Midbrain circuits that set locomotor speed and gait selection.

Locomotion is a fundamental motor function common to the animal kingdom. It is implemented episodically and adapted to behavioural needs, including exploration, which requires slow locomotion, and escape behaviour, which necessitates faster speeds. The control of these functions originates in brainstem structures, although the neuronal substrate(s) that support them have not yet been elucidated. Here we show in mice that speed and gait selection are controlled by glutamatergic excitatory neurons (GlutNs) segregated in two distinct midbrain nuclei: the cuneiform nucleus (CnF) and the pedunculopontine nucleus (PPN). GlutNs in both of these regions contribute to the control of slower, alternating-gait locomotion, whereas only GlutNs in the CnF are able to elicit high-speed, synchronous-gait locomotion. Additionally, both the activation dynamics and the input and output connectivity matrices of GlutNs in the PPN and the CnF support explorative and escape locomotion, respectively. Our results identify two regions in the midbrain that act in conjunction to select context-dependent locomotor behaviours.

Multiple myeloma: an immunologic profile. II. Bone marrow studies.

Bone marrow mononuclear cell populations were studied in 35 patients without myeloma, 39 patients with multiple myeloma, and 15 patients with benign monoclonal gammopathy. Bone marrow mononuclear cell receptors, responses to mitogens or allogeneic stimuli, and suppressive effects on in vitro peripheral blood lymphocyte (PBL) function were studied. In bone marrow cell populations from patients with untreated multiple myeloma, the percent of complement receptor-bearing cells and the pokeweed mitogen- and concanavalin A-stimulated responses were significantly greater than were those in bone marrow cell populations from patients without myeloma. Sheep red blood cell receptor-bearing cells were significantly greater in marrow populations from treated multiple myeloma patients compared to those from untreated multiple myeloma patients. Sheep red blood cell receptor-bearing cells from the bone marrow of multiple myeloma patients suppressed responses of the multiple myeloma patients' PBL's to autologous mitomycin C-treated bone marrow plasma cells and to allogeneic stimuli in one-way mixed leukocyte culture. Complement receptor-bearing cells suppressed the response to pokeweed mitogen. The presence of lymphocytes in the marrow compartment that are capable of suppressing the response of myeloma patients' PBL's to plasma cell antigens may be significant in the pathogenesis of multiple myeloma.

Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial (B-22) to determine if intensifying but maintaining the total dose of cyclophosphamide (Cytoxan, Bristol-Myers Squibb Oncology, Princeton, NJ) in a doxorubicin (Adriamycin, Pharmacia, Kalamazoo, MI)-cyclophosphamide combination (AC), or if intensifying and increasing the total dose of cyclophosphamide improves the outcome of women with primary breast cancer and positive axillary nodes. PATIENTS AND METHODS: Patients (N = 2,305) were randomized to receive either four courses of standard AC therapy (group 1); intensified therapy, in which the same total dose of cyclophosphamide was administered in two courses (group 2); or intensified and increased therapy, in which the total dose of cyclophosphamide was doubled (group 3). The dose and intensity of doxorubicin were similar in all groups. Disease-free survival (DFS) and overall survival were determined using life-table estimates. RESULTS: There was no significant difference in DFS (P = .30) or overall survival (P = .95) among the groups through 5 years. At 5 years, the DFS of women in group 1 was similar to that of women in group 2 (62% v 60%, respectively; P = .43) and to that of women in group 3 (62% v 64%, respectively; P = .59). The 5-year survival of women in group 1 was similar to that of women in group 2 (78% v 77%, respectively; P = .86) and to that of women in group 3 (78% v 77%, respectively; P = .82). Grade 4 toxicity increased in groups 2 and 3. Failure to note a difference in outcome among the groups was unrelated to either differences in amount and intensity of cyclophosphamide or to dose delays and intervals between courses of therapy. CONCLUSION: Intensifying or intensifying and increasing the total dose of cyclophosphamide failed to significantly improve either DFS or overall survival in any group. It was concluded that, outside of a clinical trial, dose-intensification of cyclophosphamide in an AC combination represents inappropriate therapy for women with primary breast cancer.

Factors affecting the in vitro evolution of a myeloma cell line.

A continuously growing plasma cell line has been established from the bone marrow of a multiple myeloma patient. Initial growth of the cells was dependent on the presence of bone marrow stromal cells. Following initial outgrowth the cells were maintained by transfer onto non-autocthonous bone marrow stromal cultures. Following approximately one year of continuous growth, a subline was derived which could be grown independently of feeder cells. These stromal-cell-independent myeloma cells nevertheless retained dependence for a growth factor present in stromal-cell-conditioned media. The relevant factor in the conditioned media was determined to be interleukin-6 (IL-6). The cells also ultimately became independent of the conditioned media. These latter cells were shown to contain mRNA for IL-6 and eventually began to secrete IL-6. This cell line has thus progressed from complete dependence on stromal cells to IL-6-dependent growth in the absence of stromal cells to complete self sufficient growth. This in vitro progression may reflect an in vivo pattern of myeloma development.

The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin's lymphoma receiving initial CHOP chemotherapy: a risk factor analysis.

The purpose of this historical case series study was to evaluate the association of age on delivered dose intensity of initial CHOP (cyclophosphamide/doxorubicin/ vincristine/prednisone) chemotherapy and the occurrence of hospitalizations for febrile neutropenia for patients with intermediate-grade non-Hodgkin's lymphoma (NHL). Findings are reported for 12 managed community and academic practices. Medical records of 930 NHL patients not enrolled on clinical trial protocols were reviewed. We reported on 577 of the study patients (62%) who received initial CHOP chemotherapy. Median age of the patients was 65.1 years. Older patients (age > or = 65 years) had more hospitalizations for febrile neutropenia (28% vs. 16%; P < 0.05) than younger patients (age, 18-64 years). In patients with advanced-stage NHL (stage III/IV), older patients received fewer cycles of CHOP (< 6 cycles, 35% vs. 22%; P < 0.05) than younger patients. Older patients were planned for lower average relative dose intensity (ARDI < or = 80%; P < 0.05) and had more heart disease and comorbid conditions (P < 0.05) than younger patients. Multiple logistic regression models showed that older patients were more likely to receive a lower dose intensity (ARDI < or = 80%; odds ratio = 2.46, 95% confidence interval [CI]: 1.62-3.72) during their first 3 cycles of therapy and to experience more hospitalizations for febrile neutropenia (odds ratio = 2.17, 95% CI: 1.43-3.30). We found the dose intensity of delivered CHOP chemotherapy for elderly patients to be less than standard CHOP therapy and the risk of hospitalizations for febrile neutropenia to be greater than in younger patients. Prospective clinical trials examining supportive care measures, such as colony-stimulating factor, for elderly NHL patients are recommended.

High-dose cisplatin and mitomycin C in advanced non-small cell lung cancer: a phase II study of the Northern California Oncology Group.

To investigate chemotherapeutic dose intensity in advanced non-small-cell lung cancer (NSCLC), we evaluated a pharmacokinetically designed schedule of high-dose cisplatin (200 mg/m2 per 28-day cycle) plus mitomycin C. Between March 1987 and March 1989, 62 patients were registered for a phase II study of the Northern California Oncology Group (NCOG). The treatment schedule consisted of cisplatin in hypertonic saline given on a divided days 1 and 8 schedule (100 mg/m2 on each day) plus mitomycin C given at a dose of 8 mg/m2 on day 1 of each cycle. In 61 patients evaluable for response analysis, the overall response rate was 39% (24/61), with a complete response being achieved in 6% (4/61) of cases and a partial response, in 33% (20/61). The response according to reviewed histologic subtype included squamous, 53% of patients (10/19); large cell, 31% (4/13); and adenocarcinoma, 34% (10/29). The median survival for all patients was 29.3 weeks. The mean cisplatin and mitomycin C delivered dose intensities in this study were 45 mg/m2 per week (90% of the projected dose) and 1.5 mg/m2 per week (75%). The toxicity of this combination regimen in the 62 enrolled patients was significant but manageable. Leukopenia (WBC, less than 1,000/mm3) and thrombocytopenia (platelets, less than 25,000/mm3) occurred in 3% and 8% of patients treated, respectively. Dose-limiting renal toxicity and clinically significant ototoxicity developed in 8 patients each (13%), and a peripheral sensory neuropathy was observed in 17 cases (27%). Whether this type of dose-intensive therapy results in an improved therapeutic index in NSCLC is currently being evaluated in a randomized comparative trial versus standard-dose cisplatin therapy.

An electromechanical analyzer using histogram techniques.

In behavioral studies it is often necessary to classify events and store the number of events occurring in each classification. The classification requirements may be either functions of amplitude (i.e., intensity, force, peaks, etc.) or time (i.e., duration, interval, etc.). The following describes an analyzer capable of classifying events according to their duration, interval, or time of occurrence, and storing and displaying the number of such events in each classification.

Primary hemangiosarcoma of the spleen associated with leukocytosis and abnormal spleen scan.

A 60-year-old Filipino man, who presented with left sided abdominal pain and weight loss, was found to have splenomegaly, an abnormal spleen scan and a leukemoid reaction. Primary splenic hemangiosarcoma was found at splenectomy. Metastases first occurred in the cervical lymph nodes two years after diagnosis. Despite treatment with doxorubicin and radiation therapy there was recurrence in lymph nodes and scan evidence of liver and bone metastases. The patient died 38 months after diagnosis. A liver-spleen scan is helpful in establishing an early diagnosis, and splenectomy before rupture occurs is advisable. The role of chemotherapy needs to be defined.

Abnormalities in immune regulation precede the development of multiple myeloma.

Immunosuppression of immunoglobulin synthesis seen in patients with multiple myeloma is in part due to immunosuppressive CD5 positive B cells. In a 13 year longitudinal study of an IgA-deficient blood donor who developed multiple myeloma, the presence of immunosuppressive CD5 positive B cells and T cells preceded the diagnosis of overt multiple myeloma and the appearance of immunosuppressive monocytes. These data argue that certain immune defects may be involved in the development of myeloma and are not simply a consequence of overt malignancy.

CD5 positive immunoregulatory B cell subsets.

B-chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease often expressed as a clonal expansion of CD5+ B cells. We report the characterization of CD5+ B cells from two unique B-CLL patients. Cells from patient 1 coexpressed CD5 (leu-1), CD19 (Leu-12), CD20 (B1), and HLA-DR; they were CD10 (J5), CD21 (B2), CD22 (Leu-14), CD25 (IL2-R1), PCA-1, surface, and cytoplasmic Ig negative. They suppressed normal peripheral blood lymphocyte (PBL) pokeweed mitogen (PWM) -stimulated immunoglobulin (Ig) synthesis greater than 80%. Cells from patient 2 were CD5 (Leu-1), CD19 (Leu-12), CD20 (B1), CD21 (B2), CD22 (Leu-14), HLA-DR, IgM, and kappa positive. They were negative for CD10 (J5), CD25 (IL2-R1), and PCA-1. These cells did not suppress normal PBL PWM-stimulated Ig synthesis but produced a monoclonal IgM kappa protein with rheumatoid factor-like activity. These observations suggest that there are different CD5+ B cell subsets, one immunosuppressive and the other autoreactive.

Effects of plasmapheresis on peripheral blood mononuclear cell populations from patients with macroglobulinemia.

Effects of plasmapheresis on peripheral blood T-cell, B-cell, monocyte, and natural-killer-cell populations were studied in ten macroglobulinemia patients with hyperviscosity syndrome. Following plasmapheresis, there was a transient decrease in the number of T4+ helper cells and a longer-lasting decrease in the number of Leu-7+ natural killer cells and Mo2+ monocytes. In addition, there was a greater than 50% decrease in the in vitro ingestion capacity of monocytes. Although no significant changes in the numbers of IgM+, B1+, B4+, or PCA+ B cells (P greater than .05) were detected, there was a highly significant (P less than .01) increase in I2 antigen density on the surface of IgM+ B cells and in the bromodeoxyuridine uptake by these cells 7-9 days after plasmapheresis. These findings suggest that following plasmapheresis, IgM+ B cells are activated. Using flow cytometry to determine when maximum IgM+ B cell activation occurs by measuring I2 antigen density on the cell surface may be useful in determining the postplasmapheresis timing of chemotherapy in macroglobulinemia patients with hyperviscosity syndrome who require more aggressive treatment.

Alternative care. Patient choices for adjunct therapies within a cancer center.

PURPOSE: Prompted by an increased interest in and awareness of alternative medicine, the Sutter Cancer Center in Sacramento, California, sponsored a telephone survey of its cancer patients. The primary purpose of this 1994 survey was: 1) to determine patient perceptions and attitudes regarding alternative care providers, and 2) to determine whether the Sutter Cancer Center should provide support for these types of therapies to its patients. DESCRIPTION OF STUDY: The Center conducted a 95-item telephone survey of its patients with cancer, using an independent professional research firm. A random sample of 503 adult patients completed the 15-minute telephone survey between January 27 and March 8, 1994. The sample included more women than men (62%, 38%, respectively), and patients ranged in age from 18 to 88 years. All respondents had been treated for cancer at the Center within the past 2 years. Survey questions included areas such as cancer diagnosis, awareness of alternative therapies, attitude toward alternative therapies, and perception of oncologists' attitude toward alternative therapies. The analysis of the survey results contained two phases: descriptive analysis and comparative analysis. The descriptive aspect is included in this report. RESULTS: Of the 503 respondents, 82 (16%) had considered utilizing alternative therapy for cancer after a diagnosis was made. Most respondents were moderately familiar with alternative therapy, such as nutrition therapy (59%), herbal therapy (63%), and acupuncture (62%). Only 6% of respondents actually saw a provider of alternative therapies; providers were most frequently nutritionists, counselors, herbalists, and massage therapists. The user patient profile clearly indicates that usage is highest in patients with a diagnosis of at least 1 year. Seventy-five percent reported that they would prefer to receive a referral from their doctors, while 20% would prefer to use a telephone referral line. Two thirds of patients felt that alternative care providers should be encouraged by the medical profession, and 85% indicated that alternative care should be offered at the cancer center as part of oncology treatment. CLINICAL IMPLICATIONS: The results of this survey clearly reflect the patients' desires to integrate mainstream medicine with some forms of alternative/complementary medicine. Consequently, the Sutter Cancer Center has established a multidisciplinary group of healthcare professionals, including oncologists, nurses, social workers, and alternative practitioners, to evaluate the clinical, psychosocial, and financial impact of integrating wellness/complementary medicine into the existing treatment model at this facility. Providing alternative therapy within a cancer center ensures the availability of both the most advanced conventional treatment and care as well as accurate information and guidance with regard to alternative therapies. This service allows the patient and the cancer care team to focus not only on the patient's physical symptoms, but also on his or her overall quality of life.