Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus.

Aim: To molecularly characterize the tumor microenvironment and evaluate immunologic parameters in canine glioma patients before and after treatment with oncolytic human IL-12-expressing herpes simplex virus (M032) and in treatment naïve canine gliomas. Methods: We assessed pet dogs with sporadically occurring gliomas enrolled in Stage 1 of a veterinary clinical trial that was designed to establish the safety of intratumoral oncoviral therapy with M032, a genetically modified oncolytic herpes simplex virus. Specimens from dogs in the trial and dogs not enrolled in the trial were evaluated with immunohistochemistry, NanoString, Luminex cytokine profiling, and multi-parameter flow cytometry. Results: Treatment-naive canine glioma microenvironment had enrichment of Iba1 positive macrophages and minimal numbers of T and B cells, consistent with previous studies identifying these tumors as immunologically "cold". NanoString mRNA profiling revealed enrichment for tumor intrinsic pathways consistent with suppression of tumor-specific immunity and support of tumor progression. Oncolytic viral treatment induced an intratumoral mRNA transcription signature of tumor-specific immune responses in 83% (5/6) of canine glioma patients. Changes included mRNA signatures corresponding with interferon signaling, lymphoid and myeloid cell activation, recruitment, and T and B cell immunity. Multiplexed protein analysis identified a subset of oligodendroglioma subjects with increased concentrations of IL-2, IL-7, IL-6, IL-10, IL-15, TNFα, GM-CSF between 14 and 28 days after treatment, with evidence of CD4+ T cell activation and modulation of IL-4 and IFNγ production in CD4+ and CD8+ T cells isolated from peripheral blood. Conclusion: These findings indicate that M032 modulates the tumor-immune microenvironment in the canine glioma model.

First Measurement of Near-Threshold J/ψ Exclusive Photoproduction off the Proton.

We report on the measurement of the γp→J/ψp cross section from E_{γ}=11.8 GeV down to the threshold at 8.2 GeV using a tagged photon beam with the GlueX experiment. We find that the total cross section falls toward the threshold less steeply than expected from two-gluon exchange models. The differential cross section dσ/dt has an exponential slope of 1.67±0.39 GeV^{-2} at 10.7 GeV average energy. The LHCb pentaquark candidates P_{c}^{+} can be produced in the s channel of this reaction. We see no evidence for them and set model-dependent upper limits on their branching fractions B(P_{c}^{+}→J/ψp) and cross sections σ(γp→P_{c}^{+})×B(P_{c}^{+}→J/ψp).

A rapid and quantitative method for the evaluation of V gene usage, specificities and the clonal size of B cell repertoires.

The quantitative simultaneous description of both variable region gene usage and antigen specificity of immunoglobulin repertoires is a major goal in immunology. Current quantitative assays are labor intensive and depend on extensive gene expression cloning prior to screening for antigen specificity. Here we describe an alternative method based on high efficiency single B cell cultures coupled with RT-PCR that can be used for rapid characterization of immunoglobulin gene segment usage, clonal size and antigen specificity. This simplified approach should facilitate the study of antibody repertoires expressed by defined B cell subpopulations, the analysis of immune responses to self and nonself-antigens, the development and screening of synthetic antibodies and the accelerated study and screening of neutralizing antibodies to pathogenic threats.

Membranous glomerulopathy in an adult patient with X-linked agammaglobulinemia receiving intravenous gammaglobulin.

BACKGROUND: Immune complex deposition in the subepithelial zone of glomerular capillaries can lead to membranous glomerulopathy. OBJECTIVE: To present the case of a 23-year-old man with X-linked agammaglobulinemia (XLA) who developed idiopathic membranous glomerulopathy while receiving intravenous immunoglobulin (IVIG). METHODS: We performed an immunological workup, genetic testing, and a renal biopsy. RESULTS: XLA was confirmed with less than 0.02% CD19+ cells in the blood after sequence analysis revealed a nonfunctional BTK gene. The patient presented with microhematuria, which persisted for 3 years and spanned treatment with 5 different preparations of intravenous gammaglobulin. Immunohistochemistry revealed membranous glomerulopathy. CONCLUSION: Although endogenous serum immunoglobulin (Ig) production is severely impaired in XLA, rare B lymphocytes that have managed to mature can produce functional IgG antibodies. The pathogenic immune complexes could reflect IVIG reacting with polymorphic autoantigens, an endogenous IgG-producing clone reacting with a common idiotype present in the IVIG, or both.

Descending necrotizing mediastinitis as a complication of odontogenic infection.

Descending necrotizing mediastinitis (DNM) is a serious, life threatening complication that can occur from a common odontogenic infection. Even with advancements in antibiotics, diagnostic imaging, and surgical management, the mortality rate remains between 20 and 40%. It is imperative that the practitioner taking care of patients with odontogenic infections be sensitized to this potentially fatal complication. We report the successful management of a case of mediastinitis complicating an odontogenic infection in a 39-year-old male.

Is there adequate provision of venous thromboembolism prophylaxis following hip arthroplasty? An audit and international survey.

INTRODUCTION: The peak incidence of venous thrombo-embolism (VTE) occurs 3 weeks following hip arthroplasty surgery and current guidelines proposing VTE prophylaxis continuing for 4 weeks after surgery. This study first compares the duration of treatment and satisfaction between patients prescribed low molecular weight heparin (LMWH) and rivaroxaban, a new oral Factor Xa inhibitor, following elective hip arthroplasty; and second, surveys the duration of LMWH use in other units. SUBJECTS AND METHODS: An international survey detailing the use of LMWH was performed. A prospective audit was performed of 100 hip replacements, with 50 prescribed 40 mg once daily of subcutaneous enoxaparin and subsequently 50 patients prescribed 10 mg once daily of oral rivaroxaban. The duration of treatment, patient satisfaction and complications for both cohorts was quantified and compared against published evidence-based guidelines. RESULTS: The survey demonstrated that four out of 39 (10.2%) units that routinely prescribe LMWH do so for at least 4 weeks following surgery. The audit demonstrated that rivaroxaban afforded a superior mean duration of postoperative VTE prophylaxis (35 days vs 5.4 days; P < 0.05) and superior patient satisfaction. There was no difference in the incidence of bleeding, wound infection or thrombotic complications. CONCLUSIONS: This study demonstrates that patients are exposed to an increased VTE risk following hip replacement surgery due to the inadequate prescription of LMWH. This is poor clinical practice, contrary to current evidence-based guidelines and has potential medicolegal implications. The prescription of rivaroxaban affords a superior patient compliance compared with subcutaneous LMWH, thus ensuring that patients receive VTE prophylaxis for the current recommend period of time.

Return to work following knee arthroplasty.

A retrospective study of a consecutive cohort of 109 patients, under the age of 60, who had either a Patellofemoral replacement (PFR), Unicompartmental replacement (UKR) or a Total knee replacement (TKR). They were operated on by two senior surgeons between 2002 and 2006 at the Avon Orthopaedic Centre in Bristol. The aim of this study was to look at the effect of knee replacement on the employment status of this group of patients. Data were collected from patient's hospital records and a questionnaire regarding occupational status was sent postoperatively to the patients. Statistical analysis showed that our groups were similar which meant that further comparison between them was valid. Eighty-two percent of the patients who were working prior to surgery and who had either a TKR or UKR were able to return to work postoperatively. Only 54% of those who had a PFR were able to return to work and this was statistically significant when compared with patients in the other two groups p=0.047. The median time for return to work postoperatively for the study population was 12 weeks. Those in the PFR group took significantly longer to do so (20 weeks) compared to those who had either a UKR (11 weeks) or TKR (12 weeks) p=0.01. Patient's subjective opinion as to their ability to work following knee arthroplasty was worse in the PFR group p=0.049. This is the first study to compare employment status following Patellofemoral, Unicompartmental knee and Total Knee Replacement. TKR and UKR are effective in returning patients under 60 years old to active employment and this is typically 3 months following surgery. Patients who had a PFR did not experience the same benefits in terms of numbers returning to work, time to do so and their subjective opinion as to their ability to cope with normal duties.

Increasing insect reactions in Alaska: is this related to changing climate?

In 2006, Fairbanks, AK, reported its first cases of fatal anaphylaxis as a result of Hymenoptera stings concurrent with an increase in insect reactions observed throughout the state. This study was designed to determine whether Alaska medical visits for insect reactions have increased. We conducted a retrospective review of three independent patient databases in Alaska to identify trends of patients seeking medical care for adverse reactions after insect-related events. For each database, an insect reaction was defined as a claim for the International Classification of Diseases, Ninth Edition (ICD-9), codes E9053, E906.4, and 989.5. Increases in insect reactions in each region were compared with temperature changes in the same region. Each database revealed a statistically significant trend in patients seeking care for insect reactions. Fairbanks Memorial Hospital Emergency Department reported a fourfold increase in patients in 2006 compared with previous years (1992-2005). The Allergy, Asthma, and Immunology Center of Alaska reported a threefold increase in patients from 1999 to 2002 to 2003 to 2007. A retrospective review of the Alaska Medicaid database from 1999 to 2006 showed increases in medical claims for insect reactions among all regions, with the largest percentage of increases occurring in the most northern areas. Increases in insect reactions in Alaska have occurred after increases in annual and winter temperatures, and these findings may be causally related.

Accuracy of femoral templating in reproducing anatomical femoral offset in total hip replacement.

Restoration of hip biomechanics is a crucial component of successful total hip replacement. Preoperative templating is recommended to ensure that the size and orientation of implants is optimised. We studied how closely natural femoral offset could be reproduced using the manufacturers' templates for 10 femoral stems in common use in the UK. A series of 23 consecutive preoperative radiographs from patients who had undergone unilateral total hip replacement for unilateral osteoarthritis of the hip was employed. The change in offset between the templated position of the best-fitting template and the anatomical centre of the hip was measured. The templates were then ranked according to their ability to reproduce the normal anatomical offset. The most accurate was the CPS-Plus (Root Mean Square Error 2.0 mm) followed in rank order by: C stem (2.16), CPT (2.40), Exeter (3.23), Stanmore (3.28), Charnley (3.65), Corail (3.72), ABG II (4.30), Furlong HAC (5.08) and Furlong modular (7.14). A similar pattern of results was achieved when the standard error of variability of offset was analysed. We observed a wide variation in the ability of the femoral prosthesis templates to reproduce normal femoral offset. This variation was independent of the seniority of the observer. The templates of modern polished tapered stems with high modularity were best able to reproduce femoral offset. The current move towards digitisation of X-rays may offer manufacturers an opportunity to improve template designs in certain instances, and to develop appropriate computer software.

Echinacea purpurea supplementation stimulates select groups of human gastrointestinal tract microbiota.

BACKGROUND AND OBJECTIVE: The objective of this research was to determine the effects of the dietary supplement Echinacea purpurea on aerobic and anaerobic bacteria common to the human gastrointestinal (GI) tract. Botanical extracts have shown in vitro antimicrobial effects against certain pathogenic bacteria. It is uncertain if medicinal herbs have any effect against pathogenic bacteria or on the native GI microbiota. METHODS: Fifteen human subjects consumed 1000 mg of standardized E. purpurea for 10 days. Faecal samples were collected at baseline, 10 days and 17-18 days following supplementation. Samples were tested for select aerobic and anaerobic bacteria using plate culture microbiological methods. RESULTS AND DISCUSSION: Significant increases were found for total aerobic bacteria, Bacteroides group and Bacteroides fragilis after E. purpurea exposure. Supplementation did not significantly alter the number of enteric bacteria, enterococci, lactobacilli, bifidobacteria or total anaerobic bacteria. CONCLUSION: Echinacea supplementation has altered the GI microbiota. The health consequences associated with this change are unknown but previous research has shown increased Bacteroides concentrations associated with diarrhoea, inflammatory bowel disease and increased risk of colon cancer. Additional research should delineate the role of Echinacea in the stimulation of Bacteroides and describe the effects of other botanical supplements to the GI microbiota.

Towards a systemic understanding of a hospital waiting list.

Hospital waiting lists are a feature of publicly funded health services that result when demand appears to exceed supply. While much has been written about surgical waiting lists, little is known about the dynamics of radiology waiting lists, which is surprising given that rational treatment, and indeed the medical profession's claim to expertise, rests on establishing a diagnosis. This paper reports the findings of a case study of a problematic ultrasound waiting list. In particular, this paper highlights how the management of the ultrasound waiting list served to subordinate the needs of waiting patients and their general practitioners to the interests and values of radiologists. Radiologist concern to protect specialist expertise from encroachment by outpatient clinicians and sonographers is implicated in the growth of the ultrasound waiting list. It is argued that an adequate understanding of ultrasound waiting lists depends on grasping how radiologists are successful in structuring problems of access in ways that enhance radiologist control over ultrasound imaging. The case study reported helps to shed light on why increasing funding to clear waiting lists proves ineffective.

Long-term results of the FemSoft urethral insert for the management of female stress urinary incontinence.

A 5-year ongoing, controlled multicenter study enrolled 150 women. Outcome measures included pad weight tests (PWT), voiding diary (VD), quality of life (QOL) and satisfaction questionnaires. Outcome measures during the baseline period were compared to evaluations during follow-up. Concurrent evaluations with and without device use were also performed. Safety evaluations included urinalysis and culture, leak-point pressure (LPP) and cystoscopy. Adverse events (AE) were recorded throughout the study. One to 2 years of follow-up were collected on all study participants (mean 15 months). Statistically significant reductions in overall daily incontinence episodes (P<0.001) and PWT urine loss (P<0.001) were observed with the device at all follow-up intervals, and 93% of women had a negative PWT at 12 months. Women were satisfied with ease of use of the device, comfort and dryness, and significant improvements in QOL were observed (P<0.001). Subgroup analysis revealed that the insert was effective, despite the presence of urgency, low LPP, failed surgery and advanced age. AE included symptomatic urinary tract infection in 31.3%, mild trauma with insertion in 6.7%, hematuria in 3.3%, and migration in 1.3% of women. The results of PWT and VD demonstrated device efficacy. Women were satisfied and significant improvements in QOL were observed. AE were transient and required minimal or no treatment. The urethral insert should be considered as an option for the management of SUI.

Betwixt and between: ritual and the management of an ultrasound waiting list.

Hospital waiting lists are a feature of publicly funded health services that results when demand appears to exceed supply. While much has been written about hospital waiting lists, little is known about the dynamics of diagnostic waiting lists, or more generally why hospital waiting lists behave in perverse and often counter-intuitive ways. This paper attempts to address this gap by applying a recent development in critical systems thinking called boundary critique to understand how a particular ultrasound waiting list was managed. A new waiting list metaphor based on waiting lists as ritual forms is proposed.

Collagen implant for treating stress urinary incontinence in women with urethral hypermobility.

PURPOSE: We evaluated the use of collagen in women with stress urinary incontinence and urethral hypermobility. MATERIALS AND METHODS: We treated 90 patients with stress urinary incontinence and urethral hypermobility with 1 to 3 injections of Contigen implant (C. R. Bard, Inc., Covington, Georgia) between June 1996 and October 1998. Observations at 3, 6 and 12 months included continence grade, 7-day voiding diaries and quality of life questionnaires. Abdominal leak point pressure was determined at baseline and 12 months. RESULTS: At the 6-month followup 68 patients remained in the study, of whom 30 (44%) were dry and 24 (35%) were improved. Of the 58 patients who reached the 12-month followup 19 (33%) were dry and 19 (33%) were improved. Considering all patients entered into the study at 6 months 30 (33%) were dry and 24 (27%) were improved. Of the original 90 patients 19 (21%) were dry and 19 (21%) were improved at 12 months. The probability of maintaining initial improvement for 12 months was 44%. The success of bulking agent therapy was not predicted by the initial incontinence grade. Improved continence grade correlated with improved leak point pressure. CONCLUSIONS: This therapy is appropriate in women with urethral hypermobility who wish to avoid surgical risks and in those in whom surgery is ill advised.

Structural effects of framework mutations on a humanized anti-lysozyme antibody.

A humanized version of the mouse anti-lysozyme Ab D1.3 was previously constructed as an Fv fragment and its structure was crystallographically determined in the free form and in complex with lysozyme. Here we report five new crystal structures of single-amino acid substitution mutants of the humanized Fv fragment, four of which were determined as Fv-lysozyme complexes. The crystals were isomorphous with the parent forms, and were refined to free R values of 28-31% at resolutions of 2.7-2.9 A. Residue 27 in other Abs has been implicated in stabilizing the conformation of the first complementarity-determining region (CDR) of the H chain, residues 31-35. We find that a Phe-to-Ser mutation at 27 alters the conformation of immediately adjacent residues, but this change is only weakly transmitted to Ag binding residues in the nearby CDR. Residue 71 of the H chain has been proposed to control the relative disposition of H chain CDRs 1 and 2, based on the bulk of its side chain. However, in structures we determined with Val, Ala, or Arg substituted in place of Lys at position 71, no significant change in the conformation of CDRs 1 and 2 was observed.

Concomitant blunt enteric injuries with injuries of the liver and spleen: a dilemma for trauma surgeons.

Prompt identification of enteric injuries after blunt trauma remains problematic. With the increased utilization of nonoperative management of blunt abdominal trauma gastrointestinal disruptions may escape timely detection and repair. The purpose of this study was to evaluate blunt enteric injuries requiring operative repair in adult patients and the association of concomitant hepatic and/or splenic injuries. Over a 10-year period (January 1990 through December 1999) 1648 patients suffered blunt liver, spleen, and/or enteric injuries, with 87 (5.3%) of these requiring operative repairs of the enteric injury. These patients had enteric injury only (EI) (60.9%; 53 of 87), concomitant enteric/splenic injury (ESI) (10.3%; 9 of 87), concomitant enteric/hepatic injury (EHI) (13.8%; 12 of 87), and enteric/hepatic/splenic injury (EHSI) 14.9% (13 of 87). A delay in treatment of >8 hours from presentation of EI compared with either EHI or ESI was not significantly different between the two groups. EHSI had exploratory laparotomy more expeditiously related to hemodynamic instability. Mortality rates were higher with EHI related to hemorrhagic shock and/or severe traumatic brain injury. Morbidity was not related to a delay in diagnosis until the period of delay was greater than 24 hours. The nonoperative management of blunt solid organ injury does not delay the detection and treatment of concomitant bowel injuries compared with isolated blunt enteric injuries. Occult enteric injury with solid organ injury has a low incidence and represents a continuing challenge to the clinical acumen of the trauma surgeon.

Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults.

Risk factors for non-melanoma skin cancer among populations with evidence of precursor damage are not well described. We examined and compared risk factors associated with the development of cutaneous basal-cell (BCC) or squamous-cell (SCC) carcinoma among a group of 918 adults with significant sun damage (> or = 10 clinically assessable actinic keratoses) but no prior history of skin cancer. These adults were participants in a 5-year skin chemoprevention trial between 1985 and 1992, who had been randomized to the placebo group and followed for occurrence of skin cancer. During the study, a total of 129 first SCC and 164 first BCC lesions were diagnosed. The overall BCC and SCC incidence rates for this group of men and women, mean age 61 years, were 4,106 and 3,198 per 100,000 person-years, respectively. Different constitutional and exposure factors were independently associated with BCC compared to SCC. Only increased age independently predicted BCC occurrence among this population. In contrast, older age along with male gender, natural red hair color and adult residence in Arizona for 10 or more years independently predicted SCC occurrence. The substantial incidence of skin cancer found among this population confirms the need for active dermatological monitoring among individuals with multiple visible actinic lesions.

Polysubstance use among alcoholics.

Contemporary alcoholics often use multiple substances, but there is little systematic research on this. This study examines the drug use comorbidity of alcoholics (DSM diagnosis, frequency and quantity of drug use); the relationship between drinking and drug use; the relative severity of alcohol- and drug-related problems; and the validity of reports of illicit drug use. Data on substance use were collected from 248 treatment-seeking alcoholics using an expanded Time-line Follow-Back (TLFB) interview. Self-reports of substance use were validated with data from biological specimens (urine and hair). Lifetime diagnosis of joint alcohol and drug dependence/abuse was 64%. Two-thirds (68%) reported using drugs in the past 90 days: 33% powder cocaine; 29% crack cocaine; 15% heroin, and 24% cannabis. The mean proportions of exposed days on which users reported consuming a substance were 57% (alcohol), 26% (powder cocaine), 46% (crack cocaine), 47% (heroin), and 29% (cannabis). Subjects reported consuming an average of 14 standard drinks on a drinking day and $67 worth of drugs on a using day. Drug users reported drinking less than nonusers on a drinking day. Frequency of drinking and drug use were positively correlated; almost all drug users reported simultaneous drinking and drug use; and they rated drugs as the bigger problem. Considerable under-reporting of drug use occurred for the previous 3-4 days, but was more accurate for the previous month.