Timing of puberty : Genetic regulation

In the general population, the timing of puberty is normally distributed. This variation is determined by genetic and environmental factors, but the exact mechanisms underlying these influences remain elusive. The purpose of this study was to gain insight into genetic regulation of pubertal timing. Contributions of genetic versus environmental factors to the normal variation of pubertal timing were explored in twins. Familial occurrence and inheritance patterns of constitutional delay of growth and puberty, CDGP (a variant of normal pubertal timing), were studied in pedigrees of patients with this condition. To ultimately detect genes involved in the regulation of pubertal timing, genetic loci conferring susceptibility to CDGP were mapped by linkage analysis in the same family cohort. To subdivide the overall phenotypic variance of pubertal timing into genetic and environmental components, genetic modeling based on monozygous twins sharing 100% and dizygous twins sharing 50% of their genes was used in 2309 girls and 1828 boys from the FinnTwin 12-17 study. The timing of puberty was estimated from height growth, i.e. change in the relative height between the age when pubertal growth velocity peaks in the general population and adulthood. This reflects the percentage of adult height achieved at the average peak height velocity age, and thus, pubertal timing. Boys and girls diagnosed with CDGP were gathered through medical records from six pediatric clinics in Finland. First-degree relatives of the probands were invited to participate by letter; altogether, 286 families were recruited. When possible, families were extended to include also second-, third-, or fourth-degree relatives. The timing of puberty in all family members was primarily assessed from longitudinal growth data. Delayed puberty was defined by onset of pubertal growth spurt or peak height velocity taking place 1.5 (relaxed criterion) or 2 SD (strict criterion) beyond the mean. If growth data were unavailable, pubertal timing was based on interviews. In this case, CDGP criteria were set as having undergone pubertal development more than 2 (strict criterion) or 1.5 years (relaxed criterion) later than their peers, or menarche after 15 (strict criterion) or 14 years (relaxed criterion). Familial occurrence of strict CDGP was explored in families of 124 patients (95 males and 29 females) from two clinics in Southern Finland. In linkage analysis, we used relaxed CDGP criteria; 52 families with solely growth data-based CDGP diagnoses were selected from all clinics. Based on twin data, genetic factors explain 86% and 82% of the variance of pubertal timing in girls and boys, respectively. In families, 80% of male and 76% of female probands had affected first-degree relatives, in whom CDGP was 15 times more common than the expected (2.5%). In 74% (17 of 23) of the extended families with only one affected parent, familial patterns were consistent with autosomal dominant inheritance. By using 383 multiallelic markers and subsequently fine-mapping with 25 additional markers, significant linkage for CDGP was detected to the pericentromeric region of chromosome 2, to 2p13-2q13 (multipoint HLOD 4.44, α 0.41). The findings of the large twin study imply that the vast majority of the normal variation of pubertal timing is attributed to genetic effects. Moreover, the high frequency of dominant inheritance patterns and the large number of affected relatives of CDGP patients suggest that genetic factors also markedly contribute to constitutional delay of puberty. Detection of the locus 2p13-2q13 in the pericentromeric region of chromosome 2 associating with CDGP is one step towards unraveling the genes that determine pubertal timing.

Anterior cruciate ligament reconstruction with special reference to magnetic resonance imaging of the postoperative outcome

Anterior cruciate ligament (ACL) tear is a common sports injury of the knee. Arthroscopic reconstruction using autogenous graft material is widely used for patients with ACL instability. The grafts most commonly used are the patellar and the hamstring tendons, by various fixation techniques. Although clinical evaluation and conventional radiography are routinely used in follow-up after ACL surgery, magnetic resonance imaging (MRI) plays an important role in the diagnosis of complications after ACL surgery. The aim of this thesis was to study the clinical outcome of patellar and hamstring tendon ACL reconstruction techniques. In addition, the postoperative appearance of the ACL graft was evaluated using several MRI sequences. Of the 175 patients who underwent an arthroscopically assisted ACL reconstruction, 99 patients were randomized into patellar tendon (n=51) or hamstring tendon (n=48) groups. In addition, 62 patients with hamstring graft ACL reconstruction were randomized into either cross-pin (n=31) or interference screw (n=31) fixation groups. Follow-up evaluation determined knee laxity, isokinetic muscle performance and several knee scores. Lateral and anteroposterior view radiographs were obtained. Several MRI sequences were obtained with a 1.5-T imager. The appearance and enhancement pattern of the graft and periligamentous tissue, and the location of bone tunnels were evaluated. After MRI, arthroscopy was performed on 14 symptomatic knees. The results revealed no significant differences in the 2-year outcome between the groups. In the hamstring tendon group, the average femoral and tibial bone tunnel diameter increased during 2 years follow-up by 33% and 23%, respectively. In the asymptomatic knees, the graft showed homogeneous and low signal intensity with periligamentous streaks of intermediate signal intensity on T2-weighted MR images. In the symptomatic knees, arthroscopy revealed 12 abnormal grafts and two meniscal tears, each with an intact graft. Among 3 lax grafts visible on arthroscopy, MRI showed an intact graft and improper bone tunnel placement. For diagnosing graft failure, all MRI findings combined gave a specificity of 90% and a sensitivity of 81%. In conclusion, all techniques appeared to improve patients' performance, and were therefore considered as good choices for ACL reconstruction. In follow-up, MRI permits direct evaluation of the ACL graft, the bone tunnels, and additional disorders of the knee. Bone tunnel enlargement and periligamentous tissue showing contrast enhancement were non-specific MRI findings that did not signify ACL deficiency. With an intact graft and optimal femoral bone tunnel placement, graft deficiency is unlikely, and the MRI examination should be carefully scrutinized for possible other causes for the patients symptoms.

Kampylobakteerit Korkeasaaren eläintarhan eläimissä

Kampylobakteerit on tunnistettu vasta viimeisten 30 vuoden aikana merkittäviksi ihmisten tautien aiheuttajiksi. Termofiiliset kampylobakteerit Campylobacter jejuni ja C. coli ovat yleisin bakteeriperäisten suolistoinfektioden syy maailmanlaajuisesti. Pääasiallinen oire on ripuli. C. jejuni voi aiheuttaa myös jälkitauteja, kuten reaktiivista niveltulehdusta, nokkosihottumaa tai kyhmyruusua (erytema nodosum). Näitä kuitenkin ilmaantuu harvoin (<1 %). Tärkein jälkitauti on Guillain-Barrén syndrooma, joka on akuutti ääreishermoja demyelinisoiva sairaus. Kesällä 2008 Helsingin yliopistossa toteutettiin tutkimus, jonka tarkoituksena oli kartoittaa kampylobakteerien esiintymistä Korkeasaaren eläintarhassa ja tunnistaa löytyneet kampylobakteerit lajitasolle. Aineisto koostui 196 tarhaeläimen ulostenäytteestä, kahdeksasta Korkeasaaressa vapaana olleen valkoposkihanhen ulostenäytteestä sekä 12 ympäristönäytteestä (vesinäytteitä). Vesinäytteet olivat eläinten kahluualtaista tai häkeissä kulkevista puroista. Ulostenäytteet olivat peräisin kaikkiaan 71 eläinlajista. Tutkituista eläinlajeista 40 oli nisäkkäitä, 26 oli lintuja ja viisi oli matelijoita. Näytteistä eristettyjen isolaattien tulosten perusteella ulostenäytteistä 21 (10,7 %) oli positiivisia kampylobakteerien suhteen. Eläinlajeja tarkasteltaessa kampylobakteerien suhteen positiivisia oli 17 (23,9 %) eläinlajia. Näistä kymmenen oli lintuja, kuusi nisäkkäitä ja yksi matelija. Positiiviseksi C. jejunin suhteen osoittautui 18 ulostenäytettä. Yhdestä emun näytteestä löytyi C. jejunin lisäksi myös C. coli. Kahdessa näytteessä, rubiini-ibis ja kannuskilpikonna, kasvoi jokin muu kampylobakteeri kuin C. jejuni tai C. coli. Eläinlajeja tarkasteltaessa voidaan todeta, että 15 (21,1 %) todettiin positiivisiksi C. jejunin suhteen. Näistä kymmenen oli lintuja ja viisi nisäkkäitä. C. coli löytyi vain yhdestä (1,4 %) eläinlajista (linnusta) sekä jokin muu kampylobakteeri kuin C. jejuni tai C. coli löytyi kahdesta (2,8 %) eläinlajista (yksi lintu ja yksi matelija). Vain yksi ulostenäyte osoittautui positiiviseksi arkobakteerin suhteen. Kyseessä oli rubiini-ibiksen näyte. Samasta näytteestä löydettiin myös C. jejuni. Kahdesta valkoposkihanhien näytteestä löytyi sekä helikobakteeri että C. jejuni. Viisi ympäristönäytettä osoittautui positiiviseksi arkobakteerien suhteen. Kolme positiivista näytettä oli lintualtaista ja kaksi nisäkkäiden altaista. Rubiini-ibiksen altaasta löytyi arkobakteerin lisäksi myös C. jejuni. Lähes kaikissa vesinäytteissä (9/12) oli koliformisia bakteereja Colilert® testillä yli määritysrajan (>2419,6 bakteeria 100 ml:ssa näytettä). Suurimmasta osasta vesinäytteitä (8/12) saatiin tulokseksi myös yli menetelmän määritysrajan E. colia. Kaikenkaikkiaan tulosten perusteella voi päätellä, että vierailijoiden riski saada kampylobakterioosi Korkeasaaren eläintarhassa on suhteellisen pieni. Ainoana suurempana riskitekijänä voisi pitää valkoposkihanhien ulostetta. Sitä on maassa runsaasti ja sitä saattaa myös kulkeutua kenkien mukana jopa kotiin asti. Eläintarhan työntekijöiden tulee muistaa hyvä käsihygienia oltuaan kosketuksissa joko eläimien kanssa tai käytyään näiden tarhoissa. Työntekijät saattavat myös levittää eläintarhan eläinten ulostetta saappaissaan vierailijoidenkin kulkureiteille.

Pain measurement and management in elderly patients : Clinical studies in long term hospital care and after cardiac surgery

The proportion of patients over 75 years of age, receiving all different types of healthcare, is constantly increasing. The elderly undergo surgery and anaesthetic procedures more often than middle-aged patients. Poor pain management in the elderly is still an issue. Although the elderly consumes the greatest proportion of prescribed medicines in Western Europe, most clinical pharmacological studies have been performed in healthy volunteers or middle-aged patients. The aim of this study was to investigate pain measurement and management in cognitively impaired patients in long term hospital care and in cognitively normal elderly patients after cardiac surgery. This thesis incorporated 366 patients, including 86 home-dwelling or hospitalized elderly with chronic pain and 280 patients undergoing cardiac surgery with acute pain. The mean age of patients was 77 (SD ± 8) years and approximately 8400 pain measurements were performed with four pain scales: Verbal Rating Scale (VRS), the Visual Analogue Scale (VAS), the Red Wedge Scale (RWS), and the Facial Pain Scale (FPS). Cognitive function, depression, functional ability in daily life, postoperative sedation and postoperative confusion were assessed with MMSE, GDS, Barthel Index, RASS, and CAM-ICU, respectively. The effects and plasma concentrations of fentanyl and oxycodone were measured in elderly (≥ 75 years) and middle-aged patients (≤ 60 years) and the opioid-sparing effect of pregabalin was studied after cardiac surgery. The VRS pain scores after movement correlated with the Barthel Index. The VRS was most successful in the groups of demented patients (MMSE 17-23, 11-16 and ≤ 10) and in elderly patients on the first day after cardiac surgery. The elderly had a higher plasma concentration of fentanyl at the end of surgery than younger patients. The plasma concentrations of oxycodone were comparable between the groups. Pain intensity on the VRS was lower and the sedation scores were higher in the elderly. Total oxycodone consumption during five postoperative days was reduced by 48% and the CAM-ICU scores were higher on the first postoperative day in the pregabalin group. The incidence of postoperative pain during movement was lower in the pregabalin group three months after surgery. This investigation demonstrates that chronic pain did not seem to impair daily activities in home-dwelling Finnish elderly. The VRS appeared to be applicable for elderly patients with clear cognitive dysfunction (MMSE ≤17) and it was the most feasible pain scale for the early postoperative period after cardiac surgery. After cardiac surgery, plasma concentrations of fentanyl in elderly were elevated, although oxycodone concentrations were at similar level compared to middle-aged patients. The elderly had less pain and were more sedated after doses of oxycodone. Therefore, particular attention must be given to individual dosing of the opioids in elderly surgical patients, who often need a smaller amount for adequate analgesia than middle-aged patients. The administration of pregabalin reduced postoperative oxycodone consumption after cardiac surgery. Pregabalin-treated patients had less confusion, and additionally to less postoperative pain on the first postoperative day and during movement at three months post-surgery. Pregabalin might be a new alternative as analgesic for acute postoperative and chronic pain management in the elderly. Its clinical role and safety remains to be verified in large-scale randomized and controlled studies. In the future, many clinical trials in the older category of patients will be needed to facilitate improvements in health care methods.

Visual Impairment in Finnish Children : Prevalence, causes and morbidity of full-term and preterm children with visual impairment born from 1972 through 1989

The prevalence and the causes of childhood visual impairment in Finland during the 1970s and the 1980s were investigated, with special attention to risk factors and further prevention of visual impairment in children. The primary data on children with visual impairment were obtained from the Finnish Register of Visual Impairment, one of the patient registers kept up by the National Research and Development Centre for Welfare and Health (Stakes). The data were supplemented from other registers in Stakes and from patient records of the children in Finnish central hospitals. Visual impairment had been registered in 556 children from a population of 1,138,326 children between ages 0-17, born from 1972 through 1989. The age-specific prevalence of registered visual impairment was 49/100,000 in total. Of them, 23/100,000 were blind children and 11/100,000 were children born prematurely. Boys were impaired more often and more severely than girls. Congenital malformations (52%), systemic diseases (48%), and multiple impairments (50%) were common. The main ophthalmic groups of visual impairment were retinal diseases (35%), ocular malformations (29%), and neuro-ophthalmological disorders (29%). Optic nerve atrophy was the most common diagnosis of visual impairment (22%), followed by congenital cataract (11%), retinopathy of prematurity (10%), and cerebral visual impairment (8%). Genetic factors (42%) were the most common etiologies of visual impairment, followed by prenatal (30%) and perinatal (21%) factors. The highest rates of blindness were seen in cerebral visual impairment (83%) and retinopathy of prematurity (82%). Retinopathy of prematurity had developed in the children born at a gestational age of 32 weeks or earlier. Significant risks for visual impairment were found in the association with preterm births, prenatal infections, birth asphyxia, neonatal respiratory difficulties, mechanical ventilation lasting over two weeks, and hyperbilirubinemia. A rise in blind and multi-impaired children was seen during the study period, associating with increases in the survival of preterm infants with extremely low birth weight. The incidence of visual impairment in children born prematurely was seven times higher than in children born at full term. A reliable profile of childhood visual impairment was obtained. The importance of highly qualified antenatal, neonatal, and ophthalmological care was clearly proved. The risks associated with pre- and perinatal disorders during pregnancy must be emphasized, e.g. the risks associated with maternal infections and the use of tobacco, alcohol, and drugs during pregnancy. Obvious needs for gene therapies and other new treatments for hereditary diseases were also proved.