Characterization of anomalous relaxation using the time-fractional Bloch equation and multiple echo T2 *-weighted magnetic resonance imaging at 7T

PURPOSE To study the utility of fractional calculus in modeling gradient-recalled echo MRI signal decay in the normal human brain. METHODS We solved analytically the extended time-fractional Bloch equations resulting in five model parameters, namely, the amplitude, relaxation rate, order of the time-fractional derivative, frequency shift, and constant offset. Voxel-level temporal fitting of the MRI signal was performed using the classical monoexponential model, a previously developed anomalous relaxation model, and using our extended time-fractional relaxation model. Nine brain regions segmented from multiple echo gradient-recalled echo 7 Tesla MRI data acquired from five participants were then used to investigate the characteristics of the extended time-fractional model parameters. RESULTS We found that the extended time-fractional model is able to fit the experimental data with smaller mean squared error than the classical monoexponential relaxation model and the anomalous relaxation model, which do not account for frequency shift. CONCLUSIONS We were able to fit multiple echo time MRI data with high accuracy using the developed model. Parameters of the model likely capture information on microstructural and susceptibility-induced changes in the human brain.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case–control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of ‘pore’ function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln–270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory ‘pore’ function.

Deuterium-carbon correlation in static oriented systems using DAPT - A windowless multiple pulse sequence

We present a new method for establishing correlation between deuterium and its attached carbon in a deuterated liquid crystal. The method is based on transfer of polarization using the DAPT pulse sequence proposed originally for two spin half nuclei, now extended to a spin-1 and a spin-1/2 nuclei. DAPT utilizes the evolution of magnetization of the spin pair under two blocks of phase shifted BLEW-12 pulses on one of the spins separated by a 90 degree pulse on the other spin. The method is easy to implement and does not need to satisfy matching conditions unlike the Hartmann-Hahn cross-polarization. Experimental results presented demonstrate the efficacy of the method.

A non-orthogonal cooperative multiple access (NCMA) protocol and low ML decoding complexity codes

A half-duplex constrained non-orthogonal cooperative multiple access (NCMA) protocol suitable for transmission of information from N users to a single destination in a wireless fading channel is proposed. Transmission in this protocol comprises of a broadcast phase and a cooperation phase. In the broadcast phase, each user takes turn broadcasting its data to all other users and the destination in an orthogonal fashion in time. In the cooperation phase, each user transmits a linear function of what it received from all other users as well as its own data. In contrast to the orthogonal extension of cooperative relay protocols to the cooperative multiple access channels wherein at any point of time, only one user is considered as a source and all the other users behave as relays and do not transmit their own data, the NCMA protocol relaxes the orthogonality built into the protocols and hence allows for a more spectrally efficient usage of resources. Code design criteria for achieving full diversity of N in the NCMA protocol is derived using pair wise error probability (PEP) analysis and it is shown that this can be achieved with a minimum total time duration of 2N - 1 channel uses. Explicit construction of full diversity codes is then provided for arbitrary number of users. Since the Maximum Likelihood decoding complexity grows exponentially with the number of users, the notion of g-group decodable codes is introduced for our setup and a set of necesary and sufficient conditions is also obtained.

Depressive Disorders in Primary Health Care

The Vantaa Primary Care Depression Study (PC-VDS) is a naturalistic and prospective cohort study concerning primary care patients with depressive disorders. It forms a collaborative research project between the Department of Mental and Alcohol Research of the National Public Health Institute, and the Primary Health Care Organization of the City of Vantaa. The aim is to obtain a comprehensive view on clinically significant depression in primary care, and to compare depressive patients in primary care and in secondary level psychiatric care in terms of clinical characteristics. Consecutive patients (N=1111) in three primary care health centres were screened for depression with the PRIME-MD, and positive cases interviewed by telephone. Cases with current depressive symptoms were diagnosed face-to-face with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I/P). A cohort of 137 patients with unipolar depressive disorders, comprising all patients with at least two depressive symptoms and clinically significant distress or disability, was recruited. The Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II), medical records, rating scales, interview and a retrospective life-chart were used to obtain comprehensive cross-sectional and retrospective longitudinal information. For investigation of suicidal behaviour the Scale for Suicidal Ideation (SSI), patient records and the interview were used. The methodology was designed to be comparable to The Vantaa Depression Study (VDS) conducted in secondary level psychiatric care. Comparison of major depressive disorder (MDD) patients aged 20-59 from primary care in PC-VDS (N=79) was conducted with new psychiatric outpatients (N =223) and inpatients (N =46) in VDS. The PC-VDS cohort was prospectively followed up at 3, 6 and 18 months. Altogether 123 patients (90%) completed the follow-up. Duration of the index episode and the timing of relapses or recurrences were examined using a life-chart. The retrospective investigation revealed current MDD in most (66%), and lifetime MDD in nearly all (90%) cases of clinically significant depressive syndromes. Two thirds of the “subsyndromal” cases had a history of major depressive episode (MDE), although they were currently either in partial remission or a potential prodromal phase. Recurrences and chronicity were common. The picture of depression was complicated by Axis I co-morbidity in 59%, Axis II in 52% and chronic Axis III disorders in 47%; only 12% had no co-morbidity. Within their lifetimes, one third (37%) had seriously considered suicide, and one sixth (17%) had attempted it. Suicidal behaviour clustered in patients with moderate to severe MDD, co-morbidity with personality disorders, and a history of treatment in psychiatric care. The majority had received treatment for depression, but suicidal ideation had mostly remained unrecognised. The comparison of patients with MDD in primary care to those in psychiatric care revealed that the majority of suicidal or psychotic patients were receiving psychiatric treatment, and the patients with the most severe symptoms and functional limitations were hospitalized. In other clinical aspects, patients with MDD in primary care were surprisingly similar to psychiatric outpatients. Mental health contacts earlier in the current MDE were common among primary care patients. The 18-month prospective investigation with a life-chart methodology verified the chronic and recurrent nature of depression in primary care. Only one-quarter of patients with MDD achieved and maintained full remission during the follow-up, while another quarter failed to remit at all. The remaining patients suffered either from residual symptoms or recurrences. While severity of depression was the strongest predictor of recovery, presence of co-morbid substance use disorders, chronic medical illness and cluster C personality disorders all contributed to an adverse outcome. In clinical decision making, beside severity of depression and co-morbidity, history of previous MDD should not be ignored by primary care doctors while depression there is usually severe enough to indicate at least follow-up, and concerning those with residual symptoms, evaluation of their current treatment. Moreover, recognition of suicidal behaviour among depressed patients should also be improved. In order to improve outcome of depression in primary care, the often chronic and recurrent nature of depression should be taken into account in organizing the care. According to literature management programs of a chronic disease, with enhancement of the role of case managers and greater integration of primary and specialist care, have been successful. Optimum ways of allocating resources between treatment providers as well as within health centres should be found.

Mulibrey nanism : Clinical characteristics and pathophysiologic features of growth restriction, insulin resistance and tumour development

Background: Mulibrey nanism (MUL; Muscle-liver-brain-eye nanism; OMIM 253250) is an autosomal recessive growth disorder more prevalent in Finland than elsewhere in the world. Clinical characteristics include severe prenatal onset growth restriction, cardiopathy, multiple organ manifestations but no major neurological handicap. MUL is caused by mutations in the TRIM37 gene on chromosome 17q22-23, encoding a peroxisomal protein TRIM37 with ubiquitin E3-ligase activity. Nineteen different mutations have been detected, four of them present in the Finnish patients. Objective: This study aimed to characterize clinical and histopathological features of MUL in the national cohort of Finnish patients. Patients and methods: A total of 92 Finnish patients (age 0.7 to 77 years) participated in the clinical follow-up study. Patients hospital records and growth charts were reviewed. Physical, radiographic and laboratory examinations were performed according to a clinical protocol. Thirty patients (18 females) were treated with recombinant human GH for a median period of 5.7 years. Biopsies and autopsy samples were used for the histopathological and immunohistochemical analyses. Results: MUL patients were born small for gestational age (SGA) with immature craniofacial features after prenatal-onset growth restriction. They experienced a continuous deceleration in both height SDS and weight-for-height (WFH) postnatally. In infancy feeding difficulties and frequent pneumonias were common problems. At the time of diagnosis (median age 2.1 years) characteristic craniofacial, radiological and ocular features were the most constant findings. MUL patients showed a dramatic change in glucose metabolism with increasing age. While the children had low fasting glucose and insulin levels, 90% of the adults were insulin resistant, half had type 2 diabetes and an additional 42% showed impaired glucose tolerance (IGT). Seventy percent fulfilled the National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria for metabolic syndrome as adults. GH therapy improved pre-pubertal growth but had only minor impact on adult height (+5 cm). Interestingly, treated subjects were slimmer and had less frequent metabolic concerns as young adults. MUL patients displayed histologically a disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours present in several internal organs. A total of 232 tumorous lesions were detected in our patient cohort. The majority of the tumours showed strong expression of endothelial cell marker CD34 as well as α-smooth muscle actin (α-SMA). Fifteen of the tumours were malignant and seven of them (five Wilms tumours) occurred in the kidney. Conclusions: MUL patients present a distinct postnatal growth pattern. Short-term response of GH treatment is substantial but the long-term impact remains modest. Although MUL patients form a distinct clinical and diagnostic entity, their clinical findings vary considerably from infancy to adulthood. While failure to thrive dominates early life, MUL adults develop metabolic syndrome and have a tendency for malignancies and vascular lesions in several organs. This speaks for a central role of TRIM37 in regulation of key cellular functions, such as proliferation, migration, angiogenesis and insulin signalling.

A multiple nucleotide length polymorphism (MNLP) mediates androgen regulation of IRX4 in prostate cancer

Androgens and the androgen receptor (AR) play a crucial role in the initiation and progression of prostate cancer (PCa), regulating the expression of many PCa risk-associated genes. Iroquois Homeobox 4 (IRX4) has been recently identified with PCa risk and overexpressed in PCa. We observed a down-regulation of IRX4 expression in the cells undergoing epithelial to mesenchymal transition, suggesting its potential role in PCa progression and aim to delineate the androgenmediated regulation of IRX4 in PCa.

Disorder Induced Concomitant Polymorphism in 3-Fluoro-N-(3-fluorophenyl)benzamide

The occurrence of concomitant polymorphism in 3-fluoro-N-(3-fluorophenyl) benzamide has been identified to be due to the disorder in the crystal structure. Of the two modifications, the plate form (Form I) crystallizes in the monoclinic centrosymmetric space group C2/c with Z = 4, and the needle form (Form II) crystallizes in the noncentrosymmetric space group P21 with Z = 2. An interesting positional disorder at the bridging atoms in both forms holds the molecular conformation identical, while subtle variations brought by N−H···O hydrogen bonds along with weak C−H···F and F···F interactions result in packing polymorphism.

Distributed joint source channel coding on a multiple access channel with side information

We consider the problem of transmission of several discrete sources over a multiple access channel (MAC) with side information at the sources and the decoder. Source-channel separation does not hold for this channel. Sufficient conditions are provided for transmission of sources with a given distortion. The channel could have continuous alphabets (Gaussian MAC is a special case). Various previous results are obtained as special cases.

Critical test for Altshuler-Aronov theory: Evolution of the density of states singularity in double perovskite Sr2FeMoO6 with controlled disorder

With high-resolution photoemission spectroscopy measurements, the density of states (DOS) near the Fermi level (E-F) of double perovskite Sr2FeMoO6 having different degrees of Fe/Mo antisite disorder has been investigated with varying temperature. The DOS near E-F showed a systematic depletion with increasing degree of disorder, and recovered with increasing temperature. Altshuler-Aronov (AA) theory of disordered metals well explains the dependences of the experimental results. Scaling analysis of the spectra provides experimental indication for the functional form of the AA DOS singularity.

Joint decoding of multiple speech patterns for robust speech recognition

We are addressing a new problem of improving automatic speech recognition performance, given multiple utterances of patterns from the same class. We have formulated the problem of jointly decoding K multiple patterns given a single Hidden Markov Model. It is shown that such a solution is possible by aligning the K patterns using the proposed Multi Pattern Dynamic Time Warping algorithm followed by the Constrained Multi Pattern Viterbi Algorithm The new formulation is tested in the context of speaker independent isolated word recognition for both clean and noisy patterns. When 10 percent of speech is affected by a burst noise at -5 dB Signal to Noise Ratio (local), it is shown that joint decoding using only two noisy patterns reduces the noisy speech recognition error rate to about 51 percent, when compared to the single pattern decoding using the Viterbi Algorithm. In contrast a simple maximization of individual pattern likelihoods, provides only about 7 percent reduction in error rate.

Brain and Spinal Cavernomas : Helsinki Experience

Cavernomas are rare neurovascular lesions, encountered in up to 10% of patients harboring vascular abnormalities of the CNS. Cavernomas consist of dilated thin-walled sinusoids or caverns covered by a single layer of endothelium. Due to advancements in neuroradiology, the number of cavernoma patients coming to be evaluated in neurosurgical practice is increasing. In the present work, we summarized our results on the treatment of cavernomas. Particular attention was paid to uncommon locations or insufficiently investigated cavernomas, including 1. Intraventricular cavernomas; 2. Multiple cavernomas; 3. Spinal cavernomas; and 4. Temporal lobe cavernomas. After analyzing the patient series with these lesions, we concluded that: 1. IVCs are characterized by a high tendency to cause repetitive hemorrhages in a short period of time after the first event. In most patients, hemorrhages were not life-threatening. Surgery is indicated when re-bleedings are frequent and the mass-effect causes progressive neurological deterioration. Modern microsurgical techniques allow safe removal of the IVC, but surgery on fourth ventricle cavernomas carries increased risk of postoperative cranial nerve deficits. 2. In MC cases, when the cavernoma bleeds or generates drug-resistant epilepsy, microsurgical removal of the symptomatic lesion is beneficial to patients. In our series, surgical removal of the most active cavernoma usually the biggest lesion with signs of recent hemorrhage - was safe and prevented further bleedings. Epilepsy outcome showed the effectiveness of active treatment of MCs. However, due to the remaining cavernomas, epileptogenic activity can persist postoperatively, frequently necessitating long-term use of antiepileptic drugs. 3. Spinal cavernomas can cause severe neurological deterioration due to low tolerance of the spinal cord to mass-effect with progressive myelopathy. When aggravated by extralesional massive hemorrhage, neurological decline is usually acute and requires immediate treatment. Microsurgical removal of a cavernoma is effective and safe, improving neurological deficits. Sensorimotor deficits and pain improved postoperatively at a high rate, whereas bladder dysfunction remained essentially unchanged, causing social discomfort to patients. 4. Microsurgical removal of temporal lobe cavernomas is beneficial for patents suffering from drug-resistant epilepsy. In our series, 69% of patients with this condition became seizure-free postoperatively. Duration of epilepsy did not correlate with seizure prognosis. The most frequent disabling symptom at follow-up was memory disorder, considered to be the result of a complex interplay between chronic epilepsy and possible damage to the temporal lobe during surgery.

Mitochondrial helicase Twinkle in mtDNA copy number regulation and a late-onset disease model

Mitochondrial diseases are caused by disturbances of the energy metabolism. The disorders range from severe childhood neurological diseases to muscle diseases of adults. Recently, mitochondrial dysfunction has also been found in Parkinson s disease, diabetes, certain types of cancer and premature aging. Mitochondria are the power plants of the cell but they also participate in the regulation of cell growth, signaling and cell death. Mitochondria have their own genetic material, mtDNA, which contains the genetic instructions for cellular respiration. Single cell may host thousands of mitochondria and several mtDNA molecules may reside inside single mitochondrion. All proteins needed for mtDNA maintenance are, however, encoded by the nuclear genome, and therefore, mutations of the corresponding genes can also cause mitochondrial disease. We have here studied the function of mitochondrial helicase Twinkle. Our research group has previously identified nuclear Twinkle gene mutations underlying an inherited adult-onset disorder, progressive external ophthalmoplegia (PEO). Characteristic for the PEO disease is the accumulation of multiple mtDNA deletions in tissues such as the muscle and brain. In this study, we have shown that Twinkle helicase is essential for mtDNA maintenance and that it is capable of regulating mtDNA copy number. Our results support the role of Twinkle as the mtDNA replication helicase. No cure is available for mitochondrial disease. Good disease models are needed for studies of the cause of disease and its progression and for treatment trials. Such disease model, which replicates the key features of the PEO disease, has been generated in this study. The model allows for careful inspection of how Twinkle mutations lead to mtDNA deletions and further causes the PEO disease. This model will be utilized in a range of studies addressing the delay of the disease onset and progression and in subsequent treatment trials. In conclusion, in this thesis fundamental knowledge of the function of the mitochondrial helicase Twinkle was gained. In addition, the first model for adult-onset mitochondrial disease was generated.

Suicidal ideation and attempts among psychiatric patients with major depressive disorder

This study is part of an ongoing collaborative research and development project, the Vantaa Depression Study (VDS), between the National Public Health Institute, Helsinki and the Department of Psychiatry of Helsinki University Hospital (HUCH), Peijas hospital, Vantaa. The VDS is a prospective, naturalistic cohort study of 269 secondary-level care psychiatric out- and inpatients with a new episode of DSM-IV major depressive disorder (MDD). 269 patients (Nmales=72, Nfemales=197) with a current DSM-IV MDD were interviewed with semistructured interviews to assess all other psychiatric diagnoses. At 6- and 18-month follow-up the interviews were repeated. Suicidal behaviour was investigated both at intake and follow-up by using a psychometric scale (Scale for Suicidal Ideation) and interviewer's questions as well as the patient's psychiatric records. Patients, who reported suicidal ideation while entering the study were followed up weekly, and their level of suicidal ideation, hopelessness, anxiety and depression was measured. In this study suicidal ideation was common among psychiatric patients with MDD. Almost 60% of the depressed patients reported suicidal ideation and 15% of patients attempted suicide at the baseline. Patients with suicidal ideation or attempts had a clearly higher level of overall psychopathology than non-suicidal patients. During the 18-month follow-up period 8% of patients attempted suicide. The risk of an attempt was markedly higher (RR=7.54) during an episode of major depression compared with a period of remission. Suicide attempt during the follow-up period was predicted by lack of partner, a history of previous suicide attempts and time spent in depression. Suicidal ideation resolved for most of the suicidal patients during the first 2 to 3 months. The duration of suicidal ideation was longer for patients with an initially higher level of psychopathology. Declines both in depression and hopelessness independently predicted the subsequent decline in suicidal ideation. They both could have a causal role in reversing the suicidal process. Thus effective treatment of depression is a credible measure in suicide prevention. Patients with suicidal behaviour often received more antidepressants and had more frequent appointments with mental health professionals than non-suicidal patients. Suicidal patients had also more favourable attitudes towards antidepressant treatment and comparable adherence to treatment than those not suicidal. This study does not support the conception that patient attitudes or adherence to treatments would be a factor differentiating suicidal patients from non-suicidal. Instead, problems with adherence or attitudes seem to be generic to all psychiatric care.