Level-dependent representation of stimulus frequency in cat primary auditory cortex

The tonotopicity of the cat's primary auditory cortex (AI) is thought to provide the framework for frequency-specific processing in that field. This study was designed to assess this postulate by examining the spatial distribution of neurons within AI that are activated by a single tonal frequency delivered to the contralateral ear. Distributions obtained at each of several stimulus levels were then compared to assess the influence of stimulus amplitude on the spatial representation of a given stimulus frequency in AI. Data were obtained from 308 single units in AI of four adult, barbiturate-anesthetized cats, using extracellular recording methods. Stimuli were 40-ms tone pulses presented through calibrated, sealed stimulating systems. In each animal, the CF (stimulus frequency to which the unit is most sensitive), threshold at CF, response/level function at CF, and binaural interactions were determined for isolated neurons (usually one per track) in 60-90 electrode tracks. For each unit, regardless of its CF, responses to 40 repetitions of contralateral tones of a single frequency, presented at each of four or five sound pressure levels (SPLs) in the range from 10 to 80 dB were obtained. Different test frequencies were used in each of four cats (1.6, 8.0, 11.0, and 16.0 kHz). For tones of each SPL, we generated maps of the response rates across the cortical surface. These maps were then superimposed on the more traditional maps of threshold CF. All units whose CF was equal to the test frequency could be driven at some SPL, given an appropriate monaural or binaural configuration of the stimulus. There was a clear spatial segregation of neurons according to the shapes of their CF tone response/level functions. Patches of cortex, often occupying more than 2 mm2, seemed to contain only monotonic or only nonmonotonic units. In three cortices, a patch of nonmonotonic cells was bounded ventrally by a patch of monotonic cells, and in one of these cases, a second patch of monotonic cells was found dorsal to the nonmonotonic patch. Contralateral tones of any given SPL evoked excitatory responses in discontinuous cortical territories. At low SPLs (10, 20 dB), small foci of activity occurred along the isofrequency line representing the test frequency. Many of these cells had nonmonotonic response/level functions. (ABSTRACT TRUNCATED AT 400 WORDS)     

Involvement of different Ca2+ pools during the canine bronchial sustained contraction in Ca2+-free medium: lack of effect of PKC inhibition

OBJECTIVES: To: (1) develop a pharmaceutical care multicenter outcomes research project using clinical pharmacy residents and preceptors; (2) develop two research protocols to document pharmacists' impact on clinical, economic, and humanistic outcomes of therapy; (3) develop and implement a data collection process and methodology for outcomes research; (4) evaluate the effectiveness of the multicenter outcomes research process; and (5) prepare clinical pharmacy preceptors and residents to conduct outcomes research. DESIGN AND SETTING: Two research protocols were developed, each a randomized, parallel, open-label evaluation of patients at 10 Department of Veterans Affairs and 1 university medical center. One protocol focused on patients with chronic obstructive pulmonary disease (COPD) and the other on patients with hypertension. The study evaluated pharmacists' management of these two patient groups. PATIENTS AND OTHER PARTICIPANTS: 133 patients with hypertension and 98 patients with COPD; 33 pharmacy directors and preceptors; 45 pharmacy residents. MAIN OUTCOME MEASURES: Clinical, economic, and humanistic outcomes of pharmacists' interventions. The processes of developing a multicenter outcomes study were evaluated, including the data collection process. RESULTS: The two study protocols and an educational program for study participants were developed. A data collection process was developed and implemented, with the paper process being successful and the computer data collection process not implemented due to time constraints. Overall, the multicenter outcomes research process was successful. CONCLUSION: The study provides a framework of processes and sites for the future development of other outcomes research studies. Clinical, economic, and humanistic outcomes are reported in Parts 2 and 3.     

Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation

The autosomal dominant multiple endocrine neoplasia type 2 syndromes (MEN 2) comprise three clinically distinct entities, MEN 2A, familial medullary thyroid carcinoma and MEN 2B, which share a common clinical feature: medullary thyroid carcinoma (MTC). MEN 2B is considered to have the most aggressive form of MTC. Therefore, early detection of MEN 2B in order to prevent potentially lethal MTC is important. More than 95% of all MEN 2B cases are caused by germline mutation at codon 918 (M918T) in exon 16 of the RET proto-oncogene. In this study, we demonstrate the presence of germline codon 883 mutation (A883F) in 2 of 3 unrelated MEN 2B cases without codon 918 mutation. Our data demonstrate a novel etiologic event which may have roles in predisposition to MEN 2B when present in the germline and in the pathogenesis of sporadic MTC when somatic.     

Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer

PURPOSE: To establish the maximum-tolerated dose (MTD) and define the toxicities of a single-dose infusion of PNU-214565, a recombinant Escherichia coli-derived fusion protein of Staphylococcal enterotoxin A (SEA) and the Fab-fragment of the C242 monoclonal antibody in patients with advanced colorectal and pancreatic carcinomas. To investigate the capability of PNU-214565 to induce a superantigen (SAg) response resulting in cytokine production and tumor regression. PATIENTS AND METHODS: Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine women; 18 colorectal, three pancreatic cancers) were treated with a single 3-hour infusion of PNU-214565, with doses ranging from 0.01 to 1.5 ng/kg. All patients had prior chemotherapy and a good performance status Eastern Cooperative Oncology Group [ECOG] performance status [PS] = 0 [n = 10]; PS = 1 [n = 11]), 10 had prior radiation, and 18 had prior surgery. RESULTS: Fever and hypotension were the most common toxicities. Fever of any grade occurred in 16 of 21 patients (76%): four of 21 (19%) with grade 2 and two of 21 (9.5%) with grade 3. Hypotension of any grade occurred in 13 of 21 (62%): four of 21 with grade 2 and one of 21 (5%) with grade 3. Interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF alpha) induction correlated with toxicity. In the two patients with grade 3 fever, peak IL-2 and TNF alpha levels were 2.9 IU/mL and 165 pg/mL, and 8.3 IU/mL and 245 pg/mL, respectively. Transient, > or = 50% decreases in circulating monocytes were observed in 17 of 21 patients as early as 0.5 hours (median time, 2 hours) from the start of infusion. Decreases (mean 33%) in circulating lymphocytes were observed in seven of 21 patients. All three patients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The significance of baseline anti-SEA, human antimouse antibody (HAMA), CA242-soluble antigen levels, and T-cell receptor variable beta region (TCR V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-DR) genotypes was assessed as possible predictors of toxicity. All toxicities were transient and easily managed. No grade 3 toxicity occurred at the higher dose levels. CONCLUSION: PNU-214565, a SAg-based tumor targeted therapy, is safe when given as a single 3-hour infusion at doses up to 1.5 ng/kg. The MTD for a single dose was not determined. The safety of a repeated dose schedule is currently under investigation, beginning with doses determined to be safe in this trial.     

A new subtype of diabetes mellitus: maternally inherited diabetes and deafness (MIDD)

Diabetes mellitus comprises many subtypes, the pathogenesis of each of which involves a combination of inherited and environmental factors. Recently a new subtype of diabetes mellitus was recognized in a Dutch pedigree, designated as 'maternally inherited diabetes and deafness' (MIDD). Impaired hearing is an associated phenomenon of the disease. Approximately 1.3% of all diabetic cases in the Netherlands exhibit the MIDD subtype. MIDD shows a strictly maternal heredity. In MIDD there is a guanine-for-adenine substitution at position 3243 in mitochondrial DNA. Mitochondria carrying this mutation exhibit a decreased functionality. In carriers of the MIDD mutation the insulin secretion by the pancreas in response to stimulation by glucose is impaired.     

Adult brainstem gliomas

OBJECTIVE: To evaluate prognostic factors and survival of adult patients with brainstem gliomas. BACKGROUND: Brainstem glioma is a disease found primarily in children, with a median survival of only 9 to 12 months. However, the prognosis and survival of adults with this disease has not been determined with precision. METHODS: We conducted a retrospective analysis of patients older than 16 years at Memorial Sloan-Kettering Cancer Center with histologically proved or presumed brainstem glioma diagnosed between 1989 and 1997. We assessed the effect of gender, age at diagnosis, cranial nerve involvement, duration of symptoms, exophytic component, MRI enhancement, site of disease, treatment, and Karnofsky performance status on survival. RESULTS: Twenty-three patients were identified, but complete information was available in only 19 (12 males and 7 females). Patients ranged in age from 17 to 70 years (median, 40 years). Twelve patients were treated with radiotherapy at diagnosis and seven were observed, three of whom received subsequent radiotherapy. Median survival is 54 months (range, 3 to 98 months) and the 5-year survival is 45%. There was a trend for patients with a higher performance status at diagnosis to have longer survival, but this did not reach statistical significance. Other factors did not affect survival. CONCLUSION: Adults with brainstem gliomas may survive significantly longer than children, suggesting the disease may be less aggressive in adults. Furthermore, some patients with a long duration of symptoms or tectal or cervicomedullary tumors may be managed initially with observation alone.     

High-flow bypass using nonocclusive excimer laser-assisted end-to-side anastomosis of the external carotid artery to the P1 segment of the posterior cerebral artery via the sylvian route. Technical note

In a patient with a giant aneurysm of the basilar artery trunk, a vein graft was interposed between the external carotid artery in the neck and the P1 segment of the posterior cerebral artery. Balloon occlusion of both vertebral arteries was performed 3 days later. The sylvian route was used for the grafting procedure and the connection to the posterior cerebral artery was made by using the excimer laser-assisted nonocclusive anastomosis technique.     

Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis

The strength of the radius depends on the mechanical properties of cancellous and cortical bone. By assessing both compartments quantitatively with bone densitometry, we tried to identify the specificity of each in predicting the load at which the distal radius will fracture. Twenty human cadaver forearms were scanned for bone mineral and geometric properties with quantitative computed tomography and dual x-ray absorptiometry. In both a neutral loading situation and one in which the wrist was extended 45 degrees, the load distribution was determined with pressure-sensitive films, and a fracture simulating a fall on the hand was produced with a material testing machine. Fractures that occur with the wrist in extension were produced by a central impact of the scaphoid onto the radiocarpal joint, and those that occur under neutral loading conditions were produced by a more commonly distributed loading pattern. The load at fracture was most specifically predicted (r2=0.74) by bone mineral and geometric measures of the cortex at the shaft of the radius. Bone mineral density measures of trabecular (r2=0.64) and total (r2=0.66) bone were less successful in predicting the fracture load. After adjustment for bone size, the geometric and density measures revealed similar specificity. Cortical bone, therefore, contributes significantly to the strength of the distal radius and may play an important role in the prediction of osteoporotic wrist fractures.