Nonpeptide tachykinin receptor antagonists. III. SB 235375, a low central nervous system-penetrant, potent and selective neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.

In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited (125)I-[MePhe(7)]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K(i) = 2.2 nM and antagonized competitively NKB-induced Ca(2+) mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K(b) = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA(2) = 8.1) and guinea pig ileal circular smooth muscles (pA(2) = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K(i) > 100,000 nM) and hNK-2 receptors (K(i) = 209 nM), and was without effect, at 1 microM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED(50) of 0.56 mg/kg). Intraperitoneal SB 235375 (10-30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3-30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system.     

A stress echocardiography study of cardiac function during progressive exercise in pediatric oncology patients treated with anthracyclines

BACKGROUND: Anthracycline-treated patients (AP) are at risk for cardiac dysfunction years after treatment. Cardiac function has not been evaluated during exercise in AP. The purpose of this study was to assess exercise tolerance, left ventricular (LV) function, and hemodynamics during progressive exercise. PROCEDURE: We studied 47 AP (cumulative dose: 36-504 mg/m(2)) who were in complete remission and 12 healthy controls (CON). AP were further grouped by cumulative dose (LOW or= 260 mg/m(2)) and resting echocardiographic function. All subjects performed 3-min incremental stages on a semi-recumbent cycle ergometer until volitional fatigue. Using echocardiography and Doppler, LV dimensions, posterior wall thickness (LVPWs), peak aortic velocity (PAoV), shortening fraction (SF), rate-corrected mean velocity of fiber shortening (MVCFc), wall stress at peak systole (sigmaPS), stroke volume index (SVI), and cardiac index (CI) were determined. Measurements were performed at rest, during each stage of exercise, and in recovery. RESULTS: AP did less work than CON (P < 0.050). CON and LOW had similar resting function, while HIGH had a lower SF and MVCFc (P < 0.050) and a higher sigmaPS (P < 0.001). Resting SVI and CI were also lower in HIGH. At peak exercise, MVCFc and sigmaPS remained different in HIGH, and both AP groups had a lower SF, SVI, and CI (P < 0.001). AP had an abnormal SVI response to exercise. AP showed a smaller initial increase in SVI that was not maintained throughout exercise. CONCLUSIONS: AP have reduced exercise tolerance. There also appears to be a dose-related effect on myocardial contractility and SVI. These findings may help to guide treatment.     

Radiographic texture analysis in the characterization of trabecular patterns in periprosthetic osteolysis

RATIONALE AND OBJECTIVES: Periprosthetic osteolysis is a disease attributed to the body's reaction to fine polyethylene wear debris shed from total hip replacements. The purpose of this preliminary study was to investigate the ability of radiographic texture analysis (RTA) to characterize the trabecular texture patterns on pelvic images for osteolysis and normal total hip arthroplasty (THA) cases. MATERIALS AND METHODS: Fourier-based and fractal-based texture features were calculated for a database of digitized radiographs from 202 THA cases, 70 of which developed osteolysis. The features were calculated from regions of interest selected at two time points: less than 1 month after surgery, and at the first clinical indication of osteolysis (or randomly selected follow-up time for normal cases). Receiver operating characteristic (ROC) analysis was used to compare feature performance at baseline and follow-up for osteolysis and normal cases. RESULTS: Separation between the RTA features for osteolysis and normal cases was negligible at baseline and increased substantially for the follow-up images. The directional Fourier-based feature provided the best separation with an A(z) value from ROC analysis of 0.75 for the follow-up images, in the task of distinguishing between normal and osteolytic cases. CONCLUSIONS: The results from this preliminary analysis indicate that qualitative changes in trabecular patterns from immediately after surgery to the eventual detection of osteolysis correspond to quantitative changes in RTA features. It therefore appears that RTA provides information that could potentially be useful to aid in the detection of this disease.     

Clinical evaluation of the safety and efficacy of preservative-free triamcinolone (triesence [triamcinolone acetonide injectable suspension] 40 mg/ml) for visualization during pars plana vitrectomy

PURPOSE: To evaluate the safety and efficacy of preservative-free triamcinolone (TRIESENCE(R) suspension) for visualization during pars plana vitrectomy. METHODS: This phase III, observer-masked study was conducted in 6 centers by 10 surgeons and enrolled 60 patients undergoing pars plana vitrectomy. Preservative-free triamcinolone (up to 4 mg) was administered to all patients to enhance visualization of vitreous and membranes. During each surgery, video recordings captured visualization pre- and postinstillation of preservative-free triamcinolone. An independent, masked reader evaluated the videos for the degree of visualization using a five-point scale ranging from 0 (not visible) to 4 (clearly delineated). Surgeons used a five-point scale ranging from "strongly disagree" to "strongly agree" to assess whether preservative-free triamcinolone improved visualization. RESULTS: In 59 of 60 cases, the masked reader's scores for visualization of posterior segment structures were higher (i.e., structures were more clearly visible) after instillation of preservative-free triamcinolone. The preinstillation mean visualization score was 0.5 compared to 3.7 postinstillation (P < 0.0001). Greater than 90% of surgeon evaluations agreed or strongly agreed that preservative-free triamcinolone enhanced visualization of posterior segment structures. No safety issues were identified. CONCLUSIONS: Preservative-free triamcinolone (TRIESENCE(R) suspension) was well tolerated and effectively enhanced visualization of posterior segment structures during pars plana vitrectomy.     

Upper arm arteriovenous fistulas as a reliable access alternative for patients requiring chronic hemodialysis.

The wrist fistula is the access procedure of choice in the hemodialysis patient. However, unavailable or unusable anatomy in this aging population has made them difficult to establish. This study retrospectively compares patency, occlusion, and complication rates of upper arm arteriovenous fistulas (AVFs) as a reliable alternative. Fifty-eight upper arm AVFs were created in 52 patients between February 1995 and August 1997 at Hermann Hospital, affiliated with the University of Texas Health Science Center in Houston, Texas. Fistulas were constructed using the brachial artery (BA) side-to-end (n = 56) or side-to-side (n = 1) with either the cephalic vein (CV; n = 39), transposed basilic vein (TBV; n = 16), or other vein [basilic vein (BV; n = 1), transposed cephalic vein (TCV; n = 1), median cubital vein (MCV; n = 1)]. One-year primary patency rates for upper arm AVFs were 66 per cent, and secondary patency rates were 22 per cent. Flow rates averaged 354.6 mL/minute. Primary and secondary patency rates for fistulas created are: BA-CV (67% and 20%), BA-TBV (63% and 25%), and other upper arm AVFs 66 per cent without revisions. Primary patencies for both BA-CV and BA-TBV fistulas were similar to previously reported studies. Secondary patencies proved to be less effective. Upper arm AVFs should be considered before graft placement when wrist and forearm anatomy does not lend itself to fistula creation.     

Distribution of neurons projecting to the rostral ventrolateral medullary pressor region that are activated by sustained hypotension.

Hypotension produces a reflex increase in the activity of sympathetic vasomotor and cardiac nerves. It is believed that the reflex sympathoexcitation is due largely to disinhibition of sympathoexcitatory neurons in the rostral ventrolateral medulla, but it is possible that it may also be mediated by excitatory inputs from interneurons that are activated by a fall in blood pressure. The aim of this study in conscious rabbits was to identify and map neurons with properties that are characteristic of interneurons conveying excitatory inputs to the rostral ventrolateral medullary pressor region in response to hypotension. In a preliminary operation, a retrogradely-transported tracer, fluorescent-labelled microspheres, was injected into the functionally-identified pressor region in the rostral ventrolateral medulla. After a waiting period of at least one week, a moderate hypotension (decrease in arterial pressure of approximately 20 mmHg) was induced in conscious rabbits for 60 min by the continuous infusion of sodium nitroprusside. In confirmation of a previous study from our laboratory, [Li and Dampney (1994) Neuroscience 61, 613–634] hypotension resulted in the expression of Fos (the protein product of c-fos, a marker of neuronal activation) in many neurons in several distinct regions in the brainstem and hypothalamus. Some of these regions (nucleus tractus solitarius, area postrema, caudal and intermediate ventrolateral medulla, parabrachial complex in the pons, and paraventricular nucleus in the hypothalamus) also contained large numbers of retrogradely-labelled cells. Approximately 10% of the Fos-positive neurons in the nucleus tractus solitarius, and 15–20% of Fos-positive neurons in the caudal and intermediate ventrolateral medulla were also retrogradely-labelled from the rostral ventrolateral medullary pressor region. In other brain regions, very few double-labelled neurons were found.In previous studies from our laboratory, we have determined the distribution of neurons in the brainstem that project to the rostral ventrolateral medullary pressor region and that are also activated by hypertension [Polson et al. (1995) Neuroscience 67, 107–123] or by hypoxia. [Hirooka et al. (1997) Neuroscience 80, 1209–1224] Comparison of the present results with those from these previous studies indicate that although hypotension and hypoxia both elicit powerful reflex sympathoexcitatory responses, the central pathways subserving these effects in conscious animals are fundamentally different. Hypoxia activates rostral ventrolateral medullary sympathoexcitatory neurons mainly via a major direct excitatory projection from the nucleus tractus solitarius, as well as from the Kölliker–Fuse nucleus in the pons, while in contrast the activation of these neurons in response to hypotension appears to be due mainly to disinhibition, mediated via inhibitory interneurons. In addition, however, inputs originating from excitatory interneurons in the nucleus tractus solitarius and caudal and intermediate parts of the ventrolateral medulla appear to contribute to the hypotension-evoked activation of sympathoexcitatory neurons in the rostral ventrolateral medulla.     

Cost-effective, available-on-demand intraoperative radiation therapy

At Loma Linda University Medical Center, intraoperative radiation therapy (IORT) is used in selected cases, on an on-demand basis, in a cost-effective manner. Certain procedures and modifications are described which have enabled use of IORT on this basis.     

Caring for People with Severe Learning Difficulties in Ordinary Houses

Evaluation of community care only rarely considers management issues and the stresses which arise from new work structures and situations. This study examined the changed role of community care staff and the support required to maintain an effective service. Group interview methods were employed. Factors identified as important stressors were working together in a smaller setting, being in the public gaze and the risk-taking involved in client training programmes. It was suggested that meeting staff needs should focus on emergency cover, communication and consultation, and providing adequate training. Implications for management practices are discussed.     

The importance of aspects of treatment for fibromyalgia (Fibrositis): Differences between patient and physician views

Thirty-five individuals with fibromyalgia (fibrositis), 22 of their physicians, and 49 rheumatologists on an Arthritis Foundation referral list rated the importance of 24 aspects of fibromyalgia treatment. These encompassed symptom control, psychosocial factors, information, and physical therapy. Respondents with fibromyalgia rated their satisfaction with the way each aspect of treatment had been managed by their physician, and each completed a health status questionnaire. Fibromyalgia patients viewed 8 of the 24 aspects of treatment as significantly more important than did their own physician, and 18 of the 24 as significantly more important than did area rheumatologists. Satisfaction with the way treatment had been managed was generally low. Some evidence suggested that patients' health status was affected positively by the extent to which their physician viewed certain aspects of treatment as important. The results are expected to be useful in the design of fibromyalgia education programs for both lay and health professional audiences.