bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: a case report
Authors: Escobar Guillermo A , Robinson William A , Nydam Trevor L , Heiple Drew C , Weiss Glen J , Buckley Linda , Gonzalez Rene , McCarter Martin D
Published: January 2007

Background

Non-islet cell tumor induced hypoglycemia (NICTH) is a very rare phenomenon, but even more so in gastrointestinal stromal tumors. It tends to present in large or metastatic tumors, and can appear at any time in the progression of the disease. We present herein a case of NICTH in a GIST tumor and report an exon 9 mutation associated to it.

Case presentation

A thirty nine year-old man with a recurrent, metastatic gastrointestinal stromal tumor presented to the hospital with nausea, dizziness, loss of consciousness, and profound hypoglycemia (20 mg/dL). There was no evidence of factitious hypoglycemia. He was stabilized with a continuous glucose infusion and following selective vascular embolization, the patient underwent debulking of a multicentric 40 cm × 25 cm × 10 cm gastrointestinal stromal tumor. After resection, the patient became euglycemic and returned to his normal activities. Tumor analysis confirmed excessive production of insulin-like growth factor II m-RNA and the precursor protein, "big" insulin-like growth factor II. Mutational analysis also identified a rare, 6 bp tandem repeat insert (gcctat) at position 1530 in exon 9 of KIT.

Conclusion

Optimal management of gastrointestinal stromal tumor-induced hypoglycemia requires a multidisciplinary approach, and surgical debulking is the treatment of choice to obtain immediate symptom relief. Imatinib or combinations of glucocorticoids and growth hormone are alternative palliative strategies for symptomatic hypoglycemia. In addition, mutations in exon 9 of the tyrosine kinase receptor KIT occur in 11–20% of GIST and are often associated with poor patient outcomes. The association of this KIT mutation with non-islet cell tumor induced hypoglycemia has yet to be established.
Neglected isolated plantar dislocation of middle cuneiform : a case report
Authors: Verma Ashu , Sharma Vinod Kumar , Batra Sumit , Rohria Mahender Singh
Published: January 2007

Background

Four cases of plantar dislocation of middle cuneiform have been reported in the english literature. All of them were fresh cases and treated with open reduction. We are reporting a case of neglected plantar dislocation of middle cuneiform which was treated with excision.

Case presentation

A farmer presented with a painful plantar dislocation of middle cuneiform bone after 9 months of injury. The bone was deformed and was excised by a plantar incision. It resulted in painless foot with no disability.

Conclusion

The neglected plantar dislocated middle cuneiform bone becomes deformed due to repeated weight bearing. The gap gets filled with Fibrous tissue. Excision of the cuneiform gives good results.
Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NF-κB activation
Authors: Samant Rajeev S , Clark David W , Fillmore Rebecca A , Cicek Muzaffer , Metge Brandon J , Chandramouli Kondethimmana H , Chambers Ann F , Casey Graham , Welch Danny R , Shevde Lalita A
Published: January 2007

Background

Osteopontin (OPN), a secreted phosphoglycoprotein, has been strongly associated with tumor progression and aggressive cancers. MDA-MB-435 cells secrete very high levels of OPN. However metastasis-suppressed MDA-MB-435 cells, which were transfected with breast cancer metastasis suppressor 1 (BRMS1), expressed significantly less OPN. BRMS1 is a member of mSin3-HDAC transcription co-repressor complex and has been shown to suppress the metastasis of breast cancer and melanoma cells in animal models. Hence we hypothesized that BRMS1 regulates OPN expression.

Results

The search for a BRMS1-regulated site on the OPN promoter, using luciferase reporter assays of the promoter deletions, identified a novel NF-κB site (OPN/NF-κB). Electrophoretic mobility shift assays and chromatin immunoprecipitations (ChIP) confirmed this site to be an NF-κB-binding site. We also show a role of HDAC3 in suppression of OPNviaOPN/NF-κB.

Conclusion

Our results show that BRMS1 regulates OPN transcription by abrogating NF-κB activation. Thus, we identify OPN, a tumor-metastasis activator, as a crucial downstream target of BRMS1. Suppression of OPN may be one of the possible underlying mechanisms of BRMS1-dependent suppression of tumor metastasis.
Spot the match – wildlife photo-identification using information theory
Authors: Speed Conrad W , Meekan Mark G , Bradshaw Corey JA
Published: January 2007

Background

Effective approaches for the management and conservation of wildlife populations require a sound knowledge of population demographics, and this is often only possible through mark-recapture studies. We applied an automated spot-recognition program (I3S) for matching natural markings of wildlife that is based on a novel information-theoretic approach to incorporate matching uncertainty. Using a photo-identification database of whale sharks (Rhincodon typus) as an example case, the information criterion (IC) algorithm we developed resulted in a parsimonious ranking of potential matches of individuals in an image library. Automated matches were compared to manual-matching results to test the performance of the software and algorithm.

Results

Validation of matched and non-matched images provided a threshold IC weight (approximately 0.2) below which match certainty was not assured. Most images tested were assigned correctly; however, scores for the by-eye comparison were lower than expected, possibly due to the low sample size. The effect of increasing horizontal angle of sharks in images reduced matching likelihood considerably. There was a negative linear relationship between the number of matching spot pairs and matching score, but this relationship disappeared when using the IC algorithm.

Conclusion

The software and use of easily applied information-theoretic scores of match parsimony provide a reliable and freely available method for individual identification of wildlife, with wide applications and the potential to improve mark-recapture studies without resorting to invasive marking techniques.
Fluorine-18-l-Dihydroxyphenylalanine (18F-DOPA) Positron Emission Tomography as a Tool to Localize an Insulinoma or β-Cell Hyperplasia in Adult Patients
Authors: Kauhanen Saila , Seppänen Marko , Minn Heikki , Gullichsen Risto , Salonen Anna , Alanen Kalle , Parkkola Riitta , Solin Olof , Bergman Jörgen , Sane Timo , Salmi Jorma , Välimäki Matti , Nuutila Pirjo
Published: January 2007

Context and Objective: Fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) is a promising method in localizing neuroendocrine tumors. Recently, it has been shown to differentiate focal forms of congenital hyperinsulinism of infancy. The current study was set up to determine the potential of 18F-DOPA PET in identifying the insulin-secreting tumors or β-cell hyperplasia of the pancreas in adults.

Patients and Methods: We prospectively studied 10 patients with confirmed hyperinsulinemic hypoglycemia and presumed insulin-secreting tumor using 18F-DOPA PET. Anatomical imaging was performed with computed tomography (CT) and magnetic resonance imaging (MRI). All patients were operated on, and histological verification was available in each case. Semiquantitative PET findings in the pancreas using standardized uptake values were compared to standardized uptake values of seven consecutive patients with nonpancreatic neuroendocrine tumors.

Results: By visual inspection of 18F-DOPA PET images, it was possible in nine of 10 patients to localize the pancreatic lesion, subsequently confirmed by histological analysis. 18F-DOPA uptake was enhanced in six of seven solid insulinomas and in the malignant insulinoma and its hepatic metastasis. Two patients with β-cell hyperplasia showed increased focal uptake of 18F-DOPA in the affected areas. As compared to CT or MRI, 18F-DOPA PET was more sensitive in localizing diseased pancreatic tissue.

Conclusion: 18F-DOPA PET was useful in most patients with insulinoma and negative CT, MRI, and ultrasound results. In agreement with previous findings in infants, preoperative 18F-DOPA imaging seems to be a method of choice for the detection of β-cell hyperplasia in adults. It should be considered for the detection of insulinoma or β-cell hyperplasia in patients with confirmed hyperinsulinemic hypoglycemias when other diagnostic work-up is negative.
Biochemical Assessment of Paget's Disease of Bone
Authors: Shankar Subramanian , Hosking David J
Published: January 2007

Biochemical measurements of bone turnover provide an objective assessment of disease activity and the response to treatment. Alkaline phosphatase is the best characterized of the bone turnover markers and reflects the extent and activity of Paget's disease. However, in addition to bone-specific alkaline phosphatase (Bone ALP), there is also osteocalcin (OC) and procollagen type 1 N-terminal propeptide (P1NP) as formation markers. A variety of telopeptides (C-terminal telopeptide of type I collagen, [CTX], N-telopeptide of type I collagen [NTX]) or cross-link breakdown products of type 1 collagen can be used to assess bone resorption. Total alkaline phosphatase (Total ALP), Bone ALP, and P1NP all perform similarly in diagnosis and in evaluating the response to treatment, but the general availability, low interassay variation, and inexpensiveness of Total ALP makes it the best test for routine use. Measurement of the biological variability of the different markers in stable, untreated Paget's disease indicates how great a change (critical difference) is needed to define a true alteration in disease activity. Bone ALP, P1NP, and NTX show the highest therapy induced change/critical difference ratio during antiresorptive treatment. Some of the resorption markers show more complex changes in response to treatment. Pyridinoline (PYD) or deoxypyridinoline (DPD) cross-links of type 1 collagen are excreted in urine either as free or as peptide bound moieties, but it is the latter which decrease by the greatest amount in response to bisphosphonate therapy. Newly formed type 1 collagen contains an aspartyl-glycine motif (αCTX), which undergoes spontaneous isoaspartyl formation to βCTX as the bone ages. In untreated Paget's disease, the αCTX is raised proportionately more (16-fold) than βCTX (3-fold) and decreases in response to bisphosphonate therapy to a greater extent than βCTX (measured in the sCTX assay). As bisphosphonates have become more potent, the aim of treatment has shifted toward the achievement of a rate of bone turnover in the lower part of the reference range. This is important because the duration of remission of disease activity is strongly determined by the post treatment nadir bone turnover.
Contribution of Genetic Factors to the Pathogenesis of Paget's Disease of Bone and Related Disorders
Authors: Lucas Gavin JA , Daroszewska Anna , Ralston Stuart H
Published: January 2007

Paget's disease of bone (PDB) is a common condition with a strong genetic component that is characterized by focal increases in bone turnover, leading to bone deformity, pathological fractures, and various other complications. Several rare disorders have also been described that show phenotypic overlap with PDB. Genome-wide searches have identified several susceptibility loci for PDB and PDB-like disorders, and mutations that cause these disorders have now been identified in four genes, all of which are involved in the RANK-NF-κB signaling pathway. Mutations in SQSTM1, which encodes an important scaffold protein in this pathway, have been found to be a common cause of classical PDB. Thus far, all disease-causing mutations in SQSTM1 affect the ubiquitin-associated (UBA) domain of the gene product and cause loss of ubiquitin binding. The rare PDB-like disorders of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by duplication mutations in exon 1 of the TNFRSF11A gene, which encodes the RANK receptor. This gene does not seem to be involved in the pathogenesis of classical PDB. Inactivating mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB, and TNFRSF11B polymorphisms seem to increase the risk of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and frontotemporal dementia (IBMPFD) is caused by mutations in the VCP gene, which is involved in regulating I-κB degradation by the proteasome. The disease-causing mutations in VCP cluster in and around a domain involved in ubiquitin binding. Whereas SQSTM1 has emerged as an important gene for classical PDB, most kindreds with familial PDB do not carry SQSTM1 mutations, indicating that additional genes for PDB remain to be discovered. In light of the molecular defects that have been identified thus far, it seems likely that these genes will also be involved in the RANK-NF-κB signaling pathway or its interactions with the ubiquitin-proteasome system.
Medical Therapy in Adults With Fibrous Dysplasia of Bone
Authors: Chapurlat Roland D
Published: January 2007

In open studies, bisphosphonate therapy (pamidronate, alendronate) reduced bone pain associated with fibrous dysplasia of bone and was associated to some radiological improvement. Calcium, vitamin D, and phosphorus supplements may be useful in patients with deficiency. We are awaiting results from controlled trials testing bisphosphonates.

Introduction: Fibrous dysplasia of bone (FD), a rare disease caused by osteoblastic lineage differentiation defects, is associated with bone pain, fracture, and bone deformity, but few therapeutic options are available.

Materials and Methods: We reviewed published data on the treatment of FD with bisphosphonates (pamidronate, alendronate), calcium, vitamin D, and phosphorus. We also present new results on FD therapy with a more potent bisphosphonate, zoledronic acid, given intravenously at the dose of 4 mg every 6 months.

Results: Pamidronate therapy, given intravenously every 6 months at a dose of 180 mg in adults, relieved bone pain, decreased bone resorption, and improved the radiological aspect (filling of lytic lesions and/or thickening of cortices) in ∼50% of patients. BMD in affected sites was also significantly increased after pamidronate treatment. Those results have been obtained only in open studies, without controls, by several research groups. In a series of nine patients on long-term pamidronate treatment, but resisting to this medication and switched to intravenous zoledronic acid, no substantial improvement was observed. There is some biological rationale supporting the use of calcium and vitamin D in patients with deficiency to improve FD lesions by limiting secondary hyperparathyroidism. Phosphorus supplementation may prevent mineralization defects in those patients who have both FD and renal phosphate wasting. However, we are lacking clinical evidence for the efficacy of such supplements.

Conclusions: Bisphosphonate treatment reduces increased osteoclastic activity in FD and probably improves bone pain, but their use should be better studied in randomized controlled trials.
FGF23 Concentrations Vary With Disease Status in Autosomal Dominant Hypophosphatemic Rickets
Authors: Imel Erik A , Hui Siu L , Ecibs Michael J
Published: January 2007

We measured FGF23 concentrations in subjects with ADHR. FGF23 and serum phosphate correlated positively in controls and negatively in subjects with ADHR. Elevated FGF23 concentrations were associated with lower phosphate values. The variable phenotype in ADHR may be caused by fluctuations in FGF23.

Introduction: Autosomal dominant hypophosphatemic rickets (ADHR) is a rare disorder of phosphaturia, hypophosphatemia, inappropriately low/normal calcitriol, and rickets/osteomalacia. ADHR is caused by mutations in a circulating peptide, fibroblast growth factor 23 (FGF23). We present the first report of FGF23 concentrations in subjects with ADHR. The aim was to test the hypotheses that subjects with ADHR have elevated FGF23 concentrations and that FGF23 concentrations are associated with disease severity.

Materials and Methods: This was an observational study at a tertiary referral center. Subjects were from three kindreds with FGF23 mutations causing ADHR (n = 42). Controls were participants from these families without mutations (n = 55). Fasting blood and urine samples were obtained. Biochemistries were determined, and FGF23 concentrations were measured using two ELISAs.

Results: Three cases are presented illustrating activity of disease and FGF23 concentrations. One case shows persistent hypophosphatemia and elevation of FGF23 concentrations, whereas another shows remission of hypophosphatemia corresponding to a decrease in previously elevated FGF23 concentrations. Overall cross-sectional group differences were nonsignificant for serum phosphate and FGF23 concentrations. C-terminal FGF23 concentration in controls was 61.0 ± 28.6 (SD) RU/ml (median, 52.5 RU/ml), and in subjects with mutations was 148.8 ± 374.5 RU/ml (median, 63.1 RU/ml). Mean intact FGF23 concentration in controls was 44.7 ± 14.9 pg/ml (median, 40.4 pg/ml), and in subjects with mutations was 83.2 ± 233.0 pg/ml (median, 39.0 pg/ml). C-terminal FGF23 concentrations were at least +2 SD in 10/42(24%), and intact FGF23 concentrations were at least +2 SD in 3/34(9%). Phosphate correlated positively with C-terminal and intact FGF23 in both controls and in subjects with mutations with phosphate >2.5 mg/dl but correlated significantly negatively with C-terminal and intact FGF23 in ADHR subjects with phosphate ≤2.5 mg/dl.

Conclusions: Elevated FGF23 concentrations are associated with hypophosphatemia in ADHR, and remission of the phenotype is associated with lower FGF23 concentrations. FGF23 has an opposite relationship with phosphate in ADHR compared with controls. We conclude that ADHR symptoms and disease severity likely fluctuate with FGF23 concentrations.
Functional Involvement of PHOSPHO1 in Matrix Vesicle–Mediated Skeletal Mineralization
Authors: Roberts Scott , Narisawa Sonoko , Harmey Dympna , Millán José Luis , Farquharson Colin
Published: January 2007

PHOSPHO1 is a phosphatase highly expressed in bone. We studied its functional involvement in mineralization through the use of novel small molecule inhibitors. PHOSPHO1 expression was present within matrix vesicles, and inhibition of enzyme action caused a decrease in the ability of matrix vesicles to calcify.

Introduction: The novel phosphatase, PHOSPHO1, belongs to the haloacid dehalogenase superfamily of hydrolases and is capable of cleaving phosphoethanolamine (PEA) and phosphocholine to generate inorganic phosphate. Our aims in this study were to examine the expression of PHOSPHO1 in murine mineralizing cells and matrix vesicles (MV) and to screen a series of small-molecule PHOSPHO1-specific inhibitors for their ability to pharmacologically inhibit the first step of MV-mediated mineralization.

Materials and Methods: q-PCR and immunohistochemistry were used to study the expression and localization profiles of PHOSPHO1. Inhibitors of PHOSPHO1's PEA hydrolase activity were discovered using high-throughput screening of commercially available chemical libraries. To asses the efficacy of these inhibitors to inhibit MV mineralization, MVs were isolated from TNAP-deficient (Akp2−/−) osteoblasts and induced to calcify in their presence.

Results: q-PCR revealed a 120-fold higher level of PHOSPHO1 expression in bone compared with a range of soft tissues. The enzyme was immunolocalized to the early hypertrophic chondrocytes of the growth plate and to osteoblasts of trabecular surfaces and infilling primary osteons of cortical bone. Isolated MVs also contained PHOSPHO1. PEA hydrolase activity was observed in sonicated MVs from Akp2−/− osteoblasts but not intact MVs. Inhibitors to PHOSPHO1 were identified and characterized. Lansoprazole and SCH202676 inhibited the mineralization of MVs from Akp2−/− osteoblasts by 56.8% and 70.7%, respectively.

Conclusions: The results show that PHOSPHO1 localization is restricted to mineralizing regions of bone and growth plate and that the enzyme present within MVs is in an active state, inhibition of which decreases the capacity of MVs to mineralize. These data further support our hypothesis that PHOSPHO1 plays a role in the initiation of matrix mineralization.
Goal-Related Activity in Hippocampal Place Cells
Authors: Hok Vincent , Lenck-Santini Pierre-Pascal , Roux Sébastien , Save Etienne , Muller Robert U. , Poucet Bruno
Published: January 2007

Place cells are hippocampal neurons whose discharge is strongly related to a rat's location in its environment. The existence of place cells has led to the proposal that they are part of an integrated neural system dedicated to spatial navigation, an idea supported by the discovery of strong relationships between place cell activity and spatial problem solving. To further understand such relationships, we examined the discharge of place cells recorded while rats solved a place navigation task. We report that, in addition to having widely distributed firing fields, place cells also discharge selectively while the hungry rat waits in an unmarked goal location to release a food pellet. Such firing is not duplicated in other locations outside the main firing field even when the rat's behavior is constrained to be extremely similar to the behavior at the goal. We therefore propose that place cells provide both a geometric representation of the current environment and a reflection of the rat's expectancy that it is located correctly at the goal. This on-line feedback about a critical aspect of navigational performance is proposed to be signaled by the synchronous activity of the large fraction of place cells active at the goal. In combination with other (prefrontal) cells that provide coarse encoding of goal location, hippocampal place cells may therefore participate in a neural network allowing the rat to plan accurate trajectories in space.
Generation of Distinct Types of Periglomerular Olfactory Bulb Interneurons during Development and in Adult Mice: Implication for Intrinsic Properties of the Subventricular Zone Progenitor Population
Authors: De Marchis Silvia , Bovetti Serena , Carletti Barbara , Hsieh Yi-Chun , Garzotto Donatella , Peretto Paolo , Fasolo Aldo , Puche Adam C. , Rossi Ferdinando
Published: January 2007

The subventricular zone (SVZ) of the lateral ventricle develops from residual progenitors of the embryonic lateral ganglionic eminence (LGE) and maintains neurogenic activity throughout life. Precursors from LGE/SVZ migrate to the olfactory bulb (OB) where they differentiate into local interneurons, principally in the granule layer and glomerular layer (GL). Byin situdye labeling, we show that neonatal and adult SVZ progenitors differentially contribute to neurochemically distinct types of periglomerular interneurons in the GL. Namely, calbindin-positive periglomerular cells are preferentially generated during early life, whereas calretinin- and tyrosine hydroxylase-expressing neurons are mainly produced at later ages. Furthermore, homochronic/heterochronic transplantation demonstrates that progenitor cells isolated from the LGE or SVZ at different stages (embryonic day 15 and postnatal days 2 and 30) engraft into the SVZ of neonatal or adult mice, migrate to the OB, and differentiate into local interneurons, including granule and periglomerular cells as well as other types of interneurons. The total number of integrated cells and the relative proportion of granule or periglomerular neurons change, according to the donor age, whereas they are weakly influenced by the recipient age. Analysis of the neurochemical phenotypes acquired by transplanted cells in the GL shows that donor cells of different ages also differentiate according to their origin, regardless of the host age. This suggests that progenitor cells at different ontogenetic stages are intrinsically directed toward specific lineages. Neurogenic processes occurring during development and in adult OB are not equivalent and produce different types of periglomerular interneurons as a consequence of intrinsic properties of the SVZ progenitors.
A Single Amino Acid Substitution (Cys249Trp) in Crb1 Causes Retinal Degeneration and Deregulates Expression of Pituitary Tumor Transforming GenePttg1
Authors: van de Pavert Serge A. , Meuleman Jan , Malysheva Anna , Aartsen Wendy M. , Versteeg Inge , Tonagel Felix , Kamphuis Willem , McCabe Chris J. , Seeliger Mathias W. , Wijnholds Jan
Published: January 2007

Different mutations in the human Crumbs homolog-1 (CRB1) gene cause a variety of retinal dystrophies, such as Leber congenital amaurosis, early onset retinitis pigmentosa (e.g., RP12), RP with Coats-like exudative vasculopathy, and pigmented paravenous retinochoroidal atrophy. Loss of Crb1 leads to displaced photoreceptors and focal degeneration of all neural layers attributable to loss of adhesion between photoreceptors and Müller glia cells. To gain insight into genotype–phenotype relationship, we generatedCrb1C249Wmice that harbor an amino acid substitution (Cys249Trp) in the extracellular sixth calcium-binding epidermal growth factor domain of Crb1. Our analysis showed that Crb1C249Was wild-type protein trafficked to the subapical region adjacent to adherens junctions at the outer limiting membrane (OLM). Hence, these data suggest correct trafficking of the corresponding mutant CRB1 in RP12 patients.Crb1C249Wmice showed loss of photoreceptors in the retina, relatively late compared with mice lacking Crb1. Scanning laser ophthalmoscopy revealed autofluorescent dots that presumably represent layer abnormalities after OLM disturbance. Gene expression analyses revealed lower levels of pituitary tumor transforming gene 1 (Pttg1) transcripts inCrb1C249W/−knock-in andCrb1−/−knock-out compared with control retinas. Exposure to white light decreased levels ofPttg1inCrb1mutant retinas. We hypothesize deregulation ofPttg1expression attributable to a C249W substitution in the extracellular domain of Crb1.
Cortical Discrimination of Complex Natural Stimuli: Can Single Neurons Match Behavior?
Authors: Wang Le , Narayan Rajiv , Graña Gilberto , Shamir Maoz , Sen Kamal
Published: January 2007

A central finding in many cortical areas is that single neurons can match behavioral performance in the discrimination of sensory stimuli. However, whether this is true for natural behaviors involving complex natural stimuli remains unknown. Here we use the model system of songbirds to address this problem. Specifically, we investigate whether neurons in field L, the homolog of primary auditory cortex, can match behavioral performance in the discrimination of conspecific songs. We use a classification framework based on the (dis)similarity between single spike trains to quantify neural discrimination. We use this framework to investigate the discriminability of single spike trains in field L in response to conspecific songs, testing different candidate neural codes underlying discrimination. We find that performance based on spike timing is significantly higher than performance based on spike rate and interspike intervals. We then assess the impact of temporal correlations in spike trains on discrimination. In contrast to widely discussed effects of correlations in limiting the accuracy of a population code, temporal correlations appear to improve the performance of single neurons in the majority of cases. Finally, we compare neural performance with behavioral performance. We find a diverse range of performance levels in field L, with neural performance matching behavioral accuracy only for the best neurons using a spike-timing-based code.
Functional Heterogeneity of Retinal Dopaminergic Neurons Underlying Their Multiple Roles in Vision
Authors: Zhang Dao-Qi , Zhou Tong-Rong , McMahon Douglas G.
Published: January 2007

Dopaminergic neurons play key roles in the CNS, mediating basic mechanisms of vision, movement, motivation, and mood. The most accessible dopaminergic neurons of the vertebrate CNS are the dopaminergic amacrine cells of the retina. Here, we have characterized the intrinsic neural activity, synaptic input, and light responses of retinal dopaminergic neuronsin situ, using targeted electrophysiological recordings of fluorescent neurons inTH::RFP (tyrosine hydroxylase gene promoter::red fluorescent protein) transgenic mice. Dopaminergic amacrine cells exhibit two classes of intrinsic bursting in the dark, shaped by inhibitory synaptic inputs, and two classes of light responses, ON-transient and ON-sustained, as well as light-independent activity, tuned to mediate specific dopaminergic functions in vision. The functional heterogeneity revealed in dopaminergic amacrine cells provides a cellular basis for the multiple roles of dopaminergic amacrine neurons in vision and is likely a general property of dopaminergic neurons throughout the CNS.
The Cationic Amino Acid Transporters CAT1 and CAT3 Mediate NMDA Receptor Activation-Dependent Changes in Elaboration of Neuronal Processes via the Mammalian Target of Rapamycin mTOR Pathway
Authors: Huang Yunfei , Kang Bingnan N. , Tian Jing , Liu Yi , Luo Hongbo R. , Hester Lynda , Snyder Solomon H.
Published: January 2007

Neuronal activity influences protein synthesis and neuronal growth. Availability of nutrients, especially leucine and arginine, regulates the mammalian target of rapamycin (mTOR) pathway that controls cell growth. We show that NMDA receptor activation markedly reduces arginine transport by decreasing surface expression of the cationic amino acid transporters (CAT) 1 and 3. Depletion of CAT1 and CAT3 by RNA interference blocks influences of NMDA receptor activation on the mTOR pathway and neuronal process formation. Thus, the CATs mediate influences of NMDA receptor activation on the mTOR pathway that regulates neuronal processes.
The RNA-Binding Protein HuD Binds Acetylcholinesterase mRNA in Neurons and Regulates its Expression after Axotomy
Authors: Deschênes-Furry Julie , Mousavi Kambiz , Bolognani Federico , Neve Rachael L. , Parks Robin J. , Perrone-Bizzozero Nora I. , Jasmin Bernard J.
Published: January 2007

After axotomy, expression of acetylcholinesterase (AChE) is greatly reduced in the superior cervical ganglion (SCG); however, the molecular events involved in this response remain unknown. Here, we first examined AChE mRNA levels in the brain of transgenic mice that overexpress human HuD. Bothin situhybridization and reverse transcription-PCR demonstrated that AChE transcript levels were increased by more than twofold in the hippocampus of HuD transgenic mice. Additionally, direct interaction between the HuD transgene product and AChE mRNA was observed. Next, we examined the role of HuD in regulating AChE expression in intact and axotomized rat SCG neurons. After axotomy of the adult rat SCG neurons, AChE transcript levels decreased by 50 and 85% by the first and fourth day, respectively.In vitromRNA decay assays indicated that the decrease in AChE mRNA levels resulted from changes in the stability of presynthesized transcripts. A combination of approaches performed using the region that directly encompasses an adenylate and uridylate (AU)-rich element within the AChE 3′-untranslated region demonstrated a decrease in RNA–protein complexes in response to axotomy of the SCG and, specifically, a decrease in HuD binding. After axotomy, HuD transcript and protein levels also decreased. Using a herpes simplex virus construct containing the human HuD sequence to infect SCG neuronsin vivo, we found that AChE and GAP-43 mRNA levels were maintained in the SCG after axotomy. Together, the results of this study demonstrate that AChE expression in neurons of the rat SCG is regulated via post-transcriptional mechanisms that involve the AU-rich element and HuD.
Astrocyte and Muscle-Derived Secreted Factors Differentially Regulate Motoneuron Survival
Authors: Taylor Anna R. , Gifondorwa David J. , Newbern Jason M. , Robinson Mac B. , Strupe Jane L. , Prevette David , Oppenheim Ronald W. , Milligan Carolanne E.
Published: January 2007

During development, motoneurons (MNs) undergo a highly stereotyped, temporally and spatially defined period of programmed cell death (PCD), the result of which is the loss of 40–50% of the original neuronal population. Those MNs that survive are thought to reflect the successful acquisition of limiting amounts of trophic factors from the target. In contrast, maturation of MNs limits the need for target-derived trophic factors, because axotomy of these neurons in adulthood results in minimal neuronal loss. It is unclear whether MNs lose their need for trophic factors altogether or whether, instead, they come to rely on other cell types for nourishment. Astrocytes are known to supply trophic factors to a variety of neuronal populations and thus may nourish MNs in the absence of target-derived factors. We investigated the survival-promoting activities of muscle- and astrocyte-derived secreted factors and found that astrocyte-conditioned media (ACM) was able to save substantially more motoneuronsin vitrothan muscle-conditioned media (MCM). Our results indicate that both ACM and MCM are significant sources of MN trophic supportin vitroandin ovo, but only ACM can rescue MNs after unilateral limb bud removal. Furthermore, we provide evidence suggesting that MCM facilitates the death of a subpopulation of MNs in a p75NTR- and caspase-dependent manner; however, maturation in ACM results in MN trophic independence and reduced vulnerability to this negative, pro-apoptotic influence from the target.
Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1
Authors: Wang Ji-Wu , Imai Yuzuru , Lu Bingwei
Published: January 2007

Aberrant phosphorylation of tau is associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular mechanisms by which tau phosphorylation is regulated under normal and disease conditions are not well understood. Microtubule affinity regulating kinase (MARK) and PAR-1 have been identified as physiological tau kinases, and aberrant phosphorylation of MARK/PAR-1 target sites in tau has been observed in AD patients and animal models. Here we show that phosphorylation of PAR-1 by the tumor suppressor protein LKB1 is required for PAR-1 activation, which in turn promotes tau phosphorylation inDrosophila. Diverse stress stimuli, such as high osmolarity and overexpression of the human β-amyloid precursor protein, can promote PAR-1 activation and tau phosphorylation in an LKB1-dependent manner. These results reveal a new function for the tumor suppressor protein LKB1 in a signaling cascade through which the phosphorylation and function of tau is regulated by diverse signals under physiological and pathological conditions.
Tolerability and effectiveness of fluoxetine, metformin and sibutramine in reducing anthropometric and metabolic parameters in obese patients
Authors: Guimarães Camila , Pereira Leonardo R.L. , Iucif Júnior Nélson , Cesarino Evandro José , Almeida Carlos A.N. de , Carvalho Dermeval de , Queiroz Regina H.C.
Published: January 2007

The aim of this study is to assess the effects of sibutramine (S) 15 mg/day, fluoxetine (F) 60 mg/day, and metformin (M) 1,700 mg/day, as an adjunct therapy to a 1,500 kcal/day diet, in reducing anthropometric and metabolic parameters. S (n= 8), F (n= 9), and M (n= 8) were compared to placebo (n= 10) in 35 obese patients in a 90-day trial. Side effects were also studied during the treatment. The data demonstrated that F therapy resulted in a greater average reduction in BMI (11.0%), weight (10.0%), abdominal circumference (11.0%) and %fatty-tissue (12.8). An elevation in HDL-cholesterol (25.8%) and a reduction in average triglyceride levels (28.3%) were also shown. S presented a 7.91% reduction in the abdominal circumference and a 9.65 reduction in %fatty-tissue was also found. M group presented reductions in BMI (4.03%), waist circumference (6.92%), HOMA (23.5%) and blood pressure (6.08% in systolic and 2.08% in diastolic). In general, the three drugs can be considered well tolerated. We concluded that F and S demonstrated a greater mean reduction in anthropometric and metabolic parameters when compared to M, however all of them are useful for that purpose, when the subjects’ characteristics are considered.
Gasto energético de repouso medido vs. estimado e relação com a composição corporal de mulheres
Authors: Fett Carlos A. , Fett Waléria C.R. , Marchini Julio S.
Published: January 2007

OBJETIVOS: Medir o gasto energético de repouso (GER, kcal/d), comparar as equações de predição disponíveis na literatura e associar a composição corporal. MÉTODOS: Vinte e oito sedentárias foram voluntárias [peso: 79 ± 12 kg; estatura: 164 ± 5 cm; idade: 36 ± 11 anos; índice de massa corporal (IMC): 29 ± 4 kg/m²]. A composição corporal foi estimada por antropometria, o GER foi medido por calorimetria indireta e estimado pelas principais equações da literatura. Foram desenvolvidas equações para estimativa do GER sendo a melhor a GER-Nosso. RESULTADOS: Diferentes tempos de coleta produziram resultados similares para o GER medido. O GER estimado pelas fórmulas de Harris & Benedict, FAO/WHO/UNO somente peso e peso mais altura, Schofield e GER-Nosso foram estatisticamente iguais ao GER medido. As equações do Siervo & Falconi, Schofield e Henry & Rees não foram correlacionadas ao GER medido. O melhor preditor isolado do GER foi a massa corporal e a melhor associação quando ajustado por unidade (kg) foi a massa magra. A equação desenvolvida no presente trabalho foi: GER(kcal/d)= 21837 - 14,448 * Peso(kg) + 54,963 * Massa Magra(kg) - 9,341 * Estatura(cm) - 4,349 * Idade(anos) - 19753 * Densidade Corporal(g/ml). CONCLUSÃO: As equações de predição do GER podem induzir a erros de predição e parecem ser população-específicas. O melhor resultado de predição foi para fórmula desenvolvida com os dados antropométricos das voluntárias (medido= 1617 ± 237 kcal/d; GER-Nosso= 1616 ± 167 kcal/d).
Resposta divergente da testosterona e do cortisol séricos em atletas masculinos após uma corrida de maratona
Authors: França Sheyla Carla A. , Barros Neto Turíbio Leite , Agresta Marisa Cury , Lotufo Renato Fraga M. , Kater Claudio E.
Published: January 2007

O exercício físico altera a homeostase, pois requer rápida mobilização de fontes metabólicas. Neste estudo, analisamos a resposta dos níveis séricos de testosterona (T) e cortisol (C) e das enzimas de desgaste muscular CK, CKMB e LDH, em 20 atletas masculinos sadios (25 a 40 anos), participantes de uma maratona (42,2 km). Coletas de sangue venoso foram feitas em 3 períodos: (i) pela manhã, 48 h antes da maratona (controle), (ii) logo após o término da corrida (final) e (iii) na manhã seguinte, 20 h após a realização da prova (recuperação). Ao final, T estava significantemente mais baixa (de 673 para 303 ng/dl) e C mais elevado (de 20,3 para 42,5 µg/dl) que no período controle. Na recuperação, ambos praticamente retornaram aos níveis basais. CK, CKMB e LDH estavam significantemente mais elevadas ao final da corrida e mais ainda na recuperação (exceto a CKMB), caracterizando o desgaste muscular. Enquanto CK e LDH apresentaram significante correlação negativa com a T (-0,412 e -0,546, respectivamente), CKMB correlacionou-se positivamente com o C (0,4521). Concluímos que a correlação inversa entre T e C, e o comportamento das enzimas CK, CKMB e LDH, permite comprovar que uma corrida de maratona causa intenso stress físico, provocando desequilíbrio hormonal e lesão celular severa.
MicroRNAs: nova classe de reguladores gênicos envolvidos na função endócrina e câncer
Authors: Ricarte Filho Júlio C.M. , Kimura Edna Teruko
Published: January 2007

MicroRNAs (miRNAs) representam uma nova classe de RNAs endógenos de ~22 nucleotídeos, que atuam como silenciadores pós-transcricionais, inibindo a tradução de RNAs mensageiros-alvo. Descobertos há pouco mais de uma década em Caenorhabditis elegans, os miRNAs são hoje reconhecidos como reguladores fundamentais da expressão gênica em plantas e animais. Até o momento, identificaram-se 462 genes de miRNA no genoma humano e estima-se que esse número supere 1000 miRNAs distintos. Análises bioinformáticas indicam que um único miRNA atue em diversos RNAs mensageiros, influenciando múltiplas vias de sinalização concomitantemente e apresentando enorme potencial regulatório. Apesar da biologia dos miRNAs ser ainda pouco entendida, essas moléculas já foram relacionadas a diversos processos biológicos. Além disso, a expressão anômala destes pequenos RNAs tem sido associada a diferentes patologias humanas, inclusive aquelas relacionadas ao sistema endócrino e câncer.
Hirsutismo: diagnóstico diferencial
Authors: Marcondes José Antonio M.
Published: January 2007

O hirsutismo é um dos sinais das síndromes hiperandrogênicas. Uma abordagem prática consiste em dividir as síndromes hiperandrogênicas em virilizantes e não virilizantes, de acordo com a presença ou ausência de sinais de virilização. Um caso de uma paciente com hirsutismo e com uma concentração basal e após estímulo com ACTH(1-24) elevada de 17-OHP é discutido. A ausência de sinais de virilização e a história clínica tornavam pouco prováveis etiologias como neoplasias virilizantes e a hipertecose de ovário. Dentre as causas das síndromes não virilizantes, a presença de distúrbio menstrual e hiperandrogenemia descartou o hirsutismo idiopático. De acordo com o Consenso de Rotterdam, considerou-se o diagnóstico de síndrome dos ovários policísticos, procedendo-se à exclusão da forma não clássica da hiperplasia adrenal congênita por deficiência da 21-hidroxilase. A concentração de 17-OHP após estímulo foi de 14 ng/dL, sendo que, na dependência do limite de corte considerado, seria compatível com esta doença. Embora a região promotora do gene não tenha sido estudada, do ponto de vistas prático pode-se considerar que este diagnóstico tenha sido excluído, uma vez que mutações nessa região são raras.
Quantitative aspects of brain perfusion dynamic induced by BOLD fMRI
Authors: Andrade Katia C. , Pontes-Neto Octavio M. , Leite Joao P. , Santos Antonio Carlos , Baffa Oswaldo , Araujo Draulio B. de
Published: January 2007

The increase of relative cerebral blood flow (rCBF) may contribute for a change in blood oxygenation level dependent signal (BOLD). The main purpose of this study is to investigate some aspects of perfusional alterations in the human brain in response to a uniform stimulation: hypercapnia induced by breath holding. It was observed that the BOLD signal increased globally during hypercapnia and that it is correlated with the time of breath holding. This signal increase shows a clear distinction between gray and white matter, being greater in the grey matter.
Clinical assessment of language development in children at age 3 years that were born preterm
Authors: Schirmer Carolina Rizzotto , Portuguez Mirna Wetters , Nunes Magda Lahorgue
Published: January 2007

OBJECTIVE: To evaluate the influence of gestational age and birth weight on language development and neurodevelopmental outcome at age 3 years in children born preterm. METHOD: Cross sectional study including 69 children followed in our developmental outpatient clinic. Patients were consecutively included at the time of the 3 years of age appointment and stratified for birth weight (<1500 grams and between 1500-2500 grams). All patients were assessed for receptive and expressive language , Denver II and Bayley II tests and clinical neurological examination. For analysis patients were divided in two groups normal language acquisition (NLA) and delay in language acquisition (DLA). RESULTS: NLA children had higher scores on mental and psychomotor (p=<0.01, p=0.012) indexes of Bayley II. Newborns with less than 1500 grams had lower scores on all Bayley scale at age 36 months (p=0.002, p=0.007 and p<0.001). Multivariate analysis suggests an association between gestational age (p=0.032), abnormal behavior (p<0.001) and delay in language acquisition. Denver test at 12 and 24 months of age was a good predictor of delayed receptive and expressive language at three years of age (p=<0.01 and p=<0.01). CONCLUSION: Children born prematurely with low birth weight had an increased risk of language acquisition delay, and those had also lower cognitive and behavior scores when compared to NLA.
ECI-4 screening of attention deficit-hyperactivity disorder and co-morbidity in Mexican preschool children: preliminary results
Authors: Poblano Adrián , Romero Erika
Published: January 2007

OBJECTIVE: To examine prospectively usefulness of Early Childhood Inventory-4 (ECI-4) in identifying attention deficit-hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). METHOD: A sample of children <6 years of age were evaluated in school settings with ECI-4 and results compared with those of Conners Rating Scales-Revised (CRS-R) 6 months later. Sample consisted of 34 healthy children (20 boys, 14 girls) prospectively followed-up. RESULTS: Frequency of children fulfill DSM-IV AD-HD criteria in ECI-4 parent scale was 17%, and in teacher scale was 32%. Frequency of children fulfill DSM-IV AD-HD criteria in parent CRS-R was 20%, and for teacher questionnaire was 23%. Correlations were significant among teacher ECI-4 and both teacher and parent CRS-R scales. Sensitivity and specificity of teacher and parent ECI-4 scales were not good. Frequency of ODD identified in parent ECI-4 scale was 5%, and for teacher 17%. Frequency of ODD in CRS-R for parents and teachers questionnaires was 17%. CD was not identified by parents in ECI-4 scale, but in teacher scale frequency was 14%. CONCLUSION: These facts support partially the use of ECI-4 screening of ADHD in Spanish-speaking preschool children.
Prevalence and impact of headache and migraine among Pomeranians in Espirito Santo, Brazil
Authors: Domingues Renan B. , Aquino Camila C.H. , Santos Jasper G. , Silva André L. Pirajá da , Kuster Gustavo W.
Published: January 2007

This is the first study to assess the prevalence of headache and migraine among Pomeranian descendents in Brazil. A high prevalence of headache in the last 6 months was found (53.2%). Most headache sufferers were diagnosed as having migraine (55%). More women reported to have headache than men (65% and 33.8%, respectively). Migraine was the most common headache found among women (62.2%). Among men migraine was responsible for only 37.8% of the cases of headache. A high impact of headache was found, especially among migraineurs. Most of the headache sufferers declared to seek medical assistance for headache (67%) and most of them used to take common analgesics for headache relief. None of them was under prophylactic therapy.