Trk C receptor signaling regulates cardiac myocyte proliferation during early heart development in vivo.

Neurotrophin-3 (NT-3) is a member of the neurotrophin family of growth factors, best characterized by its survival- and differentiation-inducing effects on developing neurons bearing the trk C receptor tyrosine kinase. Through analysis of NT-3 and trk C gene-targeted mice we have identified NT-3 as critically regulating cardiac septation, valvulogenesis, and conotruncal formation. Although these defects could reflect cardiac neural crest dysfunction, the expression of NT-3 and trk C by cardiac myocytes prior to neural crest migration prompted analysis of cell-autonomous actions of NT-3 on cardiac myocytes. Retroviral-mediated overexpression of truncated trk C receptor lacking kinase activity was used to inhibit activation of trk C by endogenous NT-3, during early heart development in ovo. During the first week of chicken development, expression of truncated trk C reduced myocyte clone size by more than 60% of control clones. Direct mitogenic actions of NT-3 on embryonic cardiac myocytes were demonstrated by analysis of BrdU incorporation or PCNA immunoreactivity in control and truncated trk C-expressing clones. Inhibition of trk C signaling reduced cardiac myocyte proliferation during the first week of development, but had no effect at later times. These studies demonstrate that endogenous NT-3:trk C signaling regulates cardiac myocyte proliferation during cardiac looping and the establishment of ventricular trabeculation but that myocyte proliferation becomes NT-3 independent during the second week of embryogenesis.

Evaluation of dose-intense Ifosfamide, with and without edatrexate, in adults with sarcoma.

Purpose. To define the maximally tolerated dose (MTD) of ifosfamide when given with G-CSF on an every other week schedule, and to define the MTD of edatrexate that can be given every two weeks with an intense schedule of ifosfamide.Patients and Methods. Forty-one patients with metastatic or unresectable, locally advanced sarcoma participated in this 2-step phase I trial.The starting dose of ifosfamide was 10 gm/m(2) given by continuous intravenous infusion over 4 days every 2 weeks.When the MTD was defined, edatrexate, beginning at a dose of 40 mg/m(2) intravenously every 2 weeks was added in subsequent cohorts of patients.Results. Myelosuppression was the most prominent toxicity. Fatigue, nausea, and vomiting were observed in the majority of patients. Ifosfamide 12 gm/m(2) given every 2 weeks approached or exceeded the MTD. Edatrexate 100 mg/m(2) could be given safety as an intravenous bolus with ifosfamide 10 gm/m(2) every 2 weeks. Therapeutic responses were observed in patients with measurable disease.Conclusions. This study demonstrates the feasibility of administering a dose-intense schedule of ifosfamide alone or ifosfamide with edatrexate that might be applied in the adjuvant or neo-adjuvant setting.

Beneficial effects of psychiatric intervention on recovery after coronary artery bypass graft surgery.

The effects of perioperative psychiatric intervention were studied in 33 patients undergoing coronary artery bypass graft (CABG) surgery. All patients were evaluated preoperatively using the Mini-Mental State Exam and the Psychological Adjustment to Illness Scale-Self-Report. Participants in the study group (N = 16) had a structured psychiatric interview prior to surgery and were followed daily with supportive psychotherapy throughout their hospitalization. The number of medical complications was higher in the control group. No significant differences were found in neurologic or psychologic complications. The study group used significantly more oxycodone-acetaminophen (Percocet), but less morphine-sulfate or benzodiazepine on postoperative days 3, 4, and 6. The mean length of stay was 3 days shorter for patients in the study group. In the current era of escalating health care costs and high technology, clinical protocols and research studies that evaluate the cost effectiveness and efficacy of psychiatric intervention in medically ill patients should be pursued.

Anxiety disorders and psychiatric referral in the general medical emergency room.

A retrospective chart review of patients seen in the medical emergency room between July 1983 and July 1984 indicated that only one third of the patients who received a final diagnosis that included anxiety were referred for psychiatric follow-up. This was in sharp contrast to the referral pattern from the ER of depressed or psychotic patients. In the present study, referred and nonreferred patients were compared on 17 variables to determine those factors that influenced decision to refer. Among the five factors that discriminated between the criterion groups were age, depression, and lack of concomitant medical findings.

Modification of the pigeon's visual startle reaction by the sensory environment.

A series of seven experiments related amplitude and latency of the pigeon's startle response, elicited by an intense visual stimulus, to antecedent auditory and visual events in the sensory environment. The data indicated that (a) within broad limits the amplitude of the reflex is a positive function of the intensity of the sensory background prevailing at the time of startle elicitation, (b) a change in the sensory environment occurring 15-2,000 msec prior to the startle-eliciting stimulus inhibits the amplitude of the response, and (c) a change in the sensory environment less than 10 msec prior to the startle-eliciting stimulus reduces the latency of the response. These findings are consistent with previous research on acoustic elicited startle in the rat. The overall configuration of the results suggests that a pathway including the reticulospinal tract and the bulbopontine reticular nuclei could be the major mediator of startle. In these terms, latency-reduction effects would occur because of partial activation of this pathway, amplitude inhibition would occur because of cerebellar influence, and amplitude facilitation would reflect cerebral or striatal influences.

Modification of the rat's acoustic startle response by antecedent visual stimulation.

Male hooded and albino rats were exposed to a light flash followed at various temporal intervals by a startle-eliciting 117 db. (re 20 muN/m2) burst of white noise. The visual stimulus engendered startle response inhibition (maximally when the lead time was 64-250 msec) as well as startle response latency reduction (maximally when the lead time was 2-8 msec). The temporal functions for the effects of visual stimuli paralleled those previously reported for startle modification by acoustic events. Further study revealed that, given optimal lead times, inhibition is produced reliably by weaker visual stimuli (3 X 10-6 cd-sec/cm2) than latency reduction (3 X 10-4 cd-sec/cm2). This differential sensitivity to visual stimuli is also analogous to previously reported findings for events in the acoustic environment. It reveals that the neural mechanisms that mediate latency reduction and inhibition can be engaged by either acoustic or visual stimulation.

The role of small changes in the acoustic environment in modifying the startle reflex.

When either the intensity or frequency spectrum of an approximately 70-db. SPL narrow-band noise was abruptly changed by a small amount, the rat's response to a startle stimulus presented 64 msec later was inhibited. When similar small frequency changes preceded the startle stimulus by ony 5 msec, the latency of the startle response was reduced, but even relatively large changes in intensity of the antecedent stimulus had no effect on response latency. These findings provide added support for the generalization that the neural processes associated with startle are engaged by small changes in the auditory environment. They also point to a measure of separation between the processes responsible for inhibition and those responsible for latency shift.