Cardiopulmonary function in high altitude residents of Ladakh

We studied residents of high altitude in Ladakh, India, to determine the effects of altitude, age, gender, and ethnicity on gas exchange and pulmonary function. Physical examinations, including pulse oximetry, hemoglobin concentration, end-tidal PCO2, and pulmonary function, were conducted on resting Ladakhi and Tibetan subjects at altitudes of 3300, 4200, and 4500 m. A total of 574 men and women, ranging in age from 17 to 82, were studied. At 3300 m, Ladakhis had higher heart rates than Tibetans in both genders and higher PETCO2 in women. Above 4000 m, 21 of the 141 men studied (15%) had Hb concentrations higher than 20 g/dL, with one confirmed case of Monge's disease. There was no gender difference in SaO2 at any altitude except for pregnant women. At 4600 m, Tibetans had significantly higher peak flows and lower PETCO2 than Ladakhis. Ladakhi men had higher diastolic BP than women (91 vs. 81), with no difference in systolic BP. There was no gender difference in BP for Tibetans. An important spirometry finding for both groups was high air flows, with mid-maximal expiratory flow (MMEF) at 130% to 150% of predicted values, compared with 85% for sojourner controls, and FEV1/FVC at 115%, compared with sojourner controls at 98%. Improved lung mechanics may be an important adaptation to the lifelong sustained increase in resting ventilation as well as to indoor biomass smoke and outdoor dust exposure of these populations at high altitude.     

Pancreatectomy with islet autotransplantation for the treatment of severe chronic pancreatitis: the first 40 patients at the leicester general hospital

BACKGROUND: Surgical resection of the pancreas is considered a final resort in the treatment of chronic pancreatitis. However, the opportunity to perform an islet autotransplant at the same time provides the potential to prevent the onset of diabetes. METHODS: Pancreatectomy together with islet autotransplantation has been offered in our center since 1994. A total of 40 patients have now undergone this procedure. The follow-up times range from 6 months to 7 years. The data presented here include the annual postoperative oral glucose tolerance test and glycosylated hemoglobin (HbA(1c)) results, together with insulin and opiate requirements. RESULTS: Nineteen male and 21 female patients (median age 44, range 21-65) have been transplanted. Pancreatitis was related to alcohol in 45% and was idiopathic in 40%. A median of 130108 (24332-1, 165538) islet equivalent (IEQ) were transplanted, which related to 2020 (320-23311) IEQ per kilogram of body weight. At 2 years posttransplant, 18 patients had a median HbA(1c) of 6.6% (5.2-19.3%), fasting C-peptide of 0.66 ng/mL (0.26-2.65 ng/mL), and required a median of 12 (0-45) units of insulin per day. At 6 years, these figures were 8% (6.1-11.1%), 1.68 ng/mL (0.9-2.78 ng/ml) and 43 U/day (6-86 U/day), respectively. The majority of patients no longer require opiate analgesia, 68% have been able to return to work, and one patient has had a baby. CONCLUSIONS: Islet autotransplantation offers a valuable addition to surgical resection of the pancreas, as a treatment for chronic pancreatitis; and even in cases in which insulin independence is not achieved, the potential beneficial effects of C-peptide make the procedure worthwhile.     

HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. III. Effect of matching at the HLA-A,B amino acid triplet level on kidney transplant survival

BACKGROUND: HLAMatchmaker is a recently developed computer-based algorithm to determine donor-recipient HLA compatibility at the molecular level. Originally designed for highly alloimmunized patients, this algorithm is based on the concept that immunogenic epitopes are represented by amino acid triplets on exposed parts of protein sequences of HLA-A, -B, and -C chains accessible to alloantibodies. Donor HLA compatibility is determined by intralocus and interlocus comparisons of triplets in polymorphic sequence positions. For most patients, HLAMatchmaker can identify certain mismatched HLA antigens that are zero-triplet mismatches to the patient's HLA phenotype and should, therefore, be considered fully histocompatible. The present study was designed to determine how class I HLA matching at the triplet level affects kidney transplant outcome. METHODS: We analyzed two multicenter databases of zero-HLA-DR-mismatched kidneys transplanted from 1987 to 1999. One database consisted of 31,879 primary allografts registered by U.S. transplant centers in the United Network for Organ Sharing database and the other consisted of 15,872 transplants in the Eurotransplant program. RESULTS: HLA-A,B mismatched kidneys that were compatible at the triplet level exhibited almost identical graft survival rates as the zero-HLA-A,B antigen mismatches defined by conventional criteria. This beneficial effect of triplet matching was seen for both nonsensitized and sensitized patients and also for white and nonwhite patients. CONCLUSIONS: These findings suggest that the application of HLAMatchmaker will increase the number of successful transplants, at least in the HLA-DR match combinations.     

Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model

Purpose In an effort to study the importance of stromal involvement in angiogenesis, we developed a novel, multicellular model that utilizes three of the primary cell types involved in tumor angiogenesis.Methods Fluorescently labeled human microvascular endothelial cells (HMVECs), 10T1/2 cells and myofibroblasts were incubated in the presence of a three-dimensional tumor cell cluster resuspended in collagen and embedded in Matrigel.Results HMVECs cultured in the presence of a human SKOV-3 ovarian carcinoma tumor cell cluster, surrounded the tumor cell cluster, while myofibroblasts invaded the cluster, localizing within the tumor cell mass. In contrast, 10T1/2 cells, a pluripotent mouse mesenchymal cell line with pericyte-like properties, did not demonstrate the same invasive phenotype. HMVECs cultured in the presence of myofibroblasts invaded the tumor cell cluster and colocalized with the myofibroblasts as demonstrated by fluorescent microscopy and immunohistochemistry. The angiogenesis inhibitors SU6668 and paclitaxel inhibited stromal invasion, while a broad-spectrum matrix metalloproteinase inhibitor did not.Conclusions This model emphasizes the critical interaction between endothelial cells and myofibroblasts and provides a more complete in vitro model for studying angiogenesis and tumor progression.     

Loss of heterozygosity of chromosome 1q in gastrinomas: occurrence and prognostic significance

A proportion of gastrinomas demonstrates aggressive growth, and most deaths occur in this group. Little is known about the molecular pathogenesis of growth of this tumor, and there are no predictive factors that are useful in an individual patient. Chromosome 1 (Chr 1) loss of heterozygosity (LOH) is frequent in a number of nonendocrine tumors and in a few endocrine tumors, and its presence can correlate with tumor aggressiveness and survival. In gastrointestinal endocrine tumors including gastrinomas, little data are available on Chr 1 LOH, and the limited results are contradictory. In the present study we determine whether Chr 1 LOH occurs in gastrinomas and is associated with aggressive growth by performing Chr 1 allelotyping with microsatellite markers in microdissected tumor tissue from 27 human gastrinomas and the leukocyte DNA of the patients. Detailed clinical pathological correlations were possible, because tumor growth in all of the patients was prospectively assessed with yearly imaging studies. Twelve gastrinomas (44%) had Chr 1 LOH, and in all of the cases 1q LOH occurred. 1q LOH was associated with aggressive growth (P = 0.0004), presence of liver metastases (P = 0.019), and postoperative development of hepatic metastases (P = 0.017). Eight (75%) of the 12 tumors with 1q LOH had 1q31-32 LOH over a 17.3 cM region, whereas LOH in 6 tumors (50%) occurred at 1q21-23 over a 12.3 cM area. The presence of 1q31-32 LOH and 1q21-23 LOH correlated with aggressive tumor growth (P = 0.0056 and P = 0.0031, respectively), and with postoperative development of liver metastases (P = 0.0114 and P = 0.011, respectively). These data suggest that 1q LOH is not infrequent in gastrinomas and could be a molecular/genetic prognostic factor for aggressive growth that could be useful clinically. The high frequent allelic loss at 1q31-32 as well as 1q21-23, which was associated with tumor aggressive growth, suggests these two regions harbor putative tumor suppressor gene(s) that are important for aggressive growth of this tumor.     

Analysis of the Na,K-ATPase alpha- and beta-subunit expression profiles of bladder cancer using tissue microarrays

BACKGROUND: The purpose of this study was to determine the clinical significance of Na,K-ATPase alpha- and beta-subunit expression in a histopathologically well-characterized group of patients representing a wide spectrum of tumor grades and disease stages with transitional cell carcinomas (TCC). METHODS: Na,K-ATPase alpha- and beta-subunit protein expression patterns were analyzed using immunohistochemistry on urothelial cancer tissue microarrays (TMA) of 146 patients diagnosed with urothelial carcinoma. For each subunit, the maximum staining intensity and the percentage of positive cells staining at the maximal intensity were analyzed. RESULTS: Compared with the benign fields, the mean protein expression for both Na,K-ATPase alpha- and beta-subunits were found to be decreased overall in in situ and invasive tumors, as well as in tumor-adjacent dysplastic fields. When Na,K-ATPase alpha- and beta-subunit expression levels were dichotomized into distinct groups, they were both found to be significant predictors of recurrence risk in multivariate logistic regression analysis (P = 0.0062, odds ratio [OR] = 2.6 and P = 0.013, OR = 0.43, for Na,K-ATPase alpha- and beta-subunits, respectively). The authors also found that patients with high alpha- and low beta-subunit expression had a high risk for early recurrence, whereas patients with a low alpha- and high beta-subunit expression had a significantly longer median recurrence-free time (17 months and 125 months, respectively, log rank statistics P = 0.0005). CONCLUSIONS: The results suggested that Na,K-ATPase alpha- and beta-subunit expression levels may be useful predictors of clinical outcomes such as recurrence-free time of bladder cancer patients.     

Responding to a bioterrorist attack: environmental investigation of anthrax in New Jersey

A bioterrorism attack using the United States postal system to deliver a hazardous biological agent to specific targets created multiple environmental and occupational exposure risks along the path of the anthrax-containing letters. On October 18, 2001, a suspected case of cutaneous anthrax was confirmed in a postal worker from the Trenton Processing and Distribution Center where at least four suspect letters were postmarked. Over the next three weeks, a team of investigators collected samples at 57 workplaces in New Jersey as part of a comprehensive environmental investigation to assess anthrax contamination as a result of this bioterrorist attack. A total of 1369 samples were collected with positive sample results found in two mail processing and distribution centers, six municipal post offices, and one private company. This large-scale epidemiological and public health investigation conducted by state and federal agencies included environmental evaluations utilizing general industrial hygiene principles. Issues of sampling strategy, methods, agency cooperation and communication, and site assessment coordination are discussed.