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BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels. DESIGN AND METHODS: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls. RESULTS: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (⩾98 cm) had significantly lower high density lipoprotein (HDL) levels, Apo A1 and albumin values compared with the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, associated adversely with insulin levels and HOMA IR in cases but not in the controls. CONCLUSIONS: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long-term health of women with PCOS.

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Digital footprints, the automatically accumulated by-products of our technology-saturated lives, offer an exciting opportunity for psychiatric research. The commercial sector has already embraced the electronic trails of customers as an enabling tool for guiding consumer behaviour, and analogous efforts are ongoing to monitor and improve the mental health of psychiatric patients. The untargeted collection of digital footprints that may or may not be health orientated comprises a large untapped information resource for epidemiological scale research into psychiatric disorders. Real-time monitoring of mood, sleep and physical and social activity in a substantial portion of the affected population in a naturalistic setting is unprecedented in psychiatry. We propose that digital footprints can provide these measurements from real world setting unobtrusively and in a longitudinal fashion. In this perspective article, we outline the concept of digital footprints and the services and devices that create them, and present examples where digital footprints have been successfully used in research. We then critically discuss the opportunities and fundamental challenges associated digital footprints in psychiatric research, such as collecting data from different sources, analysis, ethical and research design challenges.

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Diabetic nephropathy is the most serious complication of type 1 diabetes. There is no treatment to protect the kidneys from poorly controlled diabetes, and therefore prevention of the initial metabolic insults is currently the only effective approach to reducing the high mortality related to diabetic nephropathy. Metabolic phenotyping brings us one step closer to understanding the unique set of regulatory perturbations that predispose to kidney injury and paves the way for multiparametric risk assessment.

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OBJECTIVES: The aim of this study was to investigate the associations between lipid profiles and retinopathy in the large nationwide FinnDiane Study and to examine interactions and correlations between retinopathy, nephropathy and lipid variables. DESIGN AND SUBJECTS: A total of 1465 patients with type 1 diabetes, available lipid profiles, ophthalmic records and fundus photographs were included in the study. The Early Treatment of Diabetic Retinopathy Study scale was used to assess the severity of retinopathy. In an independent cohort of 1100 patients, laser treatment was used to define severe diabetic retinopathy. RESULTS: HDL cholesterol was associated with proliferative retinopathy (PDR), and triglycerides were associated with mild nonproliferative retinopathy (NPDR) independently of nephropathy and other conventional risk factors (P < 0.01). Significant interactions were seen between albumin excretion rate (AER), retinopathy status and lipid parameters (including triglycerides, non-HDL cholesterol and apolipoprotein B; P < 0.001). Highly different correlations between AER and lipid variables were observed in patients without retinopathy or with mild NPDR compared with patients with moderate to severe NPDR or PDR. Similar interactions and correlations were observed in an independent cohort stratified by laser treatment. In patients without retinopathy or with mild NPDR, AER was low despite HDL cholesterol in the lowest or triglycerides, total cholesterol or LDL cholesterol in the highest quartiles. CONCLUSIONS: Nephropathy had a strong effect on the associations between lipid variables and retinopathy, whilst dyslipidaemia was associated with nephropathy only in the presence of retinopathy. This finding suggests the existence of shared pathogenic mechanisms between retinopathy and nephropathy which could be targeted to prevent complications in patients with metabolic risk factors.

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BACKGROUND: Circulating cholesterol (C) and triglyceride (TG) levels are associated with vascular injury in type 1 diabetes (T1DM). Lipoproteins are responsible for transporting lipids, and alterations in their subclass distributions may partly explain the increased mortality in individuals with T1DM. DESIGN AND SUBJECTS: A cohort of 3544 individuals with T1DM was recruited by the nationwide multicentre FinnDiane Study Group. At baseline, six very low-density lipoprotein VLDL, one intermediate-density lipoprotein IDL, three low-density lipoprotein LDL and four higher high-density lipoprotein HDL subclasses were quantified by proton nuclear magnetic resonance spectroscopy. At follow-up, the baseline data were analysed for incident micro- or macroalbuminuria (117 cases in 5.3 years), progression from microalbuminuria (63 cases in 6.1 years), progression from macroalbuminuria (109 cases in 5.9 years) and mortality (385 deaths in 9.4 years). Univariate associations were tested by age-matched cases and controls and multivariate lipoprotein profiles were analysed using the self-organizing map (SOM). RESULTS: TG and C levels in large VLDL were associated with incident albuminuria, TG and C in medium VLDL were associated with progression from microalbuminuria, and TG and C in all VLDL subclasses were associated with mortality. Large HDL-C was inversely associated with mortality. Three extreme phenotypes emerged from SOM analysis: (i) low C (<3% mortality), (ii) low TG/C ratio (6% mortality), and (iii) high TG/C ratio (40% mortality) in all subclasses. CONCLUSIONS: TG-C imbalance is a general lipoprotein characteristic in individuals with T1DM and high vascular disease risk.

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BACKGROUND AND OBJECTIVE: Accumulating evidence suggests that serum lipids are associated with cognitive decline and dementias. However, majority of the existing information concerns only serum total cholesterol (TC) and data at the level of lipoprotein fractions and subclasses is limited. The aim of this study was to explore the levels and trends of main cholesterol and triglyceride measures and eight lipoprotein subclasses during normal aging and the development of mild cognitive impairment by following a group of elderly for six years. DESIGN: Longitudinal. SETTING: City of Kuopio, Finland. PARTICIPANTS: 45 elderly individuals of which 20 developed mild cognitive impairment (MCI) during the follow-up. MEASUREMENTS: On each visit participants underwent an extensive neuropsychological and clinical assessment. Lipoprotein levels were measured via 1H NMR from native serum samples. RESULTS: Serum cholesterol and many primarily cholesterol-associated lipoprotein measures clearly decreased in MCI while the trends were increasing for those elderly people who maintained normal cognition. CONCLUSION: These findings suggest that a decreasing trend in serum cholesterol measures in elderly individuals may suffice as an indication for more detailed inspection for potential signs of cognitive decline.

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Diabetic kidney disease (DKD) is a devastating complication that affects an estimated third of patients with type 1 diabetes mellitus (DM). There is no cure once the disease is diagnosed, but early treatment at a sub-clinical stage can prevent or at least halt the progression. DKD is clinically diagnosed as abnormally high urinary albumin excretion rate (AER). We hypothesize that subtle changes in the urine metabolome precede the clinically significant rise in AER. To test this, 52 type 1 diabetic patients were recruited by the FinnDiane study that had normal AER (normoalbuminuric). After an average of 5.5 years of follow-up half of the subjects (26) progressed from normal AER to microalbuminuria or DKD (macroalbuminuria), the other half remained normoalbuminuric. The objective of this study is to discover urinary biomarkers that differentiate the progressive form of albuminuria from non-progressive form of albuminuria in humans. Metabolite profiles of baseline 24 h urine samples were obtained by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) to detect potential early indicators of pathological changes. Multivariate logistic regression modeling of the metabolomics data resulted in a profile of metabolites that separated those patients that progressed from normoalbuminuric AER to microalbuminuric AER from those patients that maintained normoalbuminuric AER with an accuracy of 75% and a precision of 73%. As this data and samples are from an actual patient population and as such, gathered within a less controlled environment it is striking to see that within this profile a number of metabolites (identified as early indicators) have been associated with DKD already in literature, but also that new candidate biomarkers were found. The discriminating metabolites included acyl-carnitines, acyl-glycines and metabolites related to tryptophan metabolism. We found candidate biomarkers that were univariately significant different. This study demonstrates the potential of multivariate data analysis and metabolomics in the field of diabetic complications, and suggests several metabolic pathways relevant for further biological studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0291-6) contains supplementary material, which is available to authorized users.

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Sweetpotato (Ipomoea batatas) plants become infected with over 30 RNA or DNA viruses in different parts of the world but little is known about viruses infecting sweetpotato crops in Central America, the center of sweetpotato domestication. Small-RNA deep-sequencing (SRDS) analysis was used to detect viruses in sweetpotato in Honduras and Guatemala, which detected Sweet potato feathery mottle virus strain RC and Sweet potato virus C (Potyvirus spp.), Sweet potato chlorotic stunt virus strain WA (SPCSV-WA; Crinivirus sp.), Sweet potato leaf curl Georgia virus (Begomovirus sp.), and Sweet potato pakakuy virus strain B (synonym: Sweet potato badnavirus B). Results were confirmed by polymerase chain reaction and sequencing of the amplicons. Four viruses were detected in a sweetpotato sample from the Galapagos Islands. Serological assays available to two of the five viruses gave results consistent with those obtained by SRDS, and were negative for six additional sweetpotato viruses tested. Plants coinfected with SPCSV-WA and one to two other viruses displayed severe foliar symptoms of epinasty and leaf malformation, purpling, vein banding, or chlorosis. The results suggest that SRDS is suitable for use as a universal, robust, and reliable method for detection of plant viruses, and especially useful for determining virus infections in crops infected with a wide range of unrelated viruses.

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AIMS/HYPOTHESIS: We hypothesised that the blunted baroreflex sensitivity (BRS) typical of type 1 diabetes is caused by a higher degree of tissue hypoxia in diabetes, and tested whether oxygen increased BRS and ventilation less, equally or more than in healthy control participants (the latter suggesting higher tissue hypoxia). In addition, we also considered the possible interference between oxygen and breathing pattern. METHODS: In 96 participants with type 1 diabetes and 40 age-matched healthy controls, we measured BRS (average of six different standard methods), oxygen saturation, end-tidal carbon dioxide and ventilation changes during spontaneous and controlled breathing at 15 and six breaths/min, in normoxia and during 5 l/min oxygen administration. RESULTS: BRS was blunted and blood pressure higher in diabetic participants during spontaneous breathing (p < 0.05). BRS increased with oxygen during spontaneous breathing in diabetic (p < 0.001) but not in control participants, and with oxygen the difference in BRS was no longer significant. Slow breathing in normoxia restored BRS to a similar extent to giving oxygen. Oxygen increased systolic and diastolic blood pressure, RR interval, heart rate variability, minute ventilation and tidal volume to a greater extent in diabetic patients than in controls, and decreased carbon dioxide similarly to controls. CONCLUSIONS/INTERPRETATION: The increased response to hyperoxia suggests a pre-existing condition of tissue hypoxia that functionally restrains parasympathetic activity in patients with type 1 diabetes. Autonomic abnormalities can be partially and temporarily reversed by functional manoeuvres such as slow breathing or oxygen administration through enhancement of parasympathetic activity and/or correction of tissue hypoxia.

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AIMS/HYPOTHESIS: Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. METHODS: Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine-Gray proportional-hazards models. RESULTS: The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA(1c) and insulin dose (all p < 0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine-Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA(1c), triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. CONCLUSIONS/INTERPRETATION: Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications.

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AIMS/HYPOTHESIS: We studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes. METHODS: A total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4 +/- 2.0 (mean +/- SD) years. RESULTS: High triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL(3)-cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA(1c), male sex and AER were all independent predictors of renal disease. High total cholesterol, LDL-cholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL(2)-cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression. CONCLUSIONS/INTERPRETATION: Lipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.

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AIMS: Evidence suggests that chronic hyperglycaemia predicts not only microvascular disease but also macrovascular disease, however it is not known whether it is the glucose variability per se or the total glucose exposure that confers risk. The objective of this study was to investigate whether daily glucose variability influence blood pressure and arterial stiffness, an early sign of macrovascular disease, at baseline and during a hyperglycaemic clamp in patients with type 1 diabetes. METHODS: Twenty-two non-smoking male patients with type 1 diabetes without any diabetic complications, participated in the study. The patients were monitored for 72-h using a continuous glucose monitoring system. Before and during a 2-h hyperglycaemic clamp, blood pressure as well as pulse wave analysis and pulse wave velocity (PWV) were performed to assess arterial stiffness. RESULTS: No correlation was observed between mean amplitude of glycaemic excursions (MAGE) and arterial stiffness at baseline. There was a correlation between mean daily glucose and aortic PWV even after adjusting for BMI, HbA(1c), and duration of diabetes in a multiple regression analysis (r=0.48; P<0.01). MAGE (r=0.52; P<0.01) correlated independently with the change in aortic DBP during the clamp. CONCLUSIONS: This study suggests that high mean daily blood glucose but not glucose variability per se is associated with arterial stiffness in patients with T1D. Daily glucose variability is positively associated with the change in central blood pressure during a hyperglycaemic clamp.

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AIMS/HYPOTHESIS: Substantial evidence exists for the involvement of the renin-angiotensin system (RAS) in diabetic nephropathy. Angiotensin I converting enzyme 2 (ACE2), a new component of the RAS, has been implicated in kidney disease, hypertension and cardiac function. Based on this, the aim of the present study was to evaluate whether variations in ACE2 are associated with diabetic nephropathy. MATERIALS AND METHODS: We used a cross-sectional, case-control study design to investigate 823 Finnish type 1 diabetic patients (365 with and 458 without nephropathy). Five single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan technology. Haplotypes were estimated using PHASE software, and haplotype frequency differences were analysed using a chi(2)-test-based tool. RESULTS: None of the ACE2 polymorphisms was associated with diabetic nephropathy, and this finding was supported by the haplotype analysis. The ACE2 polymorphisms were not associated with blood pressure, BMI or HbA(1)c. CONCLUSIONS/INTERPRETATION: In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. Further studies are necessary to assess a minor effect of ACE2.

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We studied the cortical activation underlying perception of variations in speech fundamental frequency (F0) as indexed by the amplitude, latency and source location of the auditory N100m response registered with magnetoencephalography (MEG). Ten subjects were presented with Finnish vowels with either a constant or an ascending/descending F0. We found that the human auditory cortex is sensitive to these time-varying changes in the F0 of speech: vowels with a constant F0 elicited more prominent N100m responses than did vowels with ascending or descending changes in F0. These results suggest that the speech-related behavior of the N100m arises out of cortical sensitivity to variations in the F0 and its harmonics which underlie the perception of pitch and intonation. The present observations are interpreted in terms of the interrelatedness of speech production and perception.

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Brain processes phase-locked to stimuli can be readily observed with electro- and magnetoencephalography (EEG & MEG, respectively) using stimulus-triggered averaging of the measured signal. The detection of non-phase-locked brain processes depends on the method used for analyzing the unaveraged data. Here we introduce a technique, partition-referenced moment (PRM) power spectrum, which uses established spectral estimation algorithms but yields a power spectrum with sharp, easily distinguishable peaks in an otherwise level spectrum even when the signal (such as EEG & MEG) is of the one-over-frequency-slope type. Employing this method and wavelet transforms, we show that transient auditory brain responses are followed by dispersed small-magnitude power reductions. Power reductions occurred around 400-600 ms and were specific to ongoing 10 Hz-oscillations. The PRM-method also indicated ongoing oscillations in the 15-30 Hz frequency range where power reductions occurred at around 200-400 ms. Thus, the presented methods enable the straightforward detection of ongoing brain oscillations and their association with event-related power changes.

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Voiced speech is created by the fluctuating vocal folds generating the glottal pulseform. This excitation signal is the source of the speech fundamental frequency and its harmonic integer multiples. Periodic glottal excitation is required for the elicitation of speech-specific cortical processes indexed by the auditory N100m response. Here, we studied the cortical processing underlying the perception of the vowels /a/ and /u/ produced using normal and aperiodic phonation. The behavior of the N100m, registered with magnetoencephalography (MEG), was studied in 10 subjects. The amplitude and latency of the N100m as well as the center of gravity of the activated cortical areas varied as a function of stimulus periodicity. Further, the presence of glottal excitation had differential effects on the latency of the N100m elicited by the vowels /a/ and /u/. Thus, changes affecting the perceptual quality of speech signals without changing their phonetic content modify the dynamics of human auditory cortex.

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We studied the cortical processing of spatial stimuli by magnetoencephalographic (MEG) measurements using broadband noise bursts presented from eight sound source directions in the horizontal plane. The stimuli were individually created for each subject by using three-dimensional (3D) sound techniques. The subjects carried out a behavioral task where their accuracy for localizing the 3D stimuli was established. We found that the auditory N100m response was sensitive to the sound source direction, exhibiting contralaterally more preponderant responses in both the left and the right hemisphere. Generally, responses were more prominent in the right hemisphere. The behavioral performance of the subjects correlated positively with N100m amplitude organization, showing that the dynamics of auditory cortex predict behavioral sound detection.

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The generation mechanism of stimulus-evoked electro- and magnetoencephalographic (EEG & MEG) responses has remained controversial. One view holds that evoked responses are independent components, additive to ongoing brain activity. The other view holds that evoked responses are generated via stimulus-induced phase reorganization of ongoing brain activity. This issue has been commonly addressed with signal processing techniques that assume a high level of stationarity (i.e., unchanging properties over time) of the measured signal. Here we used signal analysis methods suitable for analyzing non-stationary signals. We found that auditory stimulation leads to a large power increase of the poststimulus signal compared to prestimulus level. Linear superposition of the (time-domain) averaged response and the unaveraged prestimulus signal accounted for 90% of the power increase. Further, we found that auditory stimulation does not lead to a phase-coherent state of ongoing oscillations. Taken together our results show that auditory evoked responses are directly additive to ongoing oscillations and only 10% of the observed power increases are explained by non-phase-locked brain activity. When examining evoked brain activity with methods providing simultaneous frequency and time information, emphasizing temporal accuracy is likely to provide more accurate descriptions of non-stationary processes of the human brain.

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Cortical activity underlying speech perception has been studied mostly by using isolated vowels with constant formant frequencies. Speech, however, is characterized by formant transitions whereby formant frequencies change as a function of time. We used magnetoencephalography (MEG) to investigate cortical activity elicited by isolated vowels and diphthongs containing formant transitions. Ten subjects were presented with two isolated vowels /a/ and /u/ and diphthongs /au/ and /ua/. Stimulus duration was 200 ms, and the diphthongs started and ended with a 50-ms constant-formant period and included a 100-ms linear transition period. Apart from studying the auditory N100m response, we examined subsequent brain activity in a 500-ms poststimulus time window, as the transitions were expected to elicit activity also in later stages of cognitive processing. All the stimuli elicited prominent N100m responses. Thereafter, both the isolated vowels and diphthongs elicited sustained brain activity lasting up to 500 ms. The present observations indicate that identification of the speech sounds as well as changes in their identity are reflected in the auditory N100m. Notably, the stimuli appeared to elicit left-hemispheric activity resembling the N400, typically obtained by using more complicated speech stimuli such as words and sentences.

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