An alternative introduction to reading and evaluating the primary literature for beginning graduate students.

Students are challenged in transitioning from acquiring knowledge and understanding through reading textbooks to their learning to select, read, evaluate, and synthesize the primary literature. A customary approach to teaching this transition to beginning graduate students is for a faculty member to assign "readings" from the recent literature that promise to become key publications; such assignments generally underscore recent, novel scientific content. We advocate here an alternative approach for coaching students very early in their training: first, to read, analyze, and discuss a paper that highlights critically important features of effective and valid experimental design; and, second, to study a paper that can be shown historically to have fundamentally changed the way in which physiological function is understood. We consider as an example of the first goal a study that purports to demonstrate a principle of thermoregulation, but that interaction between students and instructor reveals the study's lack of an essential control. The second goal requires sufficient time for the publication to concretely validate its contribution(s). The purpose is to identify those essential properties of the selected paper that contributed to its having become a truly exemplary study. We present a 1957 paper by Dr. A. C. Burton ( Am Heart J 54: 801-810, 1957) as an illustration and analyze the study with respect to those attributes that contributed to its lasting importance. These alternative approaches to introduce inexperienced students to the original literature can produce critical insight into the process and can help students inculcate essential practices, guiding them to more productive careers.

Extended longitudinal analysis of arterial pressure and heart rate control in unanesthetized rats with type 1 diabetes.

We recorded arterial pressure (BP) and heart rate (HR) in type-1 diabetic rats vs. controls for >6 months. Diabetic rats (DIAB) were maintained on insulin from the day glucose >250 mg/dl ("Day 0"). Weight was similar between groups until ~3 weeks before Day 0 when the weight in DIAB transiently lagged the controls (CONT); this difference was maintained throughout the study, but both groups otherwise gained weight in parallel. Plasma glucose attained 371 ± 109 (SD) mg/dl by day 1 in DIAB. Mean BP was similar across groups, and declined through the initial 4-6 months in both the CONT (at -0.06 ± 0.04 mmHg/day) and in the DIAB (at -0.14 ± 0.21 mmHg/day; NS vs. CONT). HR in the CONT (Month 1: 341 ± 13 bpm) exceeded DIAB (325 ± 25 bpm) through ~6 months after Day 0, and also decreased progressively over this period in CONT (-0.19 ± 0.14 bpm/day) and DIAB (-0.29 ± 0.23 bpm/day; NS vs. CONT) before leveling. The BP power within 0.35-0.45 Hz changed during the 90 min before vs. after the transition from dark to light, and light to dark; there were no between group differences. The slope of the log-log linear portion of the BP power spectrum between 1.0/h and 1/min was similar across groups, and increased in both from month 1 to month 6. Regulatory mechanisms maintain similar profiles in BP and HR in diabetic vs. control animals through the initial half year of the disease.

Atomoxetine changes rat's HR response to stress from tachycardia to bradycardia via alterations in autonomic function.

Atomoxetine is a central norepinephrine reuptake inhibitor used to treat attention deficit hyperactivity disorder. We tested the effects of atomoxetine upon the heart rate (HR) and mean arterial blood pressure (mBP) response to aversive conditioning. In Protocol 1 the mBP and HR responses to a stress (15s tone followed by shock) were tested in 8 Sprague-Dawley rats given saline pretreatment for 3 days; the rats' responses were then tested for 3 additional days following atomoxetine (1mg/kg, sc). Atomoxetine decreased (p<0.05) baseline mBP from 128+/-11 mm Hg (mean+/-SD) to 117+/-19 mm Hg; baseline HR slowed from 380+/-23 bpm to 351+/-21 bpm. The mBP increase to acute stress was similar after saline vs. after drug, but the peak was attained more slowly. After atomoxetine HR tended to slow during stress rather than accelerate. In Protocol 2 the cardiovascular responses were tested (n=6) for 3 days post-saline and for 3 days after a higher dose of atomoxetine (2mg/kg, sc). The average HR acceleration during the last 10s of the stress after saline (+7.5+/-14.7 bpm) was replaced by a HR slowing (-6.2+/-10.5 bpm). We conclude that drug treatment (a) decreases baseline sympathetic tone and/or elevates cardiac parasympathetic tone; (b) slows sympathetic arousal to acute stress without changing its magnitude; and, (c) enables the emergence of elevated parasympathetic tone during the stress. These autonomic consequences are consistent with atomoxetine's anxiolytic and transient sedative effects.

Blood pressure power within frequency range approximately 0.4 Hz in rat conforms to self-similar scaling following spinal cord transection.

This study quantified the effect of interrupting the descending input to the sympathetic preganglionic neurons on the dynamic behavior of arterial blood pressure (BP) in the unanesthetized rat. BP was recorded for approximately 4-h intervals in six rats in the neurally intact state and in the same animals after complete spinal cord transection (SCT) between T(4) and T(5). In the intact state, power within the frequency range of 0.35-0.45 Hz was 1.53 +/- 0.38 mmHg(2)/Hz (mean +/- SD by fast Fourier transform). One week after SCT, power within this range decreased significantly (P < 0.05) to 0.43 +/- 0.62 mmHg(2)/Hz. To test for self-similarity before and after SCT, we analyzed data using a wavelet (i.e., functionally, a digital bandpass filter) tuned to be maximally sensitive to fluctuations with periods of approximately 2, 4, 8, 16, 32, or 64 s. In the control state, all fluctuations with periods of >/=4 s conformed to a "self-similar" (i.e., fractal) distribution. In marked contrast, the oscillations with a period of approximately 2 s (i.e., approximately 0.4 Hz) were significantly set apart from those at lower frequencies. One day and seven days after the complete SCT, however, the BP fluctuations at approximately 0.4 Hz now also conformed to the same self-similar behavior characteristic of the lower frequencies. We conclude that 1) an intact sympathetic nervous system endows that portion of the power spectrum centered around approximately 0.4 Hz with properties (e.g., a periodicity) that differ significantly from the self-similar behavior that characterizes the lower frequencies and 2) even within the relatively high frequency range at 0.4 Hz self-similarity is the "default" condition after sympathetic influences have been eliminated.

Heart rate-arterial blood pressure relationship in conscious rat before vs. after spinal cord transection.

This experiment quantified the initial disruption and subsequent adaptation of the blood pressure (BP)-heart rate (HR) relationship after spinal cord transection (SCT). BP and HR were recorded for 4 h via an implanted catheter in neurally intact, unanesthetized rats. The animals were then anesthetized, and their spinal cords were severed at T(1)-T(2) (n = 5) or T(4)-T(5) (n = 6) or sham lesioned (n = 4). BP was recorded for 4 h daily over the ensuing 6 days. The neurally intact rat showed a positive cross correlation, with HR leading BP at the peak by 1.8 +/- 0.8 (SD) s. The cross correlation in unanesthetized rats (n = 2) under neuromuscular blockade was also positive, with HR leading. After SCT at T(1)-T(2), the cross correlation became negative, with BP leading HR, and did not change during the next 6 days. The cross correlation also became negative 1-3 days after SCT at T(4)-T(5), but in four rats by day 6 and thereafter the cross correlation progressively reverted to a positive value. We propose that the positive cross correlation with HR leading BP in the intact rat results from an open-loop control that depends on intact supraspinal input to sympathetic preganglionic neurons in the spinal cord. After descending sympathetic pathways were severed at T(1)-T(2), the intact vagal pathway to the sinoatrial node dominated BP regulation via the baroreflex. We suggest that reestablishment of the positive correlation after SCT at T(4)-T(5) was attributable to the surviving sympathetic outflow to the heart and upper vasculature reasserting some effective function, perhaps in association with decreased spinal sympathetic hyperreflexia. The HR-BP cross correlation may index progression of sympathetic dysfunction in pathological processes.