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Aims Thermal injury to the oesophagus is an important cause of life-threatening complication after ablation for atrial fibrillation (AF). Thermal protection of the oesophageal lumen by infusing cold liquid reduces thermal injury to a limited extent. We tested the ability of a more powerful method of oesophageal temperature control to reduce the incidence of thermal injury. Methods and results A single-centre, prospective, double-blinded randomized trial was used to investigate the ability of the ensoETM device to protect the oesophagus from thermal injury. This device was compared in a 1:1 randomization with a control group of standard practice utilizing a single-point temperature probe. In the protected group, the device maintained the luminal temperature at 4°C during radiofrequency (RF) ablation for AF under general anaesthesia. Endoscopic examination was performed at 7 days post-ablation and oesophageal injury was scored. The patient and the endoscopist were blinded to the randomization. We recruited 188 patients, of whom 120 underwent endoscopy. Thermal injury to the mucosa was significantly more common in the control group than in those receiving oesophageal protection (12/60 vs. 2/60; P = 0.008), with a trend toward reduction in gastroparesis (6/60 vs. 2/60, P = 0.27). There was no difference between groups in the duration of RF or in the force applied (P value range= 0.2–0.9). Procedure duration and fluoroscopy duration were similar (P = 0.97, P = 0.91, respectively). Conclusion Thermal protection of the oesophagus significantly reduces ablation-related thermal injury compared with standard care. This method of oesophageal protection is safe and does not compromise the efficacy or efficiency of the ablation procedure.

Atrioesophageal fistula is a life-threatening complication of ablation treatment for atrial fibrillation. Methods to reduce the risk of esophageal injury have evolved over the last decade, and diagnosis of this complication remains difficult and therefore challenging to treat in a timely manner. Delayed diagnosis leads to treatment occurring in the context of a critically ill patient, contributing to the poor prognosis associated with this complication. The associated mortality risk can be as high as 70%. Recent important advances in preventative techniques are explored in this review. Preventative techniques used in current clinical practice are discussed, which include high-power short-duration ablation, esophageal temperature probe monitoring, cryotherapy and laser balloon technologies, and use of proton pump inhibitors. A lack of randomized clinical evidence for the effectiveness of these practical methods are found. Alternative methods of esophageal protection has emerged in recent years, including mechanical deviation of the esophagus and esophageal temperature control (esophageal cooling). Although these are fairly recent methods, we discuss the available evidence to date. Mechanical deviation of the esophagus is due to undergo its first randomized study. Recent randomized study on esophageal cooling has shown promise of its effectiveness in preventing thermal injuries. Lastly, novel ablation technology that may be the future of esophageal protection, pulsed field ablation, is discussed. The findings of this review suggest that more robust clinical evidence for esophageal protection methods is warranted to improve the safety of atrial fibrillation ablation.

Background Environmental enteropathy (EE) refers to villus blunting, reduced absorption, and microbial translocation in children and adults in tropical or deprived residential areas. In previous work we observed an effect of micronutrients on villus height (VH). Objective We aimed to determine, in a randomized controlled trial, if amino acid (AA) or multiple micronutrient (MM) supplementation can improve intestinal structure or barrier dysfunction in Zambian adults with EE. Methods AA (tryptophan, leucine, and glutamine) and/or MM supplements were given for 16 wk in a 2 × 2 factorial comparison against placebo. Primary outcomes were changes in VH, in vivo small intestinal barrier dysfunction assessed by confocal laser endomicroscopy (CLE), and mechanistic (or mammalian) target of rapamycin complex 1 (MTORC1) nutrient responsiveness in lamina propria CD4+ lymphocytes. Results Over 16 wk AA, but not MM, supplementation increased VH by 16% (34.5 μm) compared with placebo (P = 0.04). Fluorescein leak, measured by CLE, improved only in those allocated to both AA and MM supplementation. No effect was seen on MTORC1 activation, but posttreatment MTORC1 and VH were correlated (ρ = 0.51; P = 0.001), and change in MTORC1 was correlated with change in VH in the placebo group (ρ = 0.63; P = 0.03). In secondary analyses no effect was observed on biomarkers of microbial translocation. Metabolomic analyses suggest alterations in a number of microbial- and host-derived metabolites including the leucine metabolite β-hydroxy-β-methylbutyrate, which was increased by AA supplementation and correlated with VH. Conclusions In this phase 2 trial, AA supplementation protected against a decline in VH over the supplementation period, and improved barrier function when combined with micronutrients. Leucine and MTORC1 metabolism may be involved in the mechanism of effect. This trial was registered at www.pactr.org as PACTR201505001104412

BackgroundThermal injury to the esophagus is a known complication of ablation for atrial fibrillation (AF) and accounts for most procedure-related mortality. Thermal protection of the esophageal lumen by infusing cold liquid can reduce thermal injury to a limited extent. A method to control the local luminal esophageal temperature is investigated by this study.ObjectiveTo investigate the ability of a powerful temperature control device to protect the esophagus from ablation-related thermal injury.MethodsA single-center, prospective, double-blinded randomized controlled trial was used to investigate the ability of the ensoETM device to protect the esophagus from thermal injury. This method was compared in a 1:1 randomization to a control group of standard practice utilizing a single-point temperature probe. In the study group, the device was used to keep the luminal temperature at 4°C during radiofrequency (RF) ablation for AF. Endoscopic examination was performed at 7 days post-ablation and esophageal injury was scored. The patient and the endoscopist were blinded to the randomization.ResultsWe recruited 188 patients, of whom 120 underwent endoscopy. Thermal injury to the mucosa was significantly more common in the control group than in those receiving esophageal protection (12/60 versus 2/60; P=0.008), with a trend toward reduction in gastroparesis (6/60 Vs 2/60, p=0.27). There was no difference between groups in RF duration, force, power and combined ablation index (P value range= 0.2-0.9). Procedure duration and fluoroscopy duration were similar (P=0.97, P=0.91 respectively).ConclusionThermal protection of the esophageal lumen significantly reduces ablation-related thermal injury compared to standard care. This method of esophageal protection is safe and does not compromise the efficacy of the ablation procedure.CONDENSED ABSTRACTThermal injury to the esophagus causes most ablation-related deaths. We investigated the ability of a powerful method of esophageal temperature control to protect from thermal lesions during ablation, using a double-blinded randomized clinical trial to compare this to standard care. Patients randomised to receive thermal protection experienced significantly fewer lesions to the esophageal mucosa and a trend towards reduction in gastroparesis. Procedure efficacy and efficiency were not compromised.

Drug abuse, also called substance abuse is a disorder that is characterized by a destructive pattern that leads to problems and distress. It continues to be a significant problem in the world, with millions of adolescents and adults use illicit drugs, including the Philippines. To identify if the person is drug user, methods like urine testing, blood testing, hair and sweat testing has been used in different drug testing centres. Errors and faults may easily alter the interpretation of test result depending on the process of collecting a sample. One can cause false positive result if there is contamination and adulteration. However, testing’s requires time to comprehend the result. Therefore, study was made to provide alternative drug testing methodology with the main capability is to develop a light illuminating system that regulates the amount of light entering to the pupil, the image processing method to identify pupil size with an accuracy of not less than 95%, and also giving a result within less than 5 minutes. The objective of the project is to develop a device that can determine if a person is impaired by drugs or not. A total of 20 positive drug patients that are newly admitted at Camp Bagong Diwa Rehabilitation Center Philippines and 10 people who didn’t took drug were sampled. Based on the testing conducted, 20 positive drug patient was identified to be True by the device while the 10 patients who didn’t took drug at all was identified to have 1 patient only to be positive & resulted as error. After thorough testing and evaluation by the client, the device yielded to 96.67% accuracy and the requests of the client being small and portable is achieved. The accuracy of the device proved that the objectives were met based on the needs of the client.

Background: Male factor is a predominant cause of infertility. Success rates of intrauterine insemination(IUI) for male factor depend upon minimum semen parameters such as progressive motility > 30%, strict morphology > 4%, total motile count in the native sample (TMSC) >5 million and inseminating motile count (IMC) > 5 million. Couples with parameters lesser than these are usually advised IVF-ICSI. In developing countries, affordability for IVF is an important deterrent to its widespread utilisation. Aims: To evaluate pregnancy rates after the use of a pooled consecutive ejaculate in infertile men with semen parameters of < 5 million TMSC, and to compare with pregnancy rates achieved among couples with semen parameters > 5 million TMSC after processing of a single ejaculate. Settings and Design: Private infertility practice. Retrospective study from Oct 2012 to June 2019. Methods and Materials: All consecutive patients (n=1979) who underwent IUI in the given study period were included. Patients undergoing donor sperm insemination and low IMC (

Background Cytomegalovirus (CMV) disease is a common and clinically significant complication following intestinal or multivisceral transplantation. CMV disease is more common in cases of serologic mismatch between donor and recipient. Though in some cases it may be asymptomatic, in the immunosuppressed population it often manifests with evidence of systemic infection or end-organ disease. Methods We conducted a retrospective review of all patients undergoing intestinal or multivisceral transplantation over 8 years at our institution. Results Forty-eight transplantations were performed, with 40% of the patients (19/48) having ≥1 episode of CMV viremia, which rose to 90% in the “donor-positive, recipient-negative” (DPRN) serologic mismatch group. The median time to 1st episode following transplantation was 22.3 weeks (range, 1–78) and median duration of each episode was 4.9 weeks (range, 1.6–37.4). Six of the 19 viremic patients (31.6%) developed virologic resistance with 4 of these occurring in the DPRN group. Four of the 6 patients with drug-resistant CMV died with CMV viremia. All patients with drug resistance acquired ganciclovir resistance; these patients were more challenging to manage with second-line toxicity-limited treatments, including foscarnet, cidofovir, and leflunomide. CMV immunoglobulin has been used and we briefly discuss the use of CMV-specific adoptive T-lymphocyte transfer in the management of 1 case. Conclusions Post-transplantation CMV disease continues to be challenging to manage, and there is little consensus on optimal management strategies in this patient group, with a significant requirement for novel therapies; these may be pharmacologic or cell based. Extensive multidisciplinary discussion is important for most cases, but particularly for those patients who acquire virologic resistance.

Introduction: Antifungal agents are routinely used in the post-transplant setting for both prophylaxis and treatment of presumed and proven fungal infections. Micafungin is an echinocandin-class antifungal with broad antifungal cover and favorable side effect profile but, notably, it has no activity against molds of the order Mucorales. Presentation of case: A 47-year-old woman underwent multivisceral transplantation for intestinal failure-associated liver disease. She had a prolonged post-operative recovery complicated by invasive candidiasis and developed an intolerance to liposomal amphotericin B. In view of her immunosuppression, she was commenced on micafungin as prophylaxis to prevent invasive fungal infection. However, she developed acute graft versus host disease with bone marrow failure complicated by disseminated mucormycosis which was only diagnosed post mortem. Discussion: Non-Aspergillus breakthrough mold infections with micafungin therapy are rare with only eight other cases having been described in the literature. Breakthrough infections have occurred within one week of starting micafungin. Diagnosis is problematic and requires a high degree of clinical suspicion and microscopic/histological examination of an involved site. The management of these aggressive infections involves extensive debridement and appropriate antifungal cover. Conclusion: A high level of suspicion of invasive fungal infection is required at all times in immunosuppressed patients, even those receiving antifungal prophylaxis. Early biopsy is required. Even with early recognition and aggressive treatment of these infections, prognosis is poor. Keywords: Antifungal therapy, Micafungin, Mucormycosis, Multivisceral transplantation, Immunosuppression, Fungal infection

BACKGROUND: Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia.METHODS/PRINCIPAL FINDINGS: We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013).CONCLUSIONS/SIGNIFICANCE: Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization.

Purpose of Review The term ‘tropical enteropathy’ originated in observations in the 1960s that small intestinal morphology and function differed in the tropics from the norms found in temperate climates. It was subsequently shown that this enteropathy is more closely related to environmental conditions than latitude, and it was re-labelled ‘environmental enteropathy’. It is now recognised that environmental enteropathy (also now called environmental enteric dysfunction) has implications for the health and linear growth of children in low- and middle-income countries, and it may underlie poor responses to oral vaccination in these countries. The purpose of this review is to define and clarify this enteropathy despite the confusing terminology it has attracted and to contrast it with other enteropathic states. Recent Findings Recent work has begun to demonstrate the nature of the mucosal lesion and the relationship with microbial translocation which is currently thought to link a failure of mucosal barrier function and the cascade of systemic inflammation which inhibits growth. The evidence is still correlative rather than definitive, but derives some additional support from animal models. There are some common features between environmental enteropathy and other enteropathies, but there are important differences also. The mechanism of the link between enteropathy and vaccine failure is not understood, and neither is it clear how the more severe form of enteropathy, which we refer to as malnutrition enteropathy, is driven by nutrient depletion and intestinal infection. Summary Tropical enteropathies form a group of disorders which include environmental and nutritional enteropathies. The long-term health implications of these disorders for health in low-income countries are just being explored, but the scale of their effects is very large, with millions of people affected.

Introduction Environmental enteropathy (EE) is associated with growth failure, micronutrient malabsorption and impaired responses to oral vaccines. We set out to define cellular mechanisms of impaired barrier function in EE and explore protective mechanisms. Methods We studied 49 adults with environmental enteropathy in Lusaka, Zambia using confocal laser endomicroscopy (CLE); histology, immunohistochemistry and mRNA sequencing of small intestinal biopsies; and correlated these with plasma lipopolysaccharide (LPS) and a zinc uptake test. Results CLE images (median 134 for each study) showed virtually ubiquitous small intestinal damage. Epithelial defects, imaged by histology and claudin 4 immunostaining, were predominantly seen at the tips of villi and corresponded with leakage imaged in vivo by CLE. In multivariate analysis, circulating log-transformed LPS was correlated with cell shedding events (β = 0.83; P = 0.035) and with serum glucagon-like peptide-2 (β = -0.13; P = 0.007). Zinc uptake from a test dose of 25mg was attenuated in 30/47 (64%) individuals and in multivariate analysis was reduced by HIV, but positively correlated with GLP-2 (β = 2.72; P = 0.03). There was a U-shaped relationship between circulating LPS and villus surface area. Transcriptomic analysis identified 23 differentially expressed genes in severe enteropathy, including protective peptides and proteins. Conclusions Confocal endomicroscopy, claudin 4 immunostaining and histology identify epithelial defects which are probably sites of bacterial translocation, in the presence of which increased epithelial surface area increases the burden of translocation. GLP 2 and other protective peptides may play an important role in mucosal protection in EE., Author Summary Environmental enteropathy is a widespread problem in adults and children in many disadvantaged populations, particularly in the tropics. It is not attributable to one specific infectious agent, but likely due to several insults of environmental origin. It is associated with growth failure in children, impaired responses to oral vaccines, and contributes to micronutrient deficiencies. Many of these problems can be related to immune activation, but the pathways of immune activation are unknown. Here we show that translocation of gut microbes and their molecular components is associated with defects in the epithelial lining of the gut, imaged using advanced endoscopic techniques. We also report evidence that these defects are associated with failure of endocrine and paracrine repair mechanisms which in health should restore the integrity of the intestinal barrier. These observations may open up new approaches for therapy for a neglected tropical disorder which impairs the health of millions of adults and children.

The purpose of this study was to measure the tensile properties of fresh human calcaneal (Achilles) tendons. Twenty fresh cadaveric (age range = 57–93 years) bone-Achilles tendon complexes were harvested within 24 hr postmortem. The calcaneus together with 15 cm of the Achilles tendon extending proximally from the insertion on the calcaneus was clamped and biomechanically tested. Each tendon was firmly fixed in clamps in an MTS Systems Corporation MTS testing machine and tension was applied at a displacement rate of 8 cm per minute until the tendon failed. The tensile force and tensile strain (as measured using an extensometer) were recorded and plotted using onboard software. The narrow age range of our donors prevented any meaningful correlation between age and tensile properties; however, the results showed that: 1) the average ultimate tensile strength (UTS) of the human Achilles tendon was 1189 N (range = 360–1,965), 2) there was a correlation between left and right legs for UTS, 3) there was a correlation between left and right legs in regard to cross sectional area, and 4) there was no correlation between UTS and cross-sectional area. Clin. Anat. 17:30–35, 2004. © 2003 Wiley-Liss, Inc.

Background: Hidradenitis suppurativa is a disabling disease. Although medical management can at times control the disease, the treatment of choice is surgical excision. Surgical defects have been managed by second-intention healing, simple surgical closure, or complex surgical repairs. Objective: Our purpose was to determine the benefit of carbon dioxide laser excision with healing by second intention to treat lesions of hidradenitis suppurativa. Methods: We treated seven patients who had axillary and inguinoperineal hidradenitis suppurativa with carbon dioxide laser excision followed by second-intention healing. A total of 12 procedures were performed (five bilateral and two unilateral). Follow-up periods were 10 to 27 months. Results: After a healing time of 4 to 8 weeks, scars were flat and linear. Only one recurrence of hidradenitis suppurativa has been observed; this occurred along the margin of the surgical scar in a previously treated area. Some patients, however, had continued disease activity in untreated areas. All subjects were satisfied with the results of the procedure, and complications were minimal. Conclusion: Carbon dioxide laser excision with second-intention healing is safe and effective for hidradenitis suppurativa.

Introduction Amongst patients on longterm parenteral nutrition, rates of osteoporosis vary between 41–67%. 1,2 In the United States, 77.4% of patients awaiting intestinal transplantation had low bone mineral density (BMD). 3 It is not known how prevalent low BMD is amongst patients undergoing intestinal transplantation in the United Kingdom. Method We retrospectively reviewed the notes and bone densitometry scans (DEXA) for all patients who had undergone isolated intestinal, modified multivisceral, or full multivisceral transplantation from December 2007 to December 2014. Results 49 patients were transplanted including 5 acutely (4 mesenteric ischaemia, 1 intestinal failure associated liver disease) with no time for pre-operative DEXA. It was not known whether pre-operative DEXA was performed in 6 patients. Of the remainder, 33/38 (87%) had DEXA performed a median of 329 days (range 12–986) prior to transplantation. Osteoporosis was seen in 13/33 (39%) with a median hip T-score -2.7 (range -1.3 to -4.8), median spine T-score -3.1 (range -1.6 to -5.4), and median age at transplant 46 years (range 18–64). Osteopenia was seen in 11/33 (33%) with 9/33 (27%) having normal BMD. Of those who did not have pre-operative DEXA but who were scanned within 1 year (n = 10), 7 had reduced BMD. Specifically, patients undergoing acute transplant demonstrated reduced BMD (osteopenia) in 2/5 (age 27 and 33 at transplant). Patients were managed with a combination of calcium/Vitamin D and/or bisphosphonates, with two patients referred to a metabolic bone clinic. There were no cases of fragility fractures. Of the surviving patients who have had sequential DEXA, including ≥2 scans post-transplant (n = 7), there is a trend towards increasing BMD over subsequent years. Conclusion Prevalence of low BMD is 72% in patients undergoing intestinal or multivisceral transplantation at our centre and these patients are often under the age of 50 years sometimes with profound osteoporosis (e.g. T -5.4). Poor bone health is not restricted to those on long term parenteral nutrition with intestinal failure but is also seen in patients with acute indications requiring transplant such as mesenteric infarction. As patients survive longer the sequelae of osteoporosis become important – addressing reduced BMD pre-operatively is important as improving bone health may take some years. Use of corticosteroid immunosuppression increases risk of reduced BMD in this cohort. Disclosure of interest None Declared. References Pironi L, et al . Clin Nutr. 2002;21:289–296. Cohen-Solal M, et al . J Bone Miner Res. 2003;18(11):1989–1994. Resnick J, et al . Am J Transplant. 2010;10:2331–2340.

Introduction Environmental enteropathy (EE) is associated with growth failure in children in low income countries, malabsorption, and impaired responses to oral vaccines. EE is characterised by morphological changes (villous blunting), increased permeation of macromolecules, microbial translocation, and impaired absorption. We set out to image the leakiness of the enteropathic small intestine using confocal laser endomicroscopy (CLE) of the duodenum following fluorescein injection, and correlate this with other markers of structure, absorption and microbial translocation. Method Fifty adults were recruited from a poor community in Lusaka where we have previously established that EE is ubiquitous, and then underwent CLE on the day after permeability (lactulose 5g, rhamnose 1g) and net zinc absorption from a 25mg test dose were measured. Between 35 and 225 CLE images per procedure were quantified for a range of cellular abnormalities and fluorescein leakage. Duodenal biopsies were assessed morphometrically and claudin-4 expression quantified. Of the 50 participants, one had pyloric stenosis and in 8 the image quality was sub-standard, so full data are available from 41 (14 men, mean age 32 y, 11 HIV seropositive). Watson scores were 1 in 4 people, 2 in 6, and 3 in 31, which contrasts markedly with published control data in healthy German adults in which nearly all were grade 1 ( P .0001). Results Leakage of fluorescein into the duodenal lumen was inevitably present when visible cell defects or microerosions were present, and was inversely associated with net absorption of zinc (r = -0.39; P = 0 .04). Direct markers of microbial translocation (LPS and LPS binding protein) were correlated (in HIV seropositives only) with gastric pH (r = 0.72; P = 0 .01) and with a serum marker of epithelial damage, fatty acid binding protein (FABP, r = −0.62; P = 0 .04). FABP was strongly correlated with leakage, especially in HIV infection (r = −0.69; P = 0 .007). Leakage was also inversely correlated with the intensity of expression of claudin-4 along the basolateral surface of the enterocyte (r = −0.49; P = 0 .01). In multiple linear regression, LPS was strongly correlated with cell shedding and GLP-2 in serum. Conclusion These data indicate that the damaged epithelium of EE leads to leakage of circulating molecules into the gut, and may explain at least one measure of absorptive defect. Pathways of translocation maybe more complex, with some translocation that cannot be explained by cell disruption. Translocation pathways are not well reflected by lactulose permeation. A clearer understanding of mechanisms will be important to reducing translocation in the enteropathic gut. Disclosure of interest None Declared.

Introduction Environmental enteropathy (EE), originally termed tropical enteropathy, is very common in overcrowded living conditions in developing countries. It predisposes to growth failure in the young, and probably to poor performance of oral vaccines. By permitting microbial translocation it probably contributes to insidious systemic immune activation. In order to understand the impairment of barrier function in EE, we performed confocal laser endomicroscopy (CLE) in 62 healthy volunteers from a poor community in Lusaka, Zambia. Methods These asymptomatic volunteers were drawn from a community in Misisi with which we have been conducting studies for 15 years. On day 1 a 3 h lactulose: mannitol permeability and zinc absorption test was performed. On day 2 CLE of the duodenal mucosa was performed with diazepam/pethidine sedation and 5–10 ml 2% intravenous fluorescein, and images collected for 10 min exactly (mean number of images analysed 135, SD57). Biopsies were subsequently taken to analyse villous morphology and tight junction protein expression (data not yet available). Results In the first 22 volunteers (12 female, 10 male) studied, a wide range of villous architectural patterns was observed from leaf-like to convolutions. Similarly, a wide range of barrier abnormalities was observed, with some volunteers showing severe fluorescein leakage within one minute of fluorescein injection. Epithelial breaks, particularly multicellular breaks termed microerosions, were strongly correlated with the rate of fluorescein efflux (Spearman’s rho 0.92; P Conclusion CLE permits imaging of small intestinal epithelial barrier defects and suggests that cellular breaches are major routes of intestinal permeability but independent of villous architecture. Disclosure of Interest None Declared.

Background: ICAM-1 and P-selectin are molecules that facilitate adhesion of circulating leukocytes to vessel walls. We have investigated the role of donor-derived ICAM-1 and P-selectin in acute and chronic cardiac allograft rejection. Methods C57BL/6J (H-2 b ) mice were used as donors for heterotopic heart transplantation into CBA/Ca (H-2 k ) recipients. The donors were wild-type or homozygous for gene mutations of ICAM-1 or P-selectin. We measured acute rejection in non-immunosuppressed recipients by daily palpation and sacrificed mice at Days 2, 4, and 6 for immunohistochemical analysis. For chronic rejection, recipients received monoclonal antibody against CD4+ T cells. We removed hearts at Days 60 to 62 for histologic assessment of vasculopathy using quantitative morphometry to measure intimal thickening. Results Time (days) to rejection was 7.1 ± 0.57 for wild-type ( n = 10), 7.0 ± 0.71 for ICAM-1 −/− (not significantly different, n = 7) and 6.1 ± 0.33 ( p = 0.001) for P-selectin −/− donors. ICAM-1 deficiency was associated with delayed infiltrate at Day 4 compared with wild-type. In the model of chronic rejection, elastin-positive vessels showed a mean occlusion of 34% ± 3% in transplanted wild-type hearts; vessels were divided into those showing 0% to 20%, 20% to 50%, and 50% to 100% occlusion. We observed no difference in the number of affected vessels or the amount of vascular thickening in donors lacking ICAM-1 or P-selectin compared with wild-type controls. Conclusions The absence of ICAM-1 or P-selectin in donor tissues neither lengthens the time of allograft survival nor inhibits the vascular lesions associated with chronic rejection. Indeed, the absence of P-selectin may exacerbate alloimmune injury.

Many of the standard forms of therapy for large or multiple superficial basal cell carcinomas are limited by significant postoperative pain, excessive scarring, and prolonged wound healing time. Combining traditional curettage with carbon dioxide laser vaporization creates a procedure that allows excellent visualization, due to the bloodless surgical field produced by the laser, minimal nonspecific thermal damage, rapid healing, and diminished postoperative pain. In addition, the speed and ease with which this procedure can be performed allow successful treatment of many lesions in a single outpatient session. We wish to report our results using this technique for the treatment of 52 patients with 370 superficial basal cell carcinomas.

The chronic stage of acne keloidalis nuchae is characterized by symptomatic keloidal papules and plaques on the occipital scalp and posterior neck. We describe our results with the use of the carbon dioxide laser in eight patients with treatment-refractory acne keloidalis nuchae.

A case of necrobiotic xanthogranuloma treated with plasmapheresis is reported. This entity is characterized by multiple inflammatory, ulcerative nodules and atrophic plaques with a xanthomatous quality that develop in conjunction with a paraproteinemia. Successful healing of ulcerated lesions and lowering of the paraproteinemia was achieved by plasmapheresis in our patient with necrobiotic xanthogranuloma when cytotoxic therapy failed.

Multiple symmetric lipomatosis is a fascinating disease of uncertain etiology that manifests as massive lipomatous deposits in specific areas of the body. The clinical syndrome and possible pathogenesis are discussed, Classic surgical lipectomy has been the only treatment thus far reported; we report a patient successfully treated with liposuction.

Diazolidinyl urea (Germall II) is a preservative recently used in cosmetics. It is effective against most contaminating microorganisms, especially Pseudomonas. We report the first case of an acute allergic contact dermatitis from diazolidinyl urea that was contained in a hair gel.

A case of primary localized cutaneous amyloidosis is presented to illustrate the spectrum of cutaneous amyloidosis. The clinical, pathologic, and pathogenic characteristics of amyloidosis syndromes are briefly reviewed and summarized.

Cutaneous squamous cell carcinoma is a more aggressive tumor than basal cell carcinoma. It can be associated with extension far from the site of origin and lymph node metastasis. Its etiology is similar to that of basal cell carcinoma. Treatment for the aggressive and uncontrollable tumor seems best accomplished with a combination of conventional surgery with total microscopic marginal control.

Hemoglobin North Chicago, beta 36 [C2] Pro----Ser is a new high oxygen affinity hemoglobin variant. It was discovered in a 52-year-old male with erythrocytosis since age 20 who had been treated with different regimens for polycythemia vera including several courses of 32P. The variant is electrophoretically silent with normal stability and increased oxygen affinity (P50 16.6 mm Hg at 37 degrees C, pH 7.4). Characterization of the structure of hemoglobin North Chicago involved the use of HPLC, secondary ion mass spectral analysis of the tryptic peptides and conventional fingerprinting. Hemoglobin North Chicago manifested bizarre hydrophobicity of its beta-chains, as demonstrated by reverse phase HPLC and Triton X-100 electrophoresis. This behavior is not expected from the substitution of proline to serine. Proline residue beta 36 [C2] is one of the invariant residues of the beta-chains of all known mammals and most vertebrates. This residue is involved in the alpha 1 beta 2 contacts of hemoglobin molecule and its substitution to serine is possibly associated with conformational changes and alteration of hemoglobin function.

A double-blind, double-paired comparison, placebo-controlled study was undertaken to determine the optimal agent for sclerotherapy of spider telangiectasias of the lower extremities. Sodium tetradecyl sulfate 0.5%, polidocanol 0.25%, heparsal, and normal saline control were evaluated in terms of clinical effectiveness and patient acceptance. Although all of the agents, except for the control, were effective, polidocanol was found to have the fewest adverse reactions and afforded the greatest patient comfort.

The authors report a case of generalized granuloma annulare which responded favorably to hydroxychlor-oquine use. Possible pathogenic mechanisms for the disease and past therapeutic modalities are discussed.

Erythermalgia is a condition of the extremities characterized by redness, increased temperature, and burning pain. A case of erythermalgia and coincident vasculitis of the feet is reported. The literature on the subject is reviewed, and a possible mechanism of pathogenesis is discussed.

A controlled study of cyclophosphamide (Cytoxan) therapy in acute leukemia was conducted in 142 children in relapse to previous therapies. An oral regimen, using daily doses of 3mg/kg/day induced remission (complete or good partial) in 31.5% of the group; the intravenous regimen, using 15 mg/kg once weekly, induced similar remission in only 10.2% of the children so treated. All children who attained complete or partial remissions entered the study in a status of moderate disease while those in a more severe status of disease failed to attain satisfactory remissions to either regimen. Bone marrow remissions (A-1 ratings) were attained in 27.5% of the group treated orally and in only 2.9% of those treated with the intravenous regimen. Leukopenia was the only significant hematologic sign of toxicity with either route of therapy. Signs of inflamation of the urinary tract occurred in approximately 10% of the patients. Nausea and vomiting were much more common with intravenous therapy. Cyclophosphamide, administered orally, is effective for the treatment of acute leukemia for children in early relapse but is not effective in patients in severe relapse to previous therapy.

A patient with multiple congenital vascular anomalies is described. The lesions are a nevus flammeus on the face, a nevus anemicus on the trunk, and asymmetric reticulated mottling of a lower extremity that had undergone spontaneous ulceration. The characteristics of these lesions are reviewed and the difficulty of differential diagnosis of the reticulated lesion is discussed. The ulcerations healed after administration of reserpine intraarterially followed by oral administration of phenoxybenzamine hydrochloride.

There were an estimated 656 cases of vaporizer-related injuries seen in hospital emergency departments in 1979. Two cases of burns with respiratory involvement are described. Both children were directly exposed to steam from commercial vaporizers and suffered cutaneous and respiratory burns. These cases emphasize the hazards of steam vaporizers, devices that have no proven therapeutic benefits.

A case of multicentric reticulohistiocytosis with thyroid involvement is reported. This systemic condition has an unknown cause and is manifested by the development of nodules containing an infiltrate of characteristic histiocytic and multinucleated giant cells in the synovium, skin, subcutaneous tissues, and occasionally bone or other tissues.

A description of the technique used in preventing inadvertent injury to the eye during periorbital or eyelid laser surgery is given.

The carbon dioxide laser in both conventional and superpulsed modes was used to treat 13 patients with chronic actinic cheilitis. The procedure was well tolerated. Focal, but not functionally restricting, scarring developed in three patients. The cosmetic result was otherwise excellent. No recurrences have been noted.

Analysis of 1,620 basal cell carcinomas treated at the Cleveland Clinic Foundation from 1981 to 1983 confirms that the majority of basal cell carcinomas occur on the face and that the relative risk for recurrent tumor is high in certain locations, especially the nose. Alternately, tumors found on the neck/scalp, trunk, and arms have a low relative risk of recurrence when compared to all other anatomic locations. More primary and fewer recurrent tumors now presenting to our unit have been referred for Mohs surgery as primary therapy. This results in higher cure rates for treatment of all basal cell carcinoma.

Techniques and results of CO2 laser vaporization of epidermal nevi in 15 patients over a 5-year period is presented. This procedure provides an alternative and effective surgical method for the successful removal of such lesions.

Ten patients with dermatofibrosarcoma protuberans, all of whom had been treated previously by conventional excisional surgery without success, were treated with Mohs micrographic surgery. A team approach utilizing margin control by Mohs-trained physicians and reconstruction by surgical specialists was employed. Average follow-up exceeds 3 1/2 years, with no recurrences. Microscopically controlled excision appears to be the treatment of choice for dermatofibrosarcoma protuberans.

Cutaneous benign neurofibromas are the most common skin manifestation of Von Recklinghausen neurofibromatosis (NF). An autosomal dominant disorder, NF has extraordinary clinical variability and multisystem involvement; many patients develop hundreds of cutaneous neurofibromas in a lifetime. This problem can easily and rapidly be treated using the CO2 laser with results equal to or better than excision. The procedure is very helpful for patients with large numbers of small- or medium-sized cutaneous neurofibromas.

Sebaceous carcinoma of the eyelid is a rare neoplasm usually arising from the meibomian gland. This tumor has distinctive histologic features characterized by unique foamy cytoplasm. The cases of three patients with this tumor who were treated by Mohs' surgery, followed by ophthalmologic cosmetic repair, are presented and discussed.

Acute leukemia was treated in 46 children and 29 adults by five different therapeutic regimens. The largest group, consisting of 55 patients, received steroids (cortisone or prednisone) with 6-mercaptopurine; 9 received 6-mercaptopurine only, 5 received steroids only, and 6 received other forms of treatment. The remission rate for all the children treated was 77%; some went on to a second remission, and one went to a third. The rate of remissions for adults was only 17%, and there were no second remissions in any of the adult patients. The data on survival times proved difficult to compare. The duration of life was nearly the same in each group, as was the duration of therapy needed to induce remission. The duration of remission appeared to be longest in those patients who received a combination of 6-mercaptopurine and steroids, but the limited size of the other groups made comparison difficult. The steroid treatment caused a noticeable weight gain and some other undesired effects but no electrolyte imbalance, hypertension, or peptic ulcer. The undesired effect of 6-mercaptopurine was occasional, sudden, excessive leukopenia. The 50% survival time in the group who received 6-mercaptopurine was 9 months, and the 10% survival time was 19 months.

A COOPERATIVE STUDY of a treatment of myeloma by 21 institutions has been in progress for four years.1A uniform protocol, criteria, and data flow sheets have been followed and evaluated by the committee. Comparison survival data with previous forms of treatment was obtained in an ancillary myeloma study by the same cooperative group in the same institutions.2Cyclophosphamide (Cytoxan) was selected as an alkylating agent suitable for use in a low oral dose, longrange program. These results are based on a study of 165 patients who received the drug for at least 60 days (an "adequate trial"). Twenty percent (42) of the patients who started the study did not reach adequate trial status because of death (17), complications (8), or loss to follow-up (17). Materials and Methods Participating investigators placed on study as many patients as possible from their respective institutions. The diagnosis of multiple myeloma was

BACKGROUND: Environmental enteropathy (EE) is an asymptomatic abnormality of small bowel structure and function, which may underlie vaccine inefficacy in the developing world. HIV infection co-exists in many of these populations. There is currently no effective treatment. We conducted a secondary analysis of a randomised controlled trial of high dose multiple micronutrient (MM) supplementation on small bowel architecture in EE in participants with or without HIV infection. METHODS: In a double-blind parallel-group trial of the effect of MM on innate immune responses to oral vaccines, consenting Zambian adults were randomised to receive 6 weeks of 24 micronutrients as a daily capsule or placebo. HIV status was established after randomisation. Proximal jejunal biopsies were obtained after the supplementation period. Villous height, crypt depth, villous width, villous perimeter per 100 μm muscularis mucosa (a measure of epithelial surface area), and villous cross sectional area per 100 μm muscularis mucosa (a measure of villous compartment volume) were measured in orientated biopsy sections using semi-automated image analysis. Analysis was by intention to treat. RESULTS: 18 patients received MM and 20 placebo. 6/18 MM and 9/20 placebo patients had HIV. In HIV negative patients given MM compared to placebo, mean villous height was 24.0% greater (293.3 v. 236.6 μm; 95% CI of difference 17.7-95.9 μm; P = 0.006), mean villous area was 27.6% greater (27623 v. 21650 μm2/100 μm; 95% CI of difference 818-11130 μm2/100 μm; P = 0.03), and median villous perimeter was 29.7% greater (355.0 v. 273.7 μm/100 μm; 95% CI of difference 16.3-146.2 μm/100 μm; P = 0.003). There was no significant effect on crypt depth or villous width. No effect was observed in HIV positive patients. There were no adverse events attributable to MM. CONCLUSIONS: MM improved small bowel villous height and absorptive area, but not crypt depth, in adults with EE without HIV. Nutritional intervention may therefore selectively influence villous compartment remodelling. In this small study, there was a clear difference in response depending on HIV status, suggesting that EE with superimposed HIV enteropathy may be a distinct pathophysiological condition.

To the Editor.— The review article by Zarrabi et al entitled "Chronic Lymphocytic Leukemia Terminating in Acute Leukemia," 1 questions the origin of the acute leukemic termination of chronic lymphocytic leukemia (CLL). The issue raised is whether the occurrence of acute leukemia (AL) with CLL is a second malignancy or a "blast crisis (transformation)," which occurs as a natural evolution of CLL. We would like to demonstrate that the number of cases with CLL and AL reported, and the number predicted, could occur by chance. Since 1936, 2 19 cases of CLL and an associated AL have been reported 1 in the American medical literature. Demographic and morphologic characteristics of the patients with AL have not been consistently reported. The average death rate in 1967 for all ages and sexes was 1.6 per 100,000 for CLL, and 2.4 per 100,000 for AL. 3 The average annual population in the United

To the Editor.— In the May 1984Archives, Drs Goldman and Bauman1described the argon laser treatment of a patient with extensive postsolar poikiloderma of the neck. This patient initially responded well to test treatment in July 1982. Her actual treatment was begun on Sept 16 of that year and follow-up photographs taken on Oct 8, 1984 showed excellent whitening of the treated area. Because of distance problems, her later follow-up visits were in the Department of Dermatology at the Cleveland Clinic. Unfortunately, the patient had developed threadlike scar formation in the treated bands (Figure). This resulted in a texture change as well as total depigmentation in those treated areas. Any attempt to blend the untreated bands would require the same treatment parameters. Several test attempts to do this have resulted only in worsening of the scar. The word of caution here is that although the argon laser may be an exceptionally good modality for treating