Functional Immune Anatomy of the Liver-As an Allograft.

The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Banff fibrosis study: multicenter visual assessment and computerized analysis of interstitial fibrosis in kidney biopsies.

Increasing interstitial fibrosis (IF) in native and kidney transplant biopsies is associated with functional decline and serves as a clinical trial end point. A Banff 2009 Conference survey revealed a range in IF assessment practices. Observers from multiple centers were asked to assess 30 renal biopsies with a range of IF and quantitate IF using two approaches on trichrome, Periodic acid-Schiff (PAS) and computer-assisted quantification of collagen III immunohistochemistry (C-IHC) slides, as well as assessing percent of cortical tubular atrophy% (TA%) and Banff total cortical inflammation score (ti-score). C-IHC using whole slide scans was performed. C-IHC assessment showed a higher correlation with organ function (r = -0.48) than did visual assessments (r = -0.32--0.42); computerized and visual C-IHC assessment also correlated (r = 0.64-0.66). Visual assessment of trichrome and C-IHC showed better correlations with organ function and C-IHC, than PAS, TA% and ti-score. However, visual assessment of IF, independent of approach, was variable among observers, and differences in correlations with organ function were not statistically significant among C-IHC image analysis and visual assessment methods. C-IHC image analysis correlated among three centers (r > 0.90, p < 0.0001, between all centers). Given the difficulty of visual IF assessment standardization, C-IHC image could potentially accomplish standardized IF assessment in multicenter settings.

A taxonomic revision of Neobuprestis kerremans (Coleoptera : Buprestidae) with the description of a new genus and two new species.

The genus Neobuprestis Kerremans 1903 is redefined and a new genus Burnsiellus gen. n. is defined. The putative relationships of Neobuprestis and Burnsiellus gen. n. are discussed. A key to the species of the two genera are provided. Balthasarella Obenberger 1958 is made a subgenus of Neobuprestis and its type species B. melandryoides Obenberger 1958 is synonymised with Strigoptera frenchi Blackburn 1892. Strigoptera marmorata Blackburn (1892), Neobuprestis albosparsa Carter (1924), Neobuprestis trisulcata Carter (1932) are transferred to Burnsiellus gen. n. from Neobuprestis. Two new species are described: Neobuprestis (Balthasarella) williamsi sp. n., Burnsiellus lobatum sp.n.

The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study.

Anastrozole, an orally active, nonsteroidal aromatase inhibitor, was evaluated in a randomized, double-blind, single-center study to determine its efficacy as neoadjuvant therapy in postmenopausal women with newly diagnosed, estrogen receptor-rich, locally advanced or large (>3 cm), operable breast cancers. Twenty-four eligible patients were recruited into the study and received either 1 mg (n = 12) or 10 mg (n = 12) of anastrozole daily over a 3-month period. Tumor volumes were estimated clinically, by using caliper measurements and ultrasound (at baseline and after 1, 2, and 3 months' treatment) and by mammography (at baseline and after 3 months). Tumor volume was also measured in surgical specimens. Twenty-one patients were classified as T2, two patients as T3, and one patient as T4B at baseline. Three patients had clinical evidence of lymph node involvement. When considering the difference between the volume as measured by each assessment and the actual pathological volume, the interquartile range and the difference between the maximum and minimum values were smaller for ultrasound when compared with those measured with calipers and mammography. Therefore, of the three clinical assessments of tumor volume used in this study, the data suggest that ultrasound may be the most accurate. The median reductions in tumor volumes as measured by ultrasound for those patients with a measurable 12-week assessment were 80.5 and 69.6% for anastrozole (1 and 10 mg, respectively) after 12 weeks of treatment and 75.5% when both doses were grouped together. Moreover, of these patients, 11 of 12 given 1 mg and 7 of 11 given 10 mg of anastrozole were found on ultrasound to have a >50% reduction in tumor volume after 12 weeks of treatment. Of the 17 patients who would have required a mastectomy at initiation of treatment, 15 were suitable for breast conservation after anastrozole treatment. These results suggest that anastrozole is highly effective as neoadjuvant therapy in postmenopausal women with estrogen receptor-rich, large, operable breast cancer. Future studies comparing anastrozole with tamoxifen as a neoadjuvant treatment should be considered.

Lessons from the use of aromatase inhibitors in the neoadjuvant setting.

Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole. Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume (PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they should now be compared with tamoxifen as first-line treatment in a randomised study.

p53-independent DNA repair and cell cycle arrest in embryonic stem cells.

The role of p53 in DNA repair and cell cycle checkpoint after ultraviolet irradiation was investigated in an embryonic stem cell line homozygous for a targeted deletion of p53. Results indicate that loss of p53 does not alter the capacity of ES cells to respond to DNA damage. Wild-type and p53-deficient cells showed similar cessation of DNA synthesis after UV damage and similar ultimate capacity to repair a transiently transfected reporter plasmid. Interestingly, in the absence of DNA damaging treatment, the transit of p53-deficient cells through S phase was slower than wild-type cells. We suggest that this may result from the absence of a p53-dependent response to endogenous DNA damage: without p53 sensing endogenous damage leading to immediate repair, such damage may persist and thus delay DNA synthesis.

Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes.

Despite knowledge of oestrogen receptor status, it is not always possible to predict which breast cancers will respond to tamoxifen. We have previously reported that decreased expression of Bcl-2 and/or Ki-S1 were associated with tumour response to neo-adjuvant tamoxifen in 50 elderly women with oestrogen receptor (ER)-positive breast cancer. In this study, we confirm that the expression of Bcl-2 and Ki-S1 are surrogates for the frequency of apoptosis and mitosis respectively, within these untreated breast cancers, with an inverse relationship between Bcl-2 expression and the apoptotic index (P<0.05), and a positive relationship between Ki-S1 expression and the mitotic index (P<0.01). However, after 3 months' tamoxifen treatment these relationships were no longer apparent. Moreover, amongst the 27 tumours in which Bcl-2 expression was reduced during the 3 months' therapy, there was a significant correlation between the response to therapy and the increase in apoptosis (P<0.05), whereas in those tumours in which Bcl-2 did not fall with therapy, there was a significant correlation between response and the decrease in mitosis (P<0.05). These data suggest there are at least two mechanisms for effective tamoxifen therapy: increased apoptosis as a consequence of reduced Bcl-2 expression, and decreased proliferation.

Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence.

BACKGROUND: Alcoholic liver disease has emerged as a leading indication for hepatic transplantation, although it is a controversial use of resources. We aimed to examine all aspects of liver transplantation associated with alcohol abuse. METHODS: Retrospective cohort analysis of 123 alcoholic patients with a median of 7 years follow-up at one center. RESULTS: In addition to alcohol, 43 (35%) patients had another possible factor contributing to cirrhosis. Actuarial patient and graft survival rates were, respectively, 84% and 81% (1 year); 72% and 66% (5 years); and 63% and 59% (7 years). After transplantation, 18 patients (15%) manifested 21 noncutaneous de novo malignancies, which is significantly more than controls (P=0.0001); upper aerodigestive squamous carcinomas were overrepresented (P=0.03). Thirteen patients had definitely relapsed and three others were suspected to have relapsed. Relapse was predicted by daily ethanol consumption (P=0.0314), but not by duration of pretransplant sobriety or explant histology. No patient had alcoholic hepatitis after transplantation and neither late onset acute nor chronic rejection was significantly increased. Multiple regression analyses for predictors of graft failure identified major biliary/vascular complications (P=0.01), chronic bile duct injury on biopsy (P=0.002), and pericellular fibrosis on biopsy (P=0.05); graft viral hepatitis was marginally significant (P=0.07) on univariate analysis. CONCLUSIONS: Alcoholic liver disease is an excellent indication for liver transplantation in those without coexistent conditions. Recurrent alcoholic liver disease alone is not an important cause of graft pathology or failure. Potential recipients should be heavily screened before transplantation for coexistent conditions (e.g., hepatitis C, metabolic diseases) and other target-organ damage, especially aerodigestive malignancy, which are greater causes of morbidity and mortality than is recurrent alcohol liver disease.

Dual Y-chromosome painting and immunofluorescence staining of archival human liver transplant biopsies.

Combining fluorescence in situ hybridization (FISH) and indirect immunofluorescence staining of protein markers provides a highly specific method for identifying chromosomes in phenotypically defined cells and tissues. We developed a technique enabling dual chromosome painting and immunofluorescence staining of archival formalin-fixed, paraffin-embedded material, and used this to phenotype chimeric cells in female-to-male human liver transplants.

Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization.

A consecutive series of 130 review-confirmed cases of noninvasive ductal carcinoma of breast (DCIS) in women without previous breast carcinoma was analyzed. Histologic variables assessed included histologic pattern, nuclear grade, necrosis, and involved duct counts. These were correlated with presentation, extent of DCIS in the breast, completeness of excision, and outcome. Comedo DCIS had an occult presentation significantly more often than noncomedo DCIS. Micropapillary DCIS was significantly more likely than other patterns to involve multiple quadrants of breast, irrespective of nuclear grade or necrosis. Solid DCIS was significantly more often completely excised when compared with all other patterns, while high-grade DCIS was significantly more often incompletely excised compared with low-grade DCIS. Follow-up showed invasive recurrence in 16% of cases treated by primary local excision only and 3% cases treated by mastectomy or with re-excision. Of local excision cases with follow-up longer than 3 years, 22% had invasive recurrence. Invasive recurrence only followed high-grade DCIS and most often followed comedo DCIS. The need for strict definition of categories of DCIS is stressed.

Ventriculo-atrial shunt causing tricuspid endocarditis: its percutaneous removal.

A 21-year-old patient developed tricuspid endocarditis with the distal sections of two redundant ventriculo-atrial shunts remaining in the right atrium. We report their percutaneous removal using a Dotter basket.

Implantation of a dual chamber pacemaker in a patient with persistent left superior vena cava.

A patient underwent dual chamber pacemaker implantation by puncture of the left subclavian vein. During the procedure we observed persistence of the left superior vena cava. An active fixation atrial lead was required to prevent instability induced by the odd course of the electrode and produced excellent long term pacing and sensing.

Early experience of directional coronary atherectomy: clinical results, complications and histopathological findings.

OBJECTIVE: To report the early experience, clinical results and histopathologic findings of Directional Coronary Atherectomy from a UK centre experienced in coronary angioplasty. DESIGN: Prospective study of the first 45 Directional Coronary Atherectomy (DCA) procedures using the Simpson coronary atherectomy device. RESULTS: Forty-five procedures were performed in 33 male and 5 female patients (mean age, 55.1 years). Directional Coronary Atherectomy was performed to 50 lesions (39 de novo, 11 restenosis; 44 left anterior descending, 3 right, 2 circumflex coronary arteries and 1 saphenous vein graft). Clinical and primary angiographic success was achieved in 43 of 45 cases (95.5%) and in 47 of 50 lesions (94%) after DCA alone. Before DCA the mean diameter stenosis was 88.7% (range, 50-100%) but following DCA (and percutaneous coronary angioplasty (PTCA) if necessary) the mean diameter stenosis was 3.5% (range, 0-15%; P < 0.001). Complications included occlusive dissection requiring coronary artery bypass surgery in two patients; abrupt closure of right coronary artery in one patient successfully reopened by PTCA and thrombolysis, complicated by excessive blood loss; reversible coronary artery spasm due to minor nose-cone trauma in four patients and temporary side branch loss in one patient. There were no coronary artery perforations, guide catheter complications, peripheral vascular trauma or deaths. On average 5.6 specimens (range, 1-18) were removed per case. Histology showed fibrous intimal plaque in 98%, media in 39% and adventitia in 7%. Neo-intimal hyperplasia was found in all restenosis lesions but also in 30% of de novo lesions. CONCLUSIONS: This small initial series indicates that directional coronary atherectomy is an effective and safe procedure for the treatment of obstructive coronary artery disease in carefully selected patients. With care, a high success rate can be achieved even during a learning phase. The technique is particularly effective for morphologically complex lesions that are unfavourable for PTCA. The procedure is unlike PTCA and requires additional training if pitfalls are to be avoided, high success rates achieved and complication rates kept low.

Normothermic arrest with continuous hyperkalaemic blood: initial experience.

The requirement for hypothermia in myocardial protection has recently been questioned. Between October 1990 and May 1991, diastolic arrest was achieved using continuous perfusion with normothermic, hyperkalaemic blood in 257 consecutive patients undergoing cardiac surgery. The mean age was 59.8 +/- 9.3 years (range 28-84 years). Coronary artery surgery was performed in 210 patients, valve replacements in 18, combined procedures in 22, and 7 patients had miscellaneous procedures. Eleven patients (4.3%) had undergone previous cardiac surgery, and 65 (25.3%) required urgent or emergency operations. Hyperkalaemic blood (7-20 mmol/l) was delivered antegradely in 190 (72.8%) patients (mean aortic root pressure 60-80 mmHg), retrogradely in 62 (25.3%) patients (mean coronary sinus pressure less than 40 mmHg), and by a combined route in 5 (1.9%). Sinus rhythm returned immediately after removal of the aortic clamp in 235 (91.4%) patients. Weaning from bypass was achieved without circulatory support in 207 (82.5%) patients. Of 233 patients undergoing non-emergency coronary artery surgery, single valve or combined procedures, 11 died, giving an operative mortality of 4.7%. Of 155 patients with good left ventricular function requiring coronary artery surgery, 3 (1.9%) died. The in-hospital mortality for the group as a whole was 7.3%. Sixteen (6.2%) patients sustained perioperative myocardial infarctions; of these 6 died. We conclude that continuous, normothermic, hyperkalaemic arrest is a simple and safe method of myocardial protection. It may avoid the damage associated with hypothermia, ischaemia and reperfusion.

Changes in non-structural carbohydrate composition during bulbing in sweet and high-solid onions in field experiments.

The composition of non-structural carbohydrate (NSC) content of predominantly long-day onion germplasm has been assessed over several years and in a bi-location trial. It was observed that genetic rather than environmental factors determined the NSC composition of onion bulbs. Glucose was the NSC component which was most closely correlated with genotype. Fructose was the only NSC component that was significantly affected by environment. Sucrose and 1-kestose (DP3 fructans) were not correlated to a large extent to the other NSC components, indicating their transient role in the fructan metabolism. Strong negative correlations were observed between reducing sugars (i.e. fructose and glucose) and dry matter content (DM). Furthermore, it was shown that accessions differed significantly in their fructan accumulation pattern; high DM accessions showed accumulation of fructans over the whole bulbing period, whereas, low DM accessions quickly reached a plateau. Implications for the breeding of high quality onions are discussed.

Raising our sites: dissemination of supported education.

In order to promote replication of supported education, an exemplary rehabilitation model for adults with psychiatric disabilities, funds were accessed through a Community Action Grant from the Center for Mental Health Services of the Substance Abuse and Mental Health Services Administration. Three communities in Michigan participated in a multistage process designed to maximize community ownership by encouraging local adaptations involving all stakeholder groups and providing technical assistance. The stages in the process were organizing the community for supported education development, acquiring knowledge about supported education basics, collecting information (needs assessment and barrier identification), and developing the plan. All three sites have begun implementation, providing services to adults with psychiatric disabilities who wish to pursue post-secondary education. The approach employed has applicability for other local communities.

Observed maternal strategies and children's health locus of control in low-income Mexican American families.

This study examined the relationship among mothers' health locus of control (HLOC) beliefs, their socialization strategies, and their children's HLOC beliefs in 80 low-income Mexican American families. Maternal socialization strategies were assessed from videotaped interactions of mothers and children engaged in a structured task. Factor analysis of the coded strategies yielded 4 factors: Tell Answer, Teaching, Clarify, and Reinforce. Findings indicated that maternal-health-internally scores negatively predicted mothers' use of the Tell Answer strategies and positively predicted their use of Teaching strategies. Mothers who believed that Powerful Others (e.g., health professionals) controlled their health were more likely to use the Tell Answer strategy. In contrast, mothers who believed that health was due to chance were less likely to use Teaching. Maternal use of Teaching strategies predicted children's internal HLOC, whereas maternal Tell Answer strategies predicted children's external HLOC. Findings suggest that mothers' HLOC beliefs influence the socialization strategies they use and that these strategies are associated with children's HLOC beliefs.

Unicef and baby food manufacturers. Unicef continues to base its actions and programmes on the best interests of the child.

PIP: This article presents the response of Carol Bellamy, executive director of the UN International Children's Emergency Fund (UNICEF), to the article by Yamey about the alliances UNICEF is seeking to form with manufacturers of infant formula that do not comply with the international code of marketing of breast milk substitutes. Bellamy confirms that UNICEF will continue to refuse donations from manufacturers of infant formula whose marketing practices violate this code and subsequent World Health Assembly resolutions. It is noted that there has been considerable discussion within the organization regarding this issue. This emerged when UNICEF participated in discussions with five large pharmaceutical companies on the possibility of obtaining various drugs to fight HIV/AIDS at discounted prices on behalf of developing countries. One of these companies is widely viewed as violating the code. This has been misinterpreted as a sign that UNICEF is weakening its support for breast-feeding and the code. However, Bellamy indicates that UNICEF believes that in the face of AIDS, their support for breast-feeding must be strengthened, not diminished. At the same time, UNICEF will uphold its support of the code and will continue to call violators of the code to account publicly.^ieng

[Therapeutic high-doses of digoxin with blood level determinations in 31 out of 150 elderly hospitalized patients treated over a year]. / Surdosages thérapeutiques en digoxine contrôlés biologiquement chez 31 malades âgés sur 150 sujets traités en un an.

The assay by immunoenzymatic method of the blood level of digoxine in 150 old people, (m = 79 years), hospitalized during one year shows a level of more than 2 ng/ml in 31 of them, (m = 2.91 ng/ml). However, the dosage is normal or low, m = 0.206 mg/j. A renal impairment often discussed is not the mechanism: 17 patients with a blood creatinine over 135 mumol/l have a mean blood level of digoxine of 2.98 ng/ml for 2.91 in the 14 another ones without renal impairment. Physicians should be still more cautious when prescribing digoxin.