Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders.

Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer\u27s disease and Parkinson\u27s disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of antigen-specific CD4+ T cells from the periphery to the CNS and consequent immune cell interactions with resident glial cells affect neuroinflammation and neuronal survival. The destructive or protective mechanisms of these interactions are linked to the relative numerical and functional dominance of effector or regulatory T cells. Temporally, immune responses at disease onset or during progression may exhibit a differential balance of immune responses in the periphery and within the CNS. Immune responses with predominate T cell subtypes may differentially manifest migratory, regulatory and effector functions when triggered by endogenous misfolded and aggregated proteins and cell-specific stimuli. The final result is altered glial and neuronal behaviors that influence the disease course. Thus, discovery of neurodestructive and neuroprotective immune mechanisms will permit potential new therapeutic pathways that affect neuronal survival and slow disease progression

Telomere dynamics and homeostasis in a transmissible cancer

Devil Facial Tumour Disease (DFTD) is a unique clonal cancer that threatens the world\u27s largest carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii) with extinction. This transmissible cancer is passed between individual devils by cell implantation during social interactions. The tumour arose in a Schwann cell of a single devil over 15 years ago and since then has expanded clonally, without showing signs of replicative senescence; in stark contrast to a somatic cell that displays a finite capacity for replication, known as the “Hayflick limit”

Osteosarcoma

Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases

Nurses\u27 Alumnae Association Bulletin - Volume 17 Number 1

Alumnae Notes Committee Reports Digest of Alumnae Association Meetings Greetings from Miss Childs Greetings from the Educational Director Greetings from the President Graduation Awards - 1951 Jefferson\u27s New Hospital Addition Marriages Necrology Neurosurgery Department New Arrivals New Drugs Notes on the Cause of Leukemia Nursing Staff Saul Among the Prophets Staff Activities, 1951-1952 Students\u27 Corner The Hospital Pharmacy The Student Nurse Association of Pennsylvania White Haven and Barton Memorial Division

Neonatal BCG vaccination reduces interferon gamma responsiveness to heterologous pathogens in infants from a randomised controlled trial

Background Bacille Calmette-Guérin (BCG) vaccination has beneficial non-specific (heterologous) effects that protect against non-mycobacterial infections. We have previously reported that BCG vaccination at birth alters in vitro cytokine responses to heterologous stimulants in the neonatal period. This study investigated heterologous responses in 167 infants in the same trial seven months after randomisation. Methods A whole blood assay was used to interrogate in vitro cytokine responses to heterologous stimulants (killed pathogens) and Toll-like receptor (TLR) ligands. Results Compared to BCG-naïve infants, BCG-vaccinated infants had increased production of MIG and IFN-γ in response to mycobacterial stimulation and decreased production of IFN-γ in response to heterologous stimulation. Reduced IFN-γ responses to heterologous stimulants and TLR ligands were attributable to a decrease in the proportion of infants who mounted a detectable IFN-γ response. BCG-vaccinated infants also had increased production of MIG and IL-8, and decreased production of IL-10, MIP-1α and MIP-1ß, the pattern of which varied by stimulant. IL-1Ra responses following TLR1/2 (Pam3CYSK4) stimulation were increased in BCG-vaccinated infants. Both sex and maternal BCG vaccination status influenced the effect of neonatal BCG vaccination. Conclusions BCG vaccination leads to changes in IFN-γ responsiveness to heterologous stimulation. BCG-induced changes in other cytokine responses to heterologous stimulation varies by pathogen

Expression of R-Spondin 1 in Apc(Min/+) Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling

BACKGROUND & AIMS: Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in ApcMin/thorn mutant mice. METHODS: An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into ApcMin/thornmice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry. RESULTS: Intestines from Apcthorn/thorn mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fctransduced ApcMin/thorn mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of ApcMin/thorn mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from ApcMin/thorn mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from ApcMin/thorn mice expressing RSPO1Fc back to the same level as in the adenomas from mice given the control vector. CONCLUSIONS: Expression of RSPO1 in ApcMin/thorn mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.Peer reviewe

What Can WMAP Tell Us About The Very Early Universe? New Physics as an Explanation of Suppressed Large Scale Power and Running Spectral Index

The Wilkinson Microwave Anisotropy Probe microwave background data may be giving us clues about new physics at the transition from a ``stringy'' epoch of the universe to the standard Friedmann Robertson Walker description. Deviations on large angular scales of the data, as compared to theoretical expectations, as well as running of the spectral index of density perturbations, can be explained by new physics whose scale is set by the height of an inflationary potential. As examples of possible signatures for this new physics, we study the cosmic microwave background spectrum for two string inspired models: 1) modifications to the Friedmann equations and 2) velocity dependent potentials. The suppression of low ``l'' modes in the microwave background data arises due to the new physics. In addition, the spectral index is red (n<1) on small scales and blue (n>1) on large scales, in agreement with data.Comment: 18 pages, 2 figures, submitted for publication in Physical Review D, references added in this versio

Positive mindset and exercise capacity in school-aged children and adolescents with congenital heart disease

IntroductionPatients with congenital heart disease (CHD) have variable degrees of peak oxygen consumption (VO2) that can be improved with supervised fitness training. The ability to exercise is affected by anatomy, hemodynamics, and motivation. Motivation is in part related to mindset, or personal attitudes and beliefs, and a more positive mindset around exercise has been associated with better outcomes. It is unknown whether variations in measured peak VO2 in patients with CHD are related to having a positive mindset.MethodsPatient's ages 8–17 years with CHD were administered quality of life and physical activity questionnaires at the time of their routine cardiopulmonary exercise test. Those with severe hemodynamic burden were excluded. Patients were grouped based on disease classification. Mindset was evaluated via validated questionnaires including a PROMIS Meaning and Purpose (MaP) survey and an Anxiety survey. Pearson correlation coefficients were calculated to estimate the magnitude of the association between percent predicted peak oxygen consumption (pppVO2) and questionnaire scores overall and within CHD subgroups.ResultsEighty-five patients participated; median age was 14.7 years, 53% were female, 66% had complex CHD, 20% had simple CHD, and 14% had single ventricle heart disease. Mean MaP scores were significantly lower in all CHD groups compared to population norms (p &lt; 0.001). As a group, MaP scores were positively associated with the amount of reported physical activity (p = 0.017). In patients with simple CHD, MaP scores were positively associated with pppVO2 (p = 0.015). The association was even stronger for MaP:Anxiety, with worse ratios associated with lower pppVO2 (p = 0.005). Patients with complex and single ventricle CHD did not show a similar association.ConclusionsPatients with CHD, regardless of severity, had lower meaning and purpose scores than the general population, and these scores were associated with amount of reported physical activity. In the simple CHD subset, having a more positive mindset was associated with higher peak VO2 and a more negative mindset with lower peak VO2. This relationship was not seen with more significant CHD. While underlying CHD diagnoses are not modifiable, mindset and peak VO2 are, and consideration should be given to measuring both as each may be a target for intervention

A New Paraprobiotic-based Treatment for Control of Haemonchus Contortus in Sheep

Haemonchus contortus is a critical parasite of goats and sheep. Infection by this blood-feeding gastrointestinal nematode (GIN) parasite has significant health consequences, especially in lambs and kids. The parasite has developed resistance to virtually all known classes of small molecule anthelmintics used to treat it, giving rise in some areas to multidrug resistant parasites that are very difficult to control. Thus, new anthelmintics are urgently needed. Bacillus thuringiensis (Bt) crystal protein 5B (Cry5B), a naturally occurring protein made by a bacterium widely and safely used around the world as a bioinsecticide, represents a new non-small molecule modality for treating GINs. Cry5B has demonstrated anthelmintic activities against parasites of monogastric animals, including some related to those that infect humans, but has not yet been studied in a ruminant. Here we show that H. contortus adults are susceptible to Cry5B protein in vitro. Cry5B produced in its natural form as a spore-crystal lysate against H. contortus infections in goats had no significant efficacy. However, a new Active Pharmaceutical Ingredient (API) paraprobiotic form of Cry5B called IBaCC (Inactivated Bacterium with Cytosolic Crystals), in which Cry5B crystals are encapsulated in dead Bt cell wall ghosts, showed excellent efficacy in vitro against larval stages of H. contortus and relative protein stability in bovine rumen fluid. When given to sheep experimentally infected with H. contortus as three 60 mg/kg doses, Cry5B IBaCC resulted in significant reductions in fecal egg counts (90%) and parasite burdens (72%), with a very high impact on female parasites (96% reduction). These data indicate that Cry5B IBaCC is a potent new treatment tool for small ruminants in the battle against H. contortus