bluuebunny/crossref_metadata_2025 huggingface dataset:
Major histocompatibility antigens and antigen‐processing molecules in retinoblastoma
Authors: Krishnakumar Subramanian , Sundaram Amirthalakshmi , Abhyankar Dhiraj , Krishnamurthy Vanitha , Shanmugam Mahesh Palanivelu , Gopal Lingam , Sharma Tarun , Biswas Jyotirmay
Published: February 2004

BACKGROUND

Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLAs mediate interactions of tumor cells with cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Retinoblastoma is the most common intraocular malignant tumor in childhood and is characterized by direct spread to the optic nerve and orbit as well as hematogeneous and lymphatic spread. Little is known about the role of HLA expression in the progression of this malignant disease.

METHODS

HLA Class I antigen, β2‐microglobulin (β2‐m), HLA Class II antigens, and the antigen‐processing molecules (APMs) of the HLA Class I pathway, including proteasomal subunits (low–molecular mass polypeptide 2 [LMP‐2] and LMP‐10), the transporter‐associated protein (TAP‐1) subunit, the binding protein tapasin, and the chaperone molecule calnexin, were studied in 30 archival retinoblastoma specimens by immunohistochemistry. Immunoanalysis was performed based on the International Histocompatibility Working Group Project Description.

RESULTS

HLA Class I antigen, β2‐m, HLA Class II antigen, and APMs were positive in 12 tumors with no invasion and were decreased in 13 tumors with choroidal and optic nerve invasion. The difference in HLA and APM expression between the 2 groups was statistically significant (P < 0.001).

CONCLUSIONS

Decreased expression of HLA was observed in aggressive tumors and in poorly differentiated tumors. The current findings support a role for both CTLs and NK cell‐mediated control of tumor growth in the clinical course of retinoblastoma. Cancer 2004;100:1059–69. © 2004 American Cancer Society.
National estimates of medical costs incurred by nonelderly cancer patients
Authors: Howard David H. , Molinari Noelle‐Angelique , Thorpe Kenneth E.
Published: February 2004

Cancer‐attributable spending as a percent of aggregate medical spending by nonelderly individuals is between 4.7% and 6.3%. A program to provide insurance coverage to nonelderly cancer patients would cost the government at least $30 billion, and possibly as much as $47 billion, annually.
Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976–2000
Authors: Wang Sophia S. , Sherman Mark E. , Hildesheim Allan , Lacey James V. , Devesa Susan
Published: February 2004

BACKGROUND

Although cervical carcinoma incidence and mortality rates have declined in the U.S. greatly since the introduction of the Papanicolaou smear, this decline has not been uniform for all histologic subtypes. Therefore, the authors assessed the differential incidence rates of squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the cervix by race and disease stage for the past 25 years.

METHODS

Data from nine population‐based cancer registries participating in the U.S. Surveillance, Epidemiology, and End Results (SEER) Program were used to compute incidence rates for cervical carcinoma diagnosed during 1976–2000 by histologic subtype (SCC and AC), race (black and white), age, and disease stage (in situ, localized, regional, or distant).

RESULTS

In black women and white women, the overall incidence of invasive SCC declined over time, and the majority of tumors that are detected currently are in situ and localized carcinomas in young women. The incidence of in situ SCC increased sharply in the early 1990s. AC in situ (AIS) incidence rates increased, especially among young women. In black women, invasive AC incidence rose linearly with age.

CONCLUSIONS

Changes in screening, endocervical sampling, nomenclature, and improvements in treatment likely explain the increased in situ cervical SCC incidence in white women and black women. Increasing AIS incidence over the past 20 years in white women has not yet translated into a decrease in invasive AC incidence. Etiologic factors may explain the rising invasive cervical AC incidence in young white women; rising cervical AC incidence with age in black women may reflect either lack of effective screening or a differential disease etiology. Cancer 2004;100:1035–44. © 2004 American Cancer Society.
Improved prediction of recurrence after curative resection of colon carcinoma using tree‐based risk stratification
Authors: Radespiel‐Tröger Martin , Hohenberger Werner , Reingruber Bertram
Published: February 2004

BACKGROUND

Patients who are at high risk of recurrence after undergoing curative (R0) resection for colon carcinoma may benefit most from adjuvant treatment and from intensive follow‐up for early detection and treatment of recurrence. However, in light of new clinical evidence, there is a need for continuous improvement in the calculation of the risk of recurrence.

METHODS

Six hundred forty‐one patients with R0‐resected colon carcinoma who underwent surgery between January 1, 1984 and December 31, 1996 were recruited from the Erlangen Registry of Colorectal Carcinoma. The study end point was time until first locoregional or distant recurrence. The factors analyzed were: age, gender, site in colon, International Union Against Cancer (UICC) pathologic tumor classification (pT), UICC pathologic lymph node classification, histologic tumor type, malignancy grade, lymphatic invasion, venous invasion, number of examined lymph nodes, number of lymph node metastases, emergency presentation, intraoperative tumor cell spillage, surgeon, and time period. The resulting prognostic tree was evaluated by means of an independent sample using a measure of predictive accuracy based on the Brier score for censored data. Predictive accuracy was compared with several proposed stage groupings.

RESULTS

The prognostic tree contained the following variables: pT, the number of lymph node metastases, venous invasion, and emergency presentation. Predictive accuracy based on the validation sample was 0.230 (95% confidence interval [95% CI], 0.227–0.233) for the prognostic tree and 0.212 (95% CI, 0.209–0.215) for the UICC TNM sixth edition stage grouping.

CONCLUSIONS

The prognostic tree showed superior predictive accuracy when it was validated using an independent sample. It is interpreted easily and may be applied under clinical circumstances. Provided that their classification system can be validated successfully in other centers, the authors propose using the prognostic tree as a starting point for studies of adjuvant treatment and follow‐up strategies. Cancer 2004;100:958–67. © 2004 American Cancer Society.
Age‐related vulnerabilities of older adults with colon adenomas
Authors: Clipp Elizabeth C. , Carver Elizabeth H. , Pollak Kathryn I. , Puleo Elaine , Emmons Karen M. , Onken Jane , Farraye Francis A. , McBride Colleen M.
Published: February 2004

BACKGROUND

This report addresses the interface between cancer and aging in the context of colorectal carcinoma (CRC), the second leading cause of cancer death in the U.S. overall and the first leading cause among individuals age ≥ 75 years. Because polyp risk increases with age, interventions to prevent recurrent polyps among older adults likely would reduce CRC morbidity and mortality.

METHODS

Data for this study derive from Project Prevent, a multisite, randomized controlled trial designed to reduce behavioral risk factors for CRC among 1247 adults who underwent the removal of ≥ 1 adenomatous colon polyps. Middle‐aged and older patients were compared on key cognitive‐behavioral mechanisms associated with CRC risk and established age‐related factors associated with adverse health outcomes. Relations between cognitive‐behavioral mechanisms and age‐related vulnerability factors identified subgroups of older polyp patients that may have an enhanced risk for CRC.

RESULTS

Compared with middle‐aged patients, older patients were less concerned about developing CRC, less motivated to reduce their risk, and less confident that their behavior change efforts would succeed. As expected, they also reported more age‐related physical, social, and economic vulnerabilities, as expected. Evidence for enhanced CRC risk was found for older patients with multiple comorbid conditions, low social support for change, and perceptions of income inadequacy.

CONCLUSIONS

The presence of age‐related vulnerability factors may enhance the risk of CRC among older cancer patients by creating barriers to behavioral change. Efforts to reduce the cancer burden in older populations will require attention beyond early detection and surveillance to interventions that account for the unique physical and psychosocial characteristics of older adults. Cancer 2004;100:1085–94. © 2004 American Cancer Society.
Inflammatory breast carcinoma: Outcomes with trimodality therapy for nonmetastatic disease
Authors: Liauw Stanley L. , Benda Rashmi K. , Morris Christopher G. , Mendenhall Nancy Price
Published: February 2004

BACKGROUND

The objectives of this study were to summarize a single‐institution experience in treating patients with inflammatory breast carcinoma (IBC) using trimodality therapy and to identify prognostic factors for outcome.

METHODS

Sixty‐one women underwent radiation therapy with curative intent for IBC between 1982 and 2001. All but five women received trimodality therapy. Neoadjuvant chemotherapy was given to the majority of women (n = 43 patients), although some received “up‐front” surgery as first therapy (n = 18 patients).

RESULTS

With a median potential observation time after diagnosis of 14 years, freedom from locoregional disease progression was 78%, freedom from distant metastasis was 45%, and the cause‐specific survival rate was 47% at 5 years. Approximately 40% of the 56 patients who received trimodality therapy remained free of disease. Multivariate analysis demonstrated three factors that were found to be associated significantly with improved cause‐specific survival: pathologic tumor size < 4 cm (P = 0.0001), up‐front surgery (P = 0.0078), and local disease control (P = 0.0003). Factors that were found to be associated with better freedom from locoregional disease progression were pathologic tumor size (< 4 cm; P = 0.0157), age (> 55 years; P = 0.0596), and radiation dose (≥ 60 grays [Gy]; P = 0.0621).

CONCLUSIONS

IBC is an aggressive disease that is treated effectively in select patients by multimodality therapy. Patient outcomes may be improved with therapies that result in better local and systemic control. Further studies are warranted to address the optimal sequence of trimodality therapy and the optimal administration of each agent. Cancer 2004;100:920–8. © 2004 American Cancer Society.
The replication error phenotype is associated with the development of distant metastases in hormonally treated patients with breast carcinoma
Authors: Chagpar Anees , Magliocco Anthony , Kerviche Annette , Tan Leonard , Walley Barbara , DeCoteau John F.
Published: February 2004

BACKGROUND

The positive replication error (RER+) phenotype defines a distinct subgroup of tumors with specific clinical, pathologic, and molecular features that have been documented well in hereditary nonpolyposis colon carcinoma (HNPCC). More recently, this phenotype also has been described in breast carcinoma.

METHODS

To determine the effect of RER phenotype on prognosis in patients with breast carcinoma, the authors examined matched archival tumor and normal tissue from 100 women with Stage I and Stage II breast carcinoma, all of whom were treated with hormonal therapy. Patients had been followed for a minimum of 5 years or until death. Seven microsatellite loci were examined, including hMLH1 (3p22, D3S1611), hMSH2 (2p16, D2S123), NM23‐H1 (17q21), TP53‐Dint (17p13), TP53‐Penta (17p13), APC (5q21, D5S346), and HPC1 (1q24, D1S2883). The RER+ phenotype was defined as the presence of allelic shifts at three of the seven loci examined.

RESULTS

Twenty‐five percent of patients were classified with the RER+ phenotype based on these criteria. The two groups, women with positive RER status and women with negative RER status, were comparable in terms of other factors that may influence prognosis: age, tumor size, lymph node status, disease stage, and estrogen receptor status. The development of distant metastases to the lung, liver, or brain was correlated significantly with the positive RER phenotype, with a relative risk of 2.625 (95% confidence interval, 1.059–6.057).

CONCLUSIONS

The presence of high‐frequency RER+ may predict for the development of distant metastatic disease in patients with early‐stage breast carcinoma whoa re treated with hormonal therapy. Cancer 2004;100:913–9. © 2004 American Cancer Society.
Physician recommendations regarding tamoxifen and patient utilization of tamoxifen after surgery for ductal carcinoma in situ
Authors: Yen Tina W. F. , Hunt Kelly K. , Mirza Nadeem Q. , Thomas Eva S. , Singletary S. Eva , Babiera Gildy V. , Meric‐Bernstam Funda , Buchholz Thomas A. , Feig Barry W. , Ross Merrick I. , Ames Frederick C. , Theriault Richard L. , Kuerer Henry M.
Published: February 2004

BACKGROUND

To date, the impact of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B‐24 trial reported in 1999 on the use of tamoxifen after surgery for ductal carcinoma in situ (DCIS) is unknown. The current study was designed to evaluate the impact of NSABP B‐24 on current practices at a comprehensive cancer center.

METHODS

The records of 350 consecutive patients with DCIS who were treated at the authors' institution between July 1999 and June 2002 were obtained from a prospective database and analyzed. Whether patients were offered tamoxifen, whether patients accepted tamoxifen, and the associated reasons were recorded along with tamoxifen‐related side effects and patient compliance with therapy. Clinical and pathologic factors were evaluated for their impact on recommendations regarding tamoxifen. Differences were assessed by chi‐square analysis.

RESULTS

Of the 350 patients, 73 were excluded because of evidence of invasive carcinoma on final pathology review. Of the remaining 277 patients, 166 patients (60%) were offered tamoxifen, and 90 patients (54%) chose to take tamoxifen. Of 111 patients who were not offered tamoxifen, 39 patients (35%) had documented explanations, which included bilateral mastectomy (n = 25 patients), medical reasons (n = 10 patients), and already received tamoxifen for other reasons at the time of diagnosis (n = 4 patients). Of 94 patients who received tamoxifen, 20 patients (21%) discontinued use because of side effects or complications. Tamoxifen was more likely to be recommended for women who underwent segmental resection compared with women who underwent total mastectomy (P = 0.002) and for women with smaller pathologic DCIS tumors (P = 0.001). In addition, these two factors were interrelated.

CONCLUSIONS

Physicians and patients remain cautious regarding the use of tamoxifen after local treatment for DCIS. The current findings have implications for current trials evaluating aromatase inhibitors and other chemopreventive agents for this disease. Cancer 2004;100:942–9. © 2004 American Cancer Society.
Believing is seeing
Authors: Balducci Lodovico
Published: February 2004

Health beliefs play an important role in the implementation of cancer prevention and treatment, and health beliefs may differ between older patients and younger patients. In their report in this issue, Clipp et al. make the case for assessing health beliefs in future clinical trials and correlating these beliefs with treatment outcome.

See also pages 1085–94, this issue.
Poorly differentiated carcinomas of the thyroid with trabecular, insular, and solid patterns
Authors: Volante Marco , Landolfi Stefania , Chiusa Luigi , Palestini Nicola , Motta Manuela , Codegone Alessandra , Torchio Bruno , Papotti Mauro G.
Published: February 2004

BACKGROUND

The term poorly differentiated (PD) carcinoma was proposed 20 years ago to define aggressive, follicular‐derived thyroid carcinomas with behavior intermediate between follicular/papillary and anaplastic carcinomas. Among the variable histologic patterns recognized in such tumors, trabecular‐insular‐solid (TIS) areas usually are predominant. Conversely, some authors pointed out that PD carcinomas are characterized by unequivocal, high‐grade histology with atypias, high mitotic counts, and necrosis rather than by a specific growth pattern.

METHODS

The clinicopathologic features of a series of 183 thyroid carcinomas with predominant (n = 165 tumors) or focal (n = 18 tumors) TIS growth patterns were studied by univariate and multivariate overall survival analyses and were compared with clinical outcomes. Subgroups included tumors with predominant oxyphilic features (n = 66 tumors) and (residual) papillary carcinoma features (n = 24 tumors). Control groups of papillary (n = 68 tumors), follicular (n = 71 tumors), and anaplastic (n = 35 tumors) carcinomas also were included for overall survival analysis.

RESULTS

TIS carcinomas had an intermediate behavior between papillary/follicular and anaplastic carcinomas (P < 0.0001). Univariate and multivariate statistical analyses demonstrated that age > 45 years (P = 0.007), the presence of necrosis (P < 0.0001), and a mitotic count > 3 per 10 high‐power fields (P = 0.01) were associated with poor outcome. A simplified scoring system based on statistically significant parameters allowed the identification of three prognostic subgroups (P < 0.0001).

CONCLUSIONS

PD TIS carcinomas overall followed a more aggressive course compared with differentiated thyroid carcinomas, irrespective of the extent of the TIS component. However, a numeric scoring system applied to specific clinicopathologic parameters further may identify three prognostic categories of patients who have significantly different survival rates at 5 years and 10 years. Cancer 2004;100:950–7. © 2004 American Cancer Society.
γ‐Aminobutyric acid is present in a spatially discrete subpopulation of hair cells in the crista ampullaris of the toadfish Opsanus tau
Authors: Holstein Gay R. , Martinelli Giorgio P. , Henderson Scott C. , Friedrich Victor L. , Rabbitt Richard D. , Highstein Stephen M.
Published: February 2004

Although γ‐aminobutyric acid (GABA) and glutamate are known to be present in the vestibular sensory epithelia of a variety of species, the functional relationship between these two transmitters is not clear. The present study addresses the three‐dimensional spatial distribution of GABA and glutamate immunoreactivity in the vestibular labyrinth of the oyster toadfish by using whole end organs labeled by immunofluorescence with monoclonal anti‐GABA and/or antiglutamate antibodies and visualized as whole mounts by multiphoton confocal microscopy. We find glutamate‐immunoreactive hair cells present throughout the sensory epithelium. In contrast, prominent GABA immunoreactivity is restricted to a small population of hair cells located in the central region of the crista. Double immunofluorescence reveals two distinct staining patterns in GABA‐labeled hair cells. Most (∼80%) GABA‐labeled cells show trace levels of glutamate, appropriate for the metabolic/synthetic role of cytoplasmic glutamate. The remainder of the GABA‐stained cells contain substantial levels of both GABA and glutamate, suggesting transmitter colocalization. In the toadfish utricle, glutamatergic hair cells are present throughout the macula. GABA‐immunoreactive hair cells follow the arc of the striola, and most GABA‐labeled receptor cells coexpress glutamate. The localization of GABA was explored in other species as well. In the pigeon, GABAergic hair cells are present throughout the crista ampullaris. Our findings demonstrate that multiple, neurochemically distinct types of hair cells are present in vestibular sensory epithelia. These observations, together with the excitatory activity generally associated with 8th nerve afferent fibers, strongly suggest that GABA serves an important, specific, and complex role in determining primary afferent response dynamics. J. Comp. Neurol. 471:1–10, 2004. © 2004 Wiley‐Liss, Inc.
Cellular patterns in the inner retina of adult zebrafish: Quantitative analyses and a computational model of their formation
Authors: Cameron David A. , Carney Laurel H.
Published: February 2004

The mechanisms that control cellular pattern formation in the growing vertebrate central nervous system are poorly understood. In an effort to reveal mechanistic rules of cellular pattern formation in the central nervous system, quantitative spatial analysis and computational modeling techniques were applied to cellular patterns in the inner retina of the adult zebrafish. All the analyzed cell types were arrayed in nonrandom patterns tending toward regularity; specifically, they were locally anticlustered. Over relatively large spatial scales, only one cell type exhibited consistent evidence for pattern regularity, suggesting that cellular pattern formation in the inner retina is dominated by local anticlustering mechanisms. Cross‐correlation analyses revealed independence between the patterns of different cell types, suggesting that cellular pattern formation may involve multiple, independent, homotypic anticlustering mechanisms. A computational model of cellular pattern formation in the growing zebrafish retina was developed, which featured an inhibitory, homotypic signaling mechanism, arising from differentiated cells, that controlled the spatial profile of cell fate decisions. By adjusting the spatial profile of this decaying‐exponential signal, the model provided good estimates of all the cellular patterns that were observed in vivo, as objectively judged by quantitative spatial pattern analyses. The results support the hypothesis that cellular pattern formation in the inner retina of zebrafish is dominated by a set of anticlustering mechanisms that may control events at, or near, the spatiotemporal point of cell fate decision. J. Comp. Neurol. 471:11–25, 2004. © 2004 Wiley‐Liss, Inc.
Identification and morphogenesis of the eminentia thalami in the zebrafish
Authors: Wullimann Mario F. , Mueller Thomas
Published: February 2004

This study documents early zebrafish brain expression patterns (2–5 days postfertilization) of proliferating neural (PCNA) as well as early‐determined (Pax6, Zash‐1a, Zash‐1b, neurogenin1, neuroD) and differentiating (Hu‐proteins) neuronal cells. These patterns are used to outline the spatiotemporal local dynamics of secondary neurogenesis as well as neuronal migration and differentiation in the region of the eminentia thalami. The analysis presented not only allows identification for the first time of the eminentia thalami in the zebrafish model system (because it forms a neurogenin1/neuroD‐guided locus of neurogenesis in contrast to adjacent preoptic region and ventral thalamus) but furthermore shows that the entopeduncular complex is a derivative of the embryonic zebrafish eminentia thalami, which has never been reported for a teleost before. An analysis of the relevant literature shows that the mammalian entopeduncular nucleus/avian paleostriatum primitivum/reptilian globus pallidus clearly are part of the basal ganglia (i.e., the pallidum). In amniote embryos, an anterior entopeduncular area is recognized at the base of the medial ganglionic eminence (i.e., the future pallidum; part of alar plate of prosomere 5), separate from the more posterior eminentia thalami (alar prosomere 4). There is a comparable periventricular eminentia thalami in (young and adult) amphibians and teleosts. However, the migrated anterior entopeduncular nucleus of anuran amphibians likely is homologous to part of the pallidum of other vertebrates and has no developmental relationship to the eminentia thalami. In contrast, the migrated teleostean entopeduncular complex does not correspond to a pallidal division but is indeed the adult derivative of the early‐recognized eminentia thalami as shown in this study. J. Comp. Neurol. 471:37–48, 2004. © 2004 Wiley‐Liss, Inc.
PACAP mRNA is expressed in rat spinal cord neurons
Authors: Pettersson Lina M.E. , Heine Tony , Verge Valerie M.K. , Sundler Frank , Danielsen Nils
Published: February 2004

This study examines the expression of pituitary adenylate cyclase activating polypeptide (PACAP) mRNA in the rat spinal cord during normal conditions and in response to sciatic nerve transection. Previously, PACAP immunoreactivity has been found in fibers in the spinal cord dorsal horn and around the central canal and in neurons in the intermediolateral column (IML). Furthermore, in the dorsal root ganglia, PACAP immunoreactivity and PACAP mRNA expression have been observed preferentially in nerve cell bodies of smaller diameter terminating in the superficial laminae of the dorsal horn. However, neuronal expression of PACAP mRNA in adult rat spinal cord appeared limited to neurons of the IML. By using a refined in situ hybridization protocol, we now detect PACAP mRNA expression in neurons primarily in laminae I and II, but also in deeper laminae of the spinal cord dorsal horn and around the central canal. In addition, PACAP mRNA expression is observed in a few neurons in the ventral horn. PACAP expression in the ventral horn is increased in a population of large neurons, most likely motor neurons, both after distal and proximal sciatic nerve transection. The proposed role of PACAP in nociception is strengthened by our findings of PACAP mRNA‐expressing neurons in the superficial laminae of the dorsal horn. Furthermore, increased expression of PACAP in ventral horn neurons, in response to nerve transection, suggests a role for PACAP in repair/regeneration of motor neurons. J. Comp. Neurol. 471:85–96, 2004. © 2004 Wiley‐Liss, Inc.
Localized ablation of olfactory receptor neurons induces both localized regeneration and widespread replacement of neurons in spiny lobsters
Authors: Harrison Paul J.H. , Cate Holly S. , Derby Charles D.
Published: February 2004

The peripheral olfactory system of the spiny lobster Panulirus argus—located on paired antennules—undergoes continual postembryonic development. This process includes continuous addition of olfactory receptor neurons (ORNs) related to indeterminate growth, continuous replacement, and regeneration when necessitated by damage. We have shown previously that new olfactory tissue is continually added to the proximal margin of these populations, called the proximal proliferation zone (PPZ). Here, we show that focal damage to mature portions of the olfactory system causes localized degeneration of ORNs over 1–10 days after damage. Studies using the cell proliferation marker 5‐bromo‐2′‐deoxyuridine show that localized degeneration was followed by rapid and localized regeneration of olfactory tissue. Rapidly dividing cells were recorded up to 40 days after damage, with regeneration of ORN clusters complete within 80 days. Focal damage appeared to stimulate widespread cell replacement (cell death and proliferation) within mature, undamaged ORN clusters. This response was observed in ORN clusters outside the damaged zone, including mature clusters in the contralateral antennule. The degree of widespread cell replacement was less than local repair after local damage, but it increased with more extensive damage. However, changes in on‐going proliferation in the PPZ were not detected, at least not 20 days or longer after damage, suggesting damage‐induced widespread proliferation may be specific to mature populations of ORNs. We speculate that localized regeneration involves activity of resident precursor cells not destroyed by the ablation and that unidentified regulatory signals released in response to localized damage induce widespread ORN replacement. J. Comp. Neurol. 471:72–84, 2004. © 2004 Wiley‐Liss, Inc.
Synaptobrevin‐2‐like immunoreactivity is associated with vesicles at synapses in rat circumvallate taste buds
Authors: Yang Ruibiao , Stoick Cristi L. , Kinnamon John C.
Published: February 2004

Synaptobrevin is a vesicle‐associated membrane protein (VAMP) that is believed to play a critical role with presynaptic membrane proteins (SNAP‐25 and syntaxin) during regulated synaptic vesicle docking and exocytosis of neurotransmitter at the central nervous system. Synaptic contacts between taste cells and nerve processes have been found to exist, but little is known about synaptic vesicle docking and neurotransmitter release at taste cell synapses. Previously we demonstrated that immunoreactivity to SNAP‐25 is present in taste cells with synapses. Our present results show that synaptobrevin‐2‐like immunoreactivity (‐LIR) is present in approximately 35% of the taste cells in rat circumvallate taste buds. Synaptobrevin‐2‐LIR colocalizes with SNAP‐25‐, serotonin‐, and protein gene product 9.5‐LIR. Synaptobrevin‐2‐LIR also colocalizes with immunoreactivity for type III inositol 1,4,5‐triphosphate receptor (IP3R3), a taste‐signaling molecule in taste cells. All IP3R3‐LIR taste cells express synaptobrevin‐2‐LIR. However, approximately 27% of the synaptobrevin‐2‐LIR taste cells do not display IP3R3‐LIR. We believe, based on ultrastructural and biochemical features, that both type II and type III taste cells display synaptobrevin‐2‐LIR. All of the synapses that we observed from taste cells onto nerve processes express synaptobrevin‐2‐LIR, as well as some taste cells without synapses. By using colloidal gold immunoelectron microscopy, we found that synaptobrevin‐2‐LIR is associated with synaptic vesicles at rat taste cell synapses. The results of this study suggest that soluble NSF attachment receptor (SNARE) machinery may control synaptic vesicle fusion and exocytosis at taste cell synapses. J. Comp. Neurol. 471:59–71, 2004. © 2004 Wiley‐Liss, Inc.
Ground plan of the polychaete brain—I. Patterns of nerve development during regeneration in Dorvillea bermudensis (Dorvilleidae)
Authors: Müller Monika C.M. , Henning Line
Published: February 2004

The nervous systems of adult specimens and regenerating fragments of Dorvillea bermudensis (“Polychaeta,” Dorvilleidae) were stained with antisera directed against acetylated α‐tubulin and analyzed by indirect fluorescence and confocal laser scanning microscopy. The anlage of each circumesophageal connective is initially doubled in regenerates and starts with the outgrowth of two nerves from each side of the ventral cord of the amputee. The inner nerves on each side, which become the ventral roots, fuse medially to form the ventral cerebral commissure, whereas the outer nerves become the dorsal roots. As development proceeds, both roots split again, to form the four cerebral commissures. In later stages, the two circumesophageal connectives of each side merge, the point of fusion progressing from the ventral cord toward the brain. In D. bermudensis, this process stops halfway along the connective, thus producing the typical polychaete pattern according to Orrhage ([ 1995] Acta Zool 79:215–234): Each single circumesophageal connective divides near the brain into dorsal and ventral roots, which themselves split into two branches to form the four cerebral commissures. From the results presented here, we conclude that each circumesophageal connective is basically a paired structure but is partially fused in species possessing dorsal roots and completely fused in species lacking them. This may also be true for Clitellata, in which dorsal roots have hitherto not been found. At the posterior end, the outgrowing fibers form five connectives, of which the two outermost of each side fuse in an anteroposterior direction, forming the main connectives. Outgrowing fibers of the stomatogastric nerve stumps soon form the stomatogastric ring, which subsequently is linked with the new brain via stomatogastric connectives. J. Comp. Neurol. 471:49–58, 2004. © 2004 Wiley‐Liss, Inc.
Nitric oxide regulates swimming in the jellyfish Aglantha digitale
Authors: Moroz Leonid L. , Meech Robert W. , Sweedler Jonathan V. , Mackie George O.
Published: February 2004

The cnidarian nervous system is considered by many to represent neuronal organization in its earliest and simplest form. Here we demonstrate, for the first time in the Cnidaria, the neuronal localization of nitric oxide synthase (NOS) in the hydromedusa Aglantha digitale (Trachylina). Expression of specific, fixative‐resistant NADPH‐diaphorase (NADPH‐d) activity, characteristic of NOS, was observed in neurites running in the outer nerve ring at the base of the animal and in putative sensory cells in the ectoderm covering its tentacles. At both sites, diphenyleneiodonium (10‐4 M) abolished staining. Capillary electrophoresis confirmed that the NO breakdown products NO2‐ and NO3‐ were present at high levels in the tentacles, but were not detectable in NADPH‐d–negative areas. The NADPH‐d–reactive neurons in the tentacles send processes to regions adjacent to the inner nerve ring where swimming pacemaker cells are located. Free‐moving animals and semi‐intact preparations were used to test whether NO is involved in regulating the swimming program. NO (30–50 nM) and its precursor L‐arginine (1 mM) stimulated swimming, and the effect was mimicked by 8‐Br‐cGMP (50–100 μM). The NO scavenger PTIO (10–100 μM) and a competitive inhibitor of NOS, L‐nitroarginine methyl ester (L‐NAME, 200 μM), significantly decreased the swimming frequency in free‐moving animals, while its less‐active stereoisomer D‐nitroarginine methyl ester (D‐NAME, 200 μM) had no such effect. 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxaline‐1‐one (ODQ, 5–20 μM), a selective inhibitor of soluble guanylyl cyclase, suppressed spontaneous swimming and prevented NO‐induced activation of the swimming program. We suggest that an NO/cGMP signaling pathway modulates the rhythmic swimming associated with feeding in Aglantha, possibly by means of putative nitrergic sensory neurons in its tentacles. J. Comp. Neurol. 471:26–36, 2004. © 2004 Wiley‐Liss, Inc.
Organization of area 3a in macaque monkeys: Contributions to the cortical phenotype
Authors: Krubitzer Leah , Huffman Kelly J. , Disbrow Elizabeth , Recanzone Gregg
Published: February 2004

The detailed organization of somatosensory area 3a was examined in macaque monkeys using multiunit electrophysiological recording techniques. By examining topographic relationships, changes in receptive field size, and the type of stimulus that neurons responded to, functional boundaries of area 3a were determined and related to architectonic boundaries. One striking observation was that the location of area 3a varied with respect to the central sulcus. In one‐half of the cases area 3a was on the rostral bank and fundus of the central sulcus and in the other half of the cases it was on the caudal bank and fundus of the central sulcus. In terms of topographic organization, we found that area 3a contains a complete representation of deep receptors and musculature of the contralateral body, and that the general organization of body part representations mirrors that of the primary somatosensory area, 3b. These results as well as results from studies of area 3a in ours and other laboratories indicate that area 3a is part of a network involved in proprioception, postural control, and the generation of coordinated movements. Further, comparative analysis of area 3a in a variety of species suggests that its construction is based, to a large extent, on the use of a particular body part rather than on innervation density. J. Comp. Neurol. 471:97–111, 2004. © 2004 Wiley‐Liss, Inc.
Pharmacological studies on nitro‐naproxen (naproxen‐2‐nitrooxyethylester)
Authors: Jain Naveen K. , Patil Chandrashekhar S. , Kartasasmita R. E. , Decker M. , Lehmann J. , Kulkarni Shrinivas K.
Published: February 2004

Naproxen‐2‐nitrooxyethylester (S‐(+)‐2‐(6‐methoxy‐2‐naphthyl)propanoic acid‐2‐nitrooxyethylester, LE‐EK06) was synthesized from naproxen and 2‐nitrooxyethylbromide as a novel nitric oxide–releasing derivative of naproxen. Molar equivalents of LE‐EK06 (6.93–27.73 mg/kg, p.o.) to naproxen dose‐dependently exhibited greater antinociceptive activity in comparison to naproxen in a writhing assay. The compound (5.54–22.18 mg/kg, p.o.) showed greater anti‐inflammatory activity at 2 h after as comparable to its effect at 4 h after carrageenan challenge in rats. Further, LE‐EK06 (9.45 mg/kg, p.o.) was more potent in the carrageenan‐evoked hyperalgesia. LE‐EK06 (11.09 mg/kg, p.o.) and naproxen (8.0 mg/kg, p.o.) showed a comparable inhibitory effect on exudate formation and migration of polymorphonuclear leukocytes (PMNs) in a carrageenan‐induced pleurisy test. Further, the compound (11.09 mg/kg, p.o.) significantly reduced myeloperoxidase activity in carrageenan‐treated paw and demonstrated significantly less gastrotoxicity in acute and chronic (21 days) studies. The scanning electron microscopy revealed that LE‐EK06 showed only mild gastric damage (slight disruption of mucus layer) in comparison to naproxen. The present study suggested that naproxen‐2‐nitrooxyethylester (LE‐EK06) represents a novel gastric sparing NSAID. Drug Dev. Res. 61:66–78, 2004. © 2004 Wiley‐Liss, Inc.
Tramadol interaction with fluoxetine: An isobolographic analysis
Authors: Singh Vijay Pal , Patil Chandrashekhar S. , Jain Naveen K. , Kulkarni Shrinivas K.
Published: February 2004

Tramadol, a weak opioid agonist with effects on adrenergic and serotonergic neurotransmission, is used to treat conditions varying from postoperative to chronic malignant pain. Additionally, selective serotonin reuptake inhibitors (SSRIs) are used as adjuvants or prophylactics for the associated residual pain component. The present work evaluates, by isobolographic analysis, the interaction between a combination of racemic (±) tramadol, an opioid agonist, and fluoxetine, an SSRI, using a chemical analgesiometric test (abdominal writhing). Intraperitoneal administration of both tramadol (0.5–20 mg/kg) and fluoxetine (5–40 mg/kg) produced dose‐dependent antinociception. Co‐administration of fixed ratios of ED50 fractions of fluoxetine and tramadol resulted in an additive effect. However, the least dose of fluoxetine (2.1 mg/kg) and tramadol (0.21 mg/kg) used in fixed ratios for antinociceptive effect individually showed antidepressant activity in a modified Porsolt forced swim test. The interaction studies in the writhing test suggested that such combinations might be devoid of any additional advantage over the individual drug regimen in acute cases of pain with co‐morbidity of depression. Further, the nature of interaction for such combinations in chronic pain models needs further assessment. Drug Dev. Res. 61:79‐85, 2004. © 2004 Wiley‐Liss, Inc.
Study and development of encapsulated forms of 4, 5′, 8‐Trimethylpsoralen for topical drug delivery
Authors: Lboutounne H. , Guillaume Y. C. , Michel L. , Makki S. , Humbert Ph. , Millet J.
Published: February 2004

Trimethylpsoralen (TMP) is often used to treat skin diseases (i.e., psoriasis, vitiligo, etc.). This drug permeates moderately the skin barrier. In the present study, we investigated the effect of formulation on the improvement of TMP skin bioavailability. Three formulations were performed. Each form (liposomes, nanospheres, and EtOH solution) contained 0.05% of TMP. For each preparation, the quantity deposited on the skin surface was 250 µg (Q0). The TMP percutaneous penetration through ex‐vivo human skin was processed by Franz® cells (n=4) using a human albumin solution (1.4% w/v) as receiver medium. The percentages of the extracted TMP that permeated through the skin and that were retained in the skin over 24 h, were calculated with respect to Q0. The values obtained were reported, respectively, as follows: EtOH solution (1.33 vs. 0.08%), liposomes (0.93 vs. 0.93%), and PLG‐nanospheres (0.79 vs. 3.01%). So, considering the correlation between the cumulated amounts of TMP permeated through the skin and the TMP stocked in the skin, the nanosphere form showed the higher quantity of TMP accumulated in the skin structures. On the other hand, the maximum value of the flux (ng/cm2/h) in the steady state of TMP incorporated in each formulation was at 6 h for all formulations: 173.5±1.06 (EtOH solution) > 120.4±1.06 (liposomes) > 93.82±0.88 (PLG‐nanospheres). These results indicate that the controlled release of TMP by incorporation in PLG‐nanospheres may increase drug content in the skin, while maintaining a minimal percutaneous absorption. Finally, this work shows that the PLG‐nanospheres could constitute a promising approach for controlling TMP release in order to maintain its topical activity. Drug Dev. Res. 61:86–94, 2004. © 2004 Wiley‐Liss, Inc.
Effects of the novel antidepressant milnacipran in a chronic mild stress model of depression
Authors: Papp Mariusz , Panconi Emmanuel , Gruca Piotr
Published: February 2004

The chronic mild stress (CMS) model of depression may serve as a suitable research tool for studying the action of novel antidepressants (i.e., both efficacy and onset of action). The CMS‐induced sub‐sensitivity to reward is reversed by chronic treatment with antidepressant drugs. The effect of the serotonin and norepinephrine reuptake inhibitor (SNRI), milnacipran, was investigated on the CMS model in rats in comparison with imipramine. The CMS model of depression consisted in subjecting rats to several mild stressors for a prolonged period of time, which resulted in a decrease in their responsiveness to rewarding stimuli. This deficit was monitored by a decrease in the consumption of a 1% sucrose solution. Stressed and control animals received daily for 5 weeks injections of vehicle, imipramine (10 mg/kg) or milnacipran (3, 10, and 30 mg/kg). CMS caused a decrease in the consumption of the 1% sucrose solution. The deficit in sucrose consumption in stressed animals was reversed by imipramine and milnacipran. The effect of milnacipran was gradual, dose‐dependent, and was maintained for one week after stopping drug treatment. Neither imipramine nor milnacipran modified the behavior of control animals. Milnacipran is active in the CMS model of depression as expected from its clinically demonstrated antidepressant effect. Drug Dev. Res. 61:101–106, 2004. © 2004 Wiley‐Liss, Inc.
The medicinal chemistry of tea
Authors: Wheeler Derek S. , Wheeler William J.
Published: February 2004

The medicinal effects of tea (Camellia sinensis) have a long, rich history. The first references to tea date back nearly 5,000 years and are justifiably obscure. Tea has been consumed literally for thousands of years, and it is this long safety record of tea consumption that makes these compounds an attractive target for drug discovery. Much attention has been focused on the role of tea flavanoids in the promotion of health in recent years. However, future studies will need to clarify further the mechanisms of action of these and related compounds, as well as their absorption, metabolism, and potential toxicity. We review here some of the currently available information pertaining to the chemistry, synthesis, pharmacokinetics, and pharmacodynamics of these compounds, which will hopefully serve as a starting point for the continued investigation of these compounds in the clinical setting. Drug Dev. Res. 61:45–65, 2004. © 2004 Wiley‐Liss, Inc.
Lipase selectivity toward fatty acids commonly found in fish oil
Authors: Halldorsson Arnar , Kristinsson Bjorn , Haraldsson Gudmundur G.
Published: February 2004

The main objective of this study was to compare the fatty acid selectivity of numerous commercially available lipases toward the most ubiquitous fatty acids present in fish oils in form of their corresponding ethyl esters. Special interest was taken in their ability to separate the n‐3 long‐chain polyunsaturated fatty acids (PUFA), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), from the more saturated fatty acids as well as exploiting the putative discrimination between these highly valuable n‐3 PUFA. Hydrolysis of sardine oil ethyl esters in a Tris buffer solution by 12 microbial lipases is described. The results reveal that all of the lipases strongly discriminate against the n‐3 PUFA and prefer the more saturated fatty acids as substrates. Most of the lipases discriminate between EPA and DHA in favor of EPA, however, 2 bacterial lipases from Pseudomonas were observed to prefer DHA to EPA. Digestive lipolytic enzymes isolated from salmon and rainbow trout intestines displayed reversed fatty acid selectivity when their fish oil triacylglycerol hydrolysis was studied. Thus, the n‐3 PUFA including EPA and DHA were observed to be hydrolyzed at a considerably higher rate than the more saturated fatty acids.
Direct esterification of fatty acids with phenylalkanols by using dicyclohexylcarbodiimide
Authors: Rauf Abdul , Parveen Humaira
Published: February 2004

A mild one‐pot esterification method of fatty acids with alcohols at room temperature is described. The reaction of undec‐10‐enoic acid (I) with 1‐phenylethanol in the presence of N,N'‐di‐cyclohexylcarbodiimide and 4‐(N,N‐dimethylamino)pyridine gave 1'‐phenylethyl undec‐10‐enoate in quantitative yield. Similar reactions were also carried out with (Z)‐octadec‐9‐enoic acid, (Z)‐12‐hydroxyoctadec‐9‐enoic and (Z)‐9‐hydroxyoctadec‐12‐enoic acids. In addition, compound (I) was allowed to react with diphenyl methanol to form its corresponding ester. The structure elucidation of the prepared esters is based on the elemental analysis and spectral data (IR, 1H‐ and 13C‐NMR, MS).
First approach on rice bran oil extraction using limonene
Authors: Mamidipally Pavan K. , Liu Sean X.
Published: February 2004

Edible oil extraction with petroleum derivatives as solvents has caused safety, health, and environmental concerns everywhere. Thus, finding a safe alternative solvent will have a strong and positive impact on environments and general health of the world population, considering the scale of oil extraction operations worldwide. The extraction of oil from rice bran by d‐limonene and hexane (for comparison) has been carried out at their respective boiling points at various solvent‐to‐meal ratios and for various extraction times. The preliminary data suggested that the optimum solvent‐to‐meal ratio and extraction time required for d‐limonene extraction of rice bran oil to be 5:1 and 1 h respectively. The initial quality characteristics (free fatty acid content, oil color, phospholipid content) of crude oil extracted under these optimum conditions were analyzed using various analytical methods based on the standard methods of AOCS and were found to be comparable to the oil extracted with hexane. The initial positive result has paved the way for further studies on issues related to meal qualities as well as to a scale‐up of the method in the near future.
Variations in the composition of acyl lipids and triacylglycerol molecular species of pumpkin seeds (Cucurbita spp.) following microwave treatment
Authors: Yoshida Hiromi , Tomiyama Yuka , Hirakawa Yuki , Mizushina Yoshiyuki
Published: February 2004

Whole pumpkin seeds (Cucurbita spp.) of two cultivars were exposed to microwaves for 6, 12, 20 or 30 min at a frequency of 2450 MHz. The kernels were separated from the whole seeds, and were investigated not only for the different acyl lipids and their fatty acid compositions, but also for the molecular species of triacylglycerols (TAGs). A modified argentation TLC procedure, developed to optimize the separation of the complex mixture of total TAGs, provided 11 different groups of TAGs, based on both the degree of unsaturation and the chain‐length of fatty acid groups. With a few exceptions, dioleopalmitin (5.8–18.8 wt‐%), dipalmitolinolein (8.1–8.8 wt‐%), triolein (6.3–20.5 wt‐%), palmitoleolinolein (15.0–16.1 wt‐%), dioleolinolein (16.7–23.0 wt‐%), dilinoleopalmitin (4.6–15.4 wt‐%) and dilinoleolein (6.7–19.4 wt‐%) were the main TAG components. When pumpkin seeds were microwaved for 20 min or more, significant differences (p <0.05) occurred in the acyl lipids as well as their fatty acid distributions with a few exceptions. Therefore, microwave roasting caused a significant decrease (p <0.05), not only in TAGs molecular species containing more than 4 double bonds, but also in the amounts of diene species present in triacylglycerols. These results contribute to the study of the functional properties of pumpkin seed products.