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Aims To evaluate the effect of the pre-pregnancy body surface area (BSA) on the risk of gestational diabetes mellitus (GDM). Methods The study population consisted of all primiparous women with singleton pregnancies (n = 328,892) without previously diagnosed diabetes or chronic hypertension in Finland between 2006 and 2019. The information on GDM, oral glucose tolerance test (OGTT) results, and maternal backgrounds was derived from the Finnish Medical Birth Register. The pre-pregnancy BSA was calculated by using the Mosteller formula. Logistic regression models were used to estimate the association between BSA and GDM/ OGTT separately by the body mass index groups. Results A lower BSA predicted an increased risk for GDM and pathological OGTT among the underweight (b = − 2.69, SE = 0.25, p b = − 2.66, SE = 0.23, p b = − 0.30, SE = 0.10, p = 0.002; b = − 0.67, SE = 0.09, p b = − 0.31, SE = 0.10, p = 0.001) pregnant women. Within the obese class II or greater, a higher BSA predicted a higher risk for GDM (b = 0.74, SE = 0.12, p b = 0.79, SE = 0.13, p Conclusion This study showed that in comparison with women with a higher BSA, underweight, and normal weight pregnant women with a smaller BSA may be more susceptible to GDM and have a pathological OGTT.

The aim of this study was to evaluate if maternal height affects the link between the inverse association on smoking during pregnancy and preeclampsia.The study population consisted of all women with singleton pregnancies (n = 803 698) in Finland during the years 2004-2018, excluding women with unknown smoking and diagnosis of prepregnancy chronic hypertension. Information on smoking and background factors were derived from the Finnish Medical Birth Register. Smoking was categorized in three classes: no, quitted in the first trimester and continued throughout the pregnancy. Information on preeclampsia was derived from the Finnish Hospital Discharge Register and the Finnish Medical Birth Register. Multiple logistic regression models were used to estimate first the association between smoking and preeclampsia, and finally whether maternal height modified the association.In the standard comparison, we found evidence of an association between preeclampsia and continued smoking [adjusted odds ratio = 0.74, 95% confidence interval (95% CI) = 0.67-0.81], but no association was found between quitted smoking and preeclampsia. Thus, the interaction of continued smoking and maternal height by z-scores was estimated. Among taller mothers, continued smoking was associated with a higher risk for preeclampsia than in smoking mothers with average height (β = 0.33, SE = 0.14, P = 0.02).Our results partly challenge the smoking-preeclampsia paradox: smoking seems not to protect tall mothers against preeclampsia. We speculate the findings through a new theory about the pathophysiology of preeclampsia. It seems that tall pregnant smokers must raise their blood pressure aggressively to ensure perfusion in the dysfunctional placenta.

Background As Alzheimer’s disease (AD) pathology presents decades before dementia manifests, unbiased biomarker cut-points may more closely reflect presence of pathology than clinically defined cut-points. Currently, unbiased cerebrospinal fluid (CSF) tau cut-points are lacking. Methods We investigated CSF t-tau and p-tau cut-points across the clinical spectrum using Gaussian mixture modelling, in two independent cohorts (Amsterdam Dementia Cohort and ADNI). Results Individuals with normal cognition (NC) (total n = 1111), mild cognitive impairment (MCI) (total n = 1213) and Alzheimer’s disease dementia (AD) (total n = 1524) were included. In both cohorts, four CSF t- and p-tau distributions and three corresponding cut-points were identified. Increasingly high tau subgroups were characterized by steeper MMSE decline and higher progression risk to AD (cohort/platform-dependent HR, t-tau 1.9–21.3; p-tau 2.2–9.5). Limitations The number of subjects in some subgroups and subanalyses was small, especially in the highest tau subgroup and in tau PET analyses. Conclusions In two independent cohorts, t-tau and p-tau levels showed four subgroups. Increasingly high tau subgroups were associated with faster clinical decline, suggesting our approach may aid in more precise prognoses.

OBJECTIVE To examine if the 2-h value of an oral glucose tolerance test (OGTT) can predict cognitive decline. RESEARCH DESIGN AND METHODS This study is based on a subpopulation of the Finnish population-based Health 2000 Survey and its follow-up, the Health 2011 study. Altogether, 961 individuals aged 45–74 (mean 55.6 years; 55.8% women) underwent OGTT in 2001–2002. Categorical verbal fluency, word-list learning, and word-list delayed recall were tested at baseline and at follow-up in 2011. Statistical analyses were performed with multivariable linear models adjusted for previously reported risk factors for cognitive decline. RESULTS A higher 2-h glucose value in the OGTT at baseline predicted worse performance (slope: −0.08; P = 0.01) and greater decline (slope: −0.07; P = 0.007) in the word-list delayed recall test after 10 years. CONCLUSIONS Our results indicate that higher 2-h glucose values in the OGTT predict a decline in episodic memory after 10 years.

Background: Type 2 diabetes (T2DM) increases the risk for Alzheimer’s disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline. Objective: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning. Methods: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n = 6062) to attend follow-up examinations in 2014–2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOE ɛ4 carriers per group. Statistical analyses were performed with multivariable linear models. Results: At follow-up the IR+group performed worse on executive functions (p = 0.02) and processing speed (p = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed. Conclusion: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here.

Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. Methods [11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19–80 years; BMI range 17.6–36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies. Electronic supplementary material The online version of this article (10.1007/s00259-019-04403-7) contains supplementary material, which is available to authorized users.

ObjectiveTo examine whether early β–amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia.MethodsWe examined 54 volunteers (mean age 70.0 years, 56% women, 51% APOE ɛ4 carriers) with the translocator protein (TSPO) tracer [11C]PBR28 to assess neuroinflammation and with [11C] Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in 6 regions of interests by using the cerebellar cortex as a pseudo-reference and reference region, respectively. Fasting venous glucose, insulin, and high-sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n = 11) underwent CSF sampling, and Aβ40, Aβ42, total tau, phospho-tau, soluble TREM2, and YKL-40 levels were measured.ResultsAmong the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p = 0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid-negative ([11C]PiB composite score ≤1.5) (TSPO genotype–, age- and sex-adjusted slope 0.26, p = 0.008) but not among amyloid-positive (slope −0.004, p = 0.88) participants. Higher CSF soluble TREM2 (rs = 0.72, p = 0.01) and YKL-40 (rs = 0.63, p = 0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer disease.ConclusionsWhile there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology.

AIM Intrahepatic cholestasis of pregnancy (ICP) is reported to be associated with an increased risk of sudden fetal death. The possible mechanism is thought to be cardiac arrhythmia. Prolonged QT interval of the electrocardiogram (ECG) is associated with arrhytmogenic events. The aim of the study was to compare the fetal ECG QT interval during labor in pregnancies complicated with ICP to healthy controls. METHODS The fetal ECG and QT interval was reviewed retrospectively. The intrapartum QT interval was measured in 61 fetuses born to mothers with ICP and in a control group of similar size. The corrected QT interval (QTc) was calculated using Bazett's formula: QT/√RR. The occurrence of ST segment depression was also included in the analysis. RESULTS The groups were similar regarding to maternal age, parity, BMI, gestational age and smoking habits. The rate of labor induction was significantly higher in ICP patients (P

Objectives The existence of circulating tumor cells has emerged as an important factor for prognosis and survival. The CellSearch method is the only circulating tumor cell detection method approved by the US Food and Drug Administration for clinical use. It relies on the detection of EpCAM (epithelial cell adhesion molecule) and is approved for colon cancer, breast cancer and prostate cancer. We now investigated whether CellSearch can be used to quantify circulating tumor cells in head and neck squamous cell cancer. Study Design and Methods In this study, we investigated the expression of EpCAM in 12 head and neck squamous cell cancer cell lines using Western blot and how this affected their detectability with CellSearch in peripheral blood. Results We found a great variation in the expression of EpCAM between our head and neck squamous cell cancer cell lines. This was accompanied by variations in counting efficiency. Conclusion We suggest that for reliable quantification of circulating tumor cells in blood from patients with head and neck squamous cell cancer cell, an epitope independent method is preferable. Level of Evidence NA

OBJECTIVE The aim of this study was to examine whether insulin resistance, assessed by HOMA of insulin resistance (HOMA-IR), is an independent predictor of cognitive decline. RESEARCH DESIGN AND METHODS The roles of HOMA-IR, fasting insulin and glucose, HbA1c, and hs-CRP as predictors of cognitive performance and its change were evaluated in the Finnish nationwide, population-based Health 2000 Health Examination Survey and its 11-year follow-up, the Health 2011 study (n = 3,695, mean age at baseline 49.3 years, 55.5% women). Categorical verbal fluency, word-list learning, and word-list delayed recall were used as measures of cognitive function. Multivariate linear regression analysis was performed and adjusted for previously reported risk factors for cognitive decline. RESULTS Higher baseline HOMA-IR and fasting insulin levels were independent predictors of poorer verbal fluency performance (P = 0.0002 for both) and of a greater decline in verbal fluency during the follow-up time (P = 0.004 for both). Baseline HOMA-IR and insulin did not predict word-list learning or word-list delayed recall scores. There were no interactions between HOMA-IR and apolipoprotein E ε4 (APOEε4) genotype, hs-CRP, or type 2 diabetes on the cognitive tests. Fasting glucose and hs-CRP levels at baseline were not associated with cognitive functioning. CONCLUSIONS Our results show that higher serum fasting insulin and insulin resistance predict poorer verbal fluency and a steeper decline in verbal fluency during 11 years in a representative sample of an adult population. Prevention and treatment of insulin resistance might help reduce cognitive decline later in life.

Overweight during pregnancy predisposes both the mother and foetus to health complications. Maternal complications include gestational diabetes, obstetric problems and type 2 diabetes later in life. Complications for the offspring are not only restricted to the foetal period or birth, such as prematurity and foetal macrosomia, but may also have long-term metabolic health implications through the mechanism of early nutrition programming. One of the key metabolic components characterising overweight in the non-pregnant state is low-grade inflammation manifested by elevated levels of circulatory pro-inflammatory cytokines. In pregnancy, in addition to adipose tissue and placenta, inflammatory response may originate from the gut. The extent to which overweight induces metabolic maladaptation during pregnancy and further compromises maternal and child health is currently poorly understood. In this review, we evaluate recent scientific literature and describe the suggested links between overweight, gut and low-grade inflammation associated metabolic disorders. We focus on overweight pregnant women and gestational diabetes, and discuss how specific dietary factors, probiotics and long-chain polyunsaturated fatty acids (fish oil), might confer health benefits in combatting against metabolic risk factors.

PurposeTo investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28.Methods[11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; n=78 with HAB and n=62 MAB genotype; age range 19-80 years; BMI range 17.6 - 36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (n=53), Turku PET centre (n=62) and Yale University PET Center (n=25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts.ResultsThere were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects.ConclusionThese findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer’s disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes—two diseases characterized by systemic insulin resistance—are associated with an increased risk for AD. Along with the well-defined patterns of fasting [18F]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [18F]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders.

The melanocortin system is involved in the control of adiposity through modulation of food intake and energy expenditure. The single nucleotide polymorphism (SNP) rs17782313 near the MC4R gene has been linked to obesity, and a previous study using magnetoencephalography has shown that carriers of the mutant allele have decreased cerebrocortical response to insulin. Thus, in this study, we addressed whether rs17782313 associates with brain glucose uptake (BGU). Here, [18F]-fluorodeoxyglucose positron emission tomography (PET) data from 113 Finnish subjects scanned under insulin clamp conditions who also had the rs17782313 determined were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. Statistical analysis was performed with statistical parametric mapping. There was no difference in age, BMI, and insulin sensitivity as indexed by the M value between the rs17782313-C allele carriers and non-carriers. Brain glucose uptake during insulin clamp was not different by gene allele, and it correlated with the M value, in both the rs17782313-C allele carriers and non-carriers. The obesity risk SNP rs17782313 near the MC4R gene is not associated with brain glucose uptake during insulin clamp in humans, and this frequent mutation cannot explain the enhanced brain glucose metabolic rates in insulin resistance.

BACKGROUND Increased intestinal permeability may precede adverse metabolic conditions. The extent to which the composition of the gut microbiota and diet contribute to intestinal permeability during pregnancy is unknown. OBJECTIVE The aim was to investigate whether the gut microbiota and diet differ according to serum zonulin concentration, a marker of intestinal permeability, in overweight pregnant women. METHODS This cross-sectional study included 100 overweight women [mean age: 29 y; median body mass index (in kg/m(2)): 30] in early pregnancy (

The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3), has been reported to positively regulate the human cathelicidin anti-microbial peptide (CAMP) gene coding for LL-37, but the mechanisms are not completely understood. We have determined the expression of CAMP, vitamin D receptor (VDR), and the retinoid X receptor (RXR) isoforms in human skin and gingival tissue biopsies and investigated the signaling pathways involved in 1,25D3-induced upregulation of CAMP. Human skin and gingival biopsies exhibited few VDR-immunoreactive cells within the stratum basale, whereas rat colon enterocytes (positive control) possessed abundant VDR immunoreactivity. Nuclear VDR immunoreactivity was demonstrated in human skin keratinocytes (HaCaT cells). Gene analysis revealed that human skin biopsies expressed higher levels of both CAMP and RXRα mRNA than human gingival biopsies, whereas VDR and RXRβ transcript levels were similar in skin and gingiva. In HaCaT cells, treatment with 1,25D3 (5 nM and 1 μM) for 4 and 24 h up-regulated CAMP mRNA several fold, and treatment with 1,25D3 for 24 h increased protein expression of the pro-form of LL-37 (hCAP-18) by about 13 times. The 1,25D3-evoked stimulation of HaCaT CAMP expression was associated with attenuated VDR mRNA and protein expression. Treatment with RXRα short interfering RNA reversed the 1,25D3-induced CAMP expression in HaCaT cells, showing that RXRα is involved in the up-regulation of CAMP by 1,25D3. We conclude that the 1,25D3-evoked stimulation of CAMP expression in human skin keratinocytes is dependent on RXRα but is not associated with the up-regulation of VDR expression.

Background Clinical observations have suggested repeated gonadotropin-releasing hormone (GnRH) exposure to cause intestinal dysfunction and loss of enteric neurons. This has been further studied and confirmed in a rat in vivo model involving iterated GnRH treatments. Mechanisms behind are enigmatic since no GnRH receptors are found to be expressed in enteric neurons neither in man nor rat. Both species, however, harbor substantial subpopulations of luteinizing hormone (LH) receptor-immunoreactive myenteric neurons which suggests that intestinal GnRH-induced neuropathy may be mediated by LH release. Aims To reveal if exposures of GnRH or LH to rat myenteric neurons in vitro cause neuronal loss. Methods Primary cultured adult rat myenteric neurons were exposed to single or repeated treatments of the GnRH analog buserelin or the LH analog lutrotropin alpha, and neuronal survival was determined by cell counting. Possible presence of GnRH- or LH receptor -immunoreactive neurons was determined by immunocytochemistry. Results Exposure to the LH, but not the GnRH, analog caused significantly reduced neuronal survival. LH, but not GnRH, receptors were found to be expressed on cultured myenteric neurons. Conclusion Myenteric neurons express LH receptors in vitro and LH exposure causes reduced neuronal survival. This suggests that GnRH-induced enteric neuropathy in vivo is mediated by way of LH release and activation of enteric neuronal LH receptors.

Objectives Hepatic arterial treatment (HAT) for liver metastases in patients with metastatic breast cancer (MBC) has only been investigated in few studies. Materials and methods Two phase II trials were initiated simultaneously to evaluate capecitabine in combination with oxaliplatin in patients with MBC and liver metastases. These two trials are reported together. Continuous capecitabine (1300 mg/m2) was combined with oxaliplatin (85 mg/m2) alternating between systemic treatment and HAT followed by degradable starch microspheres with EmboCept® S every second week. Four patients participated in a pharmacokinetic analysis of oxaliplatin. Each patient had samples taken when receiving oxaliplatin systemically and as HAT with and without EmboCept® S. Results Totally, 52 patients received HAT: 14 with liver metastases only and 38 patients with additional limited metastatic disease. The patients had previously received a median of 2 (range 0–6) chemotherapeutic regimens for MBC. The response rate was 42.3% (95% confidence interval (CI) 28.7–56.8%) with 7.7% complete and 34.6% partial responses. Median progression free survival was 10.8 months (95% CI 6.9–14.7 months) and median overall survival 27.6 months (95% CI 20.4–34.8 months). The toxicity was moderate with hand-foot syndrome (15.4%), neuropathy (9.6%), fatigue (9.6%), and abdominal pain (9.6%) being the most common grade 3 adverse events. There was no clear difference between systemic blood concentrations of oxaliplatin when given systemic or as HAT. Conclusion HAT oxaliplatin in combination with capecitabine is safe and efficient in patients with MBC. The results are promising with high response rates and a long median progression free and overall survival.

ObjectiveTo examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE ε4 genotype.MethodsThis observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [11C]Pittsburgh compound B–PET imaging in 2014–2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE ε4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR >2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR−, n = 30) consisted of individuals with HOMA-IR APOE ε4 carriers, resulting in 50% (n = 15) APOE ε4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression.ResultsAn amyloid-positive PET scan was found in 33.3% of the IR− group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1–8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE ε4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (β = 0.11, 95% confidence interval 0.002–0.22, p = 0.04).ConclusionsThese results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia.

The purpose of the study was to examine in vivo placental transfer of metformin, its association with neonatal outcome in metformin-treated gestational diabetes (GDM) patients, and influence of metformin exposure on maternal glycemic control and weight gain. Two hundred and seventeen GDM patients were randomized to metformin or insulin in Turku University Hospital, Finland. Metformin concentrations were determined by mass spectrometry in maternal serum at 36 gestational weeks (gw) and at birth, and in umbilical cord blood. Main outcome measures were birth weight, gw at birth, umbilical artery pH and neonatal hypoglycemia, maternal weight gain, HbA1c and fructosamine concentration. Median umbilical cord/maternal serum metformin concentration ratio was 0.73. There were no differences in birth weight measured in grams or SD units (p = 0.49), or gw at birth (p always ≥0.49) between insulin- and metformin-treated patients stratified by trough metformin concentration tertiles measured at 36 gw. Rate of neonatal hypoglycemia (p = 0.92) and umbilical artery pH value (p = 0.78) was similar in insulin- and metformin-treated patients stratified by cord metformin concentration tertiles. Maternal glycemic control was similar in metformin concentration tertiles at 36 gw. Maternal weight gain was 223 g greater per week (p = 0.038) in the lowest metformin tertile compared to other tertiles combined. Maternal and fetal exposure to metformin is similar. Maternal or fetal metformin concentrations do not predict maternal glycemic control or neonatal outcome, but low maternal exposure may lead to greater maternal weight gain.

Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)>3.0 mg/mmol and ≤ 30 mg/mmol, is an early marker of endothelial damage of the renal glomeruli. Recent research suggests an association among microalbuminuria, albuminuria (UACR > 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro- plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro- plus macroalbuminuria associated with poorer word-list learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline.

To test the efficacy and safety of ursodeoxycholic acid (UDCA) in the treatment of patients with intrahepatic cholestasis of pregnancy (ICP).In the randomized (double-blind, placebo-controlled) study 20 pregnant women with ICP received (random allocation of) either 450 mg/day UDCA or placebo for 14 days during the third trimester of pregnancy. The severity of pruritus was registered and itching scores were assessed before the treatment and weekly thereafter. The effects of UDCA on liver function and fetoplacental hormone production were measured with covering laboratory testing: serum levels of alanine aminotransferase (ALAT), total bile acids (TBA), estradiol, progesterone, prolactin, cholesterol, HDL-cholesterol, triglycerides, activated partial thromboplastin time, fibrinogen D-dimers (FIDD) and platelet count were assessed before the treatment and weekly thereafter. Data on pregnancy and delivery outcome were recorded and analyzed.UDCA was well tolerated. A significant improvement in itching scores was detected in 2 weeks in the group receiving UDCA. Serum levels of ALAT and TBA fell after 2 weeks treatment. The other laboratory values were not modified by the treatment.UDCA improves maternal itching scores and liver function tests without interfering with the fetoplacental estrogen production in patients with ICP. UDCA is well tolerated by pregnant women. No fetal or neonatal side-effects could be detected.

Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old).After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated.Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice.In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.

Colostrum is an indispensable source of antibodies (IgG) protecting the newborn pig against infection. We studied the effect of feeding colostrum and purified IgG on early structure and development of the gastrointestinal tract (GIT). Newborn littermate pigs were fed either colostrum, an elemental diet (ED), or an ED supplemented with purified serum IgG (ED + IgG) for 24 h or then only ED up to 72 h. Afterwards, pigs were slaughtered. Colostrum-fed pigs or ED supplemented with IgG (ED + IgG) increased thickness (P < 0.001) of stomach mucosa and muscularis (P < 0.05) compared to the ED group not receiving IgG. Feeding an ED supplemented with IgG improved morphology of the GIT towards that of colostrum-fed piglets and indicates a beneficial effect of IgG on GIT development in neonatal pigs. Immunohistochemical studies indicate that ED feeding may influence the expression of nitric oxide synthase in jejunal myenteric (but not submucous) neurons of newborn pigs.

In addition to brain injury stroke patients often suffer gastrointestinal complications. Neuroimmune interactions involving galectin-3, released from microglia in the brain, mediates the post-stroke pro-inflammatory response. We investigated possible consequences of stroke on the enteric nervous system and the involvement of galectin-3. We show that permanent middle cerebral artery occlusion (pMCAO) induces loss of enteric neurons in ileum and colon in galectin-3+/+, but not in galectin-3−/−, mice. In vitro we show that serum from galectin-3+/+, but not from galectin-3−/−, mice subjected to pMCAO, caused loss of C57BL/6J myenteric neurons, while myenteric neurons derived from TLR4−/− mice were unaffected. Further purified galectin-3 (10−6 M) caused loss of cultured C57BL/6J myenteric neurons. Inhibitors of transforming growth factor β-activated kinase 1 (TAK1) or AMP activated kinase (AMPK) counteracted both the purified galectin-3 and the galectin-3+/+ pMCAO serum-induced loss in vitro. Combined we show that stroke (pMCAO) triggers central and peripheral galectin-3 release causing enteric neuronal loss through a TLR4 mediated mechanism involving TAK1 and AMPK. Galectin-3 is suggested a target for treatment of post-stroke complications.

Aims We compared metformin with insulin as treatment of gestational diabetes mellitus (GDM). Furthermore, we aimed to characterize metformin-treated patients needing additional insulin to achieve prespecified glucose targets. Methods We conducted a single centre randomized controlled study with non-inferiority design comparing metformin and insulin in the treatment of 217 GDM patients having birth weight as primary outcome variable. Results There were no significant differences in mean birth weight expressed in grams [+15 (90% confidence interval (CI): −121 to 89)] or SD units [+0.04 (90% CI: −0.27 to 0.18)] between the metformin and insulin groups. There were no significant differences in neonatal or maternal data between the groups. Only 23 (20.9%) of the 110 patients in the metformin group needed additional insulin. Compared with the patients on metformin only, those needing additional insulin were older (p = 0.04), their oral glucose tolerance test had been performed earlier and diabetes therapy started earlier in gestation (p = 0.01 and p = 0.004, respectively). The risk for additional insulin was 4.6-fold in women with baseline serum fructosamine concentration above median compared with those below median. Conclusions Metformin is an effective alternative to insulin in the treatment of GDM patients. Serum fructosamine may help in predicting the adequacy of metformin treatment alone.

A few patients have been shown to develop severe abdominal pain and gastrointestinal dysmotility during treatment with gonadotropin‑releasing hormone (GnRH) analogs. A rat model of enteric neuropathy has been developed by administration of the GnRH analog buserelin to rats. Loss of enteric neurons and ganglioneuritis throughout the gastrointestinal tract has been described, without other histopathological changes. The aim of the present study was to investigate the long‑term effects of this rat model on body weight, and on morphology and inflammatory changes in the gastrointestinal tract. Rats were administered subcutaneous injections of buserelin or saline once daily for 5 days and allowed to recover for 3 weeks. This regimen was repeated four times. The rats were weighed weekly and were sacrificed 16 weeks after the fourth treatment. The bowel wall was measured by morphometry, and the presence of enteric neurons, mast cells, eosinophils and T‑lymphocytes was evaluated. Buserelin‑treated rats were shown to have a lower body weight at sacrifice, as compared with the controls (P

Predictive strategies for the treatment efficacy of cetuximab are currently not available for head and neck cancer. We investigated the correlation between the expression of epidermal growth factor receptor (EGFR) ligands and EGFR expression, and the growth inhibitory activity of cetuximab in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines.The growth inhibiting effect of cetuximab was measured for eight HNSCC cell lines and correlated with the autocrine production of five EGFR ligands as measured by ELISA, and the mRNA expression of two ligands, as measured by quantitative RT-PCR. EGFR expression was assessed by western blot analysis.There was a good correlation between the expression of four of the EGFR ligands (TGF-α, amphiregulin, epiregulin and epigen) and the growth inhibiting effect of cetuximab. TGF-α had the highest predictive potential but had to be combined with epigen for full prediction. EGFR expression also correlated with cetuximab sensitivity but less clearly.The results indicate that the expression of several EGFR ligands has to be used to predict sensitivity to cetuximab in HNSCC. This has to be further evaluated in clinical samples.

Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs.Fifteen placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of repaglinide by using antipyrine as a reference of passive-diffusion transfer compound. Genotyping was performed for all placentas.Maternal-to-fetal transfer of repaglinide and antipyrine were 1.5% and 13.2%, respectively, and fetal-to-maternal transfers were 6.7% and 40.3%, respectively. Fetal-to-maternal transfer of repaglinide was statistically significantly higher than maternal-to-fetal transfer (P0.0001). The number of placentas was not sufficient for proper statistical analysis, but the fetal-to-maternal transfer seemed to be affected by the SLCO1B3 polymorphism.The placental transfer of repaglinide from mother to fetus was low. Since a higher transfer rate of repaglinide was observed in fetal-to-maternal than maternal-to-fetal direction, active transport by OATP-transporters may be an important factor in fetal exposure to repaglinide.

Aims of the present stud were to describe the distribution of corticotropin releasing factor (CRF) immunoreactivity in rat small and large intestines, to quantify the percentage of CRF-immunoreactive (CRF-IR) enteric neurons, to reveal possible CRF immunoreactivity in cultured myenteric neurons from rat ileum and to examine if additions of CRF, urocortin 1 (Ucn1), CRF antagonist or vasoactive intestinal peptide (VIP) affect neuronal survival in vitro. Co-localization of CRF- and VIP-immunoreactivity was examined, as well as a possible interplay between CRF and VIP in neuroprotection. Further we wanted to elucidate if mast cells affect neuronal survival via CRF signaling. Networks of CRF-containing nerve cell bodies and fibers were detected in rat intestine. CRF-IR neurons contained to a high degree also VIP. A low number of cultured myenteric neurons was CRF-IR. CRF, Ucn1 or CRF-antagonist did not promote neuronal survival of cultured myenteric neurons, while VIP significantly enhanced neuronal survival. Simultaneous presence of CRF attenuated the VIP mediated increase in neuronal survival. Co-culturing neurons and mast cells resulted in a marked reduction in neuronal survival, not executed via CRF signaling pathways. Conclusion: CRF is present in enteric neurons and counteracts the neuroprotective effect of VIP in vitro. (c) 2010 Elsevier B.V. All rights reserved. (Less)

article i nfo Background: Sympathetic over activity has been suggestedto impact on the risk of cardiovascular diseases. The origin of abnormalities in the autonomic nervous system is unknown, but it is susceptible to environmental influences during the critical periods of human development. Aims: To examine the influence of maternal characteristics on fetal cardiac autonomic nervous activation. Study design: Prospective, observational study. Subjects: 41 fetuses from normal pregnancy born after 36 gestational weeks. Outcome measures: Maternal characteristics that affect fetal intrauterine well-being intrauterine environ- mental factors were evaluated, including pre-pregnancy body mass index as well as GHbA1c, blood pressure and 3-day food diaries from each trimester of pregnancy. To assess intrapartum fetal cardiac sympathovagal activation fetal ECG was recorded for 1 h during delivery. Heart rate variability was measured using power spectrum analysis of low-to-high frequency ratio of fetal heart rate variability. Results: Cardiac sympathetic activation measured during delivery was associated with maternal pre-pregnancy body mass index (r=0.33,p=0.03), placental weight (r=0.4,p=0.008) and the immaturity of the fetus (r= �0.3, pb0.05). Conclusion: Early intrauterine environmental factors such as maternal pre-pregnancy body mass index are associated with fetal sympathetic activation with a potential for cardiovascular programming.

Overweight, characterized by low-degree systemic inflammation, predisposes women to impaired glucose metabolism during pregnancy. Adipokine leptin participates in the regulation of energy balance and immune action. Objective of the study was to evaluate if aberrations in glucose metabolism during pregnancy are related to leptin concentration and whether serum leptin concentration is affected by diet composition. Normal-weight (n = 61) and overweight or obese (BMI > 25, n = 42) pregnant women visited study clinic at third trimester of pregnancy and one month postpartum. Serum fasting leptin and insulin as well as plasma glucose concentrations were measured, insulin resistance (HOMA) and sensitivity (QUICKI) calculated, and dietary intake from food records determined. In overweight women leptin concentration was significantly higher both in pregnancy, 45.27 (95% CI 39.40–51.14) ng/ml, and postpartum, 31.84 (27.38–36.30) ng/ml, than in normal-weight women, 31.09 (95% CI 27.80–34.37) ng/ml and 16.23 (13.93–18.53) ng/ml, respectively. Equally, blood glucose concentration during pregnancy was higher, 4.82 (4.67–4.97)mmol/l, and insulin concentration, 15.34 (12.00–18.68) mU/l, more pronounced in overweight compared to normal-weight women, 4.51 (4.42–4.61) mmol/l and 8.28 (7.21–9.36) mU/l, respectively. Significantly higher HOMA and lower QUICKI were also detected in overweight compared to normal-weight women. At third trimester of pregnancy, leptin concentration correlated positively with insulin concentration in normal-weight (r = 0.561, P = 0.002) and overweight women (r = 0.736, P

Mast cell-nerve interactions play a key role in intestinal inflammation and irritable bowel disease. Loss of enteric neurons has been reported in inflammatory conditions but the contribution of mast cells in this event is unknown. To study neuronal survival and plasticity of myenteric neurons in contact with mast cells a co-culture system using myenteric neurons from rat small intestine and peritoneal mast cells was set up. Dissociated myenteric neurons were cultured for 4 days before addition of mast cells isolated by peritoneal lavage. Neuronal survival and expression of vasoactive intestinal peptide (VIP) and nitric oxide synthase (NOS) were studied by immunocytochemistry and neuronal cell counting. Myenteric neurons cultured without mast cells were used to study the rate of neuronal survival after the addition of various mast cell mediators, proteinase-activated receptor(2) (PAR(2)) agonist, VIP or corticosteroid. A striking mast cell-induced neuronal cell death was found after co-culturing. It was counteracted by the addition of mast cell stabiliser doxantrazole, protease inhibitors, PAR(2) antagonist FSLLRY-amide, corticosteroid or VIP. In myenteric neurons cultured without mast cells the PAR(2) agonist SLIGRL-amide, prostaglandin D(2) and interleukin (IL) 6 reduced neuronal survival while histamine, serotonin, heparin, IL1beta and tumour necrosis factor alpha had no effect; corticosteroid and VIP enhanced neuronal survival. The relative numbers of VIP-, but not NOS-expressing myenteric neurons increased after co-culturing. Mast cell-induced neuronal cell death is suggested to be mediated via PAR(2) activation, IL6 and prostaglandin D(2). Corticosteroid and VIP are neuroprotective and able to prevent cell death of myenteric neurons in co-culture.

Erythropoiesis-stimulating agents (ESAs) are used in cancer therapy to reverse anaemia. It has been suggested that ESAs might improve treatment outcome by reducing tumour hypoxia, but ESAs might also increase tumour growth. In this work, the effect of recombinant human erythropoietin (rHuEpo) beta was investigated on a human head and neck squamous carcinoma cell (HNSCC) line in vitro. The cell line was previously growth stimulated in combination with surgery in a xenograft model and the investigation was initiated to see if rHuEpo directly affects the tumour cell line, alone or in combination with cell stress, or if the in vivo effect should be attributed to secondary effects.The cell line LU-HNSCC-7 was grown in vitro and treated with rHuEpo alone or in combination with radiation, cisplatin, hypoxia or tumour extracts. The expression of the Epo receptor (EpoR) was investigated by western blotting after one- and two-dimensional electrophoresis, RT-PCR and through analysis of the effect on EpoR signalling.The cell line was shown not to express EpoR. Furthermore, it was only possible to detect a minor effect on cell growth (1.4 times over control, p0.001) under specific conditions and at supra-pharmacological concentrations of rHuEpo beta. No effect was detected on cell migration. None of the cell stressing treatments could enhance the minor growth stimulatory effect of rHuEpo beta.The conclusion is that rHuEpo beta does not stimulate tumour growth of the investigated cell line through a direct interaction with tumour cells. We hypothesise that interactions with stromal cells and the stimulation of wound healing responses might, at least partly, explain the negative effects of ESA administration during cancer treatment. We propose that EpoR expression in HNSCC tumour cells might not be a good marker for prediction of ESA induced worsening of outcomes after cancer treatment.

The role of the enteric nervous system in intestinal inflammation is not fully understood and the plethora of cellular activities concurrently ongoing in vivo renders intelligible studies difficult. In order to explore possible effects of bacterial lipopolysaccharide (LPS) on enteric neurons we utilised cultured myenteric neurons from rat small intestine. Exposure to LPS caused markedly reduced neuronal survival and increased neuronal expression of vasoactive intestinal peptide (VIP), while the expression of Toll-like receptor 4 (TLR4) was unchanged. TLR4 was expressed in approximately 35% of all myenteric neurons irrespective of if they were cultured in the presence or absence of LPS. In neurons cultured in medium, without LPS, 50% of all TLR4-immunoreactive neurons contained also VIP. Addition of LPS to the neuronal cultures markedly increased the proportion of TLR4-immunoreactive neurons also expressing VIP, while the proportion of TLR4 neurons devoid of VIP decreased. Simultaneous addition of LPS and VIP to the neuronal cultures resulted in a neuronal survival comparable to controls. CONCLUSIONS: LPS recognition by myenteric neurons is mediated via TLR4 and causes neuronal cell death. Presence of VIP rescues the neurons from LPS-induced neurodegeneration. (Less)

To evaluate and compare plasma glutathione S-transferase alpha (GSTA) concentrations in the third trimester of pregnancy in patients with intrahepatic cholestasis of pregnancy (ICP) and in healthy pregnant women.Non-randomized clinical study.Maternity unit and Department of Clinical Chemistry, Turku University Central Hospital, Turku, Finland.Twenty-seven women with ICP and 49 healthy pregnant women.GSTA concentrations were assessed in plasma samples in the third trimester of pregnancy using an enzyme-linked immunoassay (HEPKIT Alpha, Biotrin, Sinsheim-Reihen, Germany).Plasma GSTA, serum alanine and bile acid concentrations were compared between study and control group. Correlation between plasma GSTA levels and serum alanine aminotransferase and bile acid levels in the ICP patients were tested by Spearman correlation coefficients. Main perinatal outcome was compared between the groups.GSTA concentration in the control group was 1.62 microg/l (range: 0.25-6.1). In the ICP patients, the mean plasma GSTA concentration was 51.0 microg/l (range: 2.1-183.5), the mean serum alanine aminotransferase concentration was 145.70 U/l (range: 6-393) and the mean bile acid concentration was 19.2 micromol/l (range: 3-63). There was a statistically significant correlation in ICP patients between plasma GSTA concentration and serum alanine aminotransferase concentration (r=0.694, p=0.0001), but not with serum bile acid concentration. Nor was there any statistically significant correlation between gestational weeks and plasma GSTA concentration in the study group.Plasma GSTA measurements may provide a more sensitive and specific diagnostic tool for diagnosis of ICP than the evaluation of transaminases or bile acid concentrations alone. Further studies are needed to evaluate the role of GSTA in the follow-up of patients with ICP and its prognostic value for threatening fetal distress in patients with ICP.

Objective To compare Continuous Glucose Monitoring System (CGMS ® ) with self-monitoring of plasma glucose (SM) in detecting patients with gestational diabetes mellitus (GDM) needing antidiabetic drug treatment. Research design and methods Pregnant women at 22–34 gestational weeks had at least two abnormal high values out of three in OGTT. Patients were randomly allocated to have CGMS ® ( n =36) or SM ( n =37). Dietary counselling was similar in both groups. Patients tested their plasma glucose 5 times per day. Need of antidiabetic treatment was determined using the following cut-off values: fasting plasma glucose >5.5mmol/L twice or >5.5mmol/l once and postprandial value>7.8mmol/l, or postprandial value at least twice above 7.8mmol/l. Results In 11 out of 36 patients (31%) monitored with CGMS ® antihyperglycemic drug therapy was introduced (8/36 insulin only, 2/36 metformin only, 1/36 insulin+metformin) whereas only 3/37 (8%) in the self-monitoring group were drug-treated (difference between groups, p =0.0149). There were no statistically significant differences between the groups regarding maternal age, pre-pregnancy BMI, HbA1c, gestational weeks at delivery, rate of pregnancy-induced hypertension, rate of caesarean section, infant birth weight or neonatal hypoglycaemia. Conclusions Continuous glucose monitoring system detects a markedly higher proportion of GDM mothers needing antihyperglycemic medication compared with self-monitoring of plasma glucose. Further large-scale studies are needed to evaluate whether CGMS ® guided initiation of antihyperglycemic therapy results in less macrosomia and perinatal complications related to GDM.

OBJECTIVE: Periodontal ligament (PDL) cells express oestrogen receptor beta (ERbeta) protein, but cellular functions regulated by ERbeta in these cells have not been identified. In this study we determine if ERbeta is localised to mitochondria and if oestrogen regulates mitochondrial function in human PDL cells obtained from teeth extracted for orthodontic reasons. DESIGN: Subcellular distribution of ERbeta was determined by confocal microscopy of cells co-stained with ERbeta antibody and the mitochondrion-selective probe MitoTracker and by immunogold electron microscopy. Expression of the mitochondrial enzyme cytochrome c oxidase subunit I, involved in oxidative phosphorylation, was determined by Western blotting in cells treated with or without physiological concentrations of the endogenous oestrogen 17beta-oestradiol. RESULTS: ERbeta immunoreactivity was observed both in the nuclei and the cytoplasm. MitoTracker-labelling was observed in the cytoplasm, especially in the perinuclear region, but not in the nuclei. Co-localisation of ERbeta and MitoTracker was observed in cells derived from both male and female subjects. Mitochondrial localisation of ERbeta was confirmed by immunogold electron microscopy. Cells treated with or without 17beta-oestradiol (100 nM) displayed an identical pattern of staining for mitochondria. Treatment with 100 nM 17beta-oestradiol attenuated cytochrome c oxidase subunit I expression by about 30%, while combined treatment with 17beta-oestradiol and the ER blocker ICI 182780 (10 microM) had no effect. CONCLUSION: This study demonstrates mitochondrial localisation of ERbeta and oestrogen-induced decrease in the expression of cytochrome c oxidase subunit I in human PDL cells, suggesting that oestrogen probably via ERbeta influences mitochondrial function and PDL cell energy (Less)

Aims: Cocaine- and amphetamine-regulated transcript (CART)-peptide is found in the brain and participates in the control of feeding behavior. It is also expressed in the peripheral nervous system and is suggested to have neuromodulatory and/or neurotrophic effects in rat intestine. The aims of this study were to investigate the presence of CART-peptide in the normal ganglionic as well as aganglionic intestine from patients with Hirschsprung's disease and the pepticle's possible coexistence with other neurotransmitters. Methods: Intestinal specimens from nine patients with Hirschsprung's disease were examined using immunohistochemistry. A double immunostaining technique was used in order to elucidate the presence of CART-peptide in NOS and VIP-containing enteric neurons. Results: in ganglionic intestine, CART-peptide was found in numerous nerve fibers, predominantly within the smooth muscle layers and in myenteric nerve cell bodies. A high degree of co-localization of CART with NOS and VIP was seen. Only very few CART immunoreactive nerve fibers and no nerve cell bodies were found in the aganglionic intestine. Conclusions: This is the first report on the presence of CART-peptide in the human intestine. In the ganglionic intestine CART was detected mainly in myenteric neurons, while only very few CART-IR nerve fibers were found in the aganglionic intestine. This, together with the coexistence of CART with NOS and VIP, indicates an intrinsic origin of the CART-containing neurons and suggests that CART may influence NO and VIP-induced effects. (Less)

UNLABELLED The effects of maternal magnesium sulphate treatment on neonatal mineral status and parathyroid hormone secretory response were studied in 8 exposed and 27 control preterm infants during the first 2 wk of life. Antenatal magnesium sulphate resulted in hypermagnesaemia during the first 3-7 d of life without affecting other serum mineral concentrations. CONCLUSION Early hypermagnesaemia was associated with hypercalciuria during the first 3 d and parathyroid hormone suppression up to the age of 2 wk in the exposed infants.

Good metabolic control maintained throughout pregnancy reduces maternal and fetal complications in diabetic women. The long-acting insulin analogue glargine has 24-h persistence and a peakless action profile, and could contribute to more stable daily plasma glucose levels and improved glycemic control. We evaluated the metabolic control associated with insulin glargine during pregnancy in comparison with conventional basal insulin therapy.Retrospective case-control analysis of glycemic control and pregnancy complications in 100 type 1 diabetic pregnancies with intermediate-acting NPH insulin or insulin glargine prior to conception and throughout pregnancy.Overall,glycemic control was not different between the groups, though the decrease in HbA1c from the first to the third trimester was greater with insulin glargine (0.8 versus 0.3%, p=0.04). The rate of hypoglycemia was comparable.Our findings suggest that, as regards metabolic control, insulin glargine in women with type 1 diabetes is comparable with NPH insulin as basal insulin therapy. No adverse effects were associated with glargine use at the time of conception and during pregnancy.

Background To exam the biochemical, obstetric management and pregnancy outcome in women with intrahepatic cholestasis of pregnancy (ICP) and treatment with ursodeoxycholic acid (UDCA). Methods Pregnancy outcome in patients with ICP (N = 307) was studied and patients treated with UDCA (N = 208) vs. no UDCA were compared. The data of the antenatal visits, deliveries and neonatal outcome of 307 pregnancies with ICP was collected from the hospital computerized delivery room log book. UDCA was used in 208 pregnancies. The diagnosis was made by maternal pruritus and elevation of total fasting bile acid (BA) (>6 μmol/l) and elevation of serum alanine aminotransferases (ALT) (>45 U/l). Maternal and neonatal data was analysed and data of the patients who used UDCA during pregnancy was analysed separately and compared with the data from patients without medication. Results UDCA was well tolerated. Mothers receiving UDCA had ICP diagnosed five weeks earlier than mothers without medication. At the diagnosis, levels of total BA and ALT were higher in the group using UDCA compared to the group without medication. Most deliveries were induced and perinatal outcome was good. Apgar scores at 5 min were significantly lower in UDCA group (p 0.05). There were 30 patients with total BA > 40 μmol/l at diagnosis, 24 with UDCA and 6 without medication and those deliveries were induced soon after diagnosis. The preterm labour was also more common in these patents (p 40 μmol/l), ALT levels were also significantly higher and ICP was diagnosed earlier (p

Type 2 diabetes is an independent risk factor for cognitive decline. Insulin resistance occurring during midlife may increase the risk of cognitive decline later in life. We hypothesised that insulin resistance is associated with poorer cognitive performance and that sex and APOE*E4 might modulate this association.The association of insulin resistance and APOE*E4 genotype on cognitive function was evaluated in a nationwide Finnish population-based study (n = 5,935, mean age 52.5 years, range 30-97 years). HOMA-IR was used to measure insulin resistance. Cognitive function was tested by word-list learning, word-list delayed-recall, categorical verbal fluency and simple and visual-choice reaction-time tests. Linear regression analysis was used to determine the association between HOMA-IR and the results of the cognitive tests.Higher HOMA-IR was associated with poorer verbal fluency in women (p 0.0001) but not in men (p = 0.56). Higher HOMA-IR was also associated with poorer verbal fluency in APOE*E4 -negative individuals (p = 0.0003), but not in APOE*E4 carriers (p = 0.28). Furthermore, higher HOMA-IR was associated with a slower simple reaction time in the whole study group (p = 0.02).To our knowledge, this is the first comprehensive, population-based study, including both young and middle-aged adults, to report that female sex impacts the association of HOMA-IR with verbal fluency. Our study was cross-sectional, so causal effects of HOMA-IR on cognition could not be evaluated. However, our results suggest that HOMA-IR could be an early marker for an increased risk of cognitive decline in women.

Introduction Metformin seems to reduce gestational weight gain compared with insulin in women with gestational diabetes (GDM). Women with GDM requiring insulin are more likely to develop abnormal glucose tolerance postpartum than women treated with diet only. In this prospective follow-up study of a randomized clinical trial, we investigated the effect of metformin treatment in women with GDM on weight gain and glucose tolerance postpartum. Materials and Methods Women with GDM with two or more pathologic glucose values at 2-h 75-g oral glucose tolerance test (OGTT) were recruited. Those needing medication to achieve sufficient glycemic control were randomized at 22–34 weeks of gestation to either metformin (n = 110) or insulin (n = 107) treatment until delivery. A third GDM group (n = 128) requiring no medication had only diet treatment. Weight, OGTT and glycosylated hemoglobin (HbA1c) were determined at 6–8 weeks and 1 year postpartum. Results At least one postpartum visit was attended by 104, 101 and 120 women in the metformin, insulin and diet-only groups, respectively. No significant differences were found in the change of weight, HbA1c or OGTT glucose values between the groups during the study (p ≥ 0.121 in all comparisons). One year postpartum the diet-only group had less impaired glucose tolerance compared with the metformin and insulin groups (7.1%, 19.1% and 15.6%, respectively; overall p = 0.039) and a lower incidence of diabetes (p = 0.027). Conclusions Short-term metformin therapy does not affect weight, HbA1c or OGTT glucose values postpartum compared with insulin or diet-only treatments. Women with GDM requiring no medication are least likely to develop impaired glucose tolerance or diabetes postpartum.

The receptors for VIP and PACAP were characterized in vitro on rat ileal and colonic longitudinal smooth muscle with adherent myenteric ganglia. Colon strips from PAC1 receptor knockout and wildtype mice were also examined. VIP, PACAP-38 and PACAP-27 all caused concentration dependent relaxations. In rat ileum three different types of smooth muscle VIP/PACAP receptors were defined: (1) a PACAP-27 preferring receptor coupled to apamin sensitive Ca(2+)-dependent K+ channels, (2) a PAC1 receptor activated by both PACAP-27 and PACAP-38, and (3) a VIP specific receptor regulated by NPY. The receptors identified in rat colon were: (1) a PAC1 receptor localized on NO synthesizing neurones. Activation leads to increased NO production. (2) A smooth muscle PAC1 receptor. The responses elicited by both receptors were abolished by apamin. (3) A smooth muscle VIP specific receptor. PAC1 receptor knockout mice did not respond to PACAP-27 or PACAP-38, whereas VIP induced a relaxatory response indicating the presence of a VIP specific receptor. In wildtype mice all three peptides elicited relaxatory responses. Pharmacological characterization of intestinal VIP/PACAP receptors indicates the existence of receptors, such as a PACAP-27 preferring receptor and a VIP specific receptor, distinct from those that have been cloned (VPAC1, VPAC2, and PAC1).

Total parenteral nutrition (TPN) is often crucial for patients not being able to feed enterally or having intestinal absorptive deficits. Enteral nutrition is, however, frequently regarded vital for maintaining functional and structural intestinal integrity. The aim of this study was to investigate possible effects of TPN on rat distal small intestine compared to enterally fed identically housed controls, regarding the enteric nervous system (ENS), motility in vitro, and morphology. This study shows that motor responses evoked by electrical stimulation or exposure to vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide-27 (PACAP-27), and nitric oxide (NO) donor were unchanged. By using immunohistochemistry, the numbers of submucous (P < 0.05) and myenteric (P < 0.05) nerve cells were found to increase, expressed as numbers per unit length. The percentage of neurons expressing VIP, PACAP-27, NO-synthase, and galanin remained unchanged, however. By in situ hybridization the number of submucous neurons expressing neuropeptide Y-mRNA was found to decrease (P < 0.05); the other populations were unaltered. Morphometry revealed an increased submucosal thickness (P < 0.05), while intestinal circumference markedly decreased (P < 0.0001) in TPN-treated rats. In conclusion, TPN treatment resulted in reduced intestinal circumference leading to condensation of enteric neurons. No marked changes in neurotransmitter expression of the enteric neurons or in motor activity were noted.