CD56+ T cells are increased in kidney transplant patients following cytomegalovirus infection.

BACKGROUND: CD56+ T cells previously have been identified as potentially cytotoxic lymphocytes, and relative numbers are increased in some infectious diseases. PATIENTS AND METHODS: Relative proportions of CD56+ T cells were measured by flow cytometry in groups of renal transplant patients differing in cytomegalovirus (CMV) status of donor (D) and recipient (R). These measurements were related to episodes of CMV viremia. RESULTS: Patient groups in which recipients (R+) or donors (D+/R-) were CMV+ had significantly higher proportions of CD56+ T cells (5.11 ± 0.69% and 5.42 ± 1.01%, respectively) than the D-/R- group (1.9 ± 0.35%; P = 0.0018 and 0.017, respectively). In the high-risk D+/R- group, it was found that patients who had post-transplant CMV viremia had higher levels than those who remained CMV negative (9.09 ± 2.34% vs. 3.16 ± 1.22%; P = 0.01). CD56+ T cells from R+ and D+/R- groups had higher proportions of both CD4+ and CD8+ cells than the D-/R- group. When activation markers were examined, some CD56+ T cells from both CMV+ groups had a TEM phenotype, with significantly more expressing CD45RO and NKG2C, and less expressing CD28, CD62L, CD127, and CD161 compared to the D-/R- group. Some CD56+ T cells showed specificity for CMV antigens and similar proportions of CD8+ cells were positive for class I HLA-CMV tetramers containing immunodominant CMV peptides compared to the majority CD56- T cells. CONCLUSION: The results show significant increases in proportions of CD56+ T cells in relation to CMV infection in renal transplant patients and suggest that these cells have a cytotoxic function against CMV-infected cells.

Detection of herpes viruses in the cerebrospinal fluid of adults with suspected viral meningitis in Malawi.

PURPOSE: We looked for herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively), varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) DNA in Malawian adults with clinically suspected meningitis. METHODS: We collected cerebrospinal fluid (CSF) from consecutive adults admitted with clinically suspected meningitis to Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi, for a period of 3 months. Those with proven bacterial or fungal meningitis were excluded. Real-time polymerase chain reaction (PCR) was performed on the CSF for HSV-1 and HSV-2, VZV, EBV and CMV DNA. RESULTS: A total of 183 patients presented with clinically suspected meningitis. Of these, 59 (32 %) had proven meningitis (bacterial, tuberculous or cryptococcal), 39 (21 %) had normal CSF and 14 (8 %) had aseptic meningitis. For the latter group, a herpes virus was detected in 9 (64 %): 7 (50 %) had EBV and 2 (14 %) had CMV, all were human immunodeficiency virus (HIV)-positive. HSV-2 and VZV were not detected. Amongst those with a normal CSF, 8 (21 %) had a detectable herpes virus, of which 7 (88 %) were HIV-positive. CONCLUSIONS: The spectrum of causes of herpes viral meningitis in this African population is different to that in Western industrialised settings, with EBV being frequently detected in the CSF. The significance of this needs further investigation.

Plasma obestatin and autonomic function are altered in orexin-deficient narcolepsy, but ghrelin is unchanged.

Narcolepsy-cataplexy is characterised by orexin deficiency, sleep disturbance, obesity and dysautonomia. Ghrelin and obestatin affect both energy intake and sleep. Our aim was to investigate ghrelin, obestatin and metabolic/autonomic function in narcolepsy-cataplexy. Eight narcolepsy-cataplexy patients (seven CSF orexin-deficient) and eight matched controls were studied. The subjects had a fixed energy meal with serial blood samples and measurement of heart rate variability (HRV). Fasting plasma obestatin was more than threefold higher in narcolepsy subjects (narcolepsy 89.6 ± 16 pg/ml vs. control 24.9 ± 3 pg/ml, p < 0.001). There was no change in HRV total power, but post-prandial low-frequency (LF) power and high-frequency (HF) power were lower in the narcolepsy group [area under the curve (AUC): HF power narcolepsy 1.4 × 10(5) ± 0.2 × 10(5) vs. control 3.3 × 10(5) ± 0.6 × 10(5 )ms(2)/h, p < 0.001]. On multiple regression analyses, the only significant predictor of plasma obestatin was HF power, which was inversely correlated with obestatin (ß = -0.65 R (2) = 38 %, p = 0.009). Fasting and post-prandial plasma ghrelin were similar in both groups (narcolepsy 589.5 ± 88 pg/ml vs. control 686.9 ± 81 pg/ml, p = 0.5; post-prandial AUC-narcolepsy 161.3 ± 22 ng/ml/min vs. control 188.6 ± 62 ng/ml/min, p = 0.4). Only the narcolepsy group had significant suppression of plasma ghrelin after the meal (ANOVA, p = 0.004). In orexin-deficient narcolepsy, fasting plasma ghrelin is unaltered, and post-prandial suppression is preserved. Fasting plasma obestatin is increased and correlates with autonomic dysfunction. As obestatin affects NREM sleep, we suggest that increased plasma levels contribute to the disrupted sleep-state control in narcolepsy.

Management of suspected viral encephalitis in adults--Association of British Neurologists and British Infection Association National Guidelines.

In the 1980s the outcome of patients with herpes simplex encephalitis was shown to be dramatically improved with aciclovir treatment. Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis. Several comprehensive reviews of the investigation and management of encephalitis have been published. However, their impact on day-to day clinical practice appears to be limited. The emergency management of meningitis in children and adults was revolutionised by the introduction of a simple algorithm as part of management guidelines. In February 2008 a group of clinicians met in Liverpool to begin the development process for clinical care guidelines based around a similar simple algorithm, supported by an evidence base, whose implementation is hoped would improve the management of patients with suspected encephalitis.

Psoriasin (S100A7) associates with integrin ß6 subunit and is required for αvß6-dependent carcinoma cell invasion.

Expression of the integrin αvß6 is upregulated in a variety of carcinomas where it appears to be involved in malignant progression, although the biology of this integrin is not fully explored. We have generated oral carcinoma cells that express αvß6 composed of wild-type αv and a mutant ß6 that lacks the unique C-terminal 11 amino acids (aa). We found that these residues, although not required for αvß6-dependent adhesion or migration, are essential for αvß6-dependent invasive activity. We have used a proteomic approach to identify novel binding partners for the ß6 subunit cytoplasmic tail and report that psoriasin (Psor) (S100A7) bound preferentially to the recombinant ß6 cytoplasmic domain, though not in the absence of the unique C-terminal 11aa. Endogenous cellular Psor co-precipitated with endogenous ß6 and colocalised with αvß6 at the cell membrane and intracellular vesicles. Knockdown of Psor, with small interfering RNA, had no effect on αvß6-dependent adhesion or migration but abrogated αvß6-mediated oral carcinoma cell invasion both in Transwell and, the more physiologically relevant, organotypic invasion assays, recapitulating the behaviour of the ß6-mutant cell line. Membrane-permeant Tat-peptides encoding the unique C-terminal residues of ß6, bound directly to recombinant Psor and inhibited cellular Psor binding to ß6; this blocked αvß6-dependent, but not αvß6-independent, invasion. These data identify a novel interaction between Psor and ß6 and demonstrate that it is required for αvß6-dependent invasion by carcinoma cells. Inhibition of this interaction may represent a novel therapeutic strategy to target carcinoma invasion.

An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis.

BACKGROUND: Voltage-gated potassium channel antibody-positive limbic encephalitis (VGKC+LE) frequently improves with immunotherapy, although the optimum regimen is unknown. The effectiveness of a combination immunomodulatory regimen was tested in consecutive VGKC+LE patients. METHODS: This was an open-label prospective study of nine VGKC+LE patients. All patients had plasma exchange (50 ml/kg), intravenous immunoglobulin (2 g/kg) and intravenous methylprednisolone (1 g×3), followed by maintenance oral prednisolone (1 mg/kg/day). Mycophenolate (2 g/day) was used in the first three patients. Assessments included serial clinical, cognitive, brain MRI and VGKC antibody testing. RESULTS: Within 1 week, seizures and hyponatraemia remitted in all affected patients. Cognitive function improved in all patients within 3 months. MRI appearances improved substantially within 9 months, with remission of inflammation in the majority of patients. All achieved immunological remission with normal VGKC antibody titres within 1-4 months. Major adverse events of therapy included one septicaemia and one thrombosis on plasma exchange and one death from sepsis after incidental bowel surgery. One patient remains in remission after 40 months of follow up, 26 months after being off all treatment. CONCLUSIONS: Our immunotherapy regimen was effective for the treatment of the clinical, cognitive and immunological features of VGKC+LE. Radiological improvement was seen in the majority. Pending randomised controlled trials, this regimen is proposed for the treatment of VGKC+LE.

Acute central nervous system infections in adults--a retrospective cohort study in the NHS North West region.

BACKGROUND: Over the last 15 years, bacterial meningitis has received considerable attention, including national guidelines, whilst viral central nervous system (CNS) infections have been relatively neglected. A recent pilot study suggested that management of patients with suspected viral encephalitis was often suboptimal. AIM: To examine the relative incidence, clinical features and management of suspected acute CNS infections in adults across the NHS North West Region. DESIGN: A multicentre cross-sectional retrospective cohort study at 10 hospitals across the region over 3 months (from September to December 2007). Following a screen of all patients who had cerebrospinal fluid (CSF) analysis or received intravenous aciclovir and/or third-generation cephalosporin, those with clinical features suspicious of a CNS infection were included. Management was compared with the national meningitis and regional encephalitis guidelines. RESULTS: Three hundred and eighty-five patients were screened; 217 patients had a suspected CNS infection and 44 (20%) had a CNS infection: 18 aseptic meningitis (one herpes simplex virus [HSV]-2), 13 purulent meningitis (four Streptococcus pneumoniae) and 13 encephalitis (three HSV-1). The median (range) time from admission to suspicion of CNS infection and to LP was longer for patients with encephalitis than meningitis [4 (0.3-312) vs. 0.3 (0.1-12) h, P<0.001, and 23 (4-360) vs. 12 (2-48) h, P=0.042, respectively]; and the median time to treatment was longer for aciclovir than cephalosporin [7 (0.5-312) vs. 3 (0.3-312) h, P=0.002]. DISCUSSION: Encephalitis was as common as purulent meningitis, and HSV as common as Streptococcus pneumoniae. However, the management of patients with encephalitis was worse than meningitis. National encephalitis guidelines are needed.

Validation of a laboratory-developed real-time PCR protocol for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in urine.

OBJECTIVE: To evaluate a sensitive and specific, real-time PCR assay with internal control for Chlamydia trachomatis and Neisseria gonorrhoeae DNA detection in urine specimens. METHODS: The diagnostic performance of a laboratory-developed quadruplex assay (LDQA) targeting the cryptic plasmid and MOMP genes of C trachomatis, the porA pseudogene of N gonorrhoeae and a synthetic internal control was assessed using 1028 urine specimens. The LDQA was compared with the Roche COBAS Taqman CT test and the COBAS Amplicor NG assay with supplemental confirmation tests. The subsequent performance of the LDQA in detecting N gonorrhoeae was monitored in comparison with bacterial culture from swabs. RESULTS: 88 (8.6%) urines were determined as C trachomatis positive in the diagnostic evaluation. LDQA sensitivity and specificity were calculated to be 100% and 99.9%, respectively, for C trachomatis. The LDQA showed high specificity with isolates of other Neisseria species and gave complete concordance with resolved data for N gonorrhoeae detection. However, the incidence of N gonorrhoeae infection was low, with 17 (1.7%) positive patients. A post-implementation audit of 14 316 patients gave the LDQA N gonorrhoeae urine PCR protocol (porA, OPA, 16s rDNA) a sensitivity of 96.9% and specificity of 99.8% in comparison with bacterial culture from swabs. CONCLUSIONS: The LDQA was found to be an effective method for the detection of C trachomatis and N gonorrhoeae DNA in urine samples, and the PCR protocol has replaced bacterial culture for the screening of N gonorrhoeae in asymptomatic men and women in the laboratory.

Favourable one-year ART outcomes in adult Malawians with hepatitis B and C co-infection.

BACKGROUND: Few studies have investigated the impact of chronic hepatitis B and C infection on antiretroviral therapy (ART) outcomes in sub-Saharan Africa. Hepatotoxicity may be a particular concern in co-infected patients taking nevirapine-stavudine-lamivudine. METHODS: We conducted a prospective cohort study of 300 Malawian adults starting ART and describe one-year ART outcomes according to viral hepatitis status. RESULTS: At baseline, patients had advanced HIV disease (29.3% were in WHO stage 4; mean CD4 = 157 cells/microL; mean log(10)HIV-1 RNA = 5.24 copies/ml). Co-infection with hepatitis B, C and B + C were present in 6.7%, 5.7% and 1.7% respectively. At 50 weeks, all-cause mortality was 43 (14.3%). Sixteen (5.3%) had transferred to another unit. Eight (2.7%) were lost to follow up. Sixteen (5.3%) had stopped ART. 217 (72.3%) were alive on ART, of whom 82.5% had an HIV-1 RNA <400 copies/ml at week 50. During the first 50 weeks of ART, severe hepatotoxicity (liver enzyme values >5 times upper level of normal) occurred in 9%, but did not result in any ART discontinuations. Clinical hepatitis or jaundice was not observed. There were no significant differences in occurrence of hepatotoxicity, other side effects, mortality, severe morbidity, immune reconstitution or virological failure between hepatitis B and/or C co-infected patients and those who were not. Viral hepatitis co-infection was not associated with severe hepatotoxicity, mortality, severe morbidity or virological failure in multivariate analyses. CONCLUSION: Our data suggest that screening for viral hepatitis B and C and liver enzyme monitoring may not require high priority in ART programmes in sub-Saharan Africa.

Reliability of rapid testing for hepatitis B in a region of high HIV endemicity.

Hepatitis B (HBV) and HIV co-infection is common in resource-poor settings. A recent study from Malawi revealed poor correlation between hepatitis B surface antigen (HBsAg) point-of-care tests and reference tests in patients co-infected with HIV. We studied a cohort of 300 Malawian adults entering a treatment programme for HIV. Sera were tested for HBsAg first using the Determine rapid test and re-tested using a commercial enzyme immunoassay (EIA). All tests were done under optimal conditions in Liverpool, UK. Sera from all 25 patients positive for HBsAg using the rapid test and from 50 who were negative, were re-tested using the EIA, with complete concordance of results. The kappa correlation was 1, specificity 100% (93-100%) and sensitivity 100% (86-100%) compared to the reference test. Patients had advanced immune suppression (mean CD4=175 cells x 10(6)/l). In a non-field setting, the results of point-of-care Determine rapid hepatitis B tests appear reliable in patients with HIV-1 co-infection.

Ezrin interacts with cortactin to form podosomal rosettes in pancreatic cancer cells.

BACKGROUND AND AIMS: Pancreatic cancer is a highly invasive malignancy. Ezrin, a plasma membrane-cytoskeletal linker protein, is associated with the invasive behaviour of cancers. The purpose of this study was to elucidate a possible molecular mechanism for the invasive phenotype. METHODS: Using a combination of techniques, such as western blotting, co-immunoprecipitation, confocal and light microscopy, invasion and adhesion assays, organotypic cultures and human samples as well as RNA interference (RNAi) and expression of various mutant ezrin constructs, the dynamic molecular nature of podosomes in pancreatic cancer was dissected out. RESULTS: Podosome and podosomal rosette formation in pancreatic carcinoma (PaCa3) cells is ezrin dependent and associated with adhesion to fibronectin with subsequent digestion of this substrate. Ezrin binds to increasing amounts of cortactin during formation of the podosomal rosette, with the C-terminal region, specifically the actin-binding domain, mediating this molecular linkage. Further, it is shown that phosphorylation of Tyr353 and Thr567 sites on ezrin (conventionally shown to translocate ezrin to the plasma membrane) is not required for podosome formation. The podosomal rosette is revealed to be a highly dynamic and transient structure, which can metamorphose into other cellular processes, such as filopodia or lamellipodia, and thereby enable epithelial cancer cells to "palpate" the underlying substrate and modify their cytoskeletal behaviour accordingly. In human tumour tissues and organotypic cultures, specific subcellular expression of ezrin (basal membranous; cellular processes invading stroma) in pancreatic cancer cells can be correlated with tumour progression and disease-free survival (log-rank test (Mantel-Cox), p = 0.019). CONCLUSION: Podosomes and their rosettes are driven by ezrin-cortactin interaction and this plays a role in pancreatic cancer invasion.

Immunosuppressant drugs for myasthenia gravis.

Along with corticosteroids, immunosuppressant drugs are mainstays of disease-modifying therapy for myasthenia gravis (MG). However, their efficacies and optimum use are unclear. We identified seven randomised controlled trials (RCT) of immunosuppressants in generalised MG that qualified for Cochrane Review: (1) azathioprine plus initial prednisolone versus prednisolone; (2) azathioprine plus prednisolone versus prednisolone plus placebo; (3) ciclosporin versus placebo (4) ciclosporin plus prednisolone versus prednisolone plus placebo; (5) cyclophosphamide plus prednisolone versus prednisolone plus placebo; (6) mycophenolate mofetil (MMF) alone or plus either ciclosporin or prednisolone versus placebo alone or plus either ciclosporin or prednisolone; (7) tacrolimus plus corticosteroids with or without plasma exchange versus corticosteroids with or without plasma exchange. All trials were small (14 to 41 participants) and their designs heterogeneous. The RCT evidence, albeit limited, was that ciclosporin (alone or with corticosteroids) or cyclophosphamide (with corticosteroids) improved MG significantly within 1 year compared with placebo. There was no clear evidence of benefit for azathioprine, MMF, or tacrolimus within 1 year. Larger, better-designed, longer trials are needed.

Cytomegalovirus retinitis in the absence of HIV or immunosuppression.

PURPOSE: Cytomegalovirus (CMV) retinitis classically occurs in advanced human immunodeficiencyvirus (HIV) infection but is rare in other forms of immunosuppression. The authors report a case of CMV retinitis in an HIV-negative man with idiopathic CD4 lymphocytopenia (ICL). This is the first such case to be confirmed by polymerase chain reaction (PCR) of aqueous humor. METHODS: Case report. RESULTS: A 69-year-old retired Chinese seaman presented with gradual visual deterioration. He was a diet controlled diabetic on regular steroids for presumed asthma. Examination showed no diabetic eye disease but confirmed acute retinal necrosis (ARN). Anterior chamber tapping of the aqueous humor was PCR positive for CMV. HIV antibody and RNA tests were negative but his full blood count revealed lymphocytopenia, with a low CD4+ subset. He responded to a 3-week course of intravenous ganciclovir therapy followed by suppressiveoral valganciclovir. CONCLUSIONS: CMV is associated with sight-threatening retinitis in HIV infection at CD4+ counts below 50 cells/microL and in transplant recipients or heavily immunosuppressed patients. Systemic steroids are a risk factor for clinical disease in these groups. It is extremely rare to report CMV eye disease in previously healthy individuals. This case illustrates that the condition does occur in association with ICL. Corticosteroids may be implicated in disease reactivation. Molecular METHODS are necessary to confirm the diagnosis.

Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome.

Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.

Prevalence of infection with hepatitis B and C virus and coinfection with HIV in medical inpatients in Malawi.

BACKGROUND: Coinfection with hepatitis B (HBV) or hepatitis C (HCV) adversely affects the prognosis of HIV infection and vice versa, and results in complex interactions with antiretroviral therapy. These infections are common in sub-Saharan Africa but there are few data on prevalence of coinfection. All three components of the most common ART regimen used in Africa, stavudine, lamivudine and nevirapine, can cause hepatic problems and lamivudine resistant HBV is known to emerge after HBV monotherapy in coinfected patients. Point of care (POC) tests for HBV and HCV are widely used but have not been validated in field tests in sub-Saharan Africa. METHODS: Prospective observational study of sequential adult inpatients in medical wards of a large urban teaching hospital in Malawi in 2004. Comparison of demographic risk factors with HIV antibody status determined using local double POC test protocols, and with HBsAg and HCV antibody prevalence as estimated in a reference laboratory in Liverpool, UK. Results of locally performed POC tests for HBV using Determine HBsAg (Abbott) and for HCV antibody using HCV-SPOT (Genelabs) were compared with results of reference methods in the UK. RESULTS: Of 226 adults (39% male), median (range) age 35 (14-80) years, 81% had a history of traditional scarification, 12% a history of blood transfusion and 11% a history of jaundice. HIV antibodies were present in 76.1%, HBsAg in 17.5% and HCV in 4.5%, with HIV/HBV coinfection in 20.4% and HIV/HCV coinfection in 5% of those with HIV. There was no correlation between prevalence of any of the three viruses and demographic risk factors or presence of either of the other two viruses. Point of care tests gave misleading results with prevalence estimates of 38% for HBV and 4.5% for HCV. For both of these POC tests the performance indices were unacceptable for individual patient management or epidemiological survey purposes. CONCLUSIONS: The high prevalence of hepatitis/HIV coinfections may impact on treatment with antiretroviral therapy, especially if there are unintended interruptions of therapy, and studies are needed to document the possible clinical impact on ART programmes. The poor performance of POC tests for HBV and HCV may be due to local operational problems or to unexpected technical issues not revealed by early validation tests. These tests are widely used in resource poor settings and should be revalidated in prospective field studies in areas of the tropics with high HIV prevalence rates.

An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis.

BACKGROUND: This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with myasthenia gravis (MG). METHODS: Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America [MGFA] criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety. RESULTS: A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%). CONCLUSIONS: Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.

Early onset of breast cancer in a group of British black women.

Since there are no published data on breast cancer in British black women, we sought to determine whether, like African-American women, they present at a younger age with biologically distinct disease patterns. The method involved a retrospective review of breast cancer to compare age distributions and clinicopathological features between black women and white women in the UK, while controlling for socioeconomic status. All women presented with invasive breast cancer, between 1994 and 2005, to a single East London hospital. Black patients presented significantly younger (median age of 46 years), than white patients (median age of 67 years (P=0.001)). No significant differences between black and white population structures were identified. Black women had a higher frequency of grade 3 tumours, lymph node-positive disease, negative oestrogen receptor and progesterone receptor status and basal-like (triple negative status) tumours. There were no differences in stage at presentation; however, for tumours of < or =2 cm, black patients had poorer survival than white patients (HR=2.90, 95% CI 0.98-8.60, P=0.05). Black women presented, on average, 21 years younger than white women. Tumours in younger women were considerably more aggressive in the black population, more likely to be basal-like, and among women with smaller tumours, black women were more than twice as likely to die of their disease. There were no disparities in socioeconomic status or treatment received. Our findings could have major implications for the biology of breast cancer and the detection and treatment of the disease in black women.

Immunosuppressive agents for myasthenia gravis.

BACKGROUND: The benefits of different immunosuppressants for myasthenia gravis (MG) are unclear. OBJECTIVES: Assessment of immunosuppressant drug efficacy in MG. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to July 2007), EMBASE (from January 1980 to July 2007), review and trial bibliographies and contacted trial authors. SELECTION CRITERIA: Types of studies: Randomised and quasi-randomised controlled trials. TYPES OF PARTICIPANTS: Any age, any type or severity of MG regardless of concomitant treatment. Types of interventions: Any immunosuppressive agent. Types of outcome measures: Primary: (1) Improvement or not at six months. Secondary: (1) Improvement or not at one year (2) Need for other treatment, for example corticosteroid dose, at six months (3) Number of exacerbations during the first year (4) Acetylcholine receptor antibody titre after at least six months (5) Occurrence of one or more adverse events at any time after the introduction of treatment. DATA COLLECTION AND ANALYSIS: One author extracted and two checked the data. MAIN RESULTS: Seven trials are included but few reported the outcomes selected for this review. A meta-analysis of ciclosporin versus placebo from two trials (59 participants) - one as monotherapy (20 participants) and the other with corticosteroids (39 participants) - showed that it resulted in improvement of participants in the ciclosporin group compared with those in the placebo group, with a relative rate of improvement of 2.44 (95% confidence interval (CI) 1.13 to 5.27). In addition the weighted mean difference in QMG score between the ciclosporin and placebo groups was -0.34 (95% CI -0.52 to -0.17). Azathioprine (plus prednisolone for first month) had no significant benefit over prednisolone alone (41 participants). The effects of azathioprine plus prednisolone versus prednisolone plus placebo were similar (34 participants). Cyclophosphamide was reported to be statistically more efficacious than placebo at 12 months in corticosteroid-dependent participants (23 participants), but no raw data were available. Trials of mycophenolate mofetil and tacrolimus did not provide relevant endpoint data for this review. All trials had low numbers of participants. Adverse event reporting was variable. Trial protocol heterogeneity prevented comparison of the different immunosuppressants. AUTHORS' CONCLUSIONS: In generalised MG, limited evidence from small RCTs suggests that ciclosporin, as monotherapy or with corticosteroids, or cyclophosphamide with corticosteroids, significantly improve MG.Limited evidence from RCTs shows no significant benefit from azathioprine (as monotherapy or with steroids), mycophenolate mofetil (as monotherapy or with either corticosteroids or ciclosporin) or tacrolimus (with corticosteroids or plasma exchange). Bigger, better-designed, longer trials are needed.

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.