Effects of Preweaning Undernutrition and Continued Postweaning Protein Deficiency or Nutritional Rehabilitation on Polyphosphoinositides in Rat Brain

Metabolically inert polyphosphoinositides seem to play an important role in the structural development of neurons, glia, and myelin. The metabolically active pool of PhIpp appears to be important for the functional development of glia and myelin during the postweaning period, whereas PhIp seems to be more important for the functional development of neurons during the preweaning period. Neonatal undernutrition reduces the concentrations of structural polyphosphoinositides and metabolic PhIp while metabolic PhIpp remains unaltered. These effects can be reversed by postweaning nutritional rehabilitation. A continued postweaning protein deficiency of neonatally undernourished rats affects structural PhIpp more than PhIp. Metabolically active PhIpp is drastically reduced.     

The Ca2+-Transporting Activity of Rat Liver Microsomes in Response to Protein Undernutrition: Implications for Liver Tumor Promotion

The effect of protein undernutrition on the activity of the smoothendoplasmic reticulum (microsomal) Ca²⁺-ATPase (SERCA) wasinvestigated. After 12 weeks of ad libitum ingestion of low proteindiet (5% protein), a significant depression (p<0.05) of liver ERCa²⁺-ATPase activity (68.6% depression) was observed. However,no significant effects on cytochrome P₄₅₀ activity and relative liverweight were found. It is proposed that low protein diet by inhibitingthe rat liver SERCA activity, might increase the cytosolic free calciumion concentration ([Ca²⁺]) and promote the development of livertumor. The possible mechanisms of low protein diet induced inhibition ofSERCA activity are highlighted.     

Effects of Undernutrition on Glutamatergic Parameters in Rat Brain

Early restriction of nutrients during the perinatal period has marked repercussions on CNS ontogeny, Leading to impaired functions. This study investigated the effects of pre- and postnatal (up to 75 days) undernutrition (diet: 8% protein; normonourished group: 25% protein) on some glutamatergic and behavioral parameters of rats. Undernutrition reduced: (i) seizures caused by ICV quinolinic acid (QA) administration; (ii) Na-independent [³H]glutamate binding in cell plasma membranes of cerebral cortex, and (ii) basal [³H]glutamate release from synaptosomal preparation. Behavioral parameters related to locomotion, anxiety, or memory were not affected. These results indicate that our model of undernutrition decreased the sensitivity to QA as convulsing agent and point to some putative glutamatergic parameters involved in this effect.     

Evaluation of Vitamin D Repletion Regimens to Correct Vitamin D Status in Adults

ObjectiveTo determine the efficacy and safety of commonly prescribed regimens for the treatment of vitamin D insufficiency.MethodsWe performed a retrospective analysis of 306 consecutive patients who were prescribed ergocalciferol (vitamin D₂) for correction of vitamin D insufficiency at the Atlanta Veterans Affairs Medical Center between February 2003 and May 2006. Serum levels of parathyroid hormone, 25-hydroxyvitamin D (25-OHD), and calcium were compared before and after treatment with ergocalciferol. Patients who did not have a 25-OHD determination (n = 41) were excluded from analysis. Vitamin D deficiency, insufficiency, and sufficiency were defined as a serum 25-OHD level of < 20 ng/mL, 21 to 29 ng/mL, and > 30 ng/mL, respectively.ResultsWe identified 36 discrete prescribing regimens. The 3 most common regimens were ergocalciferol 50,000 IU once weekly for 4 weeks followed by 50,000 IU once monthly for 5 months (n = 48); ergocalciferol 50,000 IU once monthly for 6 months (n = 80); and ergocalciferol 50,000 IU 3 times weekly for 6 weeks (n = 27). Each of these 3 treatments significantly increased serum 25-OHD (P < .01), but vitamin D sufficiency was achieved in only 38%, 42%, and 82% of study subjects, respectively. Regimens with > 600,000 IU of ergocalciferol given for a mean of 60 ± 40 days achieved sufficiency in 64% of cases, without vitamin D toxicity.ConclusionIn this study, regimens that contained at least 600,000 IU of ergocalciferol appeared to be the most effective in achieving vitamin D sufficiency. Guidelines for the treatment of vitamin D insufficiency in healthy adults should be developed. (Endocr Pract. 2009;15:95-103)     

Allopurinol-Enhanced Postischemic Recovery in the Isolated Pat Heart Involves Repletion of High-Energy Phosphates

The effects of allopurinol (AP) on functional and metabolic recovery of the isolated rat heart after global ischemia were studied. Hearts were subjected to aerobic perfusion (30 min), cardioplegic infusion (5 min), normothermic ischemia (37 min), and reperfusion (50 min) which was started with secondary cardioplegic infusion (10 min). AP was injected into rats (44 mg/kg body wt ip 2 h before heart excision) and added to cardioplegic solution (2 mM) prior and after ischemia. AP treatment significantly improved postischemic recovery of the function and reduced the leakage of lactate dehydrogenase from reperfused hearts. These beneficial effects were accompanied by a better preservation of tissue content of ATP, the total adenine nucleotides, phosphocreatine, and the total creatine at the end of reperfusion. Inhibition of xanthine oxidase by AP substantially decreased pre- and postischemic release of xanthine and uric acid and increased postischemic release of hypoxanthine into the coronary effluent. Despite this, AP treated hearts did not exhibit a reduction in hydroxyl radical adduct formation in the effluents at reperfusion assessed by the spin-trap measurements. The results suggest that AP may protect the heart from ischemia/reperfusion injury due to enhanced energy provision rather than by prevention of oxygen-derived free radical formation.     

Undernutrition and the development of brain neurotransmitter systems

While there are homeostatic mechanisms to protect the brain against wide fluctuations in the availability of essential nutrients, food deprivation is known to influence brain neurochemistry. Given the growing problem of infant undernutrition and the fact that the developing nervous system appears to be especially vulnerable to this type of insult, numerous studies have been conducted to define the relationship between nutritional factors and cellular growth and maturation in the brain. The data suggest that the development of both neural and nonneural elements are significantly affected by undernutrition. This includes processes and substances important for neurotransmission such as transmitter synthesis, degradation and receptor sites. Because many neuropsychiatric conditions can be traced to dysfunctions in synaptic neurochemistry, it is possible that some of the central nervous system abnormalities which result from childhood undernutrition may be a consequence of a modification in synaptic biochemistry. The present report reviews data relating to this issue with the aim of assessing its relevance to developmental neurobiology.     

Citing a Data Repository: A Case Study of the Protein Data Bank

The Protein Data Bank (PDB) is the worldwide repository of 3D structures of proteins, nucleic acids and complex assemblies. The PDB’s large corpus of data (> 100,000 structures) and related citations provide a well-organized and extensive test set for developing and understanding data citation and access metrics. In this paper, we present a systematic investigation of how authors cite PDB as a data repository. We describe a novel metric based on information cascade constructed by exploring the citation network to measure influence between competing works and apply that to analyze different data citation practices to PDB. Based on this new metric, we found that the original publication of RCSB PDB in the year 2000 continues to attract most citations though many follow-up updates were published. None of these follow-up publications by members of the wwPDB organization can compete with the original publication in terms of citations and influence. Meanwhile, authors increasingly choose to use URLs of PDB in the text instead of citing PDB papers, leading to disruption of the growth of the literature citations. A comparison of data usage statistics and paper citations shows that PDB Web access is highly correlated with URL mentions in the text. The results reveal the trend of how authors cite a biomedical data repository and may provide useful insight of how to measure the impact of a data repository.     

Undernutrition,subsequent risk of mortality and civil war in Burundi

The paper investigates the effect of child undernutrition on the risk of mortality in Burundi. Using anthropometric data from a longitudinal survey (1998–2007) we find that undernourished children, measured by the height-for-age z-scores (HAZ) in 1998 had a higher probability to die during subsequent years. In order to address the problem of omitted variables correlated with both nutritional status and the risk of mortality, we use the length of exposure to civil war prior to 1998 as a source of exogenous variation in a child's nutritional status. Children exposed to civil war in their area of residence have worse nutritional status. The results indicate that one year of exposure translates into a 0.15 decrease in the HAZ, resulting in a 10% increase in the probability to die. For boys, we find a 0.34 decrease in HAZ per year of exposure, resulting in 25% increase in the probability to die. For girls, the results are statistically not significant at the usual thresholds. We show the robustness of our results and we derive policy conclusion for a nutrition intervention in times of conflict.     

Combined Prebiotic and Microbial Intervention Improves Oral Cholera Vaccination Responses in a Mouse Model of Childhood Undernutrition

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Osteocyte-Derived Insulin-Like Growth Factor I Is Not Essential for the Bone Repletion Response in Mice

The present study sought to evaluate the functional role of osteocyte-derived IGF-I in the bone repletion process by determining whether deficient expression of Igf1 in osteocytes would impair the bone repletion response to one week of dietary calcium repletion after two weeks of dietary calcium deprivation. As expected, the two-week dietary calcium depletion led to hypocalcemia, secondary hyperparathyroidism, and increases in bone resorption and bone loss in both Igf1 osteocyte conditional knockout (cKO) mutants and WT control mice. Thus, conditional disruption of Igf1 in osteocytes did not impair the calcium depletion-induced bone resorption. After one week of calcium repletion, both cKO mutants and WT littermates showed an increase in endosteal bone formation attended by the reduction in osteoclast number, indicating that deficient Igf1 expression in osteocytes also did not have deleterious effects on the bone repletion response. The lack of an effect of deficient osteocyte-derived IGF-I expression on bone repletion is unexpected since previous studies show that these Igf1 osteocyte cKO mice exhibited impaired developmental growth and displayed complete resistance to bone anabolic effects of loading. These studies suggest that there is a dichotomy between the mechanisms necessary for anabolic responses to mechanical loading and the regulatory hormonal and anabolic skeletal repletion following low dietary calcium challenge. In conclusion, to our knowledge this study has demonstrated for the first time that osteocyte-derived IGF-I, which is essential for anabolic bone response to mechanical loading, is not a key regulatory factor for bone repletion after a low calcium challenge.     

Multiorgan Detection and Characterization of Protease-Resistant Prion Protein in a Case of Variant CJD Examined in the United States

Background

Variant Creutzfeldt–Jakob disease (vCJD) is a prion disease thought to be acquired by the consumption of prion-contaminated beef products. To date, over 200 cases have been identified around the world, but mainly in the United Kingdom. Three cases have been identified in the United States; however, these subjects were likely exposed to prion infection elsewhere. Here we report on the first of these subjects.

Methodology/Principal Findings

Neuropathological and genetic examinations were carried out using standard procedures. We assessed the presence and characteristics of protease-resistant prion protein (PrP^res) in brain and 23 other organs and tissues using immunoblots performed directly on total homogenate or following sodium phosphotungstate precipitation to increase PrP^res detectability. The brain showed a lack of typical spongiform degeneration and had large plaques, likely stemming from the extensive neuronal loss caused by the long duration (32 months) of the disease. The PrP^res found in the brain had the typical characteristics of the PrP^res present in vCJD. In addition to the brain and other organs known to be prion positive in vCJD, such as the lymphoreticular system, pituitary and adrenal glands, and gastrointestinal tract, PrP^res was also detected for the first time in the dura mater, liver, pancreas, kidney, ovary, uterus, and skin.

Conclusions/Significance

Our results indicate that the number of organs affected in vCJD is greater than previously realized and further underscore the risk of iatrogenic transmission in vCJD.     

Repletion of atypical protein kinase C following RNA interference-mediated depletion restores insulin-stimulated glucose transport

The role of atypical protein kinase C (aPKC) in insulin-stimulated glucose transport in myocytes and adipocytes is controversial. Whereas studies involving the use of adenovirally mediated expression of kinase-inactive aPKC in L6 myocytes and 3T3/L1 and human adipocytes, and data from knock-out of aPKC in adipocytes derived from mouse embryonic stem cells and subsequently derived adipocytes, suggest that aPKCs are required for insulin-stimulated glucose transport, recent findings in studies of aPKC knockdown by small interfering RNA (RNAi) in 3T3/L1 adipocytes are conflicting. Moreover, there are no reports of aPKC knockdown in myocytes, wherein insulin effects on glucose transport are particularly relevant for understanding whole body glucose disposal. Presently, we exploited the fact that L6 myotubes and 3T3/L1 adipocytes have substantially different (30% nonhomology) major aPKCs, viz. PKC-zeta in L6 myotubes and PKC-lambda in 3T3/L1 adipocytes, that nevertheless can function interchangeably for glucose transport. Accordingly, in L6 myotubes, RNAi-targeting PKC-zeta, but not PKC-lambda, markedly depleted aPKC and concomitantly inhibited insulin-stimulated glucose transport; more importantly, these depleting/inhibitory effects were rescued by adenovirally mediated expression of PKC-lambda. Conversely, in 3T3/L1 adipocytes, RNAi constructs targeting PKC-lambda, but not PKC-zeta, markedly depleted aPKC and concomitantly inhibited insulin-stimulated glucose transport; here again, these depleting/inhibitory effects were rescued by adenovirally mediated expression of PKC-zeta. These findings in knockdown and, more convincingly, rescue studies, strongly support the hypothesis that aPKCs are required for insulin-stimulated glucose transport in myocytes and adipocytes.     

Repletion of copper-deficient rats with dietary copper restores duodenal hephaestin protein and iron absorption

Copper (Cu) deficiency in rats reduces the relative concentration of duodenal hephaestin (Hp), reduces iron (Fe) absorption, and causes anemia. An experiment was conducted to determine whether these effects could be reversed by dietary Cu repletion. Five groups of eight weanling male rats each were used. Group 1 was fed a Cu-adequate diet (5.0 mg Cu/kg; CuA) and Group 2 was fed a Cu-deficient diet (0.25 mg Cu/kg; CuD) for 28 days. The rats were fed 1.0 g each of their respective diets labeled with 59Fe (37 kBq/g), and the amount of label retained was measured one week later by whole-body-counting (WBC). Group 3 was fed a CuA diet and Groups 4 and 5 were fed a CuD diet for 28 days. Group 5 was then fed the CuA diet for another week while Groups 3 and 4 continued on their previous regimens. Rats in Groups 3, 4, and 5 were fed 1.0 g of diet labeled with 59Fe, and the amount of label retained was measured by WBC one week later. Rats were killed and duodenal enterocytes isolated for Hp protein analysis, whole blood was analyzed for hematological parameters, and various organs for 59Fe content. CuD rats absorbed less (P<0.05) Fe than CuA rats, the relative amount of duodenal Hp was less (P<0.05) in CuD rats, and the CuD rats developed anemia. After the CuD rats had been repleted with Cu for one week, Fe retention rose to values even higher (P<0.05) than those in CuA rats. After two weeks, the relative amount of duodenal Hp was higher (P<0.05) than normal, and most signs of anemia were reversed. Liver 59Fe was elevated in CuD rats, but was restored to normal upon Cu repletion. These findings suggest a strong association between duodenal Hp abundance and Fe absorption in the CuD rat, and that reduced Fe absorption is an important factor in the cause of anemia.     

Effects of Reduced Weight Maintenance and Leptin Repletion on Functional Connectivity of the Hypothalamus in Obese Humans

Treating obesity has proven to be an intractable challenge, in part, due to the difficulty of maintaining reduced weight. In our previous studies of in-patient obese subjects, we have shown that leptin repletion following a 10% or greater weight loss reduces many of the metabolic (decreased energy expenditure, sympathetic nervous system tone, and bioactive thyroid hormones) and behavioral (delayed satiation) changes that favor regain of lost weight. FMRI studies of these same subjects have shown leptin-sensitive increases in activation of the right hypothalamus and reduced activation of the cingulate, medial frontal and parahippocampal gryi, following weight loss, in response to food stimuli. In the present study, we expanded our cohort of in-patient subjects and employed psychophysiological interaction (PPI) analysis to examine changes in the functional connectivity of the right hypothalamus. During reduced-weight maintenance with placebo injections, the functional connectivity of the hypothalamus increased with visual areas and the dorsal anterior cingulate (dorsal ACC) in response to food cues, consistent with higher sensitivity to food. During reduced-weight maintenance with leptin injections, however, the functional connectivity of the right hypothalamus increased with the mid-insula and the central and parietal operculae, suggesting increased coupling with the interoceptive system, and decreased with the orbital frontal cortex, frontal pole and the dorsal ACC, suggesting a down-regulated sensitivity to food. These findings reveal neural mechanisms that may underlie observed changes in sensitivity to food cues in the obese population during reduced-weight maintenance and leptin repletion.