Acute encephalopathy in children in Muzaffarpur, India: a review of aetiopathogenesis

The acute encephalopathy occurring in children in Muzaffarpur, India, also recognised in other litchi-cultivating areas of India, Bangladesh, Vietnam and China, had previously been linked to litchi consumption. Recently, it has been identified as hypoglycaemic encephalopathy of an unusual aetiology with three key factors: undernutrition, prolonged fasting and litchi consumption. A second set of investigators has independently reconfirmed the diagnosis and the three-factor aetiology. Skipping the evening meal with an intake of large amounts of litchi in undernourished children is causative. Early-morning hypoglycaemia with an inadequate glycogen store leads to initiation of gluconeogenesis and fatty acid β-oxidation, but methylene cyclopropyl alanine and glycine present in the litchi aril block the fatty acid β-oxidation cycle. The outcomes are uncorrected hypoglycaemia and encephalopathy due to the entry of metabolic intermediates that cross the blood-brain barrier and affect neuronal function. Suggested measures include early 10% dextrose infusion. Awareness about the disease is of prime importance. The diagnosis and aetiopathogenesis are still under question from a part of the scientific community. This review was undertaken to present a comprehensive view of hypoglycaemic encephalopathy and to remove some of the lingering doubts.

Antidiabetic Potency of Bangladeshi Medicinal Plants

Diabetes mellitus is a degenerative disease being responsible for about 1.5 million deaths globally. In Bangladesh, the stress of diabetes is on rising and resulting in serious health implications along with significant economic crisis. Due to undesirable and inherent side effects, researchers are now shifting from the conventional therapy and trying to prevent and manage diabetes through traditional medicine. World Health Organization (WHO) also recommends the practice of customary herbal medicine for diabetes management, and support and encourage the augmentation of research to evaluate the hypoglycemic properties of the diverse medicinal plant species. Consequently, in the current review, the antihyperglycemic potency of some Bangladeshi medicinal plants has been evaluated and verified utilizing human as well as experimental animals. The results elucidate the glucose-lowering effects of the plants via different cellular mechanisms, including restoration of pancreatic β-cell, controlling the action of carbohydrate metabolizing enzymes, enhancing peripheral glucose utilization, increase in muscle glycogen store as well as activation of the insulin signaling cascade. In summary, this work may invigorate the researchers for more specific and focused research to provide a better and broad understanding of the antihyperglycemic mechanism and can act as an effective tool for choosing the plants with robust potential for unbolting of novel antidiabetic agents.

Abstract 128: Mitochondrial CaMKII Plays Important Physiological and Pathological Roles

Calcium/calmodulin-dependent protein kinase II (CaMKII) is known for its roles in fight-or-flight responses, where it mobilizes ATP-consuming processes to maximize power output by regulating cellular Ca 2+ . We hypothesized that CaMKII may also influence ATP-generating processes in a feedforward mechanism to match ATP consumption with demand. Most cellular ATP is produced by oxidative phosphorylation (OXPHOS) in mitochondria; therefore, we generated transgenic animals whose mitochondrial CaMKII activity is boosted or inhibited by overexpressing mitochondrial targeted CaMKII (mtCaMKII), or a specific CaMKII inhibitor (mtCaMKII N ). We found that mitochondria from mtCaMKII mice have increased activity of pyruvate dehydrogenase and various TCA cycle enzymes. However, these mitochondria failed to provide sufficient ATP for cardiac function, likely due to detrimental remodeling of electron transport chain complex I. As a result, mtCaMKII mice develop a unique dilated cardiomyopathy soon after birth, which could be rescued by overexpressing the mitochondrial but not the myofibrillar form of creatine kinase. mtCaMKII N mice are protected against lipopolysaccharides (LPS)-induced mortality, ischemia/reperfusion injury, adverse cardiac remodeling after myocardial infarction and asthma. Furthermore, Drosophila melanogaster overexpressing mtCaMKII N have longer lifespan under heat stress (29 o C) and are resistant to paraquat, an ROS-inducing agent. However, in the mice, inhibiting mitochondrial CaMKII reduces metabolic fitness required to sustain the isoproterenol-induced fight-or-flight response, leading to elevated utilization of the cardiac glycogen store and increased lactate production. mtCaMKII N mice have reduced spontaneous activity and a higher tendency to gain fat mass when fed a high-fat diet; mtCaMKII N flies have a shorter lifespan in the absence of thermal stress (25 o C). We are using phosphoproteomics, metabolomics and in silico modeling approaches to determine the mechanisms by which mtCaMKII regulates energy metabolism and stress responses. Our results have provided important insights into the physiological and pathological roles of mitochondrial CaMKII.

Thermodynamics of cercarial survival and metabolism in a changing climate

SUMMARYCercariae are non-feeding free-living stages in the life cycles of trematodes, highly influenced by temperature. Their life span is brief, limited by the depletion of a non-renewable glycogen store. Warmer temperatures under the influence of climate change may promote the transmission of parasites and therefore understanding their thermobiology forms an important step in discerning the future dynamics of parasite populations. An empirical relationship exists between cercarial mean expected life span and the half-life of the population (t0·5) and therefore t0·5 is a good indicator of glycogen utilization. In this study experimental data on the effects of temperature on cercarial survival is compiled from the scientific literature and evaluated in terms of metabolism using Q10 and Arrhenius activation energy (E* or μ), common measures of temperature-mediated reaction rates. Cercariae have a variable response to temperature, which does not appear to be influenced by their life-history attributes or size. There were little differences in Q10 and E* values between most temperature ranges. In almost half the studies examined (7 of 16) cercariae demonstrated a discrete zone of thermostability over a range equivalent to typical individual mean summer temperatures. Distinct intraspecific differences in temperature responses between 3 laboratory strains of Schistosoma mansoni and 2 natural strains of Echinoparyphium recurvatumsensu stricto were apparent. The importance of these results for cercarial biology under global climate change is discussed.

Enlargement of glycogen store in rat liver and muscle by fructose-diet intake and exercise training

Murakami, Taro, Yoshiharu Shimomura, Noriaki Fujitsuka, Masahiro Sokabe, Koji Okamura, and Shuichi Sakamoto. Enlargement of glycogen store in rat liver and muscle by fructose-diet intake and exercise training. J. Appl. Physiol.82(3): 772–775, 1997.—This study investigated the effect of long-term intake of a fructose diet and exercise training on glycogen content in liver and skeletal muscle in female rats. Thirty-six rats (8 wk old) were divided into two dietary groups and were fed with a control (chow) diet or fructose diet (containing 20% fructose) for 12 wk. During this period, one-half of the rats in each dietary group were trained by using a motor-driven treadmill (running speed of 25 m/min and duration of 90 min/day, 5 days/wk). The liver glycogen was increased by intake of a fructose diet and exercise training, and the content was in the following order: control-diet and sedentary rats < fructose-diet and sedentary rats ≤ control-diet and trained rats < fructose-diet and trained rats in the ratio of 1:3.4:3.6:5.0. The glycogen content in gastrocnemius muscle showed the same trend as that in liver; the ratio was 1:1.3:1.3:1.6. These results indicate that both long-term intake of the fructose diet and exercise training synergistically increased glycogen in both tissues.

PDC activity and acetyl group accumulation in skeletal muscle during prolonged exercise

Seven subjects cycled to exhaustion [58 +/- 7 (SE) min] at approximately 75% of their maximal oxygen uptake (VO2max). Needle biopsy samples were taken from the quadriceps femoris muscle at rest, after 3, 10, and 40 min of exercise, at exhaustion, and after 10 min of recovery. After 3 min of exercise, a nearly complete transformation of the pyruvate dehydrogenase complex (PDC) into active form had occurred and was maintained throughout the exercise period. The total in vitro activated PDC was unchanged during exercise. The muscle concentration of acetyl-CoA increased from a resting value of 8.4 +/- 1.0 to 31.6 +/- 3.3 mumol/kg dry wt at exhaustion and that of acetylcarnitine from 2.9 +/- 0.7 to 15.6 +/- 1.6 mmol/kg dry wt. This was accompanied by corresponding decreases in reduced CoA (CoASH) from 45.3 +/- 3.1 to 25.9 +/- 3.1 mumol/kg dry wt and in free carnitine from 18.8 +/- 0.7 to 5.7 +/- 0.5 mmol/kg dry wt. Acetyl group accumulation, in the form of acetyl-CoA and acetylcarnitine, was maintained throughout exercise to exhaustion while the glycogen content decreased by 90%. This suggests that availability of acetyl groups was not limiting to exercise performance despite the nearly total depletion of the glycogen store. The increased acetyl-CoA-to-CoASH ratio during exercise caused inhibition of neither the PDC transformation nor the calculated catalytic activity of active PDC.

Resistance of hepatic glycogen to depletion in obese Zucker rats

Glycogen stores (liver and carcass) have been studied in lean and obese Zucker rats. The animals were submitted to one of three feeding conditions: ad libitum, a 48-h fast, or a 48-h fast and food ad libitum for 24 h, and to two environmental conditions, either thermoneutrality or an acute cold exposure (2 days at 4–7 °C). After a 2-day fast at 25 °C, the liver glycogen store was reduced by 45 times in the lean rats, while it was decreased by only 3 times in the obese rats. Under these conditions, the liver glycogen store was 45 times higher in the obese than in the lean rats. After 2 days in the cold, liver glycogen store was 4.4 times higher in obese rats than in lean rats. After a 2-day fast in the cold, the liver glycogen store in the obese rats was 30 times higher than in the lean rats. In comparison to fasting at thermoneutrality, fasting in the cold did not lead to a further reduction in hepatic glycogen in obese Zucker rats. The differences observed in the mobilization of the hepatic glycogen store between obese and lean rats have not been found in the mobilization of the carcass glycogen store. Drastic conditions, such as a 2-day fast in the cold, did not exhaust the glycogen store in obese Zucker rats. The present observations point out that obese Zucker rats cannot mobilize the entire hepatic glycogen store, as seen in lean control rats. The role of this abnormality in the high hyperlipogenesis that maintains the obese state is still to be evaluated.Key words: glycogen, fasting and refeeding, cold exposure, obesity, liver.

Long-term anoxia in crucian carp: changes in the levels of amino acid and monoamine neurotransmitters in the brain, catecholamines in chromaffin tissue, and liver glycogen

Crucian carp (Carassius carassius L.), which are extremely anoxia-tolerant, were exposed to 17 days of anoxia at 8 degrees C. One group of fish was transferred to normoxic water for 1–8 h immediately after the anoxic period. All the eight amino acids measured in brain (including four putative neurotransmitters) were more or less strongly affected by anoxia. Gamma-aminobutyric acid (GABA) displayed a nearly fivefold increase during anoxia. It is hypothesized that the increased level of this inhibitory transmitter, maybe in combination with the decrease seen in excitatory amino acids (glutamate and aspartate), causes a lowered brain activity and, hence, is a key factor behind the decrease in physical activity and systemic energy metabolism seen in anoxic Carassius. The brain levels of serotonin, dopamine and norepinephrine were remarkably well preserved after anoxia (although their synthesis is oxygen-dependent), suggesting adaptive mechanisms. However, anoxia reduced the norepinephrine level in kidney (chromaffin tissue) by 92% and, in contrast to previous results on shorter anoxic periods (3–7 days), the peripheral catecholamine store showed little sign of recovery during the subsequent normoxia. Anoxia was found to deplete the liver glycogen store severely, and the few fish that died after 15–17 days of anoxia contained no detectable liver glycogen.

Glucose formation in human skeletal muscle. Influence of glycogen content

Eight men exercised at 66% of their maximal isometric force to fatigue after prior decrease in the glycogen store in one leg (low-glycogen, LG). The exercise was repeated with the contralateral leg (control) at the same relative intensity and for the same duration. Muscle (quadriceps femoris) glycogen content decreased in the LG leg from 199 +/- 17 (mean +/- S.E.M.) to 163 +/- 16 mmol of glucosyl units/kg dry wt. (P less than 0.05), and in the control leg from 311 +/- 23 to 270 +/- 18 mmol/kg (P less than 0.05). The decrease in glycogen corresponded to a similar accumulation of glycolytic intermediates. Muscle glucose increased in the LG leg during the contraction, from 1.8 +/- 0.1 to 4.3 +/- 0.6 mmol/kg dry wt. (P less than 0.01), whereas no significant increase occurred in the control leg (P greater than 0.05). It is concluded that during exercise glucose is formed from glycogen through the debranching enzyme when muscle glycogen is decreased to values below about 200 mmol/kg dry wt.