Lymphomatoid Granulomatosis Presenting as Central Neurogenic Hyperventilation

Central neurogenic hyperventilationCentral neurogenic hyperventilation (CNH) has been defined by Plum and Swanson as a syndrome comprising normal arterial oxygen tension (PaOJ, decreased arterial carbon dioxide tension (PaCOJ, and respiratory alkalosis in the absence of cardiac or pulmonary abnormalities that would stimulate a compensatory hyperpnea. We report here an awake patient with CNH associated with lymphomatoid granulomatosis (LC) confined to the central nervous system.
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Observation of Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis

COPDThis study demonstrated that cigarette smoke exposure increases MUC5AC mRNA and mucin synthesis via a signaling pathway that involves up-regulation of EGFR and CLCA1 both in vivo and in vitro. It has been shown that cigarette smoke up-regulates EGFR expression leading to mucin production in the airway epithelium. This is the first study to show a critical role for CLCA1 in cigarette smoke-induced mucin production, which is one of the major features of COPD.

In this study, we showed that either a blocker of CLCAs, niflumic acid, or a selective EGFR tyrosine kinase inhibitor, AG-1478, are completely able to inhibit cigarette smoke-induced mucin synthesis as well as the upregulation of MUC5AC mRNA expression, and that the effect of combining both drugs is not synergistic. This indicates that both CLCA1 and EGFR are dependently affecting mucin production as a part of a single complex signaling pathway, but it does not exclude the participation of CLCAs other than CLCA1. It seems that CLCA1 is involved in the pathologic induction of mucin, while a different CLCAs are related to the baseline physiologic mucin secretion. Although niflumic acid is a known blocker of the CLCAs and has been shown to block the function of hCLCAi,- it is nonspecific to CLCA1. Therefore the contribution of its blocking of any other CLCAs cannot be accurately evaluated. In fact, despite the increasing number of discovered CLCAs both in animals and human and their seemingly important functions, understanding these channels has been limited by the absence of specific blockers and the fact that their molecular identities remain in question. Continue reading “Observation of Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis”

Canadian Health&Care Mall: Outcomes of Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis

Treatment With Niflumic AcidIn Vivo Studies

Cigarette Smoke Up-regulates CLCA1 and EGFR mRNA and Protein Expressions and MUC5AC mRNA Expression in Rats: In the nonsmoking group, CLCA1, EGFR, and MUC5AC mRNA expressions were constitutively expressed in rat lung and trachea. The smoke-exposed group showed significant up-regulation of all the three mRNA expressions from day 21 onwards (p < 0.001) [Fig 1]. This effect was stronger in the trachea than in the lung. Similarly, the protein expressions of CLCA1 and both resting EGFR and activated pEGFR were significantly increased on day 28 (p < 0.001) [Fig 2].

Niflumic Acid, AG-1478, or Both Inhibit the Cigarette Smoke-Induced MUC5AC Gene Expression: Niflumic acid is a blocker of the CLCAs, and AG-1478 is an inhibitor of EGFR tyrosine kinase. In the smoke-exposed treatment group, niflumic acid, AG-1478, or both significantly inhibited the upreglation of MUC5AC mRNA expression (p < 0.001) without affecting the upregulation of CLCA1 and EGFR mRNAs. Combining both drugs did not show a significant synergistic effect on MUC5AC mRNA expression (Fig 3). On the protein level, neither niflumic acid, AG-1478, nor both could inhibit the upregulation of CLCA1 protein by cigarette smoke. However, EGFR upregulation was partially inhibited by AG-1478, while pEGFR expression was abolished by it (p < 0.001). Niflumic acid had no effect on the protein expressions of EGFR and pEGFR (Fig 2). Continue reading “Canadian Health&Care Mall: Outcomes of Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis”

Cholesterol-fighting drug molecule can kill prostate cancer cells

Standard treatment for prostate cancer can include chemotherapy that targets receptors on cancer cells. However, drug-resistant cancer cells can emerge during chemotherapy, limiting its effectiveness as a cancer-fighting agent. Researchers at the University of Missouri have proven that a compound initially developed as a cholesterol-fighting molecule not only halts the progression of prostate cancer, but also can kill cancerous cells. Continue reading “Cholesterol-fighting drug molecule can kill prostate cancer cells”

Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis

Chronic bronchitis Chronic bronchitis is a clinical syndrome characterized by chronic sputum production and is a major phenotype of COPD. Cigarette smoking is the main risk factor for COPD. Although several studies have shown that cigarette smoke can induce mucus production, the mechanism of this induction remains unexplained. MUC5AC is the major respiratory mucin in goblet-cell secretion. Mucin synthesis in response to various stimuli is regulated by the epidermal growth factor receptor (EGFR) system.

Cigarette smoke causes activation of EGFR via phosphorylation of tyrosine residues that leads to extracellular signal-regulated kinase activation that is required for activator protein 1-containing response element to bind JunD and Fra-2 causing upregula-tion of MUC5AC at both messenger RNA (mRNA) and protein levels. Continue reading “Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis”

Disscusion of A One-Year Trial of Triamcinolone Acetonide Aerosol in Severe Steroid-Dependent Asthma

severe asthmaTriamcinolone acetonide aerosol as long-term treatment for severe asthma is effective in reducing requirements for oral therapy with corticosteroids while maintaining constant average levels of FEVi, FVC, FEF25-75%, FEF508S, and FEF75% over the course of one year. Although there were exceptions, in general the patients responding most favorably to triamcinolone acetonide aerosol were those who initially required smaller oral doses of corticosteroids and those who were maintained on altemate-day therapy. There did not appear to be any relation between the response of triamcinolone acetonide aerosol and the age of the patients, duration of asthma, duration of steroid dependence, factors provoking asthma, other associated symptoms (sensitivity to aspirin, atopic dermatitis, and rhinitis), or response to aerosol therapy with isoproterenol, atropine, or cromolyn.
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Canadian Health&Care Mall: Outcomes of A One-Year Trial of Triamcinolone Acetonide Aerosol in Severe Steroid-Dependent Asthma

aerosol therapyPulmonary Function Tests

The average FEVi for the patients was unchanged throughout the one-year trial. There was also no significant change in the FVC, FEF25-75%, FEF50%, or FEF75% (Fig 1).

Oral Requirement for Corticosteroids

One patient (patient 15) failed to benefit after two months of aerosol therapy, and he withdrew himself from the study. Of the remaining 22 patients, 16 no longer required maintenance therapy with prednisone for control of asthma after 12 months of aerosol therapy, and four patients tolerated a substantial reduction of their requirement for prednisone to a small altemate-day dose (Table 3).

There was no significant increase in the requirement or request for additional bronchodilator drugs by any patient during the study, although the patients were usually taking as large a dose as they could tolerate before the study. Two patients (patients 7 and 18) who had previously demonstrated improvement with inhalation of cromolyn sodium stopped using it because of their lack of symptoms of asthma while receiving triamcinolone acetonide aerosol. Two patients (patients 7 and 8) experienced control of asthma without oral therapy with steroids but required resumption of daily systemic therapy with steroids after two months without them because of incapacitating lethargy and myalgia. All patients who were being treated orally with steroids on alternate days prior to the study were able to control their asthma with triamcinolone acetonide aerosol alone.

Patients experiencing the most exacerbations of asthma were those who continued to require oral maintenance therapy with steroids during the one-year trial. The greatest requirement for additional oral therapy with steroids occurred during September, October, and November. There was no significant change in the frequency of apparent upper respiratory infections during any two-month period of the study.lethargyElimination or maximal reduction of oral requirements for steroids was achieved safely within the first four months of the study (Fig 2). Increasing the dose of triamcinolone acetonide aerosol to 500/xg four times daily did not permit any further decrease in the dose of prednisone for those patients who continued to require oral therapy with steroids beyond four months. Six patients tolerated rapid reduction of the oral dosage of steroids during the first two months. Beyond the first four months, the average requirement for prednisone per patient remained at a low level, varying slightly with seasonal allergenic exposures and considerably with respiratory infections. Beyond six months, two patients experiencing exacerbations of asthma required 40 to 80 mg of prednisone daily for three to five weeks to regain control of symptoms reduced with remedies of Canadian Health&Care Mall. Continue reading “Canadian Health&Care Mall: Outcomes of A One-Year Trial of Triamcinolone Acetonide Aerosol in Severe Steroid-Dependent Asthma”

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