Immunosuppression

Our aim was to study histopathological changes in lung tissue at the light microscopic and ultrastructural level during recovery from immunosuppression and Pneumocystis carinii pneumonia. Male Wistar rats were immunosuppressed by per oral dexamethasone for 12 weeks to induce P. carinii pneumonia, after which dexamethasone was stopped. Recovery was monitored 1, 2 and 4 weeks after cessation of the immunosuppression. In immunosuppressed animals, CD4+ and CD8+ lymphocytes were both decreased in situ. CD8+ lymphocytes increased above control level at week one. Like CD8+ cells, the ED1+ macrophages increased rapidly in situ. This was accompanied by a progressively increasing migration (more transient for lymphocytes) of macrophages into bronchoalveolar fluid, associated with morphological signs of activation and phagocytosis and proliferation of type II pneumocytes. Bronchoalveolar lavage (BAL) fluid tumour necrosis factor-alpha (TNF-alpha) increased from subnormal levels to a 4 week pea...

It is argued that HLA matching is not worthwhile in heart transplantation. However, transplanting HLA compatible hearts enhances graft survival and should significantly reduce infection and malignancies related to aggressive immunosuppression. It is our view that the problem is technical and we offer a potential solution. J Heart Lung Transplant 1999;18:226-230.

New immunosuppressive drugs used in kidney transplantation decreased the incidence of acute rejection. It was hypothesized that, with their power, the importance of HLA matching was decreased. To evaluate the influence of HLA matching, immunosuppression, and other possible risk factors, we analyzed data of 1314 consecutive deceased donor kidney transplantation. We divided the patient population into 4 cohorts, according to the era of transplantation: era 1, before 1990, azathioprine (Aza) and cyclosporine (Csa) no microemulsion; era 2, between 1990 and 1995, Csa microemulsion; era 3, between 1996 and 2000, wide use of mycophenolate mofetil (MMF) and anti-thymocyte globulin (ATG); and era 4, after 2000, marked by sirolimus and tacrolimus (TAC) use. Multivariate analysis compared death-censored graft survival. Using as reference the results obtained with 0 HLA mismatches, we verified, during era 1 and era 2, an increased risk of graft loss for all of the subgroups with HLA mismatch Ͼ0. However, during era 3 and era 4, the number of HLA mismatches did not influence graft survival. Although acute rejection and delayed graft function, which decreased in the later periods, remained as prognostic factors for graft loss. Considering the immunosuppressive protocol with CsaϩAzaϩPred as reference, protocols used after 1995 with PredϩCsaϩATG, with PredϩCsaϩMMF, and with PredϩTacϩMMF presented better survival results. Results showed that the significance of HLA matching decreased while the results improved with the new immunosuppressant drugs. These observations support the hypothesis that the weakened importance of HLA matching may be a consequence of the increasing efficacy of the immunosuppression.

Recent studies on the immunosuppressive effects of ultraviolet radiation (UVR) and the related resistance to infections in rodents and humans are presented. The waveband dependency of trans-to-cis isomerisation of urocanic acid in the stratum corneum and the role of DNA damage in UVR-induced erythema and immunosuppression were investigated to further elucidate the underlying mechanisms. Furthermore, human experimental studies on UVR-induced immunomodulation were performed. It appeared that the doses needed to suppress various immune parameters in humans (e.g. NK activity, contact hypersensitivity) were higher than those needed in experiments in rodents. Still, extrapolation of experimental animal data to the human situation showed that UVR may impair the resistance to different systemic infections at relevant outdoor doses. In observational human studies we aimed to substantiate the relevance of UVR for infections in humans. It was shown that sunny season was associated with a slightly retarded but clinically non-relevant antibody response to hepatitis B vaccination. Furthermore, sunny season appeared to be associated with a small decline in the number of CD4+ T-helper cells in a cohort of HIV-infected persons and a 1567-5769/02/$ -see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 7 -5 7 6 9 ( 0 1 ) 0 0 1 7 8 -3

56 patients receiving chemotherapy for non-Hodgkin lymphoma or Hodgkin's disease with curative intent were monitored for up to one year after initiation of treatment. During chemotherapy (mean duration 5.2 months), 26 of the patients (46') suffered from 38 febrile episodes. In only 16 instances was an extraoral cause for the septicaemia found. However, severe dental infection, reflected in an elevated radiological index for the jaws, was found more frequently in patients suffering febrile episodes than in those without (P= 0.02). Moderate to severe gingival inflammation was observed during 22 (58%) of episodes. During 71% of the episodes various pathological findings were also recorded in the oral mucosa. No source of infection other than an oral one was found in 42% of the patients. Our results emphasise the importance of oral foci as the possible infection source in patients receiving intensive chemotherapy.

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

A rejection occurs commonly in simultaneous pancreas/kidney (SPK) transplant recipients and continues to be a cause of graft loss despite the potent immunosuppressive agents available. The induction of peripheral tolerance via bone marrow (BM) infusion has been successful in experimental animals. In the 1960s and 197Os, Anthony P. Monaco pioneered the concept of the establishment of a hematopoietic chimera to set the stage for a state of tolerance toward allogeneic transplants (skin, vascularized whole organ, etc) experimentally.'

Natural killer (NK) cells express receptors that are specific for MHC class I molecules. These receptors play a crucial role in regulating the lytic and cytokine expression capabilities of NK cells. In humans, three distinct families of genes have been defined that encode for receptors of HLA class I molecules. The first family identified consists of type I transmembrane molecules belonging to the immunoglobulin (Ig) superfamily and are called killer cell Ig-like receptors (KIR). A second group of receptors belonging to the Ig superfamily, named ILT (for immunoglobulin like transcripts), has more recently been described. ILTs are expressed mainly on B, T and myeloid cells, but some members of this group are also expressed on NK cells. They are also referred to as LIRs (for leukocyte Ig-like receptor) and MIRs (for macrophage Ig-like receptor). The ligands for the KIR and some of the ILT receptors include classical (class Ia) HLA class I molecules, as well as the nonclassical (class Ib) HLA-G molecule. The third family of HLA class I receptors are C-type lectin family members and are composed of heterodimers of CD94 covalently associated with a member of the NKG2 family of molecules. The ligand for most members is the nonclassical class I molecule HLA-E. NKG2D, a member of the NKG2 family, is expressed as a homodimer, along with the adaptor molecule DAP10. The ligands of NKG2D include the human class I like molecules MICA and MICB, and the recently described ULBPs. Each of these three families of receptors has individual members that can recognize identical or similar ligands yet signal for activation or inhibition of cellular functions. This dichotomy correlates with particular structural features present in the transmembrane and intracytoplasmic portions of these molecules.

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.

The FKBP-12-binding ligand FK506 has been successfully used to stimulate nerve regeneration and prevent the rejection of peripheral nerve allografts. The immunosuppressant rapamycin, another FKBP-12-binding ligand, stimulates axonal regeneration in vitro, but its influence on nerve regeneration in peripheral nerve isografts or allografts has not been studied. Sixty female inbred BALB/cJ mice were randomized into six tibial nerve transplant groups, including three isograft and three allograft (C57BL/6J) groups. Grafts were left untreated (groups I and II), treated with FK506 (groups III and IV), or treated with rapamycin (groups V and VI). Nerve regeneration was quantified in terms of histomorphometry and functional recovery, and immunosuppression was confirmed with mixed lymphocyte reactivity assays. Animals treated with FK506 and rapamycin were immunosuppressed and demonstrated significantly less immune cell proliferation relative to untreated recipient animals. Although every animal demonstrated some functional recovery during the study, animals receiving an untreated peripheral nerve allograft were slowest to recover. Isografts treated with FK506 but not rapamycin demonstrated significantly increased nerve regeneration. Nerve allografts in animals treated with FK506, and to a lesser extent rapamycin, however, both demonstrated significantly more nerve regeneration and increased nerve fiber widths relative to untreated controls. The authors suggest that rapamycin can facilitate regeneration through peripheral nerve allografts, but it is not a neuroregenerative agent in this in vivo model. Nerve regeneration in FK506-treated peripheral nerve isografts and allografts was superior to that found in rapamycin-treated animals. Rapamycin may have a role in the treatment of peripheral nerve allografts when used in combination with other medications, or in the setting of renal failure that often precludes the use of calcineurin inhibitors such as FK506. (Plast. Reconstr. Surg. 109: 2405, 2002 Functional recovery following peripheral nerve injury is predicated on a robust and timely reinnervation of sensory receptors and motor end plates. 1-3 A reliable neuroregenera-tive agent with minimal systemic toxicity would hasten functional recovery following extensive proximal peripheral nerve injury. The immunosuppressant FK506 possesses a well-studied neuroregenerative effect, stimulating neurite extension in the presence of nerve growth factor in vitro, 4,5 and enhancing nerve regeneration in nerve crush, 5-8 transection, 7,9 isograft, 10,11 and allograft models. 12-14 FK506 has also been used to facilitate axonal regeneration through human peripheral nerve allografts. Given its immunosuppressive and calcineurin-related side effects, including renal failure 16 and hypertension, 17 the use of FK506 solely to stimulate nerve regeneration cannot be justified. The utility of FK506 in the context of preexisting composite tissue and peripheral nerve allograft tolerance has also been challenged. 18 Studies demonstrating successful transplantation of skin 19 and solid organ allografts using a monoclonal antibody to block the costimulatory pathway of T-cell activation demonstrated an almost immediate abrogation of these effects with the addition of a calcineurin inhibitor such as FK506. 19 -23 The inability of FK506 to coexist with novel tolerizing therapies such as anti-CD40L monoclonal antibody will have significant implication for clinical peripheral nerve and hand allotransplantation when the neuroregenerative effects of FK506 are desirable. Like FK506, rapamycin is an immunosuppressant that binds FKBP-12 and has demonstrated a neuroenhancing effect in vitro. 5,6,26 -30 To our knowledge, however, neither the in vivo

Background. Technical failure rates are higher for pancreas allografts (PA) compared with other solid organs. Posttransplant surveillance and prompt availability of rescue teams with multidisciplinary expertise both contribute to improve this result. We herein report a single institution's experience with posttransplant surveillance and rescue of PA. Methods. A retrospective survey was performed of a consecutive series of 177 whole organ pancreas transplants in 173 patients. Antithrombotic prophylaxis was used in all recipients and tailored on anticipated individual risk of thrombosis. During the first posttransplant week, all PA were monitored with daily Doppler ultrasonography. Surgical complications were defined as all adverse events requiring relaparotomy during the initial hospital stay or the first 3 posttransplant months. Results. A total of 26 relaparotomies were performed in 25 patients (14.7%). One recipient needed two relaparotomies (0.6%). Graft rescue was attempted in patients without permanent parenchymal damage at repeat surgery and in 12 recipients diagnosed with nonocclusive vascular thrombosis. Overall 25 grafts (96.3%) were rescued and one was lost. One-year recipient and graft survivals in patients with versus without complications potentially leading to allograft loss were 92.6% and 63.0% versus 94.4% and 94.3%, respectively. Excluding complications for which graft rescue was not possible, 1-year graft survival rate increased to 78.7%. Conclusions. Close posttransplant surveillance can allow rescue of a relevant proportion of PA developing nonocclusive venous thrombosis or other surgical complications. Further improvement awaits better understanding of biological reasons for posttransplant complications jeopardizing PA survival and the development of more effective preventive measures.

Multi-proxy approach was used to reconstruct the environmental conditions of remote lakes in the High Tatra Mountains (Slovakia) over the past few centuries (approximately 500-1000 years). Short sediment cores (*30 cm) taken from three morphologically similar glacial lakes distributed along altitudinal gradient (subalpine to alpine conditions) were analysed for organic matter content (LOI), diatoms and chironomids. Both descriptive and correlative approaches were used for analysing stratigraphical data. Predictive canonical correspondence analysis and co-correspondence analysis were applied to directly relate physical and biological proxies to each other. The relationship between LOI and biotic proxies was inconsistent across groups and lakes. Concordant patterns in diatom and chironomid composition were found in two non-acidified lakes. Common trends in those assemblages indicated major past environmental events such as the Little Ice Age, air pollution and lake acidification. In contrast, no relationship between the composition of diatom and chironomid assemblages was found in the formerly acidified lake, suggesting different responses of assemblages to acidification. While chironomids showed shifts that are attributable to recovery, diatoms assemblage remained relatively stable throughout the uppermost layers of the sediment record. On the other hand, climatic-driven changes in assemblages detected in the deeper layers were more pronounced in diatoms than in chironomids.

By preserving part of the native liver, auxiliary partial orthotopic liver transplantation (APOLT) provides the advantage of potential immunosuppression (ISP) withdrawal if the native liver recovers but has had limited acceptance, especially in the United States, due to technical complications and low rates of native liver regeneration. No previous study has evaluated APOLT specifically for preadolescent children with fulminant hepatic failure (FHF). This population might benefit especially based on greater capacity for liver regeneration. Data from 13 preadolescent children who underwent APOLT were compared to 13 matched controls who underwent orthotopic liver transplantation (OLT) for FHF from 1996 to 2013. There were no significant differences in patient demographics or survival between the 2 groups. However, all surviving OLT recipients (10/13) remain on ISP, while all but 1 surviving APOLT recipient (12/13) showed native liver regeneration, and the first 10 recipients (76.9%) are currently off ISP with 2 additional patients currently weaning. In our experience, APOLT produced excellent survival and high rates of native liver regeneration in preadolescent children with FHF. This represents the largest series to date to report such outcomes. Liberating these children from lifelong ISP without the downside of increased surgical morbidity makes APOLT an attractive alternative. In conclusion, we therefore propose that, with the availability of technical expertise and with the technical modifications above, APOLT for FHF should be strongly considered for preteenage children with FHF.

Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects.

R ENAL transplantation is the best therapeutic option for patients with terminal chronic renal failure. Currently, in most transplant centers the 1-year graft survival of cadaveric renal transplants is higher than 80%. However, the half-life of a graft in patients with graft functioning at 1-year posttransplant is close to 7 years. 3 Chronic rejection is a major cause of graft failure, after the first year, in kidney transplant recipients. Many factors influence long-term graft survival, mainly HLA mismatch and occurrence of acute rejection. 4,5 Acute rejection is a common event following renal transplant, especially during the first 6 months, when the levels of immunosuppressive drugs are reduced. Furthermore, recent data suggest that acute rejection after 60 days post-TX is associated with a poorer prognosis compared to acute rejection within the first 60 days. 6 For this reason, one of the difficulties in long-term management of transplant patients is the adequacy of the immunosuppressive therapy.

Regulatory T lymphocytes (Treg) play a central role in the control of immune responses and thus maintain immune tolerance and homeostasis. In mice, expression of the CD8 co-receptor and low levels of the co-stimulatory molecule CD28 characterizes a Treg population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo. It has remained unclear if CD8(+) CD28(low) Treg develop in the thymus or represent a population of chronically activated conventional T cells differentiating into Treg in the periphery, as suggested by their CD28(low) phenotype. Here we demonstrate that functional CD8(+) CD28(low) Treg are present in the thymus and that these cells develop locally and are not recirculating from the periphery. Differentiation of CD8(+) CD28(low) Treg requires major histocompatibility complex (MHC) class I-expression on radioresistant but not on hematopoietic thymic stromal cells. In contrast to other Treg, CD8(+) CD28(low) Treg d...

Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the ben-efits of transplantation to patients who are older or who lack family donors. Recent results with alternative sources of stem cells and a variety of conditioning regimens to achieve their engraftment have been promising, with survival in small pediatric case series rivaling conventional transplantation results. (Blood.

Extracorporeal photopheresis (ECP) was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n ¼ 10), III (n ¼ 7) or IV (n ¼ 6)). The median duration of ECP was 7 months (1-33) and the median number of ECP cycles in each patient was 10. Twelve patients (52%) had complete responses. Eleven patients (48%) survived and 12 died, 10 of GVHD with or without infections and two of leukaemia relapse. The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day þ 90 from ECP) (P ¼ 0.08), and the average dose of i.v. methylprednisolone from 2.17 to 0.2 mg/kg/d (P ¼ 0.004). Complete responses were obtained in 70, 42 and 0% of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40%. Patients treated within 35 days from onset of aGVHD had higher responses (83 vs 47%; P ¼ 0.1). A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 vs 16%; P 0.08). ECP is a treatment option for patients with steroid refractory aGVHD and should be considered early in the course of the disease.

Delayed type hypersensitivity (DTH) reactions are antigen-specific, cell-mediated immune responses which, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, fungi, and certain tumors) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. We have shown that acute stress administered immediately before antigenic challenge results in a significant enhancement of a skin DTH response in rats. A stress-induced trafficking or redeployment of leukocytes to the skin may be one of the factors mediating this immunoenhancement. Here we investigate the effects of varying the duration, intensity, and chronicity of stress on the DTH response and on changes in blood leukocyte distribution and glucocorticoid levels. Acute stress administered for 2 h prior to antigenic challenge, significantly enhanced the DTH response. Increasing the duration of stress from 2 h to 5 h produced the same magnitude enhancement in cutaneous DTH. Moreover, increasing the intensity of acute stress produced a significantly larger enhancement of the DTH response which was accompanied by increasing magnitudes of leukocyte redeployment. In contrast, chronic stress suppressed the DTH response when it was administered for 3 weeks before sensitization and either discontinued upon sensitization, or continued an additional week until challenge, or extended for one week after challenge. The stress-induced redeployment of peripheral blood lymphocytes was attenuated with increasing exposure to chronic stress and correlated with attenuated glucocorticoid responsivity. These results suggest that stress-induced alterations in lymphocyte redeployment may play an important role in mediating the bi-directional effects of acute versus chronic stress on cell-mediated immunity in vivo. ᭧ 1997 Academic Press

Background. Heart transplantation has a dramatic impact on both life expectancy and quality of life in patients with terminal heart failure. The aim of the study was to evaluate psychologic, social, occupational, and somatic status of patients living long-term, 9 to 13 years after orthotopic heart transplantation.

We assessed the effects of Zizyphus lotus L. (Desf.) polyphenols (ZLP) on T-cell signaling and proliferation. Our results showed that ZLP exerted no effect on the increases in intracellular free calcium concentrations, [Ca 2+ ] i, in human Jurkat T-cells. However, ZLP modulated the thapsigargin-induced increases in [Ca 2+ ] i in these cells. ZLP treatment was found to decrease the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). In addition, ZLP induced a rapid (t 1/2 = 33 s) and dose-dependent decrease in intracellular pH (pH i ) in human Jurkat T-cells. Furthermore, ZLP significantly curtailed T-cell proliferation by diminishing their progression from S to G2/M phase of cell cycle, and the expression of interleukin-2 (IL-2) mRNA. Taken together, the results of the present study demonstrate that ZLP modulate cell signaling and exert immunosuppressive effects in human T-cells.

This article attempts to put into a risk-related perspective modern red blood cell (RBC) transfusion therapy. When making the decision to transfuse, RBCs or blood products, it is important to weigh the risks and benefits of the proposed therapy. It is equally important to evaluate the risk of not transfusing and the morbidity and mortality associated with that decision. After nearly a century of use, RBC transfusions continue to be associated with a variety of risks. Although the initial risks of mismatch and infectious disease transmission are ever decreasing, new risk considerations, particularly immunosuppression, are being uncovered. Because of the nearly universal worldwide fear of transfusion-related transmission of infectious disease a more conservative transfusion policy has generally taken hold. Transfusion avoidance philosophies and then increased use of autologous RBCs have become commonplace. This article puts a decision-oriented slant on the risk and benefit of transfusion therapy. The issues behind the inability to discern a defined benefit as well as a commentary on the newly perceived risks is provided. Overall, when increased oxygen delivery is required, the addition of RBCs has an apparent survival benefit in some specific patients. In these patients the risk of transfusion-related complication is minimized compared to the mortality outcome. For cancer and trauma patients, if transfusion is immunosuppressive and therefore detrimental, alternatives must be considered. The newest question is whether the act of transfusion, independent of the form, allogeneic or autologous, is of itself immunosuppressive.

Since the introduction of the hepatitis B vaccine and other preventive measures, the worldwide prevalence of hepatitis B infection has fallen. However, chronic infection remains a challenging global health problem, with more than 350 million people chronically infected and at risk of hepatic decompensation, cirrhosis, and hepatocellular carcinoma. An improved understanding of hepatitis B virology, immunology, and the natural course of chronic infection, has identifi ed hepatitis B virus replication as the key driver of immune-mediated liver injury and disease progression. The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998. Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments, and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts disease progression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during long term therapy. The development of new drugs and strategies is needed to improve treatment outcomes.

Multi-proxy approach was used to reconstruct the environmental conditions of remote lakes in the High Tatra Mountains (Slovakia) over the past few centuries (approximately 500-1000 years). Short sediment cores (*30 cm) taken from three morphologically similar glacial lakes distributed along altitudinal gradient (subalpine to alpine conditions) were analysed for organic matter content (LOI), diatoms and chironomids. Both descriptive and correlative approaches were used for analysing stratigraphical data. Predictive canonical correspondence analysis and co-correspondence analysis were applied to directly relate physical and biological proxies to each other. The relationship between LOI and biotic proxies was inconsistent across groups and lakes. Concordant patterns in diatom and chironomid composition were found in two non-acidified lakes. Common trends in those assemblages indicated major past environmental events such as the Little Ice Age, air pollution and lake acidification. In contrast, no relationship between the composition of diatom and chironomid assemblages was found in the formerly acidified lake, suggesting different responses of assemblages to acidification. While chironomids showed shifts that are attributable to recovery, diatoms assemblage remained relatively stable throughout the uppermost layers of the sediment record. On the other hand, climatic-driven changes in assemblages detected in the deeper layers were more pronounced in diatoms than in chironomids.

In 1960, Burnet and Medawar were awarded the Nobel Prize for their work on immunology and transplantation, and, as Silverstein noted in earlier work, the two were never actually nominated together for the specific prize. Both were exceptional scientists and both deserved a separate prize for their respective line of work. Burnet should have received a prize for his work on clone selection-theory, and Medawar, for his transplantation studies, but not for the formulation of immunological tolerance. The term was officially designated in the late 50's and early 60's, and attributed to organ transplants, but its foundation goes back much further. Silverstein, in his excellent paper on the Nobel Prize conundrum, suggested that Ray Owen should have received the award for his work on cattle chimerism. These authors would also like to point out even more obscure, yet pioneering studies of virology suggest that the formulation of immunological tolerance goes back even further, to the work established by Rockefeller alumni, German virologist and veterinarian, Dr. Erich Traub and actually it was he who should have been credited as the discoverer and pioneer of Immunological Tolerance

The purpose of this exploratory study is to better understand the current dynamics of the Malaysian market for smartphone and the usage behaviors of consumers. This paper presents the result of a survey on the trend of smartphone from the perspective of end consumers. The data was collected from 1814 respondents across major cities in Malaysia. This study has looked into the familiarity of users towards smartphones, choices of smartphone brand and service providers, and most importantly the determinants that influence their purchasing decision. Additionally, the consumers' preferences on smartphone specifications such as design, computing power, operating platform, and price were investigated. Furthermore, consumers' usage behaviors such as using smartphone for email, web browsing, gaming, and document reading were examined. The statistics presented provides fundamental information regarding the trends in the smartphone market and usage behaviors in Malaysia. Such information are useful for academics for the development of future works in the field, whereas for smartphone manufacturers, application developers and other stakeholders, they are able to plan their direction in the Malaysian smartphone market.

The ISO 9001 (2000) define "Quality" as the ability of a set of inherent properties and characteristics of a product, system or process to fulfill requirements of customers and other interested parties. The "Plan de Calidad de Obra (PCO)" is an instrument that follows to get the necessary quality in Civil Works contracts. Graphical documentation generated during construction project elaboration or even during Civil Engineering works execution with planes, makes obligatory a meticulous treatment of this information that results transcendental in the consecution of the definitive products (projects or works) quality objective. In this work it's shown the principal graphical documentation procedures defined in the PCO attending to the edition, modification, distribution, storage, and other relevant aspects related to graphical information.

For the past 35 years, learning theorists have been providing models that depend on mental representations, even in their most simple, deterministic, and mechanistic approaches. Hence, cognitive involvement (typically thought of as expectancy) is assumed for most instances of classical and operant conditioning, with current theoretical differences concerning the level of cognition that is involved (e.g., simple association vs. rule learning), rather than its presence. Nevertheless, many psychologists not in the mainstream of learning theory continue to think of cognitive and conditioning theories as rival families of hypotheses. In this article, the data pertaining to the role of higher-order cognition in conditioning is reviewed, and a theoretical synthesis is proposed that provides a role for both automatic and cognitively mediated processes.

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

The current global declaration of a viral pandemic from the SARS-CoV-2 virus causing a clinical picture of disease termed COVID-19, has become a topic of much attention and controversy. The position and outlook on the situation, more or less, polarizes between two starkly contrasting views, and those in the middle who accept a position being a variation between the two. However, due to the less-than-transparent governments around the world,  the public health systems of the Western world engaged in serious fraud and misconduct, along with the authoritarian measures taken, such as strict lockdowns, social distancing, masks, isolation, quarantines, and the push for mandatory vaccinations. In light of this, many began to question the situation, with talking points from the alternative media to question everything about the crisis, including whether there was any virus circulating to begin with, or if viruses in general ever actually existed, some attributing the situation to a harmful effect of 5G electromagnetic frequency radiation (EMF).  The truth, as I have it, stands in the middle of the two opposing sides. I will now cover this in more detail to clarify and give my official position and outlook on the facts, illusions, falsehoods, apparent paradoxes, and the deeper intricacies therein.

Ralph Brothers' parents both died of acute myocardial infarctions at an early age. Ralph inherited dyslipidemia and glucose intolerance, and his blood pressure is above normal. Determined to prevent an early death, he has altered his diet, initiated regular exercise, purchased glucose and blood pressure monitoring devices, and he also takes blood pressure medications regularly. He has a happy family and work life with a comfortable income.

Cancers express tumor-associated antigens that should elicit immune response to antagonize the tumor growth, but spontaneous immune rejection of established cancer is rare, suggesting an immunosuppressive environment hindering host antitumor immunity. Among the specific and active tumor-mediated mechanisms, CD4 + CD25 high T regulatory cells (Treg) are important mediators of active immune evasion in cancer. In this review, we will discuss Treg subpopulations and the mechanisms of their suppressive functions. Treg depletion improves endogenous antitumor immunity and the efficacy of active immunotherapy in animal models for cancer, suggesting that inhibiting Treg function could also improve the limited successes of human cancer immunotherapy. We will also discuss specific strategies for devising effective cancer immunotherapy targeting Treg.

Guillain-Barré syndrome (GBS) is a classic failure of the immune system with a life-threatening attack upon a critical self-component. The active phase of the disease is short, concordant with the latency of a primary adaptive immune response. Triggers for GBS include infection and (rarely) vaccination; cross-reactivity between infectious and neural epitopes has been well demonstrated, particularly for Campylobacter jejuni and motor axonal forms of GBS in which non-protein gangliosides are antigenic. Most people are probably exposed to a GBS trigger, but only rarely does the disease develop. We propose that GBS illustrates competing determinants of the immune system's decision about whether to mount a response, and that in unlucky affected individuals, copresentation of cross-reactive antigens with danger signals activating pattern-recognition receptors overcomes normal self-recognition such that a primary response is initiated that attacks the nerve. Then, in most cases of GBS, the response rapidly turns off, and second attacks rarely occur. This suggests active restoration of tolerance, and specific privileged site attributes of nerve and declining danger signals as the trigger wanes may contribute to this restoration. Standard immunosuppression has not been effective in GBS. We suggest this is because immune tolerance is already being restored by the time such therapies are initiated. This in turn suggests that improvements in GBS outcomes are likely to come from better protection of the nerve cells under attack while normal resumption of tolerance is permitted to proceed rather than exploring more aggressive immunosuppressive approaches.