodilation was measured invasively using thermodilution in the leg as the response to intra-arterially infused methacholine chloride. Resting blood pressure was measured concurrently by cuff and intra-arterially. The association of endothelium-dependent vasodilation and blood pressure measurements with season was evaluated, comparing responses in lean and obese subjects. Endothelium-dependent vasodilation differed between lean and obese subjects, and varied across seasons (p=0.02), but without an interaction between season effect and obesity status. The proportion of obese versus lean subjects differed significantly across seasons in our dataset, and after adjusting for this factor the apparent seasonal variation in endothelium-dependent vasodilation was lost (p=0.12), and was not present in either lean or obese subjects separately. Systolic arterial blood pressure varied across seasons, and this effect remained significant after adjusting obesity status (p=0.019 and p=0.043 for blood pressures measured intra-arterially and by cuff respectively). In our cross-sectional dataset, seasonal variations in blood pressure were seen but we did not observe an association between season and endothelium-dependent vasodilation in lean or obese subjects.

A randomized, open labeled, comparative study to assess the efficacy and safety of controller medications as add on to inhaled corticosteroid and long-acting ß2 agonist in the treatment of moderate-to-severe persistent asthma.

BACKGROUND: The goal of asthma therapy is to achieve clinical control and near normal lung functions. Many patients with persistent asthma fail to achieve this goal with a single controller medication add on to a inhaled corticosteroid. We have checked whether another controller medication add on to inhaled corticosteroid and long-acting ß2 agonist helps in achieving the asthma goal or not. OBJECTIVES: To identify the effect of controller medication add on to inhaled corticosteroid and the long-acting ß2 agonist on the clinical symptom, lung function, and compliance in patients with asthma. MATERIALS AND METHODS: We conducted a randomized, open-labeled, comparative trial in 50 participants with moderate-to-severe persistent asthma. The study duration was of 10 weeks. During the first two weeks of the run-in period all the participants received a dry powder inhaler drug delivery of budesonide (400 mcg/day) and formoterol (12 mcg/day) combination. At the end of the run-in period the participants were randomly allocated into three groups: group A (n = 16) received oral montelukast (10 mg/day); group B (n = 17) received oral doxophylline (400 mg/day), and group C (n = 17) received inhaled budesonide (400 mcg) as add on to the above-mentioned drugs of the run-in period. The primary outcome was improvement in forced expiratory volume at 1 second (FEV1 ). RESULTS: All the participants of the three groups had significant improvement in FEV1 (P < 0.001) and asthma symptoms at the end of 10 weeks. The mean increase in FEV1 (% of predicted) from the baseline, in groups A, B, and C was: 24.6; 21.33, and 19.86%, respectively. CONCLUSIONS: All add on controller medications helped, with a significant improvement of lung functions and asthma symptoms.

Strengthened capacity of India´s bedaquiline Conditional Access Programme for introducing new drugs and regimens.

BACKGROUND: Addressing TB in India is critical to meeting global targets. With the scale-up of diagnostic networks and the availability of new TB drugs, India had the opportunity to improve the detection and treatment outcomes in drug-resistant TB (DR-TB).OBJECTIVE: To document how the introduction of new drugs and regimens is helping India improve the care of DR-TB patients.DESIGN: In 2016, India´s National TB Programme (NTP) introduced bedaquiline (BDQ) under a Conditional Access Programme (BDQ-CAP) at six sites after providing extensive training and strengthening laboratory testing, pre-treatment evaluation, active drug safety monitoring and management (aDSM) and follow-up systems.RESULTS: An interim analysis reflected earlier and better culture conversion rates: 83% of the 620 patients converted within a median time of 60 days. However, 248 serious adverse events were reported, including 73 deaths (12%) and 100 cardiotoxicity events (16.3%). Encouraged by the evidence of safety and efficacy of BDQ, the NTP took steps to systematically expand its access to cover the entire population by 2018.CONCLUSION: The cautious yet focused approach used to introduce BDQ under BDQ-CAP paved the way for the rapid introduction of delamanid, as well as the shorter treatment regimen and the all-oral regimen for DR-TB.

Quantitative electron microscopic autoradiography of insulin, glucagon, and somatostatin binding sites on islets.

After monolayer cultures of rat islets were exposed to [(125)I]insulin,[(125)I]glucagon, and [(125)I]tyrosinyl somatostatin, specific autoradiographic grains associated with each radioactively labeled ligand were found on B, A, and D cells. The density of labeling of the B, A, and D cells with each labeled ligand correlated well with the known actions of the three hormones on each of the islet cells.

Antiserum to somatostatin prevents stress-induced inhibition of growth hormone secretion in the rat.

Plasma growth hormone levels fall and remain low for several hours after stress in the rat. When antiserums to somatostatin are administered to rats prior to stress, growth hormone secretory pulses are partially restored. The results provide evidence that circulating somatostatin plays a prominent role in stress-induced inhibition of growth hormone secretion in the rat.

Somatostatin: widespread abnormality in tissues of spontaneously diabetic mice.

Diabetic mice of the C57BL/6J obob and C57BL/Ks dbdb strains show a reduction in pancreatic somatostatin concentration accompanied in the obob strain by a striking decrease in the number of somatostatin-containing cells in the islets. Somatostatin concentration is also decreased in the stomach but increased in the hypothalamus. These findings suggest different control mechanisms for somatostatin in the hypothalamus compared to the gut and pancreas and exclude a primary genetic abnormality of somatostatin cells in the mutants.

Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity.

Somatostatin and dopamine are two major neurotransmitter systems that share a number of structural and functional characteristics. Somatostatin receptors and dopamine receptors are colocalized in neuronal subgroups, and somatostatin is involved in modulating dopamine-mediated control of motor activity. However, the molecular basis for such interaction between the two systems is unclear. Here, we show that dopamine receptor D2R and somatostatin receptor SSTR5 interact physically through hetero-oligomerization to create a novel receptor with enhanced functional activity. Our results provide evidence that receptors from different G protein (heterotrimeric guanine nucleotide binding protein)-coupled receptor families interact through oligomerization. Such direct intramembrane association defines a new level of molecular crosstalk between related G protein-coupled receptor subfamilies.

Confocal mosaicing microscopy in skin excisions: a demonstration of rapid surgical pathology.

Precise micro-surgical removal of tumour with minimal damage to the surrounding normal tissue requires a series of excisions, each guided by an examination of frozen histology of the previous. An example is Mohs surgery for the removal of basal cell carcinomas (BCCs) in skin. The preparation of frozen histology is labour-intensive and slow. Confocal microscopy may enable rapid detection of tumours directly in surgical excisions with minimal need for frozen histology. Mosaicing of images enables observation of nuclear and cellular morphology in large areas of surgically excised tissue. In skin, the use of 10-1% acetic acid as a reflectance contrast agent brightens nuclei in 0.5-5 min and enhances nuclear-to-dermis contrast and detectability of BCCs. A tissue fixture was engineered for precisely mounting surgical excisions to enable mosaicing of 36 x 36 images to create a field of view of 12 x 12 mm. This large field of view displays the excision at 2x magnification, similar to that routinely used by Mohs surgeons when examining frozen histology. Comparison of mosaics to histology demonstrates detectability of BCCs. Confocal mosaicing presently requires 9 min, instead of 20-45 min per excision for preparing frozen histology, and thus may provide a means for rapid pathology-at-the-bedside to expedite and guide surgery.

Mass spectrometry tools and metabolite-specific databases for molecular identification in metabolomics.

The chemical identification of mass spectrometric signals in metabolomic applications is important to provide conversion of analytical data to biological knowledge about metabolic pathways. The complexity of electrospray mass spectrometric data acquired from a range of samples (serum, urine, yeast intracellular extracts, yeast metabolic footprints, placental tissue metabolic footprints) has been investigated and has defined the frequency of different ion types routinely detected. Although some ion types were expected (protonated and deprotonated peaks, isotope peaks, multiply charged peaks) others were not expected (sodium formate adduct ions). In parallel, the Manchester Metabolomics Database (MMD) has been constructed with data from genome scale metabolic reconstructions, HMDB, KEGG, Lipid Maps, BioCyc and DrugBank to provide knowledge on 42,687 endogenous and exogenous metabolite species. The combination of accurate mass data for a large collection of metabolites, theoretical isotope abundance data and knowledge of the different ion types detected provided a greater number of electrospray mass spectrometric signals which were putatively identified and with greater confidence in the samples studied. To provide definitive identification metabolite-specific mass spectral libraries for UPLC-MS and GC-MS have been constructed for 1,065 commercially available authentic standards. The MMD data are available at http://dbkgroup.org/MMD/.

Laparoscopic management of uterine perforation: report of three cases.

We present three cases of uterine perforation which were managed laparoscopically at the Aga Khan University Hospital Nairobi, between January and December 2008. Our objective was to determine the outcomes of uterine perforations and to create awareness on the availability of the laparoscopic management at such complications and to recommend the procedure as a suitable option to laparotomy.

Metabolic control of gene expression: in vivo studies with transgenic mice.

Transgenic animals provide a comprehensive model for investigating genes encoding inducible enzymes involved in metabolism, since the molecular mechanisms regulating gene transcription can be studied in the whole animal. Studies on the promoters of the genes encoding two key enzymes in the gluconeogenic and glycolytic pathways--phosphoenol-pyruvate carboxykinase and pyruvate kinase are described as examples of this approach. Work on the phosphoenolpyruvate carboxykinase promoter using transgenic mice has been particularly informative: the cis-acting elements involved in hormonal regulation, tissue specificity and developmental inhibition of gene expression have been identified and their function in vivo examined.

Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis.

Although it has been demonstrated that transformed progenitor cell population can contribute to tumor initiation, factors contributing to this malignant transformation are poorly known. Using in vitro and xenograft-based models, previous studies demonstrated that miR-489 acts as a tumor suppressor miRNA by targeting various oncogenic pathways. It has been demonstrated that miR-489 directly targets HER2 and inhibits the HER2 signaling pathway; however, its role in mammary gland development and HER2-induced tumor initiation hasn't been studied. To dissect the role of miR-489, we sorted different populations of mammary epithelial cells and determined that miR-489 was highly expressed in mammary stem cells. MMTV-miR-489 mice that overexpressed miR-489 in mammary epithelial cells were developed and these mice exhibited an inhibition of mammary gland development in early ages with a specific impact on highly proliferative cells. Double transgenic MMTV-Her2-miR489 mice were then generated to observe how miR-489 overexpression affects HER2-induced tumorigenesis. miR-489 overexpression delayed HER2-induced tumor initiation significantly. Moreover, miR-489 overexpression inhibited tumor growth and lung metastasis. miR-489 overexpression reduced mammary progenitor cell population significantly in preneoplastic mammary glands of MMTV-Her2 mice which showed a putative transformed population in HER2-induced tumorigenesis. The miR-489 overexpression reduced CD49fhiCD61hi populations in tumors that have stem-like properties, and miR-489 overexpression altered the HER2 signaling pathway in mammary tumors. Altogether, these data indicate that the inhibition of HER2-induced tumorigenesis by miR-489 overexpression was due to altering progenitor cell populations while decreasing tumor growth and metastasis via influencing tumor promoting genes DEK and SHP2.

Correction: Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis.

In the published version of this paper the author A. Awgulewitsch's surname was incorrectly given as Awagulerwitsch instead of Awgulewitsch. This has now been corrected in the HTML version of the paper, the PDF was correct at the time of publication.