Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.

PURPOSE: To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways. METHODS: A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks. ENDPOINTS: primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF. RESULTS: Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10) HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14). CONCLUSIONS: NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect=150 mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.

Refractory hypercalcemia in an infant secondary to talc pleurodesis resolving after renal transplantation.

Talc pleurodesis is the definitive therapy of recurrent pneumothorax and has not been associated with metabolic complications. We report an anephric male infant who developed severe hypercalcemia 6 months following talc pleurodesis for recurrent peritoneal dialysis-related hydrothorax. The etiology of hypercalcemia was related to persistently elevated 1,25-dihydroxyvitamin D(3) (1,25[OH]2D) levels. The source appeared to be the extrarenal production of 1,25(OH)2D from macrophages in a large thoracic talc granuloma. Hypercalcemia was controlled with a combination of a low calcium diet, low calcium dialysis, ketoconazole and hydroxychloroquine, but elevated 1,25(OH)2D levels persisted. At 32 months of age the child underwent renal transplantation with alemtuzumab pre-conditioning. The hypercalcemia resolved immediately, with normalization of serum 1,25(OH)2D levels and without hypercalciuria. This case demonstrates that hypercalcemia is a potential complication of talc pleurodesis from the extrarenal production of 1,25(OH)2D and that alemtuzumab, a monoclonal antibody directed against the CD52 antigen (which is expressed on almost all macrophages), may have a role in the treatment of hypercalcemia associated with granulomatous conditions.

American Society of Transplantation executive summary on pediatric lung transplantation.

Lung transplantation in children poses distinctly different challenges from those seen in the adult population. This consensus statement reviews the experience in the field of pediatric lung transplantation and highlights areas that deserve further investigation.

Approaches to the treatment of Sjögren's syndrome.

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by complaints of sicca symptoms (dry eye and mouth) and can be associated with other autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, etc). As a result, SS can be difficult to diagnose. Currently, there are several criteria standards for SS, including the San Diego criteria and the European Study Group criteria. According to the San Diego criteria, the incidence of SS is about 0.5%, whereas for the European Study Group it ranges from 3% to 5%. This almost 10-fold difference in SS incidence has led to confusion for both the clinician and researcher. The tearing reflex involves a neural loop in which afferent nerve signals from the ocular surface are relayed centrally to the medulla. The input from the afferent nerves is then processed and sent back via efferent nerves stimulating blood vessels and secretory glands to provide and pump water for tears. Immune factors, such as cytokines, have a profound effect on the tearing mechanism by damaging secretory glands and releasing antibodies to influence the response of muscarinic M3 receptors. Thus, the interaction of neural and immune factors affects the secretory response of glands and contributes to the pathogenesis of SS sicca symptoms. The recent development of muscarinic agonists, such as pilocarpine and cevimeline, serves an important step in recognizing the interaction between the immune and neuroendocrine systems.

Update in Sjögren syndrome.

Sjögren syndrome (SS), the second most common autoimmune rheumatic disease, refers to keratoconjunctivitis sicca and xerostomia resulting from immune lymphocytes that infiltrate the lacrimal and salivary glands. However, differential diagnosis remains confusing due to the high prevalence of vague symptoms of dryness, fatigue, and myalgias in the general population. The problems of diagnosis are further compounded by the finding of "positive" antinuclear antibodies in a high percent of the general population. Unless minor salivary gland biopsies are read by experienced observers, nonspecific changes of sialadenitis are frequently confused with the focal lymphocytic infiltrates that are characteristic of SS. The distinction between fibromyalgia patients with low titer antinuclear antibodies and primary SS remains difficult. Even in patients fulfilling strict criteria for SS, the genomic search for critical genes has proven difficult due to the multigenic pattern of inheritance and strong role of currently undefined environmental factors. No single environmental factor has been detected in the majority of SS patients. SS-like syndrome has been detected in certain patients with HTLV-1 and hepatitis C infection, providing clues to pathogenesis. Even in SS patients with marked sicca symptoms, minor salivary gland biopsy shows that almost 50% of glandular cells are still detected on biopsy. These results imply the importance of immune factors such as cytokines and autoantibodies in decreasing neuro-secretory circuits and induction of glandular dysfunction. Of potential importance, an antibody against muscarinic M3 receptor that can decrease secretory function when injected into rodents is frequently found in the sera of SS patients. Newly developed topical and oral therapies can ease the oral and ocular dryness. Orally administered agonists of the muscarinic M3 receptor (pilocarpine and cevimeline) have recently been approved by the US Food and Drug Administration to increase salivary secretion. Topical ocular use of low-dose corticosteroids or cyclosporin may decrease conjunctival surface inflammation. In a Phase II double-blind study, orally administered interferon alpha (150 U) led to improved saliva flow and symptoms. In pregnant patients with evidence of fetal distress, oral dexamethasone is preferred because this agent crosses the placenta effectively. In animal models, antagonists of tumor necrosis factor and inhibitors of de novo pyrimidine synthesis appear promising.

Human bronchial epithelial cells secrete laminin 5, express hemidesmosomal proteins, and assemble hemidesmosomes.

Epithelial cells attach to the basement membrane through adhesive contacts between the basal cells of the epithelium and the proteins of the extracellular matrix (ECM). The hemidesmosome (HD) is a specialized cell-ECM contact, that mediates the attachment of the epithelial cell basal surface to the ECM. In bronchial epithelial cells, the protein components that constitute the HD have not been demonstrated. Using immunohistochemical techniques, we determined that normal human bronchial epithelial (NHBE) cells express the HD cell surface integrin alpha6beta4 and produce laminin 5, the ECM protein associated with HDs. Furthermore, expression of the HD-associated structural proteins, bullous pemphigoid antigens 1 (BPAG 1) and 2 (BPAG 2), was demonstrated in NHBE cells by immunofluorescence microscopy and immunoblot analyses. In addition, we confirmed the presence of laminin 5 in the basement membrane (BM) of bronchial epithelial biopsy specimens and of BP230, BP180, and the alpha6beta4 integrin heterodimer at the site of bronchial epithelial cell-ECM interaction in vivo. Finally, using electron microscopy, we were able to demonstrate intact HDs in a glutaraldehyde-fixed NHBE cell monolayer. These findings suggest that bronchial epithelium forms HDs and that the laminin 5-alpha6beta4 integrin interaction may be important in stabilizing epithelial cell adhesion to the BM in the lung.

Keratinocyte growth factor stimulates bronchial epithelial cell proliferation in vitro and in vivo.

Airway epithelial cell (AEC) proliferation is crucial to the maintenance of an intact airway surface and the preservation of host defenses. The factors that regulate AEC proliferation are not known. Keratinocyte growth factor (KGF), also known as FGF-7, is a member of the fibroblast growth factor family and a known epithelial cell mitogen. We studied the influence of KGF on the growth of cultured human bronchial epithelial cells and on bronchial cells of rats treated with KGF in vivo. First, we demonstrated the mRNA for the KGF receptor (KGFR) in both normal human bronchial epithelial (NHBE) cells and BEAS-2B cells (a human bronchial epithelial cell line). KGF caused a dose-dependent increase in DNA synthesis, as assessed by thymidine incorporation, in both cell types, with a maximal twofold increase in NHBE cells after 50 ng/ml KGF (P < 0.001). KGF also induced a doubling in NHBE cell number at 10 ng/ml (P < 0.001). Finally, we determined the effect of intratracheal administration of KGF to rats on proliferation of AEC in vivo. Measuring bromodeoxyuridine (BrdU) incorporation in AEC nuclei, KGF increased BrdU labeling of rat AEC in both large and small airways by approximately threefold compared with PBS-treated controls (P < 0.001). Thus KGF induces proliferation of bronchial epithelial cells both in vitro and in vivo.

Current issues in the diagnosis and treatment of Sjögren's syndrome.

Modification of the European Cooperative Group (EEC) criteria for Sjögren's Syndrome (SS) should lead to less confusion in diagnosis and therapeutic trials. The proposed EEC modification will require either a positive minor salivary gland biopsy or a positive autoantibody against Sjögren's-associated A (Ro) or B (La) antigen. This modification will decrease the proportion of women fulfilling EEC criteria from 3-5% to about 0.5%, which is similar to San Diego and San Francisco criteria. Genetic studies have shown increased frequency of alleles for peptide transporter genes TAP1 (0101) and TAP2 (0101) genes as well as tumor necrosis factor microsatellite a2 alleles. Although these markers confer markedly increased risk, they are found in only a small proportion of patients. An increased frequency of drug (antibiotic) allergy and other allergic manifestations appears present in patients with SS and may be linked to HLA-DR3. Hepatitis C as a cause of sicca symptoms, positive anti-nuclear autoantibodies, and mixed cryoglobulinemia is increasingly reported in different parts of the world. Antibodies against muscarinic M3 receptor and expression of costimulatory molecules (CD80 and CD86) by ductal epithelial cells may play a role in pathogenesis. Treatment with pilocarpine is effective in double-blind trials and low dose oral alpha interferon looks promising in initial open studies. In pregnant patients who exhibit evidence of neonatal heart block, treatment with dexamethasone is preferred over prednisone, since the placenta is unable to metabolically activate the latter compound.

Ozone effects on the immediate-phase response to allergen in the nasal airways of allergic asthmatic subjects.

Epidemiologic and clinical trials have suggested that exposure to ozone increases airway hyperresponsiveness and inflammatory response to inhaled nasal allergen challenge in allergic asthmatic subjects. Previous studies have demonstrated an increased late-phase response to nasal allergen challenge; however, the early-phase response is unknown. We sought to characterize the early-phase response by measuring mast-cell inflammatory mediators and cellular influx at time points immediately following ozone exposure and subsequent allergen challenge. A cohort of mild, asymptomatic dust mite--sensitive asthmatic subjects was identified. Each subject underwent two separate exposures to both 0.4 ppm ozone and clean air in a randomized manner. Nasal lavage was performed before and after each exposure. Nasal allergen was then administered to a defined clinical end point, followed by nasal lavage. Differential cell counts and mast-cell products were identified in each lavage specimen. The mast-cell mediators tryptase and prostaglandin D2 were analyzed, as was a marker of epithelial cell permeability, albumin. Although allergen produced an increase in early-onset mediator release (mast cell-derived), no enhancement was noted after exposure to ozone. Neutrophil and eosinophil inflammatory mediators were not increased after ozone exposure or enhanced after allergen exposure, although ozone did enhance eosinophilic influx after exposure to allergen. Ozone exposure does not promote early-phase--response mediator release or enhance the response to allergen challenge in the nasal airways of extrinsic asthmatic subjects. Ozone, however, may promote an inflammatory cell influx, which helps induce a more significant late-phase response in this population.

Red eye unresponsive to treatment.

Red eyes that fail to respond quickly and completely to topical antibiotic treatment require more extensive evaluation to relieve the symptoms and avert possible sight-threatening complications. The initial differential diagnosis of red eye, which includes iritis, acute glaucoma, keratitis and corneal ulcer, and rarer disorders, must be reexamined. A commonly misdiagnosed cause of red eye is the dry eye syndrome. As a primary or secondary problem, the dry eye syndrome must be treated appropriately to avert sight-threatening complications and to alleviate substantial discomfort. The dry eye syndrome may represent the presenting sign of Sjögren's syndrome or it may be due to medication use, with important systemic and ocular implications.

Electrodiagnosis of upper limb weakness in acute quadriplegia.

Clinical and neuropathologic observations after cervical spinal cord injury suggest varying involvement of gray and white matter. The resulting upper limb weakness may reflect varying degrees of upper motoneuron (UMN) and/or lower motoneuron (LMN) involvement. This study uses electrophysiologic measures, including compound muscle action potential (M response) amplitude, root mean square (RMS) of the surface electromyographic activity during voluntary muscle contractions and the firing rate of motor units, to distinguish UMN and LMN weakness in upper extremities after acute quadriplegia. M response amplitude did not correlate with strength; many muscles had large M responses given their strength. These muscles manifest: (1) high M/RMS ratios (ratio of electrically elicited to voluntarily recruited electromyographic activity) and (2) slow firing rates of single motor units during maximal isometric contractions. For muscles with normal M amplitudes, M/RMS ratio correlates inversely with strength. For muscles with normal M/RMS ratios, M amplitude correlates positively with strength. Cluster analysis was used to distinguish UMN, LMN or Mixed types of weakness. Distinguishing these different types of weakness in acute quadriplegia may allow individualized rehabilitation for the type of weakness present.

Interferon alpha-2a for subfoveal neovascularization in age-related macular degeneration.

BACKGROUND: The current study is a prospective randomized clinical trial to determine the effect of interferon alpha-2a on eyes with subfoveal subretinal neovascularization secondary to age-related macular degeneration (AMD). METHODS: Twenty eyes of 19 patients with subfoveal neovascularization secondary to AMD were prospectively evaluated. Ten eyes were randomized to subcutaneous interferon alpha-2a (3 million units/m2) every other day for 8 weeks, whereas 10 eyes were randomized to observation alone as controls. Fluorescein angiography, best-corrected visual acuity tests, and macular visual field assessments were performed, and all eyes were followed for a minimum of 6 months. RESULTS: At the 2-month follow-up visit, the interferon group manifested somewhat slower neovascular growth than controls, but the results were not statistically significant. At the 6-month follow-up visit, there was no difference in visual acuity, average macular sensitivities, or extent of neovascularization. The rate of neovascular progression was significantly related to the extent of previous macular photocoagulation in both groups. CONCLUSION: Though the rate of neovascular progression was slowed during the second month of interferon treatment, the effect did not persist once interferon was discontinued. No long-term benefit appeared to be present. Unfortunately, lengthening the time of administration, increasing the dosage, or increasing the frequency of administration would likely give rise to unacceptable side effects.

Resonant-mass detectors of gravitational radiation.

A network of second-generation low-temperature gravitational radiation detectors is nearing completion. These detectors, sensitive to mechanical strains of order 10(-18), are possible because of a variety of technical innovations hat have been made in cryogenics, low-noise superconducting instrumentation, and vibration isolation techniques. Another five orders of magnitude improvement in energy sensitivity of resonant-mass detectors is possible before the linear amplifier quantum limit is encountered.

Adverse drug reaction reporting: a working system.

Adverse drug reactions (ADRs) are a severe problem. Up to 30% of hospitalized medical patients may have an ADR, and up to 5% of hospitalizations may be caused by an ADR. Reporting systems that track these reactions vary widely as to their capture rates. In a 12-month period, with the aid of the Medical Record Department at St. Elizabeth Hospital Medical Center, 150 adverse drug reactions were catalogued. Fifty-eight of these resulted in admission, while 92 occurred during hospitalization. Cardiovascular agents and antibiotics produced the most reports. Reactions are evaluated and tabulated by the Department of Pharmacy, and subsequently presented to the Pharmacy (P&T) Committee as part of the quality assurance program, which meets the standards mandated by the Joint Commission on Accreditation of Hospitals. The reporting system is described in this article.

Ocular and oral problems in arthritis. How to recognize, when to refer.

Recognition of oral and ocular problems is important in the management of arthritis. Although the focus of attention is usually on joint problems, patients with these chronic disorders require a comprehensive approach to their total medical care. Physicians need to watch for physical signs of significant inflammation and should alert their patients to watch for significant symptoms.

Primary Sjogren syndrome: clinical and immunopathologic features.

Primary Sjogren syndrome is an autoimmune condition in which dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) result from lymphocytic infiltration of lacrimal and salivary glands. Clinical and laboratory features of 60 primary Sjogren syndrome patients seen at our clinic during the past three years are presented. These patients illustrate the wide spectrum of extraglandular features that may occur as a result of lymphoid infiltration of lung, kidney, skin, stomach, liver, and muscle. They further emphasize the difficulty in classifying a patient as primary or secondary Sjogren syndrome (ie, sicca symptoms associated with systemic lupus erythematosus, rheumatoid arthritis, or scleroderma), particularly early in the disease course. As an initial step in understanding the pathogenesis, the lymphocytes that infiltrate the salivary glands and lymph nodes were characterized by using monoclonal antibodies that recognize distinct lymphocyte subsets and by using in vitro functional assays. These studies have demonstrated that affected tissues have infiltrates of T cells with helper/inducer activity and with a high frequency of "activation antigens." The immunohistologic techniques are useful in differentiating "benign" and "pseudolymphoma" lesions (both due predominantly to T cells) from non-Hodgkin lymphoma (usually due to B-cell infiltrates). Although there is no "cure" for primary Sjogren syndrome patient's symptoms may be significantly improved by measures aimed at prevention of ocular and dental complications and by the recognition of extraglandular features that may be amenable to specific treatment.