Evaluation of the ATN model in a longitudinal memory clinic sample with different underlying disorders.

INTRODUCTION: To evaluate the usefulness of the 2018 NIA-AA (National Institute on Aging and Alzheimer's Association) research framework in a longitudinal memory clinic study with different clinical outcomes and underlying disorders. METHODS: We included 420 patients with mild cognitive impairment or subjective cognitive impairment. During the follow up, 27% of the patients converted to dementia, with the majority converting to Alzheimer's disease (AD) or mixed dementia. Based on the baseline values of the cerebrospinal fluid biomarkers, the patients were classified into one of the eight possible ATN groups (amyloid beta [Aß] aggregation [A], tau aggregation reflecting neurofibrillary tangles [T], and neurodegeneration [N]). RESULTS: The majority of the patients converting to AD and mixed dementia were in ATN groups positive for A (71%). The A+T+N+ group was highly overrepresented among converters to AD and mixed dementia. Patients converting to dementias other than AD or mixed dementia were evenly distributed across the ATN groups. DISCUSSION: Our findings provide support for the usefulness of the ATN system to detect incipient AD or mixed dementia.

Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling.

The continuously growing mouse incisor is an excellent model to analyze the mechanisms for stem cell lineage. We designed an organ culture method for the apical end of the incisor and analyzed the epithelial cell lineage by 5-bromo-2'-deoxyuridine and DiI labeling. Our results indicate that stem cells reside in the cervical loop epithelium consisting of a central core of stellate reticulum cells surrounded by a layer of basal epithelial cells, and that they give rise to transit-amplifying progeny differentiating into enamel forming ameloblasts. We identified slowly dividing cells among the Notch1-expressing stellate reticulum cells in specific locations near the basal epithelial cells expressing lunatic fringe, a secretory molecule modulating Notch signaling. It is known from tissue recombination studies that in the mouse incisor the mesenchyme regulates the continuous growth of epithelium. Expression of Fgf-3 and Fgf-10 were restricted to the mesenchyme underlying the basal epithelial cells and the transit-amplifying cells expressing their receptors Fgfr1b and Fgfr2b. When FGF-10 protein was applied with beads on the cultured cervical loop epithelium it stimulated cell proliferation as well as expression of lunatic fringe. We present a model in which FGF signaling from the mesenchyme regulates the Notch pathway in dental epithelial stem cells via stimulation of lunatic fringe expression and, thereby, has a central role in coupling the mitogenesis and fate decision of stem cells.

Anisotropy and spiral organizing centers in patterned excitable media.

Chemical wave behavior in a patterned Belousov-Zhabotinsky system prepared by printing the catalyst of the reaction on membranes with an ink jet printer is described. Cellular inhomogeneities give rise to global anisotropy in wave propagation, with specific local patterns resulting in hexagonal, diamond, and pentagonal geometries. Spiral wave sources appear spontaneously and serve as organizing centers of the surrounding wave activity. The experimental methodology offers flexibility for studies of excitable media with made-to-order spatial inhomogeneities.

Measurement of EMG activity with textile electrodes embedded into clothing.

Novel textile electrodes that can be embedded into sports clothing to measure averaged rectified electromyography (EMG) have been developed for easy use in field tests and in clinical settings. The purpose of this study was to evaluate the validity, reliability and feasibility of this new product to measure averaged rectified EMG. The validity was tested by comparing the signals from bipolar textile electrodes (42 cm(2)) and traditional bipolar surface electrodes (1.32 cm(2)) during bilateral isometric knee extension exercise with two electrode locations (A: both electrodes located in the same place, B: traditional electrodes placed on the individual muscles according to SENIAM, n=10 persons for each). Within-session repeatability (the coefficient of variation CV%, n=10) was calculated from five repetitions of 60% maximum voluntary contraction (MVC). The day-to-day repeatability (n=8) was assessed by measuring three different isometric force levels on five consecutive days. The feasibility of the textile electrodes in field conditions was assessed during a maximal treadmill test (n=28). Bland-Altman plots showed a good agreement within 2SD between the textile and traditional electrodes, demonstrating that the textile electrodes provide similar information on the EMG signal amplitude to the traditional electrodes. The within-session CV ranged from 13% to 21% in both the textile and traditional electrodes. The day-to-day CV was smaller, ranging from 4% to 11% for the textile electrodes. A similar relationship (r(2)=0.5) was found between muscle strength and the EMG of traditional and textile electrodes. The feasibility study showed that the textile electrode technique can potentially make EMG measurements very easy in field conditions. This study indicates that textile electrodes embedded into shorts is a valid and feasible method for assessing the average rectified value of EMG.

QKI6B mRNA levels are upregulated in schizophrenia and predict GFAP expression.

Schizophrenia is a highly heritable disorder with a heterogeneous symptomatology. Research increasingly indicates the importance of the crucial and often overlooked glial perturbations within schizophrenia. Within this study, we examined an isoform of quaking (a gene encoding an RNA-binding protein that is exclusively expressed in glial cells), known as QKI6B, and a prototypical astrocyte marker, glial fibrillary acidic protein (GFAP), postulated to be under the regulation of QKI. The expression levels of these genes were quantified across post-mortem brain samples from 55 schizophrenic individuals, and 55 healthy controls, using real-time PCR. We report, through an analysis of covariance (ANCOVA) model, an upregulation of both QKI6B, and GFAP in the prefrontal cortex of brain samples of schizophrenic individuals, as compared to control samples. Previous research has suggested that the QKI protein directly regulates the expression of several genes through interaction with a motif in the target's sequence, termed the Quaking Response Element (QRE). We therefore examined if QKI6B expression can predict the outcome of GFAP, and several oligodendrocyte-related genes, using a multiple linear regression approach. We found that QKI6B significantly predicts the expression of GFAP, but does not predict oligodendrocyte-related gene outcome, as previously seen with other QKI isoforms.

Slit1 is specifically expressed in the primary and secondary enamel knots during molar tooth cusp formation.

The shape and diversity of the mammalian molar teeth is suggested to be regulated by the primary and secondary enamel knots, which are putative epithelial signaling centers of the tooth. In search of novel molecules involved in tooth morphogenesis, we analyzed mRNA expression of Slit1, -2 and -3, earlier characterized as secreted signals needed for axonal pathfinding and their two receptors Robo1 and -2 (Roundabout1 and -2) in the developing mouse first molar. In situ hybridization analysis showed that Slit1 mRNAs were expressed in the primary enamel knot of the bud and cap stage tooth germ and later the expression continued in the secondary enamel knots of the late cap and bell stage tooth. In contrast, expression of Slit2 and -3 as well Robo1, and -2 was largely restricted to mesenchymal tissue components of the tooth until the bell stage. At the late bud stage, however, Robo1 transcripts were evident in the primary enamel knot, and at the cap stage a pronounced expression was noted in the middle of the tooth germ covering the primary enamel knot and dental papilla mesenchyme. During the bell stage, Robo1 and Slit2 expression became restricted to the dental epithelia, while Slit3 continued in the dental mesenchyme. Prior to birth, Robo1 and -2 were co-localized in the predontoblasts. These results indicate that Slits and Robos display distinct, developmentally regulated expression patterns during tooth morphogenesis. In addition, our results show that Slit1 is the second known gene specifically located in the primary and secondary enamel knots.

Expression of class 3 semaphorins and neuropilin receptors in the developing mouse tooth.

The semaphorins are a large family of secreted or cell-bound signals needed for the development of the nervous system. We compared mRNA expression of class 3 semaphorins (Sema3A, 3B, 3C and 3F) and their two receptors (Neuropilin-1 and -2) in the embryonic mouse first molar tooth germ (E10-18) by radioactive in situ hybridization. All genes showed distinct developmentally regulated expression patterns during tooth organogenesis. Interestingly, Sema3A and 3C were first detected in the early dental epithelium, and later both genes were present in the epithelial primary enamel knot, a putative signaling center of the embryonic tooth regulating tooth morphogenesis. Prior to birth, Sema3A was also observed in tooth-specific cells, preodontoblasts, which later differentiate into odontoblasts secreting dentin, and in the mesenchymal dental follicle cells surrounding the tooth germ. Sema3B appeared transiently in the dental mesenchyme in the bud and cap stage tooth while Sema3F was expressed in both epithelial and mesenchymal components of the tooth. Of note, Npn-1 expression pattern was largely complementary to that of Sema3A, and transcripts were restricted to the dental mesenchymal cells. Npn-1 expression was first seen in the developing dental follicle, and later transcripts also appeared in the dental papilla mesenchyme. In contrast, Npn-2 signal was seen in both epithelial and mesenchymal tissues such as in the primary enamel knot and preodontoblasts.

Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene.

The main morphological features of the mammalian tooth crown are cusps, but the developmental mechanisms that cause the formation of cusps are unknown. Tooth cusp formation commences at cap-stage with the appearance of the enamel knot, which is a cluster of non-dividing epithelial cells. In this study, enamel knot was first seen in embryonic mice molar teeth at the onset of cap-stage. Later in tooth development, secondary enamel knot structures were observed at the cusp tips and their appearance corresponded to the formation of individual cusp morphology. Comparisons of the pattern of cell proliferation in embryonic mouse molars and the expression of fibroblast growth factor-4 (Fgf-4) gene revealed that expression of Fgf-4 mRNA is strictly localized to the non-dividing cells of the enamel knot. However, when FGF-4 protein was introduced onto isolated dental tissues in vitro, it stimulated the proliferation of both dental epithelial and mesenchymal cells. Based on these results, we suggest that the enamel knot may control tooth morphogenesis by concurrently stimulating cusp growth (via FGF-4 synthesis) and by directing folding of cusp slopes (by not proliferating itself).

CK isoenzymes and transaminases after coronary cardiography, cardiac surgery and non-cardiac thoracotomy.

The diagnosis of a heart infarct in the early postoperative period is often difficult. In the present study, the levels of serum CK, its isoenzymes (MM, MB and BB), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) were followed up after coronary arteriography (12 patients), cardiac surgery (23 patients) and non-cardiac thoracotomy (28 patients). Elevation of MB was not detected after coronary arteriography, except in two patients, who had had even before the examination a mildly positive MB finding and electrocardiographic changes indicative of subendocardial infarction. After cardiac surgery the MB findings were positive in all but two patients, who had undergone aortic valve surgery. However, the average MB level was lower than in the 10 heart infarct patients who served as controls. After non-cardiac thoracotomy, six patients had a positive serum MB, but the value of MB was quite low as compared with values after cardiac surgery and nearly insignificant in terms of heart infarct diagnosis.

Subarachnoid haemorrhage and acute heart injury.

Seven (41%) out of 17 subarachnoid haemorrhage patients had MB isoenzyme of creatine kinase (CK) in the serum. The peak activity of MB was observed about 16 h after the onset of neurological symptoms. Of the patients with MB activity, five (71%) had pathological ECG changes suggesting acute cardiac injury. Of the patients examined, five died, and four of these had both CK-MB and CK-BB isoenzymes in the serum. In a preliminary study a test was made whether MM and BB were converted to MB in 48 h at 4 degrees C or 20 degrees C in a saline solution containing mercaptoethanol and bovine serum albumin. Such conversion was not observed. Human brain tissue extract obtained at autopsy was used in the study.

Cardiac damage after blunt chest trauma, diagnosed using CK-MB enzyme and electrocardiogram.

In the present study, 78 patients with a blunt thorax trauma were examined. Fifty-four percent of the patients had been injured in traffic. Creatinine kinase (CK) and its isoenzymes (MM, MB and BB), ASAT, ALAT, ECG and thorax X-ray were taken. In 24% of the patients examined, the activity of serum MB isoenzyme was greater than or equal to 6% of the total activity of CK, and in 40% no MB activity was observed. Pathological ECG changes were detected in 89% in the MB greater than or equal to 6% group and in 32% in the MB = 0% group. ECG changes cannot be regarded as specific indicators of cardiac contusion. Arrhythmias, conduction defects, ST segment and T wave changes, and a pathologically long QTc interval were present significantly more often (P less than 0.01) in the MB greater than or equal to 6% group than in the MB = 0% group. Roentgenologically, pulmonary contusion, cardiac dilatation and venous congestion-pulmonary edema were diagnosed more frequently in the MB greater than or equal to 6% group (P less than 0.01) than in the MB = 0% group. Eleven of the patients died. A forensic autopsy was performed on these patients, and a macroscopic heart injury was detected in five of them. Serum MB activity had been found in all these five.

Dependence of cold-related coronary and respiratory symptoms on age and exposure to cold.

Cold causes cardiopulmonary stress often perceived as shortness of breath or chest pain, and causes exacerbation of these symptoms in persons suffering heart or lung disease. We investigated the prevalence of these symptoms and their association with sex, age and cold exposure in a population-based sample of 1,785 persons who lived in three areas of Finland. The exposure to cold was measured by the annual number cold days (mean daily temperature below 0 degree C) in the resident locality and weekly hours spent in the cold in winter. Shortness of breath was 25% and chest pain 52% more common in females than in males, and their prevalence increased by 24% and 77%, respectively, for every 10 years of age. The prevalence of shortness of breath increased by 5% and chest pain by 6% for every 10 cold days in the resident locality, and by 6% and 7% for every 10 hours spent in the cold, respectively. We suggest that environmental cold, measured by the number of cold days throughout the year and weekly hours spent in the cold, may provoke cardiopulmonary symptoms independent of sex and age.

Sequelae of moderate finger frostbite as assessed by subjective sensations, clinical signs, and thermophysiological responses.

The aim of the study was to investigate prevalence and qualities of sequelae following moderate finger frostbite. The study material comprised 30 subjects, who had suffered second-degree frostbite (73% contact frostbite) 4-11 years before this study. In clinical tests 66% of the subjects had an elevated tendency for vasospasm, yet only 20% suffered from white fingers. However, no marked traces of frostbite-related alterations were observed in systemic cardiovascular reflex tests or in X-ray examinations of the frostbite area. Subjective assessments revealed a high prevalence of sequelae (63%), although the primary frostbite was moderate and local. The sequelae in the frostbite area included hypersensitivity to cold (53%), numbness of fingers (40%), and declined sensitivity of touch (33%). Also working ability was lowered due to frostbite sequelae (13%). In cold air provocation tests, the skin temperature of the frostbitten areas decreased more quickly and reached lower values than in healthy control subjects. In conclusion the suffered frostbite was associated with an increased tendency for vasospasm. Subjective sensations of the frostbitten area were associated with thermophysiological changes. The sequelae were reported to worsen in the cold environment thus emphasizing the probable occupational limitations of even moderate cold injury.

FGF signalling in craniofacial development and developmental disorders.

The Fgf signalling pathway is highly conserved in evolution and plays crucial roles in development. In the craniofacial region, it is involved in almost all structure development from early patterning to growth regulation. In craniofacial skeletogenesis, the Fgf signal pathway plays important roles in suture and synchondrosis regulation. Mutations of FGF receptors relate to syndromatic and non-syndromatic craniosynostosis. The Fgf10/Fgfr2b signal loop is critical for palatogenesis and submandibular gland formation. Perturbation of the Fgf signal is a possible mechanism of palatal cleft. Fgf10 haploinsufficiency has been identified as the cause of autosomal dominant aplasia of lacrimal and salivary glands. The Fgf signal is also a key regulator of tooth formation: in the absence of Fgfr2b tooth development is arrested at the bud stage. Fgfr4 has recently been identified as the key signal mediator in myogenesis. In this review, these aspects are discussed in detail with a focus on the most recent advances.

Comparison of the effect of glucose and fructose on the recovery of the heart preparation.

Reactions of the cardiac muscle of the rat in vitro were investigated in the present study. Cardiac muscle was perfused by Langendorf's method; perfusion pressure was 80 cm H2O and the temperature of the perfusion solution 37 degrees C. The perfusion solution was aerated with a gas mixture of oxygen (95%) and carbon dioxide (5%). Potassium citrate solution was used for heart arrest, and heart function was recovered by infusion of Locke's solution, plus glucose, fructose or sucrose. During recovery the amplitude and frequenty of heart beats, the lactic acid in the drained perfusion solution, pH and potassium concentration were measured. The use of glucose, fructose or sucrose made no significant difference to any of these parameters. Next, the metabolism of glucose and fructose in the heart was investigated by means of D(U-14C)-glucose nad D(U-14C)-fructose. Radioactive lactic acid was detected in the drained perfusion solution with D(U-14C)-glucose, but not when D(U-14C)-fructose was used. The radioactivity incorporated into glycogen by the heart was also larger with D(U-14C)-glucose than with D(U-14C)-fructose. On a metabolic basis the use of glucose for resuscitation would seem to be more appropriate than fructose.

Activity of creatine kinase isoenzymes in the serum after acute alcohol intake and in chronic alcoholism.

The activities of CK and its isoenzymes were determined in the sera of six test subjects just before, and 6 and 24 h after, alcohol intake. The CK activity was higher after alcohol intake, but the change was not significant. CK-MB isoenzyme was not observed. The activities of CK and its isoenzymes were also determined in serum from 14 chronic alcoholics, who had consumed alcohol for several days before the blood sampling. Pathologically high activity of creatine kinase was found in six of them, but CK-MB and CK-BB isoenzymes were not found.

Creatine kinase MB and M-mode echocardiographic changes in cardiac contusion.

Cardiac contusion was suspected in 95 patients with severe blunt chest trauma of whom 93 did not require hospitalization. Creatine kinase (CK) MB isoenzyme activity was elevated over 4.0 U/l in 10 (10.5%) patients (CK MB positive) by between 2% and 8% (mean +/- SE 4.1 +/- 0.6%), when the total CK was 296 +/- 74 (mean +/- SE). Two patients had a pericardial rub. M-mode echocardiography was performed on 16 patients: 7 CK MB positive (CK MB+) and 9 CK MB negative (CK MB-) without the physician's knowledge of the CK MB status of the patients. The left ventricular end-diastolic diameter, in healthy subjects 48.3 +/- 4.9 mm, was increased to 55.4 +/- 1.8 mm (p less than 0.01) in CK MB+ patients and to 56.3 +/- 6.0 mm (p less than 0.01) in CK MB- patients. The end-systolic left ventricular diameter, in healthy subjects 36.7 +/- 5.2 mm, was increased to 42.4 +/- 6.7 mm (p less than 0.01) in CK MB+ patients and to 41.3 +/- 6.5 mm (p less than 0.01) in CK MB- patients. The mean ejection fraction was 48.6 +/- 11.0 in CK MB+ and 53.6 +/- 11.8 in CK MB- group. Minor contractile abnormalities occurred in all CK MB+ patients in 2 or more left ventricular regions and in 7 out of 9 CK MB- patients in 1 or 2 regions. The regional motion pattern was hypokinesia with sharp systolic deflections at abnormal areas and hyperkinesia on normal segments. Aortic root was enlarged in all patients with contusion and CK MB+. There was no apparent increase in left atrial size. "Flattened" ST-segment and T-waves were seen in 5 CK MB+ patients but not in the CK MB- patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression and function of FGFs-4, -8, and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis.

To elucidate the roles of fibroblast growth factors (FGF) in the regulation of tooth morphogenesis we have analyzed the expression patterns of Fgf-4, -8, and -9 in the developing mouse molar and incisor tooth germs from initiation to completion of morphogenesis by in situ hybridization analysis. The expression of these Fgfs was confined to dental epithelial cells at stages when epithelial-mesenchymal signaling regulates critical steps of tooth morphogenesis. Fgf-8 and Fgf-9 mRNAs were present in the oral epithelium of the first branchial arch at E10 and 1 day later expression became more restricted to the area of presumptive dental epithelium and persisted there until the start of epithelial budding. Fgf-8 mRNAs were not detected later in the developing tooth. Fgf-4 and Fgf-9 expression was upregulated in the primary enamel knot, which is a putative signaling center regulating tooth shape. Subsequently, Fgf-4 and Fgf-9 were expressed in the secondary enamel knots at the sites of tooth cusps. Fgf-9 expression spread from the primary enamel knot within the inner enamel epithelium where it remained until E18. In the continuously growing incisors Fgf-9 expression persisted in the epithelium of the cervical loops. The effects of FGFs were analyzed on the expression of the homeobox-containing transcription factors Msx-1 and Msx-2, which are associated with tissue interactions and regulated by the dental epithelium. Locally applied FGF-4, -8, and -9 stimulated intensely the expression of Msx-1 but not Msx-2 in the isolated dental mesenchyme. We suggest that the three FGFs act as epithelial signals mediating inductive interactions between dental epithelium and mesenchyme during several successive stages of tooth formation. This data suggest roles for FGF-8 and FGF-9 during initiation of tooth development, and for FGF-4 and FGF-9 during regulation of tooth shape. FGF-9 may also be involved in differentiation of odontoblasts. The coexpression of Fgfs with other signaling molecules including Shh and several Bmps and their partly similar effects suggest that the FGFs participate in the signaling networks during odontogenesis.