The Effect of Intrauterine Growth Restriction on Long-Term Outcome in Very or Extremely Low Birth Weight Infants

The project consisted of two long-term follow-up studies of preterm children addressing the question whether intrauterine growth restriction affects the outcome. Assessment at 5 years of age of 203 children with a birth weight less than 1000 g born in Finland in 1996-1997 showed that 9% of the children had cognitive impairment, 14% cerebral palsy, and 4% needed a hearing aid. The intelligence quotient was lower (p<0.05) than the reference value. Thus, 20% exhibited major, 19% minor disabilities, and 61% had no functional abnormalities. Being small for gestational age (SGA) was associated with sub-optimal growth later. In children born before 27 gestational weeks, the SGA had more neuropsychological disabilities than those appropriate for gestational age (AGA). In another cohort with birth weight less than 1500 g assessed at 5 years of age, echocardiography showed a thickened interventricular septum and a decreased left ventricular end-diastolic diameter in both SGA and AGA born children. They also had a higher systolic blood pressure than the reference. Laser-Doppler flowmetry showed different endothelium-dependent and -independent vasodilation responses in the AGA children compared to those of the controls. SGA was not associated with cardio-vascular abnormalities. Auditory event-related potentials (AERPs) were recorded using an oddball paradigm with frequency deviants (standard tone 500 Hz and deviant 750-Hz with 10% probability). At term, the P350 was smaller in SGA and AGA infants than in controls. At 12 months, the automatic change detection peak (mismatch negativity, MMN) was observed in the controls. However, the pre-term infants had a difference positivity that correlated with their neurodevelopment scores. At 5 years of age, the P1-deflection, which reflects primary auditory processing, was smaller, and the MMN larger in the preterm than in the control children. Even with a challenging paradigm or a distraction paradigm, P1 was smaller in the preterm than in the control children. The SGA and AGA children showed similar AERP responses. Prematurity is a major risk factor for abnormal brain development. Preterm children showed signs of cardiovascular abnormality suggesting that prematurity per se may carry a risk for later morbidity. The small positive amplitudes in AERPs suggest persisting altered auditory processing in the preterm in-fants.

La música orquestal peruana de 1945 a 2005 : Identidades en la diversidad

Peruvian orchestral music 1945–2005. Identities in diversity Peruvian music for orchestra has not been studied as a whole before, and is hardly known by Peruvian musicians and public. The aim of the thesis is to give a panoramic view of Peruvian orchestral music after 1945, study the particular historical context in which these works were created and how they reflect the search for a musical identity of its own, be it individual, local, national or Latin American. Identity is a construction that changes permanently, and individuals can share many identities at the same time. This is a central issue in multicultural societies as the Peruvian, and music is an important mean for constructing cultural identity. The hypothesis of this research is that orchestral work is a medium for Peruvian composers to express their relationship with traditional and popular musics of the country in different ways, from quotation of melodies to a more abstract appropiation of concepts or suggestive title references. Representative works by selected composers, of different techniques, styles or special reception are chosen and analyzed. Research methodology includes analysis of works with various methods according to their stylistic and technical features, in order to find the particular ways in which composers have approached or expressed diverse identities. The investigation shows that Peruvian orchestral music includes works in the main stylistic trends and using the main compositional techniques of the modernist and postmodern periods. It also shows that the construction and expression of particular identities through the study and use of other Peruvian musical traditions is a constant interest shared by composers of different age and esthetic. In a multicultural society as the Peruvian, characterized by its diversity, different forms of transcultural composition are an important mean of dealing with identity issues in music. This thesis also includes for the first time a list of all orchestral works composed in the country or by Peruvian composers in the period, their composers and genres. KEYWORDS: Peruvian music, contemporary music for orchestra, identity

Systemic Inflammation in Preterm Infants

Even though mortality among preterm infants has decreased, their risk for chronic complications such as bronchopulmonary dysplasia (BPD) and neurological disability remains significant. One common risk factor for these is exposure to inflammation. The fetus may be exposed prenatally during maternal chorioamnionitis. Pre-eclampsia is also associated with low-grade maternal inflammation. Postnatally, local and systemic inflammation is present during respiratory distress syndrome (RDS). Furthermore, septic infections in the preterm infant are an important source of inflammatory stimuli and can lead to death in only a few hours. The diagnosis of septic infection is difficult, since reliable diagnostic markers are unavailable. This thesis evaluates peri- and postnatal systemic inflammation in preterm infants in septic infections, in RDS treated with mechanical ventilation and surfactant treatment, and in preterm infants prenatally exposed to chorioamnionitis and pre-eclampsia. Surface expressions of the activation markers CD11b, CD54, and CD62L, determined by flow cytometry on circulating phagocytes and T lymphocytes, serve as indicators of systemic inflammation. The main findings: I) In preterm infants with developing late-onset sepsis and fulminant necrotizing enterocolitis, a significant increase in CD11b expression on circulating phagocytes is already present on the day of onset of clinical symptoms. II) In preterm infants with RDS, circulating phagocytes become activated within hours after start of mechanical ventilation. In preterm infants treated for RDS with nasal continuous positive airway pressure, no such activation occurs. III) In preterm infants, RDS is associated during the first days of life with fewer circulating helper and cytotoxic T lymphocytes, of which the greater proportions are activated. Even greater proportions of circulating T cells are activated in infants subsequently developing BPD. IV) In preterm infants born after maternal pre-eclampsia, RDS-associated phagocyte CD11b up-regulation is greater than in preterm infants not exposed to pre-eclampsia during the first week of life. These findings suggest that I) an increase in CD11b expression on circulating phagocytes can identify preterm infants with late-onset sepsis as early as at sampling for blood culture and may thus aid in the diagnosis. II) In preterm infants with RDS, initiation of mechanical ventilation, but not the use of nasal continuous positive airway pressure, promotes a systemic inflammatory reaction; exogenous surfactant does not seem to promote inflammation. III) In addition to activation of circulating cells of the innate immunity in preterm infants with RDS, the circulating cells of the adaptive immunity are activated. The activation of adaptive immunity may link acute inflammation and development of chronic inflammation-associated problems such as BPD. IV) Maternal pre-eclampsia may prime neonatal immunity to react more strongly to postnatal stimuli. In conclusion, the preterm infant is exposed to numerous potentially injurious events such as intrauterine inflammation, respiratory distress syndrome (RDS), and systemic infections, all evoking systemic inflammation. Due to ongoing development of the lung and the brain, this may, in addition to acute injury, lead to aberrant lung and brain development and to clinical syndromes of BPD and neurologic sequelae.

Neuromagnetic studies on cortical somatosensory functions in infants and children : Normal development and effect of early brain lesions

Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.

Preterm delivery and selected biomarkers : phosphorylated insulin-like growth factor-binding protein-1 and matrix metalloproteinase-8 – in cervical fluid

Premature delivery is a major cause of neonatal morbidity and mortality. The incidence of premature deliveries has increased around the world. In Finland 5.3%, or about 3,000 children per year are born prematurely, before 37 weeks of gestation. The corresponding figure in the United States is about 13%. The morbidity and mortality are highest among infants delivered before 32 weeks of gestation - about 600 children each year in Finland. Approximately 70% of premature deliveries are unexplained. Preterm delivery can be caused by an asympto-matic infection between uterus and the fetal membranes, such can begin already in early pregnancy. It is difficult to predict preterm delivery, and many patients are therefore unnecessarily admitted to hospital for observation and exposed to medical treatments. On the other hand, the high risk women should be identified early for the best treatment of the mother and preterm infant. --- In the prospective study conducted at the Department of Obstetric and Gynecology, Helsinki University Central Hospital two biochemical inflammation related markers were measured in the lower genital tract fluids of asymp-tomatic women in early and mid pregnancy in an order to see whether these markers could identify women with an increased risk of preterm delivery. These biomarkers were phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and matrix metalloproteinase-8 (MMP-8). The study involved 5180 asymptomatic pregnant women, examined during the first and second ultrasound screening visits. The study samples were taken from the vagina and cervicix. In addition, 246 symptomatic women were studied (pregnancy weeks 22 – 34). The study showed that increased phIGFBP-1 concentration in cervical canal fluid in early pregnancy increased the risk for preterm delivery. The risk for very premature birth (before 32 weeks of gestation) was nearly four-fold. Low MMP-8 concentration in mid pregnancy increased the risk of subsequent premature preterm rupture of fetal membranes (PPROM). Significantly high MMP-8 concentrations in the cervical fluid increased the risk for prema-ture delivery initiated by preterm labour with intact membranes. Among women with preterm contractions the shortened cervical length measured by ultrasound and elevated cervical fluid phIGFBP-1 both predicted premature delivery. In summary, because of the relatively low sensitivity of cervical fluid phIGFBP-1 this biomarker is not suitable for routine screening, but provides an additional tool in assessing the risk of preterm delivery. Cervical fluid MMP-8 is not useful in early or mid pregnancy in predicting premature delivery because of its dual role. Further studies on the role of MMP-8 are therefore needed. Our study confirms that phIGFBP-1 testing is useful in predicting pre-term delivery.

Thrombin regulation in newborn infants

The coagulation system of newborn infants differs markedly from that of older children and adults. The activities of most coagulation factors and anticoagulants are low, leading to altered regulation in the formation of the key enzyme, thrombin. Timely and adequate generation of thrombin is essential, as thrombin activates platelets and many coagulation factors, cleaves fibrinogen into fibrin and activates the antithrombotic and anti-inflammatory protein C pathway. On the other hand, excess thrombin may promote thrombotic complications and exacerbate harmful inflammatory reactions. Despite the characteristic features, the newborn coagulation system can be considered physiological, since healthy newborns rarely show haemorrhagic or thrombotic complications. Sick newborns, however, often encounter clinical situations that challenge their coagulation system. The aim of this study was to clarify the behaviour of the neonatal coagulation system in selected clinical situations, with a special emphasis on the generation of thrombin. Thrombin was measured by in vivo thrombin generation markers and by thrombin generation potential in vitro. The patient groups included sick newborns undergoing intensive care and receiving fresh-frozen plasma (FFP), requiring exchange transfusions (ET) or presenting with a congenital heart defect requiring open heart surgery. Additionally, healthy newborns with inherited heterozygous factor V Leiden (FVL) mutation were studied. Thrombin generation potential was also analysed in cord plasma of healthy infants and in adults. Healthy as well as sick newborn infants showed lower total thrombin generation potential in vitro but faster initiation of thrombin generation than adults. These findings were qualitatively similar when plasma was supplemented with platelets. Platelets, however, significantly altered the effect of the major anticoagulant, activated protein C (APC), on thrombin generation potential. In accordance with previous studies, thrombin generation in healthy newborn platelet-poor plasma was resistant to the anticoagulant effects of APC, but when the plasma was supplemented with platelets APC attenuated thrombin generation significantly more in newborns than in adults. In vivo generation of thrombin was elevated in nearly all of the sick newborn infants. The low-volume FFP transfusion as opposed to the change from neonatal to adult blood in ET exerted markedly different effects on neonatal thrombin generation. FFP reduced the in vivo generation of thrombin in those newborns with the highest pretransfusional thrombin generation, thus acting as an anticoagulant agent. In those infants with lower pretransfusional thrombin generation, the effect of FFP on thrombin generation was fairly neutral. On the other hand, the combination of red blood cells and FFP, used to perform ET, significantly increased the in vivo thrombin formation and shifted the balance in the newborn coagulation system to the procoagulant direction. Cardiopulmonary bypass (CPB) also significantly increased the in vivo thrombin generation, but the thrombin generation profile during CPB differed from that previously observed in adults. Escalation of thrombin at early reperfusion was not observed in newborns; in adults, its occurrence is associated with postoperative myocardial damage. Finally, in healthy newborns with FVL heterozygosity, faster initiation of thrombin generation was observed compared with controls. Interestingly, FV level was lower in FVL-heterozygous infants, possibly to counteract the procoagulant effects induced by FVL. In conclusion, unique features regarding thrombin regulation in newborn infants were observed. These features included a novel platelet effect on the regulation of the protein C pathway. The clinical challenges mainly seemed to shift the balance in the coagulation system of newborns to the procoagulant direction. Blood component transfusions markedly affected coagulation in a manner specific to the product but that could also be altered by the clinical situation. Overall, the results highlight the need for understanding developmental haemostasis for both diagnostic and therapeutic purposes.

Very Low Birth Weight Infants as Young Adults : Focus on aspects of cognition, behavior and sleep

Major advances in the treatment of preterm infants have occurred during the last three decades. Survival rates have increased, and the first generations of preterm infants born at very low birth weight (VLBW; less than 1500 g) who profited from modern neonatal intensive care are now in young adulthood. The literature shows that VLBW children achieve on average lower scores on cognitive tests, even after exclusion of individuals with obvious neurosensory deficits. Evidence also exists for an increased risk in VLBW children for various neuropsychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and related behavioral symptoms. Up till now, studies extending into adulthood are sparse, and it remains to be seen whether these problems persist into adulthood. The aim of this thesis was to study ADHD-related symptoms and cognitive and executive functioning in young adults born at VLBW. In addition, we aimed to study sleep disturbances, known to adversely affect both cognition and attention. We hypothesized that preterm birth at VLBW interferes with early brain development in a way that alters the neuropsychological phenotype; this may manifest itself as ADHD symptoms and impaired cognitive abilities in young adulthood. In this cohort study from a geographically defined region, we studied 166 VLBW adults and 172 term-born controls born from 1978 through 1985. At ages 18 to 27 years, the study participants took part in a clinic study during which their physical and psychological health was assessed in detail. Three years later, 213 of these individuals participated in a follow-up. The current study is part of a larger research project (The Helsinki Study of Very Low Birth Weight Adults), and the measurements of interest for this particular study include the following: 1) The Adult Problem Questionnaire (APQ), a self-rating scale of ADHD-related symptoms in adults; 2) A computerized cognitive test battery designed for population studies (CogState®) which measures core cognitive abilities such as reaction time, working memory, and visual learning; 3) Sleep assessment by actigraphy, the Basic Nordic Sleep Questionnaire, and the Morningness-Eveningness Questionnaire. Actigraphs are wrist-worn accelerometers that separate sleep from wakefulness by registering body movements. Contrary to expectations, VLBW adults as a group reported no more ADHD-related behavioral symptoms than did controls. Further subdivision of the VLBW group into SGA (small for gestational age) and AGA (appropriate for gestational age) subgroups, however, revealed more symptoms on ADHD subscales pertaining to executive dysfunction and emotional instability among those born SGA. Thus, it seems that intrauterine growth retardation (for which SGA served as a proxy) is a more essential predictor for self-perceived ADHD symptoms in adulthood than is VLBW birth as such. In line with observations from other cohorts, the VLBW adults reported less risk-taking behavior in terms of substance use (alcohol, smoking, and recreational drugs), a finding reassuring for the VLBW individuals and their families. On the cognitive test, VLBW adults free from neurosensory deficits had longer reaction times than did term-born peers on all tasks included in the test battery, and lower accuracy on the learning task, with no discernible effect of SGA status over and above the effect of VLBW. Altogether, on a group level, even high-functioning VLBW adults show subtle deficits in psychomotor processing speed, visual working memory, and learning abilities. The sleep studies provided no evidence for differences in sleep quality or duration between the two groups. The VLBW adults were, however, at more than two-fold higher risk for sleep-disordered breathing (in terms of chronic snoring). Given the link between sleep-disordered breathing and health sequelae, these results suggest that VLBW individuals may benefit from an increased awareness among clinicians of this potential problem area. An unexpected finding from the sleep studies was the suggestion of an advanced sleep phase: The VLBW adults went to bed earlier according to the actigraphy registrations and also reported earlier wake-up times on the questionnaire. In further study of this issue in conjunction with the follow-up three years later, the VLBW group reported higher levels of morningness propensity, further corroborating the preliminary findings of an advanced sleep phase. Although the clinical implications are not entirely clear, the issue may be worth further study, since circadian rhythms are closely related to health and well-being. In sum, we believe that increased understanding of long-term outcomes after VLBW, and identification of areas and subgroups that are particularly vulnerable, will allow earlier recognition of potential problems and ultimately lead to improved prevention strategies.

Diccionario Enciclopédico de Música en Mexico

The work is the most extensive encyclopedic compilation on Mexican music published to the date, in the form of a dictionary. It includes composer's bios, list of works, musical institutions, instruments, performers, theatres, and many other categories about the music of Mexico. Most of entries include bibliography.