Long‐term follow up of paediatric liver transplant recipients: outcomes following transfer to adult healthcare in New Zealand

Poor outcomes are reported in young people with chronic health conditions. We performed a retrospective notes review of New Zealand paediatric liver transplant recipients transferred to adult services. Two patients were lost to follow up. Out of 20, 12 were non‐adherent, and out of 12, 7 developed rejection. Other risk behaviours were common in the non‐adherent group. We conclude that dedicated services for these young people may be needed to optimise outcomes.     

RESIDENTIAL DISTANCE TO PUBLIC HOUSING AND ITS DIFFERENTIAL INFLUENCE ON INFANT MORTALITY ACROSS RACE

Infant mortality is a major problem in the United States. Understanding the relationship between geographic variation and birth outcomes is important to develop and implement targeted interventions. This study examined the relationship between contextual residential distance to public housing and infant mortality. All singleton births (N = 30,554) and infant deaths (N = 361) occurring between January 1, 1997 and December 31, 2007 in Richmond, VA were analyzed. Maternal race, education, smoking during pregnancy, method of payment, gestational age, and sex of the infant were significantly associated with infant mortality. African Americans were 1.6 times as likely to reside 1 to 2 miles or less closer to public housing (p<.0001) than European Americans. Residential contextual variables play a role in poor birth outcomes, and public health professionals should be aware of this association when developing interventions.     

Mechanobiological oscillators control lymph flow

The ability of cells to sense and respond to physical forces has been recognized for decades, but researchers are only beginning to appreciate the fundamental importance of mechanical signals in biology. At the larger scale, there has been increased interest in the collective organization of cells and their ability to produce complex, “emergent” behaviors. Often, these complex behaviors result in tissue-level control mechanisms that manifest as biological oscillators, such as observed in fireflies, heartbeats, and circadian rhythms. In many cases, these complex, collective behaviors are controlled—at least in part—by physical forces imposed on the tissue or created by the cells. Here, we use mathematical simulations to show that two complementary mechanobiological oscillators are sufficient to control fluid transport in the lymphatic system: Ca²⁺-mediated contractions can be triggered by vessel stretch, whereas nitric oxide produced in response to the resulting fluid shear stress causes the lymphatic vessel to relax locally. Our model predicts that the Ca²⁺ and NO levels alternate spatiotemporally, establishing complementary feedback loops, and that the resulting phasic contractions drive lymph flow. We show that this mechanism is self-regulating and robust over a range of fluid pressure environments, allowing the lymphatic vessels to provide pumping when needed but remain open when flow can be driven by tissue pressure or gravity. Our simulations accurately reproduce the responses to pressure challenges and signaling pathway manipulations observed experimentally, providing an integrated conceptual framework for lymphatic function.Flow of fluid within the lymphatic system is central to many aspects of physiology, including fluid homeostasis and immune function, and poor lymphatic drainage results in significant morbidity in millions of patients each year (1). Although it is known that various mechanical and chemical perturbations can affect lymphatic pumping, there are still no pharmacological therapies for lymphatic pathologies. A fundamental understanding of how various signals coordinate lymphatic vessel function is a necessary first step toward development of treatments to restore fluid balance and enhance immunosurveillance.The lymphatic system consists of fluid-absorbing initial lymphatic vessels that converge to collecting lymphatic vessels, which transport lymph through lymph nodes and back to the blood circulation (2). The collecting lymphatic vessels actively transport fluid via contractions of their muscle-invested walls. Unidirectional flow is achieved by intraluminal valves that limit back flow. Unfortunately, lymphatic pumping is not always operational, and this can lead to lymphedema and immune dysfunction (3, 4).Much is known about the mechanisms responsible for the contractions of the vessel wall. As in blood vessels, the muscle cells that line lymphatic vessels respond to changes in Ca²⁺ concentration. Membrane depolarization results in an influx of Ca²⁺ to initiate the contractions, and this process can be modulated by neurotransmitters (5) or inflammatory mediators, which generally alter the frequency and amplitude of lymphatic pumping (4, 6). Many studies have also reported that physical distension, either by applying isometric stretch or by pressurizing the vessel can affect the phasic contractions (7–10). Interestingly, endothelial (11) and smooth muscle cells (12) have stretch-activated ion channels that can initiate Ca²⁺ mobilization in response to mechanical stresses. Thus, stretch may constitute an important trigger for the contraction phase of a pumping cycle.There are also complementary mechanisms for tempering the Ca²⁺-dependent contractions. The most notable is nitric oxide (NO), a vasodilator that acts at multiple points in the Ca²⁺-contraction pathway to modulate Ca²⁺ release and uptake, as well as the enzymes responsible for force production (13). Blocking or enhancing NO activity can dramatically affect pumping behavior (4, 14–17). Furthermore, lymphatic endothelial cells produce NO in response to fluid flow (16, 18, 19). Importantly, NO dynamics are faster than observed pumping frequencies, so flow-induced NO production is another potential mechanosignal involved in lymphatic regulation (20).     

Intention-to-treat analysis of liver transplantation,resection and thermal ablation for hepatocellular carcinoma in a single centre

Background

potentially curative treatment options for hepatocellular carcinoma (HCC) include liver transplantation (LT), liver resection (LR) and thermal ablation (TA). Long term intent-to-treat (ITT) analysis from a single-centre using all three modalities contemporaneously has not been published.

Trophoblastic metaplasia in urothelial carcinoma of the bladder

Trophoblastic differentiation in bladder carcinoma is reported in four patients. Plasma gonadotrophin (beta subunit of HCG), measured in three patients, was elevated. In one patient treated with cisplatin, vinblastine and bleomycin, the beta HCG level fell significantly but progression of malignant disease was not arrested.     

Mutation of the TP53 gene and allelic imbalance at chromosome 17p13 in ductal carcinoma in situ.

A panel of 36 cases of preinvasive breast lesions, including 35 cases of ductal carcinoma in situ (DCIS), has been examined for mutation of TP53, allelic imbalance (AI) on 17p13, and expression of TP53, in a number of cases, has been studied using immunohistochemistry. Areas of DCIS, with or without adjacent invasive or benign cells, have been separately microdissected from paraffin-embedded sections and analysed by PCR for genetic changes to chromosome 17p13. TP53 mutations and AI on 17p have been identified in cases of ''pure'' DCIS as well as those with associated invasive carcinoma and, furthermore, have been identified in well-differentiated lesions as well as poorly differentiated ones.     

Role of low-affinity Fc receptors in antibody-dependent tumor cell phagocytosis by human monocyte-derived macrophages.

Human monocyte-derived macrophages (MDM) mediate efficient antibody-dependent cellular cytotoxicity (ADCC) against a variety of human tumor cell types in the presence of an anti-tumor monoclonal antibody. We have recently shown that the mechanism of this ADCC in our in vitro system involves phagocytosis of intact tumor cells. Some forms of macrophage ADCC have been reported to be inhibited by serum immunoglobulin, which competes with monoclonal antibodies for binding to the high-affinity Fc receptor (FcRI). In this study we investigated the role of the three macrophage FcR-gamma in antibody-dependent tumor cell phagocytosis. Hybridoma cells bearing surface antibody directed against either of the two low-affinity Fc receptors (FcRII or FcRIII) were efficiently phagocytosed by MDM, compared to hybridomas bearing irrelevant antibody. Soluble anti-receptor antibodies against FcRII and FcRIII were able to inhibit ADCC but only when both antibodies were simultaneously present. These data suggest that either low-affinity Fc receptor is capable of functioning independently to mediate phagocytosis of tumor cells. Consistent with a mechanism involving the low-affinity receptors rather than FcRI, antibody-dependent phagocytosis occurred in the presence of human serum, purified human IgG, and irrelevant murine antibody. Greater than 75% of the MDM in our culture system were able to ingest tumor cells when a suitable target was available. Optimal phagocytosis occurred at monoclonal antibody concentrations of 10-100 ng/ml. Like other forms of macrophage phagocytosis, ingestion of tumor cells required the presence of divalent cations (either Ca2+ or Mg2+) and an intact actin cytoskeleton (as indicated by sensitivity to cytochalasin D). Because FcRI is normally occupied in vivo by serum immunoglobulin, the participation of low-affinity FcR in tumor cell phagocytosis is potentially important in establishing the in vivo applicability of this efficient form of cytotoxicity.