Differential endosomal pathways for radically modified peptide vectors.

In the current work we characterize the uptake mechanism of two NickFect family members, NF51 and NF1, related to the biological activity of transfected plasmid DNA (pDNA). Both vectors condense pDNA into small negatively charged nanoparticles that transfect HeLa cells with equally high efficacy and the delivery is mediated by SCARA3 and SCARA5 receptors. NF1 condenses DNA into less homogeneous and less stable nanoparticles than NF51. NF51/pDNA nanoparticles enter the cells via macropinocytosis, while NF1/pDNA complexes use clathrin- or caveolae-mediated endocytosis and macropinocytosis. Analysis of separated endosomal compartments uncovered lysomotropic properties of NF51 that was also proven by cotransfection with chloroquine. In summary we characterize how radical modifications in peptides, such as introducing a kink in the structure of NF51 or including extra negative charge by phospho-tyrosine substitution in NF1, resulted in equally high efficacy for gene delivery, although this efficacy is achieved by using differential transfection pathways.

Estimation of the warfarin dose with clinical and pharmacogenetic data.

BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week). CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle.

The retinoic acid receptor-related orphan receptor (ROR) alpha has been demonstrated to regulate lipid metabolism. We were interested in the ROR alpha 1 dependent physiological functions in skeletal muscle. This major mass organ accounts for approximately 40% of the total body mass and significant levels of lipid catabolism, glucose disposal and energy expenditure. We utilized the strategy of targeted muscle-specific expression of a truncated (dominant negative) ROR alpha 1 Delta DE in transgenic mice to investigate ROR alpha 1 signaling in this tissue. Expression profiling and pathway analysis indicated that ROR alpha influenced genes involved in: (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; (ii) LXR nuclear receptor signaling and (iii) Akt and AMPK signaling. This analysis was validated by quantitative PCR analysis using TaqMan low-density arrays, coupled to statistical analysis (with Empirical Bayes and Benjamini-Hochberg). Moreover, westerns and metabolic profiling were utilized to validate the genes, proteins and pathways (lipogenic, Akt, AMPK and fatty acid oxidation) involved in the regulation of metabolism by ROR alpha 1. The identified genes and pathways were in concordance with the demonstration of hyperglycemia, glucose intolerance, attenuated insulin-stimulated phosphorylation of Akt and impaired glucose uptake in the transgenic heterozygous Tg-ROR alpha 1 Delta DE animals. In conclusion, we propose that ROR alpha 1 is involved in regulating the Akt2-AMPK signaling pathways in the context of lipid homeostasis in skeletal muscle.

NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients.

Aims: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine. Methods and results: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths. Conclusions: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.

Patient-reported Outcome in Surgically Treated Pelvic Ring Injuries at 5 Years Post-surgery.

BACKGROUND AND AIMS: Long-term prospective data on patient-reported outcome after surgical treatment of pelvic ring injuries are scarce. This study aimed at describing results at 5 years post-surgery using validated outcome measures. PATIENTS AND METHODS: Patients admitted for surgical treatment of pelvic ring injuries were prospectively included and asked to report their outcome at 1, 2 and 5 years post-surgery using two patient-reported outcome measures: the generic Short-Form 36 and the condition-specific pelvic discomfort index. Data were evaluated using mixed-effects linear models. RESULTS: There were 108 patients (68 males and 40 females), mean age 38 years. Injury type according to the AO/OTA-classification was B-type in 68 patients and C-type in 40 patients. No domain of the Short-Form 36 reached norm values at 5 years post-surgery. Females reported a worse outcome than males concerning general health (p < 0.01) at 5 years. Recovery of physical function (p < 0.01), mental health (p = 0.04), and pain (p = 0.01) was observed for males at 5 years compared to earlier assessments, while females on the contrary described more pain at this time-point (p = 0.03). Mean pelvic discomfort index at 5 years was 27, indicating moderate residual pelvic discomfort overall. Males reported less pelvic discomfort than females at 5 years (p = 0.02) and improved when compared to results at 2 years (p = 0.02), while females did not. Influence of age, fracture type, and presence of associated injuries on patient-reported outcome was limited. CONCLUSION: Surgically treated pelvic ring injuries are associated with long-standing negative effects on patient-reported outcome. Males report a better outcome than females at 5 years post-surgery.

The Ski proto-oncogene regulates body composition and suppresses lipogenesis.

OBJECTIVE: The Ski gene regulates skeletal muscle differentiation in vitro and and in vivo. In the c-Ski overexpression mouse model there occurs marked skeletal muscle hypertrophy with decreased adipose tissue mass. In this study, we have investigated the underlying molecular mechanisms responsible for the increased skeletal muscle and decreased adipose tissue mass in the c-Ski mouse. APPROACH: Growth and body composition analysis (tissue weights and dual energy X-ray absorptiometry) coupled with skeletal muscle and white adipose gene expression and metabolic phenotyping in c-Ski mice and wild-type (WT) littermate controls was performed. RESULTS: The growth and body composition studies confirmed the early onset of accelerated body growth, with increased lean mass and decreased fat mass in the c-Ski mice. Gene expression analysis in skeletal muscle from c-Ski mice compared with WT mice showed significant differences in myogenic and lipogenic gene expressions that are consistent with the body composition phenotype. Skeletal muscle of c-Ski mice had significantly repressed Smad1, 4, 7 and myostatin gene expression and elevated myogenin, myocyte enhancer factor 2, insulin-like growth factor-1 receptor and insulin-like growth factor-2 expression. Strikingly, expression of the mRNAs encoding the master lipogenic regulators, sterol-regulatory enhancer binding protein 1c (SREBP1c), and the nuclear receptor liver X-receptor-alpha, and their downstream target genes, SCD-1 and FAS, were suppressed in skeletal muscle of c-Ski mice, as were the expressions of other nuclear receptors involved in adipogenesis and metabolism, such as peroxisome proliferator-activated receptor-gamma, glucocorticoid receptor and retinoic acid receptor-related orphan receptor-alpha. Transfection analysis demonstrated Ski repressed the SREBP1c promoter. Moreover, palmitate oxidation and oxidative enzyme activity was increased in skeletal muscle of c-Ski mice. These results suggest that the Ski phenotype involves attenuated lipogenesis, decreased myostatin signalling, coupled to increased myogenesis and fatty acid oxidation. CONCLUSION: Ski regulates several genetic programs and signalling pathways that regulate skeletal muscle and adipose mass to influence body composition development, suggesting that Ski may have a role in risk for obesity and metabolic disease.

STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk.

OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.

Cancer incidence in 13811 patients skin tested for allergy.

AIM: Several studies have shown a negative correlation between cancer and atopy-related diseases. There are also a few reports of a positive relationship. We wanted to further evaluate these relationships in a prospective study. SUBJECTS AND METHODS: The incidence of malignant diseases among adult patients with atopy-related diseases (asthma, rhinitis, urticaria, eczema etc; n = 13811), who had been skin prick tested in 1976-1999 was compared with the incidence in the general population. Expected cancer incidence from the date of skin prick testing up to 1999 was obtained from cause-, sex-, calendar-year-, and 5-year-age-group specific incidence rates for the county. These rates were calculated from cancer incidence and population counts obtained from the Swedish Cancer Register. The 95% confidence intervals (CIs) for cause-specific standardized incidence ratios (SIRs) were calculated. Skin prick tests were performed with Dermatophagoides pteronyssinus, horse, dog, cat, timothy, mugwort, birch, and Cladosporium. Patients having one or several positive skin prick test reactions (> or = 2+) were regarded as atopics. RESULTS: 119 cases of cancer occurred among 6224 atopic individuals (SIR 1.0) compared with 216 cases (SIR 0.94, CI 0.82-1.08) among 6358 non-atopics. There was a slight excess of Hodgkin's lymphoma cases among atopic men (SIR 4.03, 95% CI 1-10.3), and of non Hodgkin lymphoma cases among atopic women (SIR 4.52, 95% CI 1.23-11.6). However, a large number of comparisons were made which can have caused random findings. CONCLUSIONS: The results showed no associations between atopy or allergic symptoms, and subsequent cancer risk, but supported the theory that type-I allergy is not related to cancer risk.

Changes in health over time in patients with symptoms allegedly caused by their dental restorative materials.

OBJECTIVES: In Sweden, many patients with symptoms allegedly caused by their dental materials have exchanged their restorations, but the effects of the exchange have been insufficiently investigated. Therefore, the aim of the study was to describe the change in health over time for these patients and the hypothesis was that the patients could be divided based on their symptoms and that the ability to recover differs between these groups. Furthermore, we also examined if other factors such as replacement of dental restorative materials and follow-up time had any impact on the perceived health status. METHODS: A questionnaire was sent to 614 patients who had been referred to the School of Dentistry, Umeå, Sweden, with symptoms allegedly caused by dental restorative materials. The response rate was 55%. RESULTS: The risk of having any further complaints was higher for patients with complex symptoms (P = 0.03) and these patients had exchanged their restorations to a significantly larger extent than the others (P = 0.03). The remaining complaints was more frequent among men (P = 0.02). Exchange of dental restorative materials had no significant impact on the ability to recover completely. However, the patients who had exchanged their restorations completely perceived a significantly larger alleviation of their symptoms than the others (P < 0.01), although the frequency of most of the symptoms had increased. CONCLUSIONS: Patients with complex symptoms had a more unfavorable long-term prognosis concerning persistent complaints than those with localized symptoms only. Furthermore, the results indicate that the patients might experience health improvements after removal of their dental restorative materials. The reason for this improvement, however, is unclear. Further analyses regarding other possible explanations than the 'odontological/medical' are needed.

Effects of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 on the laminar distribution of transganglionically fransported choleragenoid in the spinal cord dorsal horn following transection of the sciatic nerve in the adult rat.

Spinal cord projections from transected sciatic nerves treated with different neurotrophins were investigated in the adult rat following injections of choleragenoid into the proximal stump of the injured nerve. Transganglionically transported choleragenoid labelled primary afferent fibres in all spinal cord dorsal horn laminae except the outer part of lamina II (II(o)), which is almost devoid of labelling. Transection of the sciatic nerve, however, resulted in intense transganglionic choleragenoid labelling in lamina II(o) and in lamina I. In this study, the sciatic nerve was transected bilaterally and 4erve growth factor (6 or 24 microg), brain-derived neurotrophic factor (20 microg), neurotrophin-3 (27 microg) or cytochrome C (8 microg; control substance) was applied unilaterally during postoperative survival times of eight, 16 and 32 days. The animals received bilateral injections of choleragenoid into the injured nerve two days before they were killed. The effect of the axotomy and neurotrophin treatment was evaluated by analysing the extent of choleragenoid and substance P immunoreactivity in the somatotopically appropriate spinal cord dorsal horn regions. At eight days' postoperative survival, laminae I and II(o) on the transected, non-treated side showed much more intense choleragenoid-like immunoreactivity compared to the contralateral transected, nerve growth factor-treated (6 and 24 microg) side. A similar situation was also found in cases treated with the higher dose (24 microg) at 16 days but to a lesser degree when the lower (6 microg) dose was used. After 32 days' survival, there was no detectable side difference in the choleragenoid labelling pattern. At 16 days' survival, the mean area of choleragenoid-positive ganglion cell body profiles in the L5 dorsal root ganglion of the transected, non-treated side was significantly smaller than the mean area of the transected, nerve growth factor-treated (24 microg) neurons. An axotomy-induced depletion of substance P-like immunoreactivity was seen from eight days' survival and onwards, whereas on the nerve growth factor-treated side a clearcut substance P depletion was not observed until 32 days. Brain-derived neurotrophic factor, neurotrophin-3 and cytochrome C had no detectable effects on the distribution of choleragenoid labelling or substance P-like immunoreactivity in the dorsal horn following sciatic nerve transection. In conclusion, peripheral nerve injury-induced expansion of primary afferent choleragenoid labelling in the spinal cord dorsal horn is counteracted by treating the axotomized nerve with nerve growth factor.

Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat.

We provide evidence for activation of the complement cascade in the dorsal horn of the spinal cord and in the gracile nucleus in the brainstem following sciatic nerve transection in the adult rat. Immunocytochemical analyses showed immunoreactivity for endogenous immunoglobulin G as shown by immunostaining with F(ab')2 antibodies, as well as complement factors C1, C1q, C3, C3d and C9 in the appropriate central termination areas of the injured sciatic nerve. Results from double labelling immunocytochemistry showed a strong association between immunoglobulin and complement factors on the one hand and reactive microglia on the other. However, some complement immunoreactivity was also found in the neuropil, possibly representing secreted complement. In situ hybridization with an oligonucleotide probe showed a marked increase in C3 messenger RNA, indicating local synthesis of C3 protein. In parallel with activation of complement, there was an increased immunoreactivity for the putative complement inhibitor clusterin, which co-localized with glial fibrillary acidic protein-positive astrocytes. In situ hybridization showed an increased labelling of clusterin messenger RNA. These findings indicate that complement activation and up-regulation of complement inhibitors are prominent central responses to peripheral sensory nerve injury. These responses may therefore be important elements underlying so-called transganglionic degenerative changes in primary sensory axons and terminals.

The psychosocial work environment and skin symptoms among visual display terminal workers: a case referent study.

BACKGROUND: This study is a part of the interdisciplinary project The Office Illness Project in Northern Sweden, which was initiated with a questionnaire study in late 1988. Previously published results from the project have shown that facial skin symptoms reported among visual display terminal (VDT) workers are associated with a number of exogenous factors. This part of the project investigated the relation between the psychosocial work environment and facial skin complaints. METHODS: From an initial questionnaire study among 4943 office workers, 163 VDT workers were selected for a case referent study of facial skin symptoms. The data comprise a self-administered questionnaire filled out by 149 subjects and interviews with representatives of the organizations concerned. RESULTS: Psychosocial conditions, especially lack of social support from co-workers, were associated with an increased risk of reporting skin symptoms. Stratification by sex showed that the associations between some psychosocial factors and health differed between men and women. The results indicate that there might be an interaction between psychosocial factors and electric fields in the workplace which increases the risk of reporting skin symptoms. CONCLUSIONS: This study supports the idea that the aetiological basis of facial skin symptoms among VDT-workers includes physical as well as psychosocial factors, and that the interaction between such factors might be significant in the understanding of skin complaints among VDT workers.

The Sick Building Syndrome (SBS) in office workers. A case-referent study of personal, psychosocial and building-related risk indicators.

BACKGROUND: The Office Illness Project in Northern Sweden, comprising both a screening questionnaire study of 4943 office workers and a case-referent study of Sick Building Syndrome (SBS) in 464 subjects was recently completed. Previously published results from the survey showed that female gender asthma/rhinitis, high psychosocial work load, paper and visual display terminal (VDT) work were related to an increased prevalence of SBS symptoms. METHODS: The case-referent study presented in this paper used data from the questionnaire supplemented with information from a clinical examination, a survey of psychosocial factors at work building data from inspection and measurements taken at the work sites. RESULTS: Personal factors such as atopy and photosensitive skin, psychosocial conditions and physical exposure factors influencing indoor air quality (IAQ), such as outdoor air flow rates and the presence of photocopiers were related to an increased prevalence of the reported SBS symptoms. The results were established using multivariate analysis. CONCLUSIONS: The rate response relationship between actually measured ventilation rates and the prevalence of perceived SBS symptoms presents strong evidence for the association between IAQ factors and health.

Facial skin symptoms in visual display terminal (VDT) workers. A case-referent study of personal, psychosocial, building- and VDT-related risk indicators.

BACKGROUND: The Office Illness Project in northern Sweden, comprising both a screening questionnaire study of 4943 office workers and a case-referent study of facial skin symptoms in 163 subjects was recently completed. Previously published results from the survey showed that female gender, asthma/rhinitis, high psychosocial work load, visual display terminal (VDT) and paperwork were related to an increased prevalence of facial skin symptoms. METHODS: The case-referent study presented in this paper used data from the questionnaire supplemented by information from a clinical examination, a survey of psychosocial factors at work, building data and VDT-related factors from inspection and measurements taken at the work site. RESULTS: Psychosocial conditions and exposure to electromagnetic fields or conditions associated with such factors were related to an increased occurrence of skin symptoms. The results also indicated that personal factors such as atopic dermatitis and physical exposure factors influencing indoor air quality, such as paper exposure and cleaning frequency were related to an increased prevalence of symptoms. CONCLUSIONS: The results suggest that skin symptoms reported by VDT users have a multifactorial background.

BDNF and NT-3 rescue sensory but not motoneurones following axotomy in the neonate.

Following axotomy of the sciatic nerve in the neonatal rat, there is loss of almost half of the sensory neurones of the lumbar dorsal root ganglia (DRG) and a similar number of spinal motoneurones. Consistent with effects in vitro, the neurotrophins BDNF and NT-3 have previously been shown to afford partial rescue of motoneurones at 1 week following axotomy. Using stereological quantitative methods we show here that at the longer time point of 3 weeks, local application of BDNF or NT-3 to the proximal stump of a lesioned sciatic nerve failed to rescue motoneurones (44% and 51% loss, respectively), but provided almost complete rescue of the loss of 41% of DRG neurones seen in L4 and L5 of vehicle-treated control animals.

Epidemiology of repeat ectopic pregnancy: a population-based prospective cohort study.

OBJECTIVE: To study infectious pathology at index ectopic pregnancy and to determine what other factors predispose a woman to repeat ectopic pregnancy. METHODS: All women (n = 697) with their first (index) ectopic pregnancy histologically verified between January 1, 1978, and December 31,1993, at the only two hospitals in one Norwegian county were eligible. Included were permanent residents of the county who were 37 years of age or younger and who had not had tubal surgery before the index pregnancy. When the study closed on November 1, 1994, the participants had been observed prospectively for fertility events from approximately 1 to 17 years. Included in the final analyses were 353 women who had from one to five natural conceptions, for a total of 555 pregnancies. Chi-square test was used in univariate analysis, and the generalized estimating equations approach was used to analyze correlated responses and covariates that changed over time. RESULTS: Pregnancy order is the stronger correlate of subsequent ectopic pregnancy. The frequency of repeat ectopic pregnancy decreased by one-third for each pregnancy from the first to the third pregnancy. The odds of having another ectopic pregnancy were nearly three times higher for women with a diagnosis of infectious pathology than for women who had no infectious pathology. Other correlates of repeat ectopic pregnancy include age 24 years or younger at first ectopic pregnancy, history of repeat ectopic pregnancy, initiation of infertility work-up, and conception with an intrauterine device at index pregnancy. Method of surgery was not associated with repeat ectopic pregnancy. CONCLUSION: The most crucial reproductive event after first ectopic pregnancy is the first event to occur. Women who have experienced two ectopic pregnancies should be considered candidates for assisted reproduction.

Airflows after inhalation of terbutaline sulphate aerosol from a 750-ml spacer for four weeks.

Terbutaline sulphate was administered to 40 adult asthmatic patients via an ordinary metered-dose inhaler (MDI) or one connected to a 750-ml spacer in an open, randomized, crossover study. Spirometry was obtained before the start of the study and again after four weeks of treatment with each inhaler. The patients recorded on a diary card the severity of their asthma symptoms and the peak expiratory flow rate (PEFR) in the morning before and after drug administration and in the evening. Preinhalation spirometric values were higher after four weeks with the 750-ml spacer than at the start of the study (P less than or equal to 0.05). Daily morning and evening PEFR values were higher after use of the 750-ml spacer than after use of the ordinary MDI (P less than 0.05). Daily symptom scores were generally low. A significantly better effect (P less than or equal to 0.05) with the 750-ml spacer was achieved only in daytime dyspnea. The investigators conclude that the attachment of a 750-ml spacer to an ordinary metered-dose inhaler can improve the efficacy of terbutaline sulphate in the long-term treatment of asthma.

Flow dependence of the aortic valve area in patients with aortic stenosis: assessment by application of the continuity equation.

It has been argued that the aortic valve area (AVA) in patients with aortic stenosis increases with flow. Others, however, have attributed the apparent increase to flow dependence of the empiric constant in the Gorlin formula. We examined the changes in AVA during changes in transvalvular flow induced by dipyridamole infusion in 34 patients with aortic stenosis. Two-dimensional and Doppler echocardiography was used and AVA was calculated according to the continuity equation, which does not include empiric constants. Flow increased in 29, decreased in four, and was unchanged in one patient. There was a linear correlation between percent change in flow and percent change in AVA: delta AVA% = 1.1 + delta flow%. 0.56 (r = 0.72; p < 0.001) In conclusion, AVA was found to be flow dependent. The magnitude of change in AVA observed by noninvasive recordings agrees with previous invasive studies according to the Gorlin formula.

Facial skin symptoms in office workers. A five-year follow-up study.

This longitudinal study is a part of the interdisciplinary project. The Office Illness Project in Northern Sweden, which was initiated with a questionnaire study in late 1988. Among 3233 visual display terminal (VDT) workers, an initial case-referent group of 163 individuals was selected. The data acquisition included two questionnaires, assessments at the workplaces, interviews with personnel staff of the organizations concerned, and a clinical examination of the respondents. Subjects participating in the case-referent study 1988 filled out a questionnaire in the beginning of 1994. The primary objective of this study is to discuss changes in and causes of facial skin symptoms among VDT workers in the long term. The results show that (1) facial skin symptoms among VDT workers seem to be of a transitory nature for most of those with isolated skin symptoms, whereas the prognosis for those with a more complex symptom picture is more negative, (2) assumptions that measures taken in the work environment-including those involving the VDT and other electric devices-would have a positive effect on symptoms were not supported, and (3) the strongest external risk indicators for lasting skin symptoms seem to be found in the psychosocial work environment. Therefore, one important issue for the understanding of facial skin symptoms is organizational climate and personnel policies. The results also imply that individual factors, both constitutional and psychological, must be considered.