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M Norman

Publications and source records attributed to M Norman.

At least 19 recordsLinked to original sources
PubMed2006

Alterations in glucose homeostasis in SSTR1 gene-ablated mice.

SSTR1 is found on the majority of human pancreatic beta cells, however, its role in insulin secretion has yet to be elucidated. In this study, we used the SSTR1 knockout mouse model to examine the role of SSTR1 in insulin secretion and glucose homeostasis in mice. Despite the reported effect of SSTR1 in inhibiting growth hormone secretion, SSTR1-/- mice had significantly reduced body weight with growth retardation. Perfusion of isolated mouse pancreata at 3 months of age demonstrated a significant increase in insulin secretion in SSTR1-/- mice compared with that of WT controls. We also found that at 3 months of age, SSTR1-/- mice had significantly decreased levels of systemic insulin secretion and were glucose intolerant. However, SSTR1 gene-ablated mice had a much higher rate of insulin clearance compared to WT mice at the same age. When challenged at 12 months of age, we found SSTR1-/- mice had increased glucose tolerance with exaggerated increase of insulin levels at the end of the experiment. Immunochemical analysis showed that the pancreatic islets of SSTR1-/- mice had significantly decreased levels of somatostatin staining and a significant decrease of SSTR5 expression. These results demonstrate that SSTR1 plays an important role in the regulation of insulin secretion in the endocrine pancreas in mice.

Age Factors↗
PubMed2006

Discordant twin growth in utero and differences in blood pressure and endothelial function at 8 years of age.

OBJECTIVE: Low birth weight is associated with increased prevalence of hypertension and cardiovascular disease in adults. The aim of this study was to evaluate genetic and intrauterine environmental contributions to blood pressure (BP) and vascular functions in twins with discordant growth in utero. SUBJECTS: We studied 31 twin pairs (21 monozygous and nine dizygous), mean age 8 years) with large within-pair differences in birth weight. Among the monozygous pairs, nine had suffered from twin-to-twin-transfusion syndrome (TTTS). METHODS: Apart from BP, we determined diameters and elasticity of the carotid artery and abdominal aorta with ultrasonography, and endothelial function in skin vessels with a laser Doppler technique, before and after transdermal delivery of acetylcholine and nitroglycerin. RESULTS: Eight of 62 twin subjects had a systolic BP above the 90th percentile in a North-American reference population. Among these, seven/eight were monozygous with a history of poor fetal growth and/or TTTS. In monozygous twin pairs without TTTS, systolic BP and pulse pressure were higher and vascular endothelial function was impaired in the lower birth weight twin. In the TTTS group, the lighter twin had a narrower carotid artery but there was no within-pair difference in arterial elasticity. Pre-eclampsia during the index pregnancy enhanced within-pair differences in BP but abolished within-pair differences in endothelial function. CONCLUSIONS: Severe fetal growth retardation contributes to higher BP, arterial narrowing and endothelial dysfunction in childhood. Pre-eclampsia may act both as an effect modifier and confounder of these associations.

Acetylcholine↗
PubMed2005

The effect of global SSTR5 gene ablation on the endocrine pancreas and glucose regulation in aging mice.

INTRODUCTION: The purpose of this study was to examine the effect of global gene ablation of SSTR5 on the endocrine pancreas, insulin secretion, and glucose tolerance in aging mice, as SSTR5 is a primary regulator of insulin secretion in the mouse pancreas. METHODS: Global SSTR5-/- mice were generated and genotypes were verified using Southern blot and RT-PCR. Glucose tolerance and in vivo insulin secretion in SSTR5-/- and WT mice were examined using intraperitoneal glucose tolerance test (IPGTT;1.2-2.0 mg/kg) at 3 and 12 months of age (n = 8 per group). Basal and glucose-stimulated insulin secretion in vitro was studied using the isolated perfused mouse pancreas model at 3 and 12 months. Pancreata were removed and levels of insulin, glucagon, somatostatin, and SSTR1 were studied using immunohistochemical analysis along with H&E staining of the pancreata. RESULTS: Genotyping verified the absence of SSTR5 in SSTR5-/- mice. IPGTT demonstrated that 3-month-old SSTR5-/- mice were glucose intolerant despite similar insulin secretion both in vivo and in vitro and enlarged islets. At 12 months of age, SSTR5-/- mice had basal hypoglycemia and improved glucose intolerance associated with hyperinsulinemia in vivo and in vitro and enlarged islets. SSTR5-/- mice had increased insulin clearance at 3 and 12 months of age. SSTR1 expression was significantly increased in islets at 3 months of age, but was nearly absent in islets at 12 months of age, as was somatostatin staining in SSTR5-/- mice. CONCLUSIONS: These results suggest that both SSTR5 and SSTR1 play a pivotal role in insulin secretion and glucose regulation in mice and that their regulatory effects are age-related.

Aging↗
PubMed2005

Birth-related increase in intracolonic hydrogen gas and nitric oxide as indicator of host-microbial interactions.

BACKGROUND: Bacterial colonization of the intestine early in life might have implications for allergy development. We studied early host-bacterial interactions in the gut by simultaneous measurements of hydrogen gas (H(2)) and faecal short chain fatty acid pattern (SCFAs), i.e. bacterial products, as well as of nitric oxide (NO), a marker of mucosal immune activation. METHODS: A novel minimally invasive technique was used for repeated measurements of luminal colonic H(2) and NO in 32 healthy newborn infants delivered vaginally or by Caesarean section. Luminal gas was sampled and analysed at five occasions: immediately after birth, day 1, days 3-5, 1 and 5-6 months after birth. RESULTS: Colonic H(2), NO and faecal SCFAs were undetectable at birth. The H(2) and SCFAs appeared within 24 h and continued to increase during the 6 months follow-up. Nitric oxide remained very low until 3-5 days after birth at which time it markedly increased. In some apparently healthy infants NO transiently reached levels similar to those seen in adults with inflammatory bowel disease. CONCLUSION: Intracolonic measurements of H(2) and NO may be useful to monitor the developmental colonization process as well as mucosal responses.

Aging↗
PubMed2004

Deficiency of somatostatin (SST) receptor type 5 (SSTR5) is associated with sexually dimorphic changes in the expression of SST and SST receptors in brain and pancreas.

The actions of somatostatin (SST) are mediated through five somatostatin receptor subtypes, termed SSTR1-5. Although SSTRs commonly display an overlapping pattern of tissue distribution, subtype-selective responses have been shown to occur in the same tissue. In the present study, we have investigated the changes in SSTR subtypes at the cellular and molecular level in both the brain and the pancreatic islets of mice deficient in SSTR5 (SSTR5KO). Expression levels of insulin and glucagon were also determined in the pancreas of these mice. Semi-quantitative RT-PCR and Western blot analysis showed significant increases in the expression of SSTR2 and 3 with a corresponding reduction in SSTR4 in the brains of female SSTR5KOs, while no changes were observed in male KOs. Strikingly, SST mRNA and SST-like immunoreactivity (SST-LI) were reduced in the brain of male KO animals but not in their female counterparts. In male SSTR5KO islets, there was an increase in the number of cells immunoreactive for SSTR1-3, whereas in female islets only SSTR3 expression was increased. Pancreatic SST-LI and SST mRNA, as well as immunoreactivity for insulin were reduced in male but not in female KO mice. These data indicate that deficiency of SSTR5 leads to subtype-selective sexually dimorphic changes in the expression of both brain and pancreatic SSTRs.

Animals↗
PubMed2004

Expression of prolactin receptor mRNA in oestrogen receptor positive breast cancers pre- and post-tamoxifen therapy.

AIM: Previous in vitro studies have shown that tamoxifen down-regulates prolactin receptors in breast cancer cells. The aim of this study was to determine whether similar changes might provide the basis for a predictive test in patients. METHODS: Biopsy specimens were obtained from 28 post-menopausal women immediately before initiation of treatment with tamoxifen (20 mg daily) and after treatment for 7 days. Prolactin receptor mRNA, determined by reverse-transcription polymerase chain reaction, was then expressed relative to 18S ribosomal RNA. RESULTS: There was good evidence for a decline in receptor expression in response to treatment with tamoxifen in the whole group (p = 0.036) but with a particularly marked decrease (>60%) in a sub-group of 11 patients. No clear correlation with tumour type or grade, or with several other markers (progesterone receptor, c-erb B-2, pS2, or Bcl-2) was apparent. CONCLUSION: Tamoxifen reduces expression of mRNA encoding the prolactin receptor in a sub-group of breast tumours and might provide the basis for a predictive test for tamoxifen therapy.

Aged↗
PubMed2004

Nasal versus full face mask for noninvasive ventilation in chronic respiratory failure.

This study was undertaken to determine the efficacy of nasal mask (NM) versus full face mask (FFM) for the delivery of noninvasive ventilation (NIV) in subjects with nocturnal hypoventilation. A total of 16 patients (11 males) were enrolled, all with nocturnal hypoventilation currently treated at home with NIV via pressure preset devices. Subjects underwent full polysomnography on three occasions; on the first night current therapy on NM was reviewed, followed by two experimental studies in randomised order using either NM or FFM. NIV settings and oxygen flow rate were the same under both conditions. Notably, 14 of the 16 subjects required the use of a chinstrap to minimise oral leak. Apnoea-hypopnoea indices were within normal limits under both conditions (1.7 +/- 3.4 NM versus 1.6 +/- 2.4 h FFM). The type of interface did not significantly affect gas exchange during sleep (minimum average arterial oxyhaemoglobin saturation total sleep time 93.4 +/- 2.1 NM versus 92.8 +/- 2.5% FFM, Delta transcutaneous carbon dioxide nonrapid eye movement sleep to rapid eye movement sleep (0.58 +/- 0.36 NM versus 0.50 +/- 0.40 kPa FFM). Sleep efficiency was significantly reduced on the FFM (78 +/- 9 NM versus 70 +/- 14% FFM), although arousal indices were comparable under both conditions (15.6 +/- 9.8 NM versus 15.8 +/- 8.8 h FFM). Full face masks appear to be as effective as nasal masks in the delivery of noninvasive ventilation to patients with nocturnal hypoventilation. However, a chinstrap was required to reduce oral leak in the majority of subjects using the nasal mask.

Adult↗
PubMed2004

A mutant receptor with enhanced dominant-negative activity for the blockade of human prolactin signalling.

An effective mechanism for interfering with prolactin signalling would provide a powerful tool for clarifying the importance of prolactin in breast cancer, as well as for investigating functions of prolactin in other tissues. Based on our previous identification of a dominant-negative mutation in the growth hormone receptor that causes familial short stature, we investigated the potential for using a similar truncated mutant of the prolactin receptor (PRLR1-242). Like the mutant growth hormone receptor, PRLR1-242 exerts an exceptionally powerful dominant-negative effect. A probable explanation for the strong dominant-negative activity of this class of mutation is that, lacking internalisation motifs, the truncated mutants accumulate at the cell surface and form non-functional heterodimers with wild-type receptors. In accordance with evidence for heterodimer formation between the two receptors, PRLR1-242 also blocks signalling by the growth hormone receptor. When expressed from an adenoviral vector, PRLR1-242 inhibits activation of STAT5 (signal transducer and activator of transcription 5) by prolactin in T47-D breast cancer cells, and blocks the ability of prolactin to induce proliferation in these cells. Thus PRLR1-242 provides an effective means of blocking the responsiveness of target tissues to human prolactin.

Adenoviridae↗
PubMed2003

RAPD-PCR and PFGE as tools in the investigation of an outbreak of beta-haemolytic Streptococcus group A in a Swedish hospital.

We evaluated the random amplified polymorphic DNA (RAPD) and pulsed-field gel electrophoresis (PFGE) techniques for studying an outbreak of beta-haemolytic streptococci group A (GAS) occurred at two maternity wards at Danderyd hospital, Stockholm, Sweden. All the isolates were of T-type 8,25. The RAPD technique revealed that all RAPD-PCR profiles were identical. PFGE showed that all the patterns but one were identical. These patterns were compared with 10 different T-type GAS from the strain collection of the Swedish Institute for Infectious Disease Control (SMI) and T-type 8,25 from different years and locations. The SMI strains exhibited patterns different from each other and all different from the isolates from Danderyd hospital. Moreover, RAPD could not differentiate among the T-type 8,25 isolates from different years and locations but PFGE showed differences among the amplicons. Our results indicated that the RAPD and PFGE techniques could be efficient tools in epidemiological studies of GAS.

Cross Infection↗
PubMed2003

Lung perfusion scintigraphy prior to lung volume reduction surgery.

PURPOSE: The aim of this study was to evaluate whether lung perfusion scintigraphy (LPS) contributes to the preoperative classification of emphysema heterogeneity in patients undergoing LVRS (lung volume reduction surgery) compared to classification based only on computed tomography (CT). MATERIAL AND METHODS: Forty-five potential candidates for LVRS were examined with CT and LPS. The distribution of emphysema within the lungs was visually classified into three categories: markedly heterogeneous, intermediately heterogeneous, or homogeneous. The results of the two imaging techniques were compared to an objective, CT-based computerized classification of heterogeneity. RESULTS: Visual evaluation of all 90 lungs resulted in 50 correct classifications based on CT, in 40 based on LPS and in 68 correct classifications based on the combination of CT and LPS. The combination was superior to CT alone (p<0.01) in classification of emphysema heterogeneity. There was no significant difference between the evaluations based on either CT or LPS. CONCLUSION: The combined information from CT and LPS are superior in assessing emphysema heterogeneity prior to LVRS.

Female↗
PubMed2002

Perinatal water intoxication due to excessive oral intake during labour.

UNLABELLED: The increased body water in pregnant women and the birth-related activation of water-sparing systems contribute to a high risk of perinatal water intoxication if the mother drinks too much water during labour. This study reports on four newborn term infants and one mother presenting with life-threatening symptoms due to hyponatraemia from excessive oral intake during labour. Awareness of this diagnosis in the delivery unit is very important, because the clinical picture may mimic that of pre-eclampsia or dehydration. CONCLUSION: Guidelines are proposed to prevent and treat perinatal water intoxication due to excessive oral intake during labour.

Adult↗
PubMed2001

Yersinia YopE is targeted for type III secretion by N-terminal, not mRNA, signals.

Pathogenic Yersinia species inject virulence proteins, known as Yops, into the cytosol of eukaryotic cells. The injection of Yops is mediated via a type III secretion system. Previous studies have suggested that YopE is targeted for secretion by two signals. One is mediated by its cognate chaperone YerA, whereas the other consists of either the 5' end of yopE mRNA or the N-terminus of YopE. In order to characterize the YopE N-terminal/5' mRNA secretion signal, the first 11 codons of yopE were systematically mutagenized. Frameshift mutations, which completely alter the amino acid sequence of residues 2-11 but leave the mRNA sequence essentially intact, drastically reduce the secretion of YopE in a yerA mutant. In contrast, a mutation that alters the yopE mRNA sequence, while leaving the amino acid sequence of YopE unchanged, does not impair the secretion of YopE. Therefore, the N-terminus of YopE, and not the 5' end of yopE mRNA, serves as a targeting signal for type III secretion. In addition, the chaperone YerA can target YopE for type III secretion in the absence of a functional N-terminal signal. Mutational analysis of the YopE N-terminus revealed that a synthetic amphipathic sequence of eight residues is sufficient to serve as a targeting signal. YopE is also secreted rapidly upon a shift to secretion-permissive conditions. This 'rapid secretion' of YopE does not require de novo protein synthesis and is dependent upon YerA. Furthermore, this burst of YopE secretion can induce a cytotoxic response in infected HeLa cells.

5' Untranslated Regions↗
PubMed2001

Low-flow oxygen and bilevel ventilatory support: effects on ventilation during sleep in cystic fibrosis.

We measured ventilation in all sleep stages in patients with cystic fibrosis (CF) and moderate to severe lung disease, and compared the effects of low-flow oxygen (LFO2) and bilevel ventilatory support (BVS) on ventilation and gas exchange during sleep. Thirteen subjects, age 26 +/- 5.9 yr (mean +/- 1 SD), body mass index (BMI) 20 +/- 3 kg/m2, FEV1 32 +/- 11% predicted, underwent three sleep studies breathing, in random order, room air (RA), LFO2, and BVS +/- O2 with recording of oxyhemoglobin saturation (SpO2) (%) and transcutaneous carbon dioxide (TcCO2) (mm Hg). During RA and LFO2 studies, patients wore a nasal mask with a baseline continuous positive airway pressure (CPAP) of 4 to 5 cm H2O. Minute ventilation (V I) was measured using a pneumotachograph in the circuit and was not different between wake and non-rapid eye movement (NREM) sleep on any night. However, V I was reduced on the RA and LFO2 nights from awake to rapid eye movement (REM) (p < 0.01) and from NREM to REM (p < 0.01). On the BVS night there was no significant difference in V I between NREM and REM sleep. Both BVS and LFO2 improved nocturnal SpO2, especially during REM sleep (p < 0.05). The rise in TcCO2 seen with REM sleep with both RA and LFO2 was attenuated with BVS (p < 0.05). We conclude that BVS leads to improvements in alveolar ventilation during sleep in this patient group.

Adult↗
PubMed2001

Noninvasive pressure preset ventilation for the treatment of Cheyne-Stokes respiration during sleep.

Cheyne-Stokes respiration (CSR) during sleep is common in patients with congestive heart failure (CHF). This pattern of breathing fragments sleep, leading to daytime symptoms of sleepiness and fatigue. It was hypothesized that by controlling CSR with noninvasive pressure preset ventilation (NPPV), there would be a decrease in sleep fragmentation and an improvement in sleep quality. Nine patients (eight males, one female; mean +/- SD 65 +/- 11 yrs) with symptomatic CSR diagnosed on overnight polysomnography (apnoea/hypopnoea index (AHI) 49 +/- 10 x h(-1), minimum arterial oxygen saturation (Sa,O2, 77 +/- 7%) and CHF (left ventricular ejection fraction 25 +/- 8%) were studied. After a period of acclimatization to NPPV (variable positive airway pressure (VPAP) II ST, Sydney, NSW, Australia and bilevel positive airway pressure (BiPAP), Murraysville, PA, USA), sleep studies were repeated on therapy. NPPV almost completely abolished CSR in all patients with a reduction in AHI from 49 +/- 10 to 6 +/- 5 x h(-1) (p<0.001). Residual respiratory events were primarily due to upper airway obstruction at sleep on-set. Arousal index was markedly decreased from 42 +/- 6 to 17 +/- 7 x h(-1) (p <0.001). Sleep architecture showed a trend toward improvement with a reduction in stage 1 and 2 (79 +/- 7% during the diagnostic night versus 72 +/- 10% during NPPV, (p=0.057)), whilst sleep efficiency, slow-wave sleep (SWS), and rapid eye movement (REM) were not altered. Controlling Cheyne-Stokes respiration with noninvasive pressure preset ventilation resulted in reduced arousal and improved sleep quality in the patients with congestive heart failure. Noninvasive pressure preset ventilation should be considered a potential therapy for Cheyne-Stokes respiration in congestive heart failure in those patients who do not respond or fail to tolerate nasal continuous positive airway pressure therapy.

Aged↗
PubMed2001

Predicting sleep-disordered breathing in patients with cystic fibrosis.

STUDY OBJECTIVES: To examine predictors of sleep-disordered breathing in patients with cystic fibrosis (CF) and moderate-to-severe lung disease using a comprehensive evaluation of both sleep and daytime function. DESIGN: Cross-sectional analysis of sleep studies, lung function, respiratory muscle strength, and evening and morning arterial blood gas measurements in patients with stable CF. A questionnaire addressing sleep quality was administered. Forward stepwise regression analysis was used to identify the parameters that best predict sleep-related desaturation, hypercapnia, and respiratory disturbance. SETTING: Sleep investigation unit and lung function laboratory. PATIENTS: Thirty-two patients with CF and FEV(1) < 65% predicted, in stable clinical condition. Patients were aged 27 +/- 8 years (mean +/- 1 SD) with FEV(1) of 36 +/- 10% predicted, evening PaO(2) of 68 +/- 8 mm Hg, and PaCO(2) of 43 +/- 5 mm Hg. RESULTS: Evening PaO(2) (p < 0.0001) and morning PaCO(2) (p < 0.01) were predictive of the average minimum oxyhemoglobin saturation per 30-s epoch of sleep (r(2) = 0.74; p < 0.0001). Evening PaO(2) (p < 0.001) was predictive of the rise in transcutaneous carbon dioxide (TcCO(2)) seen from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep (r(2) = 0.37; p < 0.001). In addition, there was some relationship between expiratory respiratory muscle strength and the REM respiratory disturbance index (r(2) = 0.22; p < 0.01). CONCLUSION: Evening PaO(2) was found to contribute significantly to the ability to predict both sleep-related desaturation and the rise in TcCO(2) from NREM sleep to REM sleep in this subgroup of patients with CF.

Adult↗
PubMed2001

Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-alpha in the diagnosis of early-onset neonatal sepsis.

OBJECTIVE: To evaluate the diagnostic value of peripheral circulatory reactive hyperemia and serum levels of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) in early-onset neonatal sepsis. METHODS: Reactive hyperemia in the dorsal hand and serum levels of IL-6, IL-8, and TNF-alpha were studied in newborn infants (n = 32; gestational age 39 +/- 3 weeks) who had been admitted to the neonatal unit because of suspected sepsis <48 hours after birth. On admission, reactive hyperemia after a standardized arterial occlusion was measured with laser Doppler technique, and blood samples were taken for cytokine analyses. On the basis of predetermined criteria, the infants subsequently were classified as septic (n = 12) or not (n = 20). RESULTS: The degree of reactive hyperemia was higher in the group with sepsis (median + 170% perfusion increase) than in that without (+37%). On admission, serum levels of IL-6, IL-8, and TNF-alpha all were higher in septic (median values: 1620, 331, and 22 pg/mL, respectively) than in nonseptic neonates (median values: 42, 63, and 13 pg/mL, respectively). In the group with sepsis, the degree of reactive hyperemia correlated to log IL-6 (r = 0.80) and log IL-8 values (r = 0.71). CONCLUSION: Newborn infants with septicemia have increased reactive hyperemia and elevated cytokine levels very early in their disease. Reactive hyperemia in skin can be analyzed at the bedside and noninvasively and therefore may serve as an additional diagnostic tool in neonatal sepsis.

Biomarkers↗
PubMed2001

Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells.

Both 17beta-estradiol and prolactin play important roles in the mammary gland, raising the possibility of functional cross-talk between the two signaling pathways. Here, we demonstrate that estrogen receptor-alpha (ERalpha) and -beta (ERbeta) are both able to potentiate transcription from a Stat5-responsive promoter when activated by prolactin. Potentiation was observed not only in the presence of 17beta-estradiol, but also in the presence of anti-estrogens such as tamoxifen and ICI 182,780. The magnitude of the response was dependent on cell-type: in the HC11 mouse mammary epithelial cell line ERbeta potentiates transcription efficiently whereas ERalpha showed low activity. Conversely, in COS-7 cells, both estrogen receptors were active. We show that activation domains in the N-terminus (AF-1) and the C-terminus (AF-2) of the ERs are dispensable for potentiation. The effects are dependent on the presence of an intact DNA-binding/hinge domain, which we show is capable of interacting with Stat5b in vitro and in HC11 cell extracts. We conclude that ERalpha and ERbeta act as coactivators for Stat5b through a mechanism which is independent of AF-1 and AF-2.

Animals↗