Mental Health of Expatriates in Finnish Enterprises in Brazil

Expatriation has become increasingly common due to the global trade expansion. Many large companies base their production facilities in far-flung countries, where experts are sent from their own countries to launch the operations. Working in a foreign environment demands from so-called expatriates considerable adaptability. This study aimed to investigate if following expatriation mental health difficulties were experienced by the employees themselves or their family members. This study investigated by a questionnaire and interviews how expatriate employees in Finnish companies operating in different regions of Brazil and their families adjusted. Investigated employees were required to be at least 6 months in expatriation. Data were collected in Brazil during their stay at least 3 months after the arrival. The survey covered 121 expatriate employees, that operated in 17 different companies, from which 71 employees from 10 different companies responded to the questionnaire. All the employees from the two largest enterprises and their spouses were invited to focus groups; in total 43 persons (22 employees and 21 employees’ spouses) participated in a group or individual interviews. No significant mental health difficulties were found among the expatriate employees. Only a tenth of the expatriate employees reported strain. The experience of strain symptoms was found to be related to long working days, intense working rhythm and lack of friends. Work satisfaction seemed to be an important mediator in the coping process. While abroad, the expatriate employees were highly recognized for their work. Due to the immature organization of work they could often use their creative capacities to improve the work flow. The opportunity to see the effects of their own contribution with their own eyes to the development of the enterprise made them feel good. The association between the expatriate employees’ adjustment and that of their spouses’ was evident. The spouses’ situation was markedly different than that of the expatriate employees’ themselves. Expatriation changed the family members’ previous division of tasks considerably. The expatriate spouses had to change their roles more than the expatriate employees themselves; since most of them were highly educated women, who were leaded through an identity crisis due to at least temporary renunciation of own work and career.

Genetic regulatory networks in avian B cells

Biology is turning into an information science. The science of systems biology seeks to understand the genetic networks that govern organism development and functions. In this study the chicken was used as a model organism in the study of B cell regulatory factors. These studies open new avenues for plasma cell research by connecting the down regulation of the B cell gene expression program directly to the initiation of plasma cell differentiation. The unique advantages of the DT40 avian B cell model system, specifically its high homologous recombination rate, were utilized to study gene regulation in Pax5 knock out cell lines and to gain new insights into the B cell to plasma cell transitions that underlie the secretion of antibodies as part of the adaptive immune response. The Pax5 transcription factor is central to the commitment, development and maintenance of the B cell phenotype. Mice lacking the Pax5 gene have an arrest in development at the pro-B lymphocyte stage while DT40 cells have been derived from cells at a more mature stage of development. The DT40 Pax5-/- cells exhibited gene expression similarities with primary chicken plasma cells. The expression of the plasma cell transcription factors Blimp-1 and XBP-1 were significantly upregulated while the expression of the germinal centre factor BCL6 was diminished in Pax5-/- cells, and this alteration was normalized by Pax5 re-introduction. The Pax5-deficient cells further manifested substantially elevated secretion of IgM into the supernatant, another characteristic of plasma cells. These results for the first time indicated that the downregulation of the Pax5 gene in B cells promotes plasma cell differentiation. Cross-species meta-analysis of chicken and mouse Pax5 gene knockout studies uncovers genes and pathways whose regulatory relationship to Pax5 has remained unchanged for over 300 million years. Restriction of the hematopoietic stem cell fate to produce T, B and NK cell lineages is dependent on the Ikaros and its molecular partners, the closely related Helios and Aiolos. Ikaros family members are zinc finger proteins which act as transcriptional repressors while helping to activate lymphoid genes. Helios in mice is expressed from the hematopoietic stem cell level onwards, although later in development its expression seems to predominate in the T cell lineage. This study establishes the emergence and sequence of the chicken Ikaros family members. Helios expression in the bursa of Fabricius, germinal centres and B cell lines suggested a role for Helios in the avian B-cell lineage, too. Phylogenetic studies of the Ikaros family connect the expansion of the Ikaros family, and thus possibly the emergence of the adaptive immune system, with the second round of genome duplications originally proposed by Ohno. Paralogs that have arisen as a result of genome-wide duplications are sometimes termed ohnologs – Ikaros family proteins appear to fit that definition. This study highlighted the opportunities afforded by the genome sequencing efforts and somatic cell reverse genetics approaches using the DT40 cell line. The DT40 cell line and the avian model system promise to remain a fruitful model for mechanistic insight in the post-genomic era as well.

Generic and professional caring in a Chinese setting: an ethnopraphic study

The objective of the present study is to describe the cultural care practices, meanings, values and beliefs which form the basis of caring in a Chinese context. The research has its starting point in a caring science perspective and a qualitative research approach with interpretative ethnography as methodological guideline. The theoretical perspective is formed by elements of the theory of caritative caring, developed by Eriksson, and the theory of Culture Care Diversity and Universality, developed by Leininger. Previous research of suffering, culture and caring is described and also a presentation of actual transcultural nursing research as well as a presentation of the social structure dimensions of Chinese culture is included in the theoretical background. The empirical part includes patients and relatives, nurses and Hu Gongs as informants. The data collected are analysed based on Geertz’s idea of forming “thick descriptions” through examining the “what, how and why” of people’s actions. The findings show that the family has a prominent position in Chinese caring practices. The patient plays an unobtrusive role and a mutual dependence between the patient and the family members is evident. The professional nursing care is an extended act which includes the family in the caring relationship. The care practices of the Chinese nurse are characterized by great professional nursing skills. Suffering is described by the informants as being caused by disease, pain and social circumstances. “Social suffering” is described as worse than physical or mental suffering. Culturally competent and congruent care is a prerequisite for avoiding cultural pain, imposition and blindness when caring for the suffering human being. The findings of the present study necessitate a broadening in caring theory to include the family in the caring relationship. A further conclusion is that a broadening in our perception and understanding of culture would promote the delivery of culturally competent and congruent care. Suffering need to be seen as enclosed in cultural patterns of how it is expressed, interpreted, understood and relieved. Care and caring need to be seen as embedded in culture and the care practices values and beliefs have to be congruent with the cultural patterns where the care is provided.

The Cellular Oxygen Sensor PHD2 in Cancer Growth

Adequate supply of oxygen is essential for the survival of multicellular organisms. However, in several conditions the supply of oxygen can be disturbed and the tissue oxygenation is compromised. This condition is termed hypoxia. Oxygen homeostasis is maintained by the regulation of both the use and delivery of oxygen through complex, sensitive and cell-type specific transcriptional responses to hypoxia. This is mainly achieved by one master regulator, a transcription factor called hypoxiainducible factor 1 (HIF-1). The amount of HIF-1 is under tight oxygen-dependent control by a family of oxygen-dependent prolyl hydroxylase domain proteins (PHDs) that function as the cellular oxygen sensors. Three family members (PHD1-3) are known to regulate HIF of which the PHD2 isoform is thought to be the main regulator of HIF-1. The supply of oxygen can be disturbed in pathophysiological conditions, such as ischemic disorders and cancer. Cancer cells in the hypoxic parts of the tumors exploit the ability of HIF-1 to turn on the mechanisms for their survival, resistance to treatment, and escape from the oxygen- and nutrient-deprived environment. In this study, the expression and regulation of PHD2 were studied in normal and cancerous tissues, and its significance in tumor growth. The results show that the expression of PHD2 is induced in hypoxic cells. It is overexpressed in head and neck squamous cell carcinomas and colon adenocarcinomas. Although PHD2 normally resides in the cytoplasm, nuclear translocation of PHD2 was also seen in a subset of tumor cells. Together with the overexpression, the nuclear localization correlated with the aggressiveness of the tumors. The nuclear localization of PHD2 caused an increase in the anchorage-independent growth of cancer cells. This study provides information on the role of PHD2, the main regulator of HIF expression, in cancer progression. This knowledge may prove to be valuable in targeting the HIF pathway in cancer treatment.

Perheyritysten sukupolvenvaihdoksiin liittyvät inhimilliset seikat reviirikäyttäytymisen näkökulmasta

Tutkimuksen tavoitteena on ymmärtää perheyritysten sukupolvenvaihdoksiin liittyviä inhimillisiä tekijöitä reviirikäyttäytymisen avulla. Tarkasteltavia inhimillisiä seikkoja ovat esimerkiksi osapuolten väliset suhteet, tunteet ja käyttäytyminen. Reviirikäyttäytymisen teorialla on selitetty esimerkiksi ihmisten, ryhmien ja organisaatioiden käyttäytymistä, mutta perheyritysten sukupolvenvaihdoksissa sitä ei ole koskaan aiemmin hyödynnetty. Reviirikäyttäytymisenä pidetään toimintaa, jolla yksilö ilmaisee omistajuuden tunteitaan hänelle tärkeää ja merkityksellistä objektia kohtaan. Tutkimuksen perusteella perheenjäsenten välillä esiintyy reviirikäyttäytymistä. Luopuja ja seuraaja merkitsevät ja puolustavat reviireitään, sillä työtehtävistä ja vastuista joudutaan neuvottelemaan toisen osapuolen kanssa. Tutkimushavainnot selittävät luopujan ja seuraajan reviirikäyttäytymistä, ja auttavat ymmärtämään heidän tunteiden ja käyttäytymisen motiiveja. Lisäksi tutkimus kuvaa ja selittää reviirikäyttäytymisen seurauksia, jotka voivat olla sekä positiivisia että negatiivisia. Tutkimuksen loppuun on koottu neuvoja, joiden avulla perheyritykset pystyvät kohtaamaan sukupolvenvaihdoksiin kuuluvia inhimillisiä haasteita.

Câncer colo-retal hereditário

The colorectal cancer has become a world public health problem as a consequence of the great number of new cases which have been diagnosed each year and the existence of some conditions related to the disease's natural history that can be identified and the cancer prevented. Knowing the fact that 20% out of all colorectal cancers develops as part of a hereditary cancer syndrome, it is crucial that the physician (not only the surgeon) be updated with this entity, being able to recognize, and mainly, implement screening programs to identify family members at risk of developing cancer and to allow the intervention to prevent the occurrence of the adenoma-carcinoma sequence.

Syntyykö Suomeen puulaaksoja - Suomen puutuoteteollisuuden pk-yritysten tila ja tulevaisuus

Metsäteollisuus on tullut Suomeen ulkomaisen pääoman ja tietotaidon avulla vajaat kaksisataa vuotta sitten. Se on toiminut melkein koko jatkosodan jälkeisen ajan suojatussa ympäristössä ja ulkomaisesta kilpailusta riippumattomassa toimintaympäristössä. Kuten Porter ja muut ovat todistaneet, tällainen toimintaympäristö ei kehitä kansainvälisesti kilpailukykyistä teollisuutta globaaleilla markkinoilla. Liittyminen Euroopan unioniin ja sittemmin Euroopan rahaliittoon saattoi puunjalostusteollisuuden täysin uudenlaiseen kilpailutilanteeseen. Sama tapahtui myös alan pk-yrityksille, jotka olivat joutuneet toimimaan heikosti kilpailluilla raaka-ainemarkkinoilla. Tutkimus on tulevaisuudentutkimus, jossa tutkimusongelmia lähestytään kolmen teorian avulla. Porterin klusteriteoria tarjoaa mahdollisuuden arvioida metsäteollisuutta sekä kokonaisuutena että toimivana monimuotoisena organisaationa, jossa kustannukset ja hinta muodostuvat arvoketjun toimijoiden osakustannuksista. Bionomiateoria eli darvinistinen talousteoria testaa suomalaisen puunjalostusteollisuuden pk-yritysten kilpailukykyä ja paineita hakeutua edullisemmille toiminta- alueille. Evoluutioteoria tarkastelee sukupolvenvaihdoksen problematiikkaa. Sukupolvenvaihdoksen onnistuminen muodostuu puutoimialan elämän ja kuoleman kysymykseksi. Tämä on etenkin pk-yrityksiä kohtaava ongelma. Asiaa selvitettiin Mauno Rintalan suorittamalla kyselytutkimuksella Puuteollisuusyrittäjien jäsenistön keskuudessa. Ongelma johtuu suurista sodan jälkeen syntyneistä ikäluokista. Nämä vuosina 1945– 50 syntyneet ovat siirtymässä eläkkeelle vuosien 2005 ja 2015 välillä. Kyseisissä ikäluokissa yritystiheys on noin kaksi kertaa suurempi kuin sen jälkeisissä ikäluokissa. Suoritetun kyselyn sekä muiden suomalaisten ja kansainvälisten tutkimusten perusteella näyttää siltä, että eläkkeelle siirryttäessä vain noin 30 %:lla yrityksistä on jatkaja tiedossa suvusta tai lähipiiristä. Tämä merkitsee sitä, että 70 % eläköityvän ikäluokan omistamista yrityksistä poistuu pysyvästi markkinoilta. Suomessa poistuma merkitsee noin 40 % koko yritysvarannosta eli noin 80 000 yritystä. Tilastot toimivien yritysten määrästä ovat kuitenkin hyvin ristiriitaisia, joten todellista määrää on mahdoton arvioida. Noin suuren määrän poistuminen markkinoilta uhkaa jo hyvinvointivaltion perusrakenteita. Tutkimustulos edellyttää nopeita toimenpiteitä teollisten pkyritysten pelastamiseksi ja säilyttämiseksi Suomessa. Sukupolvenvaihdoksen onnistuminen on tässä prosessissa ensiarvoisessa asemassa. Kaikkien edellä mainittujen yritysten poistuminen markkinoilta edellyttäisi noin 400 000 uuden yrityksen perustamista, koska ainoastaan noin 20 % yrityksistä selviää ensimmäiset kolme vuotta. Tutkimukseen perustuen esitetään prosessimalli sukupolvenvaihdoksen suorittamiseksi. Suomen tärkeimmissä kilpailijamaissa valtioiden metsäomistus on määräävässä asemassa. Meillä metsät ovat yksityisessä omistuksessa ja vain pieni osa valtion omistuksessa. Puumarkkinat toimivat markkinatalouden ehdoilla ilman valtion ohjausta. Ongelmaksi on kehittymässä puun saanti. Metsänomistus on sukupolvien myötä hajaantunut hyvin pieniksi metsälöiksi. Nykyiset metsänomistajat asuvat kaupungeissa ja ovat pääosin palkkatyössä. He eivät ole samalla tavoin riippuvaisia puutuloista kuin heidän esi-isänsä. Metsäverotuksen uudistuminen lisää puun saannin epävarmuutta. Se on muuttumassa pinta-alaverotuksesta puun myynnin verotukseen. Puun myynti on vilkasta ennen järjestelmien vaihtumista ja vähäisempää sen jälkeen. Myös näitä ongelmia on pyritty ratkomaan uudenlaisen metsänomistusmallin avulla. Puuteollisuus on hyvin vanha teollisuudenala. Raaka-aine muodostaa määräävän osan kustannuksista. Muutokset ovat hitaita ja todelliset innovaatiot pitkäkestoisia. Uusia innovaatioita tapahtuu harvoin. Kannattavuutta parannetaan tuoteprosessien ja arvoketjujen kehittämisen kautta. Yhteiskunnan osuus alan kehittämisessä ja säilyttämisessä on ratkaiseva. Asioiden moninaisuus tekee tutkimuksen vaikeaksi, mutta sitäkin tärkeämmäksi kansantalouden kannalta. Tällaisissa suurissa murroksissa korostuu kaikkien päättävien tahojen henkinen valmius ja tahto tehdä oikeita ratkaisuja oikeaan aikaan.

Perhe yrityksen dominanttina omistajana: hyödyt yritykselle ja vähemmistöosakkaille

Pro gradu -tutkielman tavoitteena on ollut tutkia millaisia hyötyjä perheestä voi olla omistamalleen yritykselle ja sen vähemmistöosakkaille. Tutkielman kontekstina ovat perheyritykset ja erityisesti perheen kokemus omasta roolistaan omistajana. Tutkimus on toteutettu laadullisena tutkimuksena ja aineistona ovat olleet puolistrukturoidut haastattelut suomalaisissa listatuissa perheyhtiöissä. Tutkimuksen tuloksina voidaan osoittaa, että perheen vaikutus yrityksen menestymiseen on monitahoinen ja perheenjäsenet pyrkivät toimimaan pitkäjänteisesti yhteisen hyvän eteen. Tästä on hyötyä yritykselle ja sen vähemmistöosakkaille pitkällä aikajänteellä.

Coercion, Perceived Care and Quality of Life Among Patients in Psychiatric Hospitals

The goals of the study were to describe patients’ perceptions of care after experiencing seclusion/restraint and their quality of life. The goal was moreover to identify methodological challenges related to studies from the perspective of coerced patients. The study was conducted in three phases between September 2008 and April 2012. In the first phase, the instrument Secluded/ Restrained Patients’ Perception of their Treatment (SR-PPT) was developed and validated in Japan in cooperation with a Finnish research group (n = 56). Additional data were collected over one year from secluded/restrained patients using the instrument (n = 90). In the second phase, data were collected during the discharge process (n = 264). In the third phase, data were collected from electronic databases. Methodological and ethical issues were reviewed (n = 32) using systematic review method. Patients perceived that co-operation with the staff was poor; patients’ opinions were not taken into account, treatment targets collated and treatment methods were seen in different ways. Patients also felt that their concerns were not well enough understood. However, patients received getting nurses’ time. In particular, seclusion/restraint was considered unnecessary. The patients felt that they benefited from the isolation in treating their problems more than they needed it, even if the benefit was seen to be minor. Patients treated on forensic wards rated their treatment and care significantly lower than in general units. During hospitalization secluded/restrained patients evaluated their quality of life, however, better than did non-secluded/restrained patients. However, no conclusion is drawn to the effect that the better quality of life assessment is attributable to the seclusion/restraint because patients’ treatment period after the isolation was long and because of many other factors, as rehabilitation, medication, diagnostic differences, and adaptation. According to the systematic mixed studies review variation between study designs was found to be a methodological challenge. This makes comparison of the results more difficult. A research ethical weakness is conceded as regards descriptions of the ethical review process (44 %) and informed consent (32 %). It can be concluded that patients in psychiatric hospital care and having a voice as an equal expert require special attention to clinical nursing, decision-making and service planning. Patients and their family members will be consulted in plans of preventive and alternative methods for seclusion and restraint. The study supports the theory that in ethical decision-making situations account should be taken of medical indications, in addition to the patients’ preferences, the effect of treatment on quality of life, and this depends on other factors. The connection between treatment decisions and a patient’s quality of life should be evaluated more structurally in practice. Changing treatment culture towards patients’ involvement will support daily life in nursing and service planning taking into account improvements in patients’ quality of life.

Selective inhibition of human tankyrases

Tankyrases belong to the Diphtheria toxin-like ADP-ribosyltransferase (ARTD) enzyme superfamily, also known as poly(ADP-ribose) polymerases (PARPs). They catalyze a covalent post-translational modification reaction where they transfer ADP-ribose units from NAD+ to target proteins. Tankyrases are involved in many cellular processes and their roles in telomere homeostasis, Wnt signaling and in several diseases including cancers have made them interesting drug targets. In this thesis project, selective inhibition of human tankyrases was studied. A homogeneous fluorescence-based assay was developed to screen the compound libraries. The assay is inexpensive, operationally easy, and performs well according to the statistical analysis. Assay suitability was confirmed by screening a natural product library. Flavone was identified as the most potent inhibitor in the library and this motivated us to screen a larger flavonoid library. Results showed that flavones were indeed the best inhibitor of tankyrases among flavonoids. To further study the structure-activity relationship, a small library of flavones containing single substitution was screened and potency measurements allowed us to generate structure-activity relationship. Compounds containing substitutions at 4´-position were more potent in comparison to other substitutions, and importantly, hydrophobic groups improved isoenzyme selectivity as well as the potency. A flavone derivative containing a hydrophobic isopropyl group (compound 22), displayed 6 nM potency against TNKS1, excellent isoenzyme selectivity and Wnt signaling inhibition. Protein interactions with compounds were studied by solving complex crystal structures of the compounds with TNKS2 catalytic domain. A novel tankyrase inhibitor (IWR-1) was also crystallized in complex with TNKS2 catalytic domain. The crystal structure of TNKS2 in complex with IWR-1 showed that the compound binds to adenosine site and it was the first known ARTD inhibitor of this kind. To date, there is no structural information available about the substrate binding with any of the ARTD family members; therefore NAD+ was soaked with TNKS2 catalytic domain crystals. However, analysis of crystal structure showed that NAD+ was hydrolyzed to nicotinamide. Also, a co-crystal structure of NAD+ mimic compound, EB-47, was solved which was used to deduce some insights about the substrate interactions with the enzyme. Like EB-47, other ARTD1 inhibitors were also shown to inhibit tankyrases. It indicated that selectivity of the ARTD1 inhibitors should be considered as some of the effects in cells could come from tankyrase inhibition. In conclusion, the study provides novel information on tankyrase inhibition and presents new insight into the selectivity and potency of compounds.

Choosing the target loci : heat shock factors HSF1 and HSF2 as regulators of cell stress and development

Heat shock factors (HSFs) are an evolutionarily well conserved family of transcription factors that coordinate stress-induced gene expression and direct versatile physiological processes in eukaryote organisms. The essentiality of HSFs for cellular homeostasis has been well demonstrated, mainly through HSF1-induced transcription of heat shock protein (HSP) genes. HSFs are important regulators of many fundamental processes such as gametogenesis, metabolic control and aging, and are involved in pathological conditions including cancer progression and neurodegenerative diseases. In each of the HSF-mediated processes, however, the detailed mechanisms of HSF family members and their complete set of target genes have remained unknown. Recently, rapid advances in chromatin studies have enabled genome-wide characterization of protein binding sites in a high resolution and in an unbiased manner. In this PhD thesis, these novel methods that base on chromatin immunoprecipitation (ChIP) are utilized and the genome-wide target loci for HSF1 and HSF2 are identified in cellular stress responses and in developmental processes. The thesis and its original publications characterize the individual and shared target genes of HSF1 and HSF2, describe HSF1 as a potent transactivator, and discover HSF2 as an epigenetic regulator that coordinates gene expression throughout the cell cycle progression. In male gametogenesis, novel physiological functions for HSF1 and HSF2 are revealed and HSFs are demonstrated to control the expression of X- and Y-chromosomal multicopy genes in a silenced chromatin environment. In stressed human cells, HSF1 and HSF2 are shown to coordinate the expression of a wide variety of genes including genes for chaperone machinery, ubiquitin, regulators of cell cycle progression and signaling. These results highlight the importance of cell type and cell cycle phase in transcriptional responses, reveal the myriad of processes that are adjusted in a stressed cell and describe novel mechanisms that maintain transcriptional memory in mitotic cell division.

Molecular characteristics of Machado-Joseph disease mutation in 25 newly described Brazilian families

Machado-Joseph disease (MJD) is a form of autosomal dominant spinocerebellar ataxia first described in North-American patients originating from the Portuguese islands of the Azores. Clinically this disorder is characterized by late onset progressive ataxia with associated features, such as: ophthalmoplegia, pyramidal and extrapyramidal signs and distal muscular atrophies. The causative mutation is an expansion of a CAG repeat in the coding region of the MJD1 gene. We have identified 25 unrelated families segregating the MJD mutation during a large collaborative study of spinocerebellar ataxias in Brazil. In the present study a total of 62 family members were genotyped for the CAG repeat in the MJD1 gene, as well as 63 non-MJD individuals (126 normal chromosomes), used as normal controls. We observed a wide gap between the size range of the normal and expanded CAG repeats: the normal allele had from 12 to 33 CAGs (mean = 23 CAGs), whereas the expanded alleles ranged from 66 to 78 CAGs (mean = 71.5 CAGs). There were no differences in CAG tract length according to gender of affected individuals or transmitting parent. We observed a significant negative correlation between age at onset of the disease and length of the CAG tract in the expended allele (r = -0.6, P = 0.00006); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2 = 0.4). There was instability of the expanded CAG tract during transmission from parent to offspring, both expansions and contractions were observed; however, there was an overall tendency for expansion, with a mean increase of +2.4 CAGs. The tendency for expansion appeared to the greater in paternal (mean increase of +3.5 CAGs) than in maternal transmissions (mean increase of +1.3 CAGs). Anticipation was observed in all transmissions in which ages at onset for parent and offspring were known; however, anticipation was not always associated with an increase in the expanded CAG repeat length. Our results indicate that the molecular diagnosis of MJD can be confirmed or excluded in all suspected individuals, since alleles of intermediary size were not observed.

Specific insulin and proinsulin secretion in glucokinase-deficient individuals

Glucokinase (GCK) is an enzyme that regulates insulin secretion, keeping glucose levels within a narrow range. Mutations in the glucokinase gene cause a rare form of diabetes called maturity-onset diabetes of the young (MODY). An early onset (less than 25 years), autosomal dominant inheritance and low insulin secretion stimulated by glucose characterize MODY patients. Specific insulin and proinsulin were measured in serum by immunofluorimetric assays (IFMA) during a 75-g oral glucose tolerance test (OGTT). Two kindreds (SA and LZ) were studied and compared to non-diabetic unrelated individuals (control group 1) matched for age and body mass index (BMI). In one kindred, some of these subjects were also obese (BMI >26 kg/m2), and other family members also presented with obesity and/or late-onset NIDDM. The MODY patients were also compared to a group of five of their first-degree relatives with obesity and/or late-onset NIDDM. The proinsulin profile was different in members of the two MODY kindreds. Fasting proinsulin and the proinsulin/insulin ratio were similar in MODY members of kindred LZ and subjects from control group 1, but were significantly lower than in MODY members of kindred SA (P<0.02 and P<0.01, for proinsulin and proinsulin/insulin ratio, respectively). Moreover, MODY members of family SA had higher levels of proinsulin and proinsulin/insulin ratio, although not significantly different, when compared to their first-degree relatives and to subjects from control group 2. In conclusion, we observed variable degrees of proinsulin levels and proinsulin/insulin ratio in MODY members of two different kindreds. The higher values of these parameters found in MODY and non-MODY members of kindred SA is probably related to the obesity and late-onset NIDDM background present in this family.

Novel genes and regulatory systems in epididymal differentiation and sperm maturation of the mouse.

Mammalian spermatozoa gain their fertilizing ability during maturation in the epididymis. Proteins and lipids secreted into the epididymal lumen remodel the sperm membrane, thereby providing the structure necessary for progressive motility and oocyte interaction. In the current study, genetically modified mouse models were utilized to determine the role of novel genes and regulatory systems in the postnatal development and function of the epididymis. Ablation of the mouse β-defensin, Defb41, altered the flagellar movements of sperm and reduced the ability of sperm to bind to the oocyte in vitro. The Defb41-deficient iCre knock-in mouse model was furthermore utilized to generate Dicer1 conditional knock-out (cKO) mice. DICER1 is required for production of mature microRNAs in the regulation of gene expression by RNA interference. Dicer1 cKO gave rise to dedifferentiation of the epididymal epithelium and an altered expression of genes involved in lipid synthesis. As a consequence, the cholesterol:polyunsaturated fatty acid ratio of the Dicer1 cKO sperm membrane was increased, which resulted in membrane instability and infertility. In conclusion, the results of the Defb41 study further support the important role of β-defensin family members in sperm maturation. The regulatory role of Dicer1 was also shown to be required for epididymal development. In addition, the study is the first to show a clear connection between lipid homeostasis in the epididymis and sperm membrane integrity. Taken together, the results give important new evidence on the regulatory system guiding epididymal development and function

Abnormalities of hippocampal signal intensity in patients with familial mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (MTLE) is associated with hippocampal atrophy and hippocampal signal abnormalities. In our series of familial MTLE (FMTLE), we found a high proportion of hippocampal abnormalities. To quantify signal abnormalities in patients with FMTLE we studied 152 individuals (46 of them asymptomatic) with FMTLE. We used NIH-Image® for volumetry and signal quantification in coronal T1 inversion recovery and T2 for all cross-sections of the hippocampus. Values diverging by 2 or more SD from the control mean were considered abnormal. T2 hippocampal signal abnormalities were found in 52% of all individuals: 54% of affected subjects and 48% of asymptomatic subjects. T1 hippocampal signal changes were found in 34% of all individuals: 42.5% of affected subjects and 15% of asymptomatic subjects. Analysis of the hippocampal head (first three slices) revealed T2 abnormalities in 73% of all individuals (74% of affected subjects and 72% of asymptomatic subjects) and T1 abnormalities in 59% (67% of affected subjects and 41% of asymptomatic subjects). Affected individuals had smaller volumes than controls (P < 0.0001). There was no difference in hippocampal volumes between asymptomatic subjects and controls, although 39% of asymptomatic patients had hippocampal atrophy. Patients with an abnormal hippocampal signal (133 individuals) had smaller ipsilateral volume, but no linear correlation could be determined. Hippocampal signal abnormalities in FMTLE were more frequently found in the hippocampal head in both affected and asymptomatic family members, including those with normal volumes. These results indicate that subtle abnormalities leading to an abnormal hippocampal signal in FMTLE are not necessarily related to seizures and may be determined by genetic factors.