Moribund State Research Articles

Dr ALM’s Medicolegal Series – Part 2 – Expert Opinion

Abstract A patient was admitted in a hospital for fever with chills and was treated for Typhoid fever but the patient deteriorated and referred to another hospital in moribund state. In the second hospital she was diagnosed to be suffering from Malaria but the patient died. The husband of the patient moved District Consumer Forum which held the doctors and hospital negligent because of wrong treatment. Aggrieved by the order of the District Forum, the hospital preferred an appeal to the State Consumer Disputes Redressal Commission (FA No. 89 of 2005) and the insurance company, preferred another appeal (FA no. 1066 of 2005). The State Forum vide its order dated 31.10.2008 allowed the appeals and turned down the order of District Consumer Forum. The patient side moved National Commission. In the order of the State Commission there is a casual reference to the effect that “there is also no expert opinion to state that the line of treatment adopted by the appellant/opposite party No.1 Hospital is wrong or is negligent”. The National Commission turned down the order of State Commission and restored the order of District Forum.In the opinion of The National Commission, before forming an opinion that expert evidence is necessary, the Fora under the Act must come to a conclusion that the case is complicated enough to require the opinion of an expert or that the facts of the case are such that it cannot be resolved by the members of the Fora without the assistance of expert opinion. This Court makes it clear that in these matters no mechanical approach can be followed by these Fora. Each case has to be judged on its own facts. The following points are stressed by The National Commision. Wrong diagnosis is negligence. Recordings in the case sheet is very important and Over writing in the case sheet leads to suspicion.The evidence act sections 61, 64,74 and 75 need not be applied in the consumer council. Expert opinion is required only in complicated cases of Medical Negligence and NOT in simple, straight forward cases and in complicated cases, before issuing a notice to the doctor, The Consumer Forum has to satisfy itself that there is prima facie medical negligence by referring the case to the medical board with concerned specialists. Where expert opinion is needed the consumer fora can refer the case to civil court. There should not be “straight jacket approach” in getting expert opinion in all cases of medical negligence and the power of seeking opinion is vested with the consumer council.

Time-resolved RNA-seq analysis to unravel the in vivo competence induction by Streptococcus pneumoniae during pneumonia-derived sepsis.

Competence development in Streptococcus pneumoniae (pneumococcus) is tightly intertwined with virulence. In addition to genes encoding genetic transformation machinery, the competence regulon also regulates the expression of allolytic factors, bacteriocins, and cytotoxins. Pneumococcal competence system has been extensively interrogated in vitro where the short transient competent state upregulates the expression of three distinct phases of "early," "late," and "delayed" genes. Recently, we have demonstrated that the pneumococcal competent state develops naturally in mouse models of pneumonia-derived sepsis. To unravel the underlying adaptive mechanisms driving the development of the competent state, we conducted a time-resolved transcriptomic analysis guided by the spatiotemporal live in vivo imaging system of competence induction during pneumonia-derived sepsis. Mouse lungs infected by the serotype 2 strain D39 expressing a competent state-specific reporter gene (D39-ssbB-luc) were subjected to RNA sequencing guided by monitoring the competence development at 0, 12, 24, and, at the moribund state, >40 hours post-infection (hpi). Transcriptomic analysis revealed that the competence-specific gene expression patterns in vivo were distinct from those under in vitro conditions. There was significant upregulation of early, late, and some delayed phase competence-specific genes as early as 12 hpi, suggesting that the pneumococcal competence regulon is important for adaptation to the lung environment. Additionally, members of the histidine triad (pht) gene family were sharply upregulated at 12 hpi followed by a steep decline throughout the rest of the infection cycle, suggesting that Pht proteins participate in the early adaptation to the lung environment. Further analysis revealed that Pht proteins execute a metal ion-dependent regulatory role in competence induction.IMPORTANCEThe induction of pneumococcal competence for genetic transformation has been extensively studied in vitro but poorly understood during lung infection. We utilized a combination of live imaging and RNA sequencing to monitor the development of a competent state during acute pneumonia. Upregulation of competence-specific genes was observed as early as 12 hour post-infection, suggesting that the pneumococcal competence regulon plays an important role in adapting pneumococcus to the stressful lung environment. Among others, we report novel finding that the pneumococcal histidine triad (pht) family of genes participates in the adaptation to the lung environment and regulates pneumococcal competence induction.

Glomerular injury induced by vinyl carbamate in A/J inbred mice: a novel model of membranoproliferative glomerulonephritis.

Ethyl carbamate (EC) is a process contaminant found in fermented foods and alcoholic beverages. Metabolic conversion of ethyl carbamate generates vinyl carbamate (VC), a carcinogenic metabolite. EC, as a Group 2A probable human carcinogen, and the more potent VC, are known to cause tumors in rodents. However, their effects on the kidney are unknown and were explored here. Female A/J inbred mice received an intraperitoneal injection of vehicle or VC. Beginning 5weeks after VC injection, mice showed signs of moribund state. Mouse necropsies revealed renal glomerular injury that histopathologically recapitulated human membranoproliferative glomerulonephritis (MPGN), as evidenced by light microscopy, immunostaining for immunoglobulins and complements, and electron microscopy. To determine the molecular pathomechanisms, a post-hoc analysis was performed on a publicly available RNA-Seq transcriptome of kidneys from control rats and rats treated with fermented wine containing high concentrations of EC. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the differentially expressed genes revealed that the complement and coagulation cascades were a top predicted biological process involved. Furthermore, pathway-based data integration and visualization revealed that key regulators of complement activation were altered by high EC treatment. Among these, complement factors (CF) D and H, critical positive and negative regulators of the alternative pathway, respectively, were most affected, with CFD induced by 3.49-fold and CFH repressed by 5.9-fold, underscoring a hyperactive alternative pathway. Consistently, exposure of primary glomerular endothelial cells to EC or VC resulted in induction of CFD and repression of CFH, accompanied by increased fixation of C3 and C5b9. This effect seems to be mediated by Ras, one of the top genes that interact with both EC and VC, as identified by analyzing the chemical-gene/protein interactions database. Indeed, EC or VC-elicited complement activation was associated with activation of Ras signaling, but was abolished by the Ras inhibitor farnesyl thiosalicylic acid. Collectively, our findings suggest that VC, a metabolite of EC, induces glomerular injury in mice akin to human MPGN, possibly via perturbing the expression of complement regulators, resulting in an effect that favors activation of the alternative complement pathway.

Safety Assessment of AYUSH SC-3 through Acute and 90 Days Repeated Dose Oral Toxicity Study

The present study is focused on establishing the safety of the formulation through acute and 90 days of repeated oral dose toxicity as per the Organization for Economic Cooperation and Development (OECD) guidelines. During the acute toxicity test, the drug was orally administered at a limited test dose of 2000 mg/kg. Clinical signs, feed and body weight were recorded. At the end of 14 days, the animals were euthanized and subjected to a detailed post-mortem examination (necropsy). As per OECD, 408 the 90 days repeated dose oral toxicity study was carried out with three different doses of test drug i.e., 1500, 1000 and 500 mg/kg. Cage side observations, body weight and feed intake were recorded. Upon termination of the study, urine analysis, haematology and clinical biochemical examinations were performed. Finally, the rats were subjected to euthanasia, a gross necropsy was conducted and vital organs were weighed and made prone for histopathological evaluation. Cage-side observation of AYUSH-SC-3 treated animals showed no signs of toxicity, and the mortality or moribund state was observed in both of the studies. No significant change in body weight and feed intake was seen in AYUSH-SC-3 treated animals. Gross morphology and necropsy findings of the animals revealed no treatment-related. Haematological and biochemical parameters of rats treated with AYUSH-SC-3 were found to be non-significant when compared to the control group. Necropsy findings and relative organ weights did not change significantly. Further, the histopathological analysis of major organs showed no major lesions and treatment-related changes. The LD50 of AYUSH SC-3 is greater than 2000 mg/kg and NOAEL is up to 1500 mg/kg.

Prediction of Maternal Morbidity and Mortality Risk Among Women with Medical Disorders Presenting to Emergency Obstetric care (EMOC): A Prospective Observational Study.

Medical disorders complicating pregnancy have recently emerged as the most common cause for maternal morbidity and mortality and it is important to predict mortality risk when they present in moribund state to emergency obstetric care so as to take and timely effective measures to prevent mortality. This prospective observational study was conducted over 6 months among pregnant and post-partum women with medical disorders who sought emergency obstetric care at a tertiary care hospital. Severity of morbidity was assessed using SOFA and APACHE II scores at admission. Of the 128 women, 87.5% were pregnant, and 12.5% were post-partum. Hypertensive disorders, cardiac disorders, neurological disorders and infective disorders were 24.2%, 22.6%, 14% and 9.4%, respectively. The optimal cut-off SOFA score was 2 (AUC = 0.739) with 66% sensitivity and 71% specificity and APACHE II score cut-off was 6 (AUC = 0.732) with a sensitivity of 60% and specificity of 78% in predicting severe maternal morbidity. The median scores of APACHE II and SOFA are 14 and 4, respectively, for non-survivors and for survivors it was 4 and 1. Hypertensive disorder was the most common medical disorder, but severity was high in cardiac disorder. SOFA and APACHE II scores are good predictors of morbidity and mortality risk.

Rethinking curriculum implementation in time of COVID-19 and beyond: lessons learnt from rural science teachers

The COVID-19 pandemic has influenced the way teaching and learning is carried out in South African schools. Policy decisions to curb the spread of the virus were superficially conceived as a health problem as opposed to an understanding of the interconnectedness of education in society. For teaching and learning to continue, schools were compelled to either rotate their learners or embrace remote teaching. Irrespective of the numerous curriculum reforms, curriculum implementation in South Africa has been in a moribund state with little attention given to rural science teachers. In this article, we explore how science teachers in rural areas implemented the curriculum during the COVID-19 pandemic and what lessons could be learnt from their experience to foster the curriculum implementation discussion in South Africa. We used a qualitative research approach and phenomenology as our research methodology. Nine rural science teachers were purposively selected for a semi-structured interview. An interpretative phenomenological analysis was used to analyse the data. Our findings revealed that the government’s response to the pandemic appeared to have overlooked already existing fundamental problems associated with curriculum implementation in rural areas. We learnt in this study that curriculum implementation is narrowly conceived as a classroom pedagogic exercise. As an implication, there is a need for curriculum implementation reforms in South Africa, one that would consider contextual curriculum theorising and the experiences of rural science teachers.

Healthcare delivery in Sub-Saharan Africa: exploring the impact of leadership theories and styles

Health care delivery involves the dispensation and provision of services that promote and maintainthe health of the people. The World Health Organization recognizes leadership and governance asone of the major pillars of an efficient healthcare delivery system. Effective leadership is integralto organizational success. The World Bank rates the healthcare delivery systems in sub-SaharanAfrica as one of the worst globally. Previous studies have demonstrated that poor leadership has asubstantial contribution to the moribund state of healthcare delivery in the sub-continent.Transactional leaders incentivize workers to boost their morale but gives no room for errors whichare bound to happen in sociological systems. Transformational leaders motivate and empower thesubordinates who can misuse the authority given to them. Contingency leaders analyze situationsbefore taking critical decisions but there are many unknown variables. The traits theory says thatgreat leaders are born. This however discourages inclusivity and diversity. Additionally, leaderscan be trained but they don’t turn out to have the same effectiveness despite undergoing similartraining. Functional leaders aim to eliminate bureaucracy and prioritize organization’s goalsbut organizational change management is complicated in reality. For the integrated approach,everything matters but nobody knows everything.This narrative review aims to examine how each leadership theory and style could be applied toadvance healthcare delivery in sub-Saharan Africa and found different leadership styles with theassociated merits and demerits but the hybrid approach that analyzes relevant variables would bethe optimal approach to reinvigorate healthcare delivery in sub-Sahara Africa.

Stimulating Antitumoral Immunity by Percutaneous Cryoablation and Combination Immunoadjuvant Therapy in a Murine Model of Hepatocellular Carcinoma

PurposeTo test the hypothesis that antitumoral immunity can be induced after cryoablation (cryo) of hepatocellular carcinoma (HCC) through coadministration of the immunostimulant CpG and an immune checkpoint (programmed cell death 1 [PD-1]) inhibitor. Materials and MethodsSixty-three immunocompetent C57BL/6J mice were generated with 2 orthotopic HCC tumor foci: 1 for treatment and 1 to observe for antitumoral immunity. Tumors were treated with incomplete cryo alone or intratumoral CpG and/or a PD-1 inhibitor. The primary endpoint was death or when the following criteria for sacrifice were met: tumor > 1 cm (determined using ultrasound) or moribund state. Antitumoral immunity was assessed using flow cytometry and histology (tumor and liver) as well as enzyme-linked immunosorbent assay (serum). Analysis of variance was used for statistical comparisons. ResultsAt 1 week, the nonablated satellite tumor growth was reduced by 1.9-fold (P = .047) in the cryo + CpG group and by 2.8-fold (P = .007) in the cryo + CpG + PD-1 group compared with that in the cryo group. Compared with cryo alone, the time to tumor progression to endpoints was also prolonged for cryo + CpG + PD-1 and cryo + CpG mice, with log-rank hazard ratios of 0.42 (P = .031) and 0.27 (P < .001), respectively. Flow cytometry and histology showed increased cytotoxic T-cell infiltration (P = .002) and serum levels of the proinflammatory cytokine interferon-γ (P = .015) in tumors and serum of cryo + CpG mice compared with those in tumors and serum of mice treated with cryo alone. High serum levels of the anti-inflammatory cytokine tumor growth factor-β and the proangiogenesis chemokine C-X-C motif chemokine ligand 1 were correlated with a shorter time to endpoints and faster tumor growth. ConclusionsCryo combined with the immunostimulant CpG promoted cytotoxic T-cell infiltration into tumors, slowed tumor growth, and prolonged the time to progression to endpoints in an aggressive murine HCC model.

The effect of optimal port operations on global maritime transportation: a study of selected ports in Nigeria

PurposeThe study examined the effect of optimal port operations on global maritime transportation among selected ports in Nigeria.Design/methodology/approachIt considered research questions such as are the ports in Nigeria functional, are the ports functioning to optimal capacity and are there challenges affecting smooth operations in the Nigerian ports? The study tested the null hypothesis which states that there is no positive and significant relationship between a functional port system and maritime transportation in Nigeria. The nonparametric statistics, chi-square, were used to analyze data. Data were gathered through a questionnaire administered to three major ports in Nigeria, namely Lagos Port Complex (LPC), Port Harcourt Old port and Warri Port.FindingsFrom the analysis, findings showed that there exists a positive and significant relationship between operations in the ports and maritime transportation in Nigeria. Practical implications: The study showed that the moribund state of some ports and terminals will result in loss of jobs and huge revenue, therefore, compounding the menace of unemployment with its associated vices.Originality/valueThe study concludes that the operations of a functional port affect the economic growth of maritime nations. Thus, it is recommended that government and the private sector should collaborate to raise adequate capital for port development and improve the super structures (infrastructures) for optimal port operations in the country among others.

Completely Solving the Quintic by Iteration

In the late nineteenth century, Felix Klein revived the problem of solving the quintic equation from the moribund state into which Galois had placed it. Klein’s approach was a mix of algebra and geometry built on the structure of the regular icosahedron. His method’s key feature is the connection between the quintic’s Galois group and the rotational symmetries of the icosahedron. Roughly a century after Klein’s work, Doyle and McMullen developed an algorithm for solving the quintic that also exploited icosahedral symmetry. Their innovation was to employ a symmetrical dynamical system in one complex variable. In effect, the dynamical behavior provides for a partial breaking of the polynomial’s symmetry and the extraction of two roots following one iterative run of the map. The recent discovery of a map whose dynamics breaks all of the quintic’s symmetry allows for five roots to emerge from a single pass. After sketching some algebraic and geometric background, the discussion works out an explicit procedure that deploys the special map in order to solve the quintic in a complete sense.

Severity Classification of Clinical Signs and Defining the Moribund State as an Experimental Endpoint for Acute Toxicity Testing Using Japanese Medaka (Oryzias latipes).

Use of the moribund state as an endpoint for acute toxicity testing in fish is complicated by the lack of consensus about the sublethal signs that define the state or that can predict imminent death. Defining the moribund state in fish requires determination of the association between each observable sublethal sign and transition to imminent death. To establish a criterion for defining the moribund state in Japanese medaka (Oryzias latipes), we determined death/clinical-sign ratios, defined as the proportion of fish with each clinical sign that transitioned to imminent death, for 13 clinical signs observed in individually housed fish exposed to one of two typical toxicants, three pharmaceuticals, two pesticides, and one metal. Also, the time from onset of each clinical sign to transition to imminent death (referred to as the survival time) was determined by continuous monitoring. Three of the observed clinical signs-immobility, lethargy, and immobility at the surface-were found to be indicators of the moribund state, with each of these signs having a death/clinical-sign ratio of 1.0. Evaluation of the survival time after onset of the other 10 signs enabled determination of whether timely euthanasia would be appropriate, thereby providing a means of reducing the suffering of laboratory fish in the period before death. Environ Toxicol Chem 2022;41:1089-1095. © 2022 SETAC.

Transgenic rat models for cerebral amyloid angiopathy type‐1 and ‐2 and related vascular cognitive impairment and dementia (VCID)

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease commonly found in the elderly population and in patients with Alzheimer's disease and is significant driver of vascular cognitive impairment and dementia (VCID). CAA exists in two forms: type-1 which affects small microvessels and capillaries and type-2 which primarily affects small arteries and arterioles. Our understanding of how these different forms of CAA promote VCID is hampered by reliable preclinical models. Recently, we generated novel transgenic rat models of CAA type-1 and CAA type-2 to investigate the development and pathological consequences of each type of CAA and their impact on VCID. Cohorts of CAA type-1 and CAA type-2 transgenic rats and wild-type rats were aged from three to twenty four months of age. Magnetic resonance imaging (MRI) was performed to determine the effects of progressive CAA pathology on white matter changes and emergence of cerebral microbleeds. Quantitative histological analyses were performed to measure progressive severity of CAA, neuroinflammation and cerebral microbleeds. A battery of behavioral task assessments was performed to reveal the impact of CAA on cognitive performance. CAA type-1 rats developed microvascular CAA starting at ≈3 months of age that became severe at 12 months leading to a moribund state. CAA type-2 rats developed CAA pathology later starting ≈12 months of age and progressed to 24 months. Histological analysis showed CAA type-1 rats exhibited early-onset perivascular neuroinflammation and microvascular pathology including capillary occlusions and microbleeds. In contrast, CAA type-2 rats presented little evidence of perivascular neuroinflammation and less extensive microbleeds. MR imaging showed that CAA type-1 rats presented with white matter loss at ≈6 months of age. Behavioral analysis revealed that CAA type-1 rats displayed a distinct form sensorimotor slowing that was not observed in CAA type-2 rats. CAA type-1 rats recapitulate many of the pathological features of human microvascular CAA including perivascular neuroinflammation and white matter loss and exhibit cognitive changes. In contrast, CAA type-2 rats lack these particular pathological features and did not display cognitive changes. These findings suggest that CAA-associated neuroinflammation and white matter loss may play an important role in VCID.

Serum Perilipin 2 (PLIN2) Predicts Multiple Organ Dysfunction in Critically Ill Patients.

Perilipin 2 (PLIN2) is a lipid droplet protein with various metabolic functions. However, studies investigating PLIN2 in the context of inflammation, especially in systemic and acute inflammation, are lacking. Hence, we assessed the relevance of serum PLIN2 in critically ill patients. We measured serum PLIN2 serum in 259 critically ill patients (166 with sepsis) upon admission to a medical intensive care unit (ICU) compared to 12 healthy controls. A subset of 36 patients underwent computed tomography to quantify body composition. Compared to controls, serum PLIN2 concentrations were elevated in critically ill patients at ICU admission. Interestingly, PLIN2 independently indicated multiple organ dysfunction (MOD), defined as a SOFA score > 9 points, at ICU admission, and was also able to independently predict MOD after 48 h. Moreover, serum PLIN2 levels were associated with severe respiratory failure potentially reflecting a moribund state. However, PLIN2 was neither a predictor of ICU mortality nor did it reflect metabolic dysregulation. Conclusively, the first study assessing serum PLIN2 in critical illness proved that it may assist in risk stratification because it is capable of independently indicating MOD at admission and predicting MOD 48 h after PLIN2 measurement. Further evaluation regarding the underlying mechanisms is warranted.

Rodenticide ingestion is an important cause of acute hepatotoxicity in Tamil Nadu, southern India.

Though rodenticidal hepatotoxicity is reported from India, there is no systematic study to assess its magnitude. This study aimed to assess exposure to rodenticide as a risk factor for acute hepatotoxicity in Tamil Nadu, India. We retrospectively analyzed acute hepatotoxicity caused by ingestion of hepatotoxin or potentially hepatotoxic drug overdose across 15 hospitals in 6 districts of Tamil Nadu from 1 January 2019 to 30 June 2019. Study exclusion criteria were idiosyncratic drug-induced liver injury and chronic liver diseases. Of the702 patients, 685 gave history of consuming rodenticide; hepatotoxicity in the other patients resulted fromparacetamol overdose (n=10) and due toother drugs (n=7); 97% patients had a suicidal intent. Of 671 patients with complete data, ratio of number of patients with hepatotoxicity due to rodenticide to paracetamol overdose was 450:6 (i.e. 75:1). The 451 rodenticidal hepatotoxicity patients (255 males, 75% were 15-34 years old) underwent conservative management (n=396), plasma exchange (n=54) and plasma exchange followed by liver transplant (n=1); 159 patients (35%) had poor outcome (131 died, 28 discharged in moribund state). Based on our observations, we estimate a case burden of 1584 rodenticidal hepatotoxicity patients (95% CI: 265-6119) with poor outcome in 554 patients in Tamil Nadu from January2019 to June 2019. Population attributable risk for rodenticide as cause of hepatotoxicity was 22.7%. Rodenticide ingestion was an important cause of acute hepatotoxicity in Tamil Nadu. Most patients were young and one-third had poor outcome. Public health interventions are needed to address this.

Omega-3 Polyunsaturated Fatty Acid Intervention Against Established Autoimmunity in a Murine Model of Toxicant-Triggered Lupus.

Workplace exposure to respirable crystalline silica dust (cSiO2) has been etiologically linked to the development of lupus and other human autoimmune diseases. Lupus triggering can be recapitulated in female NZBWF1 mice by four weekly intranasal instillations with 1 mg cSiO2. This elicits inflammatory/autoimmune gene expression and ectopic lymphoid structure (ELS) development in the lung within 1 week, ultimately driving early onset of systemic autoimmunity and glomerulonephritis. Intriguingly, dietary supplementation with docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid (PUFA) found in fish oil, beginning 2 week prior to cSiO2 challenge, prevented inflammation and autoimmune flaring in this novel model. However, it is not yet known how ω-3 PUFA intervention influences established autoimmunity in this murine model of toxicant-triggered lupus. Here we tested the hypothesis that DHA intervention after cSiO2-initiated intrapulmonary autoimmunity will suppress lupus progression in the NZBWF1 mouse. Six-week old NZWBF1 female mice were fed purified isocaloric diet for 2 weeks and then intranasally instilled with 1 mg cSiO2 or saline vehicle weekly for 4 consecutive weeks. One week after the final instillation, which marks onset of ELS formation, mice were fed diets supplemented with 0, 4, or 10 g/kg DHA. One cohort of mice (n = 8/group) was terminated 13 weeks after the last cSiO2 instillation and assessed for autoimmune hallmarks. A second cohort of mice (n = 8/group) remained on experimental diets and was monitored for proteinuria and moribund criteria to ascertain progression of glomerulonephritis and survival, respectively. DHA consumption dose-dependently increased ω-3 PUFA content in the plasma, lung, and kidney at the expense of the ω-6 PUFA arachidonic acid. Dietary intervention with high but not low DHA after cSiO2 treatment suppressed or delayed: (i) recruitment of T cells and B cells to the lung, (ii) development of pulmonary ELS, (iii) elevation of a wide spectrum of plasma autoantibodies associated with lupus and other autoimmune diseases, (iv) initiation and progression of glomerulonephritis, and (v) onset of the moribund state. Taken together, these preclinical findings suggest that DHA supplementation at a human caloric equivalent of 5 g/d was an effective therapeutic regimen for slowing progression of established autoimmunity triggered by the environmental toxicant cSiO2.

Oral toxicity evaluation of gokshuradi guggulu, an ayurvedic formulation

Gokshuradi guggulu is an important classical polyherbal formulation used in Ayurvedic system of medicine for the treatment of various chronic diseases like kidney stones and diabetes. However, no scientific attempts were made to evaluate its oral toxicity. Hence, the present study evaluated the acute and 28 days repeated dose sub-acute oral toxicities of gokshuradi guggulu in rats. Gokshuradi guggulu was tested for its compliance using physicochemical and analytical parameters as per standards prescribed in Ayurvedic Pharmacopeia of India. In acute oral toxicity study, Wistar rats were orally administered a single dose of gokshuradi guggulu (2700 mg/kg) and clinical signs and mortality or moribund stage were observed for 14 days along with weekly body weight. On day 15, the rats were euthanized and the gross morphology was carried out during necropsy. In sub-acute (repeated dose) oral toxicity study, the rats were orally administered gokshuradi guggulu (270, 1350 and 2700 mg/kg) once daily up to 28 days. Clinical signs and mortality or moribund stage, weekly body weight, weekly feed and water consumptions, biochemical and hematological investigations, urine analysis, and major organ weights and histopathology were carried out. In acute and sub-acute toxicity studies, gokshuradi guggulu administration did not show any alteration in parameters or any adverse effect as compared to vehicle treated group. There was no mortality or moribund state observed in any group in both studies. Administration of gokshuradi guggulu in acute and 28 days repeated doses did not exhibit any toxicity or adverse effect at the doses used and NOAEL was found to be 2700 mg/kg.

Building Trust to Save Lives in a Metro Manila Public-Private Network of Care: A Descriptive Case Study of Quirino Recognized Partners in Quezon City, Philippines

ABSTRACT At an overcrowded government multi-specialty hospital serving the most densely populated area of Metro Manila, inward referrals of women in a moribund state and high volumes of low-risk maternity cases added to significant overcrowding and quality challenges in the maternity wards, resulting in high rates of maternal and neonatal death and near-miss. This case study of the public-private Network of Care, Quirino Recognized Partners (QRP), describes a series of pragmatic steps taken to build and maintain the network, particularly: building trust through agreements with private and public birth centers within a ten-kilometer radius, rolling out antenatal use of a clinical and socio-economic risk scoring tool, reaching out to potential clients, and establishing clear communication channels and protocols for care. These actions, consistent with the schematic of an effective Network of Care, helped decongest the hospital, build rapport and teamwork among health providers, and improve maternal and neonatal outcomes throughout the network. The purpose of this descriptive case study was to explore how QRP was established to solve for particular contextual problems, especially congestion and poor maternal and neonatal health outcomes, with express attention to how actions taken related to the domains of Networks of Care. Data collected through semi-structured interviews with relevant health care and other workers, institutional documents, observations, and field notes were interpreted through the domains of Networks of Care and reported through rich description.

Design and Development of a Low Cost Solar Powered Drip Irrigation System for Auchi Polytechnic Demonstration Farm

Auchi Polytechnic and the Communities surrounding her, have being experiencing significant issues with water scarcity and quality for many decades. Again, with the moribund state of the Water Corporation Service here in Auchi, there is an unprecedented demand for water concerns about water use by agriculture. Hence, a lot of farming activities takes place only during the raining season. This study aimed to design a solar powered borehole for drip irrigation system. Drip lines were laid, 2 mm holes was made at distance of 30 cm on the 6 m PVC pipes. Components of drip irrigation system consist essentially of main line, submains, laterals and emitters. The main line delivers water to the submains and the submains to the laterals. The set up was tested to determine the uniformity of water emission from the drip emitters into the field, maize, pepper, tomatos was used as the test crops and there was uniform growth observed across the entire field. The low cost drip system developed in this study showed a high level of efficiency and uniformity of water emission across the entire study area. Keywords : Low Cost Solar Powered, Irrigation System, Farm DOI: 10.7176/JNSR/11-18-05 Publication date: September 30 th 2020

Abstract 4190: A promising blood-brain-barrier penetrant MDM2-p53 antagonist, BI-MDM2, increases survival in orthotopic, glioblastoma patient-derived xenograft models

Abstract Robust function of the p53 tumor suppressor pathway is critical when treating with DNA-damage inducing agents such as radiation therapy (RT), which is a key component of standard care for GBM. MDM2 is an important negative regulator of p53 stability and MDM2 is amplified in approximately 14% of GBM. Based on the concept that suppression of MDM2 can reactivate p53 function and potentially have single agent or combinatorial effects, multiple MDM2 inhibitors have been developed. Here we report in vitro and in vivo efficacy and pharmacodynamic (PD) effects of a BBB-penetrant MDM2-p53 antagonist, BI-MDM2, in GBM patient-derived xenograft (PDX) models. In vitro studies in p53 wild-type (WT) lines with or without MDM2 amplification demonstrate IC50 values in cell viability assays of 2-12 nM in serum-free culture and 5-35 nM in serum-containing culture after seven days of treatment. In vivo studies were performed in p53 WT lines: the MDM2-amplified GBM108, and the non-amplified GBM14, grown as orthotopic tumors in nude mice. Weekly oral treatment at 2 mg/kg of BI-MDM2 doubled median survival (placebo, 28 days (d) vs 2 mg/kg BI-MDM2, 57 d. p&amp;lt;0.0001) while weekly dosing at 10 mg/kg extended the median over 5 fold (176 d. p&amp;lt;0.0001) with half of the mice still living at 223 days post-inoculation. To assess the PD properties of this compound, mice bearing orthotopic GBM108 were treated three weeks after inoculation with a single dose of 2 or 10 mg/kg BI-MDM2. Normal brain, tumor, and plasma were collected at 24 and 48 hours (h) after dosing and downstream p53 transcriptional targets, p21 and PUMA were evaluated by qRT-PCR. p21 mRNA relative quantification detection at 24h increased by 1.5-10.5-fold in the 2 mg/kg group of animals compared to vehicle while the 10 mg/kg dose led to an increase by 2-25 fold compared to vehicle. PUMA was minimally affected by the 2 mg/kg dose but increased 1.2-17-fold over vehicle in the 10 mg/kg group at 24h. The observed increases in p21 and PUMA varied little between the 24 and 48h timepoints. In an orthotopic GBM14 PDX efficacy study, BI-MDM2 was combined with 20 Gy RT delivered in 10 fractions over 2 weeks with dosing limited to 2 weeks of therapy or until mice reached a moribund state. While two doses of 10 mg/kg BI-MDM2 alone had a modest effect on survival (41 d vs 31 d with placebo; p=0.002), continued dosing until moribund further extended median survival (82 d with BI-MDM2; p=0.001). The combination of two doses of BI-MDM2 with 2 weeks of RT extended survival as compared to RT alone (107 d vs. 69 d, respectively; p=0.019), while with extended drug dosing combined with 2 weeks of RT, median survival has not yet been reached (&amp;gt;125 d). Taken together, these results suggest that BI-MDM2 is a promising therapeutic agent that may provide significant anti-tumor efficacy either alone or in combination with RT in both MDM2 amplified and non-amplified p53 WT patients. Citation Format: Ann C. Mladek Tuma, Shiv Gupta, Surabhi Talele, Afroz Shareef Mohammad, Katrina K. Bakken, Helen He, Zeng Hu, Margaret A. Connors, Danielle M. Burgenske, Brett L. Carlson, William F. Elmquist, Ulrike Weyer-Czernilofsky, Jann N. Sarkaria. A promising blood-brain-barrier penetrant MDM2-p53 antagonist, BI-MDM2, increases survival in orthotopic, glioblastoma patient-derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4190.

Schwab’tan Sonra Eğitim Programları Alanı: Anka Kuşu mu yoksa Sisifos mu?

In an essay published in 1969, Schwab argued that the field of curriculum was in a moribund state in that it was unable by its back-then present principles and methods to do curriculum work. Schwab also discussed that curricular energies had to be turned to practical rather than theoretical so that the field could do its function. Schwab’s arguments have met numerous infavor and counter arguments in the field since they were subject of studies of various scholars. Especially reconceptualists, opponents of a curricular movement, have occupied a significant space in the curriculum scholarship. In the present article, the author aimed at examining the significance of Schwab’s arguments in the present age of curriculum studies especially within the American context. The primary argument of the author was that the field was not moribund, yet there were talks of a crisis in the field. The author, moreover, discussed that it was essential to revitalize the relation of the field to schools and schooling as Schwab formulated it by emphasizing a practical conception of the field in order to overcome the crisis talks in the field.