Showing papers by "Southern Illinois University School of Medicine published in 2005"
TL;DR: There is considerable evidence to suggest that the genetic and endocrine mechanisms that influence aging and longevity in mice may play a similar role in other mammalian species, including the human.
Abstract: The important role of IGF and insulin-related signaling pathways in the control of longevity of worms and insects is very well documented. In the mouse, several spontaneous or experimentally induced mutations that interfere with GH biosynthesis, GH actions, or sensitivity to IGF-I lead to extended longevity. Increases in the average life span in these mutants range from approximately 20-70% depending on the nature of the endocrine defect, gender, diet, and/or genetic background. Extended longevity of hypopituitary and GH-resistant mice appears to be due to multiple mechanisms including reduced insulin levels, enhanced insulin sensitivity, alterations in carbohydrate and lipid metabolism, reduced generation of reactive oxygen species, enhanced resistance to stress, reduced oxidative damage, and delayed onset of age-related disease. There is considerable evidence to suggest that the genetic and endocrine mechanisms that influence aging and longevity in mice may play a similar role in other mammalian species, including the human.
272 citations
TL;DR: Challenges and opportunities exist for appropriate drug delivery to the inner ear and for avoiding interference with the therapeutic efficacy of both categories of ototoxic drugs.
269 citations
TL;DR: Hematic MRI and ultrasound are both useful in identifying heavy fat accumulation associated with nonalcoholic fatty liver disease and are superior to ultrasound in detecting and quantifying minor degrees of fatty metamorphosis in the liver.
Abstract: Purpose:The value of MRI and ultrasound in quantifying hepatic steatosis is assessed and the results compared with those obtained by liver biopsies.Methods:A total of 38 patients undergoing hepatic biopsy for a variety of liver diseases were recruited for this study. Hepatic fat morphology and sever
262 citations
TL;DR: Findings suggest that Nr2e3 is a dual-function transcriptional regulator that acts in concert with Crx to promote and maintain the function of rod photoreceptors.
Abstract: Nr2e3 is an orphan nuclear receptor expressed specifically by retinal photoreceptor cells. Mutations in Nr2e3 result in syndromes characterized by excess blue cones and loss of rods: enhanced S-cone syndrome (ESCS) in humans and rd7 in mice. Using yeast two-hybrid screens with Nr2e3 as bait, the cone-rod homeobox protein Crx was identified as an interacting partner of Nr2e3. Immunoprecipitation assays confirmed this Nr2e3-Crx interaction and identified the DNA-binding domain of each protein as the interaction motif. Immunohistochemistry demonstrated that Crx and Nr2e3 are co-expressed by rod photoreceptors and their precursors. Chromatin immunoprecipitation assays on mouse retina demonstrated that Nr2e3 and Crx co-occupy the promoter/enhancer region of several rod and cone genes in the rod photoreceptor cells. The promoter/enhancer occupancy of Nr2e3 is Crx-dependent, suggesting that Nr2e3 is associated with photoreceptor gene targets by interacting with Crx. Transient transfection assays in HEK293 cells demonstrated that Nr2e3 enhances rhodopsin, but represses S- or M-cone opsin transcription when interacting with Crx. Quantitative real-time RT-PCR analysis on postnatal day 28 (P28) retina of the rd7 mouse, which lacks Nr2e3 protein, revealed an up-regulation of cone genes, but down-regulation of rod genes. Several mutant forms of human Nr2e3 identified from ESCS patients showed defects in interacting with Crx and/or in transcriptional regulatory function. Altogether, our findings suggest that Nr2e3 is a dual-function transcriptional regulator that acts in concert with Crx to promote and maintain the function of rod photoreceptors.
236 citations
TL;DR: A major role is suggested for the Akt/Foxo1 pathway in the regulation of longevity in rodents and an activated gluconeogenic pathway and increased fat metabolism may be involved in mediating the effects of reduced somatotropic and insulin signaling on longevity.
Abstract: Reduced IGF-I/insulin signaling and caloric restriction (CR) are known to extend the life span and delay age-related diseases. To address the interaction of these two interventions, we subjected normal (N) and long-lived GH receptor knockout (GHRKO) mice to CR for 20 months starting at weaning. We also used bovine GH transgenic (bGH Tg) mice, which overexpress GH and are short-lived and insulin resistant, for comparison. Circulating insulin and IGF-I levels were reduced by CR in N animals, whereas GHRKO animals exhibited very low insulin and undetectable IGF-I. Consistently, hepatic Akt phosphorylation was reduced by CR and was very low in GHRKO mice. bGH Tg mice exhibited increased active Akt. The forkhead box O1 (Foxo1) transcription factor was additively increased by CR and GHRKO at the mRNA level. However, Foxo1 protein levels were only elevated in GHRKO mice. The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha was increased at both gene and protein levels in GHRKO mice. N-CR and GHRKO mice also exhibited increased phosphorylated cAMP response element-binding protein and active p38 compared with the N ad libitum-fed mice, and the levels of these proteins were greatly diminished in bGH Tg mice. The protein levels of the deacetylase sirtuin 1 (SIRT1) were elevated in the two CR groups and, unexpectedly, also in bGH Tg mice. These results suggest a major role for the Akt/Foxo1 pathway in the regulation of longevity in rodents. An activated gluconeogenic pathway and increased fat metabolism may be involved in mediating the effects of reduced somatotropic and insulin signaling on longevity. These results also add to the evidence that targeted disruption of the GH receptor/GH-binding protein gene and CR act via overlapping, but distinct, mechanisms.
226 citations
TL;DR: It is demonstrated that both insulin and IGF-I enhance TRPV1-mediated membrane currents in heterologous expression systems and cultured dorsal root ganglion neurons, establishing a link between the insulin family of trophic factors and vanilloid receptors.
Abstract: Insulin and insulin-like growth factors (IGFs) maintain vital neuronal functions. Absolute or functional deficiencies of insulin or IGF-I may contribute to neuronal and vascular complications associated with diabetes. Vanilloid receptor 1 (also called TRPV1) is an ion channel that mediates inflammatory thermal nociception and is present on sensory neurons. Here we demonstrate that both insulin and IGF-I enhance TRPV1-mediated membrane currents in heterologous expression systems and cultured dorsal root ganglion neurons. Enhancement of membrane current results from both increased sensitivity of the receptor and translocation of TRPV1 from cytosol to plasma membrane. Receptor tyrosine kinases trigger a signaling cascade leading to activation of phosphatidylinositol 3-kinase (PI(3)K) and protein kinase C (PKC)-mediated phosphorylation of TRPV1, which is found to be essential for the potentiation. These findings establish a link between the insulin family of trophic factors and vanilloid receptors.
197 citations
TL;DR: The OPRS complements traditional evaluations by providing objective assessment of operative decision-making and technical skills and is useful in tracking resident development throughout postgraduate training and offers a structured means of certifying operative skills.
196 citations
TL;DR: Tumor resection alone did not provide adequate therapy for most children with OMS, and Adrenocorticotropic hormone, prednisone, and intravenous immunoglobulin were used with equal frequency, but ACTH was associated with the best early response.
170 citations
TL;DR: It is shown that TRPM8 is functionally downregulated by activation of protein kinase C (PKC) resulting in inhibition of membrane currents and increases in intracellular Ca2+ compared with upregulation of TRPV1 in cloned and native receptors.
Abstract: Transient receptor potential melastatin 8 (TRPM8) and transient receptor potential vanilloid 1 (TRPV1) are ion channels that detect cold and hot sensations, respectively. Their activation depolarizes the peripheral nerve terminals resulting in action potentials that propagate to brain via the spinal cord. These receptors also play a significant role in synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons. Here, we show that TRPM8 is functionally downregulated by activation of protein kinase C (PKC) resulting in inhibition of membrane currents and increases in intracellular Ca2+ compared with upregulation of TRPV1 in cloned and native receptors. Bradykinin significantly downregulates TRPM8 via activation of PKC in DRG neurons. Activation of TRPM8 or TRPV1 at first sensory synapse between DRG and DH neurons leads to a robust increase in frequency of spontaneous/miniature EPSCs. PKC activation blunts TRPM8- and facilitates TRPV1-mediated synaptic transmission. Significantly, downregulation is attributable to PKC-mediated dephosphorylation of TRPM8 that could be reversed by phosphatase inhibitors. These findings suggest that inflammatory thermal hyperalgesia mediated by TRPV1 may be further aggravated by downregulation of TRPM8, because the latter could mediate the much needed cool/soothing sensation.
164 citations
TL;DR: Findings in the present study are consistent with an age-related loss of glycinergic input, likely from vertical cells, and with findings from other sensory aging studies suggesting a selective age- related decrement in inhibitory amino acid neurotransmitter function.
Abstract: Age-related hearing loss frequently results in a loss in the ability to discriminate speech signals, especially in noise. This is attributable, in part, to a loss in temporal resolving power and ability to adjust dynamic range. Circuits in the adult dorsal cochlear nucleus (DCN) have been shown to preserve signal in background noise. Fusiform cells, major DCN output neurons, receive focused glycinergic inputs from tonotopically aligned vertical cells that also project to the ventral cochlear nucleus. Glycine-mediated inhibition onto fusiform cells results in decreased tone-evoked activity as intensity is increased at frequencies adjacent to characteristic frequency (CF). DCN output is thus shaped by glycinergic inhibition, which can be readily assessed in recordings from fusiform cells. Previous DCN studies suggest an age-related loss of markers for glycinergic neurotransmission. The present study postulated that response properties of aged fusiform cells would show a loss of inhibition, resembling conditions observed with glycine receptor blockade. The functional impact of aging was examined by comparing response properties from units meeting fusiform-cell criteria in young and aged rats. Fusiform cells in aged animals displayed significantly higher maximum discharge rates to CF tones than those recorded from young-adult animals. Fusiform cells of aged rats displayed significantly fewer nonmonotonic CF rate-level functions and an age-related change in temporal response properties. These findings are consistent with an age-related loss of glycinergic input, likely from vertical cells, and with findings from other sensory aging studies suggesting a selective age-related decrement in inhibitory amino acid neurotransmitter function.
160 citations
Journal Article•
TL;DR: Some of the basic strain and species differences in hearing are reviewed and how the acoustic environment affects different mammals is outlined.
Abstract: Hearing in laboratory animals is a topic that traditionally has been the domain of the auditory researcher. However, hearing loss and exposure to various environmental sounds can lead to changes in multiple organ systems, making what laboratory animals hear of consequence for researchers beyond those solely interested in hearing. For example, several inbred mouse strains commonly used in biomedical research (e.g., C57BL/6, DBA/2, and BALB/c) experience a genetically determined, progressive hearing loss that can lead to secondary changes in systems ranging from brain neurochemistry to social behavior. Both researchers and laboratory animal facility personnel should be aware of both strain and species differences in hearing in order to minimize potentially confounding variables in their research and to aid in the interpretation of data. Independent of genetic differences, acoustic noise levels in laboratory animal facilities can have considerable effects on the inhabitants. A large body of literature describes the nonauditory impact of noise on the biology and behavior of various strains and species of laboratory animals. The broad systemic effects of noise exposure include changes in endocrine and cardiovascular function, sleep-wake cycle disturbances, seizure susceptibility, and an array of behavioral changes. These changes are determined partly by species and strain; partly by noise intensity level, duration, predictability, and other characteristics of the sound; and partly by animal history and exposure context. This article reviews some of the basic strain and species differences in hearing and outlines how the acoustic environment affects different mammals.
TL;DR: Functional studies in primate visual cortex and preliminary studies in AI find coding changes suggestive of altered inhibitory processing in aged animals, and an age-related loss of normal adult GABA neurotransmission in AI would likely alter temporal coding properties and could contribute to the loss in speech understanding observed in the elderly.
TL;DR: Data increasingly support the concept that noradrenergic and serotonergic deficiencies contribute to seizure predisposition, and the antidepressants have the potential to overcome seizure predis position in epilepsy.
Journal Article•
TL;DR: Evidence supports the at-home use of topical salicylic acid and physician-administered cryotherapy for cutaneous warts and intralesional immunotherapy for nongenital warts may be an option for large or recalcitrant warts.
Abstract: Cutaneous warts are a common presenting complaint in children and adolescents. Common, plantar, or flat warts are cutaneous manifestations of the human papillomavirus. The treatment of warts poses a therapeutic challenge for physicians. No single therapy has been proven effective at achieving complete remission in every patient. As a result, many different approaches to wart therapy exist. These approaches are discussed to demonstrate the evidence supporting common therapies and provide a guideline for physicians. Evidence supports the at-home use of topical salicylic acid and physician-administered cryotherapy. Intralesional immunotherapy for nongenital cutaneous warts may be an option for large or recalcitrant warts.
TL;DR: It is demonstrated that the expression of the tumor suppressor gene PTEN has a significant inverse correlation with FAS expression in the case of prostate cancer in the clinical setting, and inhibition of the PTEN gene leads to the overexpression of FAS in vitro.
Abstract: Fatty acid synthase (FAS), a key enzyme of the fatty acid biosynthetic pathway, has been shown to be overexpressed in various types of human cancer and is, therefore, considered to be an attractive target for anticancer therapy. However, the exact mechanism of overexpression of the FAS gene in tumor cells is not well understood. In this report, we demonstrate that the expression of the tumor suppressor gene PTEN has a significant inverse correlation with FAS expression in the case of prostate cancer in the clinical setting, and inhibition of the PTEN gene leads to the overexpression of FAS in vitro. We also found that the combination of the expression status of these two genes is a better prognostic marker than either gene alone. Furthermore, our results indicate that the specific inhibition of FAS gene by siRNA leads to apoptosis of prostate tumor cells, and inhibition of PI 3-kinase pathway synergizes with FAS siRNA to enhance tumor cell death. These results provide a strong rationale for exploring the therapeutic use of an inhibitor of the PTEN signaling pathway in conjunction with the FAS siRNA to inhibit prostate tumor growth.
TL;DR: This intensive treatment regimen for head and neck cancer is feasible and effective in a multi-institutional setting and the total response rate was 85% at the primary site and 88% at nodal regions.
Abstract: Purpose To determine the feasibility of high-dose intra-arterial (IA) cisplatin and concurrent radiation therapy (RT) for head and neck squamous cell carcinoma in the multi-institutional setting (Multi-RADPLAT). Patients and Methods Eligibility included T4 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received cisplatin (150 mg/m2 IA with sodium thiosulfate 9 g/m2 intravenous [IV], followed by 12 g/m2 IV over 6 hours, weekly for 4 weeks) and concurrent RT (70 Gy, 2.0 Gy/fraction, daily for 5 days over 7 weeks). Between May 1997 and December 1999, 67 patients from three experienced and eight inexperienced centers were enrolled, of whom 61 were eligible for analysis. Results Multi-RADPLAT was feasible (ie, three or four infusions of IA cisplatin and full dose of RT) in 53 patients (87%). The complete response (CR) rate was 85% at the primary site and 88% at nodal regions, and the overall CR rate was 80%. At a median follow-up of 3.9 years for alive patients (range,...
TL;DR: The idea that vagus nerve stimulation enhances the neural plasticity that underlies recovery of function following brain damage and provides indirect support for the hypothesis that enhanced NE release may mediate the effect is supported.
Abstract: Intermittent, chronically delivered electrical stimulation of the vagus nerve (VNS) is an FDA-approved procedure for the treatment of refractory complex/partial epilepsy in humans. Stimulation of the vagus has also been shown to enhance memory storage processes in laboratory rats and human subjects. Recent evidence suggests that some of these effects of VNS may be due to the activation of neurons in the nucleus locus coeruleus resulting in the release of norepinephrine (NE) throughout the neuraxis. Because antagonism of NE systems has been shown to delay recovery of function following brain damage, it is possible that enhanced release of NE in the CNS may facilitate recovery of function. To evaluate this hypothesis the lateral fluid percussion injury (LFP) model of traumatic brain injury was used and a variety of motor and cognitive behavioral tests were employed to assess recovery in pre-trained stimulated, control, and sham-injured laboratory rats. Two hours following moderate LFP, vagus nerve stimulation (30.0-sec trains of 0.5 mA, 20.0 Hz, biphasic pulses) was initiated. Stimulation continued in each animal's home cage at 30-min intervals for a period of 14 days, with the exception of brief periods when the animals were disconnected for behavioral assessments. Motor behaviors were evaluated every other day following LFP and tests included beam walk, locomotor placing, and skilled forelimb reaching. In each measure an enhanced rate of recovery and /or level of final performance was observed in the VNS-LFP animals compared to nonstimulated LFP controls. Behavior in the Morris water maze was assessed on days 11-14 following injury. Stimulated LFP animals showed significantly shorter latencies to find the hidden platform than did controls. Despite these behavioral effects, neurohistological examination did not reveal significant differences in lesion extent, density of fluorojade positive neurons, reactive astrocytes or numbers of spared neurons in the CA3 subarea of the hippocampus, at least at the one time point studied 15 days post-injury. These results support the idea that vagus nerve stimulation enhances the neural plasticity that underlies recovery of function following brain damage and provides indirect support for the hypothesis that enhanced NE release may mediate the effect. Importantly, since VNS facilitated both the rate of recovery and the extent of motor and cognitive recovery, these findings suggest that electrical stimulation of the vagus nerve may prove to be an effective non-pharmacological treatment for traumatic brain injury.
TL;DR: In several of the clerkship performance measures, the PBL students performed significantly better, and in no circumstance did they perform worse than the STND students.
Abstract: Purpose To compare the characteristics and outcome data of students from a single institution with a two-track, problem based learning (PBL) and standard (STND) curriculum. Method PBL and STND students from nine graduating classes at Southern Illinois University School of Medicine were compared using common medical school performance outcomes (USMLE Step 1, USMLE Step 2, clerkship mean ratings, number of clerkship honors and remediation designations, and the senior clinical competency exam), as well as common admission and demographic variables. Results PBL students were older, and the cohort had a higher proportion of women. The two tracks had similar USMLE Step 1 and 2 mean scores and pass rates. Performance differences were significant for PBL students in two clerkships as well as in the clerkship subcategories of clinical performance, knowledge and clinical reasoning, and noncognitive behaviors. In addition, the proportion of PBL students earning honors was greater. Conclusions The traditional undergraduate educational outcomes for the PBL and STND students are very positive. In several of the clerkship performance measures, the PBL students performed significantly better, and in no circumstance did they perform worse than the STND students.
TL;DR: It was concluded that the dorsal cochlear nucleus (DCN) does not act as a simple feed-forward source of chronic tinnitus, and may also modify the experience of tinnitis, since the evidence ofTinnitus was enhanced by ipsilateral DCN ablation.
TL;DR: The difficulty of treating biofilm-associated infections may be attributed not only to the difficulty of eradicating the biofilm focus but also to the lack of susceptibility of cells disrupted from the biofilms to antimicrobial agents.
Abstract: Shed cells or disrupted parts of the biofilm may enter the circulation causing serious and very hard to treat biofilm-associated infections. The activity of antimicrobial agents against the shed cells/disrupted biofilms is largely unknown. We studied the in vitro susceptibility of intact and disrupted biofilms of thirty clinical isolates of methicillin-resistant and methicillin–susceptible Staphylococcus aureus (MRSA and MSSA) and Staphylococcus epidermidis to vancomycin, quinupristin/dalfopristin, and linezolid and compared it to that of the suspended (planktonic) cells. Bacteria in the disrupted biofilms were as resistant as those in the intact biofilms at the minimum inhibitory concentrations of the antibiotics. At higher concentrations, bacteria in the disrupted biofilms were significantly (P < 0.001) less resistant than those in the intact biofilms but more resistant than the planktonic cells. Quinupristin/dalfopristin showed the best activity against cells of the disrupted biofilms at concentrations above MICs and vancomycin, at 500 and 1,000 μg/ml, was significantly more active against the biofilms of MRSA and S. epidermidis The difficulty of treating biofilm-associated infections may be attributed not only to the difficulty of eradicating the biofilm focus but also to the lack of susceptibility of cells disrupted from the biofilm to antimicrobial agents.
TL;DR: Evaluated the efficacy and tolerability of topiramate as monotherapy using a dose‐controlled study design, finding that the former is more beneficial than the latter.
Abstract: Objectives To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design. Materials and methods We conducted a multinational, randomized, double-blind trial in adults and children (> or =6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to > or =2 lifetime unprovoked seizures, patients had to have one or two partial-onset seizures or generalized-onset tonic-clonic seizures in the 3-month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. Double-blind treatment continued until 6 months after the last patient was randomized. Results Kaplan-Meier survival analyses for time to first seizure (intent-to-treat, n = 470) favored 400 mg/day over 50 mg/day (P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference (P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure-free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day (P = 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively (P = 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures (P = 0.009) and in those with generalized-onset tonic-clonic seizures (P = 0.005). The most common dose-related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive-related adverse events were 2% in the 50-mg group and 7% in the 400-mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months. Conclusion Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step-wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage.
TL;DR: The characteristics of RTX‐induced responses in cells expressing native and cloned rat TRPV1, an ultrapotent agonist of RTX, are determined and it is revealed that whole‐cell currents are outwardly rectifying, but to a lesser extent than capsaicin‐induced currents.
Abstract: Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+ permeable non-selective cation channel activated by physical and chemical stimuli. Resiniferatoxin (RTX), an ultrapotent agonist of TRPV1, is under investigation for treatment of urinary bladder hyper-reflexia and chronic pain conditions. Here, we have determined the characteristics of RTX-induced responses in cells expressing native and cloned rat TRPV1. Whole-cell currents increase with repeated application of submaximal concentrations of RTX until a maximal response is attained and do not deactivate even after prolonged washout. Interestingly, the rate of activation and block by capsazepine of RTX-induced currents are significantly slower than for capsaicin-induced currents. RTX-induced whole-cell currents are outwardly rectifying, but to a lesser extent than capsaicin-induced currents. RTX-induced single channel currents exhibit multiple conductance states and outward rectification. The open probability (Po) of RTX-induced currents is higher at all potentials as compared to capsaicin-induced currents, which showed a strong voltage-dependent decrease at negative potentials. Single-channel kinetic analyses reveal that open-time distribution of RTX-induced currents can be fitted with three exponential components at negative and positive potentials. The areas of distribution of the longer open time constants are significantly larger than capsaicin-induced currents. The closed-time distribution of RTX-induced currents can be fitted with three exponential components as compared to capsaicin-induced currents, which require four exponential components. Current-clamp experiments reveal that low concentrations of RTX caused a slow and sustained depolarization beyond threshold while generating few action potentials. Concentrations of capsaicin required for the same extent of depolarization generated a significantly greater number of action potentials. These properties of RTX may play a role in its clinical usefulness.
TL;DR: This work shows an increase in numbers of newly generated cells and newborn neurons in the dentate gyrus of adult dwarf mice compared with normal mice using BrdU labeling and suggests that local/hippocampal IGF-I expression may have induced the increase in hippocampal neurogenesis.
Abstract: Neurogenesis occurs throughout adult life in the dentate gyrus of mammalian hippocampus and has been suggested to play an important role in cognitive function. Multiple trophic factors including IGF-I have been demonstrated to regulate hippocampal neurogenesis. Ames dwarf mice live considerably longer than normal animals and maintain physiological function at youthful levels, including cognitive function, despite a deficiency of circulating GH and IGF-I. Here we show an increase in numbers of newly generated cells [bromodeoxyuridine (BrdU) positive] and newborn neurons (neuronal nuclear antigen and BrdU positive) in the dentate gyrus of adult dwarf mice compared with normal mice using BrdU labeling. Despite the profound suppression of hippocampal GH expression, hippocampal IGF-I protein levels are up-regulated and the corresponding mRNAs are as high in Ames dwarf as in normal mice. Our results suggest that local/hippocampal IGF-I expression may have induced the increase in hippocampal neurogenesis, and increased neurogenesis might contribute to the maintenance of youthful levels of cognitive function during aging in these long-lived animals.
TL;DR: Selective and superselective neck dissection, which spare function and minimize morbidity, are viable therapeutic alternatives for patients with residual disease confined to 1 level after intra-arterial chemoradiation treatment, and possibly for other chemorodiation protocols.
Abstract: Objective To determine the efficacy of selective and superselective neck dissection for patients with bulky or residual nodal metastasis treated with concomitant intra-arterial cisplatin and radiotherapy. Design Prospective study. Setting University of Tennessee, Memphis. Patients A total of 240 patients with stage III or IV head and neck squamous cell carcinoma. Interventions Treatment with cisplatin, 150 mg/m2intra-arterially, and sodium thiosulfate, 9 g/m2intravenously, weekly for 4 weeks; and radiotherapy, 2 Gy per fraction per day, 5 times weekly, for a total of 68 to 74 Gy over 6 to 7 weeks. Main Outcome Measures Regional control, distant metastases, and overall survival for patients undergoing radical or modified radical neck dissection (n = 12), selective neck dissection (n = 65), and superselective neck dissection (levels II-III only) (n = 7). Results Among the total group of 240 patients, 106 neck dissections were performed on 84 patients who had bulky nodal disease. With a median follow-up of 58 months (range, 12-96 months), regional failure occurred in 11 (4.6%) of 240 patients: 2 (17%) of the 12 who had modified radical neck dissection, 3 (5%) of the 65 who had selective neck dissection, none of the 7 patients who had superselective neck dissection, and 6 (4%) of the 156 who had no neck dissection. The rates of overall survival and distant metastases were not significantly different among the 3 neck dissection subsets. Conclusion Selective and superselective neck dissection, which spare function and minimize morbidity, are viable therapeutic alternatives for patients with residual disease confined to 1 level after intra-arterial chemoradiation treatment, and possibly for other chemoradiation protocols.
TL;DR: Results indicate that CXCL10 expression accelerates the autoimmune process by enhancing the migration of Ag-specific lymphocytes to their target site, and in situ staining with H-2Db(NP396) tetramers revealed islet infiltration by NP-specific CD8 T cells in RIP-NP-CXCL 10 mice early after infection.
Abstract: During inflammation, chemokines are conductors of lymphocyte trafficking. The chemokine CXCL10 is expressed early after virus infection. In a virus-induced mouse model for type 1 diabetes, CXCL10 blockade abrogated disease by interfering with trafficking of autoaggressive lymphocytes to the pancreas. We have generated transgenic rat insulin promotor (RIP)-CXCL10 mice expressing CXCL10 in the beta cells of the islets of Langerhans to evaluate how bystander inflammation influences autoimmunity. RIP-CXCL10 mice have islet infiltrations by mononuclear cells and limited impairment of beta cell function, but not spontaneous diabetes. RIP-CXCL10 mice crossed to RIP-nucleoprotein (NP) mice expressing the NP of the lymphocytic choriomeningitis virus in the beta cells had massively accelerated type 1 diabetes after lymphocytic choriomeningitis virus infection. Mechanistically, we found a drastic increase in NP-specific, autoaggressive CD8 T cells in the pancreas after infection. In situ staining with H-2D(b)(NP(396)) tetramers revealed islet infiltration by NP-specific CD8 T cells in RIP-NP-CXCL10 mice early after infection. Our results indicate that CXCL10 expression accelerates the autoimmune process by enhancing the migration of Ag-specific lymphocytes to their target site.
TL;DR: Findings provide support for the notion that age is associated with diminished signal-to-noise coding by AI layer V neurons and are consistent with other research suggesting that GABAergic neurotransmission in AI may be compromised by aging.
Abstract: Advanced age is commonly associated with progressive cochlear pathology and central auditory deficits, collectively known as presbycusis. The present study examined central correlates of presbycusi...
Journal Article•
TL;DR: After the clinical breast examination is performed, the evaluation depends largely on the patient's age and examination characteristics, and the physician's experience in performing fine-needle aspiration.
Abstract: Palpable breast masses are common and usually benign, but efficient evaluation and prompt diagnosis are necessary to rule out malignancy. A thorough clinical breast examination, imaging, and tissue sampling are needed for a definitive diagnosis. Fine-needle aspiration is fast, inexpensive, and accurate, and it can differentiate solid and cystic masses. However, physicians must have adequate training to perform this procedure. Mammography screens for occult malignancy in the same and contralateral breast and can detect malignant lesions in older women; it is less sensitive in women younger than 40 years. Ultrasonography can detect cystic masses, which are common, and may be used to guide biopsy techniques. Tissue specimens obtained with core-needle biopsy allow histologic diagnosis, hormone-receptor testing, and differentiation between in situ and invasive disease. Core-needle biopsy is more invasive than fine-needle aspiration, requires more training and experience, and frequently requires imaging guidance. After the clinical breast examination is performed, the evaluation depends largely on the patient's age and examination characteristics, and the physician's experience in performing fine-needle aspiration.
TL;DR: All three of these newly discovered B7 proteins are differentially positioned at the maternal-fetal interface such that they could steer maternal leukocytes away from a harmful immune response and toward a favorable one.
Abstract: Placental trophoblast cells form a cellular barrier between the potentially immunogenic fetus and maternal leukocytes. Trophoblasts subvert maternal immunity by producing surface-bound and soluble factors that interact with maternal leukocytes. Here, we describe the distribution of three members of the expanding family of B7 immunomodulatory molecules: B7-DC, B7-H2, and B7-H3. B7-DC and B7-H3 inhibit antigen-stimulated lymphocyte activation while B7-H2 serves in a regulatory capacity, often promoting a Th2 immunophenotype. First trimester and term placentas, purified trophoblast cells, choriocarcinoma cell lines, and human umbilical vein endothelial cells were analyzed for B7 family RNA and protein expression. Transcripts and proteins for all three B7s were present throughout gestation but were differentially expressed within the trophoblast and the stroma. Whereas B7-DC was prominent on the syncytiotrophoblast of early placenta, it was absent from the trophoblast at term. In contrast, B7-H2 and B7-H3 were prominent on the extravillous trophoblast throughout gestation. Lastly, stromal cells, including macrophages and endothelial cells, differentially expressed B7-DC, B7-H2, and B7-H3, depending on gestational age. Thus, all three of these newly discovered B7 proteins are differentially positioned at the maternal-fetal interface such that they could steer maternal leukocytes away from a harmful immune response and toward a favorable one.
TL;DR: All methods used one filtration step, omitted time-consuming cleanup, but maintained clear peak resolution by HPLC, and can be used for quantitative screening of ginsenosides from roots and commercial ginseng preparations.
Abstract: Four methods were tested for extraction and recovery of six major ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1) found in roots of American ginseng (Panax quinquefolius): method A, sonication in 100% methanol (MeOH) at room temperature (rt); method B, sonication in 70% aqueous MeOH at rt; method C, water extraction (90 degrees C) with gentle agitation; and method D, refluxing (60 degrees C) in 100% MeOH. After 0.5-1 h, the samples were filtered and analyzed by high-performance liquid chromatography (HPLC)-UV. A second extraction by methods C and D was done, but 85-90% of ginsenosides were obtained during the first extraction. Lyophilization of extracts did not influence ginsenoside recovery. Method D resulted in the highest significant recoveries of all ginsenosides, except Rg1. Method C was the next most effective method, while method A resulted in the lowest ginsenoside recoveries. Method B led to similar recoveries as method C. All methods used one filtration step, omitted time-consuming cleanup, but maintained clear peak resolution by HPLC, and can be used for quantitative screening of ginsenosides from roots and commercial ginseng preparations.
TL;DR: It is concluded that the Rac1/NADPH oxidase pathway regulates p38 activation and TRPV1 expression which aids in the maintenance of peripheral neuron integrity and pain perception.
Abstract: Nerve growth factor (NGF) regulates the nociceptive properties of a subset of small diameter sensory neurons by increasing the expression of the heat-sensing transient receptor potential (TRP) channel, TRPV1. This action involves activation of the tyrosine kinase receptor (Trk) A/p38 MAPK pathway. Recent studies indicate that activation of TrkA promotes superoxide generation via NADPH oxidase. In this study, we determined whether the NADPH oxidase pathway is involved in NGF-stimulated TRPV1 expression using a rat pheochromocytoma 12 line and rat dorsal root ganglion neurons. Treatment of these cells with NGF (100 ng/mL) increased TRPV1 protein expression (approx. twofold) but not mRNA. This increase was mimicked by H2O2 and attenuated by catalase and inhibitors of NADPH oxidase. NGF stimulated NADPH oxidase activity, while 24 h exposure further increased expression of the Rac1 and gp91phox subunits of the holoenzyme. Inhibition of NADPH oxidase by transient transfection of a dominant negative Rac1 mutant (RacN17) plasmid blocked NGF-stimulated TRPV1 protein expression, while expression of a constitutively active Rac1 increased basal and NGF-stimulated TRPV1 levels. Inhibition of NADPH oxidase activity also attenuated NGF-dependent p38 MAPK activation. We conclude that the Rac1/NADPH oxidase pathway regulates p38 activation and TRPV1 expression which aids in the maintenance of peripheral neuron integrity and pain perception.