The construction of Chasma Boreale on Mars.

The polar layered deposits of Mars contain the planet's largest known reservoir of water ice and the prospect of revealing a detailed Martian palaeoclimate record, but the mechanisms responsible for the formation of the dominant features of the north polar layered deposits (NPLD) are unclear, despite decades of debate. Stratigraphic analyses of the exposed portions of Chasma Boreale-a large canyon 500 km long, up to 100 km wide, and nearly 2 km deep-have led most researchers to favour an erosional process for its formation following initial NPLD accumulation. Candidate mechanisms include the catastrophic outburst of water, protracted basal melting, erosional undercutting, aeolian downcutting and a combination of these processes. Here we use new data from the Mars Reconnaissance Orbiter to show that Chasma Boreale is instead a long-lived, complex feature resulting primarily from non-uniform accumulation of the NPLD. The initial valley that later became Chasma Boreale was matched by a second, equally large valley that was completely filled in by subsequent deposition, leaving no evidence on the surface to indicate its former presence. We further demonstrate that topography existing before the NPLD began accumulating influenced successive episodes of deposition and erosion, resulting in most of the present-day topography. Long-term and large-scale patterns of mass balance achieved through sedimentary processes, rather than catastrophic events, ice flow or highly focused erosion, have produced the largest geomorphic anomaly in the north polar ice of Mars.

Depletion of foxp3(+) T cells abrogates tolerance of skin and heart allografts in murine mixed chimeras without the loss of mixed chimerism.

The relative contribution of central and peripheral mechanisms to the generation and maintenance of allograft tolerance is of considerable interest. Here, we present new evidence that regulatory T cells (Foxp3(+) ) maintain skin and heart allograft tolerance in mixed hematopoietic chimeric mice. Transient depletion of both donor- and recipient-derived Foxp3(+) cells was necessary and sufficient to induce decisive rejection of long-accepted skin and heart allografts. In contrast, stable hematopoietic chimerism remained, and there was no detectable induction of donor-specific reactivity to hematopoietic cells. Foxp3(+) cell depletion did not result in the rejection of skin grafts of only MHC-disparate donors (B6.C-H2(d) /bByJ), indicating that MHC antigens were not the target in the graft. We conclude that two different mechanisms of tolerance are present in mixed chimeras. Hematopoietic chimerism, resistant to Foxp3(+) depletion, is probably due to deletional tolerance to MHC antigens, as supported by previous studies. In contrast, regulatory tolerance mechanisms involving Foxp3(+) cells are required to control reactivity against non-MHC antigens not present on hematopoietic lineages.

Consensus Statement of the IAP - Neurodevelopmental Chapter On Neurodevelopmental Disorders Habilitation Process: Strategic Plan for Prevention, Early Detection and Early Intervention.

JUSTIFICATION: Neurodevelopmental disorders, as per DSM-V, are described as a group of conditions with onset in the development period of childhood. There is a need to distinguish the process of habilitation and rehabilitation, especially in a developing country like India, and define the roles of all stakeholders to reduce the burden of neurodevelopmental disorders. PROCESS: Subject experts and members of Indian Academy of Pediatrics (IAP) Chapter of Neurodevelopmental Pediatrics, who reviewed the literature on the topic, developed key questions and prepared the first draft on guidelines. The guidelines were then discussed by the whole group through online meetings, and the contentious issues were discussed until a general consensus was arrived at. Following this, the final guidelines were drafted by the writing group and approved by all contributors. OBJECTIVES: These guidelines aim to provide practical clinical guidelines for pediatricians on the prevention, early diagnosis and management of neurodevelopmental disorders (NDDs) in the Indian settings. It also defines the roles of developmental pediatricians and development nurse counselor. STATEMENT: There is a need for nationwide studies with representative sampling on epidemiology of babies with early NDD in the first 1000 days in India. Specific learning disability (SLD) has been documented as the most common NDD after 6 years in India, and special efforts should be made to establish the epidemiology of infants and toddlers at risk for SLD, where ever measures are available. Preconception counseling as part of focusing on first 1000 days; Promoting efforts to organize systematic training programs in Newborn Resuscitation Program (NRP); Lactation management; Developmental follow-up and Early stimulation for SNCU/ NICU graduates; Risk stratification of NICU graduates, Newborn Screening; Counseling parents; Screening for developmental delay by trained professionals using simple validated Indian screening tools at 4, 8, 12, 18 and 24 months; Holistic assessment of 10 NDDs at child developmental clinics (CDCs) / district early intervention centre (DEICs) by multidisciplinary team members; Confirmation of diagnosis by developmental pediatrician/developmental neurologist/child psychiatrist using clinical/diagnostic tools; Providing parent guided low intensity multimodal therapies before 3 years age as a center-based or home-based or community-based rehabilitation; Developmental pediatrician to seek guidance of pediatric neurologist, geneticist, child psychiatrist, physiatrist, and other specialists, when necessary; and Need to promote ongoing academic programs in clinical child development for capacity building of community based therapies, are the chief recommendations.

A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody.

Chronic allograft vasculopathy (CAV) in murine heart allografts can be elicited by adoptive transfer of donor specific antibody (DSA) to class I MHC antigens and is independent of complement. Here we address the mechanism by which DSA causes CAV. B6.RAG1(-/-) or B6.RAG1(-/-)C3(-/-) (H-2(b)) mice received B10.BR (H-2(k)) heart allografts and repeated doses of IgG2a, IgG1 or F(ab')(2) fragments of IgG2a DSA (anti-H-2(k)). Intact DSA regularly elicited markedly stenotic CAV in recipients over 28 days. In contrast, depletion of NK cells with anti-NK1.1 reduced significantly DSA-induced CAV, as judged morphometrically. Recipients genetically deficient in mature NK cells (γ-chain knock out) also showed decreased severity of DSA-induced CAV. Direct NK reactivity to the graft was not necessary. F(ab')(2) DSA fragments, even at doses twofold higher than intact DSA, were inactive. Graft microvascular endothelial cells responded to DSA in vivo by increased expression of phospho-extracellular signal-regulated kinase (pERK), a response not elicited by F(ab')(2) DSA. We conclude that antibody mediates CAV through NK cells, by an Fc dependent manner. This new pathway adds to the possible mechanisms of chronic rejection and may relate to the recently described C4d-negative chronic antibody-mediated rejection in humans.

The Effects of Terrain Properties Upon the Small Crater Population Distribution at Giordano Bruno: Implications for Lunar Chronology.

The distribution of impact craters on the ejecta of Giordano Bruno, a recent (<10 Ma) 22-km diameter crater within the lunar highlands, exhibits substantial variations. We surveyed craters D ≥ 10 m across a 1,323 km2 area of Giordano Bruno's ejecta and compared the distribution of craters with variations in thermophysical properties derived from the Lunar Reconnaissance Orbiter Diviner instrument. We used Diviner-derived rock abundance and nighttime regolith temperatures along with thermal model-predicted surface temperatures for a diversity of terrains to identify and isolate areas of the ejecta based on thermophysical properties such as bulk density and thermal conductivity. We found that thermophysical properties of the ejecta vary considerably both laterally and vertically, and consistently differ from typical regolith, indicating the presence of higher thermal inertia materials. Crater-size frequencies are significantly lower in areas with terrain properties exhibiting higher: rock abundance, nighttime temperatures, and/or modeled thermal inertia. This discrepancy in crater distribution increases for craters smaller than ∼25 m. These thermophysical variations indicate changes in the mechanical properties of the target materials. We suggest that these variations-specifically, terrain-dependent crater scaling variations and impactor-scale heterogeneities in material properties such as the presence or absence of large boulders-may influence crater diameters or inhibit crater production altogether in Giordano Bruno's ejecta; furthermore, these factors are size-dependent.

Fluorescent Tracers for In Vivo Imaging of Lymphatic Targets.

The lymphatic system continues to gain importance in a range of conditions, and therefore, imaging of lymphatic vessels is becoming more widespread for research, diagnosis, and treatment. Fluorescent lymphatic imaging offers advantages over other methods in that it is affordable, has higher resolution, and does not require radiation exposure. However, because the lymphatic system is a one-way drainage system, the successful delivery of fluorescent tracers to lymphatic vessels represents a unique challenge. Each fluorescent tracer used for lymphatic imaging has distinct characteristics, including size, shape, charge, weight, conjugates, excitation/emission wavelength, stability, and quantum yield. These characteristics in combination with the properties of the target tissue affect the uptake of the dye into lymphatic vessels and the fluorescence quality. Here, we review the characteristics of visible wavelength and near-infrared fluorescent tracers used for in vivo lymphatic imaging and describe the various techniques used to specifically target them to lymphatic vessels for high-quality lymphatic imaging in both clinical and pre-clinical applications. We also discuss potential areas of future research to improve the lymphatic fluorescent tracer design.

Therapeutic thoracic duct drainage: A systematic review of the Eastern European experience and future potential.

Thoracic duct drainage (TDD) is gaining renewed interest, largely due to accumulation of evidence supporting the gut-lymph model, where toxic mesenteric lymph from the intestine contributes to development of multi-organ failure in acute and critical illness (ACI). Advances in minimally invasive TDD have added to this growing interest. The English TDD literature has been previously reviewed, but the more extensive Eastern European literature has not been available to English readers. Therefore, we undertook a systematic search of Eastern European human TDD studies using Scopus and PubMed databases and Russian language websites. Indications for TDD, clinical outcomes, and complications were reviewed. 113 studies, published between 1965 and 2015, were reviewed. The most common indications for TDD were hepatic failure, acute pancreatitis, and peritonitis. It was often used late and when other treatment options had been exhausted. Human TDD appeared safe and probably effective, especially when combined with lymphosorption. The benefit appeared to correlate with the volume of lymph drained. A randomized controlled trial (and some case-control studies) showed reduced mortality in patients with ACI with TDD. Other benefits included rapid normalization of blood parameters and decreased organ edema. This review provides further support for the gut-lymph model and justification for high quality randomized controlled trials of TDD in ACI. It also highlights other potential indications for TDD, such as bridging patients with liver failure to surgery or transplant.

Aqueously altered igneous rocks sampled on the floor of Jezero crater, Mars.

The Perseverance rover landed in Jezero crater, Mars, to investigate ancient lake and river deposits. We report observations of the crater floor, below the crater's sedimentary delta, finding that the floor consists of igneous rocks altered by water. The lowest exposed unit, informally named Séítah, is a coarsely crystalline olivine-rich rock, which accumulated at the base of a magma body. Magnesium-iron carbonates along grain boundaries indicate reactions with carbon dioxide-rich water under water-poor conditions. Overlying Séítah is a unit informally named Máaz, which we interpret as lava flows or the chemical complement to Séítah in a layered igneous body. Voids in these rocks contain sulfates and perchlorates, likely introduced by later near-surface brine evaporation. Core samples of these rocks have been stored aboard Perseverance for potential return to Earth.

Xenogeneic skin graft rejection is especially dependent on CD4+ T cells.

B6 mice were treated in vivo with anti-CD4, anti-CD8, or both anti-T cell antibodies together in an effort to prolong xenogeneic compared with allogeneic skin graft survival. Mice treated with anti-CD4 antibody showed prolonged survival of xenogeneic monkey or rabbit skin even after they had rejected whole MHC-disparate allogeneic mouse skin. Furthermore, the addition of cyclosporine was synergistic with the anti-CD4 antibody in prolonging graft survival. These results suggest that the cell-mediated response to xenogeneic antigens is especially dependent on CD4+ lymphocytes, a feature shared by the response to allogeneic minor histocompatibility antigens. In addition, the results suggest a possible approach to clinical immunosuppression for some forms of xenogeneic transplantation.

Skin graft rejection by beta 2-microglobulin-deficient mice.

Mice homozygous for a beta 2-microglobulin (beta 2-m) gene disruption lack beta 2-m protein and are deficient for functional major histocompatibility complex class I (MHC-I) molecules. The mutant mice have normal numbers of CD4+8- T helper cells, but lack MHC-I-directed CD4-8+ cytotoxic T lymphocytes (CTLs). In this study we used the beta 2-m mutant mice to study the importance of MHC-I-directed immunity in skin graft rejection. Our results indicate that MHC-I-directed CD8+ CTLs are not essential in the rejection of allografts with whole MHC or multiple minor H differences. However, the absence of MHC-I-guided immunity profoundly reduces the ability of mutant mice to reject H-Y disparate grafts. In addition, we show that natural killer cells which vigorously reject MHC-I-deficient bone marrow grafts, are not effective in the destruction of MHC-I-deficient skin grafts.

Kidney transplants in mice. An analysis of the immune status of mice bearing long-term, H-2 incompatible transplants.

Kidney transplants between strains of mice which are incompatible at either the K or the D end of the H-2 complex usually function for prolonged periods supporting the lives of nephrectomized recipients. This occurs with no recipient treatment. With multiple H-2 and non-H-2 determined incompatibilities, transplants may be rejected but more slowly than skin grafts. In the strain combination studied most extensively in these experiments (B10.D2 to B6AF(1)) in which the incompatibility was confined to the K end of the H-2 region, about 70 percent of recipients survived for many weeks with normal blood urea nitrogen levels. Skin grafts between untreated members of these strains were rejected promptly (mean survival time of 13.5 +/- 1.1 days) as were kidney transplants to recipients of prior skin grafts. Donor strain skin grafts to recipients of kidney transplants after kidney transplantation enjoyed greatly prolonged survival whereas skin grafts from a third party (A.SW) were rejected normally. If kidney tissue was transferred in the form of free grafts without primary vascular union, it was rejected promptly leaving its recipient highly immunized. Cellular and humoral immunity to donor antigens declined over the first few weeks after transplantation, and the spleens of long-term recipients contained no "killer cells." Recipient lymphoid cells could mount active graft versus host reactions to donor strain antigens on transfer to neonatal mice. Nevertheless, they were distinctly less able to respond specifically by the production of killer cells to donor strain antigens after sensitization in vitro. No evidence that this defect was associated with the presence of suppressor cells was forthcoming from several types of in vivo and in vitro tests.

Acute destruction by humoral antibody of rat skin grafted to mice.

A study has been made of the roles played by complement and polymorphonuclear leukocytes (PMN) in the acute destruction of xenografts of rat skin that follows injection of their hosts with antisera specifically reactive with graft antigens. The rat skin was grafted onto mice whose immune responses were suppressed by removal of the thymus and a brief course of treatment with rabbit antimouse lymphocyte serum. At about 2 wk after grafting the mice were injected intravenously or intraperitoneally with mouse antirat serum (MARS). This time interval was chosen because it avoided the complications that might be associated with either the process of healing in or with incipient rejection. Signs of graft damage were evident as early as 10 min after the injection of MARS, and in most animals so injected the grafts were completely destroyed within 24-48 h. The role of complement (C) in this acute destructive process is indicated by the results of three lines of experimentation. (a) Non-C-fixing antibodies or antibody fragments failed to cause damage to the grafts. Indeed, both chicken antirat serum and F(ab')(2) fragments from rabbit antirat serum completely protected the grafts against the effects of MARS that was administered 24 h later. (b) When mice were depleted of hemolytic C by treatment with cobra venom factor or heat-aggregated gamma globulin, the damage caused by MARS was greatly reduced or completely inhibited. (c) In mice with a genetically determined absence of C5 much greater quantities of MARS were required to cause graft damage; the tempo of the destructive process was consistently slower; and a greater number of grafts recovered from the initial inflammatory process than was the case for animals with an intact complement system. The participation of PMN in serum-mediated destruction of grafts was initially suggested by the results of microscope examination of fixed tissues. The essential role of these cells in the process is indicated by the failure of MARS to cause tissue damage in mice whose circulating PMN have been reduced to very low levels by treatment with nitrogen mustard or more specifically with an anti-PMN serum. The absence of tissue damage when circulating PMN are reduced but C levels are normal suggests that C-mediated cytolysis is unimportant in graft destruction and that the role of C lies in its ability to generate chemotactic factors. The latter may then attract the PMN that provide mediators of tissue damage.

Widespread and selective induction of major histocompatibility complex-determined antigens in vivo by gamma interferon.

gamma Interferon (IFN-gamma) caused remarkable increases in class I (H-2Kk) and class II (I-Ak) antigens throughout the body by 6-9 d. Heart, kidney, and adrenals showed increases of 4-8 times their previous levels of class I antigen content, while the pancreas and small intestine increased 13-17-fold. Lesser increases were found in spleen, liver, and lung, which showed higher resting antigenic potency. Increases of class II antigenicity of 6-10-fold were found in heart, kidney, pancreas, lung, liver, adrenal, and small intestine, with lesser increases in thymus and spleen, and none in lymph node. Topographical analysis revealed that IFN-gamma induced class I and II antigens on most tissues in a highly selective fashion. For example, the renal proximal tubules expressed large amounts of both class I and II antigens, whereas the distal tubules and collecting ducts did not. In some epithelial cells class I and II determinants were induced only on the basal aspects of the cell membrane. IFN-gamma caused a remarkable increase in class II-positive dendritic cells in the liver, pancreas, salivary glands, and thyroid. Whether these cells were of local or systemic origin is uncertain, but the finding of a simultaneous depletion of dendritic cells from lymph nodes and spleen raises the possibility that they may have been derived, at least in part, from these sites. The dynamic and selective induction of class I and II antigen expression by IFN-gamma is likely to be important in regulation of the immune response in tissues.

Complement independent antibody-mediated endarteritis and transplant arteriopathy in mice.

Complement fixation, as evidenced by C4d in the microvasculature, is a widely accepted criterion of antibody-mediated rejection. Complement fixation has been shown to be essential in acute antibody-mediated rejection, but its role in chronic rejection has not been addressed. Previous studies showed that passive transfer of complement fixing monoclonal IgG2a anti-H-2Kk into B6.RAG1-/- KO recipients of B10.BR hearts led to progressive chronic transplant arteriopathy (CTA) over 14-28 days, accompanied by C4d deposition. The present studies were designed to test whether complement was required for these lesions. We report that a noncomplement fixing donor-specific alloantibody (DSA, monoclonal IgG1 anti-H-2Kk) injected into B6.RAG1-/- KO recipients of B10.BR hearts also promotes CTA, without C4d deposition. Furthermore, a passive transfer of DSA (monoclonal IgG2a anti-H-2Kk) initiated endarteritis followed by CTA in B6.RAG1-/- mice genetically deficient in the third component of complement (RAG1-/-C3-/-). These studies indicate that antibody to class I MHC antigens can trigger chronic arterial lesions in vivo without complement participation, in contrast to acute antibody-mediated rejection. This pathway may be relevant to C4d-negative chronic rejection sometimes observed in patients with DSA, and argues that lack of C4d deposition does not exclude antibody-mediated chronic rejection.

Viral infection induces de novo lesions of coronary allograft vasculopathy through a natural killer cell-dependent pathway.

Viral infections including those due to cytomegalovirus have been associated with accelerated cardiac allograft vasculopathy (CAV) in clinical trials and some animal models. Evidence demonstrating a direct causal relationship between such infections and de novo formation of coronary vascular lesions is lacking. Heterotopic murine cardiac transplants were performed in a parental to F1 combination in animals lacking both T- and B-lymphocytes (RAG(-/-)). Coronary vasculopathy developed almost exclusively in the presence of recipient infection with lymphocytic choriomeningitis virus but not in uninfected controls. This process was also dependent upon the presence of natural killer (NK) cells as depletion of NK cells abrogated the process. These data show that a viral infection in its native host, and not previously implicated in the production of CAV, can contribute to the development of advanced coronary vascular lesions in cardiac allotransplants in mice. These data also suggest that virus-induced CAV can develop via an NK-cell-dependent pathway in the absence of T- and B-lymphocytes.

Implantation of genetically engineered fibroblasts into mice: implications for gene therapy.

In a variety of human genetic diseases, replacement of the absent or defective protein provides significant therapeutic benefits. As a model for a somatic cell gene therapy system, cultured murine fibroblasts were transfected with a human growth hormone (hGH) fusion gene and cells from one of the resulting clonal lines were subsequently implanted into various locations in mice. Such implants synthesized and secreted hGH, which was detectable in the serum. The function of the implants depended on their location and size, and on the histocompatibility of the donor cells with their recipients. The expression of hGH could be modified by addition of regulatory effectors, and, with appropriate immunosuppression, the implants survived for more than 3 months. This approach to gene therapy, here termed "transkaryotic implantation," is potentially applicable to many genetic diseases in that the transfected cell line can be extensively characterized prior to implantation, several anatomical sites are suitable for implantation, and regulated expression of the gene of therapeutic interest can be obtained.

Antiserum to lymphocytes: prolonged survival of canine renal allografts.

A horse immunized with dog lynmphocytes produced an antiserum which agglutinated canine lymphocytes in vitro and caused prolonged lymphopenia in dogs in vivo. Renal transplants in dogs treated with this antiserum survived for long periods, two of the grafts surviving beyond 350 days with normal function and histologic appearance.

Validation of developmental assessment tool for Anganwadis (DATA).

OBJECTIVE: To develop, standardize, and partly validate a developmental scale for toddlers (age, 1.6 to 3 years) attending anganwadis in India. METHODS: After the development of the 12-item Developmental Assessment Tool for Anganwadis (DATA), its internal consistency, face validity, content validity and construct validity were studied in 100 toddlers in anganwadis and were found to be appropriate. A total of 429 toddlers with a mean (SD) age of 30.9(5.2) months from 36 randomly selected anganwadis were recruited for its standardization. Raw scores were converted to standardized T-scores. Scoring pattern for domains and aggregate developmental scores were formulated. RESULTS: Except for one item in the original scale, all the items were endorsed by parents suggesting a good content validity. Cronbachs a of 0.86 suggested a high internal consistency. Factor analysis replicated the 2 factor structure explaining 56 %of variance. An aggregated developmental score based on the standardized T-scores demonstrated that a DATA score between 33 and 28 suggested at risk for developing developmental delays. A score of 27 suggested already delayed milestones. A score of 27 to 16 suggested a mild delay, a score of 15 to 5 suggested a moderate delay and 4 suggested a severe delay in development. CONCLUSION: DATA is a brief, simple and psychometrically sound measure for use in anganwadis for identifying toddlers at risk or with developmental delays. Differentially identifying toddlers at risk or with developmental delay helps in referring them for appropriate interventions.

Prevalence of eating disorders and psychiatric comorbidity among children and adolescents.

There are no prevalence or co-morbidity studies on eating disorders in India. This retrospective chart review studied the prevalence and psychiatric co-morbidity among juveniles with eating disorders. Forty-one cases with ICD 10 diagnosis of eating disorders were identified and analyzed. The prevalence of eating disorders was 1.25% Psychogenic vomiting was the commonest eating disorders and anorexia nervosa the emerging eating disorder. The most common co-morbidities were depression, intellectual disability, and dissociative disorder.