Fusariosis in haematological malignancy – the skin is the clue… Experiences from the National Cancer Institute of Sri Lanka: a case report

We present two patients with haematological malignancies who developed skin lesions while neutropaenic and were subsequently diagnosed as having fusariosis. Although fusariosis is not as common as other fungal infections such as aspergillosis and candidiasis, it has to be considered in the diagnosis of immunocompromised patients who present with skin manifestations. Awareness of fusariosis, and early diagnosis and appropriate treatment is essential to reduce mortality. </p

A Protective Role for Complement C3 Protein during Pandemic 2009 H1N1 and H5N1 Influenza A Virus Infection

Highly pathogenic H5N1 influenza infections are associated with enhanced inflammatory and cytokine responses, severe lung damage, and an overall dysregulation of innate immunity. C3, a member of the complement system of serum proteins, is a major component of the innate immune and inflammatory responses. However, the role of this protein in the pathogenesis of H5N1 infection is unknown. Here we demonstrate that H5N1 influenza virus infected mice had increased levels of C5a and C3 activation byproducts as compared to mice infected with either seasonal or pandemic 2009 H1N1 influenza viruses. We hypothesized that the increased complement was associated with the enhanced disease associated with the H5N1 infection. However, studies in knockout mice demonstrated that C3 was required for protection from influenza infection, proper viral clearance, and associated with changes in cellular infiltration. These studies suggest that although the levels of complement activation may differ depending on the influenza virus subtype, complement is an important host defense mechanism

Surviving Mousepox Infection Requires the Complement System

Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3−/− mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3−/− mice. In vitro, the complement system in naïve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4−/− or Factor B−/− mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection

A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli.

Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and elicits a strong immune response from humans and other animals. We developed a quantitative model of the nine enzyme-catalyzed steps of Escherichia coli lipid A biosynthesis, drawing parameters from the experimental literature. This model accounts for biosynthesis regulation, which occurs through regulated degradation of the LpxC and WaaA (also called KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide concentration, which we deduced from prior results, model results, and new LpxK overexpression results. The model agrees reasonably well with many experimental findings, including the lipid A production rate, the behaviors of mutants with defective LpxA enzymes, correlations between LpxC half-lives and cell generation times, and the effects of LpxK overexpression on LpxC concentrations. Its predictions also differ from some experimental results, which suggest modifications to the current understanding of the lipid A pathway, such as the possibility that LpxD can replace LpxA and that there may be metabolic channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) concentration is low and/or to control the number of KDO residues that get attached to lipid A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate concentrations are not in excess. Based on these results, we suggest that LpxK may be a much better drug target than LpxC, which has been pursued most often

Healing of ExcisionAl wounds on Lower legs by Secondary intention (HEALS) Cohort Study: A multi-centre prospective observational cohort study in patients without planned compression.

Background There is no agreed treatment pathway following excision of keratinocyte cancers. Compression therapy is considered beneficial for secondary intention healing on the lower limb, however there is a lack of supportive evidence. To plan a randomised controlled trial suitable data is needed. This paper reports a multi-centre prospective observational cohort study in this patient population, to inform a future trial design. Objectives 1. To estimate the time to healing in wounds healing by secondary intention without planned post-operative compression, following excision of keratinocyte cancers on the lower leg 2. To characterise the patient population including factors affecting healing 3. To assess the incidence of complications Methods INCLUSION CRITERIA: People over 18 years; planned excision of keratinocyte cancer on lower leg with healing by secondary intention; ankle-brachial pressure index (ABPI) greater than or equal to 0.8; written informed consent EXCLUSION CRITERIA: Planned: primary closure, skin graft or flap; compression therapy for another indication; unable to receive, comply or tolerate high compression; planned compression; suspected diagnosis other than keratinocyte cancer. Results This study recruited 58 patients from 9 secondary care dermatology clinics. In the analysis population (n=53): mean age was 81 (range 25-97) years; median time to healing was 81(95% Confidence Interval:73-92) days and at 6-month 45 patients (84.9%) had healed. Healing prognostic factors were wound parameters, and ABPI. Wound infections occurred in 16 participants(30.2%) and 4(7.5%) were admitted to hospital. Conclusions Data collected has informed the RCT preparation. A relatively high (7.5-15%) proportion of wounds not healed, incidence of infection and hospital admissions demonstrated the need for clearly establishing potentially effective treatments and improve outcomes for this population

Healing of ExcisionAl wounds on Lower legs by Secondary intention (HEALS) Cohort: Feasibility data from a multi-centre prospective observational cohort study to inform a future Randomised Controlled Trial (RCT)

Summary Background Compression therapy is considered beneficial for lower limb post-surgical wounds healing by secondary intention, however there is a lack of supportive evidence. To plan a randomised controlled trial suitable data is needed. Objectives: Determine feasibility of recruitment and estimate recruitment rate Understand the standard post-operative wound management pathway Determine uptake of optional additional clinic visit for healing confirmation Explore patient acceptability of compression bandaging and a future RCT Methods: Participant recruitment over 22 months from secondary care Dermatology clinics. Eligibility criteria: INCLUSION: over 18 years; planned excision of keratinocyte cancer on lower leg with healing by secondary intention; ankle-brachial pressure index ≥ 0.8 EXCLUSION: planned primary closure/graft or flap; unable to receive/comply/tolerate high compression; planned compression; suspected melanoma Followed up weekly (maximum 6 months) in secondary care clinics and/or by telephone. Information collected on healthcare resource use, unplanned compression, wound healing, optional clinic visit to confirm healing. Results: 58 patients recruited from 9 secondary care dermatology clinics in 22 months. Mean recruitment/centre/month was 0.8 (range 0.1-2.3). Four centres had dedicated Research Nurse support. The analysis population (n=53) attended weekly follow-up assessments. Standard care clinical contacts were: GP visits 7(1.2%), Community Nurse visits 169(28.5%), Practice nurse visits 189(31.8%), and Dermatology clinic visits 138(23.2%). Participants whose wounds healed, 34/45(75.6%) attended an optional clinic visit. Conclusions: Data were obtained to inform a future RCT. Recruitment rates are higher in centres with dedicated research support. People would be willing to take part in a trial and attend a confirmation of healing visit