Although widely used in medicine, separation technology, and other fields, the effects of cyclodextrins on the activities of phosphoryl transfer enzymes have not been previously evaluated. In vivo ...studies evaluated the function of cyclodextrins as active compounds. Despite the use of cyclodextrins as active compounds, the effects of cyclodextrins on hepatic and renal tissues remain to be fully elucidated. The primary objective of this study was to evaluate the effects of β- cyclodextrins, methyl-β-cyclodextrin (M-β- cyclodextrins), and (2-hydroxypropyl)-β-cyclodextrin (HP-β-cyclodextrins) on enzyme activities regulating the maintenance of energy homeostasis in the kidney and liver tissues in relation to toxicity. Serum levels of liver and kidney markers were measured, and oxidative stress parameters were assessed. After 60-day treatments, we observed that the administration of β-cyclodextrins and M-β-cyclodextrins inhibited the hepatic activity of pyruvate kinase, an irreversible enzyme within the glycolytic pathway. Additionally, administration of HP-β-cyclodextrins inhibited creatine kinase activity and increased the total sulfhydryl content in kidneys. Here, we demonstrated for the first time that β-cyclodextrins, M-β-cyclodextrins, and HP-β-cyclodextrins cause bioenergetic dysfunction in renal and hepatic tissues. These findings suggest that understanding the balance between cyclodextrins' efficacy and adverse effects is essential for better accepting their use in medicine.
The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 ...receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers.
Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and 11Craclopride to assess the availability of dopamine D2 receptors and with 18Ffluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function.
Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects.
Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.
Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its ...therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and (11)Craclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.
Type 1 diabetes (T1D) is the result of the selective destruction of the pancreatic β-cells by T cells of the immune system. Although spleen is a secondary lymphoid organ, it is also involved in the ...T1D pathogenesis. However, the alterations in a variety of cellular processes of this disease need to be further understood. We aimed to analyze the benefits of resveratrol, and its complexed form on diabetic complications in the spleen of rats. To this end, we investigated important enzymes of phosphoryl transfer network, and Na+, K+-ATPase activity. Wistar rats were divided into non-diabetic groups: Control, Ethanol, Resveratrol, Hydroxypropyl-β-cyclodextrin, Resveratrol-hydroxypropyl-β-cyclodextrin, and diabetic groups with the same treatments. Diabetes was induced by a single dose of 60 mg/kg of streptozocin intraperitoneally, and treatments by intragastric gavage once daily for 60 days. Hyperglycemia reduced creatine kinase activity, which was reversed by the administration of resveratrol. Na+, K+-ATPase activity was greatly affected, but it was reversed by resveratrol and resveratrol-hydroxypropyl-β-cyclodextrin. This suggest an energetic imbalance in the spleen of diabetic rats, and in case this also occurs in the diabetic patients, it is possible that resveratrol supplementation could be beneficial to the better functioning of the spleen in diabetic patients.
Methamphetamine is a popular drug of abuse that is neurotoxic to dopamine (DA) terminals when administered to laboratory animals. Studies in methamphetamine abusers have also documented significant ...loss of DA transporters (used as markers of the DA terminal) that are associated with slower motor function and decreased memory. The extent to which the loss of DA transporters predisposes methamphetamine abusers to neurodegenerative disorders such as Parkinsonism is unclear and may depend in part on the degree of recovery. Here we assessed the effects of protracted abstinence on the loss of DA transporters in striatum, in methamphetamine abusers using positron emission tomography and (11)Cd-threo-methylphenidate (DA transporter radioligand). Brain DA transporters in five methamphetamine abusers evaluated during short abstinence (<6 months) and then retested during protracted abstinence (12-17 months) showed significant increases with protracted abstinence (caudate, +19%; putamen, +16%). Although performance in some of the tests for which we observed an association with DA transporters showed some improvement, this effect was not significant. The DA transporter increases with abstinence could indicate that methamphetamine-induced DA transporter loss reflects temporary adaptive changes (i.e., downregulation), that the loss reflects DA terminal damage but that terminals can recover, or that remaining viable terminals increase synaptic arborization. Because neuropsychological tests did not improve to the same extent, this suggests that the increase of the DA transporters was not sufficient for complete function recovery. These findings have treatment implications because they suggest that protracted abstinence may reverse some of methamphetamine-induced alterations in brain DA terminals.
Considering that thiol-containing enzymes like kinases are critical for several metabolic pathways and energy homeostasis, we investigated the effects of cystine dimethyl ester and/or cysteamine ...administration on kinases crucial for energy metabolism in the kidney of Wistar rats. Animals were injected twice a day with 1.6 µmol/g body weight cystine dimethyl ester and/or 0.26 µmol/g body weight cysteamine from the 16th to the 20th postpartum day and euthanized after 12 hours. Pyruvate kinase, adenylate kinase, creatine kinase activities and thiol/disulfide ratio were determined. Cystine dimethyl ester administration reduced thiol/disulfide ratio and inhibited the kinases activities. Cysteamine administration increased the thiol/disulfide ratio and co-administration with cystine dimethyl ester prevented the inhibition of the enzymes. Regression between the thiol/disulfide ratio, and the kinases activities were significant. These results suggest that redox status may regulate energy metabolism in the rat kidney. If thiol-containing enzymes inhibition and oxidative stress occur in patients with cystinosis, it is possible that lysosomal cystine depletion may not be the only beneficial effect of cysteamine administration, but also its antioxidant and thiol-protector effect.
Methamphetamine is a popular and highly addictive drug of abuse that has raised concerns because it has been shown in laboratory animals to be neurotoxic to dopamine terminals. The authors evaluated ...if similar changes occur in humans and assessed if they were functionally significant.
Positron emission tomography scans following administration of (11)Cd-threo-methylphenidate (a dopamine transporter ligand) measured dopamine transporter levels (a marker of dopamine cell terminals) in the brains of 15 detoxified methamphetamine abusers and 18 comparison subjects. Neuropsychological tests were also performed to assess motor and cognitive function.
Methamphetamine abusers showed significant dopamine transporter reduction in the striatum (mean differences of 27.8% in the caudate and 21.1% in the putamen) relative to the comparison subjects; this reduction was evident even in abusers who had been detoxified for at least 11 months. Dopamine transporter reduction was associated with motor slowing and memory impairment.
These results provide evidence that methamphetamine at dose levels taken by human abusers of the drug leads to dopamine transporter reduction that is associated with motor and cognitive impairment. These results emphasize the urgency of alerting clinicians and the public of the long-term changes that methamphetamine can induce in the human brain.
Background: The aim of this retrospective long‐term split‐mouth study was to compare the periodontal conditions of sites treated with gingival‐augmentation procedures to untreated homologous ...contralateral sites over a long period of time (10 to 27 years).
Methods: Fifty‐five subjects with 73 sites (test group) lacking attached gingiva associated with recessions were treated by means of submarginal free gingival grafts (SMFGGs) and marginal free gingival grafts (MFGGs). The 73 contralateral homologous sites (control group), with or without recession and with or without attached gingiva, were not treated. Patients were recalled every 4 months during the follow‐up period (10 to 27 years). Clinical variables, including recession depth, amount of keratinized tissue (KT), and probing depth (PD), were measured in treated and untreated sites at baseline, at 1 year, and at the end of the follow‐up period.
Results: At the end of the follow‐up period, recession was reduced in all treated sites (1.5 ± 1.0 mm for SMFGG and 1.3 ± 0.9 mm for MFGG), whereas it was increased in the untreated sites (−0.7 ± 0.7 mm for SMFGG and −1.0 ± 0.5 mm for MFGG). In the treated sites, the increased KT remained quite stable during the follow‐up period. PD remained stable (1 mm) in the treated and untreated sites.
Conclusions: The sites treated with gingival‐augmentation surgery showed a tendency for coronal displacement of the gingival margin with a reduction in recession. The contralateral untreated sites showed a tendency for apical displacement of the gingival margin with an increase in the existing recessions.
Breast Specimen Orientation Molina, M. A.; Snell, S.; Franceschi, D. ...
Annals of surgical oncology,
02/2009, Letnik:
16, Številka:
2
Journal Article
Recenzirano
Lumpectomy specimens are commonly divided into six sides: superficial, deep, superior, inferior, medial, and lateral. Orienting stitches are placed on the specimen during surgery to allow ...reorientation by pathology. Despite those efforts, specimen disorientation may occur. The aim of this study was to assess the correlation in orientation between surgeons and pathologists. Lumpectomy specimens were routinely oriented. An additional Prolene suture was randomly placed by the surgeon on one side to be localized by pathology. The results were recorded and the disorientation rate calculated. Specimen size and presence of skin and/or muscle were also recorded. There were 122 lumpectomy specimens prospectively entered. Average specimen volume was 95.5 cm
3
. Twenty-four specimens had segments of skin or muscle. The additional sutures were evenly divided between the six sides. The overall disorientation rate was 31.1% (95% confidence interval, 23.1–40.2).The side-specific disorientation rates were 43%, 40%, 35%, 29%, 28%, and 14% for the deep, superficial, lateral, medial, superior, and inferior surfaces, respectively (no statistical difference). Presence of skin or muscle on the specimen did not contribute to better orientation. Specimen volumes, however, were highly associated with orientation. Specimens of <20 cm
3
had a disorientation rate of 78%, while larger specimen had a disorientation rate of 20% (
p
< .001). Specimen orientation with stitches placed on two surfaces is associated with a high disorientation rate. Better orientation techniques are necessary to minimize the specimen disorientation.
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