Unpacking and validating the "physiological adaptation" core concept of physiology.

A national Task Force of 25 Australian physiology educators used the Delphi protocol to develop seven physiology core concepts that were agreed to nationally. The aim of the current study was to unpack the "physiological adaptation" core concept with the descriptor "organisms adjust and adapt to acute and chronic changes in the internal and external environments across the lifespan." This core concept was unpacked by three Task Force members and a facilitator into four themes and nine subthemes that encompass the role of stressors and disturbed homeostasis in adaptation and the capacity for, and the nature of, the physiological adaptation. Twenty-two Task Force members then provided feedback and rated the themes and subthemes for level of importance and difficulty for students to learn via an online survey using a five-point Likert scale. Seventeen respondents completed all survey questions. For all themes/subthemes, importance was typically rated 1 (Essential) or 2 (Important) (n = 17, means ±SD ranged from 1.1 ± 0.3 to 2.2 ± 0.9), and difficulty was typically rated 3 (Moderately Difficult) (n = 17, means ranged from 2.9 ± 0.7 to 3.4 ± 0.9). Subtle differences in the proportion of importance scores (n = 17, Fisher's exact: P = 0.004, ANOVA: F12,220 = 2.630, P = 0.003; n = 22, Fisher's exact: P = 0.002, ANOVA: F12,281 = 2.743, P < 0.001), but not difficulty scores, were observed between themes/subthemes, and free-text feedback was minor. The results suggest successful unpacking of the physiological adaptation core concept. The themes and subthemes can inform the design of learning outcomes, assessment, and teaching and learning activities that have commonality and consistency across curricula.NEW & NOTEWORTHY An Australian Task Force of physiology educators identified physiological adaptation as a core concept of physiology. It was subsequently unpacked into four themes and nine subthemes. These were rated, by the Task Force, Essential or Important and Moderately Difficult for students to learn. The themes and subthemes can inform the design of learning outcomes, assessments, and teaching and learning activities that have commonality and consistency across curricula.

High Dietary Iron in Western Diet-Fed Male Rats Causes Pancreatic Islet Injury and Acute Pancreatitis.

BACKGROUND: High dietary iron has been linked to an increased type 2 diabetes risk. We have previously shown that intrauterine growth restriction (IUGR) and feeding a Western diet (WD) to male Sprague-Dawley rats independently, as well as together, cause pancreatic islet inflammation, fibrosis, and hemosiderosis. OBJECTIVES: To investigate whether iron has a role in the pathogenesis of this inflammatory islet injury caused by IUGR and WD intake. METHODS: Male Sprague-Dawley offspring of bilateral uterine artery ligated (IUGR) and sham-operated (Sham) dams, fostered to nonoperated dams, were fed a WD [45% sucrose, 19.4% protein and 23% fat (w/w)] containing low iron (LI, 20 mg/kg) or high iron (HI, 500 mg/kg) from weaning. Four groups were studied: Sham-LI, Sham-HI, IUGR-LI, and IUGR-HI. Serial measurements of rat body weight, blood glucose, lipids and insulin, an intraperitoneal glucose tolerance test (age 13 wk), and histological analysis of pancreas and liver (age 14 wk) were recorded. The effects of iron, IUGR, and their interaction, on these measurements have been analyzed. RESULTS: WD with HI compared with LI caused an 11% greater weight gain by age 14 wk (P < 0.001), impaired glucose tolerance [AUC for glucose (G-AUC) 17% higher; P < 0.001), acute pancreatitis (17/18, HI; 6/17, LI; P < 0.001), pancreas-associated fat necrosis and saponification (7/18, HI; 0/17 LI; P < 0.01), and a trend to islet fibrotic injury (7/18, HI; 1/17 LI; P = 0.051). Although pancreatic and hepatic steatosis was evident in almost all WD-fed rats, pancreatic and hepatic iron accumulation was prevalent only in HI-fed rats (P < 0.0001 for both), being only mild in the livers. IUGR, independent of dietary iron, also caused impairment in glucose tolerance (G-AUC: 17% higher; P < 0.05). CONCLUSIONS: A postweaning WD containing HI, independent of IUGR, causes acute pancreatitis and islet injury in Sprague-Dawley rats suggesting a role of dietary iron in the development of steatopancreatitis.

Establishing consensus for the core concepts of physiology in the Australian higher education context using the Delphi method.

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process (n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking.NEW & NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.

Impact of prothrombin and factor V Leiden mutations on the progression of fibrosis in patients with chronic hepatitis C.

BACKGROUND: The role of thrombotic factors in the pathogenesis and progression of liver fibrosis remains obscure. We aimed to study the relationship between prothrombin G20210A (PT20210) and factor V Leiden (FVL) mutations and the progression of fibrosis and liver function in chronic HCV patients. METHODS: The study included 100 subjects, 88 patients with HCV-related cirrhosis (compensated: 38, decompensated: 50), and 12 controls. Patients with other viral hepatitis or coinfection, inherited metabolic disease, autoimmune hepatitis, hepatic or extrahepatic malignancy, in addition to patients with causes of hypoalbuminemia, elevated bilirubin or prolonged INR not related to cirrhosis were excluded from the study. Relevant clinical data were collected and basic laboratory tests were performed. Liver fibrosis was assessed using APRI and FIB-4 scores. FVL and PT20210 mutations were analyzed. RESULTS: FVL and PT20210 mutations were significantly higher in decompensated vs. compensated patients (32% vs. 5.3%, P = 0.001; 20% vs. 5.3%, 0.043, respectively) and absent in controls. Both mutations significantly correlated to the duration of infection, platelet count and fibrosis scores. PT20210 mutation significantly correlated to serum albumin and INR. Both mutations significantly predicted fibrosis scores, especially PT20210 (AUROC: 0.833 for APRI and 0.895 for FIB-4). CONCLUSIONS: Both mutations are significantly correlated to fibrosis progression and liver profile and could be considered as markers predicting the need for early and different intervention.

The cross-talk between matrix metalloproteinase-9, RANKL/OPG system and cardiovascular risk factors in ovariectomized rat model of postmenopausal osteoporosis.

Epidemiology and pathogenesis of cardiovascular diseases (CVD) and osteoporosis are strikingly overlapping. This study presents matrix metalloproteinase-9 (MMP-9), as a simple molecular link more consistently associated with the pathophysiology of both osteoporosis and CVD risk factors. 40 adult female rats were randomly distributed into 4 groups [control sham-operated, untreated osteoporosis, carvedilol-treated osteoporosis and alendronate-treated osteoporosis]. After 8 weeks, blood samples were collected to estimate Lipid profile (Total cholesterol, HDL, Triglycerides), inflammatory markers (IL-6, TNF alpha, CRP and NO), and Bone turnover markers (BTM) (Alkaline phosphatase, osteocalcin and pyridinoline). The tibias were dissected to estimate MMP-9 and NF-kB gene expression, OPG, RANKL levels and for histological examination. Induction of osteoporosis resulted in a significant elevation in BTM, inflammatory markers and dyslipidemia. MMP-9 was significantly elevated and positively correlated with BTM, inflammation and dyslipidemia markers. Carvedilol and alendronate exerted a bone preservative role and attenuated dyslipidaemia and inflammation in accordance with their respective effect on MMP-9.

Combined Low Dose of Ketamine and Social Isolation: A Possible Model of Induced Chronic Schizophrenia-Like Symptoms in Male Albino Rats.

While animal models for schizophrenia, ranging from pharmacological models to lesions and genetic models, are available, they usually mimic only the positive symptoms of this disorder. Identifying a feasible model of chronic schizophrenia would be valuable for studying the possible underlying mechanism and to investigate emerging treatments. Our hypothesis starts from the observation that combining ketamine with isolation could result in long-lasting neuro-psychological deficits and schizophrenia-like features; thus, it could probably be used as the first model of chronic schizophrenia that emphasizes the characteristic of having a multifactorial etiology. By the means of this study, we investigated the effects of ketamine administration combined with isolation in inducing schizophrenia-like symptoms in male albino rats and the brain reactive oxygen species levels. Our results showed that the number of lines crossings in the open field test, the number of open arm entries in the elevated plus maze, and the spontaneous alternations percentage in the Y-maze were significantly lower in the ketamine + isolation group compared to both the control and ketamine + social housing group (p < 0.05). Furthermore, the ketamine + isolation intervention significantly increased the MDA levels and decreased the GPx levels both in the hippocampus and the cortex of the rats. In addition, our premise of creating a model capable of exhibiting both positive and negative symptoms of schizophrenia was also based on adding the aripiprazole treatment to a group of rats. Therefore, we compared the ketamine + social isolation group with the ketamine + social isolation + aripiprazole group in order to attempt to discover if the antipsychotic drug would significantly decrease the potential positive schizophrenia-like symptoms induced by social isolation and ketamine. Given that we obtained significant results, we cautiously presume that this might be an important step in developing our animal model capable of illustrating both positive and negative symptoms of schizophrenia. This study could be a first step towards the creation of a complex animal model capable of exhibiting the multifactorial origin and manifestation of schizophrenia.

The Putative Role of Natural Killer Cells in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma.

BACKGROUND: Natural Killer (NK) cells have crucial roles in immune responses against malignant transformation including hepatocellular carcinoma (HCC). The NKG2D receptor has a critical role in the NK recognition of target cells. AIM: We assessed NKG2D receptor expression as a diagnostic biomarker for HCC detection and progression in Egyptian patients with hepatitis C virus (HCV)-related HCC. METHODS: We classified 81 patients into three groups: chronic hepatitis (21), cirrhotic (30) and HCC (30) patients, with 36 individuals enrolled to the control group. We analyzed NK levels in peripheral blood and NKG2D receptor expression in NK cells using flow cytometry. RESULTS: We observed a significant decrease in NKG2D (CD314) expression on circulating NK cells and frequency of NK cells expressing NKG2D (CD314) in HCC patients. Also, in patients, larger foci lesions significantly correlated with decreased NK cell numbers. Multiple foci numbers and patients with a Child score C significantly correlated with decreased circulating NK cells expressing NKG2D and decreased NKG2D expression. CONCLUSION: The percentage of NK cells in peripheral blood and NKG2D receptor expression could function as potential biomarkers for HCC detection and progression.

Matrix metalloproteinase 9 a potential major player connecting atherosclerosis and osteoporosis in high fat diet fed rats.

BACKGROUND: Cardiovascular diseases (CVD) represent one of the major sequelae of obesity. On the other hand, the relationship between bone diseases and obesity remains unclear. An increasing number of biological and epidemiological studies suggest the presence of a link between atherosclerosis and osteoporosis, however, the precise molecular pathways underlying this close association remain poorly understood. The present work thus aimed to study Matrix Metalloproteinase 9 (MMP-9), as a proposed link between atherosclerosis and osteoporosis in high fat diet fed rats. METHODS AND FINDINGS: 40 rats were randomly divided into 4 groups: control, untreated atherosclerosis group, atherosclerotic rats treated with carvedilol (10mg/kg/d) and atherosclerotic rats treated with alendronate sodium (10mg/kg/d). After 8 weeks, blood samples were collected for estimation of Lipid profile (Total cholesterol, HDL, TGs), inflammatory markers (IL-6, TNF-α, CRP and NO) and Bone turnover markers (BTMs) (Alkaline phosphatase, osteocalcin and pyridinoline). Rats were then euthanized and the aortas and tibias were dissected for histological examination and estimation of MMP-9, N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (CTX) and NF-kB expression. Induction of atherosclerosis via high fat diet and chronic stress induced a significant increase in BTMs, inflammatory markers and resulted in a state of dyslipidaemia. MMP-9 has also shown to be significantly increased in the untreated atherosclerosis rats and showed a significant correlation with all measured parameters. Interestingly, Carvedilol and bisphosphonate had almost equal effects restoring the measured parameters back to normal, partially or completely. CONCLUSION: MMP-9 is a pivotal molecule that impact the atherogenic environment of the vessel wall. A strong cross talk exists between MMP-9, cytokine production and macrophage function. It also plays an important regulatory role in osteoclastogenesis. So, it may be a key molecule in charge for coupling CVD and bone diseases in high fat diet fed rats. Therefore, we suggest MMP-9 as a worthy molecule to be targeted pharmacologically in order to control both conditions simultaneously. Further studies are needed to support, to invest and to translate this hypothesis into clinical studies and guidelines.

DNA Methyltransferases as Potential Biomarkers for HCV Related Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major health concern in many countries including Egypt. The alteration in DNA methylation that was observed in HCC patients suggests a possible role of DNA methyltransferases (DNMTs) in the disease pathogenesis in addition to potential role as a disease biomarker. AIM: To study the change in DNMTs expression in chronic HCV infected patients as potential non- invasive biomarker for diagnosis of hepatocellular carcinoma. METHODS: 26 patients with HCC, 45 patients with liver cirrhosis, 20 chronic HCV patients and 20 apparently healthy individuals as a control group were enrolled in this study. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) was performed for all study participants. RESULTS: A significant difference in DNMTs expression was observed among the studied groups. Receiver operating characteristics (ROC) curve analysis revealed that with a cutoff value of 3.16 for DNMT 3A expression, sensitivity and specificity were 80.8 and 95.6% respectively and area under curve (AUC) was 0.958, p < 0.001 for discriminating hepatocellular carcinoma among post hepatitis C cirrhotic patients. Besides DNMT 3B relative expression cutoff value of 3.10 showed 84.6% sensitivity and 77.8% specificity and AUC was 0.888, p < 0.001. On the other hand, cutoff value 0.65 for DNMT1 relative expression showed 92.3% sensitivity and 44.4% specificity and AUC was 0.72, p= 0.002. DNMT1, DNMT 3A and DNMT 3B have significant positive correlation with the level of AFP (p-value = 0.003, 0.004 and 0.008 respectively). The relative expression of DNMT3B was significantly correlated to focal lesion size (p-value = 0.015). High DNMTs expression was significantly associated with the presence of multiple focal lesions but not with the Child Pugh grade (p> 0.05). CONCLUSION: The mRNA levels of DNMTs could be a potential biomarker for early detection of HCC development.
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Cimetidine a promising radio-protective agent through modulating Bax/Bcl2 ratio: An in vivo study in male rats.

Radiotherapy is one of the most effective modalities for treatment of neoplastic diseases. Radiation damage is to a large extent caused by overproduction of reactive oxygen species. To improve the therapeutic index, identifying effective substances for prevention or treatment of postirradiation intestinal and bone marrow injury should be prompted. This study was designed to evaluate the protective effects of cimetidine on the in rats exposed to γ-irradiation (5 Gy) and exploring the B-cell lymphoma 2 (Bcl2)/Bcl2 associated X (bax) pathway as a probable underlying mechanism. Eighteen adult male rats were randomly grouped into three: control, untreated irradiated rats, and irradiated rats pretreated with cimetidine. Seven days postirradiation the rats were culled, the bone marrow (BM) and jejunum tissue samples were collected for biochemical, histological, and immunohistological evaluation of BM cell count (BMCs), intestinal fibrosis, oxidative stress, tumor necrosis factor-α, Bcl2, and Bax. Cimetidine pretreatment significantly reversed the loss of BMCs, intestinal lining destruction, and fibrosis seen in the untreated irradiated rats and significantly decreased the underlying oxidative stress, inflammation, and Bax/Bcl2 ratio. There was a significant differential correlation between Bax/Bcl2 ratio, tissue oxidative stress level, and tissue injury. Cimetidine represents a very promising radioprotective agent with a potential differential beneficial effect on both cancer cells (inducing apoptosis) as previously proved through different studies and adjacent healthy cells (providing radioprotection via inhibiting apoptosis) as clearly demonstrated through this study, via its antioxidant effect and subsequent regulation of type 2 apoptotic pathway through modulation of Bax/Bcl2 ratio.

Dipeptidyl peptidase-4 inhibitors and aerobic exercise synergistically protect against liver injury in ovariectomized rats.

Menopause increases the risk of non-alcoholic fatty liver disease (NAFLD). We investigated the effect of incretin and/ or exercise on the hepatic fat accumulation in ovariectomized rats. Rats were divided into five groups: Group 1: Control rats, Group 2: Ovariectomized rats, Group 3: Ovariectomized rats + Dipeptidyl peptidase-4 inhibitor (DPPi) (30 mg/kg/day, orally), Group 4: Ovariectomized rats + swimming, and Group 5: Ovariectomized rats + swimming + DPPi. After 6 weeks, Alanine aminotransferase (ALT), glucose, insulin, HOMA IR (Homeostatic Model Assessment for Insulin Resistance), FFA (free fatty acids), Tumor necrosis factor alpha (TNF α), IL6, IL1B levels were measured in blood. The livers were collected for Hematoxylin and eosin (H&E) examination and evaluation of hepatic gene expression of SREBP (sterol regulatory element-binding protein1c), PPAR α (peroxisome proliferator-activated receptor alpha), ACC 1 (acetyl-CoA carboxylase), LC3 (microtubule-associated protein 1 light chain 3), SIRT (sirtuin), hepatic triglycerides, IL6, IL10, caspase 3 and AMPK (adenosine monophosphate-activated protein kinase). A significant increase in ALT level and area of liver tissue defects with a significant increase in glucose HOMA IR, serum FFA, IL6, IL1B, TNF α, liver TGs (triglycerides), inflammation, apoptosis, SREBP1c, ACC1 were found in ovariectomized rats as compared to control group with a significant decrease in PPAR α, LC3, AMPK and SIRT1. DPPi treated rats with and without exercise showed a significant improvement in ALT and area of liver tissue defects, inflammation and apoptosis and serum IL6, IL1B, TNF α, FFA, liver LC3, SIRT1, AMPK, TGs, PPAR α, ACC1 and SREBP1c as compared to the ovariectomized group. Findings from the study confirm the derangement of fat metabolism in the ovariectomized rats and showed that incretin-based therapy and exercise synergistically improved liver fat metabolism, achieved significant beneficial metabolic effects and offer full protection against NAFLD.

The protective effect of 1alpha, 25-dihydroxyvitamin d3 and metformin on liver in type 2 diabetic rats.

There is an accumulating evidence suggesting an immunomodulatory role of 1α,25(OH)2D3. Altered 1α,25(OH)2D3 level may play a role in the development of T2DM and contribute to the pathogenesis of liver diseases. Our study was designed to study and compare the effect of metformin and 1α,25(OH)2D3 supplementation on liver injury in type 2 diabetic rat. Sixty male Albino rats were divided into 5 groups; group 1: control rats. the remaining rats were fed high fat diet for 2 weeks and injected with streptozotocin (35mg/kg BW, i.p.) to induce T2DM and were divided into: group 2: untreated diabetic rats, group 3: diabetic rats treated by metformin (100mg/kgBW/d, orally), group 4: diabetic rats supplemented by 1α,25(OH)2D3 (0.5µg/kg BW, i.p.) 3 times weekly and group 5: supplemented by both 1α,25(OH)2D3 and metformin. Eight weeks later, serum glucose and insulin levels were measured, HOMA IR was calculated, lipid profile, Ca2+, ALT and AST were estimated. Liver specimens were taken to investigate PPAR-α (regulator of lipid metabolism), NF-κB p65, caspase 3 and PCNA (proliferating cell nuclear antigen) and for histological examination. The liver enzymes were elevated in the diabetic rats and the histological results revealed an injurious effect of diabetes on the liver. 1α,25(OH)2D3, metformin and both drugs treatment significantly improved liver enzymes as compared to the untreated rats. The improvement was associated with a significant improvement in the glycemic control, lipid profile and serum Ca2+ with a significant reduction in NF-κB p65 and caspase 3 and increased PPAR-α, and PCNA expression as compared to the untreated group. 1α,25(OH)2D3 induced a slightly better effect as compared to metformin. Both agents together had a synergistic action and almost completely protected the liver. Histological results confirmed the biochemical findings. Our results showed a protective effect of 1α,25(OH)2D3 and metformin on liver in diabetic rats as indicated by an improvement of the level of the liver enzymes, decreased apoptosis and increased proliferation and this was confirmed histologically, with modulating NFkB and PPAR-α. Both agents together had a synergistic effect.

A study on the effect of cimetidine and L-carnitine on myoglobinuric acute kidney injury in male rats.

Myoglobinuric acute renal failure is the most important life threatening complication of rhabdomyolysis. Iron, free radicals, nitric oxide and cytochrome p450 are involved in the pathogenesis of mARF. The aim of this study is to compare the effect of cimetidine, l-carnitine and both agents together on mARF in rats. Forty rats were divided into 5 groups; group I: control rats, group II: myoglobinuric ARF rats, group III: mARF rats received l-carnitine (200mg/kg, i.p.), group IV: mARF rats received cimetidine (150mg/kg i.p.) and group V: mARF rats received both agents together. 48h after glycerol injection, systolic blood pressure was measured. Urine and blood samples were collected to evaluate urine volume, GFR, BUN, creatinine, K, Na, serum creatine kinase, NO and glutathione levels. Kidney specimens were taken to investigate renal cytochrome p450 and for histological examinations. Cimetidine treatment significantly decreased creatinine, BUN, K, Na, SBP and creatine kinase and increased GFR and urine volume compared to group II. l-carnitine exerted similar changes except for the effect on K and GFR. NO was significantly decreased, while renal glutathione and cytochrome p450 were significantly increased in groups treated with l-carnitine or cimetidine as compared to group II. Combined treatment further improved renal functions, creatine kinase, oxidative stress parameters and SBP as compared to each therapy alone. The histological changes confirmed the biochemical findings. Cimetidine and l-carnitine have protective effects - almost equally - against mARF. Using both agents together, minimises the renal injury.