Lung transplant metalloproteinase levels are elevated prior to bronchiolitis obliterans syndrome.

Parenchymal disease in the allograft lung is associated with interstitial remodeling believed to be mediated by matrix metalloproteinases (MMPs). Recent studies suggest high levels of MMP-9 are associated with bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. Since BOS occurs late in the posttransplant period and may be preceded by episodes of acute rejection or infection, which are associated with interstitial remodeling, we examined MMP profiles in allograft bronchoalveolar lavage (BAL) fluid in the early posttransplant period (preceding BOS). Gelatin zymography, protein array analysis and specific ELISA on BAL fluids from transplanted lungs indicated that MMP-8, MMP-9 and TIMP-1 were strongly expressed in allograft BAL fluid from stable patients, or those with infection or rejection compared to BAL fluid from normal volunteers. Elevated expression of MMP-8, MMP-9 and TIMP-1 occurred early, and was sustained for the 3.2 years covered in this study. Elevations of MMP-8, MMP-9 and TIMP-1 in the first 2 years posttransplant appear to be associated with lung transplantation itself, and not infection or rejection. These data suggest that ongoing and clinically silent MMP activity could perpetuate progressive disease in the allograft lung.

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.

Instillation of allogeneic lung antigen-presenting cells deficient in expression of major histocompatibility complex class I or II antigens have differential effects on local cellular and humoral immunity and on pathology in recipient murine lungs.

Recognition of allogeneic major histocompatibility complex (MHC) molecules expressed on donor lung antigen-presenting cells (APCs) by host T lymphocytes is believed to stimulate lung allograft rejection. However, the specific roles of donor MHC molecules in the rejection response is unknown. We report a murine model in which instilling allogeneic lung APCs into recipient lungs induces pathology analogous to acute rejection, and the production of interferon (IFN)-gamma, immunoglobulin (Ig) G2a, and alloantibodies in recipient lungs. Using allogeneic lung APCs (C57BL/6, I-a(b), H-2(b)) deficient in MHC class I, II, or both for instillation into lungs of BALB/c mice (I-a(d), H-2(d)), the purpose of the current study was to determine the specific roles of donor MHC molecules in stimulating local alloimmune responses. The data show that MHC class I or II on donor APCs induced IFN-gamma and IgG2a synthesis locally, though less than that induced by wild-type cells. Both MHC class I and II were required to induce alloantibody production. Instillation of wild-type or class I- or class II-deficient APCs induced comparable pathologic lesions in recipient lungs, and more severe than that induced by MHC-deficient cells. These data show that donor MHC class I and II molecules have differential effects in the stimulation of local alloimmune responses.

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.

Type V collagen modulates alloantigen-induced pathology and immunology in the lung.

Perivascular and peribronchiolar tissues are targets of the immune response during lung allograft rejection. Collagen type V (col[V]) is located within these tissues. Col(V) may be major histocompatibility complex (MHC)-like, and MHC-derived peptides have been used to induce immunologic tolerance and prevent rejection in allografts other than the lung. The current study tests the hypothesis that col(V) could be used to downregulate immune responses to lung alloantigen in vivo. We developed a murine model in which instillations of allogeneic bronchoalveolar lavage (BAL) cells (C57BL/6, I-a(b), H-2(b)) into lungs of BALB/c mice (I-a(d), H-2(d)) induce histology similar to grades 1 and 2 acute lung allograft rejection, apoptosis of airway epithelium and vascular endothelium, and upregulate tumor necrosis factor (TNF)-alpha production locally. The current study reports that instillations of col(V) into lungs before allogeneic BAL cells prevent development of rejection pathology and apoptosis, downregulate alloantigen-induced T-lymphocyte proliferation, and abrogate local TNF-alpha production. In addition, instillation of col(V)-pulsed autologous BAL cells into lungs of mice primed with allogeneic BAL cells perpetuates rejection pathology. Collectively, these data show that col(V) is a novel antigen involved in the rejection process, and suggest that col(V) could be used to modulate the rejection response to lung allografts.

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.

Treatment costs of directly observed therapy and traditional therapy for Mycobacterium tuberculosis: a comparative analysis.

OBJECTIVE: Treatment of tuberculosis is a time-consuming and expensive process, often complicated by patient non-adherence. Directly observed therapy (DOT), an out-patient management strategy designed to ensure adherence, is not widely used because it is perceived to be too expensive. This study compared costs of tuberculosis treatment in DOT to the same factors in traditional therapy. DESIGN: A retrospective economic evaluation of 659 tuberculosis cases was reported to a major metropolitan county public health department between 1980 and 1994. Out-patient costs, in-patient costs and the cost impact of relapse and acquired resistance were estimated in 1995 dollars. RESULTS: Treatment costs were lower with DOT: $15,670 per case for in-patient care and $700 per case for out-patient care (P < 0.001). These cost differences resulted from shorter therapy duration (334 vs 550 days), fewer patient hospitalizations (58 vs 75%) and shorter hospital stays (26 vs 55 days per hospitalized patient). Relapse or acquired resistance occurred in 10.9% of patients and accounted for 35.7% of cost with traditional therapy, as compared to 1.2% of patients and 6.0% of cost with observed therapy. CONCLUSIONS: Directly observed therapy is less costly than traditional therapy.

Universal HIV screening at a major metropolitan TB clinic: HIV prevalence and high-risk behaviors among TB patients.

OBJECTIVES: This study assessed the outcome of implementing a policy of universal screening of patients with tuberculosis (TB) for HIV infection at a major metropolitan public health TB clinic. METHODS: HIV serologic testing was completed on 768 (93%) of 825 eligible patients. Ninety-eight HIV-positive cases (13%) were compared with 670 HIV-negative cases. The presence of adult HIV risk factors was determined by structured interview and review of medical records. RESULTS: One or more HIV risk factors were present in 93% of HIV-positive cases and 42% of HIV-negative cases. CONCLUSIONS: The metropolitan TB clinic is well suited for HIV screening, and HIV-antibody testing and counseling should be provided to all TB patients.

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)