Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies.

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions.

BACKGROUND: Corticosteroids and non-steroidal anti-inflammatory drugs are widely used for the treatment of rheumatic conditions, but their gastrointestinal damage significantly limits their use. Sigmoid diverticular abscess perforation (SDAP) is a very serious complication of diverticular disease. OBJECTIVE: To determine the aetiology of large bowel SDAP in rheumatic conditions. METHODS: 64 patients with SPAD and 320 controls from a similar geographical area and of similar socioeconomic status were studied. RESULTS: The results showed that independently of rheumatic diagnosis corticosteroid treatment is strongly associated with SDAP (OR 31.9 (95% CI 6.4 to 159.2; p<0.001), and non-steroidal anti-inflammatory drugs only weakly associated (OR 1.8 (95% CI 0.96 to 3.4); p = 0.069). A rheumatic diagnosis is also strongly associated with the development of SDAP (OR 3.5 (95% CI 1.9 to 6.7); p<0.001). CONCLUSIONS: SDAP has serious implications for patients and consumes many healthcare resources. Patients and physicians should be warned of this potential complication.

An unusual cause of acute renal failure in systemic sclerosis.

BACKGROUND: Scleroderma renal crisis is one of the most life threatening complications of scleroderma. Enteric hyperoxaluria complicates extensive disease or resection of the small intestine in the presence of an intact colon, and is associated with calcium oxalate nephrolithiasis. This cause of renal failure may be underestimated and should be considered in all patients with malabsorption and renal failure. CASE REPORT: A 78 year old woman with systemic sclerosis affecting the bowel developed acute renal failure caused by oxalate nephropathy. RESULTS: The patient's renal failure improved on an oxalate free diet.

Cytostatic therapy for AA amyloidosis complicating psoriatic spondyloarthropathy.

Psoriatic spondyloarthropathy (PSA) can occasionally be complicated by AA amyloid, and renal amyloidosis should be suspected in patients with PSA who have unexplained proteinuria. The diagnosis of amyloidosis can be made either histologically or by radiolabelled serum amyloid P component (SAP) scintigraphy. Prognosis is determined by the extent of organ involvement and associated impairment of function, and by the degree of response of the underlying disease to anti-inflammatory therapy. A review of the literature identified less than a dozen cases of AA amyloidosis complicating PSA, and the outcome in most cases was poor. We report here the favourable clinical course of a middle-aged Caucasian male patient with severe PSA who developed renal AA amyloidosis, in whom treatment with oral chlorambucil led to stabilization of the amyloid deposits and resolution of the associated nephrotic syndrome. We review the diagnosis and treatment of AA amyloidosis, including the management of patients with underlying inflammatory spondyloarthropathies, and propose the possible role of a therapeutic trial of anti-tumour necrosis factor alpha in patients with amyloid complicating inflammatory rheumatic diseases.

Bilateral distal fibular and tibial stress fractures associated with heavy smoking.

An unusual case of simultaneous bilateral stress fractures of the distal tibia and fibula in a 45 year old white woman is described. The onset of symptoms was not associated with a specific episode of trauma, sporting activity, or identifiable inflammatory predisposing cause. Her bone density scan, bone profile, and biochemistry were all normal. Although stress fractures are well recognised, bilateral distal tibial and fibular fractures are particularly rare. A high degree of awareness is required for early diagnosis.

Child sexual abuse in Matabeleland, Zimbabwe.

The extent, nature, causes and consequences of child sexual abuse in Matabeleland. Zimbabwe, are explored by an intersectoral working group consisting of health, legal and AIDS prevention workers who were struck in the course of their work by the regularity with which they saw sexually abused children infected with HIV and STDs. Methods used in this study are record review, focus group discussions, structured and in-depth interviews. Child sexual abuse cases form between 40-60% of the rape cases brought to the attention of hospitals, police and court and many more are believed to remain unreported. Half of the sexual abuse in children is detected through STDs and some have HIV. The majority of offenders are mature men known to the child. Factors influencing child sexual abuse are male dominance in society, men's professed inability to control sexual desire, and magic beliefs. Victims are traumatized by the abuse itself as well as by subsequent problems in family, health and in court. Since child sexual abuse may endanger the life and well-being of the child, it is a serious problem that requires urgent action.

Laboratory colonization of Anopheles quadriannulatus from sympatry with other sibling species of the Anopheles gambiae complex in Zimbabwe.

A laboratory colony of the mosquito Anopheles quadriannulatus was established from a wild population occurring sympatrically with An.arabiensis in Zimbabwe. These sibling species are members of the An.gambiae Giles complex and were distinguished primarily by means of their specific polytene chromosome banding patterns. By using an ox-baited trap, we sampled selectively for the more zoophilic An.quadriannulatus. It was confirmed that An.quadriannulatus has the diagnostic slow allozyme of aspartate aminotransferase (AAT95/95). In a mixed population under laboratory conditions, An.arabiensis displaced An.quadriannulatus within eight generations, without introgression. Colonization of An.quadriannulatus was facilitated by pooling the progeny from wild-caught mothers of confirmed identity and by using a specially adapted cage to promote mating.

Potential use of bendiocarb (Ficam VC) for malaria control in an area of Zimbabwe.

Ficam (bendiocarb) was tested for its residual efficacy and irritation in malaria vector control by using a laboratory bred colony of Anopheles arabiensis. In the study area, the insecticide remained active for up to 8 wk (96% mortality) on thatch. In similar, especially constructed huts, 74% mortality was achieved up to 20 wk on mud compared with up to 100% on thatch. In the special huts, release/capture studies indicated that the lethal effect of Ficam on the insects was more pronounced than its irritant effect. This was shown by the low recapture numbers in exit traps as compared with the hut-floor mortalities. The implications of these findings in relation to studies elsewhere and the potential of Ficam use in malaria control are discussed.

An evaluation of the residual lifespan of DDT in malaria control.

The insecticide lifespan of DDT was assessed in huts sprayed for malaria control. The age of the spray deposits ranged from 3 up to 22 months. Blood-fed female Anopheles arabiensis were either released into the huts or exposed on sprayed surfaces by a bioassay technique. Mosquitoes released were recovered in exit traps fitted on windows or dead on the floor. Only 50% or less of mosquitoes released in sprayed huts were recovered. Mortality figures for recovered mosquitoes ranged from 94% at 3 months, declining to 19% for huts sprayed 18 months previously. Of the recovered mosquitoes, 60% or more attempted to escape from sprayed huts within two hours postrelease up to 15 months postspray. Bioassays gave average mortalities of 95 and 76% on thatch and mud walls, respectively. Analysis of mud samples from test huts showed that target dose of 2 g AI/m2 of DDT was not being achieved. The results support the need for an annual spraying cycle.

Comparison of DNA probe and cytogenetic methods for identifying field collected Anopheles gambiae complex mosquitoes.

A recently developed DNA probe method was compared with the standard cytogenetic method for identifying the species of individual mosquitoes in the Anopheles gambiae complex. The complex consists of 6 morphologically indistinguishable sibling species that include the major African malaria vectors. Half-gravid, field collected mosquitoes were split into 2 portions: the abdomen was preserved for ovarian nurse cell cytotaxonomy and the head/thorax portion was desiccated for DNA extraction. Cytogenetic examination of the Kenya specimens showed 88 An. gambiae and 108 An. arabiensis. The Zimbabwe specimens consisted of 6 An. gambiae and 55 An. Quadriannulatus. All samples of the 3 species were polymorphic for the major chromosomal inversions previously recorded in field specimens from eastern and southern Africa, indicating that the collections reflected natural levels of intraspecific variation in the field populations sampled. Approximately 97% of the cytologically identified mosquitoes were also identified to species by the DNA probe method, and in every case the DNA probe and cytogenetic methods of species identification produced concordant results.

Seasonal vector density and disease incidence patterns of malaria in an area of Zimbabwe.

Anopheline mosquitoes were studied in an area of Zimbabwe to correlate their population densities with seasonality in malaria incidence. Four trapping methods were employed for adult mosquitoes: pit traps, outdoor and indoor man-baited nets and a sheep-baited net. Anopheles funestus exhibited two population peaks during the year, one in March and the other in September/October. The following over-all proportions of the An. gambiae complex were recorded: An. gambiae Giles (2.5%), An. arabiensis Patton (14.3%) and An. guadriannulatus Theobald (83.2%). Peak populations were observed in March, with most An. gambiae and An. arabiensis preferring outdoor man-baited nets. Approximately equal preference for outdoor nets and pit traps was observed for An. guadriannulatus, which was the only species present throughout the year. The implications of these findings for malaria transmission, which showed a peak in April, and the suitability of the sampling methods employed are discussed.