Geographic distribution of cervical cancer-associated human leucocyte antigens and cervical cancer incidence in Finland

Cervical cancer (CxCa) is a long-term sequelae caused by persistent human papillomavirus (HPV) infection. Genetic susceptibility to the persistent infection and CxCa is associated with certain human leucocyte antigen (HLA) types. The same susceptibility genes may also determine whether a woman will be protected against the persistent infection and against CxCa by HPV vaccination or not. A systematic review of literature identified following HLAs to be associated with CxCa: A11 (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.1-2.0); B7 (1.5, 1.1-2.0); B15 (0.6, 0.4-0.8); DR2 (1.2, 1.1-1.4) and DR6 (0.6, 0.5-0.8). In the Caucasian population, HLA-B7 and DR6, and DR2 and B15 antigens showed at least borderline associations. In view of a bone marrow donor registry at the Finnish Red Cross and the Finnish Cancer Registry, we created geographic distribution maps of index HLA frequencies and CxCa incidence in the fertile-aged Finnish population. Increased incidence of CxCa was found in a region of western coastal Finland, where frequency of two CxCa susceptibility genes (HLA-DR2 and B7) was increased, and frequency of one CxCa resistance gene (HLA-B15) was decreased. Whether or not HLA type determines also regional susceptibility to persistent HPV infection, and the success of HPV vaccination in preventing both the persistent infection and CxCa warrants further investigation.     

Dynamic neural activity recorded from human amygdala during fear conditioning using magnetoencephalography

Magnetoencephalography (MEG) was used to record the dynamics of amygdala neuronal population activity during fear conditioning in human participants. Activation during conditioning training was compared to habituation and extinction sessions. Conditioned stimuli (CS) were visually presented geometric figures, and unconditioned stimuli (US) were aversive white-noise bursts. The CS+ was paired with the US on 50% of presentations and the CS- was never paired. The precise temporal resolution of MEG allowed us to address the issue of whether the amygdala responds to the onset or offset of the CS+, and/or the expectation of the initiation or offset of the an omitted auditory US. Fear conditioning elicited differential amygdala activation for the unpaired CS+ compared to the CS-, extinction and habituation. This was especially robust in the right hemisphere at CS onset. The strongest peaks of amygdala activity occurred at an average of 270 ms in the right and 306 ms in the left hemisphere following unpaired CS+ onset, and following offset at 21 ms in the left and 161 ms in the right (corresponding to an interval of 108 ms and 248 ms after the anticipated onset of the US, respectively). However, the earliest peaks in this epoch preceded US onset in most subjects. Thus, the activity dynamics suggest that the amygdala both differentially responds to stimuli and anticipates the arrival of stimuli based on prior learning of contingencies. The amygdala also shows stimulus omission-related activation that could potentially provide feedback about experienced stimulus contingencies to modify future responding during learning and extinction.     

Childhood growth and hypertension in later life

Few studies have examined the effects of both prenatal and postnatal growth on hypertension. We report on hypertension in 2003 people aged 62 years who were randomly selected from the Helsinki birth cohort and examined in a clinic. Their heights and weights had been recorded serially up to age 11 years. A total of 644 had already been diagnosed with hypertension. Compared with normotensive people, they were obese and insulin resistant. At birth they were thin and short, and they gained weight slowly up to age 2 years; thereafter they grew rapidly so that at age 11 years their body size was around the average. The odds ratio associated with each kilogram of birthweight was 0.42 (95% CI: 0.32 to 0.56); with each 10 kg of current weight it was 1.85 (95% CI: 1.66 to 2.05). The blood pressures of another 802 people were classified as hypertensive under current definitions. They were overweight and had an atherogenic lipid profile. At birth they were short, and after birth they grew slowly so that at age 11 years they were short and thin. The odds ratio associated with each kilogram of weight at age 2 years was 0.75 (95% CI: 0.68 to 0.84); with each 10 kg of current weight it was 1.42 (95% CI: 1.28 to 1.57). We conclude that 2 different paths of childhood growth precede the development of hypertension. We suggest that they lead to hypertension through different biological mechanisms and may respond differently to medication.     

Environmental enrichment reduces mechanical hypersensitivity in neuropathic mice,but fails to abolish the phenotype of CCK2 receptor deficient mice

Genetic invalidation of CCK₂ receptors abolishes chronic constriction injury (CCI) induced mechanical hypersensitivity in mice. However, housing in environmentally enriched conditions significantly alters the phenotype of CCK₂ receptor deficient mice in all major behavioral domains. Furthermore, environmental enrichment itself has been reported to have protective effects in several rodent models of neurological diseases (brain and spinal trauma, ischemic stroke, Alzheimer's disease, etc.). In the present study we reproduced the earlier finding that mice, lacking CCK₂ receptors (−/−) are resistant to CCI-induced hypersensitivity. On the other hand, environmental enrichment substantially reduced CCI-induced mechanical hypersensitivity in wild-type (+/+) mice. Nevertheless, the phenotypic differences between wild-type (+/+) and mutant (−/−) mice in mechanical sensitivity before and after CCI-surgery were not eliminated by alternative housing conditions. These observations suggest that environmental enrichment has beneficial effects in neuropathic conditions and reinforce the causal link between CCK₂ receptors, mechanical sensitivity and the development of CCI-induced hypersensitivity.     

Prenatal Origins of Poor Sleep in Children

Study Objectives:

We examined whether small body size at birth and prenatal tobacco or alcohol exposure predict poor sleep and more sleep disturbances in children.

Design:

An epidemiologic cohort study of 289 eight-year-old children born at term.

Measurements and results:

Sleep duration and efficiency were measured by actigraphy for 7 consecutive nights (mean = 7.1, SD = 1.2). We used both continuous measures of poor sleep and binary variables of short sleep and low sleep efficiency ( ≤ 10^th percentiles). Parents completed the Sleep Disturbance Scale for Children. Lower birth weight and shorter length at birth were associated with lower sleep efficiency. For every 1-SD decrease in weight and length at birth, the odds for low sleep efficiency increased by 1.7 fold (95% confidence interval [CI]: 1.1 to 2.7) and 2.2 fold (95% CI: 1.3 to 3.7), respectively. For every 1-SD decrease in ponderal index at birth, the risk of parent-reported sleep disorders increased by 1.4 fold (95% CI: 1.0 to 2.0). Moreover, children exposed prenatally to alcohol had a 2.9-fold (95% CI: 1.1 to 7.6) and 3.6-fold (95% CI: 1.3 to 10.0) increased risk for having short sleep and low sleep efficiency, respectively. The associations were not confounded by sex, gestational length, prenatal and perinatal complications, body mass index at 8 years, asthma, allergies, or parental socioeconomic status.

Conclusions:

Poor sleep in children may have prenatal origins. Possible mechanisms include alcohol consumption during pregnancy and other conditions associated with small body size at birth.

Citation:

Pesonen AK; Röaikköonen K; Matthews K; Heinonen K; Paavonen JE; Lahti J; Komsi N; Lemola S; Jöarvenpöaöa AL; Kajantie E; Strandberg T. Prenatal origins of poor sleep in children. SLEEP 2009;32(8):1086-1092.     

Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.     

Antidepressant-like effect of agmatine is not mediated by serotonin

The aim of this study was to characterize the behavioral effects of systemically administered agmatine in animal models predictive of antidepressant- and anxiolytic-like activity and clarify whether the effects of agmatine depend on the intact serotonergic system. Only the highest dose of agmatine tested (50 mg/kg) decreased immobility of mice in the forced swimming test. The magnitude of the effect was slightly smaller than that of the tricyclic antidepressant imipramine (15 mg/kg). Agmatine did not change the locomotion of mice in the open field. Pretreatment with the tryptophane hydroxylase inhibitor PCPA for 3 days resulted in more than 70% drop in the tissue levels of 5-HT and 5-HIIA but did not counteract the antidepressant-like effect of agmatine. The administration of agmatine did not modify behavior of animals in the light-dark compartment test of anxiety. We conclude that the antidepressant-like effect of agmatine seems not to be mediated by the serotonergic system. We failed to confirm the reported anxiolytic-like activity of agmatine.     

Gastroesophageal reflux disease as a cause of death is increasing: analysis of fatal cases after medical and surgical treatment

OBJECTIVES: The population impact of modern treatment on complicated gastroesophageal reflux disease (GERD) is not well understood. Our aim was to determine the current mortality from GERD in Finland and compare this with the use of health resources. METHODS: In this population-based retrospective study, Finland's administrative databases provided figures on the nationwide use of antireflux medication, rate of antireflux surgery, and mortality from GERD. Any deceased person included had classic symptoms as well as objective findings of GERD. RESULTS: After analysis of the medical records of 306 patients, 213 were included. Annual mortality from GERD increased (P < 0.001) from 0.18/100,000 in 1987 to 0.46/100,000 in 2000. During that time, use of H2-blockers and proton pump inhibitors and the annual rate of antireflux surgery increased significantly (P < 0.001). Mortality from antireflux surgery, including fundoplication and gastric and esophageal resection, remained around 1.9/1,000 operations. Of the 213 patients whose cause of death was considered to be GERD, 180 (85%) had received medical treatment, including 4 patients whose death was related to either diagnostic or therapeutic endoscopy. Early complications of antireflux surgery caused 24 (11%) deaths; 9 (4%) were late failures of antireflux surgery. Causes of death in the medical group were hemorrhagic esophagitis (82, 47%), aspiration pneumonia (41, 23%), ulcer perforation (25, 14%), rupture with esophagitis (15, 9%), and stricture (13, 7%). CONCLUSIONS: Regardless of the increased use of health resources, mortality from GERD, especially with medical treatment, rose. Surgery for GERD was also associated with early mortality and usually could not prevent the fatal outcome.     

Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations

OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval.RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval.RESULTS—We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (P_meta = 3 × 10⁻⁵⁶) and glucose (P_meta = 1 × 10⁻¹³) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 × 10⁻⁵). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r² = 0.93 with rs780094) as the strongest association signal in the region.CONCLUSIONS—These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.Recently, in the genome-wide association Diabetes Genetics Initiative (DGI) Study for 19 traits, including plasma lipids, we provided evidence that the glucokinase (GCK) regulatory protein gene (GCKR) region was a novel quantitative trait locus associated with plasma triglyceride concentration (1). Of all single nucleotide polymorphisms (SNPs) tested, an intronic SNP at GCKR (rs780094) explained the greatest proportion of interindividual variability in plasma triglycerides (1).GCKR regulates GCK, which functions as a glucose sensor responsible for glucose phosphorylation in the first step of glycolysis. The discoveries that inactivating mutations in GCK cause maturity onset diabetes of the young type 2 (2) and activating GCK mutations lead to permanent hyperinsulinemic hypoglycemia (3) emphasize that GCK plays a major role in glucose metabolism. GCKR-deficient mice have reduced GCK expression but maintain nearly normal GCK activity and show impaired glucose clearance (4). Furthermore, adenoviral-mediated overexpression of GCKR in mouse liver increased GCK activity and lowered fasting blood glucose (5) and overexpression of GCK in liver led to lowered blood glucose and increased triglyceride concentrations (6,7). Thus, experimental evidence suggests that perturbation of the GCKR pathway has opposing effects of triglyceride and glucose metabolism.In our original report, SNP rs780094 in GCKR was associated with fasting triglyceride levels in two independent samples, each of Northern European ancestry (P = 3.7 × 10⁻⁸ and 8.7 × 10⁻⁸, respectively) (1). After initial identification and replication of a chromosomal region associated with a trait, key next steps include extension of the association finding to related phenotypes, validation of the association finding in different ethnicities, and fine- mapping to identify the putative causal variant. Recently, our initial finding was replicated in a Danish study in which a strong association was found between the rs780094 T allele and elevated fasting triglyceride levels but also lower insulin levels, better insulin sensitivity, and a moderately decreased risk of type 2 diabetes (8). In addition, recent genome-wide association studies identified an association between the same GCKR intronic SNP and C-reactive protein (CRP) levels (9,10).Hereby, we sought to examine the effect of SNP rs780094 on triglycerides and related metabolic traits, including fasting glucose concentrations, in 12 samples representing a range of ancestral groups and including a large prospective study with a mean follow-up time of 23 years. In addition, we performed fine-mapping in one of these samples to identify the strongest association signal in the region.