Ruairi Fahy | Trinity College Dublin (original) (raw)

Papers by Ruairi Fahy

Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Casp... more Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Caspases (cysteine-aspartatespecific proteases) are key molecules in apoptosis and require proteolytic removal of prodomains for activity. Caspase-1 and caspase-3 have both been connected to apoptosis in other model systems. The present study attempted to delineate what role these caspases play in spontaneous monocyte apoptosis. In serum-free conditions, monocytes showed a commitment to apoptosis as early as 4 h in culture, as evidenced by caspase-3-like activity. Apoptosis, as defined by oligonucleosomal DNA fragmentation, was prevented by a generalized caspase inhibitor, z-VAD-FMK, and the more specific caspase inhibitor, z-DEVD-FMK. The caspase activity was specifically attributable to caspase-3 by the identification of cleavage of procaspase-3 to active forms by immunoblots and by cleavage of the fluorogenic substrate DEVD-AFC. In contrast, a caspase-1 family inhibitor, YVAD-CMK, did not protect monocytes from apoptosis, and the fluorogenic substrate YVAD-AFC failed to show an increase in activity in apoptotic monocytes. When cultured with LPS (1 g/ml), monocyte apoptosis was prevented, as was the activation of caspase-3. Unexpectedly, LPS did not change baseline caspase-1 activity. These findings link spontaneous monocyte apoptosis to the proteolytic activation of caspase-3.

The Internet Journal of Pulmonary Medicine

Blockade of TNF-α using tumor necrosis factor-α antibodies is used in the management of a number ... more Blockade of TNF-α using tumor necrosis factor-α antibodies is used in the management of a number of chronic inflammatory diseases and is indicated for treatment of refractory Crohn's Disease. We report the development of Peumocystis Jirovecii (Carinii) pneumonia and acute respiratory failure in a patient five weeks after the initiation of infliximab (Remicade®) therapy.

QJM: An International Journal of Medicine

Background Sarcoidosis is occasionally seen in association with malignancy, both at the time of c... more Background Sarcoidosis is occasionally seen in association with malignancy, both at the time of cancer diagnosis or during follow up. Aim The purpose of this study is to identify patients with paraneoplastic sarcoid, their associated malignancies, and disease characteristics. Methods We identified 289 patients diagnosed histologically with sarcoidosis over a 6-year period in one centre, from 2010 to 2016. 50 of these patients had a prior or concomitant diagnosis of cancer. Results 17.3% of malignancy cases had an associated diagnosis of sarcoid. The most common malignancies were Gastrointestinal (20%), Haematological (18%), Lung (12%), Gynaecological (12%) and Head and Neck cancer (12%). 74% of sarcoid cases had pulmonary disease with sarcoid diagnostic tissue obtained most frequently via endobronchial ultrasound fine needle aspiration (68%). Most sarcoid cases (66%) were diagnosed within the first year of their malignancy diagnosis. All 50 patients had radiological findings that we...

Mycoses, 2018

Influenza virus infection is now recognised as a risk factor for invasive pulmonary aspergillosis... more Influenza virus infection is now recognised as a risk factor for invasive pulmonary aspergillosis (IPA). Delays in diagnosis contribute to delayed commencement of antifungal therapy. In addition, the emergence of resistance to first-line triazole antifungal agents puts emphasis on early detection to prevent adverse outcomes. We present 2 allogeneic stem cell transplant patients who developed IPA due to triazole-resistant Aspergillus fumigatus following influenza infection. We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance.

Amer J Respir Cell Molec Biol, 2003

The acute respiratory distress syndrome presents as hypoxia, bilateral pulmonary infiltrates on c... more The acute respiratory distress syndrome presents as hypoxia, bilateral pulmonary infiltrates on chest imaging, and the absence of heart failure sufficient to account for this clinical state. Management is largely supportive, focusing on protective mechanical ventilation, and the avoidance of fluid overload. Patients with severe hypoxaemia can be managed with early short-term use of neuromuscular blockade, prone position ventilation or extra-corporeal membrane oxygenation. The use of inhaled nitric oxide is rarely indicated and both β2 agonists and late steroids should be avoided. Mortality currently remains at approximately 30%.

Clinical Rheumatology, Apr 1, 2006

The Journal of Immunology, Aug 15, 1999

Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Casp... more Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Caspases (cysteine-aspartatespecific proteases) are key molecules in apoptosis and require proteolytic removal of prodomains for activity. Caspase-1 and caspase-3 have both been connected to apoptosis in other model systems. The present study attempted to delineate what role these caspases play in spontaneous monocyte apoptosis. In serum-free conditions, monocytes showed a commitment to apoptosis as early as 4 h in culture, as evidenced by caspase-3-like activity. Apoptosis, as defined by oligonucleosomal DNA fragmentation, was prevented by a generalized caspase inhibitor, z-VAD-FMK, and the more specific caspase inhibitor, z-DEVD-FMK. The caspase activity was specifically attributable to caspase-3 by the identification of cleavage of procaspase-3 to active forms by immunoblots and by cleavage of the fluorogenic substrate DEVD-AFC. In contrast, a caspase-1 family inhibitor, YVAD-CMK, did not protect monocytes from apoptosis, and the fluorogenic substrate YVAD-AFC failed to show an increase in activity in apoptotic monocytes. When cultured with LPS (1 g/ml), monocyte apoptosis was prevented, as was the activation of caspase-3. Unexpectedly, LPS did not change baseline caspase-1 activity. These findings link spontaneous monocyte apoptosis to the proteolytic activation of caspase-3.

Rationale: Monocytes are central to the initiation of the inflammatory response in sepsis, with c... more Rationale: Monocytes are central to the initiation of the inflammatory response in sepsis, with caspase-1 activation playing a key role. Monocyte deactivation during sepsis has been linked to poor outcomes. Objectives: Given the importance of caspase-1 in the immune response, we investigated whether monocytes from patients early in septic shock demonstrate alterations in mRNAs for caspase-1related molecules. Methods: Patients with septic shock (n 5 26; age .18 years), critically ill intensive care unit patients (n 5 20), and healthy volunteers (n 5 22) were enrolled in a prospective cohort study in a university intensive care unit. Demographic, biological, physiologic, and plasma cytokine measurements were obtained. Monocytes were assayed for ex vivo tumor necrosis factor-a production, and fresh monocyte mRNA was analyzed by quantitative reverse-transcription polymerase chain reaction for Toll-like receptors, NOD-LRR proteins, cytokines, and nuclear factor-kB-related genes. Measurements and Main Results: Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1, and Pypaf-7 were significantly lower in patients with septic shock compared with critically ill control subjects. NALP1 mRNA levels were linked to survival in patients with sepsis (P 5 0.0068) and correlated with SAPS II scores (r 5 20.63). Conclusions: These data suggest that monocyte deactivation occurs during the earliest stages of the systemic inflammatory response and that changes in inflammasome mRNA expression are part of this process.

and control subjects. We also compared active TGF-1 levels in lematic, impairing the lung's p... more and control subjects. We also compared active TGF-1 levels in lematic, impairing the lung's primary function of gas ex- the bronchoalveolar lavage (BAL) fluid of 13 de novo ARDS cases, and 7 normal control subjects. RT in situ PCR showed change. Clinically, this is seen as progressive hypoxia, de- TGF-1 mRNA expression in fibroproliferative ARDS cases. Im- creased lung compliance,

Transplant infectious disease : an official journal of the Transplantation Society, 2014

We report a case of Mycobacterium kansasii presenting as an obstructing endobronchial mass in a p... more We report a case of Mycobacterium kansasii presenting as an obstructing endobronchial mass in a patient post stem cell transplant. The patient had a complete clinical, microbiological, and radiological response to anti-tuberculous treatment. To our knowledge, this is the first case of M. kansasii presenting post transplant with an obstructing lung mass simulating relapse or post-transplant lymphoma.

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1999

Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Casp... more Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Caspases (cysteine-aspartate-specific proteases) are key molecules in apoptosis and require proteolytic removal of prodomains for activity. Caspase-1 and caspase-3 have both been connected to apoptosis in other model systems. The present study attempted to delineate what role these caspases play in spontaneous monocyte apoptosis. In serum-free conditions, monocytes showed a commitment to apoptosis as early as 4 h in culture, as evidenced by caspase-3-like activity. Apoptosis, as defined by oligonucleosomal DNA fragmentation, was prevented by a generalized caspase inhibitor, z-VAD-FMK, and the more specific caspase inhibitor, z-DEVD-FMK. The caspase activity was specifically attributable to caspase-3 by the identification of cleavage of procaspase-3 to active forms by immunoblots and by cleavage of the fluorogenic substrate DEVD-AFC. In contrast, a caspase-1 family inhibitor, YVAD-CMK, did no...

Journal of Thoracic Imaging, 2004

The injection of oil into the pleural cavity was a widely used treatment of pulmonary tuberculosi... more The injection of oil into the pleural cavity was a widely used treatment of pulmonary tuberculosis until the advent of effective anti-tuberculous therapy. Long-term complications of oleothorax can occur when the oil is not removed. The authors present an unusual complication of oleothorax, reactivation of tuberculosis, 54 years after oil instillation.

Southern Medical Journal, 2004

Objectives: To determine patterns of hypometabolism on fluorodeoxyglucose F18 positron emission t... more Objectives: To determine patterns of hypometabolism on fluorodeoxyglucose F18 positron emission tomography (FDG-PET) in patients with progressive apraxia of speech (PAS) and primary progressive aphasia (PPA) variants and to use these patterns to further refine current classification. Design: We identified all patients who had FDG-PET and PAS or PPA who were evaluated by an expert speechlanguage pathologist. Patterns of hypometabolism were independently classified by 2 raters blinded to clinical data. Three speech-language pathologists reclassified all patients into 1 of 7 operationally defined categories of PAS and PPA blinded to FDG-PET data.

Southern Medical Journal, 2000

Although exceedingly rare, fulminant hepatic failure (FHF) in immunocompetent patients can develo... more Although exceedingly rare, fulminant hepatic failure (FHF) in immunocompetent patients can develop with primary or recurrent infection due to herpes simplex virus (HSV). The diagnosis is frequently obscured by the absence of mucocutaneous involvement. Elevated transaminase values with leukopenia and a relatively low bilirubin level may provide clues to the diagnosis. We describe an immunocompetent woman who died of FHF before a definitive diagnosis of HSV type 2 hepatitis was established. Herpes simplex virus hepatitis is one of the few causes of FHF for which potentially effective therapy is available. Thus, early diagnosis is paramount and usually requires liver biopsy. Recent studies suggest that transjugular liver biopsy is safe and effective in establishing the cause of FHF. Since the diagnosis and management of FHF are frequently influenced by the results of transjugular liver biopsy, it may become a standard diagnostic tool for managing FHF in centers where such expertise exists.

Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Casp... more Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Caspases (cysteine-aspartatespecific proteases) are key molecules in apoptosis and require proteolytic removal of prodomains for activity. Caspase-1 and caspase-3 have both been connected to apoptosis in other model systems. The present study attempted to delineate what role these caspases play in spontaneous monocyte apoptosis. In serum-free conditions, monocytes showed a commitment to apoptosis as early as 4 h in culture, as evidenced by caspase-3-like activity. Apoptosis, as defined by oligonucleosomal DNA fragmentation, was prevented by a generalized caspase inhibitor, z-VAD-FMK, and the more specific caspase inhibitor, z-DEVD-FMK. The caspase activity was specifically attributable to caspase-3 by the identification of cleavage of procaspase-3 to active forms by immunoblots and by cleavage of the fluorogenic substrate DEVD-AFC. In contrast, a caspase-1 family inhibitor, YVAD-CMK, did not protect monocytes from apoptosis, and the fluorogenic substrate YVAD-AFC failed to show an increase in activity in apoptotic monocytes. When cultured with LPS (1 g/ml), monocyte apoptosis was prevented, as was the activation of caspase-3. Unexpectedly, LPS did not change baseline caspase-1 activity. These findings link spontaneous monocyte apoptosis to the proteolytic activation of caspase-3.

The Internet Journal of Pulmonary Medicine

Blockade of TNF-α using tumor necrosis factor-α antibodies is used in the management of a number ... more Blockade of TNF-α using tumor necrosis factor-α antibodies is used in the management of a number of chronic inflammatory diseases and is indicated for treatment of refractory Crohn's Disease. We report the development of Peumocystis Jirovecii (Carinii) pneumonia and acute respiratory failure in a patient five weeks after the initiation of infliximab (Remicade®) therapy.

QJM: An International Journal of Medicine

Background Sarcoidosis is occasionally seen in association with malignancy, both at the time of c... more Background Sarcoidosis is occasionally seen in association with malignancy, both at the time of cancer diagnosis or during follow up. Aim The purpose of this study is to identify patients with paraneoplastic sarcoid, their associated malignancies, and disease characteristics. Methods We identified 289 patients diagnosed histologically with sarcoidosis over a 6-year period in one centre, from 2010 to 2016. 50 of these patients had a prior or concomitant diagnosis of cancer. Results 17.3% of malignancy cases had an associated diagnosis of sarcoid. The most common malignancies were Gastrointestinal (20%), Haematological (18%), Lung (12%), Gynaecological (12%) and Head and Neck cancer (12%). 74% of sarcoid cases had pulmonary disease with sarcoid diagnostic tissue obtained most frequently via endobronchial ultrasound fine needle aspiration (68%). Most sarcoid cases (66%) were diagnosed within the first year of their malignancy diagnosis. All 50 patients had radiological findings that we...

Mycoses, 2018

Influenza virus infection is now recognised as a risk factor for invasive pulmonary aspergillosis... more Influenza virus infection is now recognised as a risk factor for invasive pulmonary aspergillosis (IPA). Delays in diagnosis contribute to delayed commencement of antifungal therapy. In addition, the emergence of resistance to first-line triazole antifungal agents puts emphasis on early detection to prevent adverse outcomes. We present 2 allogeneic stem cell transplant patients who developed IPA due to triazole-resistant Aspergillus fumigatus following influenza infection. We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance.

Amer J Respir Cell Molec Biol, 2003

The acute respiratory distress syndrome presents as hypoxia, bilateral pulmonary infiltrates on c... more The acute respiratory distress syndrome presents as hypoxia, bilateral pulmonary infiltrates on chest imaging, and the absence of heart failure sufficient to account for this clinical state. Management is largely supportive, focusing on protective mechanical ventilation, and the avoidance of fluid overload. Patients with severe hypoxaemia can be managed with early short-term use of neuromuscular blockade, prone position ventilation or extra-corporeal membrane oxygenation. The use of inhaled nitric oxide is rarely indicated and both β2 agonists and late steroids should be avoided. Mortality currently remains at approximately 30%.

Clinical Rheumatology, Apr 1, 2006

The Journal of Immunology, Aug 15, 1999

Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Casp... more Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Caspases (cysteine-aspartatespecific proteases) are key molecules in apoptosis and require proteolytic removal of prodomains for activity. Caspase-1 and caspase-3 have both been connected to apoptosis in other model systems. The present study attempted to delineate what role these caspases play in spontaneous monocyte apoptosis. In serum-free conditions, monocytes showed a commitment to apoptosis as early as 4 h in culture, as evidenced by caspase-3-like activity. Apoptosis, as defined by oligonucleosomal DNA fragmentation, was prevented by a generalized caspase inhibitor, z-VAD-FMK, and the more specific caspase inhibitor, z-DEVD-FMK. The caspase activity was specifically attributable to caspase-3 by the identification of cleavage of procaspase-3 to active forms by immunoblots and by cleavage of the fluorogenic substrate DEVD-AFC. In contrast, a caspase-1 family inhibitor, YVAD-CMK, did not protect monocytes from apoptosis, and the fluorogenic substrate YVAD-AFC failed to show an increase in activity in apoptotic monocytes. When cultured with LPS (1 g/ml), monocyte apoptosis was prevented, as was the activation of caspase-3. Unexpectedly, LPS did not change baseline caspase-1 activity. These findings link spontaneous monocyte apoptosis to the proteolytic activation of caspase-3.

Rationale: Monocytes are central to the initiation of the inflammatory response in sepsis, with c... more Rationale: Monocytes are central to the initiation of the inflammatory response in sepsis, with caspase-1 activation playing a key role. Monocyte deactivation during sepsis has been linked to poor outcomes. Objectives: Given the importance of caspase-1 in the immune response, we investigated whether monocytes from patients early in septic shock demonstrate alterations in mRNAs for caspase-1related molecules. Methods: Patients with septic shock (n 5 26; age .18 years), critically ill intensive care unit patients (n 5 20), and healthy volunteers (n 5 22) were enrolled in a prospective cohort study in a university intensive care unit. Demographic, biological, physiologic, and plasma cytokine measurements were obtained. Monocytes were assayed for ex vivo tumor necrosis factor-a production, and fresh monocyte mRNA was analyzed by quantitative reverse-transcription polymerase chain reaction for Toll-like receptors, NOD-LRR proteins, cytokines, and nuclear factor-kB-related genes. Measurements and Main Results: Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1, and Pypaf-7 were significantly lower in patients with septic shock compared with critically ill control subjects. NALP1 mRNA levels were linked to survival in patients with sepsis (P 5 0.0068) and correlated with SAPS II scores (r 5 20.63). Conclusions: These data suggest that monocyte deactivation occurs during the earliest stages of the systemic inflammatory response and that changes in inflammasome mRNA expression are part of this process.

and control subjects. We also compared active TGF-1 levels in lematic, impairing the lung's p... more and control subjects. We also compared active TGF-1 levels in lematic, impairing the lung's primary function of gas ex- the bronchoalveolar lavage (BAL) fluid of 13 de novo ARDS cases, and 7 normal control subjects. RT in situ PCR showed change. Clinically, this is seen as progressive hypoxia, de- TGF-1 mRNA expression in fibroproliferative ARDS cases. Im- creased lung compliance,

Transplant infectious disease : an official journal of the Transplantation Society, 2014

We report a case of Mycobacterium kansasii presenting as an obstructing endobronchial mass in a p... more We report a case of Mycobacterium kansasii presenting as an obstructing endobronchial mass in a patient post stem cell transplant. The patient had a complete clinical, microbiological, and radiological response to anti-tuberculous treatment. To our knowledge, this is the first case of M. kansasii presenting post transplant with an obstructing lung mass simulating relapse or post-transplant lymphoma.

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1999

Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Casp... more Apoptosis is an important mechanism for regulating the numbers of monocytes and macrophages. Caspases (cysteine-aspartate-specific proteases) are key molecules in apoptosis and require proteolytic removal of prodomains for activity. Caspase-1 and caspase-3 have both been connected to apoptosis in other model systems. The present study attempted to delineate what role these caspases play in spontaneous monocyte apoptosis. In serum-free conditions, monocytes showed a commitment to apoptosis as early as 4 h in culture, as evidenced by caspase-3-like activity. Apoptosis, as defined by oligonucleosomal DNA fragmentation, was prevented by a generalized caspase inhibitor, z-VAD-FMK, and the more specific caspase inhibitor, z-DEVD-FMK. The caspase activity was specifically attributable to caspase-3 by the identification of cleavage of procaspase-3 to active forms by immunoblots and by cleavage of the fluorogenic substrate DEVD-AFC. In contrast, a caspase-1 family inhibitor, YVAD-CMK, did no...

Journal of Thoracic Imaging, 2004

The injection of oil into the pleural cavity was a widely used treatment of pulmonary tuberculosi... more The injection of oil into the pleural cavity was a widely used treatment of pulmonary tuberculosis until the advent of effective anti-tuberculous therapy. Long-term complications of oleothorax can occur when the oil is not removed. The authors present an unusual complication of oleothorax, reactivation of tuberculosis, 54 years after oil instillation.

Southern Medical Journal, 2004

Objectives: To determine patterns of hypometabolism on fluorodeoxyglucose F18 positron emission t... more Objectives: To determine patterns of hypometabolism on fluorodeoxyglucose F18 positron emission tomography (FDG-PET) in patients with progressive apraxia of speech (PAS) and primary progressive aphasia (PPA) variants and to use these patterns to further refine current classification. Design: We identified all patients who had FDG-PET and PAS or PPA who were evaluated by an expert speechlanguage pathologist. Patterns of hypometabolism were independently classified by 2 raters blinded to clinical data. Three speech-language pathologists reclassified all patients into 1 of 7 operationally defined categories of PAS and PPA blinded to FDG-PET data.

Southern Medical Journal, 2000

Although exceedingly rare, fulminant hepatic failure (FHF) in immunocompetent patients can develo... more Although exceedingly rare, fulminant hepatic failure (FHF) in immunocompetent patients can develop with primary or recurrent infection due to herpes simplex virus (HSV). The diagnosis is frequently obscured by the absence of mucocutaneous involvement. Elevated transaminase values with leukopenia and a relatively low bilirubin level may provide clues to the diagnosis. We describe an immunocompetent woman who died of FHF before a definitive diagnosis of HSV type 2 hepatitis was established. Herpes simplex virus hepatitis is one of the few causes of FHF for which potentially effective therapy is available. Thus, early diagnosis is paramount and usually requires liver biopsy. Recent studies suggest that transjugular liver biopsy is safe and effective in establishing the cause of FHF. Since the diagnosis and management of FHF are frequently influenced by the results of transjugular liver biopsy, it may become a standard diagnostic tool for managing FHF in centers where such expertise exists.