Long-term weight-change slope, weight fluctuation and risk of type 2 diabetes mellitus in middle-aged Japanese men and women: findings of Aichi Workers' Cohort Study.

OBJECTIVE: This study aims to investigate the association of long-term weight-change slopes, weight fluctuation and the risk of type 2 diabetes mellitus (T2DM) in middle-aged Japanese men and women. METHODS: A total of 4234 participants of Aichi Workers' Cohort Study who were aged 35-66 years and free of diabetes in 2002 were followed through 2014. Past body weights at the ages of 20, 25, 30, 40 years, and 5 years before baseline as well as measured body weight at baseline were regressed on the ages. Slope and root-mean-square-error of the regression line were obtained and used to represent the weight changes and the weight fluctuation, respectively. The associations of the weight-change slopes and the weight fluctuation with incident T2DM were estimated by Cox proportional hazards models. RESULTS: During the median follow-up of 12.2 years, 400 incident cases of T2DM were documented. After adjustment for baseline overweight and other lifestyle covariates, the weight-change slopes were significantly associated with higher incidence of T2DM (hazard ratio (HR): 1.80, 95% confident interval (CI): 1.17-2.77 for men; and HR: 2.78, 95% CI: 1.07-7.23 for women), while the weight fluctuation was not (HR: 1.08, 95% CI: 1.00-1.18 for men and HR: 1.02, 95% CI: 0.84-1.25 for women). CONCLUSIONS: Regardless of the presence of overweight, the long-term weight-change slopes were significantly associated with the increased risk of T2DM; however, the weight fluctuation was not associated with the risk of T2DM in middle-aged Japanese men and women.

Sparing Native Upper Lobes in Living-Donor Lobar Lung Transplantation: Five Cases From a Single Center.

Living-donor lobar lung transplantation (LDLLT) is indicated for rapidly deteriorating patients, and the total volume of two lower lobe grafts must be sufficient for the recipient. To rescue patients with small lobar grafts, we performed five LDLLTs sparing native upper lobes. This strategy was used when upper lobes or segments were preoperatively less impaired. There were no hospital deaths. Extracorporeal circulation time and operative time were similar to those of conventional LDLLTs. The length of intensive care unit stay was also similar. Late complications attributed to the spared lungs were airway infection in one recipient and pneumothorax in two but they were successfully managed. All recipients were discharged without supplemental oxygen. The spared lung volumes measured by volumetry did not change after LDLLT. Lung perfusion scintigraphy performed at 1 year showed remaining perfusion in the spared lungs, although much less than in the grafts. These results suggested that the spared lobes kept adequate space in the thoracic cavity and kept functioning to a limited extent. The new lobar-sparing strategy appears feasible and effective in LDLLT using small grafts for selected patients when the upper lobes or segments are less impaired.

Tolerance of Lung Allografts Achieved in Nonhuman Primates via Mixed Hematopoietic Chimerism.

While the induction of transient mixed chimerism has tolerized MHC-mismatched renal grafts in nonhuman primates and patients, this approach has not been successful for more immunogenic organs. Here, we describe a modified delayed-tolerance-induction protocol resulting in three out of four monkeys achieving long-term lung allograft survival without ongoing immunosuppression. Two of the tolerant monkeys displayed stable mixed lymphoid chimerism, and the other showed transient chimerism. Serial biopsies and post-mortem specimens from the tolerant monkeys revealed no signs of chronic rejection. The tolerant recipients also exhibited T cell unresponsiveness and a lack of alloantibody. This is the first report of durable mixed chimerism and successful tolerance induction of MHC-mismatched lungs in primates.

Right and left inverted lobar lung transplantation.

Adult recipients frequently withdraw from living-donor lobar lung transplantation because of the small size of donor grafts. The right lower lobe is 120% larger than the left lower lobe. We developed a novel surgical technique in which an inverted right lower lobe graft can be transplanted into the left thorax. The first patient was a 43-year-old woman with end-stage idiopathic interstitial pneumonia. Her husband was the only eligible donor for living-donor lobar lung transplantation. His right lower lobe was estimated to provide 45% of the recipient's predicted forced vital capacity, which would provide the borderline function required for living-donor lobar lung transplantation. Since lung perfusion scintigraphy of the recipient showed a right-to-left ratio of 64:36, transplanting the right lower lobe graft into the left thorax and sparing the native right lung was considered the only treatment option. We simulated this procedure using three-dimensional models produced by a three-dimensional printer. In living-donor lobar lung transplantation, all anastomoses were performed smoothly as planned preoperatively. Because of the initial success, this procedure was performed successfully in two additional patients. This procedure enables larger grafts to be transplanted, potentially solving critical size matching problems in living-donor lobar lung transplantation.

Long-term lung transplantation in nonhuman primates.

Despite advances in surgical technique and clinical care, lung transplantation still remains a short-term solution for the treatment of end-stage lung disease. To date, there has been limited experience in experimental lung transplantation using nonhuman primate models. Therefore, we have endeavored to develop a long-term, nonhuman primate model of orthotopic lung transplantation for the ultimate purpose of designing protocols to induce tolerance of lung grafts. Here, we report our initial results in developing this model and our observation that the nonhuman primate lung is particularly prone to rejection. This propensity toward rejection may be a consequence of 1) upregulated nonspecific inflammation, and 2) a larger number of pre-existing alloreactive memory T cells, leading to augmented deleterious immune responses. Our data show that triple-drug immunosuppression mimicking clinical practice is not sufficient to prevent acute rejection in nonhuman primate lung transplantation. The addition of horse-derived anti-thymocyte globulin and a monoclonal antibody to the IL-6 receptor allowed six out of six lung recipients to be free of rejection for over 120 days.

Quantitative evaluation of native lung hyperinflation after single lung transplantation for emphysema using three-dimensional computed tomography volumetry.

OBJECTIVE: Although double lung transplantation is performed more frequently for emphysema, single lung transplantation (SLT) continues to be performed owing to limited donor organ availability. Native lung hyperinflation (NLH) is a unique complication following SLT for emphysema. Three-dimensional computed tomography (3D-CT) volumetry has been introduced into the field of lung transplantation, which we used to assess NLH in emphysema patients undergoing SLT. The primary purpose of this study was to confirm the effectiveness of 3D-CT volumetry in the evaluation of NLH following SLT for emphysema. METHODS: In 5 emphysema patients undergoing SLT at Kyoto University Hospital, 3D-CT volumetry data, pulmonary function test results, and clinical and radiological findings were retrospectively evaluated. RESULTS: Three patients did not develop a significant mediastinal shift, whereas the other 2 patients developed a mediastinal shift. In the 3 patients without a mediastinal shift, 3D-CT volumetry did not show a significant increase in native lung volume. These patients had a history of sternotomy prior to lung transplantation and firm adhesion on the mediastinal side was detected during lung transplantation. One of 2 patients with a mediastinal shift developed severe dyspnea with significantly decreased pulmonary function, and 3D-CT volumetry showed a significant increase in the native lung volume. However, the other patient did not show any dyspnea and his native lung volume decreased postoperatively (preoperatively to 6 months postoperatively: +981 mL and -348 mL, respectively). CONCLUSION: Although bilateral lung transplantation has become preferable for emphysema patients owing to postoperative NLH with SLT, patients with a history of sternotomy prior to lung transplantation might be good candidates for SLT. 3D-CT volumetry may be a useful method for detection of NLH.

A prospective study analyzing one-year multidimensional outcomes in living lung transplant donors.

The success of living-donor lobar lung transplantation (LDLLT) largely depends on donor outcome; but to date, no authors have studied health-related quality of life (HRQOL) of donors. We prospectively evaluated multidimensional outcomes before and 1 year after donor lobectomies. Patient-reported HRQOL, dyspnea, psychological status and sleep quality, and physiological pulmonary function were determined. All donors were alive without any limitations in their activities of daily living after 1 year. Postoperative pulmonary function was better than the estimated preoperative values; but, with respect to HRQOL, four of the eight subscales of the Medical Outcomes Study 36-item short form (SF-36) deteriorated significantly after donation. In addition, dyspnea assessed by the modified Medical Research Council scale also worsened significantly. In contrast, postoperative anxiety assessed by the Hospital Anxiety and Depression Scale significantly improved from baseline. The donors whose recipients died reported lower SF-36 scores with worsening sleep quality measured by Pittsburgh Sleep Quality Index. Thus, although postoperative pulmonary functions in donors were preserved, their HRQOL and dyspnea deteriorated postoperatively. Moreover, HRQOL and sleep quality were impaired in recipients who experienced poor outcomes. To capture the comprehensive outcomes in LDLLT donors after donation, patient-reported outcomes should be analyzed separately from physiological outcomes.

Adaptation over a wide range of donor graft lung size discrepancies in living-donor lobar lung transplantation.

Living-donor lobar lung transplantation (LDLLT), unlike deceased donor lung transplantation, often involves a wide range of size discrepancies between donors and recipients. The aim of this study was to evaluate the function of donor lung grafts in the recipient thorax in 14 cases of bilateral LDLLT involving 28 successfully transplanted lower-lobe grafts. Pulmonary function tests and three-dimensional computed tomography (3D-CT) volumetry were performed perioperatively. According to 3D-CT size matching, donor graft volumes ranged from 40% to 161% of the hemilateral thoracic volumes of the recipients. Graft forced vital capacity (FVC) values increased over time, reaching 102 ± 39% of preoperatively estimated values at 12 months postoperatively. Graft volumes also increased over time, reaching 120 ± 38% of the original values at 12 months postoperatively. Undersized donor grafts expanded more after LDLLT than oversized donor grafts, producing greater FVC values than those estimated preoperatively, whereas oversized donor grafts became inflated to their original size and maintained FVC values that approached the preoperative estimates. Thus, donor grafts were found to overinflate or underinflate to the extent that they could preserve their native function in the new recipient's environment.

Low-dose IL-2 for In vivo expansion of CD4+ and CD8+ regulatory T cells in nonhuman primates.

IL-2 is a known potent T cell growth factor that amplifies lymphocyte responses in vivo. This capacity has led to the use of high-dose IL-2 to enhance T cell immunity in patients with AIDS or cancer. However, more recent studies have indicated that IL-2 is also critical for the development and peripheral expansion of regulatory T cells (Tregs). In the current study, low-dose IL-2 (1 million IU/m(2) BSA/day) was administered to expand Tregs in vivo in naïve nonhuman primates. Our study demonstrated that low-dose IL-2 therapy significantly expanded peripheral blood CD4(+) and CD8(+) Tregs in vivo with limited expansion of non-Treg cells. These expanded Tregs are mainly CD45RA(-) Foxp3(high) activated Tregs and demonstrated potent immunosuppressive function in vitro. The results of this preclinical study can serve as a basis to develop Treg immunotherapy, which has significant therapeutic potential in organ/cellular transplantation.

Donor brain death inhibits tolerance induction in miniature swine recipients of fully MHC-disparate pulmonary allografts.

We have previously shown that a short course of high-dose tacrolimus induces long-term tolerance to fully mismatched lung allografts procured from healthy MHC-inbred miniature swine. Here, we investigate whether donor brain death affects tolerance induction. Four recipient swine were transplanted with fully mismatched lung grafts from donors that were rendered brain dead and mechanically ventilated for 4 h before procurement (Group 1). These recipients were compared to two control groups (Group 2: 4 h of donor ventilation without brain death [n = 5]; and Group 3: no donor brain death with <1 h of ventilation [n = 6]). All recipients were treated with a 12-day course of tacrolimus. In contrast to both groups of control animals, the swine transplanted with lung allografts from brain dead donors all rejected their grafts by postoperative day 45 and showed persistent responsiveness to donor antigen by MLR. Several additional swine underwent brain death induction and/or mechanical ventilation alone to determine the effects of these procedures on the expression of proinflammatory molecules. Significant increases in serum concentrations of IL-1, TNF-α and IL-10 were seen after brain death. Upregulation of IL-1 and IL-6 gene expression was also observed.

Overcoming memory T-cell responses for induction of delayed tolerance in nonhuman primates.

The presence of alloreactive memory T cells is a major barrier for induction of tolerance in primates. In theory, delaying conditioning for tolerance induction until after organ transplantation could further decrease the efficacy of the regimen, since preexisting alloreactive memory T cells might be stimulated by the transplanted organ. Here, we show that such "delayed tolerance" can be induced in nonhuman primates through the mixed chimerism approach, if specific modifications to overcome/avoid donor-specific memory T-cell responses are provided. These modifications include adequate depletion of CD8+ memory T cells and timing of donor bone marrow administration to minimize levels of proinflammatory cytokines. Using this modified approach, mixed chimerism was induced successfully in 11 of 13 recipients of previously placed renal allografts and long-term survival without immunosuppression could be achieved in at least 6 of these 11 animals.

Dynamic instability of central airways and peripheral airspace in rat lungs perfused with cold preservation solutions.

BACKGROUND/AIMS: For lung preservation, one of two types of solutions is commonly employed: Euro-Collins (EC) or low potassium dextran glucose (LPDG). These two solutions have been compared regarding biological, morphometrical and physiological outcomes in many experiments. However, the dynamic mechanics of perfused lung are not well understood because the dynamic characteristics cannot be assessed under static conditions; hence, the primary goal of the present study was to assess this in perfused rat lungs during the preservation period, comparing EC with LPDG at 0 or 9 h at 4°C. METHODS: Lung impedance was measured using a forced oscillation technique. Lung resistance and elastance values were obtained by the fast Fourier transform algorithm. The instability of central airways and heterogeneity of ventilation were estimated. RESULTS: In the EC group, airway resistance and instability were high after perfusion, and the lung elastance was high and more heterogeneous after cold storage. In contrast, those parameters were stable in the LPDG group during cold storage. CONCLUSION: Such dynamic stability might facilitate the handling of lung grafts and eliminate injurious cyclic ventilation stress after reperfusion. Thus, we conclude that the impedance frequency characteristic represents a novel informative parameter for investigating lung preservation techniques.

Comparison of lung and kidney allografts in induction of tolerance by a mixed-chimerism approach in cynomolgus monkeys.

BACKGROUND: We have previously reported the successful induction of renal allograft tolerance in non-human primates using a nonmyeloablative conditioning regimen to produce a mixed-chimeric state in the recipient. In the present study, we applied this same technique to lung allotransplantation in cynomolgus monkeys. METHODS: Nine pairs of fully major histocompatibility complex (MHC)-mismatched cynomolgus monkeys were used. The conditioning regimen consisted of total body irradiation, thymic irradiation, and antithymocyte globulin. The recipients underwent lung and bone marrow transplantation, followed by anti-CD154 monoclonal antibody (mAb), and a 1-month course of cyclosporine. The regimen included anti-CD8 mAb in the last 5 recipients and alpha 1-antitripsin in the last 3 recipients. The results were compared with 8 recipients that received kidney allografts using the same regimen. RESULTS: Transient chimerism developed in all lung recipients, as was previously seen in the kidney recipients. Nonetheless, the lung recipients rejected their allografts significant earlier than the kidney recipients (P < .01). CONCLUSIONS: Despite the successful induction of mixed chimerism in recipients of fully MHC-mismatched lung allografts, we have not observed long-term graft survival, as has been seen in an analogous kidney model. Strategies to overcome this problem include organ-specific modifications of the transplant regimen.

Potential for pulmonary protection by nebulized milrinone during warm ischemia.

OBJECTIVE: A method to compensate for the donor shortage may be the utilization of donation after cardiac death. The control of lung injury against warm ischemia is crucial in manipulating donors after cardiac death. Nebulization is a simple and feasible drug delivery route after cardiac death. Herein we have examined the potential effect of nebulized milrinone, a phosphodiesterase III inhibitor, on pulmonary warm ischemia. MATERIALS AND METHODS: Deeply anesthetized rats were euthanized by exsanguination. Lungs were exposed to warm ischemia with ventilation up to 2 hours. Milrinone was nebulized for 10 minutes at the beginning of warm ischemia (n = 5). In the control group (n = 5), normal saline was nebulized for the same time. At given intervals, the lungs were partially resected to measure adenine nucleotide and cyclic adenosine monophosphate levels. RESULTS: In both groups, lung tissue cyclic adenosine monophosphate levels decreased significantly at 2 hours after warm ischemia; however, there was no significant difference between the groups. Lung tissue adenosine triphosphate levels significantly decreased at 2 hours after ischemia in the control group, while they did not drop up to 2 hours in the milrinone group. Further, lung tissue adenosine triphosphate levels at 2 hours after ischemia were higher in the milrinone group than the control group. CONCLUSIONS: Our results confirmed that milrinone nebulization during warm ischemia maintained lung tissue adenosine triphosphate levels. Therefore, milrinone nebulization may have potential for lung protection against warm ischemia.

[Viral infection after lung transplantation].

We experienced 3 cases of viral infections after lung transplantation. Case 1: Fifty-two-year-old male with pulmonary emphysema underwent left single lung transplantation from a cadaveric donor. Three months after transplantation he presented Epstein-Barr virus (EBV) viremia, resulting in multiple lymphadenopathy. Biopsy showed post-transplant lymphproliferative disorder, and he was treated successfully with rituximab. He is well without recurrence around 1 and a half years after treatment. Case 2: Thitry-eight-year-old male with pulmonary emphysema underwent double lung transplantation from a cadaveric donor. Four months after transplantation he showed multiple nodules in both lungs. Percutaneous biopsy showed post-transplant lymphproliferative disorder, and he was treated successfully with rituximab. He is well without recurrence more than 2 years after treatment. Case 3 : Twenty-four-year-old woman with lymphangioleiomyomatosis underwent living-related bilateral lobar lung transplantation. Three months after lung transplantation she presented cytomegalovirus viremia. Since it proved to be ganciclovir-resistant cytomegalovirus infection, she was treated with foscarnet successfully. She is well without recurrence about 2 and a half years after treatment.

Building peace through participatory health training: a case from Cambodia.

This qualitative study examines the significance and effectiveness of participatory health training as a tool for peace building. It does so by analysing a case of training for 'health promoters' run by a Cambodian government health agency. The authors observed participants during the training and interviewed those involved in the courses. A developing capacity for coexistence and reconciliation between individuals who had been on opposite sides during the years of Khmer Rouge terror and continuous internal war was observed among both participants and trainers. Factors embodied in the training that facilitated favourable changes in self and in relations with others were identified as: (1) 'space for dialogue' was created by concrete common public health interests and urgent needs; (2) training took place 'live-in' style in a rural setting; (3) course contents and methods were consistent with peace education; (4) trainers had a conscious function as role models; and (5) there was continuity of effort and consequent accumulation of experience. To build peace, as well as conducting training directly on a technical topic, these essential factors need to be incorporated in the training programmes.

Recurrent lymphangioleiomyomatosis after living-donor lobar lung transplantation.

Living-donor lobar lung transplantation (LDLLT) has been applied to patients with various end-stage lung diseases. The recurrence of pulmonary lymphangioleiomyomatosis (LAM) after lung transplantation has been rarely reported. Herein, we report a case of recurrent pulmonary LAM after LDLLT. A 24-year-old woman presented with pneumothorax and infiltrates in the left lung 1 year after bilateral LDLLT for LAM. These symptoms and radiologic findings occurred repeatedly and then improved quickly. Thereafter, computed tomography of the chest revealed a tiny emphysematous change of the subpleural region in the left lung, which was exacerbated gradually and was finally diagnosed as LAM recurrence by transbronchial lung biopsy. In previous reports of LAM recurrence, the diagnosis was made at the time of autopsy. This is also the first reported case diagnosed early, that is, when the patient was alive and her allograft had not deteriorated badly.

[Castleman disease in the posterior mediastinum showing atypical feature in computed tomography; report of a case].

A 41-year-old man was referred to our hospital because of an abnormal mass on a chest X-ray. An enhanced computed tomography (CT) showed a well-defined round mass (30 x 45 x 66 mm in diameter) that was heterogeneously enhanced owing to central necrotic or cystic change. A 3-dimensional CT demonstrated a couple of feeding arteries to the mass. The mass was completely resected through thoracotomy. Dissection of tight adhesion between the hypervascular mass and the surrounding tissues caused relative amount of hemorrhage during the surgery. The cystic lesion of the mass was fulfilled with brown liquid. The pathological examination revealed the mass as Castleman disease, and scattered cells in the cystic lesion.

[Surgical treatment of pulmonary aspergillosis].

We studied clinically upon 10 surgical cases of pulmonary aspergillosis. There were 7 male and 3 female cases, and the median age was 59 years. Seven cases had underlying bronchopulmonary diseases, and 9 cases had underlying diseases including systemic diseases, such as diabetes mellitus. There were 3 wedge resections, and 6 lobectomies, and 1 two-staged surgery (cavernostomy + muscle transposition). Eight cases whose lesion extended beyond neither chest wall nor mediastinal pleura were treated successfully by pulmonary resections almost within one lobectomy. One case, who had a cavitary lesion and multiple patchy infiltrates in the other lobes, cured by lobectomy including a main cavitary lesion and postoperative treatment with an antifungal agent. All cases returned home almost uneventfully, but 1 case of two-staged surgery died at home suddenly of massive hemoptysis. Surgical treatments of pulmonary aspergillosis are recommended when the lesions can be resected completely, that is, when patients are relatively well, lesions extend beyond neither chest wall nor hilar bronchus or vessels, and when the lungs other than the lesions are not extensively destroyed.