TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections.

The susceptibility to urinary tract infection (UTI) is controlled by the innate immune response and Toll like receptors (TLRs) are the sentinels of this response. If productive, TLR4 signalling may initiate the symptomatic disease process. In the absence of TLR4 signalling the infected host instead develops an asymptomatic carrier state. The activation of mucosal TLR4 is also influenced by the properties of the infecting strain, and pathogens use their virulence factors to trigger 'pathogen-specific' TLR4 responses in the urinary tract but do not respond to the asymptomatic carrier strains in patients with asymptomatic bacteriuria (ABU). The TLR4 dependence has been demonstrated in mice and the relevance of low TLR4 function for protection for human disease was recently confirmed in children with asymptomatic bacteriuria, who expressed less TLR4 than age matched controls. Functional chemokines and functional chemokine receptors are crucial for neutrophil recruitment, and for the neutrophil dependent bacterial clearance. Interleukin (IL)-8 receptor deficient mice develop acute septic infections and chronic tissue damage, due to aberrant neutrophil function. This mechanism is relevant for human UTI as pyelonephritis prone children express low levels of the human CXCL8 (Il-8) receptor, CXC chemokine receptor 1 (CXCR1) and often have heterozygous CXCR1 polymorphisms. This review illustrates how intimately the innate response and the susceptibility to UTI are linked and sophisticated recognition mechanisms that rely on microbial virulence and on host TLR4 and CXCR1 signalling.

Role of streptococcal IgG Fc receptor in tissue deposition of IgG in rabbits immunized with Streptococcus pyogenes.

Induction of anti-IgG during hyperimmunization of rabbit with Streptococcus pyogenes (group A streptococci; GAS) was previously shown to require the presence of IgG Fc receptors (FcR) in the vaccine strain. In the present work, we examined whether streptococcal FcR activity might also be of importance for heart and kidney deposition of IgG, known to occur in poststreptococcal sequelae as well as during experimental immunization of animals. Each of three IgG-binding (GAS types M1, M12 and M22) and two non-binding (GAS type T27 and S. agalactiae (GBS) type Ia) streptococcal strains were used for intravenous immunization of rabbits during two periods of eight and six weeks, respectively, separated by an interval of one month. Before use, vaccine strains were treated with KSCN and carefully washed in order to remove any surface-bound immunoglobulins. No deaths occurred among injected rabbits. No tissue deposition was elicited by the GAS type T27 or the GBS strain. In contrast, the strains of types M1, M12 and M22 all induced deposits of IgG in kidney and heart tissue, beginning during the first immunization period. In two tested animals, receiving GAS of types M1 or M22, circulating immune complexes containing anti-IgG antibodies were also detected. Finally, serum autoantibodies reacting with preparations of heart and kidney, but not lung or liver, were demonstrated in each of six animals receiving M1 or M22, reaching maximum levels during reimmunization; such antibodies were not evoked by the two strains not binding IgG. Our results suggest that, in GAS with capacity for non-immune binding of IgG, triggering of anti-IgG acted to enhance tissue deposition of IgG or immune complexes in immunized rabbits. Furthermore tissue-specific antibodies were elicited only by the IgG-binding strains and occurred comparatively late during immunization, suggesting that those antibodies might have been triggered due to the exposition of hidden kidney and heart determinants.

Bacterial adherence and mucosal cytokine production.

1. Uropathogenic E. coli adhere to mucosal sites. 2. In the urinary tract, adherence is followed by inflammation, including a mucosal cytokine response. 3. Bacteria activate epithelial cells to secrete IL-6 and IL-8. IL-6 may cause the fever and acute phase response that accompany systemic urinary tract infections. IL-8 may function as a neutrophil chemoattractant. 4. E. coli up-regulate adhesion molecule expression on epithelial cell lines and neutrophil migration through epithelial cell monolayers. This process is inhibited by antibodies to CD18 and ICAM-1. 5. Cytokines released by nonepithelial cells (T cells and monocytes) modify the epithelial cell cytokine response to bacteria.

The host response to urinary tract infection.

The authors use the UTI model to identify basic mechanisms of disease pathogenesis, host response induction, and defense. Their studies hold the promise to provide a molecular and genetic explanation for susceptibility to UTI, and to offer more precise tools for diagnosis and therapy of these infections. There are few infections where the host response is understood in such detail and where pathologic host responses can be linked to distinct disease states. The susceptibility to UTI varies greatly in the population. The studies suggest that distinct molecular defects can cause the clinical entity of acute pyelonephritis with renal scarring, and suggest that the susceptibility to UTI in certain patient groups may have a genetic basis. In addition, the distinct signal transduction pathways explain the development of symptoms, and propose that defects in those signaling mechanisms may occur in patients with ABU. In the future, it may be useful to include these host response parameters in the diagnostic arsenal, to help in early detection of patients susceptible to recurrent UTI and renal scarring. These patients may then be offered therapies that strengthen their defense, and be offered close surveillance for recurrences and other complications.

Catheter-free geriatric care. Routines and consequences for clinical infection, care and economy.

In a geriatric hospital the routines of one ward were modified with the intention of removing indwelling catheters from all patients admitted to the ward. A continence training programme had been designed during the preceding 6 months. A total of 124 patients were admitted with indwelling catheters during a period of 18 months. It was possible to remove the catheters in 117 of these. Patients and their relatives reacted favourably to catheter-free care. The attitude of ward staff also was positive. The overall nursing requirements did not increase. Antibiotic prescription was 90 per cent less than in the control wards. This difference was accounted for not only by a reduction in drugs used against urinary tract infections, but also by a lower consumption of agents mainly used in the treatment of septicaemia, bronchopneumonia and wound infection. The cost of laundry and of hygiene and storage articles, including catheters, absorbing pads and other incontinence aids was 46 per cent of that in the control wards. Four years later, 65 per cent and 72 per cent of the patients from the test and control wards respectively, had died. Of the surviving patients from the test ward 78 per cent were still catheter-free.

Falls in 84- to 85-year-old people living at home.

The present study is a part of the Swedish longitudinal population study "70-year-old people in Gothenburg". The aim of the present study was to analyse retrospectively incidence, circumstances, and consequences of falls during one year among 741 home-living people aged 84-85. A comparison of social and medical characteristics of fallers and non-fallers aged 85 was performed. Information was collected by interviews and clinical examinations. In 1986/1987, 732 home-living people (244 men and 488 women), aged 85 gave information about falls during the last year. Three hundred and one (41%), 97 men and 204 women, had fallen at least once during the last year, mainly indoors. No sex difference was found in incidence. The most dominant triggering causes of falls were stumbling, dizziness, and feebleness. In 80% of the falls an injury occurred, of which every fourth was a fracture. A multivariate regression procedure showed that dizziness, vertigo and unsteadiness, transient ischemic attacks, antidepressant drugs, and poor subjectively experienced health characterized the fallers. Mortality rate of those between 85 and 88 years of age showed no association with falls.

Evaluation of an adapted model of the World Health Organization partograph used by Angolan midwives in a peripheral delivery unit.

OBJECTIVE: To study the impact of an educational intervention of midwives' use of the Angolan model of the World Health Organization's (WHO) partograph. SETTING: A peripheral delivery unit with approximately 1500 deliveries per year, run by eleven midwives in Luanda, Angola. DESIGN: The quasi-experimental, One-Group Pre-test-Post-test design was used in this study. Fifty partographs plotted with an initial dilatation < 8 cm were randomly selected from the first period of six month to form sample I, and another fifty from the second six-months period to form sample II. INTERVENTION: In-service education (theory and practice) performed by a team of midwives and an obstetrician. MEASUREMENTS AND FINDINGS: When comparing sample II with sample I, statistically significant improvements were found in seven of 10 measured variables. This indicates a positive effect of the educational intervention on a proper use of the partograph. Due to the small sample size, however, this study cannot evaluate action taken in relation to prolonged labour. IMPLICATIONS FOR PRACTICE: The in-service educational programme may be of use when introducing the WHO partograph in similar settings, and the findings of this study may indicate which parts of the programme need more emphasis. CONCLUSIONS: The midwives improved in general their documentation of the partograph. However, they tended to exceed established criteria for responsibilities at the peripheral delivery unit, a fact supported by an increased number of missed transfers. The study did not, however, answer the question why the midwives acted as they did in the referred cases.

The lived experiences of autonomous Angolan midwives working in midwifery-led, maternity units.

OBJECTIVE: to describe the lived experiences of autonomous midwives working in Angolan midwifery-led maternity units. DESIGN: a qualitative approach using semi-structured, audiotaped interviews, in Portugese. Data were analysed in a six-step process. SETTING: three midwifery-led maternity units in the most densely populated suburbs in the capital of Angola, Luanda. The average number of deliveries per unit was 2500 per year. PARTICIPANTS: 11 midwives from the three maternity units. FINDINGS: four main areas emerged: society/culture, significant others, personal self and professional self. Sub-areas, concepts and supporting statements were defined in each area. KEY CONCLUSIONS: the midwives served within a population living in rough circumstances but which maintained strong traditional roots. The midwives did not support homebirths, but did assist when needed. The midwives described their professional role as a 'calling', which was very independent. Cure, was considered more important than care, and strong emotions were expressed when discussing cases of failure. The partograph was viewed as an important instrument and continuous learning as crucial in their role as autonomous midwives. IMPLICATIONS FOR PRACTICE: the model of a midwifery-led delivery unit described in this study may be used in other countries facing the same problems as Angola. Difficulties concerning transfer should be seriously considered as well as adequate education for the midwives. A pre-requisite in order for peripheral maternity units to have any impact on maternal morbidity and mortality, is a well-organised first-referral level.

beta-N-acetyl-D-glucosaminidase (NAGase) and lysozyme activity in human parotid and submandibular saliva.

beta-N-acetyl-D-glucosaminidase (NAGase) and lysozyme activity were studied in isolated parotid and submandibular saliva collected from five healthy individuals over a 3-wk period. During the first week, saliva samples were collected three times within one specified day (9 a.m., noon, 4 p.m.). Then for each of the following 2 wk, saliva was collected at 9 a.m. of the same day. NAGase activity was determined spectrophotometrically by using p-nitrophenyl-glycoside as substrate. Lysozyme activity was determined turbidimetrically by using Micrococcus lysodeikticus cells as substrate. NAGase and lysozyme were present in all samples of parotid and submandibular saliva. NAGase activity was generally higher in saliva samples collected in the morning and decreased during the day. There was considerable variation in NAGase activity and almost no variation in lysozyme activity in samples taken from the same person. NAGase activity was higher in parotid than in submandibular saliva while lysozyme activity was somewhat higher in submandibular saliva.

Accidents in the institutionalized elderly: injuries and consequences.

A total of 308 major and 519 minor accidents involving 588 patients occurred during one year at a somatic long-term care hospital and its associated nursing homes. In relation to the number of patients, the incidence of accidents was nearly three times higher in the nursing homes than in the hospital. The most prevalent injuries in female patients were fractures and hematomas, while open wounds were more frequent among male patients. Hip fractures were about as common in women as in men, while fractures of the extremities were three times more frequent in women. The majority of the accidents occurred during daytime, in the patient's room and in many cases soon after admission. Most of the injuries were caused by falls and in more than 90% no staff was present. Accidents were reported most frequently in October-December, and least often in July-September. Two thirds of the severely injured had to be transferred to an emergency hospital for surgery or other treatment. Patients who had had major accidents also had a higher mortality rate six months after the accidents as compared to a control group. The medical and functional consequences for the patients were considerable. Measures to reduce the number of accidents among geriatric patients are therefore urgently needed.

Individual evaluation of accident risks at nursing homes.

The purpose of the study was to find a practical applicable method for estimating risk of accidents among nursing home patients by localizing specified risk factors and recording accidents during a period of one year. During 1987-January-15 to 1988-January-14, a total of 153 accidents happened to 23 men and 76 women among 335 admitted patients. The strongest accident predictors suggested by a logistic regression procedure were: impaired balance, walking with device or human assistance, drugs influencing the central nervous system, dizziness and poor night-time sleep. The conclusion is reached that it will probably be possible to reduce accidents in the institutionalized elderly by education of staff, identification of risk patients, individual nursing planning and measurements.

Binding of IgM rheumatoid factor to group A, C and G streptococci with IgG Fc receptors.

The possibility that IgM rheumatoid factors bind to streptococci was studied. Using a sequence of Sephadex G200 gel filtration, protein A-Sepharose CL-4B chromatography and preparatory electrophoresis, IgM was isolated from the sera of 2 patients with rheumatoid arthritis and then radiolabelled with 125I. There was significant binding of radiolabelled IgM to group-A streptococci types M1, M15 and M22, and to a group-C and a group-G strain, all expressing IgG Fc receptors, but none to Staphylococcus aureus, Escherichia coli or to 11 other strains of streptococci without IgG Fc receptors. The radiolabelled IgM was separated by affinity chromatography on a column containing human IgG. Types M1 and M15 bound the fraction retained on the column, whereas M22 bound both this fraction and the non-retained fraction. Commercial human IgG, even at high concentrations, did not inhibit binding. The binding reaction, which is perhaps triggered either by the IgM rheumatoid factor or by IgG complexed with rheumatoid factor, could be a useful tool for removal of anti-immunoglobulin from the blood of patients with rheumatoid arthritis.

Effects of encoding strategy, presentation modality, and scoring method on STM performance with the Peterson and Peterson technique.

The Peterson and Peterson (1959) STM experiment was replicated with variation of presentation modality and encoding strategy. The effect of various scoring criteria was also analyzed. The recall data showed that a Peterson and Peterson type forgetting curve was obtained using auditory presentation and instructions to rehearse vocally the trigrams when scoring only completely correct recall within the first 3 sec of the recall interval. With visual presentation and instructions to find meaningful trigram interpretations, the forgetting curve was higher and much more flat, especially when scoring position correct recall within the total 0-10-sec recall interval. In a buildup of PI experiment, no buildup of PI could be detected when visual presentation was used together with instructions to find meaningful trigram interpretations. The importance of the different encoding activities for recall performance was discussed.

Differential susceptibility of cell-bound streptococcal immunoglobulin Fc-receptors to autolytic degradation.

The susceptibility of IgA and IgG Fc-receptors of different streptococci to autolytic degradation was tested by incubating washed bacteria in phosphate-buffered saline at 37 degrees C for 24-72 h. Before incubation, strain M1 bound 74 per cent of 2.5 micrograms radio-labelled IgG added to 200 microliter of the suspension, and strain M4 bound 85 per cent of 2.5 micrograms radio-labelled IgA; both types of binding decreased to less than 15 per cent. Evidence was obtained that the decrease in binding was caused by digestion of the respective receptors, and not by degradation of the immunoglobulins or through inhibition by solubilized Fc-receptors. The autolytic process was inhibited by EDTA, iodoacetic acid, benzamidinium chloride, phenylmethylsulfonyl fluoride and diisopropylfluorophosphate. The IgG Fc-receptors in other types of group A streptococci (including type M4) and a group C and a group G strain were not affected by such prolonged incubation, also when strains were mixed with M-type 1 streptococci from the start of incubation. These findings, which thus revealed certain differences in stability between streptococcal Fc-receptors, are discussed in relation to the intracellular degradation of streptococci.

Binding of aggregated IgG Fab-fragments and light chains to some group A, C and G streptococci.

Receptors for IgG Fc in many group A, C and G streptococci have been reported previously. We now describe a reaction between group A, C and G streptococci and IgG Fab-parts, not involving the antigen combining sites. The bacteria proved to bind aggregated, but not monomeric, IgG Fab-fragments, indicating that multivalent interaction was a prerequisite for the binding to occur. Most of the strains exhibiting affinity for aggregated IgG Fab could also interact with aggregated K and/or lambda light chains. The capacity of the single strains to bind aggregated IgG Fab did not correlate with presence of IgG Fc-receptor activity. Furthermore, in contrast to streptococcal Fc-receptors, the streptococcal structure reacting with Fab was highly sensitive to trypsin as well as phosphatase treatment. The binding of aggregated lambda-chains to each of two strains tested was inhibited by liquoid and aggregated human albumin, suggesting that lipoteichoic acid and/or M protein are responsible for the binding of IgG Fab-fragments. A pronounced binding of aggregated IgG Fab, but not light chains, to Staphylococcus aureus, strain Cowan I, was also found. Various other bacterial species were tested for binding of the aggregates, with negative results.

Role of group A streptococcal IgG Fc-receptor in induction of anti-IgG by immunization in the rabbit.

Previous work has demonstrated that streptococcal IgG Fc-receptors (FcR) may trigger production of anti-IgG after immunization of rabbits with group A streptococci. This effect seemed dependent on in vitro binding of IgG, derived from the growth medium, to the vaccine strains. In the experiments presented here, IgG was eluted from streptococcal strains to be used for immunization of rabbits by 1 M KSCN and washing, a treatment which did not affect the capacity of the strains to bind newly added IgG. Using two IgG FcR-positive group A streptococcal strains (M-types 1 and 22) for intravenous immunization, anti-IgG was found in the sera of 26 out of 28 rabbits, examined 8 weeks after immunization. In contrast, anti-IgG was not induced in 16 rabbits receiving either group A, type T27 or group B, type Ia streptococci both of which lack surface FcR activity. Finally, immunization with purified streptococcal IgG FcR (0.35 mg, given subcutaneously combined with Freund's complete adjuvant and two weeks later intraconjunctivally without adjuvant) also induced anti-IgG. In all rabbits, anti-human rather than anti-rabbit IgG was detected. It is proposed that in vivo interaction between the bacterial FcR and rabbit IgG, resulting in conformation changes in IgG, is a prerequisite for the induction of anti-IgG. Thus, streptococcal triggering of anti-IgG, ascribable to IgG Fc-receptor activity and not requiring presence of foreign IgG, has been demonstrated in the rabbit.

Demonstration of the non-identity between the Fc receptor for human IgG from group A streptococci type 15 and M protein, peptidoglycan and the group specific carbohydrate.

After electrophoresis of an alkaline extract of type 15 group A streptococci, three main precipitation lines were obtained in diffusion experiments against commercial human polyclonal IgG (lines 1, 2 and 3). Nineteen of 23 sera (83%) from apparently healthy human individuals gave line 3, while 6 of them (26%) gave line 1. The sera giving line 1 did also give line 3. Line 2 was obtained with 2 sera only, also giving lines 1 and 3. Line 3 was caused by a streptococcal Fc-receptor for human IgG, since the line could be displaced by addition of Fc-fragments, but not Fab-fragments of pooled human IgG. Line 1 was shown to be different from line 3, since (1) line 1 was suppressed in contrast to line 3 on absorption of a human serum or commercial polyclonal human IgG with S. aureus; and (2), line 1 was suppressed by Fab-fragments but not Fc-fragments of polyclonal human IgG. Line 2 could be inhibited by addition of peptidoglycan to commercial polyclonal human IgG or a human serum investigated. Another line, 4, obtained in diffusion experiments involving electrophoretically separated alkaline extract of type 15 group A streptococci was type-specific as shown by rabbit antisera to streptococci type M1, M8, M15, and T44, and disappeared on trypsinization of the extract. The component responsible for line 4 in the streptococcal extract, judged to be type-specific M protein, had a mobility different from the component responsible for line 3 in electrophoresis.

IgG F(ab')2 of rabbit anti-M sera but not the unfractionated sera are bactericidal for some group A streptococci with IgG Fc-receptor activity. Opsonic effect ascribable to anti-IgG.

We have earlier reported on a group A streptococcal strain, type M12, which upon serial mouse passage acquired IgG Fc-receptor activity but lost the M-antigen. The passaged strain, 12P, was highly virulent for mice and grew well in normal human blood. The present study particularly concerns the opsonic effect on 12P of rabbit anti-M3, anti-M12 and anti-12P sera, as well as the corresponding IgG F(ab')2. Indirect bactericidal tests showed that the homologous anti-12P seum and IgG F(ab')2 were opsonic. The anti-M3 and anti-M12 had no effect on 12P; surprisingly, however, IgG F(ab')2 isolated from these sera displayed a clearcut opsonic activity. Data are presented which indicate that these "paradoxical" results can be explained by the binding of IgG F(ab')2 with anti-IgG specificity to human IgG, linked to the streptococcal surface through Fc-receptors. Only anti-12P serum, or IgG F(ab')2, were protective for mice on challenge with strain 12P.

Accidents in the institutionalized elderly: a risk analysis.

Among a total of 4,862 admittances to a Swedish geriatric hospital and its associated nursing homes, 827 accidents occurred in 588 patients during one year. The purpose of the present study was to establish the direct causes of these accidents and to identify possible risk factors. Information was collected from medical records, interviews with patients and staff, examination of the mental and physical state of the patients, and through reconstruction of the accidents. The investigation embraced 270 patients with 308 major accidents (fractures, sprains, open wounds, concussions and injuries to ligaments), and 318 patients with 519 minor accidents (bruises, contusions, abrasions and minor burns). Injury-free patients with nearest lower bed number in relation to patients with major accidents formed a control group. Patients with previous injuries, balance disturbances, and polypharmacy were at high risk, and intrinsic factors such as dizziness and impaired balance proved to be more significant as direct causes for the occurrence of accidents than environmental factors. The estimated risk for a patient with all these risk factors to have an accident during one year was 94%.

Interaction between streptococcal IgG Fc receptors and human and rabbit IgG domains.

Groups A, C and G streptococci were tested for their ability to bind 125I-labelled fragments of human and rabbit IgG in order to localize their sites of interaction with IgG domains. Among the Group A streptococci, strains with IgG Fc receptors bound 85% of the added IgG Fc fragments in the test systems, whereas these strains showed practically no reactivity with F(ab')2, Facb (F(ab')2 + C gamma 2 domains) or pFc' (C gamma 3 domains). The Group C and Group G strains bound 48-100% of IgG Fc, but could also bind up to 36% of the added F(ab')2 in accordance with a previously described 'alternative' Fab reactivity. However, unlabelled IgG F(ab')2 or Facb showed no, or only slight, inhibitory capacity for the binding of 125I-labelled IgG Fc to the C and G strains. Collectively, these results indicate that Groups A, C and G streptococci require both the C gamma 2 and C gamma 3 domains for interaction with IgG, and most probably also bind in the interface region between the C gamma 2 and C gamma 3 domains as has been shown for staphylococcal protein A.