Tissue Matching and Early Rejection of Cadaveric-Donor Renal Allografts: The Importance of Unidentified Donor Antigens

Tissue typing has been reviewed in a series of 100 technically successful cadaveric-donor kidney grafts. The criterion of transplant failure was immunological rejection causing total loss of function within three months of operation.No significant correlation was observed between matching grade and graft failure due to early acute rejection. This is attributed to the failure to detect at least one “LA” or “4” antigen (as defined in our laboratory), representing a potential incompatibility, in 89% of the grafts, and in the remaining 11% to the lack of an available recipient with identical “LA” and “4” typing. Undetected antigens on the donor are usually incompatible, and probably these incompatibilities unfavourably influence early graft survival.If the results of cadaveric-donor renal transplantation are to equal those of transplantation from well-matched living related donors it will be necessary to type with sera which can recognize individually all HL-A antigens, including those not yet identified, and to create an international pool of over 1,000 potential recipients.     

Current status of the organ replacement approach for malignancies and an overture for organ bioengineering and regenerative medicine

Significant achievements in the organ replacement approach for malignancies over the last 2 decades opened new horizons, and the age of “Transplant Oncology” has dawned. The indications of liver transplantation for malignancies have been carefully expanded by a strict patient selection to assure comparable outcomes with non-malignant diseases. Currently, the Milan criteria, gold standard for hepatocellular carcinoma, are being challenged by high-volume centers worldwide. Neoadjuvant chemoradiation therapy and liver transplantation for unresectable hilar cholangiocarcinoma has been successful in specialized institutions. For other primary and metastatic liver tumors, clinical evidence to establish standardized criteria is lacking. Intestinal and multivisceral transplantation is an option for low-grade neoplasms deemed unresectable by conventional surgery. However, the procedure itself is in the adolescent stage. Solid organ transplantation for malignancies inevitably suffers from “triple distress,” i.e., oncological, immunological, and technical. Organ bioengineering and regenerative medicine should serve as the “triple threat” therapy and revolutionize “Transplant Oncology.”     

Prediction of Hematopoietic Stem Cell Transplantation Related Mortality- Lessons Learned from the In-Silico Approach: A European Society for Blood and Marrow Transplantation Acute Leukemia Working Party Data Mining Study

Models for prediction of allogeneic hematopoietic stem transplantation (HSCT) related mortality partially account for transplant risk. Improving predictive accuracy requires understating of prediction limiting factors, such as the statistical methodology used, number and quality of features collected, or simply the population size. Using an in-silico approach (i.e., iterative computerized simulations), based on machine learning (ML) algorithms, we set out to analyze these factors. A cohort of 25,923 adult acute leukemia patients from the European Society for Blood and Marrow Transplantation (EBMT) registry was analyzed. Predictive objective was non-relapse mortality (NRM) 100 days following HSCT. Thousands of prediction models were developed under varying conditions: increasing sample size, specific subpopulations and an increasing number of variables, which were selected and ranked by separate feature selection algorithms. Depending on the algorithm, predictive performance plateaued on a population size of 6,611–8,814 patients, reaching a maximal area under the receiver operator characteristic curve (AUC) of 0.67. AUCs’ of models developed on specific subpopulation ranged from 0.59 to 0.67 for patients in second complete remission and receiving reduced intensity conditioning, respectively. Only 3–5 variables were necessary to achieve near maximal AUCs. The top 3 ranking variables, shared by all algorithms were disease stage, donor type, and conditioning regimen. Our findings empirically demonstrate that with regards to NRM prediction, few variables “carry the weight” and that traditional HSCT data has been “worn out”. “Breaking through” the predictive boundaries will likely require additional types of inputs.     

Hypertension,Asymmetric Renal Parenchymal Defect,Sterile Urine,and High E. coli Antibody Titre

During an 11-year period four children were seen with asymmetric renal parenchymal reduction, arterial hypertension, and sterile urine. The history and radio-logical or histological findings, or both, were consistent with “abacterial pyelonephritis” induced by bacterial infection in early childhood. All four had raised antibody titres to Escherichia coli. Three possibilities may explain the high antibody titres and insidious course of the renal damage—the presence of bacterial variants or amorphous bacterial antigen in the kidneys or the fact that because of cross-reactivity between certain E. coli O antigens and renal tissue the “E. coli antibodies” were, in fact, autoantibodies.     

Uncovering a Microbial Enigma: Isolation and Characterization of the Streamer-Generating,Iron-Oxidizing,Acidophilic Bacterium “Ferrovum myxofaciens”

A betaproteobacterium, shown by molecular techniques to have widespread global distribution in extremely acidic (pH 2 to 4) ferruginous mine waters and also to be a major component of “acid streamer” growths in mine-impacted water bodies, has proven to be recalcitrant to enrichment and isolation. A modified “overlay” solid medium was devised and used to isolate this bacterium from a number of mine water samples. The physiological and phylogenetic characteristics of a pure culture of an isolate from an abandoned copper mine (“Ferrovum myxofaciens” strain P3G) have been elucidated. “F. myxofaciens” is an extremely acidophilic, psychrotolerant obligate autotroph that appears to use only ferrous iron as an electron donor and oxygen as an electron acceptor. It appears to use the Calvin-Benson-Bassham pathway to fix CO₂ and is diazotrophic. It also produces copious amounts of extracellular polymeric materials that cause cells to attach to each other (and to form small streamer-like growth in vitro) and to different solid surfaces. “F. myxofaciens” can catalyze the oxidative dissolution of pyrite and, like many other acidophiles, is tolerant of many (cationic) transition metals. “F. myxofaciens” and related clone sequences form a monophyletic group within the Betaproteobacteria distantly related to classified orders, with genera of the family Nitrosomonadaceae (lithoautotrophic, ammonium-oxidizing neutrophiles) as the closest relatives. On the basis of the phylogenetic and phenotypic differences of “F. myxofaciens” and other Betaproteobacteria, a new family, “Ferrovaceae,” and order, “Ferrovales,” within the class Betaproteobacteria are proposed. “F. myxofaciens” is the first extreme acidophile to be described in the class Betaproteobacteria.     

Sexually-Transmitted/Founder HIV-1 Cannot Be Directly Predicted from Plasma or PBMC-Derived Viral Quasispecies in the Transmitting Partner

Objective

Characterization of HIV-1 sequences in newly infected individuals is important for elucidating the mechanisms of viral sexual transmission. We report the identification of transmitted/founder viruses in eight pairs of HIV-1 sexually-infected patients enrolled at the time of primary infection (“recipients”) and their transmitting partners (“donors”).

Methods

Using a single genome-amplification approach, we compared quasispecies in donors and recipients on the basis of 316 and 376 C2V5 env sequences amplified from plasma viral RNA and PBMC-associated DNA, respectively.

Results

Both DNA and RNA sequences indicated very homogeneous viral populations in all recipients, suggesting transmission of a single variant, even in cases of recent sexually transmitted infections (STIs) in donors (n = 2) or recipients (n = 3). In all pairs, the transmitted/founder virus was derived from an infrequent variant population within the blood of the donor. The donor variant sequences most closely related to the recipient sequences were found in plasma samples in 3/8 cases and/or in PBMC samples in 6/8 cases. Although donors were exclusively (n = 4) or predominantly (n = 4) infected by CCR5-tropic (R5) strains, two recipients were infected with highly homogeneous CXCR4/dual-mixed-tropic (X4/DM) viral populations, identified in both DNA and RNA. The proportion of X4/DM quasispecies in donors was higher in cases of X4/DM than R5 HIV transmission (16.7–22.0% versus 0–2.6%), suggesting that X4/DM transmission may be associated with a threshold population of X4/DM circulating quasispecies in donors.

Conclusions

These suggest that a severe genetic bottleneck occurs during subtype B HIV-1 heterosexual and homosexual transmission. Sexually-transmitted/founder virus cannot be directly predicted by analysis of the donor’s quasispecies in plasma and/or PBMC. Additional studies are required to fully understand the traits that confer the capacity to transmit and establish infection, and determine the role of concomitant STIs in mitigating the genetic bottleneck in mucosal HIV transmission.     

Long-Term Responses to Loss of Renal Mass: Pathophysiological Aspects: Role of Solute Excretion in Prevention of Norepinephrine-Induced Acute Renal Failure

Infusion of 0.75 μ g/kgbw/min norepinephrine (NE), for 40 minutes, into one renal artery in anesthetized dogs, induced acute renal failure (ARF). Subsequently there was nearly complete reversal of function within 8 weeks. Isotonic saline volume expansion, or renal vasodilation plus diuresis by acetylcholine (into renal artery: 20 μg/min) did not protect against this type of ARF. Volume expansion with either 5 or 20 percent mannitol partly prevented the fall of GFR 3 hours after NE, this protection being correlated with the magnitude of the osmolar clearance at the time of the insult. IV furosemide (10 mg/kg + 10 mg/kg/h; fluid losses replaced) afforded an even better protection. Proximal tubular necrosis in the “protected” kidneys was as severe as in non-protected kidneys. Glomerular cell morphology (scanning electron microscopy) was not altered by the 40-minute NE infusions. Functional “protection” appeared to depend on solute diuresis at the time of insult.     

Pre-Transplant CDKN2A Expression in Kidney Biopsies Predicts Renal Function and Is a Future Component of Donor Scoring Criteria

CDKN2A is a proven and validated biomarker of ageing which acts as an off switch for cell proliferation. We have demonstrated previously that CDKN2A is the most robust and the strongest pre-transplant predictor of post- transplant serum creatinine when compared to “Gold Standard” clinical factors, such as cold ischaemic time and donor chronological age. This report shows that CDKN2A is better than telomere length, the most celebrated biomarker of ageing, as a predictor of post-transplant renal function. It also shows that CDKN2A is as strong a determinant of post-transplant organ function when compared to extended criteria (ECD) kidneys. A multivariate analysis model was able to predict up to 27.1% of eGFR at one year post-transplant (p = 0.008). Significantly, CDKN2A was also able to strongly predict delayed graft function. A pre-transplant donor risk classification system based on CDKN2A and ECD criteria is shown to be feasible and commendable for implementation in the near future.     

Pathological States and Criminal Responsibility

The doctor is embarrassed in court when asked to testify to the effects of illness on a defendant''s capability “of appreciating the nature and quality of an act or omission or of knowing that an act or omission is wrong”. The source of his difficulty is traced to the legal concepts of “guilt”, “crime” and “punishment” which imply a legal view of man at variance with our modern biological view. To abolish this discrepancy we need not accept a medical model for criminal law where “crime” is analogous to “disease”, and “punishment” to “treatment”. A pragmatic approach to the handling of the criminal could exclude the notions of “guilt” and “punishment” and yet fulfil the rational goals of protecting society from the criminal and of compensating his victims.     

Understanding Neighborhood Environment Related to Hong Kong Children’s Physical Activity: A Qualitative Study Using Nominal Group Technique

Background

Relationships between the neighborhood environment and children’s physical activity have been well documented in Western countries but are less investigated in ultra-dense Asian cities. The aim of this study was to identify the environmental facilitators and barriers of physical activity behaviors among Hong Kong Chinese children using nominal group technique.

Methods

Five nominal groups were conducted among 34 children aged 10–11 years from four types of neighborhoods varying in socio-economic status and walkability in Hong Kong. Environmental factors were generated by children in response to the question “What neighborhood environments do you think would increase or decrease your willingness to do physical activity?” Factors were prioritized in order of their importance to children’s physical activity.

Results

Sixteen unique environmental factors, which were perceived as the most important to children’s physical activity, were identified. Factors perceived as physical activity-facilitators included “Sufficient lighting”, “Bridge or tunnel”, “Few cars on roads”, “Convenient transportation”, “Subway station”, “Recreation grounds”, “Shopping malls with air conditioning”, “Fresh air”, “Interesting animals”, and “Perfume shop”. Factors perceived as physical activity-barriers included “People who make me feel unsafe”, “Crimes nearby”, “Afraid of being taken or hurt at night”, “Hard to find toilet in shopping mall”, “Too much noise”, and “Too many people in recreation grounds”.

Conclusions

Specific physical activity-related environmental facilitators and barriers, which are unique in an ultra-dense city, were identified by Hong Kong children. These initial findings can inform future examinations of the physical activity-environment relationship among children in Hong Kong and similar Asian cities.     

Blood Pressure: A Consideration of Terminology

Concepts of hypertension have changed and changes in terminology to reflect this state of affairs are suggested. Statistically, the best mortality experience is associated with blood pressure commonly regarded as subnormal, and increments of blood pressure above this level are associated with progressive increases in mortality. The terms “normal”, “benign” and “essential” in relation to blood pressure should be abandoned. “Optimal”, “acceptable” and “hypertensive” ranges of blood pressure are suggested. Hypertension is regarded as a symptom of disease, rather than as a disease in itself, and “hypertension”, when used as a diagnostic label, should be qualified always by the primary disease, if known, or by the modifying phrase, “of unknown cause”, if not known.     

Effect of Energy Under-Reporting on Secular Trends of Dietary Patterns in a Mediterranean Population

BackgroundDiet is an important factor in the prevention of chronic diseases. Analysis of secular trends of dietary patterns can be biased by energy under-reporting. Therefore, the objective of the present study was to analyse the impact of energy under-reporting on dietary patterns and secular trends in dietary patterns defined by cluster analysis.ResultsThree clusters, “healthy”, “mixed” and “western”, were identified for both surveys. The “mixed” cluster was the predominant cluster in both surveys. Excluding EUR reduced the proportion of the “mixed” cluster up to 6.40% in the 2000 survey; this caused secular trend increase in the prevalence of the “mixed” pattern. Cross-classification analysis of all participants and PER’ data showed substantial agreement in cluster assignments: 68.7% in 2000 and 84.4% in 2005. Excluding EUR did not cause meaningful (≥15%) changes in the “healthy” pattern. It provoked changes in consumption of some food groups in the “mixed” and “western” patterns: mainly decreases of unhealthy foods within the 2000 and increases of unhealthy foods within the 2005 surveys. Secular trend effects of EUR were similar to those within the 2005 survey. Excluding EUR reversed the direction of secular trends in consumption of several food groups in PER in the “mixed” and “western” patterns.ConclusionsEUR affected distribution of participants between dietary patterns within and between surveys, secular trends in food group consumption and amount of food consumed in all, but not in the “healthy” pattern. Our findings emphasize threats from energy under-reporting in dietary data analysis.     

Impact of specific training and competition on myocardial structure and function in different age ranges of male handball players

Handball activity involves cardiac changes and demands a mixture of both eccentric and concentric remodeling within the heart. This study seeks to explore heart performance and cardiac remodeling likely to define cardiac parameters which influence specific performance in male handball players across different age ranges. Forty three players, with a regular training and competitive background in handball separated into three groups aged on average 11.78±0.41 for youth players aka “schools”, “elite juniors” 15.99±0.81 and “elite adults” 24.46±2.63 years, underwent echocardiography and ECG examinations. Incremental ergocycle and specific field (SFT) tests have also been conducted. With age and regular training and competition, myocardial remodeling in different age ranges exhibit significant differences in dilatation’s parameters between “schools” and “juniors” players, such as the end-diastolic diameter (LVEDD) and the end-systolic diameter of the left ventricle (LVESD), the root of aorta (Ao) and left atrial (LA), while significant increase is observed between “juniors” and “adults” players in the interventricular septum (IVS), the posterior wall thicknesses (PWT) and LV mass index. ECG changes are also noted but NS differences were observed in studied parameters. For incremental maximal test, players demonstrate a significant increase in duration and total work between “schools” and “juniors” and, in total work only, between “juniors” and “seniors”. The SFT shows improvement in performance which ranged between 26.17±1.83 sec to 31.23±2.34 sec respectively from “seniors” to “schools”. The cross-sectional approach used to compare groups with prior hypothesis that there would be differences in exercise performance and cardiac parameters depending on duration of prior handball practice, leads to point out the early cardiac remodeling within the heart as adaptive change. Prevalence of cardiac chamber dilation with less hypertrophy remodeling was found from “schools” to “juniors” while a prevalence of cardiac hypertrophy with less pronounced chamber dilation remodeling was noted later.     

Publication of Original Research in Urologic Journals – A Neglected Orphan?

The pathophysiologic mechanisms behind urologic disease are increasingly being elucidated. The object of this investigation was to evaluate the publication policies of urologic journals during a period of progressively better understanding and management of urologic disease. Based on the ISI Web of Knowledge Journal Citation Reports and the PubMed database, the number and percentage of original experimental, original clinical, review or commentarial articles published between 2002–2010 in six leading urologic journals were analyzed. “British Journal of Urology International”, “European Urology”, “Urologic Oncology-Seminars and Original Investigations” (“Urologic Oncology”), “Urology”, “The Journal of Urology”, and “World Journal of Urology” were chosen, because these journals publish articles in all four categories. The publication policies of the six journals were very heterogeneous during the time period from 2002 to 2010. The percentage of original experimental and original clinical articles, related to all categories, remained the same in “British Journal of Urology International”, “Urologic Oncology”, “Urology” and “The Journal of Urology”. The percentage of experimental reports in “World Journal of Urology” between 2002–2010 significantly increased from 10 to 20%. A distinct elevation in the percentage of commentarial articles accompanied by a reduction of clinical articles became evident in “European Urology” which significantly correlated with a large increase in the journal’s impact factor. No clearly superior policy could be identified with regard to a general increase in the impact factors from all the journals. The publication policy of urologic journals does not expressly reflect the increase in scientific knowledge, which has occurred over the period 2002–2010. One way of increasing the exposure of urologists to research and expand the interface between experimental and clinical research, would be to enlarge the percentage of experimental articles published. There is no indication that such policy would be detrimental to a journal’s impact factor.     

Certifying achievement in the control of Chagas disease native vectors: what is a viable scenario?

As an evaluation scheme, we propose certifying for “control”, as alternative to “interruption”, of Chagas disease transmission by native vectors, to project a more achievable and measurable goal and sharing good practices through an “open online platform” rather than “formal certification” to make the key knowledge more accumulable and accessible.     

Hospital Infections Caused by a Group of Recently Recognized Strains of Staphylococcus aureus

A survey was made of the phage-types of staphylococci responsible for cross-infection in a large veterans'' hospital between 1961 and 1964. An earlier survey had shown that in 1959 most of the infections were caused by staphylocci of the “80/81/82” group. In 1961 a new group of staphylococci were first recognized and provisionally designated as “Atypical Group III” strains; these were non-typable by the usual typing phages but showed inhibition patterns with some of the Group III phages. The “Atypical Group III” staphylococci all showed one or other of four patterns of multiple antibiotic resistance. By 1963 these resistant “Atypical Group III” staphylococci had become more frequent than “80/81/82” strains as causative agents of cross-infection, although both groups have continued to cause infections in the hospital. “Atypical Group III” strains mainly infected surgical wounds and skin ulcers, whereas “80/81/82” strains commonly produced primary skin sepsis, such as boils.     

The Histological Components of the Phoniatrical Body-Cover Model in Minipigs of Different Ages

Pigs are models in human phoniatry. However, features of maturation and ageing have not been considered with regard to the so-called body-cover model in this species. Therefore, the glottis of “young” (2–3 months; n = 6) and “old” (4–7 years; n = 6) minipigs was investigated. Their cranial (CraF) and caudal (CauF) vocal folds were histomorphometrically and stratigraphically analysed with emphasis on their amounts of collagen structures and elastic fibres. A dense subepithelial layer (SEL) was a distinct feature of CraF and CauF of both age groups; it was spread upon the underlying loose, flexible “cover” like a fibro-elastic membrane. The “cover” was characterised by the so-called superficial layer (SL), which was distinctly loose in the “young” minipigs, but had a much denser texture in the “old” minipigs. Here, the SL was dominated by elastic fibres in the CraF, but was of mixed qualities (collagenous and elastic) in the CauF. The structural requirements for the SL’s function as a loose “cover” were thus met only in the “young” animals. A clearly demarcated intermediate layer (IL)—characterised by high amounts of elastic fibres (as in humans)—was only found in the CraF of the “young” animals. In the “old” animals, it had lost its demarcation. In the depth of the CraF of the “old” animals, many thick collagen fibre bundles were detected in a location equivalent to that of the vocal muscle in the CauF. The development of their large diameters was interpreted as part of the maturation process, thereby supporting the hypothesis of their functional importance as a component of the “body.” In the CauF, the amounts of collagen structures increased throughout the entire lamina propria, resulting in a loss of demarcated stratigraphical subdivisions in the “old” minipigs. This situation resembled that described in the vocal fold of geriatric humans.