Dapsone: An Update.

Dapsone is an extensively Used drug for the treatment of leprosy as well as'some other clinical problems worldwide: Its use has been predicted to increase further, especially in non leprosy conditions. Treatment with Dapsone is sometimes known'to be associated with side-effects, which include gastrointestinal intolerance, haemolysis, methaemoglobinaemia, agranulocytosis, psychosis, peripheral neuritis and varied dermatological conditions, varying from simple rash to severe life threatening epidermolytic reactions and Dapsone hypersensitivity syndrome (DHS). DHS is a rare delayed hypersensitivity reaction involving multiple organs. the condition is associated with high morbidity and is potentially fatal. In this article, the focus is on etiopathogenesis, diagnosis and management of DHS. Awareness of the varied presentation/s of the condition, early recognition, withdrawal of the drug and proper management helps in rapid reduction in morbidity and preventing fatalities associated with it.

Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Early Onset Dapsone-induced Photosensitive Dermatitis: A Rare Side Effect of a Common Drug.

Dapsone, a potent anti-inflammatory compound, is mainly used in the treatment of leprosy, dermatitis herpetiformis, erythema elevatum diutinum and other dermatoses. Cutaneous adverse reactions range from acneiform eruptions to toxic epidermal necrolysis. A 30-year-old, married women who was treated with paucibacillary multi drug therapy, developed itchy skin lesions over the both forearms, 'V ' area of the neck and upper back after one week of the drug administration which worsened on exposure to sunlights. A clinical diagnosis of dapsone-induced photosensitive dermatitis was confirmed by histopathology and recurrence of symptoms and signs after re-exposure to the drug. Photosensitivity due to dapsone is rare and very few reports are available in the literature. Our patient had an unusually early onset compared to the previously reported cases.

Primary Neuritic Hansen's Disease presenting as Ulnar Nerve Abscess in a Human Immunodeficiency Virus Positive Patient.

Leprosy has been increasingly known to have an enigmatic relationship with human immunodeficiency virus infection. Co-infection may result in atypical manifestations of leprosy. A 45-year old human immunodeficiency virus-positive male; agricultural laborer presented with a swelling over right elbow, right hand deformity, generalized itching and recurrent vesicles overthe perinasal area. Clinical and investigational findings were consistent with mononeuritic type of Hansen's disease with right sided silent ulnar nerve abscess, partial claw hand. CD4+ count of the patientwas 430 cells/cmm. This patient also hadherpes simplex labialis, with HIV-associated pruritus. To the best of our knowledge such an atypical presentation has not been reported earlier.

Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization.

A combination AIDS vaccine approach consisting of priming with adenovirus-HIV-1MN gp160 recombinants followed by boosting with HIV-1SF2 gp120 was evaluated in chimpanzees. Long-lasting protection, requiring only three immunizations, was achieved against a low-dose challenge with the SF2 strain of HIV-1 and a subsequent high-dose SF2 challenge administered 1 year later without an intervening boost. Notably, neutralizing antibody responses against both clinical and laboratory isolates developed in three chimpanzees and persisted until the time of high-dose challenge. The possibility that cytotoxic T-lymphocytes contribute to low-dose protection of a chimpanzee lacking neutralizing antibodies is suggested. Our results validate the live vector priming/subunit booster approach and should stimulate interest in assessing this combination vaccine approach in humans.

Lung transplantation in a recipient with novel 2009 H1N1 influenza: lessons learned.

Immunosuppressed patients are at an increased risk for severe disease from influenza A (H1N1). We report a case of a patient who died of septic complications from H1N1 acquired at the time of single lung transplant.

Open window thoracostomy: modern update of an ancient operation.

INTRODUCTION: In modern day thoracic surgical practice, better understanding of the pathophysiology of intrathoracic infections, improved antibiotic therapy and advancements in thoracic surgical techniques have decreased the use of procedures such as open window thoracostomy (OWT). Despite this, there are occasions where OWT cannot be avoided, and it is of interest where its current utility lies. To determine the current efficacy of OWT, we reviewed our recent experience with a focus on the indications, timing of surgery, effectiveness in clearing infection, patient survival, and timing of closure. METHODS: After Institutional Review Board approval, charts of 78 patients were reviewed. Dates reviewed were from 1/1/1998 to 1/1/2008. Patients were predominantly male (66 %) with a median age 58 years. Median time from initial diagnosis to OWT was 70 days (range 1 to 720 days). RESULTS: Primary indication for surgery was empyema in 75 (96 %), and most patients had previous thoracic surgery. The most frequent causes of empyema were post-pneumonectomy (n = 25), post-pneumonic (n = 14), and post-lobectomy (n = 9). Bronchopleural fistulae were present in 29 (37 %) cases. Lung cancer was diagnosed in 34 (45 %) patients, and 24 underwent perioperative radiation therapy. Patient survival at 1 month, 6 months, 1 year and 5 years was 94 %, 82 %, 74 % and 60 %, respectively, with an in-hospital mortality of 6.4 %. Infection was controlled in nearly all patients (n = 72). Fifteen (19 %) patients underwent surgical closure for OWT; in 2 (2.6 %), OWT closed spontaneously. CONCLUSIONS: Currently, open window thoracostomy is used to treat complex empyema incurred from pulmonary resection, cancer and/or infection in patients that cannot be managed by more conservative strategies. Overall mortality and morbidity rates are acceptable in this debilitated patient group.

Allograft entrapment after lung transplantation: a simple solution using a pleurocutaneous catheter.

BACKGROUND: Chronic pleural effusion following lung transplantation (LTx) is often responsible for respiratory insufficiency and can lead to lung entrapment. Decortication carries considerable morbidity, and extended use of tube thoracostomy is not practical. We have utilized an indwelling pleurocutaneous catheter in the setting of intractable post-transplant effusion and have reviewed our experience to determine whether this strategy: 1) facilitates resolution of effusion, and 2) adequately palliates lung entrapment. METHODS: Twelve PleurX (Denver Biomedical, Golden, CO, USA) catheters were placed in 9 LTx patients (6 unilateral, 3 bilateral) for refractory pleural effusions after standard tube thoracostomy drainage failed (12/12). Two-thirds of the patients (8/12) also had concomitant lung entrapment. RESULTS: There was no operative mortality. Median time from LTx to catheter placement was 79 days (range 21-769). Catheter use achieved the desired outcome in 11/12 placements. Catheters remained in place for a median of 86 days (range 35-190). Direct catheter-related complications included hemothorax (1) and empyema (1). CONCLUSION: Use of an indwelling pleurocutaneous catheter effectively achieves its intended goals of pleurodesis and management of entrapped lungs after LTx.

A gene for dihydrofolate reductase in a herpesvirus.

The enzyme dihydrofolate reductase (DHFR) is found ubiquitously in both prokaryotes and eukaryotes. It is essential for de novo synthesis of purines and of deoxythymidine monophosphate for DNA synthesis. Among viruses, however, only the T-even and T5 bacteriophage have been found to encode their own DHFR. In this study a gene for DHFR was found in a specific subgroup of the gamma or lymphotropic class of herpesviruses. DNA sequences for DHFR were found in herpesvirus saimiri and herpesvirus ateles but not in Epstein-Barr virus, Marek's disease virus, herpes simplex virus, varicella-zoster virus, herpesvirus tamarinus, or human cytomegalovirus. The predicted sequence of herpesvirus saimiri DHFR is 186 amino acids in length, the same length as human, murine, and bovine DHFR. The human and herpesvirus saimiri DHFRs share 83 percent positional identity in amino acid sequence. The herpesvirus saimiri DHFR gene is devoid of intron sequences, suggesting that it was acquired by some process involving reverse transcription. This is to our knowledge the first example of a mammalian virus with a gene for DHFR.

Characterization of the interleukin 3 receptor.

A variety of homobifunctional crosslinking agents have been used to gain insight into the nature of the murine interleukin 3 (mIL-3) receptor. When [125I]mIL-3 was cross-linked to receptor sites on the surfaces of intact B6SUtA1 cells with disuccinimidyl suberate (DSS), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed the existence of two radiolabeled species with molecular weights of 140 (p140) and 70 (p70) kd (after subtraction of [125I]mIL-3). The relative intensities of the two bands did not change when the [125I]mIL-3 concentration was varied, confirming Scatchard results which suggested only one affinity class. However, when [125I]mIL-3 was crosslinked to intact cells and then incubated at 37 degrees C, the intensity of p140 decreased relative to p70, suggesting a conversion of p140 to p70. This conversion could be inhibited by sodium azide, methylamine, and bacitracin and could also be prevented by first boiling for 1 min in 2% SDS and 5% 2-mercaptoethanol. The putative protease that carried out this apparent conversion appeared to be associated both with plasma membranes prepared from these cells and also with solubilized receptors. Moreover, when p140, crosslinked with both dithiobis succinimidylpropionate and glutaraldehyde, was purified and reelectrophoresed under reducing conditions, p70 could be generated. N-glycanase digestion of p140 and p70 revealed a similar level of N-linked carbohydrate, which upon closer study appeared to consist of two chains, a 3-kd and an 8-kd moiety. Consistent with this data, we propose that the receptor is a 140-kd glycoprotein that is cleaved to a 70-kd surface protein upon mIL-3 binding and chemical crosslinking.

A simple three-step purification procedure for interleukin 3 involving absorption to fixed cells.

We have found that treatment of B6SUtA1 cells with 0.01% glutaraldehyde transformed them into mechanically resistant spheres, thereby making it possible to use these high interleukin 3 (IL-3) receptor-bearing cells as a solid phase reagent suitable for the large scale purification of murine IL-3 (mIL-3). Using this technique, mIL-3 was purified from serum-free pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCCM) approximately 16,000-fold using absorption to B6SUtA1 cells, Sephadex G75 superfine chromatography, and reverse phase high performance liquid chromatography on a C18 column. The overall yield was 16%. The final product consisted of two proteins with molecular weights of 19.5 and 16.5 kd. Both species possessed mIL-3-like activity. N-glycanase treatment of the purified preparation converted all of the 19.5-kd material into the lower molecular weight species, suggesting that the two species represented different glycosylated states of mIL-3 produced by activated T cells. This was confirmed by competition studies that showed that excess pure Escherichia coli-derived recombinant mIL-3, but not granulocyte-macrophage colony-stimulating factor (GM-CSF), could prevent the binding of both species of the PWM-SCCM-derived material to B6SUtA1 cells.

Immunogenicity of recombinant human adenovirus-human immunodeficiency virus vaccines in chimpanzees.

Recombinant human adenovirus (Ad) type 4-, 5-, and 7-vectored vaccines expressing either the HIV env or gag-protease genes were tested for immunogenicity in three chimpanzees. The first phase of the vaccination protocol consisted of a primary and two booster immunizations with Ad-HIVs by the oral route of administration, followed by a single booster immunization with Gag and/or Env subunit vaccines. The second phase of the vaccination protocol consisted of intranasal administration of Ad-HIVs previously administered by the oral route. Following the first phase adenovirus was shed into stools for only 1-7 days and modest type-specific anti-adenovirus neutralizing antibody titers were induced. Strong anti-Env binding antibody responses were detected in all three animals following the second oral booster immunization. One chimpanzee responded with a low-titered type-specific neutralizing antibody response to HIV. Cell-mediated immune responses to Env were not detected after the primary vaccination, but were detected following all booster immunizations. Administration of the Gag subunit vaccine boosted both humoral and cell-mediated immune responses to Gag antigens. In contrast, the Env subunit vaccine boosted cellular but not humoral immune responses. In the second phase of the vaccination protocol, both virus shedding and anti-adenovirus responses were enhanced. All three chimpanzees responded to the intranasal administration of Ad7-HIVs with boosted anti-HIV serum responses, including low-titered type-specific neutralizing antibodies, elicited anti-HIV antibodies at secretory sites, and stimulated cell-mediated immune responses to both Gag and Env antigens.

Timed barium esophagogram: A simple physiologic assessment for achalasia.

OBJECTIVE: Success of achalasia therapy is difficult to determine because repeated physiologic study is impractical and symptoms are subjective. Timed barium esophagography directly measures esophageal emptying and is simple to perform. This study (1) evaluates the assessment of myotomy by timed barium esophagography and (2) compares it with premyotomy and postmyotomy symptoms. METHODS: Fifty patients ingested 250 mL low-density barium and had upright films at 1, 2, and 5 minutes premyotomy. Forty-five underwent repeat timed barium esophagography 8 weeks (median) postmyotomy. Premyotomy and postmyotomy height and width of the barium column were compared and related to symptoms. RESULTS: At 1, 2, and 5 minutes premyotomy, median barium column height was 19, 17, and 15 cm, and width was 5.2, 4.8, and 4.5 cm, respectively. Surgery reduced these to 7.0, 5.0, and 1.0 cm and to 3.5, 3.0, and 1.0 cm, respectively (P <.001). Postmyotomy complete esophageal emptying was seen in 29%, 36%, and 49% at 1, 2, and 5 minutes. Postmyotomy height was unrelated (r approximately 0.2) to premyotomy height but was directly related to premyotomy width (r = 0.3-0.5; P <.05); postmyotomy width was directly related to premyotomy width (r approximately 0.6; P <.001). Premyotomy dysphagia was more severe when little change in width occurred from 1 to 5 minutes (r = 0.26, P =.07). Premyotomy regurgitation was more severe the higher the barium column (r approximately 0.4, P <.007). Surgery relieved symptoms in the majority of patients (grade 2-5 dysphagia from 72% to 4%, grade 2-5 regurgitation from 79% to 4%). Postmyotomy symptoms were unrelated to the timed barium esophagogram. CONCLUSIONS: (1) The timed barium esophagogram gives objective confirmation of successful myotomy. (2) Symptoms are unreliable in assessing esophageal emptying.

N1 esophageal carcinoma: the importance of staging and downstaging.

OBJECTIVE: To evaluate the effects of clinical staging and downstaging by induction chemoradiation therapy in patients with N1 esophageal carcinoma. METHODS: Sixty-nine consecutive patients with regional lymph node metastases (cN1) according to clinical staging received induction therapy before surgery. These were compared to 75 patients both clinically and pathologically N1 (cN1/pN1) who underwent surgery without induction therapy and 79 patients clinically and pathologically not N1 (cN0/pN0) who underwent surgery without induction therapy. Analyses focused on survival and the cost and benefit of therapy. RESULTS: For comparison, the extremes of 5-year survival were 69% for cN0/pN0 patients who underwent surgery alone and 12% for cN1/pN1 patients who underwent surgery alone. Of 69 patients who received induction therapy, 37 were pN0 at resection (downstaged); they had an intermediate survival of 37% at 5 years. Those patients not downstaged with induction therapy had a 12% 5-year survival, similar to patients with cN1/pN1 who underwent surgery alone. After adjusting for the strongest predictors of poor outcome, pN1, and increasing N1 burden, a modest increased risk of death after induction therapy was identified. However, this cost of induction therapy was more than counterbalanced by the benefit of improved survival of downstaging to pN0. CONCLUSIONS: (1) pN1 is the strongest determinant of poor outcome. (2) cN1 patients who are downstaged by induction chemoradiation therapy to pN0 have an intermediate outcome. (3) cN1 patients who are not downstaged by induction therapy have a poor outcome.

Superficial adenocarcinoma of the esophagus.

OBJECTIVE: Experience with treatment and outcome of superficial adenocarcinoma of the esophagus is limited. The purpose of this study was to evaluate the results of surgical management and identify predictors of survival. METHODS: Between September 1985 and December 1999, 122 patients underwent resection. Eighty-nine percent were men (mean age 63 +/- 10 years; range 35-83 years). Sixty (49%) patients were in endoscopic surveillance programs and 48 (39%) had the preoperative diagnosis of high-grade dysplasia. Forced expiratory volume in 1 second was less than 2 L in 12 (12%). Seventy-five (61%) patients underwent transhiatal esophagectomy. Pathologic stage was N1 in 8 (7%). Pulmonary complications necessitating reintubation (respiratory failure) occurred in 10 (8%) patients. Time-related survival models were developed for decision-making (preoperative), prognosis (operative), and hospital care (postoperative). RESULTS: Operative mortality was 2.5%. Survival at 1, 5, and 10 years was 89%, 77%, and 68%. Preoperative decision-making factors associated with ideal outcome were 1-second forced expiratory volume of more than 2 L, surveillance, preoperative diagnosis of high-grade dysplasia, and planned transhiatal esophagectomy. Prognosis was decreased in younger patients and in those with N1 disease. Postoperative respiratory failure increased mortality. CONCLUSIONS: Surgery is the treatment of choice for superficial adenocarcinoma of the esophagus. The ideal patient has a preoperative diagnosis of high-grade dysplasia found at surveillance, good pulmonary function, and undergoes a transhiatal esophagectomy. Discovery of N1 disease or development of postoperative respiratory failure reduces the benefits of surgery.

Critical appraisal of the significance of intrathoracic anastomotic leakage after esophagectomy for cancer.

BACKGROUND: Leakage from esophageal anastomoses is higher than that for other gastrointestinal anastomoses. An intrathoracic anastomotic leak is a potentially catastrophic event. METHODS: Patients with and without thoracic anastomotic leakage were compared for predisposing factors. Leak-related mortality was analyzed. RESULTS: Of 475 patients, there were 17 leaks (3.5%). Predisposing technical factors occurred significantly more frequently in patients who leaked. Sixteen such events were identified as contributory in 11 patients. The hospital mortality for patients who leaked was significantly higher (35% versus 9%, P = 0.005). Inadequate drainage and persistent sepsis accounted for 4 of the 6 deaths. The need for inotropic support postoperatively correlated with leak-related mortality (66% versus 0%, P = 0.006), while leak size, time to diagnosis, or method of drainage did not. CONCLUSIONS: Thoracic anastomotic leaks are largely preventable. Leak-related mortality for the series was 1% and was most commonly related to inadequate drainage.

The solitary pulmonary nodule: a primer on differential diagnosis.

Despite significant advances in noninvasive imaging techniques, management of the solitary pulmonary nodule (SPN) remains a challenge for chest physicians. Patients with SPNs are frequently asymptomatic, and the physical examination is seldom revealing. Accurate diagnosis is essential, because >50% of patients will require prompt disease-specific therapy. The complexity of the problem is best appreciated by reviewing the differential list, which includes nearly 80 distinct clinical entities. Consequently, a thorough understanding of the more common etiologies is necessary to adequately treat patients with SPNs.

Assessment of a pathophysiology-directed treatment for symptomatic epiphrenic diverticulum.

Epiphrenic diverticulum is a rare disease associated with distal esophageal obstruction and a weakened muscularis propria. We have adhered to an operative strategy of excision (diverticulectomy), repair of esophageal wall, and relief of functional and mechanical obstruction. We sought to assess this pathophysiology-directed treatment strategy. From 1987 to 2005, 44 patients underwent surgery for epiphrenic diverticulum. Diverticulectomy, repair, and relief of distal obstruction was performed in 35 (80%) and esophagectomy in nine (10%). Outcome (symptoms, diet, subsequent therapies and morbidity) was assessed by follow-up. Forty of 44 patients had preoperatively identifiable esophageal obstruction (91%). Distal obstruction was functional in 32 patients and mechanical in 24; these conditions coexisted in 16. After surgery, there were no in-hospital deaths; 15 patients experienced 22 in-hospital complications. Survival was 90% at 5 years and 72% at 10 years. Symptoms improved in most patients (P = 0.0004), except for gastroesophageal reflux; new symptoms of gastroesophageal reflux occurred in 9/27 (33%) without this symptom preoperatively. Diet was less restricted postoperatively (P < 0.0001). Of 35 patients undergoing diverticulectomy, three (8.6%) required dilatation and two (6%) reoperation; 6/9 esophagectomy patients required dilatations. Preoperative assessment must include evaluation for mechanical obstruction. Adherence to a pathophysiology-directed operative strategy is safe and will improve the symptoms of most patients, with little need for reintervention. However, occasional patients will experience new symptoms, particularly reflux. Esophagectomy is the alternative for patients who are not candidates for diverticulectomy, repair of esophageal wall, and relief of distal obstruction.