bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients with high‐risk aggressive lymphoma treated with frontline intensive chemotherapy and autografting
Authors: Cuttica Alessandra , Zallio Francesco , Ladetto Marco , Di Nicola Massimo , Caracciolo Daniele , Magni Michele , Marinone Carlo , Dell'Aquila Maria , Rosace Michela , Pileri Alessandro , Boccadoro Mario , Gianni Alessandro M. , Tarella Corrado
Published: August 2003

BACKGROUND

The goal of the current study was to evaluate the impact of presentation with an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3 on patients with high‐risk aggressive lymphoma who are treated with frontline intensive chemotherapy and autografting.

METHODS

Sixty‐nine consecutive patients (median age, 40 years) with either B‐cell (n= 60) or non–B‐cell (n= 9) aggressive lymphoma were treated with high‐dose sequential (HDS) chemotherapy and peripheral blood progenitor cell (PBPC) autografting. The patients who were examined had poor prognoses, with aaIPI scores of 2 (n= 37) or 3 (n= 32). The original treatment regimen, sequential delivery of cyclophosphamide, methotrexate, and etoposide, followed by PBPC autografting (o‐HDS), was used in the first 32 patients; the program was intensified by the addition of a course of high‐dose cytosine arabinoside (C‐HDS) in the next 37 patients.

RESULTS

There were 4 toxicity‐related deaths—2 in each aaIPI subgroup (treatment‐related mortality, 5.8%). The complete remission rate was significantly higher among patients with an aaIPI score of 2 (n= 32 [86%]) compared with those with an aaIPI score of 3 (n= 13 [41%];P< 0.001). Patients with an aaIPI score of 2 had significantly better outcomes than did patients with an aaIPI score of 3 in terms of both overall survival (78% vs. 34% at 8 years;P< 0.001) and event‐free survival (72% vs. 28% at 8 years;P< 0.001). Similar results were observed when the analysis was limited to the 60 patients with B‐cell‐derived lymphoma. No significant differences in outcome between patients receiving o‐HDS and patients receiving C‐HDS were observed. Multivariate analysis demonstrated that an aaIPI score of 3 was the only parameter that was significantly associated with poor overall and event‐free survival.

CONCLUSIONS

Age‐adjusted International Prognostic Index score is applicable to patients with aggressive lymphoma who are treated with frontline intensive chemotherapy and autografting. In addition, upfront use of HDS chemotherapy appears to be beneficial to patients with an aaIPI score of 2 but not to those with an aaIPI score of 3. Cancer 2003;98:983–92. © 2003 American Cancer Society.

DOI 10.1002/cncr.11610
The diagnostic and prognostic relevance of human telomerase reverse transcriptase mRNA expression detected in situ in patients with nonsmall cell lung carcinoma
Authors: Fujita Yuka , Fujikane Toshiaki , Fujiuchi Satoru , Nishigaki Yutaka , Yamazaki Yasuhiro , Nagase Atsushi , Shimizu Tetsuo , Ohsaki Yoshinobu , Kikuchi Kenjiro
Published: August 2003

BACKGROUND

The objectives of this study were to evaluate the diagnostic and prognostic relevance of human telomerase reverse transcriptase (hTERT) detected in situ in patients with nonsmall cell lung carcinoma (NSCLC) and to investigate the possible correlations between hTERT mRNA in NSCLC and the patients' clinicopathologic features, including survival.

METHODS

hTERT mRNA was detected by in situ hybridization in 146 samples from patients with NSCLC. The signal intensity of hTERT mRNA expression was evaluated by two independent observers. The expression level was defined subjectively as strong, moderate, or weak.

RESULTS

hTERT mRNA was detected mainly in the cytoplasm of tumor cells. It was detected in the cytoplasm of 100% of samples from patients with NSCLC but was not detected in normal lung tissue, except in activated lymphocytes. There was a significant correlation between hTERT mRNA expression and pathologic tumor status, pathologic disease stage (pStage), and Ki‐67 labeling index. There was no significant correlation between hTERT mRNA expression and age, gender, pathologic lymph node status (pN), histology, or tumor differentiation. The 5‐year survival rates for patients with strong and moderate hTERT mRNA expression levels were 46.9% and 77.9%, respectively; the difference was statistically significant (P = 0.0001). A multivariate analysis of survival using a stepwise procedure revealed that hTERT mRNA expression, pN status, pStage, and age were statistically significant prognostic factors (P = 0.0029, P = 0.0012, P = 0.0237, and P = 0.0496, respectively).

CONCLUSIONS

The findings suggested that hTERT mRNA expression may be useful for the diagnosis of NSCLC and also may be an independent prognostic factor for patients with NSCLC. Cancer 2003;98:1008–13. © 2003 American Cancer Society.

DOI 10.1002/cncr.11611
Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer
Authors: Bosly André , Sonet Anne , Pinkerton C. Ross , McCowage Geoffrey , Bron Dominique , Sanz Miguel A. , Van den Berg Hendrik
Published: August 2003

BACKGROUND

Hyperuricemia and tumor lysis syndrome (TLS) are serious complications that can occur during chemotherapy for hematologic malignancies, even if standard management procedures, including administration of allopurinol, are undertaken. Rasburicase, a recombinant urate oxidase that converts uric acid (UA) into the soluble compound allantoin, has been shown to control hyperuricemia faster and more reliably than allopurinol.1

METHODS

A compassionate use trial, running from January 1999 to December 2001, provided access to rasburicase for patients in nine countries who were at risk for TLS during the initiation of chemotherapy. Of the 280 patients enrolled in the study, 278 received rasburicase and were included in the analysis. A total of 166 pediatric patients who had leukemia (∼ 74%), lymphoma (∼ 24%), or solid tumors (∼ 3%) were treated with rasburicase. One hundred twelve adults with either leukemia (68%) or lymphoma (30%) also were treated. Rasburicase (0.20 mg/kg) was administered intravenously once a day for 1 to 7 days, at the investigator's discretion. Two doses daily could be administered during the first 3 days. A response was defined as a reduction in UA level or maintenance of a UA level less than 7.5 mg/dL (or less than 6.5 mg/dL, for children age < 13 years).

RESULTS

UA levels at 24–48 hours after administration of the last dose of rasburicase were available for 122 pediatric patients and 97 adult patients. The mean UA level in 29 hyperuricemic children decreased from 15.1 mg/dL to 0.4 mg/dL, whereas in 27 hyperuricemic adults, the mean level decreased from 14.2 mg/dL to 0.5 mg/dL. Prophylactic administration of rasburicase to prevent TLS during chemotherapy reduced UA levels from a mean of 4.4 mg/dL to 0.8 mg/dL in 93 nonhyperuricemic children and from 4.8 mg/dL to 0.4 mg/dL in 70 nonhyperuricemic adults (for all reductions in UA levels, P < 0.001). The response rate was 100%. Rasburicase was very well tolerated. Serious adverse events related to rasburicase were observed in one patient.

CONCLUSIONS

The results of the current study confirm that rasburicase is safe and highly effective in the prevention and treatment of chemotherapy‐induced hyperuricemia in both children and adults. Cancer 2003;98:1048–54. © 2003 American Cancer Society.

DOI 10.1002/cncr.11612
Treatment of febrile neutropenic patients with cancer who require hospitalization
Authors: Raad Issam I. , Escalante Carmen , Hachem Ray Y. , Hanna Hend A. , Husni Rola , Afif Claude , Boktour Maha R. , Whimbey Estella E. , Kontoyiannis Dimitrios , Jacobson Kalen , Kantarjian Hagop , Levett L. Martin , Rolston Kenneth V. I.
Published: August 2003

BACKGROUND

The objective of the current study was to compare the efficacy and safety of imipenem and cefepime in the treatment of adult patients with cancer who had fever and neutropenia requiring hospitalization according to Infectious Disease Society of America criteria.

METHODS

In the current prospective randomized clinical trial at a university‐affiliated tertiary cancer center, adult patients with cancer who had fever (≥ 38.3 °C or ≥ 38.0 °C for > 2 hours) and neutropenia (≤ 500/mm3 or < 1000/mm3 but declining) requiring hospitalization were randomized to receive either cefepime or imipenem. Vancomycin or amikacin was added on suspicion of gram‐positive or gram‐negative bacterial infection, respectively.

RESULTS

Patients who received an imipenem regimen or a cefepime regimen were comparable in terms of age, gender, underlying malignancy, prior transplantation, degree and trend of neutropenia, and presence of central venous catheters (P ≥ 0.3). An intent‐to‐treat analysis showed a 68% response rate to the imipenem regimen, compared with a 75% response rate to the cefepime regimen (P = 0.2). The rates of antibiotic‐related adverse events and superinfections also were comparable (P = 0.6). There was no difference in response among patients who received imipenem or cefepime alone compared with patients who also received vancomycin or amikacin (P = 1.0). Leukemia was the only independent risk factor associated with a poor outcome (odds ratio, 4.6; 95% confidence interval, 1.9–10.7; P < 0.0001).

CONCLUSIONS

Imipenem and cefepime had similar efficacy and safety profiles in the treatment of adult cancer patients with fever and neutropenia who required hospitalization. The addition of either vancomycin or amikacin may not be necessary. Cancer 2003;98:1039–47. © 2003 American Cancer Society.

DOI 10.1002/cncr.11613
Breast carcinoma in pregnant women
Authors: Middleton Lavinia P. , Amin Mitual , Gwyn Karin , Theriault Richard , Sahin Aysegul
Published: August 2003

BACKGROUND

Breast carcinoma is one of the most common carcinomas in pregnant women. The incidence of breast carcinoma may increase in the future because of the trend toward delayed childbearing and increased screening. However, very few contemporary studies have attempted to identify the combined histopathologic and immunohistochemical features of breast carcinoma in these patients.

METHODS

The authors evaluated 39 patients with breast carcinoma occurring coincident with pregnancy. This was comprised of a critical histologic review and immunohistochemical evaluation to determine the status of prognostic and predictive markers including estrogen receptor (ER), progesterone receptor (PR), HER‐2/neu, Ki‐67, and p53.

RESULTS

The mean age at presentation was 33 years (range, 24–44 years). Densities and/or masses were noted on mammograms in 14 of 16 patients with available radiographic information. The primary tumors were a mean of 4.5 cm in greatest dimension (range, 0.1–13.5 cm). Two of the 39 patients had clinical (American Joint Committee on Cancer) Stage I disease, 19 patients had Stage II disease, 16 had Stage III disease, and 2 patients had Stage IV disease at the time of presentation. Histologically, high‐grade invasive ductal carcinomas were found in 32 of 38 patients. The primary tumor was not available for review in one patient. A predominantly solid pattern of growth was observed in nine patients. Lymphovascular invasion was identified in 61% of cases. Ductal carcinoma in situ was identified in 72% of tumors and was high grade in all cases. Of the 25 patients tested, ER positivity was found in 7 patients, PR positivity was found in 6 patients, HER‐2/neu positivity was found in 7 patients, and p53 positivity was found in 12 patients. The proliferation rate as shown by Ki‐67 staining was high in 60% of the cases. Follow‐up information was available for 35 patients and the mean follow‐up period was 43 months (range, 2–163 months). Distant metastasis occurred in seven patients. The mean time to disease recurrence was 20.4 months (range, 10–33 months). Of 35 patients, 4 have died, 22 were alive with no evidence of disease, and 9 were alive with disease at the last follow‐up. The remaining four patients died of unknown causes.

CONCLUSIONS

Pregnant women with breast carcinomas generally present with advanced‐stage disease and the tumors have poor histologic and prognostic features. The findings from the follow‐up indicated that these tumors do not follow a very aggressive clinical course as was proposed in earlier reports. Breast carcinomas occurring during pregnancy share many histologic and prognostic similarities with breast carcinoma occurring in other young women. Cancer 2003;98:1055–60. © 2003 American Cancer Society.

DOI 10.1002/cncr.11614
Once‐weekly dosing of epoetin‐α increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy
Authors: Shasha Daniel , George Martine J. , Harrison Louis B.
Published: August 2003

BACKGROUND

The current study was performed to prospectively evaluate the effectiveness, clinical outcomes, and safety of once‐weekly (QW) recombinant human erythropoietin (r‐HuEPO [epoetin‐α]) in anemic cancer patients with nonmyeloid malignancies who were receiving radiation therapy (RT) concomitantly or sequentially with chemotherapy (CT).

METHODS

A total of 777 anemic patients (hemoglobin [Hb] ≤ 11 g/dL) were enrolled in this multicenter, open‐label, nonrandomized, 16‐week study. Patients initially received epoetin‐α at a dose of 40,000 units (U) subcutaneously QW, escalating to a dose of 60,000 U QW if the Hb increased to ≤ 1 g/dL after 4 weeks. Endpoints were changes in hematologic and quality of life (QOL) parameters.

RESULTS

Among the 442 patients evaluable for hematologic response, the mean increase in Hb from baseline to the time of final evaluation was 1.9 ± 1.8 g/dL (P < 0.05). An increase in Hb of ≥ 2 g/dL, in the absence of blood transfusions, occurred in 68.3% of patients (278 of 407 patients) who were on the study for ≥ 30 days. The overall response rate (Hb increase ≥ 2 g/dL or Hb ≥ 12 g/dL in the absence of blood transfusions) was 74.0% (301 of 407 patients). In 359 patients who were evaluable for QOL assessment, epoetin‐α therapy was found to significantly (P < 0.05) improve mean Linear Analog Scale Assessment (LASA) scores for energy level, ability to perform daily activities, and overall QOL from baseline to the time of final evaluation. QW epoetin‐α therapy was found to be well tolerated.

CONCLUSIONS

Treatment with QW epoetin‐α was found to increase Hb levels, decrease transfusion requirements, and improve functional status and QOL in anemic patients with nonmyeloid malignancies who were receiving RT concomitantly or sequentially with CT. Clinical benefits and the safety profile of QW epoetin‐α in this setting appear to be similar to those observed in anemic cancer patients receiving CT. Cancer 2003;98:1072–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11616
CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies
Authors: Sasada Tetsuro , Kimura Motohide , Yoshida Yuka , Kanai Michiyuki , Takabayashi Arimichi
Published: August 2003

BACKGROUND

Active suppression by CD4+CD25+ regulatory T cells plays an important role in the down‐regulation of the response of T cells to foreign and self antigens. Experimental tumor models in mice revealed that regulatory T cells inhibit antitumor immune responses. The purpose of the current study was to demonstrate the possible involvement of CD4+CD25+ regulatory T cells in immune system impairment in patients with gastrointestinal malignancies.

METHODS

The phenotypes of lymphocytes, particularly those of CD4+CD25+ T cells, were analyzed in peripheral blood in 149 patients with gastrointestinal malignancies and in ascites in 7 patients with peritoneal dissemination. In addition, cytokine production after in vitro stimulation was examined in CD4+CD25+ and CD4+CD25− T cells isolated from patients with malignant disease.

RESULTS

Compared with healthy volunteers, patients with gastrointestinal malignancies had a higher proportion of CD4+CD25+ T cells in peripheral blood, due to the presence of a drastically smaller number of CD4+CD25− T cells. Among patients with gastric carcinoma, those with higher percentages of CD4+CD25+ T cells had a poorer prognosis than did those with lower percentages. CD4+CD25+ T cells also were present in greater proportions in ascites from patients who had advanced‐stage disease with peritoneal dissemination. Isolated CD4+CD25+ T cells from patients with malignant disease produced interleukin (IL)‐4 and IL‐10 but not IL‐2 or interferon‐γ; these cells also inhibited cytokine production by CD4+CD25− T cells after in vitro stimulation.

CONCLUSIONS

The relative increase in CD4+CD25+ regulatory T cells may be related to immunosuppression and tumor progression in patients with gastrointestinal malignancies. This finding suggests that the use of immunomodulatory therapy to treat patients with gastrointestinal malignancies may be an effective strategy. Cancer 2003;98:1089–99. © 2003 American Cancer Society.

DOI 10.1002/cncr.11618
Expression of translation initiation factor eIF‐2α is increased in benign and malignant melanocytic and colonic epithelial neoplasms
Authors: Rosenwald Igor B. , Wang Songtao , Savas Lou , Woda Bruce , Pullman James
Published: August 2003

BACKGROUND

Stimulation of resting cells by growth factors leads to an increase in the rate of protein synthesis, which is necessary for cell growth and division. Translation initiation factor eIF‐2α is one of the key translation factors mediating the effects of growth factors on protein synthesis. In normal cells, expression of eIF‐2α is increased transiently, but its levels are elevated constitutively in oncogene‐transformed cells. Overexpression of constitutively active eIF‐2α in rodent cells makes them tumorigenic. In this article, the authors report their findings on the increased expression of eIF‐2α in human benign and malignant neoplasms originating from melanocytes and colonic epithelium.

METHODS

Immunohistochemistry was used to analyze the expression of eIF‐2α, eIF‐4E, and cyclin D1 in melanocytic nevi and melanomas and the expression of eIF‐2α in colonic adenomas and carcinomas.

RESULTS

The authors found that the expression of eIF‐2α was increased markedly in both benign and malignant neoplasms of melanocytes and colonic epithelium.

CONCLUSIONS

Increased expression of eIF‐2α took place in both benign and malignant neoplasms of melanocytes and colonic epithelium. These findings suggest that elevated expression of this translation initiation factor may contribute to tumor initiation and progression but that it is not sufficient for establishing a malignant phenotype in the tumors analyzed in this study. Cancer 2003;98:1080–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11619
Results of triple therapy with interferon‐alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in early chronic phase
Authors: O'Brien Susan , Giles Francis , Talpaz Moshe , Cortes Jorge , Rios Mary Beth , Shan Jianqin , Thomas Deborah , Andreeff Michael , Kornblau Steven , Faderl Stefan , Garcia‐Manero Guillermo , White Kevin , Mallard Susie , Freireich Emil , Kantarjian Hagop M.
Published: August 2003

BACKGROUND

Before the discovery of imatinib mesylate, a Bcr‐Abl selective tyrosine kinase inhibitor, three agents, interferon‐alpha (IFN‐α), cytarabine (ara‐C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)‐positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN‐α, ara‐C, and HHT in newly diagnosed Ph‐positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis.

METHODS

Ninety patients with Ph‐positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m2 IFN‐α subcutaneously (s.c. daily, ara‐C 10 mg s.c. daily, and HHT 2.5 mg/m2 by continuous infusion over 24 hours daily × 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily.

RESULTS

With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to ≤ 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN‐α dose was 1.6 MU/m2 daily, the median ara‐C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow‐up time of 46 months for the total study group, the estimated 5‐year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase.

CONCLUSIONS

The sequence of IFN‐α, ara‐C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5‐year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML. Cancer 2003;98:888–93. © 2003 American Cancer Society.

DOI 10.1002/cncr.11620
Primary central nervous system lymphoma: Phase I evaluation of infusional bromodeoxyuridine with whole brain accelerated fractionation radiation therapy after chemotherapy
Authors: Dabaja Bouthaina S. , McLaughlin Peter , Ha Chul S. , Pro Barbara , Meyers Christina A. , Seabrooke Lee F. , Wilder Richard B. , Kyritsis Athanassios P. , Preti H. Alejandro , Yung W. K. Alfred , Levin Victor , Cabanillas Fernando , Cox James D.
Published: August 2003

BACKGROUND

The current study was performed to determine the maximum tolerated dose (MTD), toxicity, and outcome of infusional 5 bromo‐2'‐deoxyuridine (bromodeoxyuridine; BUdR) given with accelerated fractionation whole brain radiation therapy (WBRT) after chemotherapy for the treatment of primary central nervous system lymphoma (PCNSL).

METHODS

Twelve patients with untreated and histologically confirmed PCNSL were entered on the study between 1994 and 1996. Chemotherapy was comprised of one course of IDHAP plus high‐dose methotrexate (HD‐MTX). IDHAP is comprised of idarubicin at a dose of 1.5 mg/m2/day × 4 days intravenously by continuous infusion (i.v. CI), dexamethasone at a dose of 40 mg i.v. on Days 1–5, cytosine arabinoside at a dose of 2000 mg/ m2 i.v. on Day 5 after cisplatin, and cisplatin at a dose of 25 mg/m2/day × 4 days i.v. CI. HD‐MTX was given at a dose of 3.5 g/m2 i.v. between Day 10 and Day 14 after IDHAP. BUdR was given as an i.v. CI over 48 hours, 2–3 days prior to WBRT and then weekly during WBRT. Dose escalation started at 1.5 g/m2/day for Cohort 1 with subsequent increments of 0.3 g/m2/day. The WBRT dose was 45 grays (Gy) at a dose of 1.5 Gy twice a day, 5 days per week. Neurocognitive testing was performed before, during, and after treatment.

RESULTS

Nine of 12 patients entered on the study received BUdR. One of 3 patients in Cohort 1 developed leukoencephalopathy (LEP), a dose‐limiting toxicity (DLT), within 2 months of the completion of therapy. Therefore, the next cohort received the same dose level. Because no toxicity was observed in Cohort 2, the third cohort received a BUdR dose of 1.8 g /m2/day. Shortly after completing enrollment in Cohort 3, 3 more patients developed LEP, including 2 from Cohort 1 who had received a dose of 1.5 g/m2/day. Thus, DLT occurred at a dose of 1.5 g/m2/day, the starting level in the current study. As a result, the trial was stopped. Eight of 12 patients achieved a complete response, 3 achieved a partial response, and 1 patient died before response assessment.

CONCLUSIONS

Hyperfractionated WBRT with concurrent BUdR after chemotherapy was found to result in modest disease control but has unacceptable neurotoxicity. Cancer 2003;98:1021–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11627
Time course of early motor and neuropathological anomalies in a knock‐in mouse model of Huntington's disease with 140 CAG repeats
Authors: Menalled Liliana B. , Sison Jessica D. , Dragatsis Ioannis , Zeitlin Scott , Chesselet Marie‐Françoise
Published: August 2003

Huntington's disease (HD) is caused by an abnormal expansion of CAG repeats in the gene encoding huntingtin. The development of therapies for HD requires preclinical testing of drugs in animal models that reproduce the dysfunction and regionally specific pathology observed in HD. We have developed a new knock‐in mouse model of HD with a chimeric mouse/human exon 1 containing 140 CAG repeats inserted in the murine huntingtin gene. These mice displayed an increased locomotor activity and rearing at 1 month of age, followed by hypoactivity at 4 months and gait anomalies at 1 year. Behavioral symptoms preceded neuropathological anomalies, which became intense and widespread only at 4 months of age. These consisted of nuclear staining for huntingtin and huntingtin‐containing nuclear and neuropil aggregates that first appeared in the striatum, nucleus accumbens, and olfactory tubercle. Interestingly, regions with early pathology all receive dense dopaminergic inputs, supporting accumulating evidence for a role of dopamine in HD pathology. Nuclear staining and aggregates predominated in striatum and layer II/III and deep layer V of the cerebral cortex, whereas neuropil aggregates were found in the globus pallidus and layer IV/superficial layer V of the cerebral cortex. The olfactory system displayed early and marked aggregate accumulation, which may be relevant to the early deficit in odor discrimination observed in patients with HD. Because of their early behavioral anomalies and regionally specific pathology, these mice provide a powerful tool with which to evaluate the effectiveness of new therapies and to study the mechanisms involved in the neuropathology of HD. J. Comp. Neurol. 465:11–26, 2003. © 2003 Wiley‐Liss, Inc.
Complementary distribution of vesicular glutamate transporters 1 and 2 in the nucleus accumbens of rat: Relationship to calretinin‐containing extrinsic innervation and calbindin‐immunoreactive neurons
Authors: Härtig Wolfgang , Riedel Anett , Grosche Jens , Edwards Robert H. , Fremeau Robert T. , Harkany Tibor , Brauer Kurt , Arendt Thomas
Published: August 2003

The caudomedial shell of the rat nucleus accumbens exhibits inhomogeneous distribution patterns of the vesicular glutamate transporters 1 (VGLUT1) and 2 (VGLUT2). This paper focuses on the question of whether patterns of VGLUT1 and VGLUT2 correspond to cytoarchitectonically and cytochemically defined subterritories of the caudomedial shell region. VGLUT2 was shown to be coexpressed with calretinin in the dense axonal plexus known to emanate from the paraventricular thalamic nucleus. In regions termed corridors, which are spared by this paraventricular thalamic innervation, axonal terminals were found to be clustered and VGLUT1‐immunoreactive. It is assumed that these fibers originate in the prelimbic cortex and/or in the parvicellular basal amygdaloid nucleus known to project to accumbal shell components. Our findings confirm the existence of two well‐separated neuronal circuits in the caudomedial shell that are dominated by two different excitatory input systems originating from either thalamic, cortical, or cortex‐like amygdaloid sources. The large lateral corridors—which resemble the accumbal core not only in respect to their VGLUT1 immunolabeling but also concerning their content of calbindin‐positive cells—may represent a component of the anatomically weakly defined accumbal shore region. J. Comp. Neurol. 465:1–10, 2003. © 2003 Wiley‐Liss, Inc.
Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract
Authors: Ward Sean M. , Bayguinov Julia , Won Kyung‐Jong , Grundy David , Berthoud Hans R.
Published: August 2003

The gastrointestinal (GI) tract responds to a variety of stimuli through local and centrally mediated pathways. Changes in the intestinal microenvironment are sensed by vagal, spinal, and intrinsic primary afferent fibers. Sensory nerve endings located close to the lumen of the GI tract respond to pH, chemical composition of lumenal contents, or distortion of the mucosa. Afferents within the muscle layers are thought to be tension sensitive, whereas those located within the myenteric plexus are also thought to respond to changes in chemical composition and humoral substances. Subpopulations of these afferent fibers are activated by capsaicin. However, the exact location of these nerves is currently not known. The vanilloid receptor (VR1) is a nonselective cation channel that is activated by capsaicin, acid, and temperature. Antibodies to VR1 make it possible to determine the location of these afferents, their morphology, and their relationships with enteric nerves and other cell types in the GI tract. VR1‐like immunoreactivity was observed on nerves within myenteric ganglia and interganglionic fiber tracts throughout the GI tract. VR1 nerves were also observed within the muscle layers and had an irregular profile, with varicose‐like swellings along their lengths. Blood vessels within the GI wall had VR1‐immunoreactive nerve fibers associated with them. VR1‐like nerves and other immunopositive cells were also observed within the mucosa. In summary, VR1‐like immunoreactivity was found in several locations within the GI tract and may provide sensory integration of chemical, physical, or inflammatory stimuli. VR1‐like fibers appear to be predominantly spinal in origin, but a few vagal VR1‐like fibers exist in the stomach. J. Comp. Neurol. 465:121–135, 2003. © 2003 Wiley‐Liss, Inc.
Evidence for estrogenic regulation of gonadotropin‐releasing hormone neurons by glutamatergic neurons in the ewe brain: An immunohistochemical study using an antibody against vesicular glutamate transporter‐2
Authors: Pompolo Sueli , Pereira Alda , Scott Christopher James , Fujiyma Fumino , Clarke Iain James
Published: August 2003

Gonadotropin‐releasing hormone (GnRH) secretion is controlled by various factors, including the excitatory neurotransmitter glutamate. Estrogen (E) regulates GnRH secretion by means of E‐responsive cells in the brain that relay the feedback effects to the preoptic area (POA). We used an antibody to vesicular glutamate transporter 2 (VGluT2) to label glutamatergic neurons in the areas of the ewe brain that control GnRH secretion. VGluT2‐immunoreactive cells were observed in the arcuate nucleus (ARC)/ventromedial hypothalamic nucleus (VMH) complex, POA, bed nucleus of stria terminalis (BnST), and A1 and A2 cell groups in the brainstem. In three ewes, E receptor‐α was detected in 52–61% of glutamatergic neurons in ARC/VMH, 37–52% of neurons in the POA, and 37–58% of neurons in the BnST. E injection (i.m. or i.v.) increased the percentage of glutamatergic cells that expressed Fos protein in the ARC (P< 0.01 andP< 0.001, respectively). In six ewes, injection of the retrograde tracer Fluoro‐Gold into the POA labeled cells in the ARC and 6–29% of these were also VGluT2‐immunoreactive. Double‐labeling of varicosities in the POA showed colocalization of VGluT2 in 12.5 ± 3% of dopamine β‐hydroxylase–immunoreactive terminals, indicating that a subset of glutamatergic inputs could arise from brainstem noradrenergic neurons cells. In the POA, 60% of GnRH neurons had close appositions that were VGluT2‐immunoreactive. We conclude that E‐responsive glutamatergic neurons arising from the brainstem, the BnST, and ARC/VMH provide input to the POA and may be involved in the regulation of GnRH secretion. J. Comp. Neurol. 465:136–144, 2003. © 2003 Wiley‐Liss, Inc.
ATBF1‐A protein, but not ATBF1‐B, is preferentially expressed in developing rat brain
Authors: Ishii Yoko , Kawaguchi Makoto , Takagawa Kiyoshi , Oya Takeshi , Nogami Shigeharu , Tamura Amane , Miura Yutaka , Ido Akio , Sakata Nobuo , Hashimoto‐Tamaoki Tomoko , Kimura Tomoatsu , Saito Takayoshi , Tamaoki Taiki , Sasahara Masakiyo
Published: August 2003

The ATBF1 gene encodes transcription factors containing four homeodomains and multiple zinc finger motifs. However, the gene products have yet to be identified and the role remains unknown in vivo. In this study, we raised an antiserum for ATBF1 and found high levels of expression of ATBF1 in developing rat brain. Western and Northern blot analyses detected a 400 kDa protein and 12.5 kb mRNA in developing rat brain, respectively; both corresponding to ATBF1‐A but not the B isoform. The protein was highly expressed in the midbrain and diencephalon and mRNA was highly expressed in the brainstem, mostly in embryo and neonatal brain. Immunohistochemistry identified postmitotic neurons in the brainstem as the major site of ATBF1 expression, and the expression levels varied depending on age of and location in the brain. Expression was transient and weak in the precursor cells at early neurogenesis. ATBF1 decreased postnatally, but remained in mature neurons, including those expressing DOPA decarboxylase (DDC). High levels of ATBF1 were expressed in precursor cells in accordance with neurogenesis and were continued to the mature neurons in specific areas such as the inferior colliculus. Expression was not significant from precursor cells to mature neurons in the cerebral cortex and hippocampus. ATBF1 and its Drosophila homolog, Zfh‐2, are known to regulate cell differentiation and proliferation via the interaction with either of the basic helix‐loop‐helix transcription factors, c‐myb, or the DDC gene. Together with these reported functions the expression features detected here suggest that ATBF1 may participate in the regulation of neuronal cell maturation or region‐specific central nervous system differentiation. J. Comp. Neurol. 465:57–71, 2003. © 2003 Wiley‐Liss, Inc.
Glomerular territories in the olfactory bulb from the larval stage of the sea lamprey Petromyzon marinus
Authors: Frontini Andrea , Zaidi Aliya U. , Hua Hong , Wolak Tomasz P. , Greer Charles A. , Kafitz Karl W. , Li Weiming , Zielinski Barbara S.
Published: August 2003

The goal of this study was to investigate the spatial organization of olfactory glomeruli and of substances relevant to olfactory sensory neuron activity in the developing agnathan, the sea lamprey Petromyzon marinus. A 45‐kD protein immunoreactive to Golf, a cAMP‐dependent olfactory G protein, was present in the ciliary fraction of sea lamprey olfactory epithelium and in olfactory sensory neurons of larval and adult sea lampreys. This result implies that Golf expression was present during early vertebrate evolution or evolved in parallel in gnathostome and agnathostome vertebrates. Serial sectioning of the olfactory bulb revealed a consistent pattern of olfactory glomeruli stained by GS1B4 lectin and by anterograde labeling with fluorescent dextran. These glomerular territories included the dorsal cluster, dorsal ring, anterior plexus, lateral chain, medial glomeruli, ventral ring, and ventral cluster. The dorsal, anterior, lateral, and ventral glomeruli contained olfactory sensory axon terminals that were Golf‐immunoreactive. However, a specific subset, the medial glomeruli, did not display this immunoreactivity. Olfactory glomeruli in the dorsal hemisphere of the olfactory bulb, the dorsal cluster, dorsal ring, anterior plexus, lateral chain, and medial glomeruli, were seen adjacent to 5HT‐immunoreactive fibers. However, glomeruli in the ventral hemisphere, the ventral ring, and ventral cluster did not display this association. The presence of specific glomerular territories and discrete glomerular subsets with substances relevant to olfactory sensory neuron activity suggest a spatial organization of information flow in the lamprey olfactory pathway. J. Comp. Neurol. 465:27–37, 2003. © 2003 Wiley‐Liss, Inc.
Somatosensory organization and behavior in naked mole‐rats: II. Peripheral structures, innervation, and selective lack of neuropeptides associated with thermoregulation and pain
Authors: Park Thomas J. , Comer Christopher , Carol Andrew , Lu Ying , Hong H.‐S. , Rice Frank L.
Published: August 2003

African naked mole‐rats are subterranean rodents that have a robust orienting response to stimulation of unique vibrissa‐like body hairs that are widely spaced over an otherwise hairless skin. To determine whether these large body hairs have a specialized organization similar to facial vibrissae, the structure and innervation of facial vibrissa follicles, body hair follicles, and intervening skin in naked mole‐rats was compared with that in rats and a furred African mole‐rat species (the common mole‐rat). Immunofluorescence and lectin‐binding analyses revealed that the body hair follicles in naked mole‐rats were exceptionally large and well innervated, similar to guard hairs of furred species. However, these body vibrissae lacked the anatomic specializations and unique types of innervation affiliated with follicle sinus complexes of facial vibrissae. In contrast to the furred species, naked mole‐rats had a paucity of Aβ‐fiber Merkel endings at all peripheral locations. Naked mole‐rats also were completely lacking in cutaneous C‐fibers immunoreactive for substance P and calcitonin gene‐related peptide. In contrast, the hairless skin of the naked mole‐rats had an exceptional abundance of presumptive Aδ‐fibers. The unusual features of the cutaneous innervation in naked mole‐rats are presumably adaptations to their subterranean environment and that they are the only known poikilothermic mammal. The features of this mammalian model system provide unique opportunities to discriminate mechanisms related to tactile spatial orientation, vascular regulation, and nociception. J. Comp. Neurol. 465:104–120, 2003. © 2003 Wiley‐Liss, Inc.
Timing of neuronal and glial ultrastructure disruption during brain slice preparation and recovery in vitro
Authors: Fiala John C. , Kirov Sergei A. , Feinberg Marcia D. , Petrak Lara J. , George Priya , Goddard C. Alex , Harris Kristen M.
Published: August 2003

Hippocampal slices often have more synapses than perfusion‐fixed hippocampus, but the cause of this synaptogenesis is unclear. Ultrastructural evidence for synaptogenic triggers during slice preparation was investigated in 21‐day‐old rats. Slices chopped under warm or chilled conditions and fixed after 0, 5, 25, 60, or 180 minutes of incubation in an interface chamber were compared with hippocampi fixed by perfusion or by immersion of the whole hippocampus. There was no significant synaptogenesis in these slices compared with perfusion‐fixed hippocampus, but there were other structural changes during slice preparation and recovery in vitro. Whole hippocampus and slices prepared under warm conditions exhibited an increase in axonal coated vesicles, suggesting widespread neurotransmitter release. Glycogen granules were depleted from astrocytes and neurons in 0‐min slices, began to reappear by 1 hour, and had fully recovered by 3 hours. Dendritic microtubules were initially disassembled in slices, but reassembled into normal axial arrays after 5 minutes. Microtubules were short at 5 minutes (12.3 ± 1.1 μm) but had recovered normal lengths by 3 hours (84.6 ± 20.0 μm) compared with perfusion‐fixed hippocampus (91 ± 22 μm). Microtubules appeared transiently in 15 ± 3% and 9 ± 4% of dendritic spines 5 and 25 minutes after incubation, respectively. Spine microtubules were absent from perfusion‐fixed hippocampus and 3‐hour slices. Ice‐cold dissection and vibratomy in media that blocked activity initially produced less glycogen loss, coated vesicles, and microtubule disassembly. Submersing these slices in normal oxygenated media at 34°C led to glycogen depletion, as well as increased coated vesicles and microtubule disassembly within 1 minute. J. Comp. Neurol. 465:90–103, 2003. © 2003 Wiley‐Liss, Inc.
Anatomical markers for the subdivisions of the barn owl's inferior‐collicular complex and adjacent peri‐ and subventricular structures
Authors: Wagner Hermann , Güntürkün Onur , Nieder Bärbel
Published: August 2003

The anatomy of the inferior‐collicular complex of the barn owl, situated below the fourth ventricle in the tectal lobe, was studied by determining the distribution of antigens with antibodies directed against tyrosine hydroxylase, γ‐aminobutyric acid (GABA)Aβ, dopamine‐ and cyclic AMP‐regulated phosphoprotein (DARPP‐32), calretinin, and calbindin. Additionally, the somata were stained with cresyl violet, and fibers were marked according to the Gallyas procedure. These markers were chosen to allow for an easy delineation of the boundaries between the subnuclei of the inferior colliculus. We could discriminate eight structures that belong to the three subnuclei of the inferior colliculus [the central nucleus (ICC), the superficial nucleus (ICS), the external nucleus (ICX)] and to the optic tectum. Periventricular tectal layers 15a and 15b stained well with all the antibodies used. The ICS, embedded in tectal layer 15a, may be divided into a dorsal and a ventral lamina. It does not have direct contact with the other nuclei of the inferior colliculus. The border between tectal layer 15a and ICX was well marked by all antibodies, but less so in Gallyas and cresyl violet stains. The ICC consists of a core and a medial and lateral shell. The core was clearly demarcated with antibodies against calretinin and calbindin. The border between the lateral shell and the ICX was marked less well than the borders between ICX and 15a, but the somata were much more darkly labeled with the DARPP‐32 antibody in ICX than in the lateral shell of ICC. None of the markers delineated the border between the medial and lateral shell of ICC. J. Comp. Neurol. 465:145–159, 2003. © 2003 Wiley‐Liss, Inc.
Broca's region: Cytoarchitectonic asymmetry and developmental changes
Authors: Amunts Katrin , Schleicher Axel , Ditterich Annette , Zilles Karl
Published: August 2003

Functional imaging and clinical studies in children and adults have provided evidence of developmental changes in the hemispheric specialization for language. Whereas cytoarchitectonic asymmetry has been demonstrated in Broca's region of adults, the anatomical correlates of developmental changes in language dominance are largely unknown. In the present postmortem study of 34 human brains (ages ranging from 3.5 months to 85 years), the cytoarchitecture of areas 44 and 45 as the putative anatomical correlates of Broca's region, their developmental changes, and interhemispheric asymmetry were analyzed. Asymmetry as estimated by Euclidean distances between feature vectors of cytoarchitectonic profiles of left and right areas 44 and 45 was already found in 1‐year‐old infants. Asymmetry tended to increase with age, which was significant in area 45, but not in area 44. An adult‐like, left‐larger‐than‐right asymmetry in the volume fraction of cell bodies [gray level index (GLI)] was reached at approximately 5 years in area 45 and 11 years in area 44. These time points indicate a delayed development of the cytoarchitectonic asymmetry in Broca's region in comparison with that of the primary motor cortex. It may be hypothesized that the delayed maturation is the microstructural basis of the development of language abilities and the influence of language practice on cytoarchitecture during childhood. Interhemispheric asymmetry in the cytoarchitecture of areas 44 and 45 continues to change throughout life. We conclude that the cytoarchitectonic asymmetry of areas 44 and 45 is a result of microstructural plasticity that endures throughout almost the whole lifespan. J. Comp. Neurol. 465:72–89, 2003. © 2003 Wiley‐Liss, Inc.
Inner retinal neurons display differential responses to N‐methyl‐D‐aspartate receptor activation
Authors: Sun Daniel , Rait Julian L. , Kalloniatis Michael
Published: August 2003

The N‐methyl‐D‐aspartate (NMDA) responses of neurons from within the inner rabbit retina were mapped using a channel permeable cation, 1‐amino‐4‐guanidobutane (agmatine, AGB). Serial sections were subsequently probed with immunoglobulins targeting AGB, glutamate, γ‐aminobutyric acid (GABA), and glycine to visualize the NMDA responses of neurochemical subpopulations of neurons. Most inner retinal subpopulations of neurons demonstrated an NMDA concentration‐dependent increase in activation. This NMDA‐induced activation displayed a distinct pattern, with the most sensitive class to least sensitive class ranking being GC > GABA cAC > GABA/Gly cAC > Gly cAC > GABA dAC (GC, ganglion cells; AC, amacrine cells; c, conventional; d, displaced; Gly, glycine). The variable NMDA response may reflect differences in NMDA receptor subunit disposition or differences in receptor density. In addition to the variable NMDA activation pattern, we found that virtually all ganglion cells (87%) showed NMDA‐gated AGB entry, compared with only 58% of amacrine cells. We conclude that a large cohort of amacrine cells do not possess functional NMDA receptors. In addition to most ganglion cells being activated by NMDA, a large subpopulation displayed the highest sensitivity to NMDA application. The functional significance of this finding is that the ganglion cell population will be the first neuronal class to be susceptible to glutamate‐induced neurotoxicity mediated through the NMDA receptor. The addition of betaxolol significantly reduced NMDA‐mediated AGB entry into most neuronal groups (ganglion cells, GABA, and glycine amacrine cells), with the greatest effect being on ganglion cells. Betaxolol had no significant effect on NMDA‐gated entry of AGB on the GABA/Gly amacrine cell population. J. Comp. Neurol. 465:38–56, 2003. © 2003 Wiley‐Liss, Inc.
Crystal growth of barium aluminum (gallium) borates
Authors: Kimura H. , Miyazaki A. , Maiwa K. , Nakamura H.
Published: August 2003

Crystals listed in the JCPDS card in the BaO‐B2O3‐Al2O3 and BaO‐B2O3‐Ga2O3 systems are of interest from a viewpoint of the Second Harmonic Generation (SHG). Ba5Al4B12O29 and Ba5Ga4B12O29 are promising new crystals with SHG activity and with congruent melting mode. These crystals can be grown by the Czochralski method with a size of 3 × 3 × 0.1‐1mm. (© 2003 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Electrochemical growth and properties of LaMn1−xCoxO3 (0 < x ≤ 1) single crystals
Authors: Khalyavin D. D. , Shiryaev S. V. , Bychkov G. L. , Barilo S. N. , Ustinovich S. N. , Szymczak H. , Szymczak R. , Allenspach P.
Published: August 2003

Single crystals of LaMn1−xCoxO3 (0 < x < 1) with distorted perovskite structure have been obtained by the electrodeposition technique at anode from flux melt using Cs2MoO4‐MoO3 binary system as solvent. An investigation of magnetic and electrical properties of the obtained crystals as well as its comparison with those for ceramic samples of the same composition were carried out. A much weaker interplay between magnetic and electrical properties and a smaller ∼8% magnetoresistance were found in the ternary oxide crystals slightly doped by Co on the verge of transition to ferromagnetic state in comparison to the data have been reported for LaMnO3+δ single crystals. (© 2003 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Influence of simultaneous doping of Tl and Bi on microstructure and critical current density of HgBa2Ca2Cu3O8+δ
Authors: Giri Rajiv , Verma G. D. , Tiwari R. S. , Srivastava O. N.
Published: August 2003

It has been found that simultaneous doping of Tl and Bi at Hg site of HgBa2Ca2Cu3O8+δ HTSC phase induces interesting microstructural variants in the form of long period polytypoid (LPP) like structure embodying native defect substructures. It has been observed that the as synthesized (HgTl0.2−xBix)Ba2Ca2Cu3O8+δ (with x = 0.05, 0.10, 0.15) phases have superconducting onset transition temperature (Tc) of about ∼133 K. However, the intragrain critical current density (Jc) for the various materials with different compositions varies significantly. It varies from 6.2 × 106 A/cm2 to 2.9 × 106 A/cm2 at 5 K and 1 T for (HgTl0.10Bi10)Ba2Ca2Cu3O8+δ and (HgTl0.15Bi0.05)Ba2Ca2Cu3O8+δ HTSC phase respectively. A correlation between the intragrain Jc and the defect substructures has been found to be present. This correlation has been described and disscussed. (© 2003 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)