Uveitis and arthritis induced by adjuvant: clinical, immunologic and histologic characteristics

The intradermal administration of complete Freund's adjuvant (CFA) containing Mycobacterium butyricum to Sprague-Dawley (SD) and Lewis strain rats results in polyarthritis and uveitis. Over 90% of the eyes examined from the SD rats given CFA had histologic evidence of anterior uveitis, clinically evident in only 20 to 28%. Many rats developed arthritis without clinical uveitis, but uveitis was rare in the absence of arthritis. Histologically, the ocular inflammation was characterized by a polymorphonuclear, and later, a lymphocytic infiltration of the iris and ciliary body with cells and fibrinous exudate in the anterior chamber and cells in the vitreous. Antibodies and cellular immunity to ocular (S antigen, alpha crystallin), articular (type II collagen, proteoglycan) and bacterial components (MDP), were demonstrated in some rats, but positive tests did not correlate with either articular or ocular disease. Ten percent of rats given type II collagen in incomplete Freund's adjuvant developed uveitis. Thus, the pathogenesis of the arthritis and uveitis in the adjuvant model may be mediated by lymphocytes which exhibit crossreactivity with antigens in these structures, although the specificity of such antigens has not been identified in our studies.     

RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary

Mucinous carcinomas represent a distinct morphological subtype which can arise from several organ sites, including the ovary, and their genetic characteristics are largely under‐described. Exome sequencing of 12 primary mucinous ovarian tumours identified RNF43 as the most frequently somatically mutated novel gene, secondary to KRAS and mutated at a frequency equal to that of TP53 and BRAF. Further screening of RNF43 in a larger cohort of ovarian tumours identified additional mutations, with a total frequency of 2/22 (9%) in mucinous ovarian borderline tumours and 6/29 (21%) in mucinous ovarian carcinomas. Seven mutations were predicted to truncate the protein and one missense mutation was predicted to be deleterious by in silico analysis. Six tumours had allelic imbalance at the RNF43 locus, with loss of the wild‐type allele. The mutation spectrum strongly suggests that RNF43 is an important tumour suppressor gene in mucinous ovarian tumours, similar to its reported role in mucinous pancreatic precancerous cysts. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Acute appendicitis in the developing world is a morbid disease

IntroductionAcute appendicitis in the developing world has a markedly different disease profile to that in the developed world.MethodsA retrospective study was undertaken over a four-year period at a university hospital in South Africa to review the disease spectrum and the clinical outcome of acute appendicitis.ResultsA total of 1,004 patients (54% male, median age: 18 years) with intraoperatively confirmed appendicitis were reviewed. Over half (56%) were from the urban district within the city of Pietermaritzburg and the remaining 44% were from the rural health district. The median duration of illness from onset to definitive care was 4 days. Sixty per cent of appendices were perforated and associated with intra-abdominal contamination. Forty per cent of patients required reoperation to control intra-abdominal sepsis. Ten per cent required admission to the intensive care unit. The median overall length of hospital stay was 5 days. The mortality rate was 1%.Rural patients had a longer median duration of illness (3 vs 5 days, p<0.001) as well as a more advanced disease profile associated with perforation and severe intra-abdominal sepsis (19% vs 71%, p<0.001). Female patients had a longer median duration of illness (3 vs 4 days, p<0.001), were more likely to present with severe intra-abdominal sepsis (31% vs 54%, p<0.001) and were more likely to require a laparotomy (50% vs 73%, p<0.001). The total cost of managing the entire cohort of 1,004 patients over the 4-year period was £2,060,972.ConclusionsAcute appendicitis in South Africa is a serious disease associated with significant morbidity. Late presentation is common. Female and rural patients have the worst clinical outcomes, with significant cost to the health system.     

Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder

Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N=40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P<0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.     

Activated natural killer cells and interleukin-2 promote granulocytic and megakaryocytic reconstitution after syngeneic bone marrow transplantation in mice

Purified populations of natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID). SCID spleen cells were cultured and activated with recombinant human interleukin-2 (rhIL- 2) in vitro. The activated NK cells were then transferred with syngeneic BALB/c bone marrow cells (BMC) and rhIL-2 into lethally irradiated syngeneic recipients to determine their effect on long-term hematopoietic reconstitution. On analysis, the transfer of rhIL-2- activated NK cells along with BMC resulted in significant increases in splenic and BM hematopoietic progenitor cells when compared with those for mice not receiving NK cells. Histologic and flow cytometric analysis showed a marked increase in granulocytic and megakaryocytic lineage cells present in the spleens of the mice receiving activated NK cells. Analysis of the peripheral blood indicated that the transfer of activated NK cells with BMC also significantly improved platelet and total white blood cell counts, with increases in segmented neutrophils. Erythroid recovery was not affected. Finally, lethally irradiated mice receiving activated NK cells and rhIL-2 along with limiting numbers of syngeneic BMC showed a marked increase in survival rate. These results show that the use of populations enriched for activated NK cells after syngeneic BM transplantation (BMT) has a profound enhancing effect on engraftment primarily affecting megakaryocytic and granulocytic cell reconstitution. Therefore, the transfer of activated NK cells and rhIL- 2 may be of clinical use to promote hematopoietic reconstitution after BMT.     

The use of non-prescribed medication in the first 3 months of life in rural South Africa

OBJECTIVE: This paper describes the use of non-prescribed medications given to a cohort of infants in the first 3 months of life in a rural South African district, and discusses some of the implications for primary health care. METHODS: As part of an ongoing study on breastfeeding, a cohort of 110 infants were visited at home at 6 and 12 weeks of age. Any medications given to the infant since the last visit, the reasons for their administration, and any visits made to traditional healers were recorded via a semi-structured questionnaire. Determinants of administration of non-prescribed medication were analysed, including maternal age, education, infant gender and socio-economic factors. RESULTS: A total of 107 (97%) infants received non-prescribed medications in the first 3 months of life: 98 (89%) rectally and 64 (58%) orally. The most common enema contained traditional Zulu medicine made from herbs, given more than once weekly, usually for perceived constipation; the most common oral medication was gripe water, given once daily, mainly for 'colic' or 'wind'. Twenty-nine (26%) mothers had consulted a traditional healer, most commonly because of concerns about a capillary naevus, thought to cause pain. Mothers with a 'clean' water supply were more likely to give non-prescribed oral medications than those without (OR=2.7 and P=0.0223), whilst those who had no education were less likely to administer them than those who had completed school (OR=0.19 and P=0.0326). CONCLUSIONS: Non-prescribed medications are given almost universally to young infants in our area, irrespective of socio-economic class. Health professionals need to be aware of the extent of, and reasons for, administration of non-prescribed medications to young infants, so that effective health messages can be targeted at mothers and caregivers.     

The IL‐23/Th17 axis is involved in the adaptive immune response to Bacillus anthracis in humans

The neutralization of toxins is considered essential for protection against lethal infection with Bacillus anthracis (BA), a select agent and bioterrorism threat. However, toxin‐neutralizing activity alone would not be expected to provide sterile immunity. Therefore, we hypothesized that the development of an adaptive immune response against BA is required for bacterial clearance. We found that human monocyte‐derived dendritic cells (hDCs) kill germinated BA bacilli, but not nongerminated BA spores. hDCs produce IL‐1β, IL‐6, IL‐12, and IL‐23, and these cytokines are differentially regulated by germination‐proficient versus germination‐deficient BA spores. Moreover, the IL‐23 response to BA spores is regulated by IL‐1R‐mediated signaling. hDCs infected with germinating BA spores stimulated autologous CD4⁺ T cells to secrete IL‐17A and IFN‐γ in a contact‐dependent and antigen‐specific manner. The T‐cell response to BA spores was not recapitulated by hDCs infected with germination‐deficient BA spores, implying that the germination of spores into replicating bacilli triggers the proinflammatory cytokine response in hDCs. Our results provide primary evidence that hDCs can generate a BA‐specific Th17 response, and help elucidate the mechanisms involved. These novel findings suggest that the IL‐23/Th17 axis is involved in the immune response to anthrax in humans.     

A composite bacteriophage alters colonization by an intestinal commensal bacterium

The mammalian intestine is home to a dense community of bacteria and its associated bacteriophage (phage). Virtually nothing is known about how phages impact the establishment and maintenance of resident bacterial communities in the intestine. Here, we examine the phages harbored by Enterococcus faecalis, a commensal of the human intestine. We show that E. faecalis strain V583 produces a composite phage (ϕV1/7) derived from two distinct chromosomally encoded prophage elements. One prophage, prophage 1 (ϕV1), encodes the structural genes necessary for phage particle production. Another prophage, prophage 7 (ϕV7), is required for phage infection of susceptible host bacteria. Production of ϕV1/7 is controlled, in part, by nutrient availability, because ϕV1/7 particle numbers are elevated by free amino acids in culture and during growth in the mouse intestine. ϕV1/7 confers an advantage to E. faecalis V583 during competition with other E. faecalis strains in vitro and in vivo. Thus, we propose that E. faecalis V583 uses phage particles to establish and maintain dominance of its intestinal niche in the presence of closely related competing strains. Our findings indicate that bacteriophages can impact the dynamics of bacterial colonization in the mammalian intestinal ecosystem.