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Vascular endothelial growth factor causally contributes to the angiogenic response upon ultraviolet B irradiation in vivo.

BACKGROUND: Ultraviolet (UV)-B irradiation has been shown to be an inducer of vascular endothelial growth factor (VEGF) in primary keratinocytes and epidermal cell lines in vitro. OBJECTIVES: To determine the expression pattern and the causal role of VEGF in the UVB-mediated angiogenic response in vivo in human skin and in a mouse model. METHODS: Skin biopsies or epidermal lysates thereof were studied for VEGF expression following UVB irradiation at a dose of 50 or 60 mJ cm-2, respectively, using immunostaining and a VEGF-specific highly sensitive sandwich enzyme-linked immunosorbent assay. The VEGF-dependent increase in vessels upon repetitive UVB irradiation was studied in skh-1 hairless mice using immunostaining for factor VIII-related antigen (FVIII RAG) in the presence and absence of intraperitoneally injected neutralizing VEGF antibodies. RESULTS: VEGF was found to be induced in the epidermis following UVB irradiation of human and mouse skin. Repetitive UVB irradiation of skh-1 hairless mice resulted in an increase in FVIII RAG positive vessels in the skin. UVB-induced angiogenic response could be partly abrogated by neutralizing antibodies against VEGF, while isotype-matched IgG control antibodies did not reveal any suppressive effect. CONCLUSIONS: Our results support previous in vitro data and show the in vivo relevance of VEGF as a paracrine inducer of cutaneous vessels after UVB irradiation.

Animals↗

Hepatitis C virus (HCV)-induced IgG-IgM rheumatoid factor (RF) complex may be the main causal factor for cold-dependent activation of complement in patients with rheumatic disease.

A low serum complement level is commonly found in patients with rheumatic diseases. We evaluated 170 patients with such diseases to determine their serum levels of CH50, C3 and C4 protein. Persistent hypocomplementaemia was found in 19 of those patients, particularly in those with systemic lupus erythematosus (SLE). Cold-dependent activation of complement (CDAC) was demonstrated in nine of the 19 (47.4%), and six of the nine patients demonstrated infection with HCV (66.7%). The nine patients that exhibited CDAC had nearly normal haemolytic complement activity when the sera were separated either at 37 degrees C or in EDTA-treated plasma. Conversely, it markedly decreased, even to the point of being immeasurable, when the sera were separated at 4-21 degrees C. No significant deficiency in C3 and C4 protein levels was found in these patients. Clinical parameters other than levels of anti-HCV antibody, transaminase, and RF were not influenced by CDAC. In an attempt to isolate the causal factor for CDAC, we isolated IgG fractions from the CDAC patients by using a protein G column, in which case precipitates were collected from the eluates. The precipitates were mixed with normal serum and incubated at 4-21 degrees C for 18 h. A decrease in the level of CH50 in normal serum was observed, which predominated (P < 0.001) when precipitates from HCV-infected patients were used. This indicated CDAC was possibly interrelated to the precipitates of such patients. This precipitate was proved to contain IgM besides IgG. It is therefore possible that an HCV-related IgG complex or an IgG-IgM RF complex may be formed at low temperature and be involved in activating the complement system in vitro.

Adult↗

A rapid molecular assay for the detection of antibiotic resistance determinants in causal agents of infective endocarditis.

AIMS: To develop and employ a PCR amplification system, directly from clinical specimens, for the rapid molecular detection of common antimicrobial resistance genes for streptococci, staphylococci and enterococci organisms causing infective endocarditis (IE). METHODS AND RESULTS: Eleven antibiotic resistance genes were targeted by PCR along with four identification-related loci. Blood culture and heart valve material from staphylococcal endocarditis patients were directly examined for methicillin resistance. PCR conditions were optimized for the following antibiotic resistance loci: staphylococci (mecA, aacA-aphD), streptococci (PBP 1A, PBP 2B, gyrB, parE) and enterococci (vanA, vanB, vanC-1, vanC-2, aacA-aphD, aphA3). The presence of methicillin resistance was confirmed in one of the eight IE patients examined. CONCLUSION: This study presents a PCR amplification system for the detection of antibiotic resistance genes. Detection of such genes may indicate susceptibility of the causal agents of IE to commonly prescribed antimicrobial agents. SIGNIFICANCE AND IMPACT OF THE STUDY: Rapid detection of antibiotic resistant organisms may reduce the use of inappropriate antibiotic agents or enable the use of the most appropriate combinations of antibiotics, other than those that would normally be prescribed empirically for IE. Such a method may be particularly valuable in cases of culture-negative endocarditis. Detection of antibiotic resistance genes by molecular-based techniques, namely PCR, will allow more directed antibiotic therapy and may also provide opportunities for earlier identification of resistant organisms.

Drug Resistance, Microbial↗

Effect of unexpected outcomes and causal attributions on key workers' expectancies of goal attainment.

Goal planning is an integral part of the role of the key worker in services for people with intellectual disability. The present study investigated the effect of the Weiner stability-expectancy principle on unexpected outcomes in goal planning. Four hundred and twenty-two actual goal attainment scales were constructed, with each scale describing the key workers' expected levels of outcome. Two hundred and twenty-six (54%) unexpected outcomes, both successful and unsuccessful, were then rated by key workers to provide a causal explanation for each outcome. These explanations were then grouped according to whether the attributions represented stable or variable causes. Finally, key workers were asked to provide a new expectancy rating to forecast future goal attainment. Two predictions from Weiner's model were confirmed by statistical analysis: (1) that success attributed to stable factors would lead to higher revised forecasts of goal attainment than success attributed to variable factors; and (2) that failure attributed to stable factors would lead to lower revised forecasts of goal attainment than failure attributed to variable factors. The results of the present study confirm that stability attributions do alter key workers' revised forecasts of goal attainment. The results are discussed in terms of the possible consequences for key worker behaviour, such as goal abandonment, differential treatment of service users and the need for a knowledgeable approach to performance appraisal by managers.

Adult↗

Nymphs of the Oriental cockroach (Blatta orientalis) as passive vectors of causal agents of avian tuberculosis and paratuberculosis.

The potential transmission of the causal agent of paratuberculosis Mycobacterium avium ssp. paratuberculosis and avian tuberculosis Mycobacterium avium ssp. avium (Actinomycetales: Mycobacteriaceae) by nymphs of the Oriental cockroach Blatta orientalis L. (Blattodea: Blattidae) was investigated by oral infection with mycobacterial suspensions and examination of their droppings and bodies. Both the subspecies of M. avium were isolated from droppings at 3 days post-infection and M. a. avium was found in homogenized bodies at 10 days post-infection. The identity of M. a. avium and M. a. paratuberculosis isolates was demonstrated by Restriction Fragment Length Polymorphism (RFLP) analysis. The M. a. avium isolate used as the inoculum and the isolates from the bodies and droppings of the nymphs were shown to be virulent in chickens. The results show that orally infected nymphs of B. orientalis can harbour and shed viable and virulent mycobacteria. This hazard should be considered in the implementation of control measures against mycobacterial infections of animals and humans, which should include destruction of all developmental stages of cockroaches and prevention of their access to materials that can be contaminated by mycobacteria.

Animals↗

The incidence of hypospadias in two English cities: a case-control comparison of possible causal factors.

OBJECTIVES: To determine the incidence and severity of hypospadias amongst children born in Southampton and Portsmouth during 1992-94, and to identify possible causal factors by comparing patients with a control group. PATIENTS AND METHODS: All patients with hypospadias born in Southampton and Portsmouth during 1992-94 were identified. The Southampton cases were matched with controls; the case notes of each affected child were reviewed. The incidence determined by this study was compared with data provided by the Central Statistics Office. RESULTS: There was no apparent increase in the incidence of hypospadias in Southampton and Portsmouth during 1982-94. However, there was a clear local variation in incidence, with a significantly lower incidence in Portsmouth than in Southampton and the rest of England and Wales. The severity of hypospadias was also more marked in Southampton than in Portsmouth. The only recognisable aetiological factor was a positive family history, supporting the concept of a polygenic mode of inheritance. All the environmental factors investigated were unrelated, but there was a suggestion of clustering in a single water-quality zone. CONCLUSIONS: This study identified no increase in the incidence of hypospadias but it did detect local variations in both the incidence and severity of the condition, and these need to be considered when planning surgical services.

Case-Control Studies↗

The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans.

Expression of lactase in the intestine persists into adult life in some people and not others, and this is due to a cis-acting regulatory polymorphism. Previous data indicated that a mutation leading to lactase persistence had occurred on the background of a 60 kb 11-site LCT haplotype known as A (Hollox et al. 2001). Recent studies reported a 100% correlation of lactase persistence with the presence of the T allele at a CT SNP at -14 kb from LCT, in individuals of Finnish origin, suggesting that this SNP may be causal of the lactase persistence polymorphism, and also reported a very tight association with a second SNP (GA -22 kb) (Enattah et al. 2002). Here we report the existence of a one megabase stretch of linkage disequilibrium in the region of LCT and show that the -14 kb T allele and the -22 kb A allele both occur on the background of a very extended A haplotype. In a series of Finnish individuals we found a strong correlation (40/41 people) with lactose digestion and the presence of the T allele. The T allele was present in all 36 lactase persistent individuals from the UK (phenotyped by enzyme assay) studied, 31/36 of whom were of Northern European ancestry, but not in 11 non-persistent individuals who were mainly of non-UK ancestry. However, the CT heterozygotes did not show intermediate lactase enzyme activity, unlike those previously phenotyped by determining allelic transcript expression. Furthermore the one lactase persistent homozygote identified by having equally high expression of A and B haplotype transcripts, was heterozygous for CT at the -14 kb site. SNP analysis across the 1 megabase region in this person showed no evidence of recombination on either chromosome between the -14 kb SNP and LCT. The combined data shows that although the -14 kb CT SNP is an excellent candidate for the cause of the lactase persistence polymorphism, linkage disequilibrium extends far beyond the region searched so far. In addition, the CT SNP does not, on its own, explain all the variation in expression of LCT, suggesting the possibility of genetic heterogeneity.

Alleles↗

Endogenously released DOPA is a causal factor for glutamate release and resultant delayed neuronal cell death by transient ischemia in rat striata.

Glutamate is implicated in neuronal cell death. Exogenously applied DOPA by itself releases neuronal glutamate and causes neuronal cell death in in vitro striatal systems. Herein, we attempt to clarify whether endogenous DOPA is released by 10 min transient ischemia due to four-vessel occlusion during rat striatal microdialysis and, further, whether DOPA, when released, functions to cause glutamate release and resultant delayed neuronal cell death. Ischemia increased extracellular DOPA, dopamine, and glutamate, and elicited neuronal cell death 96 h after ischemic insult. Inhibition of striatal L-aromatic amino acid decarboxylase 10 min before ischemia increased markedly basal DOPA, tripled glutamate release with a tendency of decrease in dopamine release by ischemia, and exaggerated neuronal cell death. Intrastriatal perfusion of 10-30 nM DOPA cyclohexyl ester, a competitive DOPA antagonist, 10 min before ischemia, concentration-dependently decreased glutamate release without modification of dopamine release by ischemia. At 100 nM, the antagonist elicited a slight ceiling effect on decreases in glutamate release by ischemia and protected neurons from cell death. Glutamate was released concentration-dependently by intrastriatal perfusion of 0.3-1 mM DOPA and stereoselectively by 0.6 mM DOPA. The antagonist elicited no hypothermia during and after ischemia. Endogenously released DOPA is an upstream causal factor for glutamate release and resultant delayed neuronal cell death by brain ischemia in rat striata. DOPA antagonist has a neuroprotective action.

Animals↗

Inflammation and advanced glycation end products in uremia: simple coexistence, potentiation or causal relationship?

The causes for the high frequency of cardiovascular disease in dialysis patients are multifactorial in origin. Disturbances in the carbohydrate and lipid metabolism, the balance between oxidants and antioxidants and the immuno-inflammatory system are thought to play a role. Chronic uremia is characterized by the accumulation of advanced glycation end products (AGEs) and advanced oxidation products (AOPP) as well as activation of the acute phase response. High serum levels of these products and acute phase reactants such as C-reactive protein (CRP), fibrinogen and serum amyloid A can be found. CRP has been shown to predict cardiovascular and overall mortality in hemodialysis patients. Whether CRP is involved causally in atherosclerosis or merely represents a marker of disease is as yet unknown. Since CRP has been detected in colocalization with modified apolipoproteins or complement components in atherosclerotic lesions, a pathophysiological role seems very likely. AGEs as well have been detected in aortas of hemodialysis patients. Incubation of endothelial cells with AGEs induced expression of adhesion molecules with consecutive attraction of monocytes to the vessel wall. Thus far, clinical studies investigating the predictive effects of AGEs on cardiovascular mortality in hemodialysis patients are lacking. There is considerable debate about what factors turn on the acute phase response in this population. Proinflammatory effects of AGEs mediated through one receptor for AGEs, RAGE, have been described. We hypothesize that there may be a link between increased hepatic CRP production and the accumulation of AGEs in uremia. AGEs may stimulate CRP production in hepatocytes either directly or indirectly via interaction with monocytes.

Acute-Phase Reaction↗

Aging: is oxidative stress a marker or is it causal?

Rapid developments in free radical biology and molecular technology have permitted exploration of the free radical theory of aging. Oxidative stress has also been implicated in the pathogenesis of a number of diseases. Studies have found evidence of oxidative damage to macromolecules (DNA, lipids, protein), and data in transgenic Drosophila melanogaster support the hypothesis that oxidative injury might directly cause the aging process. Additional links between oxidative stress and aging focus on mitochondria, leading to development of the mitochondrial theory of aging. However, despite the number of studies describing the association of markers of oxidative damage with advancing age, few, if any definitively link oxidative injury to altered energy production or cellular function. Although a causal role for oxidative stress in the aging process has not been clearly established, this does not preclude attempts to reduce oxidative injury as a means to reduce morbidity and perhaps increase the healthy, useful life span of an individual. This review highlights studies demonstrating enhanced oxidative stress with advancing age and stresses the importance of the balance between oxidants as mediators of disease and important components of signal transduction pathways.

Aging↗

Circular causality.

The problem of disentangling complex dynamic systems is addressed, especially with a view to identifying those variables that take part in the essential qualitative behaviour of systems. The author presents a series of reflections about the methods of formalisation together with the principles that govern the global operation of systems. In particular, a section on circuits, nuclei, and circular causality and a rather detailed description of the analytic use of the generalised asynchronous logical description, together with a brief description of its synthetic use (OreverseO logic). Some basic rules are recalled, such as the fact that a positive circuit is a necessary condition of multistationarity. Also, the interest of considering as a model, rather than a well-defined set of differential equations, a variety of systems that differ from each other only by the values of constant terms is emphasised. All these systems have a common Jacobian matrix and for all of them phase space has exactly the same structure. It means that all can be partitioned in the same way as regards the signs of the eigenvalues and thus as regards the precise nature of any steady states that might be present. Which steady states are actually present, depends on the values of terms of order zero in the ordinary differential equations (ODEs), and it is easy to find for which values of these terms a given point in phase space is steady. Models can be synthesised first at the level of the circuits involved in the Jacobian matrix (that determines which types and numbers of steady states are consistent with the model), then only at the level of terms of order zero in the ODE's (that determines which of the steady states actually exist), hence the title 'Circular casuality'.

Adaptation, Physiological↗

Industrial medicine and acute musculoskeletal rehabilitation. 5. Effective medical management of industrial injuries: from causality to case closure.

UNLABELLED: This self-directed learning module highlights the physician's role in treating industrial injuries, from the initial causality determination to the eventual case closure. It is part of the chapter on industrial medicine and acute musculoskeletal rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. The article reviews important factors in determining whether an injury is work-related, particularly in the presence of preexisting, underlying conditions. The article addresses the roles of functional capacity examinations and work-hardening programs in facilitating successful return to work. Interactions are outlined between work return and nonwork activities of daily living, as well as financial and psychologic barriers that may impede work return. Legal issues regarding independent medical examinations and depositions are reviewed. Guidance is offered for identifying those relatively few injured workers who may require referral for surgical or other consultations. OVERALL ARTICLE OBJECTIVES: (a) To review the important medical, administrative, and legal challenges involved in treating injured workers and to describe strategies that physiatrists use to overcome effectively these challenges.

Acute Disease↗

Drug enterocyte adducts: possible causal factor for diclofenac enteropathy in rats.

BACKGROUND & AIMS: Enteropathy is a frequent complication of diclofenac and other nonsteroidal anti-inflammatory drugs, yet little is known about the underlying mechanism. One possibility is that reactive metabolites of diclofenac form adducts with enterocyte macromolecules, as previously shown for liver. We addressed this possibility by using immunohistochemistry to detect diclofenac adducts. METHODS: Rats were treated orally with diclofenac (10-100 mg/kg) and killed after 1-24 hours, and their gastrointestinal (GI) tracts were evaluated for ulcer number and area. Adduct distribution and intensity were assessed by immunohistochemistry by using a technique to simultaneously process and stain multiple intestinal rings. RESULTS: Drug treatment led to dose-dependent formation of both adducts and ulcers only in small intestine and only in animals with intact enterohepatic circulation. Adducts formed within enterocytes by 1 hour, translocated to the brush border, preceded ulceration and vascular protein leakage, and were intense at sites of ulceration. Adducts and ulcers exhibited a parallel distribution within intestinal quintiles: 3rd > 5th >> 1st. CONCLUSIONS: Diclofenac treatment resulted in the formation of drug adducts in enterocytes. Because this molecular change occurred before ulceration, was dose dependent, and exhibited concordant distribution with extent of ulceration, the results suggest a causal role for drug adduct formation in diclofenac enteropathy.

Animals↗

Gender differences in adapting to a child's chronic illness: a causal model.

This study investigated (1) the differential impact of the child's chronic illness (CI) on 80 fathers and 80 mothers and the psychosocial variables contributing to their adaptation and (2) the suitability of the causal model based on the Double ABCX Model to predict parents' adaptation to the child's illness. Eight questionnaires relating to the variables were used. Path analysis revealed similarities and differences between fathers and mothers. Social support and coping behaviors were the main variables influencing both parents' adaptation. Differences between fathers and mothers are discussed in this article. The Double ABCX Model is fairly effective in conceptualizing the process of parents' adaptation to the child's CI.

Adaptation, Psychological↗

[Pathogenesis and causal treatment of hallux valgus].

The cause of Hallux valgus lies in the insufficiency of the intermetatarsal band between the 1st and 2nd metatarsal heads. The author believes that the reconstruction of the band provides a causal therapy. To this end, the proposed operation procedure shows, that in 91% of cases, there are from good to very good long lasting results.

Biomechanical Phenomena↗

Rupture of intracranial aneurysms during angiography and CT: coincidental or causal event? A case report.

The rare event of rupture of a saccular aneurysm of the internal carotid artery during cerebral angiography and of a fusiform aneurysm of the basilar artery following contrast enhanced CT are reported. Whereas some angiographic findings point at a causal relationship between rupture of the aneurysm and the examination procedure itself, this relationship between possible contrast medium effects and rupture of the basilar artery aneurysm during CT remains uncertain. Possible mechanisms are discussed.

Adult↗

[Causal treatment of corneal vascularization (author's transl)].

Corneal vascularization is attributable to the swelling and increased lactate concentration in the cornea, which are caused by damage to the oxidizing metabolism. Invasion of leukocytes stimulated by prostaglandins also promotes the increase in the lactate concentration. The following causal treatment is possible: 40% glucose to combat the swelling, 3% cystein to improve the oxidizing metabolism and counteract the increased lactate concentration, and 0.5% indomethacin suspension to prevent the formation of prostaglandins and hence the invasion of leukozytes.

Corneal Diseases↗

Spatiotemporal continuity and the perception of causality in infants.

Infant perception of a Michottean launching event in which one object causes another to move through collision is examined in a series of habituation-test experiments. A number of hypotheses concerning how infants aged around 30 weeks might perceive and encode launching and its noncausal variants are identified and tested. The results of the first experiment indicate that infants can perceive direct launching as an event with internal structure, that is, as composed of two temporally ordered movements. The nature of the encoding by the infants is perceptual and not specifically motor-based. The second experiment makes it seem unlikely that the infants encode independent spatial and temporal features (for example, contact and successivity), while the third experiment suggests a spatiotemporal continuity gradient. Some implications for the origins of causality are discussed.

Concept Formation↗