Determinants of outcome in critically ill patients

Assessment of the outcome of critical illness is complex. Severity scoring systems and organ dysfunction scores are traditional tools in mortality and morbidity prediction in intensive care. Their ability to explain risk of death is impressive for large cohorts of patients, but insufficient for an individual patient. Although events before intensive care unit (ICU) admission are prognostically important, the prediction models utilize data collected at and just after ICU admission. In addition, several biomarkers have been evaluated to predict mortality, but none has proven entirely useful in clinical practice. Therefore, new prognostic markers of critical illness are vital when evaluating the intensive care outcome. The aim of this dissertation was to investigate new measures and biological markers of critical illness and to evaluate their predictive value and association with mortality and disease severity. The impact of delay in emergency department (ED) on intensive care outcome, measured as hospital mortality and health-related quality of life (HRQoL) at 6 months, was assessed in 1537 consecutive patients admitted to medical ICU. Two new biological markers were investigated in two separate patient populations: in 231 ICU patients and 255 patients with severe sepsis or septic shock. Cell-free plasma DNA is a surrogate marker of apoptosis. Its association with disease severity and mortality rate was evaluated in ICU patients. Next, the predictive value of plasma DNA regarding mortality and its association with the degree of organ dysfunction and disease severity was evaluated in severe sepsis or septic shock. Heme oxygenase-1 (HO-1) is a potential regulator of apoptosis. Finally, HO-1 plasma concentrations and HO-1 gene polymorphisms and their association with outcome were evaluated in ICU patients. The length of ED stay was not associated with outcome of intensive care. The hospital mortality rate was significantly lower in patients admitted to the medical ICU from the ED than from the non-ED, and the HRQoL in the critically ill at 6 months was significantly lower than in the age- and sex-matched general population. In the ICU patient population, the maximum plasma DNA concentration measured during the first 96 hours in intensive care correlated significantly with disease severity and degree of organ failure and was independently associated with hospital mortality. In patients with severe sepsis or septic shock, the cell-free plasma DNA concentrations were significantly higher in ICU and hospital nonsurvivors than in survivors and showed a moderate discriminative power regarding ICU mortality. Plasma DNA was an independent predictor for ICU mortality, but not for hospital mortality. The degree of organ dysfunction correlated independently with plasma DNA concentration in severe sepsis and plasma HO-1 concentration in ICU patients. The HO-1 -413T/GT(L)/+99C haplotype was associated with HO-1 plasma levels and frequency of multiple organ dysfunction. Plasma DNA and HO-1 concentrations may support the assessment of outcome or organ failure development in critically ill patients, although their value is limited and requires further evaluation.

Molecular Genetics of Age-related Macular Degeneration

Age-related macular degeneration (AMD; OMIM # 603075) is an eye disease of the elderly, signs of which appear after the age of 50. In the Western world it is a leading cause of permanent visual loss with a prevalence of 8.5% in persons under 54 years of age and of 37% in persons over 75 years of age. Early forms of AMD may be asymptomatic, but in the late forms usually a central scotoma in the visual field follows severely complicating daily tasks. Smoking, age, and genetic predisposition are known risk factors for AMD. Until recently no true susceptibility genes had been identified though the composition of drusen deposits, the hallmarks of AMD, has suggested that the complement system might play a role in the pathogenesis of AMD. When four groups reported in March 2005, that, on chromosome 1q32, a Y402H variant in the complement factor H (CFH) gene confers risk for AMD in independent Caucasian samples, a new period in the field of genetic research of AMD started. CFH is a key regulator of the complement system. Thus, it is logical to speculate, that it plays a role in the pathogenesis of AMD. We performed a case-control association study to analyse whether the CFH Y402H variant contain a risk for AMD in the Finnish population. Although the population of Finland represents a genetic isolate, the CFH Y402H polymorphism was associated with AMD also in our patient sample with similar risk allele frequencies as in the other Caucasian populations. We further evaluated the effects of this variant, but no association between lesion subtype (predominantly classic, minimally classic or occult lesion) or lesion size of neovascular AMD and the CFH Y402H variant was detected. Neither did the variant have an effect on the photodynamic therapy (PDT) outcome. The patients that respond to PDT carried the risk genotype as frequently as those who did not respond, and no difference was found in the number of PDT sessions needed in patients with or without the risk genotypes of CFH Y402H. Functional analyses, however, showed that the binding of C-reactive protein (CRP) to CFH was significantly reduced in patients with the risk genotype of Y402H. In the past two years, the LOC387715/ high-temperature requirement factor A1 (HTRA1) locus on 10q26 has also been repeatedly associated with AMD in several populations. The recent discovery of the LOC387715 protein on the mitochondrial outer membrane suggests that the LOC387715 gene, not HTRA1, is the true predisposing gene in this region, although its biological function is still unknown. In our Finnish patient material, patients with AMD carried the A69S risk genotype of LOC387715 more frequently than the controls. Also, for the first time, an interaction between the CFH Y402H and the LOC387715 A69S variants was found. The most recently detected susceptibilty gene of AMD, the complement component 3 (C3) gene, encodes the central component of the complement system, C3. In our Finnish sample, an additive gene effect for the C3 locus was detected, though weaker than the effects for the two main loci, CFH and LOC387715. Instead, the hemicentin-1 or the elongation of very long chain fatty acids-like 4 genes that have also been suggested as candidate genes for AMD did not carry a risk for AMD in the Finnish population. This was the first series of molecular genetic study of AMD in Finland. We showed that two common risk variants, CFH Y402H and LOC387715 A69S, represent a high risk of AMD also in the isolated Finnish population, and furthermore, that they had a statistical interaction. It was demonstrated that the CFH Y402H risk genotype affects the binding of CFH to CRP thus suggesting that complement indeed plays an important role in the pathogenesis of AMD.

A preliminary survey of dermatomycoses in Bangalore

Clinical and mycological investigations were made on 225 cases of suspected dermatomycoses. Of these, 102 were microscopically positive. But only 63 were culturally positive, and these are analysed here with regard to clinical patterns and aetiological species, age, sex and occupational incidence and susceptibility to griseofulvin in vitro. As in most other parts of India, Trichophyton rubrum was the dominant species. A high proportion of Epidermophyton floccosum was an unusual feature seen. Of the clinical types, tinea cruris was the most common. The isolates were sensitive to griseofulvin at low concentrations of 1 to 5 μg per ml of agar medium, E. floccosum being the most sensitive.

'... the walls fell down but the blokes just coded ...' - Varieties of stability in software product development during organizational restructurings

Many Finnish IT companies have gone through numerous organizational changes over the past decades. This book draws attention to how stability may be central to software product development experts and IT workers more generally, who continuously have to cope with such change in their workplaces. It does so by analyzing and theorizing change and stability as intertwined and co-existent, thus throwing light on how it is possible that, for example, even if ‘the walls fall down the blokes just code’ and maintain a sense of stability in their daily work. Rather than reproducing the picture of software product development as exciting cutting edge activities and organizational change as dramatic episodes, the study takes the reader beyond the myths surrounding these phenomena to the mundane practices, routines and organizings in product development during organizational change. An analysis of these ordinary practices offers insights into how software product development experts actively engage in constructing stability during organizational change through a variety of practices, including solidarity, homosociality, close relations to products, instrumental or functional views on products, preoccupations with certain tasks and humble obedience. Consequently, the study shows that it may be more appropriate to talk about varieties of stability, characterized by a multitude of practices of stabilizing rather than states of stagnation. Looking at different practices of stability in depth shows the creation of software as an arena for micro-politics, power relations and increasing pressures for order and formalization. The thesis gives particular attention to power relations and processes of positioning following organizational change: how social actors come to understand themselves in the context of ongoing organizational change, how they comply with and/or contest dominant meanings, how they identify and dis-identify with formalization, and how power relations often are reproduced despite dis-identification. Related to processes of positioning, the reader is also given a glimpse into what being at work in a male-dominated and relatively homogeneous work environment looks like. It shows how the strong presence of men or “blokes” of a particular age and education seems to become invisible in workplace talk that appears ‘non-conscious’ of gender.

Epidemiology of candidemia in Finland

Candida species are an important cause of nosocomial bloodstream infections in hospitalized patients worldwide, with associated high mortality, excess length of stay and costs. Main contributors to candidemias is profound immunosuppression due to serious underlying condition or intensive treatments leading to an increasing number of susceptible patients. The rank order of causative Candida species varies over time and in different geographic locations. The aim of this study was to obtain information on epidemiology of candidemia in Finland, to identify trends in incidence, causative species, and patient populations at risk. In order to reveal possible outbreaks and assess the value of one molecular typing method, restriction enzyme analysis (REA), in epidemiological study, we analyzed C. albicans bloodstream isolates in Uusimaa region in Southern Finland during eight years. The data from the National Infectious Disease Register were used to assess the incidence and epidemiological features of candidemia cases. In Helsinki University Central Hospital (HUCH) all patients with blood culture yielding any Candida spp. were identified from laboratory log-books and from Finnish Hospital Infection Program. All the patients with a stored blood culture isolate of C. albicans were identified through microbiology laboratory logbooks, and stored isolates were genotyped with REA in the National Institute for Health and Welfare (former KTL). The incidence of candidemia in Finland is globally relatively low, but increased between between 1990s and 2000s. The incidence was highest in males >65 years of age, but incidence rates for patients <1-15 years were lower during 2000s than during 1990s. In HUCH the incidence of candidemia remained low and constant during our 18 years of observation, but a significant shift in patient-populations at risk was observed, associated with patients treated in intensive care units, such as premature neonates and surgical patients. The predominating causative species in Finland and in HUCH is C. albicans, but the proportion of C. glabrata increased considerably. The crude one-month case fatality was constantly high between 28-33%. REA differentiated efficiently between C. albicans blood culture isolates and no clusters were observed in the hospitals involved, despite of abundant transfer of patients among them. Candida spp. are an important cause of nosocomial blood stream infections in Finland, and continued surveillance is necessary to determine the overall trends and patient groups at risk, and reduce the impact of these infections in the future. Molecular methods provide an efficient tool for investigation of suspected outbreak and should be available in the future in Finland, also.

Functional limitations and quality of life in schizophrenia and other psychotic disorders

There is substantial evidence of the decreased functional capacity, especially everyday functioning, of people with psychotic disorder in clinical settings, but little research about it in the general population. The aim of the present study was to provide information on the magnitude of functional capacity problems in persons with psychotic disorder compared with the general population. It estimated the prevalence and severity of limitations in vision, mobility, everyday functioning and quality of life of persons with psychotic disorder in the Finnish population and determined the factors affecting them. This study is based on the Health 2000 Survey, which is a nationally representative survey of 8028 Finns aged 30 and older. The psychotic diagnoses of the participants were assessed in the Psychoses of Finland survey, a substudy of Health 2000. The everyday functioning of people with schizophrenia is studied widely, but one important factor, mobility has been neglected. Persons with schizophrenia and other non-affective psychotic disorders, but not affective psychoses had a significantly increased risk of having both self-reported and test-based mobility limitations as well as weak handgrip strength. Schizophrenia was associated independently with mobility limitations even after controlling for lifestyle-related factors and chronic medical conditions. Another significant factor associated with problems in everyday functioning in participants with schizophrenia was reduced visual acuity. Their vision was examined significantly less often during the five years before the visual acuity measurement than the general population. In general, persons with schizophrenia and other non-affective psychotic disorder had significantly more limitations in everyday functioning, deficits in verbal fluency and in memory than the general population. More severe negative symptoms, depression, older age, verbal memory deficits, worse expressive speech and reduced distance vision were associated with limitations in everyday functioning. Of all the psychotic disorders, schizoaffective disorder was associated with the largest losses of quality of life, and bipolar I disorder with equal or smaller losses than schizophrenia. However, the subjective loss of qualify of life associated with psychotic disorders may be smaller than objective disability, which warrants attention. Depressive symptoms were the most important determinant of poor quality of life in all psychotic disorders. In conclusion, subjects with psychotic disorders need regular somatic health monitoring. Also, health care workers should evaluate the overall quality of life and depression of subjects with psychotic disorders in order to provide them with the basic necessities of life.

Studies on neurotransmitter-stimulated phospholipid metabolism with cerebral tissue suspensions: A possible biochemical correlate of synaptogenesis in normal and undernourished rats

The phenomenon of neurotransmitter-stimulated incorporation of32Pi into phosphatidic acid and inositol phosphatides (neurotransmitter effect) in developing brain was studied in vitro as a possible measure of synaptogenesis. While the neurotransmitter effect was not observed with brain homogenates, highly consistent and significant effects were noted with brain tissue suspensions obtained by passing the tissue through nylon bolting cloth. The magnitude of the effect decreased with the increase in mesh number. Maximum stimulations obtained with the 33 mesh adult brain cortex preparations (mean±S.E.M. of6experiments) were203 ± 8%, 316 ± 11 % and150 ± 8% with 10−3 M acetylcholine (ACh) + 10−3 M eserine; 10−2 M norepinephrine (NE) and 10−2 M serotonin (5-HT), respectively. Experiments with developing rat brain at 7, 14 and 21 days of age showed that the neurotransmitter effects due to ACh, NE and 5-HT increase progressively in different regions of the brain but that there are marked regional differences. It is suggested that the neurotransmitter effect is a valid biochemical correlate of synaptogenesis. In rats undernourished from birth t0 21 days of age, by increasing the litter size, the neurotransmitter effect with ACh, NE or 5-HT was not altered in the cortex but was significantly reduced in the brain stem. In cerebellum the effects due to ACh and NE were significantly altered, while that with 5-HT was unaffected. It is concluded that cholinergic, adrenergic and serotonergic synapses are relatively unaffected in the cortex but are significantly affected in the brain stem by undernutrition. In the cerebellum of undernourished rats the adrenergic and cholinergic, but not serotonergic systems, are altered.

The role of larval nutrition in pre-imaginal biasing of caste in the primitively eusocial wasp Ropalidia marginata (Hymenoptera: Vespidae)

1. When freshly eclosed females of the primitively eusocial wasp Ropalidia marginata (Lep.) are isolated, only about 50% of them build nests and lay eggs thereby suggesting a pre-imaginal biasing of caste. 2. Wasps that lay eggs take a very variable amount of time after eclosion to start doing so. 3. Females eclosing from nests where larvae are fed at a relatively higher rate are more likely to become egg-layers and are likely to take less time after eclosion to begin to lay eggs. 4. Thus, both forms of pre-imaginal biasing of caste, namely, differences in egg laying capacity and differences in the time taken to attain reproductive maturity, appear to be influenced by larval nutrition.

Molecular profile of oligodendrogliomas in young patients

Several studies on molecular profiling of oligodendrogliomas (OGs) in adults have shown a distinctive genetic pattern characterized by combined deletions of chromosome arms 1 p and 19q, O6-methylguanine-methyltransferase (MGMT) methylation, and isocitrate dehydrogenase 1 (IDH1) mutation, which have potential diagnostic, prognostic, and even therapeutic relevance. OGs in pediatric and young adult patients are rare and have been poorly characterized on a molecular and biological basis, and it remains uncertain whether markers with prognostic significance in adults also have predictive value in these patients. Fourteen cases of OGs in young patients (age, <= 25 years) who received a diagnosis over 7 years were selected (7 pediatric patients age <= 18 years and 7 young adults aged 19-25 years). The cases were evaluated for 1p/19q status, MGMT promoter methylation, p53 mutation, and IDH1 mutation. None of the pediatric cases showed 1p/19q deletion. In young adults, combined 1p/19q loss was observed in 57% and isolated 1p loss in 14% of cases. The majority of cases in both subgroups (71% in each) harbored MGMT gene promoter methylation. TP53 and IDH1 mutations were not seen in any of the cases in both the groups. To our knowledge, this is the first study to show that molecular profile of OGs in pediatric and young adult patients is distinct. Further large-scale studies are required to identify additional clinically relevant genetic alterations in this group of patients.

Low cost calibrated mechanical noisemaker for hearing screening of neonates in resource constrained settings

Background & objectives: There is a need to develop an affordable and reliable tool for hearing screening of neonates in resource constrained, medically underserved areas of developing nations. This study valuates a strategy of health worker based screening of neonates using a low cost mechanical calibrated noisemaker followed up with parental monitoring of age appropriate auditory milestones for detecting severe-profound hearing impairment in infants by 6 months of age. Methods: A trained health worker under the supervision of a qualified audiologist screened 425 neonates of whom 20 had confirmed severe-profound hearing impairment. Mechanical calibrated noisemakers of 50, 60, 70 and 80 dB (A) were used to elicit the behavioural responses. The parents of screened neonates were instructed to monitor the normal language and auditory milestones till 6 months of age. This strategy was validated against the reference standard consisting of a battery of tests - namely, auditory brain stem response (ABR), otoacoustic emissions (OAE) and behavioural assessment at 2 years of age. Bayesian prevalence weighted measures of screening were calculated. Results: The sensitivity and specificity was high with least false positive referrals for. 70 and 80 dB (A) noisemakers. All the noisemakers had 100 per cent negative predictive value. 70 and 80 dB (A) noisemakers had high positive likelihood ratios of 19 and 34, respectively. The probability differences for pre- and post- test positive was 43 and 58 for 70 and 80 dB (A) noisemakers, respectively. Interpretation & conclusions: In a controlled setting, health workers with primary education can be trained to use a mechanical calibrated noisemaker made of locally available material to reliably screen for severe-profound hearing loss in neonates. The monitoring of auditory responses could be done by informed parents. Multi-centre field trials of this strategy need to be carried out to examine the feasibility of community health care workers using it in resource constrained settings of developing nations to implement an effective national neonatal hearing screening programme.

Development, in vitro and in vivo characterization of zoledronic acid functionalized hydroxyapatite nanoparticle based formulation for treatment of osteoporosis in animal model

We investigated the potential of using novel zoledronic acid (ZOL)-hydroxyapatite (HA) nanoparticle based drug formulation in a rat model of postmenopausal osteoporosis. By a classical adsorption method, nanoparticles of HA loaded with ZOL (HNLZ) drug formulation with a size range of 100-130 nm were prepared. 56 female Wistar rats were ovariectomized (OVX) or sham-operated at 3 months of age. Twelve weeks post surgery, rats were randomized into seven groups and treated with various doses of HNLZ (100, 50 and 25 mu g/kg, intravenous single dose), ZOL (100 mu g/kg, intravenous single dose) and HA nanoparticle (100 mu g/kg, intravenous single dose). Untreated OVX and sham OVX served as controls. After three months treatment period, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for trabecular microarchitecture. Sensitive biochemical markers of bone formation and bone resorption in serum were also determined. With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the therapy with HNLZ drug formulation was more effective than ZOL therapy in OVX rats. Moreover, HNLZ drug therapy preserved the trabecular microarchitecture better than ZOL therapy in OVX rats. Furthermore, the HNLZ drug formulation corrected increase in serum levels of bone-specific alkaline phosphatase, procollagen type I N-terminal propeptide, osteocalcin, tartrate-resistant acid phosphatase 5b and C-telopeptide of type 1 collagen better than ZOL therapy in OVX rats. The results strongly suggest that HNLZ novel drug formulation appears to be more effective approach for treating severe osteoporosis in humans. (C) 2014 Elsevier B.V. All rights reserved.

The role of androgens in fetal growth: observational study in two genetic models of disordered androgen signalling.

OBJECTIVE: To examine the role of androgens on birth weight in genetic models of altered androgen signalling. SETTING: Cambridge Disorders of Sex Development (DSD) database and the Swedish national screening programme for congenital adrenal hyperplasia (CAH). PATIENTS: (1) 29 girls with XY karyotype and mutation positive complete androgen insensitivity syndrome (CAIS); (2) 43 girls and 30 boys with genotype confirmed CAH. MAIN OUTCOME MEASURES: Birth weight, birth weight-for-gestational-age (birth weight standard deviation score (SDS)) calculated by comparison with national references. RESULTS: Mean birth weight SDS in CAIS XY infants was higher than the reference for girls (mean, 95% CI: 0.4, 0.1 to 0.7; p=0.02) and was similar to the national reference for boys (0.1, -0.2 to 0.4). Birth weight SDS in CAH girls was similar to the national reference for girls (0.0, -0.2 to 0.2) and did not vary by severity of gene mutation. Birth weight SDS in CAH boys was also similar to the national reference for boys (0.2, -0.2 to 0.6). CONCLUSION: CAIS XY infants have a birth weight distribution similar to normal male infants and birth weight is not increased in infants with CAH. Alterations in androgen signalling have little impact on birth weight. Sex dimorphism in birth size is unrelated to prenatal androgen exposure.

The effect of flexibility in working hours on fertility: A comparative analysis of selected european countries

The main aim of this paper is to measure the extent to which part-time work enhances fertility for married or cohabiting women of fertile age. The study covers eleven European countries. The data used are a pool sample of five waves of the European Community Household Panel. Given that we believe that the decisions concerning fertility and labor market status are taken jointly, we carry out a simultaneous estimation approach. Results suggest that policy makers wishing to implement adequate part-time schedules so as to enhance fertility should look at the part-time schedules available in Belgium, Ireland and The Netherlands, which enhance fertility for women who take advantage of this flexibility measure so as to reconcile family and work.

Population response of triploid grass carp to declining levels of hydrilla in the Santee Cooper Reservoirs, South Carolina

Approximately 768,500 triploid grass carp ( Ctenopharyngodon idella Valenciennes) were stocked into the Santee Cooper reservoirs, South Carolina between 1989 and 1996 to control hydrilla ( Hydrilla verticillata (L.f.) Royle). Hydrilla coverage was reduced from a high of 17,272 ha during 1994 to a few ha by 1998. During 1997, 1998 and 1999, at least 98 triploid grass carp were collected yearly for population monitoring. Estimates of age, growth, and mortality, as well as population models, were used in the study to monitor triploid grass carp and predict population trends. Condition declined from that measured during a previous study in 1994. The annual mortality rate was estimated at 28% in 1997, 32% in 1998 and 39% in 1999; however, only the 1999 mortality rate was significantly different. Few (2 out of 98) of the triploid grass carp collected during 1999 were older than age 9. We expect increased mortality due to an aging population and sparse hydrilla coverage. During 1999, we estimated about 63,000 triploid grass carp system wide and project less than 3,000 fish by 2004, assuming no future stocking. management, population size Ctenopharyngodon idella, Hydrilla

Contributions to the Geology and Paleontology of the Canal Zone, Panama, and geologically related areas in central America and the West Indies. Part 11: The biologic character and geologic correlations of the sedimentary formations of Panama in their relation to the geologic history of Central America and the West Indies

The paper presents: 1) biologic summaries for each of the formations for which paleontologic data are available, with brief discussions of the geologic age; 2) geologic correlations of the formations and the distribution of their age-equivalents in Central America, the West Indies, and the southeastern United States; 3) an outline of the paleogeography of middle America. The biologic summaries are based on the paleontologic memoirs in this vol. by Messars. Howe, Berry, Chuchman, Jackson, Canu and Bassler and Pilsbry, Miss Rathbun and myself.