Estimating the changing burden of disease attributable to interpersonal violence in South Africa for 2000, 2006 and 2012.

BACKGROUND: South Africa (SA)'s high rate of interpersonal violence persists as a leading public health problem for the country. The first South African Comparative Risk Assessment Study (SACRA1) in 2000 quantified the long-term mental and physical health burden attributable to interpersonal violence by supplementing the direct injury burden of disease attributable to interpersonal violence injuries with the substantial contribution of mental health, behavioural and reproductive health consequences accruing from exposure to intimate partner violence (IPV) and child sexual abuse. OBJECTIVES: To revise and improve these estimates by including the additional burden from other forms of child maltreatment, community violence, sexual violence by non-partners, and bullying victimisation in SA for 2000, 2006 and 2012, and trends over time. METHODS: We used comparative risk assessment methods to calculate population attributable fractions (PAFs) for interpersonal violence. This method requires inputs on the prevalence of exposure to the interpersonal violence risk factor subtypes, namely child maltreatment, bullying, IPV, sexual violence by non-partners and other community violence; the burden of related health outcomes (mortality and morbidity); and relative risks of health outcomes in individuals exposed to the risk factor v. those unexposed. We estimated the PAF for the combinations of all interpersonal violence subtypes together to estimate the burden attributable to interpersonal violence overall for 2000, 2006 and 2012. RESULTS: Between 2000 and 2012, there was a decrease in interpersonal violence age-standardised attributable death rates from 100 to 71 per 100 000. In the second South African Comparative Risk Assessment Study (SACRA2), estimates of the attributable disability-adjusted life years (DALYs) for interpersonal violence for the year 2000 were revised, from 1.7 million to 2 million DALYs, taking into account attributable mortality and disability from additional forms of violence. There was a decrease in DALYs attributable to interpersonal violence from 2 million in 2000 to 1.75 million in 2012, accounting for 8.5% of the total burden for SA, ranking second highest, after unsafe sex, among 18 risk factors evaluated in 2012. CONCLUSION: Overall, interpersonal violence-attributable DALYs decreased substantially but remain high. The reduction in age-standardised attributable death rates indicates that some policy and social intervention aspects are effective. Further strengthening of existing laws pertaining to interpersonal violence, and other prevention measures, are needed to intensify the prevention of violence, particularly gender-based violence. Additional forms of violence included in this analysis have improved our understanding of the interpersonal violence burden, but the attributable burden in males, although exceedingly high, remains an underestimate. There is a need to improve the epidemiological data on prevalence and risks for the different types of interpersonal violence, particularly for males.

Parenting, mental health and economic pathways to prevention of violence against children in South Africa.

BACKGROUND: Parenting programs based on social learning theory have increasing empirical evidence for reducing violence against children. Trials are primarily from high-income countries and with young children. Globally, we know little about how parenting programs work to reduce violence, with no known studies in low or middle-income countries (LMICs). This study examines mechanisms of change of a non-commercialized parenting program, Parenting for Lifelong Health for Teens, designed with the World Health Organization and UNICEF. A cluster randomized trial showed main effects on parenting and other secondary outcomes. We conducted secondary analysis of trial data to investigate five potential mediators of reduced violence against children: improved parenting, adolescent behaviour, caregiver mental health, alcohol/drug avoidance, and family economic strengthening. METHODS: The trial was implemented in rural South Africa with 40 sites, n = 552 family dyads (including adolescents aged 10-18 and primary caregivers). Intervention sites (n = 20) received the 14-session parenting program delivered by local community members, including modules on family budgeting and savings. Control sites (n = 20) received a brief informational workshop. Emotional and physical violence against children/adolescents and each potential mediator were reported by adolescents and caregivers at baseline and 9-13 months post-randomisation. Structural equation modelling was used to test simultaneous hypothesized pathways to violence reduction. RESULTS: Improvements in four pathways mediated reduced violence against children: 1) improved parenting practices, 2) improved caregiver mental health (reduced depression), 3) increased caregiver alcohol/drug avoidance and 4) improved family economic welfare. Improved child behaviour was not a mediator, although it was associated with less violence. CONCLUSIONS: Simultaneously bolstering a set of family processes can reduce violence. Supporting self-care and positive coping for caregivers may be essential in challenging contexts. In countries with minimal or no economic safety nets, linking social learning parenting programs with economic strengthening skills may bring us closer to ending violence against children.

Pathways from witnessing community violence to mental health problems among South African adolescents.

BACKGROUND: The intersection of violence exposure and mental health problems is a public health crisis for South African (SA) adolescents. Understanding the impact of community violence on adolescent mental health can inform future interventions. OBJECTIVES: To assess pathways between community violence exposure and internalising and externalising problems in SA adolescents receiving mental healthcare, and the roles of parent and peer relationships in these associations. METHODS: Participants (N=120 parent-adolescent pairs) were recruited from four mental health clinics in Western Cape Province to participate in a pilot test of a family-based HIV prevention study. Adolescents reported on their exposure to community violence, parental attachment, peer support of risk behaviour, and mental health. Parents reported on adolescents' internalising and externalising mental health problems. Participants received transport money (ZAR30 = USD3) and a shopping voucher or cash (ZAR50 = USD5) for their time. RESULTS: Adolescents were 12 - 18 years old (mean (standard deviation) 14.39 (1.82) years), 53% were male, and 67% and 33% reported black African and mixed-race ethnicity, respectively. Parents were 94% female and reported an average monthly income of ZAR3 973 (USD397). Boys reported significantly higher rates of witnessing community violence than girls. Among boys, significant paths emerged from community violence and low parent attachment to externalising symptoms and from community violence to peer support of risky behaviour. For girls, the only significant path was from low parent attachment to peer support of risky behaviour. CONCLUSIONS: This cross-sectional study sheds new light on the possible pathways from witnessing community violence to mental health problems among SA adolescents. Identifying factors that drive and mitigate psychological distress in the context of persistent community violence is critical to SA's future and can inform the selection and delivery of appropriate and targeted evidence-based interventions.

Hearing optimisation in neurofibromatosis type 2: A systematic review.

BACKGROUND: It is common for patients with neurofibromatosis type 2 to develop bilateral profound hearing loss hearing loss, and this is one of the main determinants of quality of life in this patient group. OBJECTIVES: The aim of this systematic review was to review the current literature regarding hearing outcomes of treatments for vestibular schwannomas in neurofibromatosis type 2 including conservative and medical management, radiotherapy, hearing preservation surgery and auditory implantation in order to determine the most effective way of preserving or rehabilitating hearing. SEARCH STRATEGY: A MESH search in PubMed using search terms (('Neurofibromatosis 2' [Mesh]) AND 'Neuroma, Acoustic'[Mesh]) AND 'Hearing Loss' [Mesh] was performed. A search using keywords was also performed. Studies with adequate hearing outcome data were included. With the exception of the cochlear implant studies (cohort size was very small), case studies were excluded. EVALUATION METHOD: The GRADE system was used to assess quality of publication. Formal statistical analysis of data was not performed because of very heterogenous data reporting. RESULTS: Conservative management offers the best chance of hearing preservation in stable tumours. The use of bevacizumab probably improves the likelihood of hearing preservation in growing tumours in the short term and is probably more effective than hearing preservation surgery and radiotherapy in preserving hearing. Of the hearing preservation interventions, hearing preservation surgery probably offers better hearing preservation rates than radiotherapy for small tumours but recurrence rates for hearing preservation surgery were high. For patients with profound hearing loss, cochlear implantation provides significantly better auditory outcomes than auditory brainstem implantation. Patients with untreated stable tumours are likely to achieve the best outcomes from cochlear implantation. Those who have had their tumours treated with surgery or radiotherapy do not gain as much benefit from cochlear implantation than those with untreated tumours. CONCLUSIONS: This review summarises the current literature related to hearing preservation/rehabilitation in patients with NF2. Whilst it provides indicative data, the quality of the data was low and should be interpreted with care. It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision-making is determined by many factors, not just the need to preserve hearing.

Severe muscle trauma triggers heightened and prolonged local musculoskeletal inflammation and impairs adjacent tibia fracture healing.

OBJECTIVES: Complicated fracture healing is often associated with the severity of surrounding muscle tissue trauma. Since inflammation is a primary determinant of musculoskeletal health and regeneration, it is plausible that delayed healing and non-unions are partly caused by compounding local inflammation in response to concomitant muscle trauma. METHODS AND RESULTS: To investigate this possibility, a Lewis rat open fracture model [tibia osteotomy with adjacent tibialis anterior (TA) muscle volumetric muscle loss (VML) injury] was interrogated. We observed that VML injury impaired tibia healing, as indicated by diminished mechanical strength and decreased mineralized bone within the fracture callus, as well as continued presence of cartilage instead of woven bone 28 days post-injury. The VML injured muscle presented innate and adaptive immune responses that were atypical of canonical muscle injury healing. Additionally, the VML injury resulted in a perturbation of the inflammatory phase of fracture healing, as indicated by elevations of CD3(+) lymphocytes and CD68+ macrophages in the fracture callus at 3 and 14d post-injury, respectively. CONCLUSIONS: These data indicate that heightened and sustained innate and adaptive immune responses to traumatized muscle are associated with impaired fracture healing and may be targeted for the prevention of delayed and non-union following musculoskeletal trauma.

Bilateral vestibular schwannomas in older patients: NF2 or chance?

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant condition with high spontaneous mutation rate which predisposes to the development of multiple nerve sheath tumours (schwannomas), meningiomas and ependymoma. The cardinal feature and main diagnostic criterion for the diagnosis of NF2 remains the development of bilateral vestibular schwannoma (BVS). With increasing use of MRI screening the possibility of a 'chance' diagnosis of BVS has been mooted with a potential frequency of one in two million people in their lifetime. Until now, however, no evidence for such an event has been published. We aimed to demonstrate that chance occurrence can occur and to estimate its frequency among those with just BVS late in life. METHODS: Two vestibular schwannomas from the same patient were DNA sequenced and underwent loss of heterozygosity analysis. RESULTS: We show that a man who developed BVS, at ages 52 and 67 years developed these tumours sporadically by demonstrating that there were no molecular events in common between the two tumours. Furthermore from a database of over 1200 patients with NF2, we have estimated that ~25% of cases of BVS over 50 years and 50% over 70 years of age where no other features of NF2 are present represent a chance occurrence rather than due to an underlying mosaic or constitutional NF2 mutation. CONCLUSIONS: Patients presenting with BVS later in life should be appraised of the potential likelihood they may not have NF2 and the resultant further reduction in risks of transmission to offspring.

Delayed presentation of late-onset cerebrospinal fluid rhinorrhoea following dopamine agonist therapy for giant prolactinoma.

UNLABELLED: Therapeutic shrinkage of prolactinomas with dopamine agonists achieves clinical benefit but can expose fistulae that have arisen as a result of bony erosion of the sella floor and anterior skull base by the invasive tumour, resulting in the potential development of cerebrospinal fluid (CSF) rhinorrhoea, meningitis, and rarely pneumocephalus. Onset of symptoms is typically within 4 months of commencing therapy. The management is typically surgical repair via an endoscopic transnasal transsphenoidal approach. A 23-year-old man presented to the Emergency Department with acute left limb weakness and intermittent headaches. Visual fields were full to confrontation. Immediate computed tomography and subsequent magnetic resonance imaging (MRI), demonstrated a 5 cm lobular/cystic mass invading the right cavernous sinus, displacing and compressing the midbrain, with destruction of the bony sella. He was referred to the regional pituitary multidisciplinary team (MDT). Serum prolactin was 159 455 mIU/l (7514.37 ng/ml) (normal ranges 100-410 mIU/l (4.72-19.34 ng/ml)). Cabergoline was commenced causing dramatic reduction in tumour size and resolution of neurological symptoms. Further dose titrations were required as the prolactin level plateaued and significant residual tumour remained. After 13 months of treatment, he developed continuous daily rhinorrhea, and on presenting to his general practitioner was referred to an otolaryngologist. When next seen in the routine regional pituitary clinic six-months later he was admitted for urgent surgical repair. Histology confirmed a prolactinoma with a low proliferation index of 2% (Ki-67 antibody). In view of partial cabergoline resistance he completed a course of conventional radiotherapy. Nine months after treatment the serum prolactin had fallen to 621 mIU/l, and 12 months after an MRI showed reduced tumour volume. LEARNING POINTS: CSF rhinorrhoea occurred 13 months after the initiation of cabergoline, suggesting a need for vigilance throughout therapy.Dedicated bony imaging should be reviewed early in the patient pathway to assess the potential risk of CSF rhinorrhoea after initiation of dopamine agonist therapy.There was a significant delay before this complication was brought to the attention of the regional pituitary MDT, with associated risk whilst left untreated. This demonstrates a need for patients and healthcare professionals to be educated about early recognition and management of this complication to facilitate timely and appropriate referral to the MDT for specialist advice and management. We changed our nurse-led patient education programme as a result of this case.An excellent therapeutic response was achieved with conventional radiotherapy after limited surgery having developed partial cabergoline resistance and CSF rhinorrhoea.

A loss of FUS/TLS function leads to impaired cellular proliferation.

Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional RNA/DNA-binding protein that is pathologically associated with cancer and neurodegeneration. To gain insight into the vital functions of FUS and how a loss of FUS function impacts cellular homeostasis, FUS expression was reduced in different cellular models through RNA interference. Our results show that a loss of FUS expression severely impairs cellular proliferation and leads to an increase in phosphorylated histone H3, a marker of mitotic arrest. A quantitative proteomics analysis performed on cells undergoing various degrees of FUS knockdown revealed protein expression changes for known RNA targets of FUS, consistent with a loss of FUS function with respect to RNA processing. Proteins that changed in expression as a function of FUS knockdown were associated with multiple processes, some of which influence cell proliferation including cell cycle regulation, cytoskeletal organization, oxidative stress and energy homeostasis. FUS knockdown also correlated with increased expression of the closely related protein EWS (Ewing's sarcoma). We demonstrate that the maladaptive phenotype resulting from FUS knockdown is reversible and can be rescued by re-expression of FUS or partially rescued by the small-molecule rolipram. These results provide insight into the pathways and processes that are regulated by FUS, as well as the cellular consequences for a loss of FUS function.

Autologous minced muscle grafts: a tissue engineering therapy for the volumetric loss of skeletal muscle.

Volumetric muscle loss (VML) results in a large void deficient in the requisite materials for regeneration for which there is no definitive clinical standard of care. Autologous minced muscle grafts (MG), which contain the essential components for muscle regeneration, may embody an ideal tissue engineering therapy for VML. The purpose of this study was to determine if orthotopic transplantation of MG acutely after VML in the tibialis anterior muscle of male Lewis rats promotes functional tissue regeneration. Herein we report that over the first 16 wk postinjury, MG transplantation 1) promotes remarkable regeneration of innervated muscle fibers within the defect area (i.e., de novo muscle fiber regeneration); 2) reduced evidence of chronic injury in the remaining muscle mass compared with nonrepaired muscles following VML (i.e., transplantation attenuated chronically upregulated transforming growth factor-ß1 gene expression and the presence of centrally located nuclei in 30% of fibers observed in nonrepaired muscles); and 3) significantly improves net torque production (i.e., ∼55% of the functional deficit in nonrepaired muscles was restored). Additionally, voluntary wheel running was shown to reduce the heightened accumulation of extracellular matrix deposition observed within the regenerated tissue of MG-repaired sedentary rats 8 wk postinjury (collagen 1% area: sedentary vs. runner, ∼41 vs. 30%), which may have been the result of an augmented inflammatory response [i.e., M1 (CCR7) and M2 (CD163) macrophage expression was significantly greater in runner than sedentary MG-repaired muscles 2 wk postinjury]. These findings support further exploration of autologous minced MGs for the treatment of VML.

Interferon and ribavirin therapy does not select for resistance mutations in hepatitis C virus polymerase.

Ribavirin has a minor and transient effect on hepatitis C virus (HCV) replication and has been suggested to select a novel mutation, F415Y, in the RNA-dependent RNA polymerase of subtype 1a viruses. Twenty-nine patients with chronic hepatitis C (subtyped by INNO LiPA as 1a, 17; 1b, 11; 1a/1b, 1) who were nonresponders to interferon-based therapies were identified retrospectively and screened at Baseline, week 24 of treatment, and 24 weeks post-treatment. Selection of resistance mutations, including at amino acid position 415 of the polymerase, was investigated. Using clonal sequencing and pyrosequencing of the NS5B gene, we screened for the F415Y resistance mutation among patients who received combination therapy with ribavirin and interferon α. Of the 15 subtype 1a patients treated with interferon plus ribavirin, only one had the F415Y change at week 24, and an F/Y mixture was still present 24 weeks after therapy. Four additional patients in this group had the F415Y change 24 weeks post-therapy. The NS5B genes were sequenced in order to identify amino acid changes associated with ribavirin therapy, but no evidence was found that ribavirin selects for particular amino acids in the RNA-dependent RNA polymerase. Ribavirin, a weak inhibitor of HCV replication, does not select for resistance mutations in the sequence of the HCV RNA polymerase.

Critical incident exposure in South African emergency services personnel: prevalence and associated mental health issues.

OBJECTIVES: To assess critical incident exposure among prehospital emergency services personnel in the developing world context of South Africa; and to assess associated mental health consequences. METHODS: We recruited a representative sample from emergency services in the Western Cape Province, South Africa, to participate in this cross sectional epidemiological study. Questionnaires covered critical incident exposure, general psychopathology, risky alcohol use, symptoms of post-traumatic stress disorder (PTSD), and psychological and physical aggression between co-workers. Open ended questions addressed additional stressors. RESULTS: Critical incident exposure and rates of general psychopathology were higher than in studies in the developed world. Exposure to critical incidents was associated with general psychopathology, symptoms of PTSD, and with aggression between co-workers, but not with alcohol use. Ambulance, fire, and sea rescue services had lower general psychopathology scores than traffic police. The sea rescue service also scored lower than traffic police on PTSD and psychological aggression. The defence force had higher rates of exposure to physical assault, and in ambulance services, younger staff were more vulnerable to assault. Women had higher rates of general psychopathology and of exposure to psychological aggression. Other stressors identified included death notification, working conditions, and organisational problems. CONCLUSIONS: Service organisations should be alert to the possibility that their personnel are experiencing work -related mental health and behavioural problems, and should provide appropriate support. Attention should also be given to organisational issues that may add to the stress of incidents. Workplace programmes should support vulnerable groups, and address death notification and appropriate expression of anger.

Routes of pyruvate synthesis in phosphorus-deficient lupin roots and nodules.

Here, nodulated lupins (Lupinus angustifolius (cv Wonga)) were hydroponically grown at low phosphate (LP) or adequate phosphate (HP). Routes of pyruvate synthesis were assessed in phosphorus (P)-starved roots and nodules, because P-starvation can enhance metabolism of phosphoenolpyruvate (PEP) via the nonadenylate-requiring PEP carboxylase (PEPc) route. Since nodules and roots may not experience the same degree of P stress, it was postulated that decreases in metabolic inorganic phosphorus (Pi) of either organ, should favour more pyruvate being synthesized from PEPc-derived malate. Compared with HP roots, the LP roots had a 50% decline in Pi concentrations and 55% higher ADP : ATP ratios. However, LP nodules maintained constant Pi levels and unchanged ADP : ATP ratios, relative to HP nodules. The LP roots had greater PEP metabolism via PEPc and synthesized more pyruvate from PEPc-derived malate. In nodules, P supply did not influence PEPc activities or levels of malate-derived pyruvate. These results indicate that nodules were more efficient than roots in maintaining optimal metabolic Pi and adenylate levels during LP supply. This caused an increase in PEPc-derived pyruvate synthesis in LP roots, but not in LP nodules.

Design and performance testing of quantitative real time PCR assays for influenza A and B viral load measurement.

BACKGROUND: The antiviral effect of anti-influenza drugs such as zanamivir may be demonstrated in patients as an increased rate of decline in viral load over a time course of treatment as compared with placebo. Historically this was measured using plaque assays, or Culture Enhanced Enzyme Linked Immunosorbent Assay (CE-ELISA). OBJECTIVES: to develop and characterise real time quantitative PCR (qPCR) assays to measure influenza A and B viral load in clinical samples, that offer improvements over existing methods, in particular virus infectivity assays. STUDY DESIGN: The dynamic range and robustness were established for the real time qPCR assays along with stability of the assay components. Cross validation of the real time PCR assays with CE-ELISA was performed by parallel testing of both serial dilutions of three different subtypes of cultured virus and a panel of influenza positive throat swab specimens. RESULTS: the assays were specific for influenza A and B and the dynamic ranges were at least seven logs. The assay variability was within acceptable limits but increased towards the lower limit of quantification, which was 3.33 log(10) viral cDNA copies/ml of virus transport medium (ten viral RNA copies/PCR). The components of the assay were robust enough to withstand extended storage and several freeze-thaw cycles. For the real time PCR assays the limit of quantification was equivalent to the virus infectivity cut off, which equates to a 93-fold increase in sensitivity. CONCLUSION: Well characterised real time PCR assays offer significant improvements over the existing methods for measuring the viral load of strains of influenza A and B in clinical specimens.

Exposure to violence and its relationship to psychopathology in adolescents.

OBJECTIVES: This study aimed to establish prevalence of adolescents' exposure to violence and related symptoms in the South African context and to explore relationships between exposure and symptoms. SETTING: Four high schools in Cape Town, South Africa. METHODS: Self report questionnaires were administered to 104 students. Types of violence explored included: witnessing or being a victim of violence perpetrated by someone known to the child or in the home and witnessing or being a victim of violence perpetrated by a stranger. The Harvard Trauma Scale, Beck Depression Inventory, and Zung Self-Rating Anxiety Scale were used to assess potentially related symptoms. RESULTS: The majority of children had been exposed to at least one type of violence, and exposure to the one type of violence was related to the other type. Symptoms of post-traumatic stress disorder and depression appear to be related to most types of exposure to violence, but anxiety symptoms only to exposure to violence perpetrated by someone known to the child or in the home. CONCLUSIONS: Rates of exposure to violence, and related symptoms, were unacceptably high. Symptoms were associated with exposure to violence.

Recombinant hyaluronate associated protein as a protective immunogen against Streptococcus equi and Streptococcus zooepidemicus challenge in mice.

The capsule of Streptococcus equi, the cause of strangles, and Streptococcus zooepidemicus, associated with equine lower airway disease, plays an important role in evasion of phagocytosis by polymorphonuclear leucocytes. It is composed of hyaluronate, making it non-immunogenic. A hyaluronate associated protein (HAP) from S. equisimilis, whose gene has been sequenced [1], was investigated (a) for its presence in S. equi and S. zooepidemicus and (b) as an immunogen able to interfere with capsule structure and protect against experimental challenge of mice. The purified capsule of S. equi contained a protein of similar molecular mass to the S. equisimilis protein (approximately 53 kDa). Polymerase chain reaction (PCR) using primers derived from the published sequence of S. equisimilis HAP yielded a product from S. equi and S. zooepidemicus of the expected size and susceptibility to restriction endonucleases. Subcloning of two large in frame StuI/SspI fragments of the HAP gene from S. equi, approximately equivalent to the two halves of the molecule, into the expression vector pGEX-3X yielded only the carboxy half in the correct orientation. This latter recombinant produced a GST fusion protein (HAP-GST) of the expected size that was affinity purified. Antibodies in rabbit antiserum to the native protein in purified hyaluronate reacted strongly in immunoblots with HAP-GST. Antiserum to HAP-GST, when soaked into filter paper strips, caused a diminution of capsule production by S. equi cultured on blood agar. Antiserum added into fresh rabbit blood was not opsonic for S. equi. Immunization with HAP-GST significantly reduced rhinitis in Balb/C mice challenged nasally with S. equi and significantly increased survival time and clearance of bacteria in CBA/CA mice challenged intraperitoneally with S. zooepidemicus.

Aggresomes: a cellular response to misfolded proteins.

Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.

Actinobacillus and Pasteurella species isolated from horses with lower airway disease.

Seventy-three bacterial isolates from 65 horses with and without evidence of lower airway disease were identified to assess whether the association with disease was accounted for by a small or large number of species. Just over half (50.5 per cent were Actinobacillus equuli, 17.8 per cent were A suis-like, 11 per cent were Pasteurella pneumotropica, 8.2 per cent were A lignieresii, 6.8 per cent were P haemolytica and 5.5 per cent were P mairii. These results suggest that a range of Actinobacillus and Pasteurella species can be isolated from the lower airways of horses, with many of the isolates being A equuli. Among the horses examined, lower airway inflammation was significantly associated with A suis-like bacteria and A lignieresii. However, these two species constituted too small a proportion of the undifferentiated Actinobacillus/Pasteurella species to explain the association of this group of bacteria with lower airway disease. Since A equuli constituted just over 50 per cent of the group of bacteria it is possible that it too is playing a significant role in lower airway disease.