NTRK expression is common in xanthogranuloma and is associated with the solitary variant.

BACKGROUND: Previously identified mutually-exclusive driver genes in juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) include mutations in MAP kinase pathway genes such as MAP2K1, BRAF, ARAF, KRAS, NRAS, PIK3CD as well as fusions in BRAF and ALK, with a subset of cases with no identified driver yet. NTRK fusion has been identified in rare cases. METHODS: We identified two consecutive index cases of localized JXG or AXG with NTRK1 fusion by next-generation sequencing (NGS) and confirmed by pan-NTRK immunostain. We expanded the study to a total of 50 cases of JXG and AXG using screening by pan-NTRK immunostain. We confirmed the specificity of our approach with negative results in 5 cases of histiocytic neoplasia lacking an NTRK fusion by NGS and 14 cases of non-neoplastic histiocytic disease. RESULTS: We found 23 cases of JXG or AXG with overexpression of NTRK by immunostain, and these cases were restricted to localized disease (23 of 43 cases, 53.5%) rather than disseminated disease (zero of seven cases). CONCLUSIONS: NTRK expression is common in JXG or AXG and associated with localized rather than disseminated disease. We speculate that the potential importance of this in JXG and AXG has not been previously appreciated due to the tendency to focus sequencing studies on disseminated disease. We confirm the presence of an NTRK1 fusion in two positive cases by NGS, however, additional genetic studies are necessary to further explore this.

Vancomycin minimum inhibitory concentration, host comorbidities and mortality in Staphylococcus aureus bacteraemia.

We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30-day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality.

Colovaginal and colovesical fistulae: the diagnostic paradigm.

BACKGROUND: Colovaginal and colovesical fistulae (CVF) are relatively uncommon conditions, most frequently resulting from diverticular disease or colorectal cancer. A high suspicion of a CVF can usually be obtained from an accurate clinical history. Demonstrating CVF radiologically is often challenging, and patients frequently undergo a multitude of investigations prior to definitive management. The aim of this study was to develop an algorithm for the investigation of suspected CVF in order to improve diagnosis and subsequent management. METHODS: Thirty-seven patients from a single NHS Trust with a diagnosis of colovaginal or colovesical fistula were included in the study. Clinical records and imaging were reviewed retrospectively, and data on demographics, symptoms, investigations, management and outcome were collated. RESULTS: A total of 87.5% patients with a colovesical fistula presented with pathognomic symptoms of faecaluria or pneumaturia. The commonest aetiologies were diverticular disease (72.9%), colonic and gynaecological neoplasia (10.8% each). Computerised tomography (CT) was the most frequently performed investigation (91.9%) and was most sensitive in detecting the fistula (76.5%) and underlying aetiology (94.1%). Colonoscopy was most sensitive in detecting an underlying colonic malignancy (100%). Resectional surgery was performed in 62.1% of cases, although morbidity and 1-year mortality was significant, with rates of 21.7 and 17.4%, respectively. CONCLUSIONS: The diagnosis of CVF is predominately a clinical one, and patients with a suspected CVF are over-investigated. Investigations should be focused on determining aetiology rather than demonstrating the fistulous tract itself. We propose that, in the majority of cases, CT and lower gastrointestinal endoscopy should suffice.

The role of ¹8fluoro-deoxy glucose combined position emission and computed tomography in the clinical management of anal squamous cell carcinoma.

AIM: Anal squamous cell carcinoma (SCC) is uncommon in the western world but continues to increase in incidence. Optimal treatment and outcome are dependent upon pretreatment staging strategies. We evaluate the role of ¹8fluoro-deoxyglucose (¹8FDG) combined position emission and computed tomography (PETCT) in the management of anal SCC. METHOD: Patients with a histologically confirmed anal SCC underwent standard staging investigations, including computed tomography, Magnetic resonance imaging and examination under anaesthetic. A tumour, node, metastasis (TNM) system was used. All patients subsequently underwent additional whole-body ¹8FDG PETCT scanning. Management was planned accordingly, blinded to ¹8FDG PETCT findings, at a multidisciplinary meeting, and reviewed again following disclosure of PETCT results. RESULTS: Forty patients (24 men), with a median age of 57 years (range 38-87 years), were prospectively recruited. All primary tumours were ¹8FDG avid. PETCT did not alter the T stage but did result in disease upstaging (N and M stages). Management was altered in five (12.5%) patients: one patient was identified to have an isolated distant metastasis, and four patients had ¹8FDG-avid lymph nodes not otherwise detected, all of which were tumour-positive on fine needle aspiration cytology/biopsy. CONCLUSION: PETCT upstages anal SCC and influences subsequent management. PETCT should be considered in the staging of anal SCC, although the definitive benefit of such a strategy requires further evaluation.

Day case laparoscopic incisional hernia repair is feasible, acceptable, and cost effective.

BACKGROUND: Day case surgery is increasingly performed in the United Kingdom. Laparoscopic techniques have increased the number of conditions suitable for a day surgical approach. Findings have shown that laparoscopic incisional hernia repair (LIHR) is superior to conventional open techniques. This study aimed to show that day case LIHR is safe, produces a good clinical outcome, and is cost effective. METHODS: Day case laparoscopic repair was performed for 31 consecutive patients (10 men; median age, 67 years; range, 39-80 years). Data were entered prospectively into a database. Patients were discharged within 8 h committed to a 10-day course of oral diclofenac 50 mg three times daily and 2 tablets of codydramol four times daily. Follow-up evaluation was by telephone consultation. Hospital costs for LIHR and open repair were compared. RESULTS: All procedures were completed laparoscopically on a day case basis. Additional unsuspected defects were found in eight cases (25.8%). The median mesh size was 140 cm2 (range, 25-375 cm2), and the median body mass index (BMI) was 28.7 kg/m2 (range, 20-37.1 kg/m2). Operations were performed or supervised by a single consultant surgeon (S.J.W.). Six postoperative seromas resolved spontaneously. Two port-site infections required oral antibiotics, and one diathermy pad burn healed with simple dressings. The median analgesia requirement was 7 days (range, 0-152 days). There were no recurrences during a median follow-up period of 15 months (range, 3-24 months). There was a saving of 616 pounds sterling per procedure. CONCLUSIONS: Day case laparoscopic repair of incisional hernias is feasible and safe and has a good clinical outcome. The hospital costs are less than for open techniques.

Laparoscopic incisional hernia repair with a self-centring suture.

BACKGROUND: Open incisional hernia repair is associated with high morbidity and recurrence rates. Laparoscopic approaches offer improved long-term results with low complication rates. METHODS: Laparoscopic repair was attempted in 117 consecutive patients (median age 68 (range 31-91) years, 50 men) undergoing 122 operations. A novel mesh centralization technique was employed. Data were recorded prospectively. Follow-up was by clinical review or telephone consultation. RESULTS: One hundred and eighteen procedures (96.7 per cent) were completed laparoscopically; four required conversion. Forty-one patients (35.0 per cent) had additional, unsuspected defects. The median mesh size was 225 (range 42-600) cm2. Median follow-up was 42 months. Small bowel enterotomy occurred in six patients. Fourteen postoperative seromas were successfully aspirated. Recurrence was detected in nine patients (7.7 per cent). One patient was readmitted with small bowel obstruction that settled with conservative management. There were no enterocutaneous fistulas. One patient died after operation from myocardial infarction. CONCLUSION: Laparoscopic incisional hernia repair using a self-centring suture provides good long-term results with low complication rates.

The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus.

Endemic pemphigus foliaceus, like the sporadic form seen in the developed world, is mediated by IgG antibodies to desmoglein-1. We studied an endemic focus in Limao Verde, Brazil, where disease prevalence is 3.4%. We previously detected IgG antibodies to desmoglein-1 in 97% of patients, but also in 55% of normal subjects in the endemic focus, with progressively lower levels in normal subjects in surrounding areas. An environmental trigger is hypothesized to explain these and other findings. In this study we sought to determine if patients and enzyme-linked-immunosorbent-assay-positive normal subjects in Limao Verde differ in IgG subclass response to desmoglein-1. We developed a sensitive and specific subclass enzyme-linked immunosorbent assay using recombinant desmoglein-1 and standardized the assay to enable comparability between the four subclasses. We found that normal subjects have an IgG1 and IgG4 response, whereas patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4 response. Patients in remission have a weak IgG4 response, and a 74.3-fold higher IgG4 response is associated with active disease. Finally, in five patients in whom we had blood samples from both before and after the onset of clinical disease, a mean 103.08-fold rise in IgG4 was associated with onset of clinical disease, but only a mean 3.45-fold rise in IgG1. These results suggest that the early antibody response in normal subjects living in the endemic area and in patients before the onset of clinical disease is mainly IgG1. Acquisition of an IgG4 response is a key step in the development of clinical disease.

The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research.

BACKGROUND: Pemphigus foliaceus is an autoimmune skin disease mediated by autoantibodies against desmoglein 1. The endemic form is thought to have an environmental cause. The Terena reservation of Limão Verde in Mato Grosso do Sul, Brazil, is a recently identified focus of the disease, with a prevalence of 3.4 percent in the population. We tested the hypothesis that normal subjects living in an endemic area have antibodies against desmoglein 1. METHODS: We used an enzyme-linked immunosorbent assay to detect antibodies against desmoglein 1 in serum samples from 60 patients with endemic pemphigus foliaceus (fogo selvagem) who lived in Limão Verde or elsewhere in Brazil, 372 normal subjects (without pemphigus foliaceus) from Limão Verde and surrounding locations, and 126 normal subjects from the United States and Japan. RESULTS: Antibodies against desmoglein 1 were detected in 59 of the 60 patients with fogo selvagem (98 percent) but in only 3 of the 126 normal subjects from the United States and Japan (2 percent). Antibodies were also detected in 51 of the 93 normal subjects from Limão Verde (55 percent) and in 54 of the 279 normal subjects from surrounding areas (19 percent). Serum samples obtained one to four years before the onset of disease were available for five patients; all five had antibodies in the initial serum samples, and the onset of disease was associated with a marked increase in antibody values. CONCLUSIONS: The prevalence of antibodies against desmoglein 1 is high among normal subjects living in an area among where fogo selvagem is endemic, and the onset of the disease is preceded by a sustained antibody response. These findings support the concept that the production of antibodies against desmoglein 1 is initiated by exposure to an unknown environmental agent.

A native soluble form of CTLA-4.

CTLA-4 is an immunoregulatory receptor expressed on the surface of activated T and B lymphocytes. The counterreceptors for CTLA-4 are the B7 family molecules. We describe alternatively spliced mRNAs expressed in hematolymphoid tissues of humans, mice, and rats that lack the transmembrane domain coded by exon 3 of the CTLA-4 gene. These alternate transcripts were detected by RT-PCR in B cells and resting T cells of both the CD4 and the CD8 phenotype. Activation of human blood mononuclear cells with PHA or anti-CD3 + anti-CD28 monoclonal antibodies appears to effect a decrease in the amount of the alternative transcript relative to the full-length transcript. Recombinant sCTLA-4 is a B7-binding protein and has immunomodulatory effects as measured by inhibition of the mixed leukocyte response. Human serum contains immunoreactive material consistent with a native soluble form of CTLA-4.

Comparison of in vitro and in vivo efficiencies of a novel unit-dose liquid aerosol generator and a pressurized metered dose inhaler.

Gamma scintigraphic imaging was employed in 10 healthy volunteers to compare the total and regional lung deposition of aerosols generated by two delivery platforms that permitted microprocessor-controlled actuation at an optimal point during inhalation. An aqueous solution containing 99mTc-DTPA was used to assess the deposition of aerosols delivered by inhalation from two successive unit-dosage forms (44 microl volume) using a prototype of a novel liquid aerosol system (AERx Pulmonary Delivery System). This was compared with aerosol deposition after inhalation of two 50 microl puffs of a 99mTc-HMPAO-labeled solution formulation from a pressurized metered dose inhaler (MDI). The in vitro size characteristics of the radiolabeled aerosols were determined by cascade impaction. For the AERx system, the predicted lung delivery efficiency based on the product of emitted dose (60.8%, coefficient of variation (CV)=12%) and fine particle fraction (% by mass of aerosol particles <5.7 microm in diameter) was 53.3% (CV=13%). For the solution MDI, the emitted dose was 62.9% (CV=13%) and the predicted lung dose was 44. 9% (CV=15%). The AERx system demonstrated efficient and reproducible dosing characteristics in vivo. Of the dose loaded into the device, the mean percent reaching the lungs was 53.3% (CV=10%), with only 6. 9% located in the oropharynx/stomach. In contrast, the lung deposition from the solution MDI was significantly less (21.7%) and more variable (CV=31%), with 42.0% of the radiolabel detected in the oropharynx/stomach. Analysis of the regional deposition of the radioaerosol indicated a homogeneous pattern of deposition after delivery from the AERx system. A predominantly central pattern of distribution occurred after MDI delivery, where the pattern of deposition was biased towards a central zone depicting the conducting airways. The AERx system, in contrast to MDIs, seems highly suited to the delivery of systemically active agents via pulmonary administration.

111In-labelled leukocyte migration to the lungs of ovalbumin-sensitized guinea-pigs after aerosol challenge with ovalbumin monitored by gamma scintigraphy.

BACKGROUND: To determine whether antigen challenge is associated with increased accumulation of leukocytes in the lungs, the pulmonary accumulation of 111In-labelled neutrophils and eosinophils was monitored by gamma scintigraphy. METHODS: Guinea-pigs were sensitized with ovalbumin (OA) 14-21 days before challenge with aerosolized OA (10 mg/ml) for 2 min, and protected against fatal anaphylaxis by mepyramine (30 mg/kg). Comparisons were made with OA-sensitized guinea-pigs challenged with saline. 5 or 24 h following the OA challenge, guinea-pigs were anaesthetized and the jugular vein and right carotid artery were cannulated, with the contralateral artery tied off. 2MBq 99mTc macroaggregated albumin (MAA) was injected intravenously to create a pulmonary perfusion image as a template for the lungs. 111In-labelled neutrophils or eosinophils were then injected via the carotid artery and gamma scintigraphic images obtained. Activity in the lung region of each animal was determined by superimposing the 99mTcMAA image of the lungs on the whole body image. RESULTS: A significant increase in activity (p<0.05) in the lung region was observed after injection of 111In-labelled neutrophils at 5 h after the OA challenge compared with saline challenge. 24 h after OA challenge there was a significant increase in activity (p<0.05) in the lung region after injection of 111In-labelled eosinophils, but no change in activity after injection of labelled neutrophils compared with the saline-challenged animals. CONCLUSION: This technique models the migration of leukocyte to the lungs seen in guinea-pigs in our previous studies, namely an eosinophilia at 24 h and a neutrophilia at 5 h after OA challenge. It will therefore be useful for investigating anti-inflammatory drugs on the airways.

The synthesis and in vitro characterization of the mucoadhesion and swelling of poly(acrylic acid) hydrogels.

The purpose of this research was to synthesize insoluble, mucoadhesive hydrogels by crosslinking linear poly(acrylic acid) with sucrose and investigate the relationship between hydrogel crosslink density, swelling, and in vitro mucoadhesion. A condensation reaction was employed to synthesize the hydrogels and crosslink density was varied by altering sucrose concentration and cure time. Equilibrium swelling at pH 7.4 was measured both gravimetrically and geometrically. In vitro mucoadhesion was determined by a tensile technique. Equilibrium swelling studies indicated that the crosslink density was proportional to both sucrose concentration and duration of cure time. In vitro mucoadhesive properties of the hydrogels improved as crosslink density increased. This was attributed to an increase in poly(acrylic acid) chain density/unit area of the equilibrium swollen hydrogel, which promoted interaction of the mucoadhesive and glycoprotein polymer chains.

Rheologies and morphologies of three actinomycetes in submerged culture.

The broth rheologies and morphologies of three actinomycetes (Saccharopolyspora erythraea, Actinomadura roseorufa, and Streptomyces rimosus) in submerged culture have been examined. The rheology of all the broths became pseudoplastic as soon as significant growth occurred with the power law index, n, falling to 0.20 to 0.25. The consistency index, K, rose with biomass concentration although in some instances it fell later in the fermentation. The mean main hyphal lengths of all cultures were in the range, 15 to 25 mum, and did not alter greatly even when large changes in K were occurring. (c) 1995 John Wiley & Sons, Inc.

IV lignocaine fails to attenuate the cardiovascular response to laryngoscopy and tracheal intubation.

I.v. lignocaine has been used with varying success to attenuate the cardiovascular responses to laryngoscopy and tracheal intubation. We determined the optimal time of administration in 45 ASA I and II Chinese patients premedicated with morphine and hyoscine, and anaesthetized with thiopentone and suxamethonium. Patients were allocated randomly to a control group or three treatment groups to receive lignocaine 1.5 mg kg-1 i.v. 1, 2, or 3 min before laryngoscopy. Analysis of variance for measured and derived cardiovascular variables failed to show any significant difference between any of the groups.

Acute extradural compression due to an intraspinal synovial cyst: CT and myelogram appearances.

Intraspinal synovial cysts, sometimes referred to as ganglion cysts, are uncommon entities thought to be related to degenerative changes of the facet joints. They usually present with low back pain and sciatica of months or years duration. We report a case of acute extradural compression in a previously asymptomatic patient demonstrated on myelography and computed tomography to be due to a cystic lesion related to the apophyseal joint, shown at operation to be a synovial cyst. The literature on this condition is reviewed.

Effect of premedication on arterial blood gases prior to cardiac surgery.

The effect of premedication on arterial blood gas tensions was studied in thirty adult surgical patients with valvular disease. They were divided into three groups, each group having a different premedication regimen. Blood gas tensions were compared in these patients when awake on the night before surgery, asleep, after premedication and just prior to induction of anaesthesia. Samples were taken while the patient breathed air and each patient acted as his/her own control. The patients were randomised into one of three premedication regimens: 1. intramuscular lorazepam, 2. intramuscular morphine and hyoscine (scopolamine) and 3. oral lorazepam plus intramuscular morphine and hyoscine. There was a statistically significant though not clinically significant rise in PaCO2 and fall in pH following premedication with lorazepam, morphine and hyoscine. There was also a significant fall in PaO2 associated with morphine and hyoscine premedication which was greater than that which occurred with unsedated sleep. Patients who are to undergo cardiac valvular surgery should receive supplementary oxygen following premedication and during transfer to the operating room.

Ventilatory effects of hypoxia and adenosine infusion in patients after bilateral carotid endarterectomy.

1. We have studied the carotid body contribution to hypoxic respiratory drive, using a hypoxic/hyperoxic switching technique, and the ventilatory response to intravenous infusion of adenosine, a recently described respiratory stimulant, in five patients with bilateral carotid endarterectomy. 2. The contribution made by the carotid bodies to total ventilatory drive during hypoxia varied from 2.5% to 45.9%. 3. The ventilatory response to adenosine infusion varied from a 7% decrease to a 25% increase in ventilation. 4. Those patients with intact hypoxic ventilatory drive showed respiratory stimulation, whereas of the two patients with attenuated chemoreflexes, one showed no stimulation and the other depression of ventilation in response to adenosine infusion. 5. We conclude that adenosine exerts its respiratory stimulant effect via an action on the peripheral chemoreceptors. This may coexist with a centrally mediated respiratory depression that is masked when the carotid bodies are intact.