Pseudomonas aeruginosa: Host defence in lung diseases

Lung infections caused by the opportunistic pathogen Pseudomonas aeruginosa can present as a spectrum of clinical entities from a rapidly fatal pneumonia in a neutropenic patient to a multi‐decade bronchitis in patients with cystic fibrosis. P. aeruginosa is ubiquitous in our environment, and one of the most versatile pathogens studied, capable of infecting a number of diverse life forms and surviving harsh environmental factors. It is also able to quickly adapt to new environments, including the lung, where it orchestrates virulence factors to acquire necessary nutrients, and if necessary, turn them off to prevent immune recognition. Despite these capabilities, P. aeruginosa rarely infects healthy human lungs. This is secondary to a highly evolved host defence mechanism that efficiently removes inhaled or aspirated pseudomonads. Many arms of the respiratory host defence have been elucidated using P. aeruginosa as a model pathogen. Human infections with P. aeruginosa have demonstrated the importance of the mechanical barrier functions including mucus clearance, and the innate immune system, including the critical role of the neutrophilic response. As more models of persistent or biofilm P. aeruginosa infections are developed, the role of the adaptive immune response will likely become more evident. Understanding the pathogenesis of P. aeruginosa, and the respiratory host defence response to it has, and will continue to, lead to novel therapeutic strategies to help patients.     

Local therapy with soluble complement receptor 1 (sCR1) suppresses inflammation in rat mono-articular arthritis

Complement activation has been implicated in the pathogenesis of human rheumatoid arthritis. We sought to determine whether inhibition of complement (C) using sCR1 could influence the development and progression of antigen arthritis in the rat, a recognized model of human chronic synovitis. The effect of C inhibition, systemically and locally, on three different stages of disease was examined: (i) prophylaxis, (ii) treatment of established inflammation, and (iii) prevention of antigen-induced flares of disease. Arthritis was assessed by knee swelling and by histological examination. Our results show that intra-articular injection of sCR1 prior to disease onset reduced joint swelling and development of arthritis, whereas systemic administration was ineffective. Treatment of established arthritis with intra-articular sCR1 3 days after disease onset caused a transient reduction in swelling, but treatment 7 days after disease onset had no effect on disease. An intra-articular dose of sCR1 given at the time of disease flares had a small, yet significant effect on knee swelling. We conclude that complement activation is important in the initiation and maintenance of inflammation in antigen arthritis. The potent effect of local C inhibition suggests that C biosynthesis and activation within the joint contributes to inflammation in this model of arthritis.     

Influence of Aetiology, Clinical and Histological Features on Survival in Chronic Active Hepatitis: An Analysis of 204 Patients

To determine which clinical and laboratory features may influencesurvival in patients with chronic active hepatitis, we undertooka retrospective study of 204 patients seen on this unit overa 15-year period and applied logistic regression analysis. Onehundred and six patients had autoimmune chronic active hepatitis,69 ‘cryptogenic’ chronic active hepatitis (no autoimmunemarkers or other aetiological factors identified), and 29 wereHBsAg-seropositive. Variceal haemorrhage, encephalopathy andascites were common presenting features in the cryptogenic groupwhile the presence of jaundice and other immunopathic diseasesdid not differ between the groups. Cirrhosis was more commonat presentation in the cryptogenic group. Remission was inducedwith corticosteroids and azathioprine in 82 per cent of patientswith autoimmune chronic active hepatis and in 77 per cent ofpatients with cryptogenic chronic active hepatitis and the annualrelapse rate was similar in the autoimmune and cryptogenic groups.Five-year survival was 87 per cent in the autoimmune group,65 per cent in the cryptogenic group, and 80 per cent in thosewith HBsAg-positive disease, and on logistic regression analysis,the presence of cirrhosis at presentation was the only independentfactor which adversely affected survival. Overall survival inthe cirrhotic patients at five and 12 years was 63 and 48 percent respectively compared with 95 and 92 per cent in thosewithout cirrhosis.     

Level of purposeful hand function as a marker of clinical severity in Rett syndrome

Aim We investigated relationships between hand function and genotype and aspects of phenotype in Rett syndrome. Method Video assessment in naturalistic settings was supplemented by parent‐reported data in a cross‐sectional study of 144 females with a mean age of 14 years 10 months (SD 7y 10mo; range 2y–31y 10mo), 110 of whom had a mutation of the methyl CpG binding protein 2 (MECP2) gene. Ordinal logistic regression was used to assess relationships between hand function and MECP2 mutation, age, a modified Kerr score, Functional Independence Measure for Children (WeeFIM), ambulation level, and frequency of hand stereotypies. Results Approximately two‐thirds of participants demonstrated purposeful hand function, ranging from simple grasping skills to picking up and manipulating small objects. In participants with a confirmed MECP2 mutation, those with the p.R168X mutation had the poorest hand function on multivariate analysis with C‐terminal deletion as the baseline (odds ratio [OR] 0.19; 95% confidence interval [CI] 0.04–0.95), whereas those with the p.R133C or p.R294X mutation had better hand function. Participants aged 19 years or older had lower hand function than those aged less than 8 years (OR 0.36; 95% CI 0.14–0.92). Factors that were associated with better hand function were lower Kerr scores for a 1‐point increase in score (OR 0.77; 95% CI 0.69–0.86), higher WeeFIM scores for a 1‐point increase in score (OR 1.08; 95% CI 1.04–1.12), and greater ambulation than those completely dependent on carers for mobility (OR 22.64; 95% CI 7.02–73.08). The results for participants with a confirmed pathogenic mutation were similar to results obtained when participants without a mutation were also included. Interpretation Our novel assessment of hand function in Rett syndrome correlated well with known profiles of common MECP2 mutations and overall clinical severity. This promising assessment could measure clinical responses to therapy.     

APPLICATION OF MASS SPECTROMETERY TO THE SEQUENCING OF PROTEINS

Mass spectrometry is now established as a viable method for determing the sequence of amino acids in proteins. The approach involves chemical and enzymic digestion of the protein (as in classical methods) to small peptides (ten residues) which are then chemically modified to increase their volatility. The chemical modifications are (i) acetylation of basic nitrogen sites and (ii) Permethylation. The derivatives so obtained may be sequenced in the mass spectrometer as mixtures of several peptides. This is achieved by a temperature gradient in the mass spectrometer source, which effects partial, or total separation of the derivatized peptides according to their volatilities. In this way, much tedious separation work (sometimes the rate-determining factor in classical approaches) may be avoided. The sequencing process is carried out from the N-terminal residue, utilizing the preferential cleavage of the ionized petide at the amide bonds; each amino acid is associated with a characteristic mass increment and thus the sequence can be determined. Mass spectrometry is especially useful in the detection and characterization of novel amino acids which might otherwise be difficult to identify. Although almost all work to date has used electron impact mass spectrometery, in the future it is possible that newer methods of ionization, such as field desorption and chemical ionization, might be profitably used.     

The cognitive effects of alcohol abuse: a controlled study

It is now well established that there is an association between excessive alcohol consumption and psychological impairment. However, there has been some difficulty in the interpretation of results as the majority of studies have relied on reporting correlations in large subject samples. It was felt therefore that if subjects were matched by variables which had been found to be confounding in previous research, a clearer picture of the effects of alcohol on cognitive functioning could be drawn. Subjects in this study were therefore divided into a ‘high’ alcohol group (over 50 units per week), and a ‘low’ alcohol group (under 20 units per week). No patients who had previously been reported as suffering from cognitive impairment were included in this study as the purpose of this research was to examine the effects of alcohol on those heavy drinkers with no obvious impairment. They were matched by age, sex, socio-economic status and educational background. Heavy drinkers showed significant deficits on a number of cognitive tests compared with their matched controls. Furthermore, the subjects in the lower educational group showed a greater decrease in scores on several sub tests than those in the higher group.     

Small pulmonary arterial vessels of Aymara Indians from the Bolivian Andes

A study was made of the qualitative histological features of the small pulmonary arterial vessels of 25 adult citizens of La Paz, Bolivia (altitude 3600 m) coming to necropsy. Abnormalities found included muscularization of pulmonary arterioles, the development of longitudinal muscle in the intima of pulmonary arteries and arterioles, and the formation of muscular tubes lining the longitudinal muscle which extended through arterioles into the precapillaries of the lung. Arteriolar muscularization was found in three of the 13 Aymaras and in two of the 12 Mestizos studied. Intimal longitudinal muscle was present in four Aymaras and five Mestizos. Muscular tubes were found in only one case, a young Aymara. The features were very similar to those found in chronic obstructive airways disease. The appearances are consistent with a growth of new vascular smooth muscle in response to alveolar hypoxia as opposed to hypoxic vasoconstriction.     

Granulomatous hidradenitis suppurativa and cutaneous Crohn's disease

Three patients with concurrent hidradenitis suppurativa and Crohn's disease are presented. The notable histological feature in each hidradenitis resection was the presence of numerous discrete epithelioid granulomas in areas of non-inflamed dermis. The purpose of the study was to determine the incidence of epithelioid granulomas in 101 hidradenitis patients and their significance in relation to systemic granulomatous disease. Discrete epithelioid granulomas were identified in 8% of the resections (10 patients). One patient had Crohn's disease and one other pulmonary sarcoidosis. Seven patients with granulomatous hidradenitis neither had nor developed any other disease during the 3-year follow-up period. Clinical review identified a further two patients with Crohn's disease but associated with non-granulomatous changes in the skin resections. Foreign body type granulomas were identified in 25% of the resections adjacent to ruptured hair follicles, sinus tracts or nearby degenerate sweat glands. The study shows that, although foreign body type granulomas are a common finding in hidradenitis, the presence of discrete epithelioid granulomas in the dermis away from the site of active inflammation is unusual and should alert the pathologist to the possibility of systemic granulomatous disease such as Crohn's disease or sarcoidosis.     

Impact of Arteriogenesis in Plastic Surgery: Choke Vessel Growth Proceeds via Arteriogenic Mechanisms in the Rat Dorsal Island Skin Flap

Objective: We examined the molecular mediators of postoperative choke‐vessel growth. Our focus was the possible overlap between choke‐vessel growth and arteriogenesis. Methods: A rat perforator flap model, encompassing four vascular territories, was used. Flaps were surgically elevated, re‐inset, and allowed to survive for one, three, five, or seven days. Tissue samples for Western and histological analyses were collected from the choke zone along the dorsal midline. Tissue from territories linked by the choke zone was analyzed to distinguish between global and local effects. The proteins examined included CD11b, ICAM‐1, and MMP‐2, three markers associated with arteriogenesis, as well as Hsp70 and vascular endothelial growth factor, markers of physiological stress and hypoxia/ischemia. Results: Arteriogenesis markers, as shown by Western analysis, increased at three and five days after flap elevation, and the increase was localized by immunohistochemistry to the growing arteries and veins. The marker of physiological stress increased at Days 5 and 7. The hypoxia‐ischemia marker did not increase in the choke zone. Conclusions: The growth of choke arteries and veins proceeds in an inflammatory environment that resembles arteriogenesis. Ischemia did not appear to play a role in choke‐vessel changes.     

The development of emotion and empathy skills after childhood brain injury

Lasting socio-emotional behaviour difficulties are common among children who have suffered brain injuries. A proportion of difficulties may be attributed to impaired cognitive and/or executive skills after injury. A recent and rapidly accruing body of literature indicates that deficits in recognizing and responding to the emotions of others are also common. Little is known about the development of these skills after brain injury. In this paper we summarize emotion-processing systems, and review the development of these systems across the span of childhood and adolescence. We describe critical phases in the development of emotion recognition skills and the potential for delayed effects after brain injury in earlier childhood. We argue that it is important to identify the specific nature of deficits in reading and responding to emotions after brain injury, so that assessments and early intervention strategies can be devised.