The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma.

BACKGROUND: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018). PATIENTS AND METHODS: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. RESULTS: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. CONCLUSIONS: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.

Fracture liaison services in Ireland-how do we compare to international standards?

In this first na tional survey of public hospitals in The Republic of Ireland, we found fracture liaison services (FLS) to be heterogeneous, limited in many cases and poorly supported. A national strategy is urgently needed to support the implementation and operation of an FLS, and thus help reduce the burden of fragility fractures for patients and the healthcare system. INTRODUCTION: Fragility/low-trauma fractures are a global concern, whose incidence is rising as the population ages. Many are preventable, and people with a prior fragility fracture are at particularly high risk of further fractures. This patient group is the target of the International Osteoporosis Foundation (IOF) Capture the Fracture campaign, advocating global adoption of fracture liaison services (FLS), with the aim of preventing secondary fragility fractures. We wished to determine the current availability and standards of an FLS in Ireland, ahead of the launch of a National FLS database. METHODS: We devised a questionnaire encompassing the thirteen IOF standards for an FLS and asked all 16 public hospitals with an orthopaedic trauma unit in Ireland, to complete for the calendar year 2019 in patients aged ≥ 50 years. RESULTS: All sites returned the questionnaire, i.e. 100% response rate. Nine hospitals stated that they have an FLS, additionally one non-trauma hospital running a FLS responded, and were included. These 10 FLS had identified and managed 3444 non-hip fractures in the year 2019. This figure represents 19% of the expected non-hip fragility fracture numbers occurring annually in Ireland. Implementation of the IOF standards was very variable. All sites reported being inadequately resourced to provide a high-quality service necessary to be effective. CONCLUSION: The existence and functioning of FLS in Ireland are heterogeneous and suboptimal. A national policy to support the implementation of this programme in line with international standards of patient care is urgently needed.

Host use patterns of Culicoides spp. biting midges at a big game preserve in Florida, U.S.A., and implications for the transmission of orbiviruses.

Culicoides spp. biting midges (Diptera: Ceratopogonidae) are vectors of pathogens that have a significant economic impact on the livestock industry. White-tailed deer (Odocoileus virginianus), a farmed species in the U.S.A., are susceptible to two Culicoides spp. borne orbiviruses: bluetongue virus and epizootic haemorrhagic disease virus. Elucidating host-vector interactions is an integral step in studying disease transmission. This study investigated the host range of Culicoides spp. present on a big game preserve in Florida on which a variety of Cervidae and Bovidae freely roam. Culicoides were captured with Centers for Disease Control and Prevention (CDC) miniature light traps run twice weekly on the preserve for 18 consecutive months (July 2015-December 2016). Host preference was quantified through forage ratios, based upon PCR-based bloodmeal analysis of Culicoides spp. and overall animal relative abundance on the preserve. Culicoides stellifer preferentially fed on Cervus spp. and fallow deer (Dama dama) and displayed a relative avoidance of Bovidae and white-tailed deer. Culicoides debilipalpis preferred white-tailed deer and avoided all Bovidae. Culicoides pallidicornis and Culicoides biguttatus showed preferences for white-tailed deer and Père David's deer (Elaphurus davidianus), respectively. These results add to current knowledge of preferred hosts of Florida Culicoides spp. and have implications for the spread of orbiviruses. Copyright © 2018 John Wiley & Sons, Ltd.

Kidney graft outcome and quality (after transplantation) from uncontrolled deceased donors after cardiac arrest.

The use of uncontrolled deceased donors after cardiac arrest (uDDCA) has been developed in France to compensate for organ shortage. The quality of these kidneys remains unclear. We analyzed kidney graft function and histology from 27 uDDCA and compared them with kidneys from 30 extended criteria donors (ECD) and from 24 simultaneous pancreas kidney (SPK) donors as a control group of optimal deceased donors. Kidneys from ECD and SPK donors were preserved by static cold storage while kidneys from uDDCA were preserved by pulsatile perfusion. The uDDCA graft function at 3 years posttransplantation (estimated with MDRD and measured with inulin clearance) did not differ from that of the ECD group (eGFR 44.1 vs. 37.4 mL/min/1.73 m(2) , p = 0.13; mGFR 44.6 vs. 36.1 mL/min/1.73 m(2) , p = 0.07 in the uDDCA and ECD groups, respectively). The histological assessment of 3-month and 1-year protocol biopsies did not show differences for interstitial lesions between the uDDCA and ECD grafts (IF score at M3 was 30 vs. 28% and at M12 36 vs. 33%, p = NS). In conclusion, the results at 3 years with carefully selected and machine-perfused uDDCA kidneys have been comparable to ECD kidneys and encourage continuation of this program and development of similar programs.

Comparison of C4d detection on erythrocytes and PTC-C4d to histological signs of antibody-mediated rejection in kidney transplantation.

C4d on erythrocytes (EC4d), C4d peritubular capillary deposition (PTC-C4d) staining and histology were compared in a cross-sectional cohort of 146 renal allograft biopsies (132 patients). EC4d levels paralleled PTC-C4d staining, but were more predictive of peritubular capillaritis (PTC). Donor-specific antibodies (DSA), PTC-C4d, EC4d and PTC were analyzed in an independent longitudinal follow-up cohort (96 biopsies, 76 patients). Seventy-six samples were PTC and EC4d concordant, 11 positive and 65 negative, 7 PTC-EC4d+ and 13 PTC+EC4d-. EC4d levels were related to DSA occurrence. With ABMR defined by PTC and DSA, all apparently discordant patients, EC4d negative, were correctly reassigned comparing EC4d level curves with rejection kinetics, with positive EC4d samples predating biopsy or late biopsies compared with ABMR flare-ups. All EC4d-positive patients without PTC or DSA had permanent high EC4d levels unrelated to rejection. EC4d was more abundant in PTC-positive (mean = 108.5%± 3.4; n = 50) than PTC-negative samples (mean = 88.1%± 1.3; n= 96; p < 0.0001). Sensitivity, specificity, positive predictive value and negative predictive value of PTC-C4d and EC4d for PTC were, respectively, 75%, 79%; 64%, 76% (p < 0.05); 28%, 46% (p < 0.05) and 93%, 94%. Values were similar for DSA. A noninvasive blood test, EC4d, and particularly longitudinally monitoring EC4d levels, may increase surrogate ABMR testing options.

An economic analysis comparing health care resource use and cost of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin versus gemcitabine and cisplatin as neoadjuvant therapy for muscle invasive bladder cancer.

PURPOSE: To compare healthcare resource utilization (HRU) and costs associated with dose-dense methotrexate, vinblastine, doxorubicin, cisplatin (ddMVAC) and gemcitabine, cisplatin (GC) as neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). METHODS: Patient treated at Dana-Farber Cancer Institute from 2010 to 2019 were identified. HRU data on chemotherapy administered, supportive medications, patient monitoring, clinic, infusion, emergency department (ED) visits and hospitalization were collected retrospectively. Unit costs for HRU components were obtained from the Centers for Medicare and Medicaid Website and HRU was compared between groups using quantile regression analysis. RESULTS: 137 patients were included; 51 received ddMVAC and 86 GC. Baseline characteristics were similar, except lower mean age (P < 0.001) and higher proportion of ECOG-PS = 0 (P < 0.001) for ddMVAC. ddMVAC required more granulocyte-colony stimulating factor support (P < 0.001), central line placement (P = 0.017), cardiac imaging (P < 0.001), and infusion visits (P < 0.001), whereas GC required more clinic visits. ED visits were higher for ddMVAC (P = 0.048), while chemotherapy cycle delays and hospitalization days were higher for GC (P = 0.008). After adjusting for ECOG-PS and age, the cost per patient was approximately 41% lower (95%CI: 28% to 52%; P < 0.001) for GC vs. ddMVAC, which translated to a median adjusted cost savings of $7,410 (95%CI: $5,474-$9,347) per patient. CONCLUSIONS: Although excess HRU did not clearly favor one regimen, adjusting for PS and age indicated lower costs with GC vs. ddMVAC. Given the similar cumulative cisplatin delivery with both regimens, the associated values and costs supports the preferential selection of GC in the neoadjuvant setting of MIBC.

Relationship of body condition score, live weight, stocking rate and grazing system to the mortality of Angora goats from hypothermia and their use in the assessment of welfare risks.

UNLABELLED: Body condition scoring is widely used for sheep and cattle but the practice is included in only one Code of Practice for the welfare of goats in Australia. There is no published scientific evidence to support or defend its use in the assessment of welfare risks to farmed goats. PROCEDURE: The significance of stocking rate, grazing system, body condition score (CS) and live weight were investigated in explaining the risk of mortality of individual and flocks of grazing Angora goats from hypothermia following a severe weather event in April. This event occurred 5 weeks after shearing the goats. Angora goats and Saxon Merino sheep were grazed alone, or mixed together in equal numbers at each of three stocking rates. RESULTS: There was no mortality amongst Angora goats provided they grazed at the lowest stocking rate even when their CS was < or = 2.0. Mortality in flocks of Angora goats was most related to the CS reached during the preceding 2 months. For flocks of Angora goats there was no mortality at CS > or = 2.5 and mortality increased sharply at mean CS < 2.0. For individual Angora goats, mortality increased as CS declined and stocking rate and grazing combinations were additive in effect on mortality. Grazing with sheep increased mortality of Angora goats at higher stocking rates. The individual goat mortality rate was not dependent on individual plot effects suggesting that these results are applicable widely. Live weight loss was not related to mortality rates of goats once CS had been accounted for. CONCLUSION: It was concluded that CS and stocking rate were highly significant determinants of welfare risk in Angora goats.

Factors associated with low vitamin D status of Australian alpacas.

OBJECTIVE: To investigate factors associated with low vitamin D status of alpacas at pasture in southern Australia. DESIGN: A 2-year survey of alpacas from two farms in South Australia and three in Victoria. Blood samples were collected from 20 to 30 alpacas on each farm on five occasions each year. Breed, gender, age and fleece colour of animals were recorded. METHOD: Blood samples were assayed for plasma 2.5-hydroxycholecalciferol (25-OH D(3)) and plasma inorganic phosphorus (Pi). Data sets from 802 animal samples were analysed by multiple regression to determine variables associated with low vitamin D status of alpacas. The relationship between plasma 25-OH D(3) and plasma Pi was also investigated. RESULTS: Vitamin D status was significantly affected by month of sampling, with low values in late winter and high values in summer. Plasma vitamin D concentrations increased with age, were higher in alpacas with light fleeces than in those with dark fleeces and were also higher in the Suri than in the Huacaya breed. Plasma Pi concentrations were generally lower in alpacas with plasma 25-OH D(3) values < 25 nmol/L. CONCLUSIONS: Young alpacas with dark fleeces are most at risk from vitamin D insufficiency in late winter in southern Australia. The present study indicates that plasma Pi values are not a reliable indicator of vitamin D status of alpacas as assessed by plasma 25-OH D(3) concentrations.

[Dual kidney transplant: the E. Herriot Hospital Lyon experience]. / Bitransplantation rénale : expérience du protocole lyonnais de l'hôpital E.-Herriot.

INTRODUCTION: In the current context of a high incidence end-stage kidney disease and a shortage of organs for kidney transplantation, the increasing use of transplants considered to be "borderline" represents a potential source of transplants. Over the last 10 years, some centers have developed a transplantation strategy, which consists of transplanting two borderline kidneys that cannot be proposed separately in a single recipient. The authors report their experience of dual kidney transplant. MATERIALS AND METHODS: Since 2001, 15 dual kidney transplants have been performed in a single centre according to a local protocol based on the correspondence between the weight of the donor kidney and the recipient's weight, weighted by the number of fibrotic glomeruli observed on the initial biopsy. In this study, the authors analyze the postoperative complications and functional results observed in patients transplanted according to this protocol. RESULTS: Dual kidney transplants represented less than 5% of all transplants performed during the study period concerned, which remained lower than the objectives initially announced by the ABM. The surgical technique was left to the surgeon's discretion. The mean follow-up was 26.3 months. Fourteen of the 15 recipients were alive with a functional graft. Surgical complications were globally more frequent when kidneys were transplanted on the same side (versus transplanted on both sides). Mean serum creatinine was 119.4 mol/l at six months (creatinine clearance according to MDRD formula: 57.3 ml/min per 1.73 m2), 118.8 mol/l at 12 months (creatinine clearance: 55.8) and 132.4 mol/l at 24 months (creatinine clearance: 44.2). One year post-transplant, mean renal function measured by inulin clearance was 55.5 ml/min per 1.73 m2. Four of the 15 patients had experienced an episode of acute rejection and three patients experienced delayed return of transplant function. CONCLUSION: In view of the results obtained, the authors consider that dual kidney transplant could be a reasonable and effective option for selected patients. Positioning of the transplants in each iliac fossa limited the surgical complication rate.

Evaluation of controlled-release devices for providing chromium sesquioxide and zinc in Huacaya alpacas at pasture.

OBJECTIVE: To assess the effectiveness of controlled-release devices (CRDs) for providing zinc and for estimating faecal output in alpacas and sheep at pasture. METHODS: The study groups of 10 alpacas and 10 sheep at pasture were paired within species and allocated at random to receive by mouth either one CRD containing chromium sesquioxide designed to function for at least 21 days or two CRDs, one containing chromium sesquioxide and the other zinc oxide designed to release over a nominal 60-day period. Faecal concentrations of chromium, zinc and ash, blood and plasma concentrations of zinc and plasma activity of alkaline phosphatase (ALP) were measured over a period of 117 days after treatment. RESULTS: The mean faecal chromium excretion profiles suggested that the CRDs performed in a similar manner in both species, releasing chromium for nearly 30 days in alpacas and for slightly more than 30 days in sheep. Using a common predetermined release rate of chromium from the CRDs, the daily faecal outputs of alpacas and sheep were estimated to be 0.54 kg dry matter and 0.33 kg dry matter, respectively. The CRD containing zinc oxide provided after 1 week an estimated daily release rate of 40 mg zinc with a lifetime of between 60 and 70 days in both species. The additional zinc did not elicit a response in blood zinc concentrations or in plasma ALP activity. CONCLUSION: The CRDs were retained in the gastrointestinal tracts of the alpacas and sheep and both types functioned as expected. The CRD delivering chromium sesquioxide at a known release rate provided an estimate of faecal dry matter output over a period of almost 3 weeks and the CRD formulated to deliver supplementary zinc did so at the nominal release rate over a period of approximately 60 days in both species. These data indicated that the standard sheep CRD is applicable for use in alpacas.

Coarser wool is not a necessary consequence of sheep aging: allometric relationship between fibre diameter and fleece-free liveweight of Saxon Merino sheep.

The mean fibre diameter (MFD) of wool is the primary determinant of price, processing performance and textile quality. This study determines the primary influences on MFD as Saxon Merino sheep age, by allometrically relating MFD to fleece-free liveweight (FFLwt). In total, 79 sheep were grazed in combinations of three stocking rates and two grazing systems (GS: sheep only; mixed with Angora goats) and studied over 3 years. Measurements were made over 14 consecutive periods (Segments), including segments of FFLwt gain or FFLwt loss. Using shearing and liveweight records and dye-bands on wool, the FFLwt and average daily gain (ADG) of each sheep were determined for each segment. The mean and range in key measurements were as follows: FFLwt, 40.1 (23.1 to 64.1) kg; MFD, 18.8 (12.7 to 25.8) µm. A random coefficient restricted maximum likelihood (REML) regression mixed model was developed to relate the logarithm of MFD to the logarithm of FFLwt and other effects. The model can be written in the form of ${\rm MFD}\,{\equals}\,\rkappa \left( {{\rm GS,}\,{\rm A}{\rm ,}\,{\rm Segment}{\rm .Plot,}\,{\rm Segment,}\,{\rm ADG}} \right){\times}{\rm FFLwt}^{{\left( {\ralpha \left( {{\rm GS}} \right){\plus}\rbeta \left(\rm A \right){\plus}\rgamma \left( {{\rm Segment}{\rm .Plot}} \right)} \right)}} $ , where $\ralpha \left( {{\rm GS}} \right)\,{\equals}\,\;\left\{ {\matrix{\!\! {0.32\left( {{\rm SE}\,{\equals}\,{\rm 0}{\rm .038}} \right)\,{\rm when}\,{\rm sheep}\,{\rm are}\,{\rm grazed}\,{\rm alone}} \hfill \cr \!\!\!\!{0.49\left( {{\rm SE}\,{\equals}\,{\rm 0}{\rm .049}} \right)\,{\rm when}\,{\rm sheep}\,{\rm are}\,{\rm mixed}\,{\rm with}\,{\rm goats}} \hfill \cr } } \right.$ ß(A) is a random animal effect, γ(Segment.Plot) a random effect associated with Segment.plot combinations, and κ a constant that depends on GS, random animal effects, random Segment.plot combination effects, Segment and ADG. Thus, MFD was allometrically related to the cube root of FFLwt over seasons and years for sheep, but to the square root of FFLwt for sheep grazed with goats. The result for sheep grazed alone accords with a primary response being that the allocation of nutrients towards the cross-sectional growth of wool follicles is proportional to the changes in the skin surface area arising from changes in the size of the sheep. The proportionality constant varied systematically with ADG, and in sheep only grazing, was about 5 when sheep lost 100 g/day and about 6 when sheep gained 100 g/day. The proportionality constant did not systematically change with chronological age. The variation in the allometric coefficient between individual sheep indicates that some sheep were more sensitive to changes in FFLwt than other sheep. Key practical implications include the following: (a) the reporting of systematic increases in MFD with age is likely to be a consequence of allowing sheep to increase in size during shearing intervals as they age; (b) comparisons of MFD between sheep are more likely to have a biological basis when standardised to a common FFLwt and not just to a common age;

Kidney preservation with IGL-1 solution: a preliminary report.

The University of Wisconsin (UW) solution is the most commonly used preservation solution. However, a new preservation solution-IGL-1-contains an inversion of K and Na concentrations and substitution of polyethylene glycol for hydroxyethyl starch in the UW solution. The present study is the first clinical experience on the outcome of kidneys preserved in IGL-1 solution. From June 2003 to June 2004, 119 cadaveric kidneys were retrieved and stored in IGL-1 solutions; among the 119 organs, this study includes 37 IGL-1-preserved kidneys that were locally transplanted versus 33 kidneys stored in University of Wisconsin (UW) solution that were also locally transplanted. The groups were comparable with regard to donor and recipient characteristics. Renal function outcome was evaluated by comparing delayed graft function (DGF) rates, the evolution of serum creatinine, daily urine output, and creatinine clearance. Biopsies were performed after reperfusion to evaluate apoptosis. The incidence of DGF was 5.71% among IGL-1 kidneys and 13.79% among UW kidneys. Creatinine values were significantly lower among the IGL-1 group from 2 to 14 days postoperative and at 1 month. Daily urinary output did not show any significant differences between the two groups. IGL-1 kidneys had a superior creatinine clearance during the first 15 postoperative days compared to UW kidneys. Kidneys preserved in IGL-1 solution showed fewer apoptotic cells compared to kidneys preserved in UW solution. This preliminary report suggests a superiority of IGL-1 for the immediate outcome of transplanted kidneys.

Wear of permanent incisors with age on commercial Australian Angora goat farms.

OBJECTIVE: To quantify if, and to what extent, permanent incisor wear differed with age of goat and farm of origin on commercial Australian Angora goat farms. DESIGN: Observations were made on three Angora goat farms in the wheat-sheep zone of Victoria, each managed according to the farmer's practices. Farmers provided a representative flock of does. METHODS: The proportion and pattern of wear of permanent incisors were recorded and percentage wear calculated. After log(y + 10) transformation, a parsimonious general linear model was developed to relate wear to farm and age, with age considered as a continuous variate. RESULTS: The range in wear of the permanent incisors was 0-100%. For each farm, the most parsimonious model for permanent first incisor wear and average wear of all permanent incisors was a separate straight line relating the transformed incisor wear to the age of doe. The models accounted for 66-73% of variance. On each farm the incisor wear was similar and low for ages up to approximately 4 years. On all farms, the amount of incisor wear increased dramatically with age, although the rate of increase differed with each farm. CONCLUSIONS: Permanent incisor wear increased with age of goat and differed with farm of origin. Angora goat farmers need to be aware of the potential for incisor wear to affect doe production and health.

Serological markers of recurrent beta cell destruction in diabetic patients undergoing pancreatic transplantation.

BACKGROUND: Besides alloimmunity to transplanted pancreatic tissue, recurrent autoimmune beta cell destruction is an additional limitation to successful clinical pancreatic allografts in type 1 diabetic patients. METHODS: We studied the prevalence of autoantibodies to glutamate decarboxylase (GAD) 65 and tyrosine phosphatase (IA-2) in 68 C-peptide-negative diabetic patients receiving pancreatic allografts. Sera from patients were obtained immediately before grafting. A second blood sample was analyzed at the time of graft failure in patients who returned to hyperglycemia and during the same follow-up period in those who experienced a functional pancreatic allograft. Patients were classified according to clinical outcome into chronic graft failure (group A, n=20), acute graft failure and/or arterial thrombosis (n=7), or functional pancreatic graft (group C, n=41). Sera from patients were screened for the presence of specific autoantibodies using an islet cell autoantibody assay, a combi-GAD and IA-2 test, and individual GAD and IA-2 assays. RESULTS: Patients from group A had significantly higher combi-test values than patients from group C (13+/-16 vs. 4.5+/-12 units, P<0.02) and higher anti-GAD65 antibody (Ab) levels (0.19+/-0.3 vs. 0.04+/-0.13 units, P<0.01) immediately before grafting. After graft failure in group A, both anti-GAD65 and anti-IA-2 Ab levels increased from baseline, but only the increase in anti-IA-2 Ab levels reached statistical significance (0.28+/-0.12 vs. 15+/-34, P=0.03). When compared with group C, patients from group A had higher anti-GAD65 Abs (0.29+/-0.35 vs. 0.05+/-0.16, P<0.001) after graft failure. Interestingly, the number of double-Ab-positive patients rose from 5% to 35% in group A, whereas it remained at 5% in group C. In pancreatic transplants with bladder drainage, the presence of anti-GAD65 and/or anti-IA2 Abs was not associated with a reduction in urinary amylase levels. This suggests that a loss of endocrine function was not associated with exocrine failure in patients from group A. CONCLUSIONS: We can conclude from the present study that peripheral autoimmune markers are useful in diabetic patients receiving pancreatic allografts.

Increased ICAM-1 and PECAM-1 transcription levels in the heart of Apo-E deficient mice in comparison to wild type (C57BL6).

Adhesion molecules and chemoattractants are thought to play a critical role in the homing of leukocytes to sites of vascular lesions. Apo-E deficiency in mice creates an atherosclerotic model that mimics vascular lesions in man. Little is known on the effect of Apo-E deficiency on expression of adhesion molecules in the hearts of these animals. In this study, male C57BL6 and Apo-E deficient mice were fed a chow diet over periods of time (0 to 20 weeks). The transcription levels of major adhesion molecules (ICAM-1, PECAM-1), present in the heart, were followed by northern blots. Immunohistochemistry was used to localize these adhesion molecules in the heart. Results show a significant increase in gene transcription levels of ICAM-1 and PECAM-1 in Apo-E animals, but not wild type, at 16 and 20 weeks of chow diet. Such increase in levels of transcription was not observed in younger Apo-E and C57BL6 animals (0, 6 weeks of diet). ICAM-1 and PECAM-1 were strongly expressed in the endocardium and heart microvessels. In contrast, VCAM-1 was poorly stained, with only an occasional expression on the endocardium and arterioles. Enhanced gene expression levels of heart ICAM-1 and PECAM-1 observed in Apo-E deficient mice, but not in control animals, appears to induce the initial stages of an inflammatory reaction. Such observations, not previously reported, may induce heart vascular remodeling.

Presence of cytoadhesins (IIb-IIIa-like glycoproteins) on human metastatic melanomas but not on benign melanocytes.

Glycoproteins IIb and IIIa, a heterodimer complex, play a vital role in blood platelet aggregation and are members of a wide family of membrane receptors known as integrins or cytoadhesins. Cellular interaction to extracellular matrix (ECM) adhesive proteins is mediated by integrins. Certain tumor cells are known to interact with ECM and blood platelets in the process of metastasis. However, it is not known if tumor cells, compared with their normal counterparts, acquire IIb-IIIa-like receptors to help them in their metastatic spread. In this study, monoclonal antibodies directed against the IIb-IIIa platelet glycoprotein complex were used on frozen biopsies of normal and various tumor tissues to detect the presence of these integrins. These studies demonstrate the presence of IIb-IIIa-like glycoproteins on the cells of metastatic malignant melanoma but not on benign melanocytes and rarely on other tumors. The presence of integrins on melanomas may help explain their propensity for frequent metastasis.

Association of human papillomavirus and colon neoplasms.

Human papillomavirus has been shown to be associated with squamous carcinomas. We evaluated benign and malignant colon tissues for the presence of human papillomavirus infection to determine if a similar relationship exists between human papillomavirus and colon neoplasms. Colon tissues were screened using an immunohistochemical technique to detect human papillomavirus antigen. In situ DNA hybridization was then performed on those tissues that yielded positive results by immunohistochemistry. Groups were compared using chi 2 analysis. Human papillomavirus antigen was present in 23% of normal colon specimens, 60% of benign tumors, and 97% of carcinomas. Human papilloma viral genome was demonstrated in 27% of benign tumors and in nearly 43% of all carcinomas tested. These data indicate that human papillomavirus infects the columnar mucosa of the colon, and that an association exists between human papillomavirus and colon neoplasia.

Cognitive-behavioral stress management intervention decreases the prevalence of depression and enhances benefit finding among women under treatment for early-stage breast cancer.

The authors tested effects of a 10-week group cognitive-behavioral stress management intervention among 100 women newly treated for Stage 0-II breast cancer. The intervention reduced prevalence of moderate depression (which remained relatively stable in the control condition) but did not affect other measures of emotional distress. The intervention also increased participants' reports that having breast cancer had made positive contributions to their lives, and it increased generalized optimism. Both remained significantly elevated at a 3-month follow-up of the intervention. Further analysis revealed that the intervention had its greatest impact on these 2 variables among women who were lowest in optimism at baseline. Discussion centers on the importance of examining positive responses to traumatic events--growth, appreciation of life, shift in priorities, and positive affect-as well as negative responses.

Evidence of recurrent type I diabetes following HLA-mismatched pancreas transplantation.

Type 1 diabetes mellitus is considered as an autoimmune disease against beta cells. Diabetes recurrence after pancreas transplantation is well known in HLA-identical twins while it is rarely reported in recipients of cadaveric pancreatic grafts. In the present case report, diabetes recurrence occurred in a recipient who underwent cadaveric combined pancreas kidney transplantation. Seven years after transplantation the patient exhibited progressive hyperglycemia needing insulin therapy while the renal graft was well functioning. The diagnosis of recurrent disease was obtained on the histological features such as selective loss of beta cells without clear signs of insulitis and on the presence of markers (GAD 65 and IA-2) for humoral autoimmunity. It is intriguing that, at the time of recurrence of type 1 diabetes, the patient had stopped steroids and azathioprine, while only cyclosporine was maintained as immunosuppressive treatment. Our case report underlines the relevance of studying the humoral autoimmune response directed to islet autoantigens in cadaveric pancreas allograft recipients. Furthermore, it suggests that an efficient immunosuppressive treatment after transplantation may be able to reduce the autoimmune response against the pancreatic allograft.

Inguinal herniation justifies sigmoidoscopy.

Controversy exists concerning the association of inguinal hernia and colonic carcinoma and, more specifically, whether the development of an inguinal hernia justifies sigmoidoscopy. To study the role of endoscopic screening in cases of inguinal hernia, we prospectively evaluated 464 patients with inguinal hernia over a 54-month period with flexible sigmoidoscopy. Each patient was over the age of 40 and male. Sigmoidoscopy documented polyps (97 patients, 21 percent) and carcinoma (22 patients, 5 percent). Multiple neoplasms were observed in 6 percent (7 of 119 patients). Occult blood was detected in the fecal specimens of 8 percent of the total group of patients, but in only 13 percent of the patients with polyps or carcinomas. A normal examination occurred in only 38 percent of the total group. By using the presence of an inguinal hernia in patients older than 40 years of age as an indication for sigmoidoscopy, we found that more than one of every four patients had an asymptomatic, concurrent malignant or premalignant colonic lesion. Flexible sigmoidoscopy should be used for screening colonic neoplasms in patients with inguinal hernia.