Oral tolerance induction by type V collagen downregulates lung allograft rejection.

Immunization with specific proteins or peptides has been used to induce immunologic tolerance to allografts other than the lung. Recently, we have reported that the immune response to lung alloantigen also involves an immune response to type V collagen [col(V)]. The purpose of the current study was to determine if oral administration of col(V) to lung allograft recipients before transplantation downregulates acute rejection episodes. The data show that, compared with controls, col(V)-fed recipients had fewer polymorphonuclear cells and lymphocytes in allograft bronchoalveolar lavage fluid, and reduced rejection pathology. Data showing that col(V)- fed allograft recipients had diminished delayed-type hypersensitivity (DTH) responses to donor alloantigens suggest that feeding col(V) prevented allograft rejection by inducing tolerance to donor antigens. Systemic production of transforming growth factor (TGF)-beta, interleukin (IL)-4, or IL-10 has been reported to be a mechanism for oral tolerance-induced suppression of immune responses. Feeding col(V) induced upregulated production of TGF-beta, but not IL-4 or IL-10 in serum. Neutralizing TGF-beta recovered the DTH response to donor antigen in tolerant allograft recipients. Collectively, these data show that oral administration of col(V) is a novel approach to induce immunologic tolerance to lung allografts, and that TGF-beta contributed to suppression of the rejection response.

Sleep and breathing disorders: the genesis of obstructive sleep apnea.

Sleep encompasses approximately a third of our lives; however, sleep and the disorders of sleep are not widely understood. Data suggest that sleep plays a restorative role in physiologic mechanisms and that long-term disruption of sleep may contribute to the development of disease. Nearly a third of the adult population is chronically afflicted by sleep disorders, and substantial economic loss is attributable to these disorders in terms of lost time, inefficiency, and accidents. Of the sleep disorders, obstructive sleep apnea (OSA) is one of the more common, clinically affecting up to 5% of the adult population. Obstructive sleep apnea contributes to the development of disease and has an adverse impact on daytime functioning in those affected by the disease. This article reviews basic sleep physiology, how these physiologic mechanisms are disrupted by OSA, and some of the techniques for treating patients with this disorder.

Dangers of sleepiness and inattention while driving.

Sleepiness occurs in almost everyone at some time during each day. If sleepiness becomes moderate to severe, it can have an impact on an individual's ability to perform tasks that are prolonged or require a high degree of concentration. Driving is a daily activity that usually involves repetitive behaviors over a prolonged period, and it may be adversely affected by an individual who is sleepy. Data from the Department of Transportation show that sleepiness and fatigue contribute to numerous accidents on the road. This article reviews information related to the effects of sleepiness on driving, the types of sleepiness, and some tools for assessing sleepiness.

Workup and indications for polysomnography in patients with sleep-related complaints.

A significant proportion of the population has chronic sleep problems necessitating an increasing involvement by the primary care physician. Also, the general patient population is becoming more familiar with these disorders and is seeking assistance. Because sleep studies are expensive and time consuming, adhering to the recognized indications for testing reduces the number of inappropriate studies. Under most circumstances, individuals with excessive daytime sleepiness and symptoms suggestive of obstructive sleep apnea are candidates for polysomnography. Other individuals with parasomnias or difficult-to-treat insomnia are also candidates for testing. In some circumstances, procedures designed to assess sleepiness may also need to be used to ascertain the impact of the disorder on daytime functioning and may be part of evaluations involving the transportation industry. Only after taking a thorough history and doing a physical examination can the physician make an accurate determination of the appropriate study type.

Cardiovascular disease and obstructive sleep apnea: implications for physicians.

Obstructive sleep apnea (OSA) has been strongly associated with several cardiovascular disorders during the past decade, and studies suggested that there might be a causal relationship. Recent studies have described several pathophysiologic mechanisms that are active in OSA and may participate in the development of cardiovascular disorders. Primarily, the repetitive respiratory events that occur in OSA cause hypoxia, hypercapnea, arousals, or disrupted sleep singly or in combination. These abnormal physiologic events result in increased sympathetic outflow, alterations in blood pressure control mechanisms, dysfunctional ventilatory regulation, and vascular alterations. As a consequence of the relative impact and the genetic predisposition, these pathophysiologic alterations may lead to or complicate a wide variety of cardiovascular disorders. Frequently, patients who have OSA present with complaints of excessive daytime sleepiness, chronic fatigue, snoring, morning headache, and nocturnal arousals. Difficult-to-control hypertension, recurrent exacerbations of congestive heart failure, and nocturnal angina are common cardiovascular manifestations of undiagnosed OSA. This article reviews the major cardiovascular disorders associated with OSA and the pathophysiologic mechanisms associated with their development.

Sleep-related gastroesophageal reflux.

Although we spend approximately one third of our lives sleeping, rarely do we consider that sleep may contribute to medical conditions. For gastroesophageal reflux, sleep or physiologic changes associated with the sleep state often promote or increase the likelihood of reflux and aspiration. These changes include the assumption of the supine position, a decrease in the arousal threshold, mechanical effects of the abdomen, and disorders associated with sleep. Of the sleep disorders, obstructive sleep apnea is associated with a high frequency of gastroesophageal reflux, probably due to the generation of negative intrathoracic pressures and obesity associated with the disease. Obstructive sleep apnea in patients with gastroesophageal reflux can lead to difficult-to-treat or refractory gastroesophageal reflux, predominantly nocturnal or early-morning symptoms, and unusual or uncommon manifestations that do not appear to reflect the underlying pathologic process. Under most circumstances, aggressive treatment regimens must be instituted for both disorders in order to effectively control symptoms. This article reviews the major information that is currently available on the relationship between obstructive sleep apnea and gastroesophageal reflux.

Hyperbaric oxygen in the treatment of migraine with aura.

Cephalalgia is one of the most common medical complaints and the search continues for relief. Early treatments for migraine included inhalation of 100% oxygen. It has been theorized that the increased levels of oxygen in the blood act as an alpha-adrenergic agent to alleviate headache pain through vasoconstriction and local metabolic effects. The presence of muscle tenderness during some migraine headaches has also been established. The purpose of this study was to document relief of cephalalgia through use of a visual analog pain scale, algometry, and manual palpation. Female subjects with confirmed migraine were randomly assigned to begin with either the control (100% oxygen, no pressure) or hyperbaric treatment (100% oxygen, pressure). Manual palpation and algometry of 10 sites were done, bilaterally, by a trained specialist. Pain was evaluated with a visual analog scale. Resolution of tenderness and edema following both treatments was observable by manual palpation while algometry showed no differences between the two. Subjective pain was significantly decreased following hyperbaric oxygen treatment but not following the control treatment. Results suggest that hyperbaric oxygen treatment reduces migraine headache pain and that the patient's subjective assessment was the best indicator of relief.

Interaction of central venous pressure, intramuscular pressure, and carotid baroreflex function.

Seven healthy volunteer men participated in an experiment involving lower body positive pressure (LBPP) of 30 Torr and acute volume expansions of 5-6% (VE-I) and 9-10% (VE-II) of their total blood volume (TBV) to differentiate the effect of increased intramuscular pressure and central venous pressure (CVP) on the maximal gain (Gmax) of the carotid baroreflex. During each experimental condition, the heart rate (HR), mean arterial pressure (MAP; intraradial artery or Finapres), and CVP (at the 3rd-4th intercostal space) were monitored continuously. Gmax was derived from the logistic modeling of the HR and MAP responses to ramped changes in carotid sinus transmural pressure using a protocol of pulsatile changes in neck chamber pressure from +40 to -65 Torr. The increase in CVP during +30-Torr LBPP was 1.5 mmHg (P < 0.05) and was similar to that observed during VE-I (1.7 mmHg, P > 0.05). The Gmax of the carotid baroreflex of HR and MAP was significantly decreased during LBPP by -0.145 +/- 0.039 beats x min(-1) x mmHg(-1) (38%) and -0.071 +/- 0.013 mmHg/mmHg (25%), respectively; however, VE-I did not affect Gmax. During VE-II, CVP was significantly greater than that elicited by LBPP, and the Gmax of the carotid baroreflex of the HR and MAP responses was significantly reduced. We conclude that carotid baroreflex responsiveness was selectively inhibited by increasing intramuscular pressure, possibly resulting in an activation of the intramuscular mechanoreceptors during LBPP. Furthermore, it would appear that the inhibition of the carotid baroreflex, via cardiopulmonary baroreceptor loading (increased CVP), occurred when a threshold pressure (CVP) was achieved.

Arterial and cardiopulmonary baroreflexes in 60- to 69- vs. 18- to 36-yr-old humans.

This study was designed to test the hypothesis that aging diminished baroreflex function during central hypovolemia. Eleven healthy young and eleven older (age 60-69 yr) individuals were assessed by using heart rate (HR) and mean arterial pressure (MAP) responses to neck pressure and suction during rest and lower body negative pressure (LBNP) of -15 Torr. The slope of forearm vascular resistance to central venous pressure during low-level LBNP was assessed as the index of cardiopulmonary baroreflex sensitivity. Baseline cardiovascular variables were not significantly different between the groups. In addition, there was no group difference in cardiopulmonary baroreflex (-3.6 vs. -3.7 units/mmHg for young vs. older, respectively) or carotid baroreflex (-0.39 vs. -0.35 beats.min-1.mmHg-1 and -0.26 vs. -0.35 mmHg/mmHg, for young vs. older, respectively) sensitivity. LBNP did not affect either HR or MAP, whereas it decreased CVP and increased FVR in both groups. LBNP significantly augmented the carotid-HR (-0.47 +/- 0.03 beats.min-1.mmHg-1) and carotid-MAP (-0.42 +/- 0.04 mmHg/mmHg) reflex gains in the young subjects only. We concluded that there was no difference in the discrete baroreflex function between the two age groups; however, the interaction of cardiopulmonary baroreceptors with carotid baroreflex function was absent in the older subjects, suggesting that the central integration of afferent neural inputs from the discrete baroreceptors was altered with aging.

Acute diplopia and a solitary lung mass: a unique presentation of light-chain myeloma.

The patient described, a 51-year-old woman, had diplopia and cephalgia of two weeks' duration. On admission, the radiologic evaluation revealed a mass in the sphenoid sinus, multiple lesions in the calvarium and a solitary lung mass. Biopsy of the lung mass revealed an atypical plasmacytic infiltration. Laboratory findings confirmed the diagnosis of light-chain myeloma presenting with a pulmonary plasmacytoma and cranial nerve involvement.

Chronic fatigue complaints in primary care: incidence and diagnostic patterns.

The complaint of chronic fatigue is ubiquitous in the primary care setting. Because of the nonspecific nature of chronic fatigue, practitioners do not focus on this complaint. Furthermore, most physicians use a problem-based approach. Such a prematurely narrowed focus could overlook the chronic fatigue complaint. Omissions in the data collection process would prove this oversight. Therefore, we postulated that a retrospective review of evaluations for chronic fatigue would demonstrate significant categorical deficiencies. These deficiencies would indicate a problem focus different than the chronic fatigue complaint itself. The authors reviewed the current literature to establish historical, physical, and laboratory findings pertinent to the evaluation of chronic fatigue. Six major categories and the associated data elements were identified for use in analyzing patient records. The patient records from the preceding 6 months were reviewed to find those containing a complaint of chronic fatigue. These records were analyzed to determine if a complete data set had been sought and if an associated diagnosis was made. A total of 425 consecutive charts from an academic family practice clinic were retrospectively reviewed; 9.9% (42) mentioned chronic fatigue. Physicians were lax in performing the mental status and physical examinations; taking the patient's psychiatric and sleep history, as well as the history of chief complaint; and ordering laboratory evaluations. The physician diagnoses included: depression (40.4%), nonspecific fatigue (35.7%), general medical disorders (16.6%), chronic fatigue syndrome (2.4%), fibromyalgia (2.4%), and sleep apnea (2.4%). From these data, the investigators conclude that the workup for chronic fatigue is often incomplete or lacks documentation. This oversight is likely due to a problem focus not directed at the chronic fatigue complaints. Also complicating the evaluation process are the multiple associated disorders, the prevalence of the complaint, and cost/benefit issues facing the primary care physician.

Autonomic nervous system control of the heart: endurance exercise training.

The purpose of this study was to assess hemodynamic responses to lower body negative pressure (LBNP) to -45 torr with selective cardiac parasympathetic (using atropine sulphate), sympathetic efferent (using metoprolol tartrate), and combined (atropine+metoprolol) blockade prior to and following 8 months of endurance exercise training in eight young men. Training resulted in significant increases of maximal oxygen uptake (27%) and blood volume (16%) and a decrease of baseline heart rate (HR, from 66 +/- 4 to 57 +/- 4 bpm). This training related bradycardia was exclusively determined by an enhanced vagal tone as there was no significant difference in intrinsic HR pre- to post-training and only atropine (pre: 100 +/- 3 vs post: 101 +/- 3 bpm), not metoprolol (pre: 56 +/- 3 vs post: 49 +/- 4 bpm), abolished the HR difference. The reflex tachycardia in the control experiment was significantly diminished following training. However, the increase in HR at LBNP -45 torr between pre- and post-training was similar after either atropine (+13 +/- 2 vs +14 +/- 1 bpm) or metoprolol (+8 +/- 1 vs +8 +/- 1 bpm). Reflex tachycardia was greater during atropine than metoprolol blockade and the sum of the HR increase during selective blockade (21 and 22 bpm) was greater when compared with the control (no blockade, 16 +/- 2 vs 11 +/- 2 bpm). There was no difference pre- to post-training in SV or Qc response to -45 torr LBNP during the control condition. However, selective beta 1-receptor blockade resulted in a greater decrease in SV to -45 torr LBNP post-training compared to pre-training (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic-cardiac reflex during dynamic exercise.

We investigated the aortic-cardiac reflex during low-intensity cycling in 10 healthy volunteers. Baroreflex function was assessed by the ratio of change in heart rate to mean arterial pressure (delta HR/delta MAP) during phenylephrine (PE) infusion. The ratio obtained during PE combined with low-level lower body negative pressure (LBNP) and calculated neck pressure (NP) was assessed as the gain of the aortic-cardiac reflex. Exercise (approximately 25% maximal O2 uptake or 25 +/- 2 W) significantly increased HR from 64 +/- 2 to 98 +/- 2 beats/min, MAP from 90 +/- 3 to 98 +/- 3 mmHg, cardiac output from 6.6 +/- 0.5 to 12.0 +/- 1.4 l/min, and O2 uptake from 3.8 +/- 0.2 to 10.4 +/- 0.6 ml.min-1.kg-1. However, delta MAP (+11.8 +/- 0.4 vs. + 11.3 +/- 0.8 mmHg), delta HR (-12.7 +/- 2 vs. -12.9 +/- 2 beats/min), and delta HR/delta MAP (1.10 +/- 0.19 vs. 1.15 +/- 0.15 beats.min-1.mmHg-1) were not statistically different between rest and exercise during PE. Although PE significantly increased central venous pressure in both supine rest (from 6.7 +/- 0.7 to 10.4 +/- 0.7 mmHg) and exercise (5.8 +/- 0.8 to 8.6 +/- 0.9 mmHg) conditions, when LBNP (-15 +/- 2 vs. -16 +/- 1 Torr for rest vs. exercise) was applied, both rest and exercise central venous pressures were returned to the preinfusion baseline values, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Inositol tetrakisphosphate stimulates a novel ATP-independent Ca2+ uptake mechanism in cardiac junctional sarcoplasmic reticulum.

The effects of inositol phosphates on Ca2+ uptake in cardiac junctional sarcoplasmic reticulum (JSR) vesicles was investigated. Inositol 1,3,4,5-tetrakisphosphate (IP4) selectively increased Ca2+ uptake 2.8 fold over basal levels whereas 1,3,4-IP3, 1,4,5-IP3 or 1,4-IP2 were without effect. Stimulation of Ca2+ uptake by IP4 was maximal within 15-60 sec at 30 degrees C and ATP-independent. Following incubation of JSR with ruthenium red, Ca2+ uptake in the presence or absence of IP4 was further enhanced 2.5 fold. Both basal and IP4-stimulated Ca2+ uptake were half-maximal and maximal in the presence of 60 nM and 180 nM Ca2+, respectively. These studies indicate that IP4 stimulates an ATP-independent Ca2+ uptake mechanism in cardiac JSR which may function to promote rapid Ca2+ loading.

The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis.

BACKGROUND: Tuberculosis has reemerged as an important public health problem, and the frequency of drug resistance is increasing. A major reason for the development of resistant infections and relapse is poor compliance with medical regimens. In Tarrant County, Texas, we initiated a program of universal directly observed treatment for tuberculosis. We report the effect of the program on the rates of primary and acquired drug resistance and relapse among patients with tuberculosis. METHODS: We collected information on all patients with positive cultures for Mycobacterium tuberculosis in Tarrant County from January 1, 1980, through December 31, 1992. Through October 1986, patients received a traditional, unsupervised drug regimen. Beginning in November 1986, nearly all patients received therapy under direct observation by health care personnel. RESULTS: A total of 407 episodes in which patients received traditional treatment for tuberculosis (January 1980 through October 1986) were compared with 581 episodes in which therapy was directly observed (November 1986 through December 1992). Despite higher rates of intravenous drug use and homelessness and an increasing rate of tuberculosis during this 13-year period, the frequency of primary drug resistance decreased from 13.0 percent to 6.7 percent (P < 0.001) after the institution of direct observation of therapy, and the frequency of acquired resistance declined from 14.0 percent to 2.1 percent (P < 0.001). The relapse rate decreased from 20.9 percent to 5.5 percent (P < 0.001), and the number of relapses with multidrug-resistant organisms decreased from 25 to 5 (P < 0.001). CONCLUSIONS: The administration of therapy for M. tuberculosis infection under direct observation leads to significant reductions in the frequency of primary drug resistance, acquired drug resistance, and relapse.

Exogenous lipoid pneumonia due to nasal application of petroleum jelly.

We describe a patient who presented with a history of unexplained exertional dyspnea and pulmonary infiltrates. She was evaluated for interstitial lung disease, presumed to be idiopathic and underwent an open lung biopsy. The pathologic findings were compatible with exogenous lipoid pneumonia and her history revealed longstanding use of intranasal petroleum jelly (Vaseline) at bedtime.

Evidence for an intramuscular ventilatory stimulus during dynamic exercise in man.

During incremental work rate exercise, ventilation (VE) typically increases in proportion to the metabolic rate until the onset of a progressive metabolic acidemia induces an additional compensatory hyperpnea. We examined the control characteristics of this compensatory mechanism in seven healthy subjects performing incremental cycle ergometry to their limit of tolerance at different levels of lower-body positive pressure (LBPP) at 0, 15, 30, and 45 Torr in order to determine if LBPP could alter the occurrence of the ventilatory threshold. Ventilatory responses and pulmonary gas exchange variables were measured breath-by-breath while 'arterialized'-venous blood was sampled from the dorsum of the heated hand for determination of [lactate], pH, and [K+]. The ventilatory threshold was progressively reduced with increasing levels of LBPP: Ventilatory threshold = 2.33-(0.0173.LBPP); (r2 = 0.59, P < 0.001). Ventilatory equivalents for oxygen (VE/VO2) and carbon dioxide (VE/VCO2) were systematically elevated at work rates above 50 W by increases in respiratory frequency which also resulted in lower PETCO2 and higher PETO2 values. As [lactate] was only slightly elevated above control (delta lactate < 1 mEq.L-1) while pH and [K+] were unchanged, it seems unlikely that the LBPP-induced hyperpnea can be attributed to activation of peripheral arterial or central chemoreceptors. These findings suggest a ventilatory stimulus may be generated by an LBPP-induced reduction in perfusion with the subsequent accumulation of intramuscular metabolites at the working limb and/or a direct effect of increased intramuscular tissue pressure.