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.

Helicobacter pylori: resistance and treatment results in Finland

Background: Helicobacter pylori infection is usually acquired in early childhood and is rarely resolved spontaneously. Eradication therapy is currently recommended virtually to all patients. While the first and second therapies are prescribed without knowing the antibiotic resistance of the bacteria, it is important to know the primary resistance in the population. Aim: This study evaluates the primary resistance of H. pylori among patients in primary health care throughout Finland, the efficacy of three eradication regimens, the symptomatic response to successful therapy, and the effect of smoking on gastric histology and humoral response in H. pylori-positive patients. Patients and methods: A total of 23 endoscopy referral centres located throughout Finland recruited 342 adult patients with positive rapid urease test results, who were referred to upper gastrointestinal endoscopy from primary health care. Gastric histology, H. pylori resistance and H. pylori serology were evaluated. The patients were randomized to receive a seven-day regimen, comprising 1) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and metronidazole 400 mg t.d. (LAM), 2) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. (LAC) or 3) ranitidine bismuth citrate 400 mg b.d., metronidazole 400 mg t.d. and tetracycline 500 mg q.d. (RMT). The eradication results were assessed, using the 13C-urea breath test 4 weeks after therapy. The patients completed a symptom questionnaire before and a year after the therapy. Results: Primary resistance of H. pylori to metronidazole was 48% among women and 25% among men. In women, metronidazole resistance correlated with previous use of antibiotics for gynaecologic infections and alcohol consumption. Resistance rate to clarithromycin was only 2%. Intention-to-treat cure rates of LAM, LAC, and RMT were 78%, 91% and 81%. While in metronidazole-sensitive cases the cure rates with LAM, LAC and RMT were similar, in metronidazole resistance LAM and RMT were inferior to LAC (53%, 67% and 84%). Previous antibiotic therapies reduced the efficacy of LAC, to the level of RMT. Dyspeptic symptoms in the Gastrointestinal Symptoms Rating Scale (GSRS) were decreased by 30.5%. In logistic regression analysis, duodenal ulcer, gastric antral neutrophilic inflammation and age from 50 to 59 years independently predicted greater decrease in dyspeptic symptoms. In the gastric body, smokers had milder inflammation and less atrophy and in the antrum denser H. pylori load. Smokers also had lower IgG antibody titres against H. pylori and a smaller proportional decrease in antibodies after successful eradication. Smoking tripled the risk of duodenal ulcers. Conclusions: in Finland H. pylori resistance to clarithromycin is low, but metronidazole resistance among women is high making metronidazole-based therapies unfavourable. Thus, LAC is the best choice for first-line eradication therapy. The effect of eradication on dyspeptic symptoms was only modest. Smoking slows the progression of atrophy in the gastric body.

The Risk of Cancer Associated with Immunosuppressive Therapy for Skin Diseases

The possible carcinogenic risk of immunosuppressive therapies is an important issue in everyday clinical practise. Carcinogenesis is a slow multi step procedure, thus a long latency period is needed before cancer develops. PUVA therapy is used for many skin diseases including psoriasis, early stage cutaneous T cell lymphoma, atopic dermatitis, palmoplantar pustulosis and chronic eczema. There has been concern about the increased melanoma risk associated to PUVA therapy, which has previously been associated with an increased risk on non-melanoma skin cancer, especially squamous cell carcinoma. The increased risk of basal cell carcinoma (BCC) is also documented but it is modest compared to squamous cell carcinoma (SCC). This thesis evaluated melanoma and noncutaneous cancer risk associated to PUVA, and the persistence of nonmelanoma cancer risk after the cessation of PUVA treatment. Also, the influence of photochemotherapy to the development of secondary cancers in cutaneous T cell lymphoma and the role of short term cyclosporine in later cancer development in inflammatory skin diseases were evaluated. The first three studies were performed on psoriasis patients. The risk of melanoma started to increase 15 years after the first treatment with PUVA. The risk was highest among persons who had received over 250 treatments compared to those under 250 treatments. In noncutaneous cancer, the overall risk was not increased (RR=1.08,95% CI=0.93-1.24), but significant increases in risk were found in thyroid cancer, breast cancer and in central nervous system neoplasms. These cancers were not associated to PUVA. The increased risk of SCC was associated to high cumulative UVA exposure in the PUVA regimen. The patients with high risk had no substantial exposure to other carcinogens. In BCC there was a similar but more modest tendency. In the two other studies, the risk of all secondary cancers (SIR) in CTCL patients was 1.4 (95% CI=1.0-1.9). In separate sites, the risk of lung cancer, Hodgkin and non-Hodgkin lymphomas were increased. PUVA seemed not to contribute to any extent to the appearance of these cancers. The carcinogenity of short-term cyclosporine was evaluated in inflammatory skin diseases. No increased risk for any type of cancer including the skin cancers was detected. To conclude, our studies confirm the increased skin cancer risk related to PUVA treatment in psoriasis patients. In clinical practice, this has led to a close and permanent follow-up of patients treated with PUVA. In CTCL patients, PUVA treatment did not contribute to the development of secondary cancers. We could not detect any increase in the risk of cancer in patients treated with short term cyclosporine, unlike in organ transplant patients under such long-term therapy.

Common and rare variants of the renin-angiotensin system and their relation to antihypertensive drug responses

Most of the diseases affecting public health, like hypertension, are multifactorial by etiology. Hypertension is influenced by genetic, life style and environmental factors. Estimation of the influence of genes to the risk of essential hypertension varies from 30 to 50%. It is plausible that in most of the cases susceptibility to hypertension is determined by the action of more than one gene. Although the exact molecular mechanism underlying essential hypertension remains obscure, several monogenic forms of hypertension have been identified. Since common genetic variations may predict, not only to susceptibility to hypertension, but also response to antihypertensive drug therapy, pharmacogenetic approaches may provide useful markers in finding relations between candidate genes and phenotypes of hypertension. The aim of this study was to identify genetic mutations and polymorphisms contributing to human hypertension, and examine their relationships to intermediate phenotypes of hypertension, such as blood pressure (BP) responses to antihypertensive drugs or biochemical laboratory values. Two groups of patients were investigated in the present study. The first group was collected from the database of patients investigated in the Hypertension Outpatient Ward, Helsinki University Central Hospital, and consisted of 399 subjects considered to have essential hypertension. Frequncies of the mutant or variant alleles were compared with those in two reference groups, healthy blood donors (n = 301) and normotensive males (n = 175). The second group of subjects with hypertension was collected prospectively. The study subjects (n=313) underwent a protocol lasting eight months, including four one-month drug treatment periods with antihypertensive medications (thiazide diuretic, β-blocker, calcium channel antagonist, and an angiotensin II receptor antagonist). BP responses and laboratory values were related to polymorphims of several candidate genes of the renin-angiotensin system (RAS). In addition, two patients with typical features of Liddle’s syndrome were screened for mutations in kidney epithelial sodium channel (ENaC) subunits. Two novel mutations causing Liddle’s syndrome were identified. The first mutation identified located in the beta-subunit of ENaC and the second mutation found located in the gamma-subunit, constituting the first identified Liddle mutation locating in the extracellular domain. This mutation showed 2-fold increase in channel activity in vitro. Three gene variants, of which two are novel, were identified in ENaC subunits. The prevalence of the variants was three times higher in hypertensive patients (9%) than in reference groups (3%). The variant carriers had increased daily urinary potassium excretion rate in relation to their renin levels compared with controls suggesting increased ENaC activity, although in vitro they did not show increased channel activity. Of the common polymorphisms of the RAS studied, angiotensin II receptor type I (AGTR1) 1166 A/C polymorphism was associated with modest changes in RAS activity. Thus, patients homozygous for the C allele tended to have increased aldosterone and decreased renin levels. In vitro functional studies using transfected HEK293 cells provided additional evidence that the AGTR1 1166 C allele may be associated with increased expression of the AGTR1. Common polymorphisms of the alpha-adducin and the RAS genes did not significantly predict BP responses to one-month monotherapies with hydroclorothiazide, bisoprolol, amlodipin, or losartan. In conclusion, two novel mutations of ENaC subunits causing Liddle’s syndrome were identified. In addition, three common ENaC polymorphisms were shown to be associated with occurrence of essential hypertension, but their exact functional and clinical consequences remain to be explored. The AGTR1 1166 C allele may modify the endocrine phenotype of hypertensive patients, when present in homozygous form. Certain widely studied polymorphisms of the ACE, angiotensinogen, AGTR1 and alpha-adducin genes did not significantly affect responses to a thiazide, β-blocker, calcium channel antagonist, and angiotensin II receptor antagonist.

Detection and progression of chronic allograft nephropathy : A study based on protocol biopsies

Background. Kidney transplantation (KTX) is considered to be the best treatment of terminal uremia. Despite improvements in short-term graft survival, a considerable number of kidney allografts are lost due to the premature death of patients with a functional kidney and to chronic allograft nephropathy (CAN). Aim. To investigate the risk factors involved in the progression of CAN and to analyze diagnostic methods for this entity. Materials and methods. Altogether, 153 implant and 364 protocol biopsies obtained between June 1996 and April 2008 were analyzed. The biopsies were classified according to Banff ’97 and chronic allograft damage index (CADI). Immunohistochemistry for TGF-β1 was performed in 49 biopsies. Kidney function was evaluated by creatinine and/or cystatin C measurement and by various estimates of glomerular filtration rate (GFR). Demographic data of the donors and recipients were recorded after 2 years’ follow-up. Results. Most of the 3-month biopsies (73%) were nearly normal. The mean CADI score in the 6-month biopsies decreased significantly after 2001. Diastolic hypertension correlated with ΔCADI. Serum creatinine concentration at hospital discharge and glomerulosclerosis were risk factors for ΔCADI. High total and LDL cholesterol, low HDL and hypertension correlated with chronic histological changes. The mean age of the donors increased from 41 -52 years. Older donors were more often women who had died from an underlying disease. The prevalence of delayed graft function increased over the years, while acute rejections (AR) decreased significantly over the years. Sub-clinical AR was observed in 4% and it did not affect long-term allograft function or CADI. Recipients´ drug treatment was modified along the Studies, being mycophenolate mophetil, tacrolimus, statins and blockers of the renine-angiotensin-system more frequently prescribed after 2001. Patients with a higher ΔCADI had lower GFR during follow-up. CADI over 2 was best predicted by creatinine, although with modest sensitivity and specificity. Neither cystatin C nor other estimates of GFR were superior to creatinine for CADI prediction. Cyclosporine A toxicity was seldom seen. Low cyclosporin A concentration after 2 h correlated with TGF- β1 expression in interstitial inflammatory cells, and this predicted worse graft function. Conclusions. The progression of CAN has been affected by two major factors: the donors’ characteristics and the recipients’ hypertension. The increased prevalence of DGF might be a consequence of the acceptance of older donors who had died from an underlying disease. Implant biopsies proved to be of prognostic value, and they are essential for comparison with subsequent biopsies. The progression of histological damage was associated with hypertension and dyslipidemia. The augmented expression of TGF-β1 in inflammatory cells is unclear, but it may be related to low immunosuppression. Serum creatinine is the most suitable tool for monitoring kidney allograft function on every-day basis. However, protocol biopsies at 6 and 12 months predicted late kidney allograft dysfunction and affected the clinical management of the patients. Protocol biopsies are thus a suitable surrogate to be used in clinical trials and for monitoring kidney allografts.

Providing QoS to Real and Data Applications in WiMAX Mesh Networks

We consider the problem of centralized routing and scheduling for IEEE 802.16 mesh networks so as to provide Quality of Service (QoS) to individual real and interactive data applications. We first obtain an optimal and fair routing and scheduling policy for aggregate demands for different source- destination pairs. We then present scheduling algorithms which provide per flow QoS guarantees while utilizing the network resources efficiently. Our algorithms are also scalable: they do not require per flow processing and queueing and the computational requirements are modest. We have verified our algorithms via extensive simulations.

Quadrature generation techniques for frequency multiplication based oscillators

Frequency multiplication (FM) can be used to design low power frequency synthesizers. This is achieved by running the VCO at a much reduced frequency, while employing a power efficient frequency multiplier, and also thereby eliminating the first few dividers. Quadrature signals can be generated by frequency- multiplying low frequency I/Q signals, however this also multiplies the quadrature error of these signals. Another way is generating additional edges from the low-frequency oscillator (LFO) and develop a quadrature FM. This makes the I-Q precision heavily dependent on process mismatches in the ring oscillator. In this paper we examine the use of fewer edges from LFO and a single stage polyphase filter to generate approximate quadrature signals, which is then followed by an injection-locked quadrature VCO to generate high- precision I/Q signals. Simulation comparisons with the existing approach shows that the proposed method offers very good phase accuracy of 0.5deg with only a modest increase in power dissipation for 2.4 GHz IEEE 802.15.4 standard using UMC 0.13 mum RFCMOS technology.

Monte Carlo Simulations of Molecular Clusters in Nucleation

A better understanding of the limiting step in a first order phase transition, the nucleation process, is of major importance to a variety of scientific fields ranging from atmospheric sciences to nanotechnology and even to cosmology. This is due to the fact that in most phase transitions the new phase is separated from the mother phase by a free energy barrier. This barrier is crossed in a process called nucleation. Nowadays it is considered that a significant fraction of all atmospheric particles is produced by vapor-to liquid nucleation. In atmospheric sciences, as well as in other scientific fields, the theoretical treatment of nucleation is mostly based on a theory known as the Classical Nucleation Theory. However, the Classical Nucleation Theory is known to have only a limited success in predicting the rate at which vapor-to-liquid nucleation takes place at given conditions. This thesis studies the unary homogeneous vapor-to-liquid nucleation from a statistical mechanics viewpoint. We apply Monte Carlo simulations of molecular clusters to calculate the free energy barrier separating the vapor and liquid phases and compare our results against the laboratory measurements and Classical Nucleation Theory predictions. According to our results, the work of adding a monomer to a cluster in equilibrium vapour is accurately described by the liquid drop model applied by the Classical Nucleation Theory, once the clusters are larger than some threshold size. The threshold cluster sizes contain only a few or some tens of molecules depending on the interaction potential and temperature. However, the error made in modeling the smallest of clusters as liquid drops results in an erroneous absolute value for the cluster work of formation throughout the size range, as predicted by the McGraw-Laaksonen scaling law. By calculating correction factors to Classical Nucleation Theory predictions for the nucleation barriers of argon and water, we show that the corrected predictions produce nucleation rates that are in good comparison with experiments. For the smallest clusters, the deviation between the simulation results and the liquid drop values are accurately modelled by the low order virial coefficients at modest temperatures and vapour densities, or in other words, in the validity range of the non-interacting cluster theory by Frenkel, Band and Bilj. Our results do not indicate a need for a size dependent replacement free energy correction. The results also indicate that Classical Nucleation Theory predicts the size of the critical cluster correctly. We also presents a new method for the calculation of the equilibrium vapour density, surface tension size dependence and planar surface tension directly from cluster simulations. We also show how the size dependence of the cluster surface tension in equimolar surface is a function of virial coefficients, a result confirmed by our cluster simulations.

Response time measurement in flow induced signal generation on semiconductors

Measurable electrical signal is generated when a gas flows over a variety of solids, including doped semiconductors, even at the modest speed of a few meters per second. The underlying mechanism is an interesting interplay of Bernoulli's principle and the Seebeck effect. The electrical signal depends on the square of Mach number (M) and is proportional to the Seebeck coefficient (S) of the solids. Here we present experimental estimate of the response time of the signal rise and fall process, i.e. how fast the semiconductor materials respond to a steady flow as soon as it is set on or off. A theoretical model is also presented to understand the process and the dependence of the response time on the nature and physical dimensions of the semiconductor material used and they are compared with the experimental observations. (c) 2007 Elsevier B.V. All rights reserved.

Developmental origins of physiological stress reactivity

The model of developmental origins of health and disease proposes that organisms during fetal period utilize cues that enable their adaptation in the postnatal environment they are likely to live, having short-term advantages when trying to survive in environment but simultaneously in the long run have costs for health. A large body of epidemiological research has found that low birth weight, a marker of intrauterine conditions, is associated with cardiovascular (CV) disease. Since the reported associations of birth weight with normal variation in the resting blood pressure (BP), a major predictor of CV disease risk, have been modest, a key candidate mediating the link has been CV and hypothalamus-pituitary-adrenal axes (HPAA) reactivity to stress. In addition, not only weight at birth but also gestational age and early postnatal growth may have independent associations to stress reactivity. The aim of this thesis was to investigate whether pre- and postnatal growth and gestational age are associated with CV and HPAA activity before, during and after stress in childhood and in late adulthood. Altogether 287 men and women aged 60-70 and 299 boys and girls aged 7-9 underwent Trier Social Stress Test. Several indices of HPAA and CV were measured and birth size and gestational age were obtained from birth records. Results showed that low birth weight was associated with low HPAA activity during psychosocial stress, and rapid gain in BMI during years 7-11 was related to heightened stress reactivity to psychosocial stress. Size at birth in children and gestational age and early postnatal (0-2 years) gain in height in adults were associated with CV stress responses; however, in a sex-specific manner. Given that CV stress responses and HPAA activity are markers of CV disease vulnerability, our results may partly explain the associations between early environment and later CV disease.

Kiista, eheys, unohdus : Vapaussodan muistaminen suojeluskunnan ja veteraaniliikkeen toiminnassa 1918-1944

Conflict, Unity, Oblivion: Commemoration of the Liberation War by the Civic Guard and the Veterans´ Union in 1918-1944 The Finnish Civil War ended in May 1918 as a victory for the white side. The war was named by the winners as the Liberation War and its legacy became a central theme for public commemorations during the interwar period. At the same time the experiences of the defeated were hindered from becoming a part of the official history of Finland. The commemoration of the war was related not only to the war experience but also to a national mission, which was seen fulfilled with the independence of Finland. Although the idea of the commemoration was to form a unifying non-political scene for the nation, the remembrance of the Liberation War rather continued than sought to reconcile to the conflict of 1918. The outbreak of the war between the Soviet Union and Finland in 1939 immediately affected the memory culture. The new myth of the Miracle of the Winter War, which referred to the unity shown by the people, required a marginalization of controversial memory of the Liberation War. This study examines from the concepts of public memory and narrative templates how the problematic experience of a civil war developed to a popular public commemoration. Instead of dealing with the manipulative and elite-centered grandiose commemoration projects, the study focuses on the more modest local level and emphasizes the significance of local memory agents and narrative templates of collective memory. The main subjects in the study are the Civil Guard and the Veterans´ Union. Essential for the widespread movement was the development of the Civic Guard from a wartime organization to a peacetime popular movement. The guards, who identified themselves trough the memories and the threats of civil war, formed a huge network of memory agents in every corner of the country. They effectively linked both local memory with official memory and the civic society with the state level. Only with the emergence of the right wing veteran movement in the 30ies did the tensions grow between the two levels of public memory. The study shows the diversity of the commemoration movement of the Liberation War. It was not only a result of a nation-state project and political propaganda, but also a way for local communities to identify and strengthen themselves in a time of political upheaval and uncertainty.

Monte Carlo simulations of molecular clusters in nucleation

A better understanding of the limiting step in a first order phase transition, the nucleation process, is of major importance to a variety of scientific fields ranging from atmospheric sciences to nanotechnology and even to cosmology. This is due to the fact that in most phase transitions the new phase is separated from the mother phase by a free energy barrier. This barrier is crossed in a process called nucleation. Nowadays it is considered that a significant fraction of all atmospheric particles is produced by vapor-to liquid nucleation. In atmospheric sciences, as well as in other scientific fields, the theoretical treatment of nucleation is mostly based on a theory known as the Classical Nucleation Theory. However, the Classical Nucleation Theory is known to have only a limited success in predicting the rate at which vapor-to-liquid nucleation takes place at given conditions. This thesis studies the unary homogeneous vapor-to-liquid nucleation from a statistical mechanics viewpoint. We apply Monte Carlo simulations of molecular clusters to calculate the free energy barrier separating the vapor and liquid phases and compare our results against the laboratory measurements and Classical Nucleation Theory predictions. According to our results, the work of adding a monomer to a cluster in equilibrium vapour is accurately described by the liquid drop model applied by the Classical Nucleation Theory, once the clusters are larger than some threshold size. The threshold cluster sizes contain only a few or some tens of molecules depending on the interaction potential and temperature. However, the error made in modeling the smallest of clusters as liquid drops results in an erroneous absolute value for the cluster work of formation throughout the size range, as predicted by the McGraw-Laaksonen scaling law. By calculating correction factors to Classical Nucleation Theory predictions for the nucleation barriers of argon and water, we show that the corrected predictions produce nucleation rates that are in good comparison with experiments. For the smallest clusters, the deviation between the simulation results and the liquid drop values are accurately modelled by the low order virial coefficients at modest temperatures and vapour densities, or in other words, in the validity range of the non-interacting cluster theory by Frenkel, Band and Bilj. Our results do not indicate a need for a size dependent replacement free energy correction. The results also indicate that Classical Nucleation Theory predicts the size of the critical cluster correctly. We also presents a new method for the calculation of the equilibrium vapour density, surface tension size dependence and planar surface tension directly from cluster simulations. We also show how the size dependence of the cluster surface tension in equimolar surface is a function of virial coefficients, a result confirmed by our cluster simulations.

Use of Polyazaheterocycles in the Assembly of New Cadmium Sulfate Frameworks: Synthesis, Structure, and Properties

The reaction of cadmium sulfate in the presence of polyazaheterocyclic organic molecules gave rise to a variety of new cadmium sulfate phases in water containing solvothermal reaction. The compounds have two- (I) and three-dimensionally (II-VI) extended structures. All the compounds have structures built up by the connectivity involving the cadmium octahedra and the sulfate tetrahedra in which the heterocyclic organic molecules act as the ligand. The linkages between the Cd2+ and (SO4)2- ions form one- (II), two- (I, III, and IV), and three- (V and VI) dimensionally extended cadmium sulfate phases. The connectivity between Cd2+ ion and the heterocyclic ligand also gives rise to one- and two-dimensional structures. The inter-connectivity between the two units gives rise to the observed structures. The presence of Cd-O-Cd chains and Cd-O-Cd layers in some of the structures is noteworthy. The adsorption/desorption studies suggest that the cadmium sulfate phases adsorb/desorb anionic dyes selectively in the presence of water/ethanol, respectively. The photocatalytic degradation studies on cationic dyes under UV-irradiation indicate modest activity. The cyanosilylation of imines using the present compounds as heterogeneous catalyst indicate good catalytic behavior. The various properties exhibited by the cadmium sulfate phases suggest that these compounds are versatile. All the compounds were characterized by powder X-ray diffraction, thermogravimetric analysis, infrared (IR) and UV-visible studies.

Diabetic cardiomyopathy and post-infarct ventricular remodelling : Effects of levosimendan in a rodent model of type II diabetes

Type 2 diabetes is a risk factor for the development of cardiovascular disease. Recently, the term diabetic cardiomyopathy has been proposed to describe the changes in the heart that occur in response to chronic hyperglycemia and insulin resistance. Ventricular remodelling in diabetic cardiomyopathy includes left ventricular hypertrophy, increased interstitial fibrosis, apoptosis and diastolic dysfunction. Mechanisms behind these changes are increased oxidative stress and renin-angiotensin system activation. The diabetic Goto-Kakizaki rat is a non-obese model of type 2 diabetes that exhibits defective insulin signalling. Recently two interconnected stress response pathways have been discovered that link insulin signalling, longevity, apoptosis and cardiomyocyte hypertrophy. The insulin-receptor PI3K/Ak pathway inhibits proapoptotic FOXO3a in response to insulin signalling and the nuclear Sirt1 deacetylase inhibits proapoptotic p53 and modulates FOXO3a in favour of survival and growth. --- Levosimendan is a calcium sensitizing agent used for the management of acute decompensated heart failure. Levosimendan acts as a positive inotrope by sensitizing cardiac troponin C to calcium and exerts vasodilation by opening mitochondrial and sarcolemmal ATP-sensitive potassium channels. Levosimendan has been described to have beneficial effects in ventricular remodelling after myocardial infarction. The aims of the study were to characterize whether diabetic cardiomyopathy associates with cardiac dysfunction, cardiomyocyte apoptosis, hypertrophy and fibrosis in spontaneously diabetic Goto-Kakizaki (GK) rats, which were used to model type 2 diabetes. Protein expression and activation of the Akt FOXO3a and Sirt1 p53 pathways were examined in the development of ventricular remodelling in GK rats with and without myocardial infarction (MI). The third and fourth studies examined the effects of levosimendan on ventricular remodelling and gene expression in post-MI GK rats. The results demonstrated that diabetic GK rats develop both modest hypertension and features similar to diabetic cardiomyopathy including cardiac dysfunction, LV hypertrophy and fibrosis and increased apoptotic signalling. MI induced a sustained increase in cardiomyocyte apoptosis in GK rats together with aggravated LV hypertrophy and fibrosis. The GK rat myocardium exhibited decreased Akt- FOXO3a phosphorylation and increased nuclear translocation of FOXO3a and overproduction of the Sirt1 protein. Treatment with levosimendan decreased cardiomyocyte apoptosis, senescence and LV hypertrophy and altered the gene expression profile in GK rat myocardium. The findings indicate that impaired cardioprotection via Akt FOXO3a and p38 MAPK is associated with increased apoptosis, whereas Sirt1 functions in counteracting apoptosis and the development of LV hypertrophy in the GK rat myocardium. Overall, levosimendan treatment protects against post-MI ventricular remodelling and alters the gene expression profile in the GK rat myocardium.

Associations of interleukin-1 (IL-1) gene variation and IL-1 receptor antagonist phenotypes with immunological responses, metabolic dysregulation and type 2 diabetes

The upstream proinflammatory interleukin-1 (IL-1) cytokines, together with a naturally occurring IL-1 receptor antagonist (IL-1Ra), play a significant role in several diseases and physiologic conditions. The IL-1 proteins affect glucose homeostasis at multiple levels contributing to vascular injuries and metabolic dysregulations that precede diabetes. An association between IL-1 gene variations and IL-1Ra levels has been suggested, and genetic studies have reported associations with metabolic dysregulation and altered inflammatory responses. The principal aims of this study were to: 1) examine the associations of IL-1 gene variation and IL-1Ra expression in the development and persistence of thyroid antibodies in subacute thyroiditis; 2) investigate the associations of common variants in the IL-1 gene family with plasma glucose and insulin concentrations, glucose homeostasis measures and prevalent diabetes in a representative population sample; 3) investigate genetic and non-genetic determinants of IL-1Ra phenotypes in a cross-sectional setting in three independent study populations; 4) investigate in a prospective setting (a) whether variants of the IL-1 gene family are predictors for clinically incident diabetes in two population-based observational cohort studies; and (b) whether the IL-1Ra levels predict the progression of metabolic syndrome to overt diabetes during the median follow-up of 10.8 and 7.1 years. Results from on patients with subacte thyroiditis showed that the systemic IL-1Ra levels are elevated during a specific proinflammatory response and they correlated with C-reactive protein (CRP) levels. Genetic variation in the IL-1 family seemed to have an association with the appearance of thyroid peroxidase antibodies and persisting local autoimmune responses during the follow-up. Analysis of patients suffering from diabetes and metabolic traits suggested that genetic IL-1 variation and IL-1Ra play a role in glucose homeostasis and in the development of type 2 diabetes. The coding IL-1 beta SNP rs1143634 was associated with traits related to insulin resistance in cross-sectional analyses. Two haplotype variants of the IL-1 beta gene were associated with prevalent diabetes or incident diabetes in a prospective setting and both of these haplotypes were tagged by rs1143634. Three variants of the IL-1Ra gene and one of the IL-1 beta gene were consistently identified as significant, independent determinants of the IL-1Ra phenotype in two or three populations. The proportion of the phenotypic variation explained by the genetic factors was modest however, while obesity and other metabolic traits explained a larger part. Body mass index was the strongest predictor of systemic IL-1Ra concentration overall. Furthermore, the age-adjusted IL-1Ra concentrations were elevated in individuals with metabolic syndrome or diabetes when compared to those free of metabolic dysregulation. In prospective analyses the systemic IL-1Ra levels were found as independent predictors for the development of diabetes in people with metabolic syndrome even after adjustment for multiple other factors, including plasma glucose and CRP levels. The predictive power of IL-1Ra was better than that of CRP. The prospective results also provided some evidence for a role of common IL-1 alpha promoter SNP rs1800587 in the development of type 2 diabetes among men and suggested that the role may be gender specific. Likewise, common variations in the IL-1 beta coding region may have a gender specific association with diabetes development. Further research on the potential benefits of IL-1Ra measurements in identifying individuals at high risk for diabetes, who then could be targeted for specific treatment interventions, is warranted. It has been reported in the recent literature that IL-1Ra secreted from adipose tissue has beneficial effects on glucose homeostasis. Furthermore, treatment with recombinant human IL-1Ra has been shown to have a substantial therapeutic potential. The genetic results from the prospective analyses performed in this study remain inconclusive, but together with the cross-sectional analyses they suggest gender-specific effects of the IL-1 variants on the risk of diabetes. Larger studies with more extensive genotyping and resequencing may help to pinpoint the exact variants responsible and to further elucidate the biological mechanisms for the observed associations. This would improve our understanding of the pathways linking inflammation and obesity with glucose and insulin metabolism.