bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ketones and brain function: Possible link to polyunsaturated fatty acids and availability of a new brain PET tracer, 11C‐acetoacetate
Authors: Pifferi Fabien , Tremblay Sébastien , Plourde Mélanie , Tremblay‐Mercier Jennifer , Bentourkia M'hamed , Cunnane Stephen C. 
Published: November 2008

Summary Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat ketogenic diet (KD) for seizure control and in rats on a KD enriched in PUFA, raise the possibility that increased brain arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) may contribute to better seizure control. Our studies with PUFA and several other reports raise the question of whether persistent ketonemia or elevated brain uptake of ketones are strictly necessary for the clinical effectiveness of the KD in intractable epilepsy. To address this question, we have developed the synthesis of carbon‐11 labeled acetoacetate (
11
C‐AcAc) for PET studies to investigate brain ketone uptake directly in humans and animals. In rats on the KD for 10 days, 11C‐AcAc uptake by the brain increased 7‐ to 8‐fold, an increase similar to that induced by 48 h fasting. In rats and humans, paired PET scans (
11
C‐AcAc followed immediately by
18
fluorodeoxyglucose) will be conducted to assess the uptake of AcAc and glucose by the brain while on the KD and in neurological disorders associated with aging.
Ketone bodies, glycolysis, and KATP channels in the mechanism of the ketogenic diet
Authors: Yellen Gary 
Published: November 2008

Summary The ketogenic diet (KD) has shown remarkable efficacy in the treatment of drug‐resistant childhood epilepsy. Our understanding of how the KD produces its anticonvulsant and antiepileptogenic effects remains incomplete, which is perhaps not surprising for a biological manipulation as sweeping as dietary change. Several hypotheses focus on ketone bodies, fuel molecules that circulate at millimolar concentrations in the blood of patients on a KD, as causative agents. Here I consider some recent evidence for one such hypothesis, involving a possible role for altered glycolysis and consequent activation of a class of potassium channels called K

ATP

channels.
Acetone as an Anticonvulsant
Authors: Likhodii Sergei , Nylen Kirk , Burnham W. McIntyre 
Published: November 2008

SummaryRecent interest in the anticonvulsant effects of acetone has stemmed from studies related to the ketogenic diet (KD). The KD, a high‐fat diet used to treat drug‐resistant seizures, raises blood and brain levels of three ketones: beta‐hydroxybutyrate, acetoacetate, and acetone. An obvious question is whether these ketones have anticonvulsant properties. We found that neither beta‐hydroxybutyrate nor acetoacetate has proven to be anticonvulsant. Acetone, however, is clearly anticonvulsant at physiological, and near‐physiological, nontoxic concentrations. Despite knowledge of acetone's anticonvulsant properties since the 1930's, acetone had never been characterized using the standard animal seizure tests. In our recent experiments, acetone was found to be active in animal models of tonic–clonic seizures, typical absence seizures, complex partial seizures, and atypical absence seizures associated with Lennox–Gastaut syndrome. Therapeutic indices are either comparable or better than that of valproate, a standard broad‐spectrum anticonvulsant. A number of acetone‐like molecules have also been tested, and these also show good potency up to a “cutoff” point of nine carbons contained in the side chain. Above this number, potency disappears, suggesting the possibility of a receptor for acetone and its analogs.
Lability of GABAA receptor function in human partial epilepsy: Possible relationship to hypometabolism
Authors: Pumain René , Ahmed Mounia Sid , Kurcewicz Irène , Trottier Suzanne , Louvel Jacques , Turak Baris , Devaux Bertrand , Laschet Jacques 
Published: November 2008

Summary The function of the γ‐aminobutyric acid type A receptor (GABA

A

R) is maintained by endogenous phosphorylation. We have shown that the corresponding kinase is the glycolytic enzyme glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), using the locally produced glycolytic ATP. In addition, using cerebral tissue obtained during curative surgery for epilepsy, we showed that both the endogenous phosphorylation and the GABA

A

R function are significantly reduced in the “epileptogenic” cerebral cortex when compared to “control” tissue. This dysfunction likely contributes to seizure generation and/or transition from the interictal to the ictal state. Glucose utilization is decreased in the epileptogenic cortex of patients with partial epilepsy in the interictal state, but the relationship to the disorder remains unclear. We propose that this hypometabolism is related to the deficiency in the endogenous phosphorylation of GABA

A

R and the resulting greater lability of GABAergic inhibition. Several lines of evidences indeed suggest that GABAergic inhibition is costly in terms of metabolic consumption. The deficiency of this glycolysis‐dependent mechanism may thus link epileptogenicity to glucose hypometabolism. The antiepileptic effect of ketogenic diets may be mediated by the subsequent rise in the NADH/NAD+ index, which favors GABA

A

R endogenous phosphorylation and should contribute to restoration of GABAergic inhibition in the epileptogenic zone.
Calorie restriction and glucose regulation
Authors: Yamada Kelvin A. 
Published: November 2008

Summary Ketogenic diets (KDs) are effective treatments for epilepsy. The mechanisms of action are poorly understood. In some experimental seizure models, calorie restriction and hypoglycemia may augment the antiseizure effects of KDs. In addition, inhibiting glycolysis or diverting glucose from the glycolytic pathway inhibits seizures and possibly epileptogenesis, suggesting an interaction between energy regulation and the anticonvulsant actions of these interventions. Children on KDs frequently exhibit poor weight gain and have lower blood glucose levels compared to children on standard, balanced diets. Young rodents on a KD also exhibit slow weight gain, lower blood glucose and insulin levels, and elevated leptin levels. This review considers the possibility that calorie restriction, low serum glucose, and KDs share common cell signaling pathways to alter brain excitability. AMP‐activated protein kinase (AMPK) is an attractive candidate signaling protein that could link energy balance to gene expression in such a way so as to reduce brain excitability.
Possible mechanisms for the anticonvulsant activity of fructose‐1,6‐diphosphate
Authors: Stringer Janet L. , Xu Kaiping 
Published: November 2008

Summary Fructose‐1,6‐diphosphate (FDP), an intracellular metabolite of glucose, has anticonvulsant activity in several models of acute seizures in laboratory animals. The anticonvulsant effect of FDP is most likely due to a direct effect since intraperitoneal and oral administration results in significant increases in brain levels. A number of mechanisms have been proposed for this action of FDP. One possibility is that peripheral administration of FDP results in changes in brain metabolism that are anticonvulsant. Glucose can be metabolized through the glycolytic or pentose phosphate pathway. There is evidence that the pentose phosphate pathway is more active in the brain than in other tissues, and that, in the presence of elevated levels of FDP, the majority of glucose is metabolized by the pentose phosphate pathway. The pentose phosphate pathway generates NADPH, which is used to reduce glutathione. The reduced form of endogenous glutathione has been shown to have anticonvulsant activity. Taken together, the data suggest a hypothesis that exogenously administered FDP gets into the brain and astrocytes where it increases the flux of glucose through the pentose phosphate pathway, generating additional NADPH for the reduction of glutathione.
The contribution of norepinephrine and orexigenic neuropeptides to the anticonvulsant effect of the ketogenic diet
Authors: Weinshenker David 
Published: November 2008

Summary The ketogenic diet (KD) is a high‐fat, low‐carbohydrate, low‐protein diet used to treat refractory epilepsy. Despite its efficacy and many years of investigation, the mechanism by which the KD exerts its anticonvulsant effect remains controversial and poorly understood. The purpose of this article is to review the available data considering two classes of molecules that may contribute to the anticonvulsant effect of the KD:  norepinephrine and the orexigenic neuropeptides galanin and neuropeptide Y.
A new rat model for vulnerability to epilepsy and autism spectrum disorders
Authors: Gilby Krista L. 
Published: November 2008

Summary Tremendous concern has arisen in response to the recent diagnostic outbreak of childhood developmental disorders, particularly involving attention deficit hyperactivity disorder (ADHD) and the autism spectrum disorders (ASD). Interestingly, similarities in clinical presentation across these disorders may suggest common predisposing factors. For instance, though not widely recognized, an increased predisposition toward seizure is a symptom that is very often associated with ADHD and ASD. Accordingly, a rat strain naturally bred to be seizure‐prone simultaneously developed behavioral and physical characteristics analogous to those observed in ADHD/ASD patients. These rats also show early signs of aberrant lipid handling, which is another symptom common to human patients with these disorders. As such, this rat strain could serve as an excellent model system through which to identify common pathophysiological events that constitute a“spectrum of vulnerability”toward ADHD/ASD and epilepsy.
Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets
Authors: Seyfried Thomas N. , Kiebish Michael , Mukherjee Purna , Marsh Jeremy 
Published: November 2008

Summary Information is presented on the calorically restricted ketogenic diet (CRKD) as an alternative therapy for brain cancer. In contrast to normal neurons and glia, which evolved to metabolize ketone bodies as an alternative fuel to glucose under energy‐restricted conditions, brain tumor cells are largely glycolytic due to mitochondrial defects and have a reduced ability to metabolize ketone bodies. The CRKD is effective in managing brain tumor growth in animal models and in patients, and appears to act through antiangiogenic, anti‐inflammatory, and proapoptotic mechanisms.
UCP‐mediated free fatty acid uncoupling of isolated cortical mitochondria from fasted animals: Correlations to dietary modulations
Authors: Davis Laurie M. , Rho Jong M. , Sullivan Patrick G. 
Published: November 2008

Summary Uncoupling proteins (UCP) translocate protons from the mitochondrial intermembrane space to the matrix, thereby “uncoupling” electron transport from the production of ATP. It has been shown that these proteins are highly expressed in animals maintained on the ketogenic diet (KD). Although the exact mechanism remains unclear, it is known that these proteins are activated within a protective antireactive oxygen species (ROS) mechanism by free fatty acids (FFA). In our current studies, mitochondrial samples were probed for the presence of UCP2, which is the most ubiquitously expressed UCP isoform. We found that both traumatic brain injury and fasting upregulated the expression of UCP2, with a synergistic upregulation in fasted injured animals. We then used mitochondria from fasted naive animals to screen a number of FFA for their activation of uncoupling as well as their ability to reduce ROS. We found that arachidonic acid (AA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), palmitoleic acid, myristic acid, and butyric acid increased mitochondrial uncoupling when added after oligomycin. These FFA, along with oleic acid, also reduced ROS in mitochondria incubated with oligomycin. In order to correlate our data to KD and fasting, both of which have been shown to be neuroprotective after neurologic insult, we determined the serum levels of FFA in KD and fasted animals using gas chromatography/mass spectroscopy. We also determined brain and cerebrospinal fluid (CSF) FFA levels from fasted animals.
The ketogenic diet in a pill: Is this possible?
Authors: Rho Jong M. , Sankar Raman 
Published: November 2008

Summary Over the past decade, much progress has been made in understanding the mechanisms of ketogenic diet (KD) action. From the complex systemic and metabolic changes induced by the KD have emerged innovative hypotheses attempting to link biochemical adaptations to its clinical effects. Despite such developments, the fundamental question of how the KD works remains as elusive as ever. At present, it is unclear which of the many potential mechanisms proposed thus far are directly relevant to the clinical effects of the KD. It is unlikely that these numerous hypotheses can be unified into a single mechanism (or a final common pathway). Nevertheless, it may be instructive to consider each of these putative mechanisms in turn and ask the following question: if the mechanism or target in question is a critical determinant of the anticonvulsant efficacy of the KD, then would a similar intervention known to be based on that mechanism yield a comparable effect? Perhaps answering this question for each mechanistic speculation might help substantiate (or invalidate) that particular hypothesis. Can the KD be packaged into a pill? At present, the answer is likely “no.” We have yet to discover a “magic bullet” that completely mirrors the anticonvulsant (and potential neuroprotective) effects of the KD. However, without a clearer understanding of the mechanistic elements comprising the complex metabolic puzzle posed by the KD, we would be left only with empiric observations, and to wonder curiously how a high‐fat diet can exert such profound clinical effects.
Intermittent Wound Perfusion for Postoperative Pain Relief Following Upper Abdominal Surgery: A Surgeon's Perspective
Authors: Sistla Sarath Chandra , Sibal Amul Kumar , Ravishankar M. 
Published: November 2008

AbstractBackground:  Although there are many methods for postoperative pain management, implementation may be limited in some settings due to practical or financial constraints. Simple, inexpensive and easily implemented analgesic methods may improve access to effective pain relief.Methods:  Fifty patients undergoing truncal vagotomy and gastrojejunostomy for pyloric stenosis secondary to chronic duodenal ulceration were studied in this prospective randomized trial. Subjects were assigned to receive either wound perfusion with 8 mL of 0.25% bupivacaine every 5 hours through a catheter placed subcutaneously or intravenous pethidine 0.2 mg/kg on demand for postoperative pain relief. Postoperative pain scores at rest were measured by visual analog scale and the opioid requirement at 0–12 hours, at 12–24 hours and at 24–36 hours were compared. Changes in respiratory parameters were also compared between the two groups.Results:  Pain scores at 0–12 hours were significantly lower in the wound perfusion group compared with the intravenous pethidine group (5.7 ± 1.3 vs. 4.3 ± 1.2, mean ± SD; P < 0.001). The number of doses of analgesic required in the wound perfusion group was significantly lower compared with the controls during the 36 hours of study (3.5 ± 1.3 vs. 1.4 ± 1.0, P < 0.001). There were no differences in respiratory parameters, vital capacity, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and peak expiratory flow rate between the two groups. The FEV1 : FVC ratio, however, was significantly higher in the intravenous pethidine group. There were no wound complications due to catheter placement or systemic toxicity due to the anesthetic.Conclusion:  Intermittent wound perfusion with 0.25% bupivacaine is a safe and efficient method to reduce pain scores and opioid requirement in the early postoperative period. Wound perfusion, however, had no beneficial effect on the postoperative respiratory function.
The upregulation of cystatin C in human gingival fibroblasts stimulated with cyclosporine A
Authors: Tsai C.‐H. , Yang S.‐F. , Huang F.‐M. , Chang Y.‐C. 
Published: November 2008

Background and Objective:  Cystatin C is a 13 kDa non‐glycosylated, basic protein belonging to the cystatin family. It is consistently and dramatically upregulated in a variety of fibrotic diseases. However, little is known about the correlation between cystatin C and cyclosporine A‐induced gingival overgrowth. The aim of this study was to compare cystatin C expression in normal, healthy gingival tissues and cyclosporine A‐induced gingival overgrowth specimens and further explore the potential mechanism that may result in cystatin C expression.Material and Methods:  Fifteen cyclosporine A‐induced gingival overgrowth specimens and five normal gingival tissues were examined by immunohistochemistry. Three human gingival fibroblast (HGF) strains were established from crown‐lengthening surgery. The reverse transcriptase‐polymerase chain reaction was used to investigate the effects on HGFs exposed to cyclosporine A. In addition, predominant periodontal pathogens (Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis) and proinflammatory cytokines (interleukin‐1α and tumor necrosis factor‐α) were added to seek the possible regulatory mechanisms of cystatin C expression.Results:  The cystatin C staining in gingival tissue was stronger in the cyclosporine A‐induced gingival overgrowth group than in the normal gingival group (p < 0.05). Intensive staining for cystatin C expression was observed mainly in the cytoplasm of fibroblasts, epithelial cells and inflammatory cells. Moreover, cystatin C expression was significantly higher in cyclosporine A‐induced gingival overgrowth specimens with higher levels of inflammatory infiltrates (p < 0.05). A concentration of 200 ng/mL cyclosporine A was found to increase cystatin C expression in HGFs in a time‐dependent manner (p < 0.05). The addition of periodontal pathogens and proinflammatory cytokines significantly increased the expression of cystatin C compared with cyclosporine A alone (p < 0.05).Conclusion:  The increased ability of protein accumulation by cystatin C is one of several factors mediating cyclosporine A‐induced gingival overgrowth. In addition, cyclosporine A may predispose to gingival overgrowth in inflammatory environments.
Overexpression of cytokeratin 17 protein in oral squamous cell carcinoma in vitro and in vivo
Authors: Wei K‐J , Zhang L , Yang X , Zhong L‐P , Zhou X‐J , Pan H‐Y , Li J , Chen W‐T , Zhang Z‐Y 
Published: November 2008

Objective:  To determine the cytokeratin 17 (CK17) expression in oral squamous cell carcinoma (OSCC) both in vitro and in vivo.Methods:  Comparative proteomic analysis of an in vitro cellular carcinogenesis model of OSCC (including a line of human immortalized oral epithelia cells (HIOECs), a line of cancerous HB96 cells and another kind of cells (HB56 cells) at the early stage of carcinogenesis was performed to identify differentially expressed proteins. CK17 was further validated in vitro (cellular carcinogenesis model and other three OSCC lines) and in vivo (tissues from six healthy persons and 30 primary OSCC patients) by Western blotting and immunohistochemistry respectively.Results:  Increased CK17 expression was identified by two‐dimensional gel electrophoresis and liquid chromatography–tandem mass chromatography in the HB56 and HB96 cells over HIOECs. Western blotting confirmed the increased CK17 expression in the HB56, HB96 cells and other three OSCC lines. Immunohistochemistry confirmed the increased CK17 expression in the cancerous tissues from OSCC patients compared with the paired adjacent non‐malignant epithelia.Conclusion:  Increased CK17 expression may play an important role in the carcinogenesis progression of OSCC; however, further studies on the molecular function of CK17 are encouraged to clear the precise mechanism of CK17 in OSCC.
Cost‐Effectiveness of a School‐Based Obesity Prevention Program
Authors: Wang Li Yan , Gutin Bernard , Barbeau Paule , Moore Justin B. , Hanes John , Johnson Maribeth H. , Cavnar Marlo , Thornburg Janet , Yin Zenong 
Published: November 2008

ABSTRACTBACKGROUND:  A school‐based obesity prevention study (Medical College of Georgia FitKid Project) started in the fall of 2003 in 18 elementary schools. Half of the schools were randomized to an after‐school program that included moderate‐to‐vigorous physical activity, healthy snacks, homework assistance, and academic enrichment. All third graders were invited to enroll. The objective of this study was to assess the cost‐effectiveness (CE) of the first‐year intervention.METHODS:  Standard CE analysis methods and a societal perspective were used. Program delivery costs incurred during the first‐year intervention and the usual after‐school care costs that would occur in the absence of the intervention were estimated (in 2003 dollars). Net intervention costs were calculated by subtracting the usual after‐school care costs from the intervention costs. The effectiveness of the intervention was measured as percent body fat (%BF) reduction compared with a control condition. The CE was assessed as the net intervention cost divided by the effectiveness of the intervention.RESULTS:  The intervention costs totaled $174,070, $558/student, or $956/student who attended ≥40% of the intervention sessions. The usual after‐school care costs were estimated at $639/student. Students who attended ≥40% of the intervention reduced %BF by 0.76% (95% confidence interval: −1.42 to −0.09) at an additional cost of $317/student.CONCLUSIONS:  Subjects who attended ≥40% of the intervention achieved a significant reduction in %BF at a relatively low cost. School‐based obesity prevention programs of this type are likely to be a cost‐effective use of public funds and warrant careful consideration by policy makers and program planners.
A Statewide Movement to Promote the Adoption of Tobacco‐Free School Policies*
Authors: Summerlin‐Long Shelley K. , Goldstein Adam O. 
Published: November 2008

ABSTRACTBACKGROUND:  Since most tobacco users become addicted to nicotine as teenagers, prevention efforts for youth remain central to comprehensive prevention programs. National and state efforts that encourage adoption and enforcement of comprehensive tobacco‐free school (TFS) policies can lead to significant reductions of youth tobacco use. In 2003, North Carolina (NC) Health and Wellness Trust Fund grantees began to focus statewide on the adoption of and compliance with TFS policies in NC schools. This study examined 46 NC districts that passed TFS policies between 2003 and early August of 2005 to see what factors were important in policy passage in order to support the continued promotion of TFS policy adoption across the state.METHODS:  Detailed interviews were conducted with 118 key informants who were intimately involved with passage of their school districts’ TFS policies, and results were coded and analyzed for common themes.RESULTS:  The study found several strategies key to adoption of TFS policies: effective leadership from organizations and individuals in positions of influence, grassroots organizing from community coalitions and youth groups, and communication strategies that optimally position policy adoption and compliance.CONCLUSION:  States that have not yet achieved TFS policy adoption can focus on leadership development, grassroots organizing, and improved communication to advance their advocacy efforts.