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J L Cohen

Publications and source records attributed to J L Cohen.

At least 19 recordsLinked to original sources
PubMed2007

Anastomotic leaks: what is the best diagnostic imaging study?

PURPOSE: Postoperative anastomotic leaks are one of the most devastating consequences of colorectal surgery. Diagnostic imaging for upper gastrointestinal anastomotic leaks has been evaluated and reported on extensively. No study has compared the utility and effectiveness of CT scans and water-soluble enemas for the identification of postoperative lower gastrointestinal anastomotic leaks. The present study was designed to evaluate and compare these two common radiographic imaging modalities in detecting lower gastrointestinal anastomotic leaks. METHODS: A retrospective chart review was performed that identified 36 patients during a seven-year period who underwent reoperative surgery for a lower gastrointestinal anastomotic leak. Patient's imaging studies were classified as positive if extravasation of contrast material was demonstrated. When negative, a study was retrospectively reviewed in an attempt to identify findings suggestive of an anastomotic leak. RESULTS: There were 36 patients identified with a postoperative lower gastrointestinal leak requiring surgical intervention. There were 28 of 36 patients (78 percent) re-explored on the basis of a radiologic study demonstrating an anastomotic leak. A total of 27 CT scans were performed, of which 4 (14.8 percent) were considered positive for an anastomotic leak. On review of the remaining negative CT scans, nine (33.3 percent) were considered descriptive positive with a large amount of fluid or air in the peritoneal cavity but without obvious extravasation of contrast. Eighteen patients were evaluated with a water-soluble enema and 15 (83.3 percent) demonstrated extravasation of contrast material. In the 26 patients with a distal anastomotic leak, 17 water-soluble enemas were performed, with 15 (88 percent) demonstrating a leak. In contrast, only 2 of 17 (12 percent) CT scans were positive in this group of patients (P < 0.001). There were ten patients who initially had a CT scan followed by a water-soluble enema. Of these patients, eight of nine (88 percent) initially had a negative CT scan but were considered to be clinically suspicious of having an anastomotic leak and subsequently had a leak demonstrated on a water-soluble enema. CONCLUSIONS: Early intervention in patients who develop an anastomotic leak can be shown to improve the ultimate outcome, especially with respect to mortality. It is usually necessary to obtain objective tests of anastomotic integrity because of the nonspecificity of clinical signs. Our study supported the superiority of water-soluble enema to CT imaging in patients in whom both modalities were used. This difference was most pronounced for distal anastomotic leaks, whereas no radiologic imaging study proved effective in evaluating proximal anastomoses.

Adult↗
PubMed2006

Strong-field atomic phase matching.

We interpret a learning-control experiment with the goal of optimizing multiphoton population transfer in atomic sodium in the strong-field limit. Despite multiple experimental constraints, a learning algorithm discovers optimal pulses that can be understood in terms of a simple dynamic picture of the atom-field interaction. We show that the shaped pulses counteract the dynamic Stark-induced stimulated emission that would otherwise impede the efficient use of a pi pulse to invert a multiphoton transition.

Journal Article↗
PubMed2005

Therapeutic potential of CD4+ CD25+ regulatory T cells in allogeneic transplantation.

The subpopulation of CD4+ CD25+ immunoregulatory T cells constitutes less than of the entire CD4+ T-cell pool in mice and 2% in humans. These cells play a crucial role in the control of autoimmune processes. More recently, in vitro and in vivo data also indicate that CD4+ CD25+ immunoregulatory T cells can regulate alloreactivity. This renders them good candidates for innovative strategies in the field of transplantation. Inducing a state of immune tolerance with immunoregulatory T cells would alleviate the need for immunosuppression, and the occurrence of late allograft failure represents a major goal of transplantation immunology. Here we discuss how these naturally occurring CD4+ CD25+ immunoregulatory T cells can be used to modulate alloreactivity in hematopoietic stem cell and solid organ transplantation.

Animals↗
PubMed2002

Effect of combined cytostatic cyclosporin A and cytolytic suicide gene therapy on the prevention of experimental graft-versus-host disease.

The immunosuppressive drug cyclosporin A (CsA) represents the standard preventive treatment of graft-versus-host disease (GVHD), the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). However, its efficacy is only partial and many patients develop lethal GVHD despite CsA. A strategy of genetic immunosuppression based on conditional elimination of donor T cells expressing the Herpes simplex type 1 thymidine kinase (TK) suicide gene was recently developed. In this system, ganciclovir (GCV) selectively kills dividing but not quiescent TK T cells. Since CsA is known to have a cytostatic effect on T cells, it could negatively interfere with the division-dependent TK gene therapy. We thus tested whether administration of CsA would antagonize elimination of alloreactive donor TK T cells mediated by GCV in a murine model of GVHD. In vivo experiments revealed that, contrary to GCV, CsA only transiently controlled alloactivation-induced T cell proliferation, and likewise could not prevent lethal GVHD. When T cells resumed proliferation under CsA, they were however still sensitive to GCV. Survival, as well as immune reconstitution, was excellent in mice treated with GCV alone or in combination with CsA. These observations should help to design improved suicide gene therapy trials in the field of allogeneic HSCT.

Animals↗
PubMed2001

Division rate and phenotypic differences discriminate alloreactive and nonalloreactive T cells transferred in lethally irradiated mice.

After non-T-cell-depleted allogeneic hematopoietic stem cell transplantation (HSCT), both alloreactive and homeostatic signals drive proliferation of donor T cells. Host-reactive donor T cells, which proliferate on alloantigen stimulation, are responsible for the life-threatening graft-versus-host disease. Non-host-reactive donor T cells, which proliferate in response to homeostatic signals, contribute to the beneficial peripheral T-cell reconstitution. The elimination of alloreactive T cells is a major therapeutic challenge for HSCT and would greatly benefit from their specific identification. After T-cell transfer in lymphopenic recipients, the present results show that alloreactive T cells rapidly divided; up-regulated CD69, CD25, and CD4 molecules; and down-regulated CD62L. In contrast, nonalloreactive T cells started to divide later and did not up-regulate CD69, CD25, and CD4. Thus, these 2 cell populations can be effectively discriminated. This should facilitate the specific depletion of alloreactive T cells in allogeneic HSCT.

Animals↗
PubMed2001

Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells.

After allogeneic hematopoietic stem cell transplantation (HSCT), mature transplanted T cells play a major role in restoration of the immune system. However, they can also induce a life-threatening complication: graft-versus-host disease (GVHD). Suicide gene therapy of GVHD aims to selectively eliminate alloreactive T cells mediating GVHD while sparing nonalloreactive T cells that should contribute to immune reconstitution. It was demonstrated previously that treatment with ganciclovir (GCV) can control GVHD in mice by killing donor T cells engineered to express the thymidine kinase (TK) suicide gene. TK allows phosphorylation of nontoxic GCV into triphosphate GCV, which is selectively toxic for dividing cells. Thus, in the TK-GCV system, the specificity of cell killing depends on the cycling status of TK T cells rather than allogeneic recognition. This is a potential drawback because in recipients of lymphopenic allogeneic HSCT, alloreactive and homeostatic signals drive the proliferation of donor T cells. It is shown here that the onset of alloreactive T-cell division occurs earlier than that of nonalloreactive T cells, thus establishing a time frame for GCV administration. A 7-day GCV treatment initiated at the time of HSCT allowed efficient prevention of GVHD, while sparing a pool of nondividing donor TK T cells. These cells later expanded and contributed to the replenishment of the recipient immune system with a diversified T-cell receptor repertoire. These results provide a rationale for designing the therapeutic scheme when using TK-GCV suicide gene therapy in allogeneic HSCT.

Animals↗
PubMed2001

Penile paraffinoma: self-injection with mineral oil.

We present a 64-year-old patient with a 9-cm firm, irregular penile mass associated with phimosis, erectile dysfunction, and voiding difficulty. After he reluctantly admitted to multiple penile mineral oil self-injections for enlargement, surgical excision was performed. Pathologic examination was consistent with mineral oil granuloma (paraffinoma). Within several weeks after surgery, his erectile dysfunction and voiding complaints resolved. Paraffinomas have been encountered with the use of various oily substances injected for cosmetic purposes. Despite early warnings, these agents continued to be used to treat conditions ranging from hemorrhoids to wrinkles and even baldness. Fortunately, most of these fads have been abandoned by medical professionals, but the complicating lesions have been documented as having lag times as long as 30 years. Complete surgical excision remains the treatment of choice to prevent recurrence. Increased public awareness is needed for the prevention of this physically and psychologically debilitating problem.

Granuloma↗
PubMed2000

Preservation of graft-versus-infection effects after suicide gene therapy for prevention of graft-versus-host disease.

The main complications following allogeneic hematopoietic stem cell transplantation are graft-versus-host disease and poor immune reconstitution leading to severe infections. Mature donor T cells present in the transplant facilitate T cell reconstitution in adults, but also induce graft-versus-host disease, which itself impairs immune reconstitution. Thus, infusing a large number of donor T cells with a diverse repertoire should accelerate functional immune reconstitution after transplantation, only if graft-versus-host disease can be controlled. We previously demonstrated that preventive treatment with ganciclovir could control graft-versus-host disease in mice if donor T cells are made to express viral thymidine kinase as a "suicide" gene. Here we evaluated the recovery of functional antiviral immune responses in such mice. Irradiated mice received an allogeneic hematopoietic stem cell transplantation with thymidine kinase-expressing T cells and were protected from graft-versus-host disease by ganciclovir treatment, and then challenged with lymphocytic choriomeningitis virus. Grafted mice could mount efficient antilymphocytic choriomeningitis virus immune responses leading to viral elimination. Furthermore, when transplanted cells were obtained from mice previously immunized against lymphocytic choriomeningitis virus, grafted mice developed memory-type accelerated responses against the virus. We conclude that efficient graft-versus-infection effects can be mediated by naive T cells and memory donor T cells that persist after suicide gene therapy for prevention of graft-versus-host disease.

Animals↗
PubMed2000

Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images.

Suboptimal left ventricular (LV) cavity visualization and endocardial border delineation often compromise the clinical utility of echocardiography. This study examines the safety and efficacy of perflutren, a novel ultrasound contrast agent, for LV cavity opacification and endocardial border delineation in patients with suboptimal baseline echocardiograms. In a multicenter, randomized, placebo-controlled, double-blind trial, 211 patients with suspected cardiac disease and suboptimal baseline echocardiograms were enrolled at 17 sites. Two intravenous injections of either placebo (saline) or perflutren (5 or 10 microl/kg) were given approximately 30 minutes apart. Images of the apical 4- and 2-chamber views were acquired and scored. Perflutren opacified the LV cavity after both dosages (5 and 10 microl/kg dosages). Clinically useful contrast was observed in 89% of patients who received perflutren and in 0% of patients who received placebo (p < 0.01). Quantitative assessment of LV opacification with videodensitometry showed similar results. The mean duration of clinically useful contrast was 90 seconds. Improvement in endocardial border delineation was demonstrated in 91% of patients who received perflutren and in 12% of those who received placebo (p < 0.001). Following perflutren, an average of 4 more segments per patient were evaluable compared with baseline. Salvage of nondiagnostic baseline examinations by perflutren was demonstrated in 48% of eligible subjects. The safety profile of perflutren was similar to placebo. These data indicate that administration of perflutren to patients with suboptimal baseline images is well tolerated and provides substantial LV cavity opacification and improvement in endocardial border delineation.

Contrast Media↗
PubMed2000

Prolonged allograft survival through conditional and specific ablation of alloreactive T cells expressing a suicide gene.

BACKGROUND: Control of antidonor activated T cells involved in allograft rejection while preserving immunocompetence is a challenging goal in transplantation. Engineered T cells expressing a viral thymidine kinase (TK) suicide gene metabolize the nontoxic prodrug ganciclovir (GCV) into a metabolite toxic only to dividing cells. We evaluated this suicide gene strategy for inducing transplantation tolerance in mice. METHODS: Transgenic mice expressing TK in mature T cells were analyzed for (i) specific T-cell depletion under GCV treatment upon various stimulations; (ii) outcome of allogeneic nonvascularized skin or heart allografts under a short 14-day GCV treatment initiated at the time of transplantation; and (iii) the capacities of T cells from such allotransplanted mice to proliferate in mixed lymphocyte reactions and to induce graft-versus-host disease in irradiated recipients with the genetic background of the donor allograft. RESULTS: Upon in vitro or in vivo GCV treatment, only activated dividing TK T cells but not B cells were efficiently depleted. Acute rejection of allogeneic grafts was prevented and a significant prolongation of graft survival was obtained, although associated with signs of chronic rejection. Prolonged skin graft survival correlated with decreased in vitro and in vivo T-cell reactivities against donor alloantigens, whereas overall immunocompetence was preserved. CONCLUSIONS: Efficient and specific depletion of alloreactive TK T cells can be achieved by administrating GCV. These results open new perspectives for the control of allogeneic graft rejection using suicide gene therapy.

Animals↗
PubMed2000

Ganciclovir-sensitive acute graft-versus-host disease in mice receiving herpes simplex virus-thymidine kinase-expressing donor T cells in a bone marrow transplantation setting.

BACKGROUND: The use of donor T cells expressing the herpes simplex thymidine kinase (HSV-TK) gene followed by ganciclovir (GCV) treatment could allow for specific modulation of the alloreactivity occurring after bone marrow transplantation. We are presently exploring such an approach in a phase I clinical trial. METHODS: To examine the beneficial effect of administrating HSV-TK-expressing donor T lymphocytes +/- GCV treatment on acute graft-versus-host disease (aGVHD) control, irradiated Balb/c or C57BL/6 mice underwent transplantation with allogeneic bone marrow cells in conjunction with CD3+ allogeneic splenocytes from transgenic mice expressing an HSV-TK transgene. GCV treatment was initiated upon the occurrence of severe aGVHD. RESULTS: GCV treatment resulted in a 40-60% long-term survival rate of GVHD-free recipients having received HSV-TK-expressing T cells, whereas only 0-6% of mice survived without GCV treatment. Lethal aGVHD occurred in all the control animals having received non-HSV-TK-expressing T cells, irrespective of GCV treatment. CONCLUSION: Our results demonstrate that the administration of donor HSV-TK-expressing T cells to hematopoietic stem cell graft recipients followed by GCV treatment at the onset of severe aGVHD significantly reduces aGVHD-induced mortality and results in GVHD-free surviving recipients.

Animals↗
PubMed2000

T-Cell suicide gene therapy for organ transplantation: induction of long-lasting tolerance to allogeneic heart without generalized immunosuppression.

Standard immunosuppressive drugs used for allogeneic organ transplantation do not specifically target alloreactive T cells and must be given for the lifetime of the patient, resulting in significant morbidity and mortality. We aimed to induce experimental immune tolerance to vascularized heart allograft using a suicide gene allowing selective elimination of dividing T cells expressing Herpes simplex virus type 1 thymidine kinase upon ganciclovir administration. We show that without ganciclovir, transgenic mice selectively expressing thymidine kinase in T cells rejected a vascularized cardiac allograft in 7 days. In contrast, allograft was definitively accepted after a 7-day course of ganciclovir initiated at the time of allotransplantation. Interestingly, T cells from both rejecting and tolerant mice proliferated in response to donor or third-party allogeneic stimulation. This state of tolerance was challenged through a second vascularized cardiac allotransplantation. Third-party allografts were rejected while those syngeneic to the first allograft were accepted without any additional treatment. These results show that short-term pharmacogenetic immunosuppression can induce long-lasting, robust, and specific tolerance to solid vascularized allograft without generalized continuous immunosuppression.

Adaptation, Physiological↗
PubMed2000

Infusion versus bolus contrast echocardiography: a multicenter, open-label, crossover trial.

BACKGROUND: In current practice, contrast echocardiography is performed with single or multiple bolus injections, which often result in an uncontrolled period of attenuation followed by transient left ventricular opacification (LVO). Because a "slow bolus" appears to reduce attenuation and prolong LVO, we hypothesized that a controlled infusion of contrast might provide a more uniform contrast effect with less attenuation and longer contrast duration. METHODS AND RESULTS: We sought to test the hypothesis by using an infusion of contrast (DEFINITY [perflutren], The DuPont Pharmaceuticals Co, Medical Imaging, North Billerica, Mass) that is stable when diluted in saline in a randomized, multicenter, controlled, crossover trial. Sixty-four patients with poor noncontrast images were recruited at 3 centers and randomly assigned to 2 single "slow" bolus injections of contrast (10 microL/kg each over a period of 30 to 60 seconds) or an infusion (1. 3 mL in 50 mL normal saline initially at 4.0 mL/min) of contrast. Patients then returned within 24 to 72 hours for the alternative form of contrast delivery. Three independent experienced echocardiographers viewed 30 seconds of videotape for all optimal baseline and optimal contrast images to score LVO and qualitatively assessed endocardial border evaluability. The duration of adequate LVO then was independently assessed by review of the entire videotape. Three independent sonographers traced single-frame, digitally captured images to measure the length of the contiguous endocardial border visualized. Both bolus and infusion administration demonstrated improved LVO (>90% by all blinded readers, P <.01) and endocardial border visualized (mean increase of 1.8 to 4.7 cm at both end-diastole and end-systole, all P <.05) as compared with baseline images. However, contrast infusion resulted in a longer duration of LVO (range of mean durations for each reader, 158 to 174 seconds longer, P <.05) and a shorter duration of attenuation (18 to 54 seconds, P <.05) compared with either bolus injection. There were no severe adverse events with contrast infusion. CONCLUSIONS: Contrast echocardiography delivered as an infusion optimizes the contrast effect by decreasing the attenuation period, extending the LVO duration, and providing a uniform contrast effect that may be useful in obtaining multiple echocardiographic views, stress echocardiography, myocardial perfusion imaging, and applications in which blood flow must be quantified.

Adult↗
PubMed2000

Transient control of a virus-induced immunopathology by genetic immunosuppression.

The ability to control T cell reactivity using suicide genes opens new perspectives for the treatment of T cell-mediated diseases. The therapeutic effect is achieved by the selective killing of thymidine kinase gene-modified activated T cells by ganciclovir (GCV). This strategy has been shown to control T cell alloreactivity efficiently after bone marrow or solid organ transplantation. Here, we aimed to determine whether an immunopathological process induced by a viral infection could be controlled by GCV when T cells express a thymidine kinase transgene. When transgenic mice were infected with the lymphocytic choriomeningitis virus, administration of GCV resulted in an efficient, but only transient, control of the immunopathological immune response. Further analysis revealed the existence of a minute population of GCV-insensitive T cells. These cells expand in response to the virus despite the presence of GCV and cause immunopathology before viral elimination is finally obtained. Thus, when confronted with a replicative virus, the efficacy of this genetic immunosuppression strategy is highly dependent on the presence of even small numbers of GCV-insensitive cells. These results emphasize the need for sufficient preclinical investigations with regard to the pathology and the nature of the immune response if suicide gene transfer is envisioned for new therapeutic indications.

Analysis of Variance↗
PubMed2000

Management of porphyria cutanea tarda in the setting of chronic renal failure: a case report and review.

The treatment of porphyria cutanea tarda (PCT) in patients with chronic renal failure poses a therapeutic challenge. In the absence of renal failure, phlebotomy and oral antimalarials have been the standard of care for PCT. However, in the presence of renal failure, associated chronic anemia often precludes the use of phlebotomy, and oral antimalarials are usually ineffective. We describe a patient with severe symptomatic PCT and chronic renal failure whose disease was successfully managed with a combination of high-dose erythropoietin and small volume phlebotomy. We also review several previously reported approaches to management of PCT in the setting of renal failure, which include small repeated phlebotomy, erythropoietin, deferoxamine, chloroquine, plasma exchange, high-efficiency/high-flux hemodialysis, cholestyramine, charcoal hemoperfusion, and kidney transplantation. An algorithm for the management of these patients is proposed.

Adult↗
PubMed1999

Immunological defects after suicide gene therapy of experimental graft-versus-host disease.

Donor T cells are beneficial for engraftment, immune reconstitution, and antileukemic effects after allogeneic marrow transplantation, but they also cause graft-versus-host disease. Treatment with ganciclovir can control graft-versus-host disease if donor T cells are genetically engineered to express viral thymidine kinase. Clinical protocols with thymidine kinase-expressing T cells currently prescribe the curative use of ganciclovir for genetic immunosuppression only after clinical manifestations of graft-versus-host disease have appeared. The aim of this work was to compare early/preventive versus delayed/curative treatment of GVHD. Here, we found that ganciclovir administered early after experimental marrow transplantation was highly effective in preventing graft-versus-host disease caused by thymidine kinase-expressing T cells, and surviving recipient mice were able to mount a T cell-dependent B cell response. In contrast, curative ganciclovir administration later after transplantation was much less effective in treating graft-versus-host disease and surviving recipients had markedly impaired immune function. These findings should be considered in the development of future clinical trials using thymidine kinase-expressing T cells; to date, such trials have envisaged the use of GCV to treat only declared graft-versus-host disease. The use of thymidine kinase-expressing T cells for conditional elimination of activated T cells after allogeneic marrow transplantation offers a promising new approach for the control of graft-versus-host disease. The versatility of the thymidine kinase/ganciclovir system offers clinical options depending on whether thymidine kinase-expressing T cells are infused at the time of bone marrow transplantation or in a delayed manner, and depending on whether GCV is administered in an early/preventive or delayed/curative manner. The rationale underlying these options is more complex than it may appear and is likely to have a profound impact on the efficacy of such treatments. In the present work, we analyze the immunological impact when GCV is administered in an early/preventive or delayed/curative manner. Our results demonstrate that the delayed/curative strategy is clearly associated with severe immunological defects. To our knowledge, this is the first report of immunodeficiency subsequent to suicide gene therapy for GVHD.

Animals↗
PubMed1999

Differing susceptibility of echocardiographic contrast agents to adverse effects of biologic factors: multicenter, videodensitometric comparison of octafluoropropane-filled microspheres with air-filled microspheres for left ventricular opacification.

BACKGROUND: Echocardiographic contrast enhancement of the left ventricle has diagnostic value in the assessment of regional and global left ventricular (LV) function. The efficacy of both octafluoropropane-filled human albumin microbubbles (OCTA) and of air-filled human albumin microbubbles (AIR) for LV endocardial delineation and qualitative LV opacification has previously been reported. However, pulmonary disease, obesity, impaired LV function, and decreased echogenicity may diminish the efficacy of contrast agents for LV opacification. The purpose of this study was to compare the susceptibility of 2 contrast agents currently approved by the Food and Drug Administration to these biologic factors. METHODS: To compare quantitative LV opacification with OCTA (0.2, 0. 5, 3.0, 5.0 mL) versus AIR (0.08 mL/kg, 0.22 mL/kg), we performed videodensitometry in 199 patients (average age 59.2 +/- 13.3 years, 79% men) studied in 2 identical, prospective, multicenter, blinded trials, of whom 74 had impaired LV function, pulmonary disease, or both, 70 were obese (body mass index >30 kg/m(2)), and 45 were nonechogenic (>/=4 of 6 endocardial segments were not seen in the apical 4-chamber view). Changes in videodensity from noncontrast to contrast agent with the same gain settings were determined at end diastole and end systole (gray scale 0 to 255 U) for 2 regions of interest: left ventricle apex-to-mid-cavity and mid-cavity-to-base. The relative influence of clinically evident pulmonary disease, impaired LV function on echocardiography, and echogenicity on LV opacification produced by both contrast agents was determined by multivariate analysis. RESULTS: Significant videodensity increases ranging from 67% to 143% were observed with both agents. At the recommended initial doses (0.5 mL for OCTA, 0.22 mL/kg for AIR), OCTA produced greater opacification than AIR in both regions of interest and at both phases of the cardiac cycle. Poor LV function was associated with decreased LV opacification for AIR but not for OCTA. Diminished echogenicity was more strongly associated with impaired opacification for AIR than for OCTA. Obesity and clinically evident pulmonary disease were associated with diminished chamber opacification with both OCTA and AIR. CONCLUSIONS: In addition to the superiority of octafluoropropane-filled microspheres to air-filled microspheres for LV opacification, the efficacy of OCTA is relatively unaffected by impaired LV function and is less susceptible to the effects of poor echogenicity than AIR.

Albumins↗