Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages.

Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P=2.66 × 10-10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P=3.07 × 10-19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the central nervous system. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter and cytoskeletal signalling occurs during early fetal brain development of BD I patients.

Long-term beneficial effects of glipizide treatment on glucose tolerance in subjects with impaired glucose tolerance.

AIMS: To assess the efficacy and long-term effects of glipizide treatment on glucose and insulin metabolism in individuals with impaired glucose tolerance (IGT). METHODS: Thirty-seven first-degree relatives of patients with type 2 diabetes fulfilling WHO criteria for IGT were randomized to treatment with either glipizide 2.5 mg once daily or matching placebo for 6 months. A 75 g, 2-h oral (OGTT) and 60 min intravenous glucose tolerance test (IVGTT) were performed at baseline and after 6 months. The subjects were followed up for another 12 months after discontinuation of treatment and a repeat OGTT was performed at 18 months. RESULTS: Thirty-three subjects fulfilled the study. Markers of insulin sensitivity - i.e. fasting insulin and HOMA(IR)-index - improved in the glipizide group (P = 0.04 and 0.02 respectively) as well as HDL cholesterol (P = 0.05) compared with placebo group after 6 months. At 18 months, both fasting and 2 h glucose concentrations were significantly lower in the glipizide group compared with the placebo group (P = 0.04 and 0.03 respectively). The prevalence of type 2 diabetes was 29.4% in the placebo group and 5.9% in the glipizide group at 18 months. This equals an 80% relative risk reduction in the active treatment group. CONCLUSIONS: Short-term treatment with glipizide improves glucose and insulin metabolism in subjects with IGT primarily by improving insulin sensitivity mediated by lowering glucose toxicity, thereby providing the beta cells rest. Larger studies are needed to establish whether these effects are sufficient to prevent progression to manifest type 2 diabetes and associated cardiovascular morbidity in subjects at increased risk of developing type 2 diabetes.

Intra-abdominal abscess in a patient with tumour necrosis factor receptor-associated periodic syndrome.

Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disorder characterized by periodic attacks of fever and inflammation, due to mutations in the gene coding for the TNF type I receptor (TNFRSF1A). A 16-year-old patient with the diagnosis of TRAPS was admitted to hospital because of fever and abdominal pain. Initially, the symptoms were interpreted as manifestations of another TRAPS attack, but the patient's condition worsened, despite treatment with corticosteroids and antibiotics. A repeated computer tomography revealed an intra-abdominal abscess, which necessitated urgent surgical intervention. This case stresses the importance of differential diagnostic vigilance when dealing with patients with rare genetic diseases.

The genetic background of tumour necrosis factor receptor-associated periodic syndrome and other systemic autoinflammatory disorders.

Systemic autoinflammatory disorders are hereditary diseases with symptoms of acute inflammation and a rise in serum acute phase proteins as a consequence, but with no signs of autoimmunity. By the end of the 1990s, four types of hereditary periodic fever had been described in the medical literature: familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS) and Muckle-Wells syndrome. Since then, the number of diseases classified as systemic autoinflammatory disorders has increased to eight. In patients of Nordic descent, cases of HIDS and TRAPS have been reported. We provide an overview of the genetic background and main clinical aspects of the different autoinflammatory disorders, with an emphasis on TRAPS.

A novel tumour necrosis factor receptor mutation in a Finnish family with periodic fever syndrome.

OBJECTIVE: To report a novel mutation of the TNF receptor type 1 gene (TNFRSF1A) in a Finnish patient and her mother, both suffering from periodic fever. METHODS: Soluble TNFRSF1A in serum was measured by enzyme-linked immunoabsorbancy, and induced TNFRSF1A shedding from monocyte cell surfaces was determined using fluorescence-activated cell sorter. Mutation detection was performed using PCR amplification and sequencing of the ten exons of TNFRSF1A. RESULTS: Low levels of soluble TNFRSF1A were detected in both patients between attacks. Sequencing revealed a missense mutation in exon 3 in the second extracellular domain of TNFRSF1A, resulting in a substitution of cysteine with arginine at residue 73 (C73R), confirming the diagnosis of TNF receptor-associated periodic syndrome (TRAPS). We were unable to demonstrate a distinct TNFRSF1A shedding defect. CONCLUSION: In patients of Nordic descent, affected by dominantly inherited recurrent fever, TRAPS is a diagnosis worthy of attention. All TNFRSF1A mutations hitherto described in the Nordic countries have been different.

Avoidance of contamination in element analysis of serum samples.

The selection of sampling needles and plastic material used for the storage of serum samples were studied. Sampling needles and plastic material were analyzed by neutron activation analysis. Leaching of elements from containers by acids and EDTA-solution was also followed. Also the long-term storage of serum samples for element analysis was investigated. Zn, Cu and Se concentration of serum was followed over the course of four years. The selection of sampling needles, as well as all plasticware which comes into contact with the serum, should be based on the knowledge of possible removal of elements from materials into the sample. Storage of serum samples at -18 degrees C does not change the copper, zinc or selenium concentration over the course of 4 years despite repeated melting and refreezing of the samples.

Cigarettes as a source of some trace and heavy metals and pesticides in man.

Trace and heavy metal and pesticide contents of different tobacco brands sold in Finland during 1920 to 1984 were determined by atomic absorption spectroscopy and gas chromatography-mass spectrometry with the purpose of investigating the variation in contents over time. In addition, the following were studied: the effect of commercial filters in cigarettes in preventing the inhalation of metals, the transfer of metals and pesticides to the mainstream smoke; and the correlation between the cadmium content of adipose tissue of smokers and their smoking habits. No differences were found in trace and heavy metal contents of different brands and packs from different decades. The pesticide residues in tobacco have followed the pattern of their use in the tobacco plantation. The dichlorodiphenyltrichloroethane (DDT) content of tobacco has decreased during the past 20 yr to about 1/200 of the peak value, i.e., from 34.5 to 0.17 micrograms/g. Cigarette filters significantly prevent the inhalation of cadmium, lead, magnesium, and iron. The mean content of cadmium in fat tissue of male smokers was four times that of non-smokers. The difference was statistically significant.

Atherosclerosis precursors in Finnish children and adolescents. XIII. Serum and hair copper and zinc concentrations.

The copper and zinc status of 3-18-year-old Finnish children was estimated by analysing 3,480 serum copper and zinc concentrations, 853 hair copper and 868 hair zinc concentrations. Both copper and zinc have been proposed to be connected with the pathogenesis of cardiovascular diseases. In addition, zinc is essential for normal growth and development. The mean serum copper concentration of 3-year-old children was 21.2 mumol/l and the concentration was significantly lower in older age groups. The average serum zinc concentration showed a narrow variation between 14.1 and 15.0 mumol/l in all age groups, nevertheless girls had significantly lower and boys higher values with increasing age. The distribution of hair copper concentration was skewed within the age groups; the median varied between 9.7 micrograms/g and 29.8 micrograms/g for 3-year-old urban girls and 18-year-old rural girls, respectively. Some rural girls had exceptionally high hair copper levels. Hair zinc concentrations increased with age. In the three youngest age groups (3, 6 and 9 years) the distribution was skewed and the levels low compared with results from the USA where a zinc concentration below 30 micrograms/g is found to be associated with the zinc deficiency syndrome.

Serum and hair zinc as predictors of clinical symptoms in acrodermatitis enteropathica.

Hair- and serum-zinc concentrations were measured in six patients with acrodermatitis enteropathica before and sequentially after cessation of zinc supplementation; supplementation was restarted when symptoms appeared. Serum zinc correlated accurately with zinc dosage and was lowest when symptoms of deficiency appeared. Hair zinc was initially age- and body size-related and was minimally influenced by the supplementation break. Adult patients had continuously normal concentrations. In paediatric patients hair zinc was low. Their serum concentrations should probably be maintained slightly above or at the upper limit of reference values for prolonged periods for normalization of hair and perhaps tissue zinc contents.

Amniotic fluid zinc in risk pregnancies.

The zinc concentration of amniotic fluid (AF) of 129 pregnant women was analyzed by the flame atomic absorption spectrometry. This prospective study was performed in order to find out whether the determination of the AF zinc concentration can be used to monitor the growth and development of the fetus. There were two groups of patients: early stage (15th-19th gestation wk) in which the amniocentesis was performed as a prenatal genetic examination, and late stage (26th-40th wk) in which the amniocentesis was performed due to obstetric reasons. The average AF zinc concentrations were 1.2 and 1.0 µmol/L in the early and late gestation group, respectively. The AF zinc concentration did not correlate with the weight, height, or Apgar scores of the newborn nor with the maternal diseases, age, or parity. The AF zinc concentration in the late gestation group was significantly lower if the fetus was male than if it was female. If the AF was greenish the zinc concentration was elevated. One malformation, congenital nephrosis, with an exceptionally high zinc concentration (9.0 µmol/L), was found.

Cadmium in Finnish breast milk, a longitudinal study.

Electrothermal atomic absorption spectrophotometry was employed to analyse cadmium in breast milk. Twenty breast milk samples were donated by seven mothers during 6 months of lactation. All milk samples represented every feeding during a period of 24 h, having foremilk an hindmilk in equal proportions. The median cadmium concentration in the 1st month was 2.0 micrograms/l (range 1.7-3.1 micrograms/l, 7 samples) and then declined to 1.5 micrograms/l (range 1.3-2.5 micrograms/l, 7 samples) and 1.6 micrograms/l (range 1.2-2.0 micrograms/l, 6 samples) in the 3rd and 6th months, respectively. At the age of 1 and 3 months when the infants were totally breast fed the average weekly intake of cadmium was 2.7 and 1.5 micrograms/kg. This is below the provisional tolerable weekly intake of man, from 6.7 to 8.3 micrograms/kg, proposed by WHO.

Body burden of cadmium in man at low level of exposure.

Specimens of heart, kidney, liver, lung, pancreas and skeletal muscle were collected at autopsy from 86 traumatic accident victims. The concentration of cadmium in the samples was determined by atomic absorption spectrophotometry. Tissue burdens and the body burden of cadmium were calculated using individual weights of different organs as a function of age. Total body burden reached its maximum level of approximately 8 mg, in the 30-39 year age group. The highest value (8.3 mg) was measured in the 40-49 year age group. The highest average value of tissue burdens at 40-49 years of age was in kidney (4.9 mg), the amount of cadmium diminishing in different tissues in the following order: liver (1.8 mg), muscle (0.15 mg), lung (0.09 mg), pancreas (0.06 mg) and heart (less than 0.01 mg). At a low level of exposure, kidneys and liver alone contain on an average 85% of the total body burden of cadmium. This value differs greatly from earlier reported figures of 45-50%.

Contamination with cadmium from micropipette tips.

Contamination by cadmium from micropipette tips from two different manufacturers was tested. Tips were washed with two different acids and the washing solutions were analysed by atomic absorption (graphite furnace). The washed tips were controlled by analysing pure acids and were found decontaminated. Clear contamination was found in yellow Eppendorf pipettes, which varied according to the consignment. The decontamination of disposable micropipette tips is emphasized when trace metal contamination should be avoided.