I Michael Goonewardene - Academia.edu (original) (raw)

Papers by I Michael Goonewardene

ABSTRACTBackgroundBetter understanding of the association between characteristics of patients hos... more ABSTRACTBackgroundBetter understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management.MethodsImmunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1,164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed.FindingsThe median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clusteri...

Medical Oncology and Tumor Pharmacotherapy, 1993

A biological response modifier, mixed bacterial vaccine (MBV), derived from Streptococcus pyogene... more A biological response modifier, mixed bacterial vaccine (MBV), derived from Streptococcus pyogenes and Serratia marcescens was used as a single agent in the treatment of 11 patients with refractory malignancies. MBV's effect on interleukin-2 (IL-2) production, plasma interferon (IFN) and tumor necrosis factor (TNF) levels was monitored. Most patients' peripheral blood mononuclear cells continued to produce baseline to elevated levels of IL-2, in spite of age and disease status. Several patients maintained moderate to high IFN levels. In general there was little correlation between IL-2 and IFN levels or with the response to therapy. One of 11 patients had minor response, 1 of 11 had partial response, 4 of 11 had temporary stabilization of disease, and 5 of 11 had progressive disease. A patient with AIDS and Kaposi's sarcoma experienced a dramatic improvement in performance status and disease stabilization. In all patients side effects occurred only following i.v. and not i.m. administration and included fever and chills. No adverse hepatic, renal or hematologic effects were observed. MBV is a well-tolerated biological response modifier with modest activity in advanced human tumors.

The Journal of Nutrition, 1990

We examined the effect of vitamin A deficiency on natural killer (NK) cell activity and interfero... more We examined the effect of vitamin A deficiency on natural killer (NK) cell activity and interferon (IFN) production. Rats were weaned at 16 or 21 d of age onto semisynthetic diets containing either 0 or 4 micrograms retinol/g diet. At the time of study, retinol-depleted rats had serum vitamin A concentrations less than 7% of those of pair-fed controls. In two studies, rats exhibited no external signs of retinol deficiency, but with further depletion some symptoms were observed. Splenic NK cell activity against chromium-51-labeled YAC-1 cells was significantly decreased in vitamin A-depleted rats (22-80% of values for control rats, depending on the degree of retinol deficiency), regardless of the ratio of effector to target cells used. When vitamin A-depleted rats were repleted orally with retinol, NK cell activity was consistently normalized. To understand the possible mechanisms involved in decreasing NK cell activity, we investigated IFN production by concanavalin A-stimulated spleen cells from vitamin A-depleted, from repleted and from control animals. IFN titers were significantly decreased (22-33% of values for control rats) in supernatants of spleen cell cultures of the vitamin A-depleted rats. Repletion with vitamin A resulted in IFN activities ranging from 80 to 130% of controls. Adding alpha/beta IFN in vitro to the spleen cells of vitamin A-depleted animals increased their NK cell activity. The number of spleen cells reacting with a monoclonal antibody specific for rat NK cells was slightly lower in retinol-depleted rats, but not enough to account for the differences in NK cell and IFN activities. These data suggest that vitamin A deficiency affect the nonspecific arm of the immune system, possibly by altering the functional capacity of cells to produce lymphokines needed for the generation of an appropriate cytolytic response.

Clinical Immunology and Immunopathology, 1994

The effect of hydrocortisone (HC) on IL-6 production by monocytes (Mo) that were cultured under e... more The effect of hydrocortisone (HC) on IL-6 production by monocytes (Mo) that were cultured under either adherent or limited-adherent culture conditions was determined. Although freshly isolated Mo produced more IL-6 in response to LPS than Mo cultured 24 hr, culture had little effect on inhibition of IL-6 by HC. In contrast, the conditions of Mo culture had a significant impact on the kinetics of IL-6 production and inhibition by HC. Adherent Mo produced significantly higher levels of IL-6 4 hr after LPS compared to limited-adherent Mo. By 12 hr of LPS stimulation, comparable quantities of IL-6 were produced by both cultures. HC inhibition was complete 4 hr after LPS stimulation of adherent Mo, while 12 hr was required for maximum inhibition of limited-adherent Mo. Production of an IL-6 inhibitor was not responsible for the increased inhibition by HC with adherence, because both IL-6 protein and bioactivity were comparably decreased. The kinetics of inhibition of TNF alpha and IL-1 beta production by HC were similarly affected by adherence. Phenotypic analysis of cultured vs freshly isolated Mo showed a decrease in Mo expressing CD14, but not CD11b, which paralleled a decrease in IL-6 production by the cultured Mo. However, there were no phenotypic differences between adherent and limited-adherent Mo. The results demonstrate that the time of Mo culture, as well as adherence, may serve to alter LPS-induced IL-6 production and its inhibition by HC.

Special Focus on the Biology of Aging, 1991

The above sections have provided numerous facts, many of which are conflicting, regarding the cha... more The above sections have provided numerous facts, many of which are conflicting, regarding the changes that occur with increasing age in T lymphocytes. Although it is impossible to state with absolute certainty the alterations that are responsible for decreased proliferation of lymphocytes from elderly subjects, the following summarizes the current status of the data: 1. The interaction of T lymphocytes with foreign stimuli appears to be generally intact. 2. Changes in numbers of CD3+, CD4+, or CD8+ cells before interaction with foreign stimuli or in the density of these markers or of mitogen receptors on the surface of aged T cells have not been consistently observed. When reported to occur, the changes are not sufficient to account for the significant decrease in T-cell proliferation that occurs with increasing age. 3. A defect in the ability of the membrane interaction with foreign stimulus to signal subsequent internal events may occur, because stimulation with phorbol esters and calcium ionophore can result in increased proliferation in some elderly subjects. 4. Decreased accumulation of cytosolic calcium after stimulation of elderly T cells occurs in mice and may be a major component of the defective activation system. This defect appears to be most apparent in the "memory" T cells (T cells expressing high levels of Pgp-1), which increase in number with increasing age. Decreases in Ca++ accumulation have not been observed in humans, but this may be due to different stimuli used. Further, investigation of an increase in "memory" T cells and of their inability to mobilize Ca++ has not been done in humans and rats. 5. Decreases in mRNA for c-myc, IL-2 receptor, and IL-2 have been reported in some, but not all, species. Whether these decreases are the result of decreases in Ca++ mobilization or are independent events in unknown. 6. Decreases in membrane expression of the activation marker RL388 and of TfR have been reported. 7. Lymphokines: a. Decreases in IL-2 production occur in mice and humans, but not in rats. In individuals with decreased IL-2 production, addition of exogenous IL-2 totally restores proliferative ability in only some individuals. Changes in IL-2R expression (number or affinity) may be an additional defect. b. Decreases in IFN-gamma occur in humans, but not in mice or rats. c. No change in IL-1 occurs in any species. Genotypic effects must be considered when evaluating the preceding observations. The heterogeneity among individuals, even within an inbred strain, cannot be discounted.(ABSTRACT TRUNCATED AT 400 WORDS)

American Journal of Hematology, 2014

A 69-year-old female presented to the emergency department with a 1-week history of low-grade fev... more A 69-year-old female presented to the emergency department with a 1-week history of low-grade fever, progressive dyspnea on exertion, fatigue, and confusion. She denied headache, nausea, vomiting, weakness, numbness or tingling in her extremities, orthopnea, chest pain, or swelling of her legs. Although previously very active, she had become homebound over the same duration and was not able to perform her daily activities. Her medications included mometasone-formoterol inhaler and zafirlukast for chronic obstructive lung disease and ibuprofen as needed for joint pain for the past 2 years, none of which was newly prescribed. She had a history of allergy to nonspecific environmental allergens. She denied any history of rash or recent travel. Confusion is a common symptom in the elderly and can have multiple etiologies, including polypharmacy, infections, hypovolemia due to medications or poor oral intake, electrolyte imbalances, cardiovascular problems, allergies, and central nervous system lesions. However, the presence of low-grade fever, dyspnea on exertion, and fatigue suggest the presence of a systemic disease with multisystem involvement. Given the relatively acute onset of her symptoms, an infectious or inflammatory etiology seems likely. Common multisystem infections that can affect cardiac and neurologic systems should be considered, including subacute bacterial endocarditis which can cause peripheral embolization to the central nervous system. Bacterial pneumonias can explain her dyspnea as well as her confusion due to delirium, however, her subacute illness time course and absence of an underlying dementing illness make this scenario less likely. Alternatively, noninfectious etiologies such as acute pulmonary embolism, diabetes mellitus, or exacerbation of her reactive airways should be considered. However, confusion is atypical with these conditions unless accompanied by shock or in the presence of a systemic thrombotic condition. Systemic malignancy and vasculitis with central nervous system and pulmonary involvement would also be a consideration here, although unlikely with her acute presentation. Her past medical history was significant for two episodes of transient word-finding difficulties and left facial droop 1 year prior with normal magnetic resonance imaging (MRI) findings. Her family history was negative for any cardiopulmonary or immunological disorders. Vital signs, including orthostatic blood pressures, were normal. On examination, she appeared confused, sluggish, and slow to respond to questions, but demonstrated no focal neurological deficits. She did not have any rashes or palpable lymph nodes. She had bilateral expiratory rales. The cardiovascular examination was normal including absence of jugular venous distension or pedal edema. Her previous history of transient ischemic attacks and sudden onset makes a cerebrovascular event a possibility. However, the presence of constitutional and cardiopulmonary symptoms, as well as the lack of focal deficits in the distribution of a single vascular territory should lead us to broaden our differential diagnoses. Her exam is not consistent with congestive heart failure. Patient’s electrocardiogram showed nonspecific ST and T wave changes. Troponin level was 15 ng/ml (<0.06 ng/ml) with a brain natriuretic peptide (BNP) of 1,045 pg/ml (0–100 pg/ml). Transthoracic echocardiogram showed preserved systolic function with ejection fraction of 65% and no evidence of valvular dysfunction or intramural thrombus. Prothrombin time was 13.2 sec (10.2–11.7 sec), with an international normalized ratio of 1.2 (0.9–1.1), partial thromboplastin time (PTT) was 31 sec (25–33 sec), D-dimer was 1,893 ng/ml (65–500 ng/ml), and lactate dehydrogenase was 251 IU/l (94–202 IU/l). She had a serum creatinine (Cr) of 2.49 mg/dl (baseline Cr-1.14 mg/dl, 2 months prior), with urinalysis showing many eosinophils and elevated protein (30 mg/dl). Computed tomography (CT) scan of the head revealed no acute abnormalities. A contrast-enhanced MRI of brain was not performed due to her renal insufficiency. The patient does not have any signs and symptoms consistent with heart disease. Her cardiac enzyme and BNP levels are alarming, but her nonspecific electrocardiographic abnormalities and absence of wallmotion abnormalities on echocardiogram argue against acute coronary syndrome (ACS). Troponin is highly specific marker for myocardial injury; however, it is nonspecific for ACS. Alternative causes such as myocarditis, pericarditis, sepsis, pulmonary embolism, cardiomyopathy, and systemic thrombotic disorders such as antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia (HIT) need to be considered here. However, the absence of previous vascular events or pregnancy losses, and a normal range PTT argue against APS. Similarly, patient had not received any heparin products, making HIT unlikely. Systemic vasculitides involving the central nervous system, kidney, and heart…

Mechanisms of Ageing and Development, 1995

We have previously demonstrated that age-related declines in Concanavalin A (ConA), induced proli... more We have previously demonstrated that age-related declines in Concanavalin A (ConA), induced proliferation and lymphokine production, occur in ad-libitum fed Brown Norway (AL BN) rats. Since caloric restriction (CR) extends lifespan, we expected that the age related changes in immune parameters would be delayed by CR. CR does act to delay age-related changes in proliferation in response to ConA. In addition, CR postpones the plateau in ConA induced interferon (IFN) production seen after 23 months of age in AL rats. However, CR does not postpone the age-related decline in ConA induced interleukin-2 (IL-2) production. Therefore, ConA induced IFN production maybe a good candidate as an early marker of physiologic aging, while ConA induced proliferative response is a possible candidate for a marker of late stages of aging.

Mechanisms of Ageing and Development, 1993

The long-lived, inbred Brown Norway (BN) rat demonstrates an age associated decrease in lymphopro... more The long-lived, inbred Brown Norway (BN) rat demonstrates an age associated decrease in lymphoproliferation in response to ConA; however, these declines only become apparent after the age of median survival, 31 months. Significant declines in IL-2 production after ConA stimulation also occur after median survival. In contrast, production of IFN after ConA stimulation increases with age in BN rats. This increase in IFN production begins about 12 months of age and plateaus at about median lifespan. The imbalance in IL-2 and IFN production may reflect a dysregulation that results in a decreased proliferative response of lymphocytes with increasing age.

Journal of Hospital Medicine, 2011

The findings and conclusions in this report are those of the author and do not necessarily repres... more The findings and conclusions in this report are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention. There has never been a more important time to promote efforts to improve the use of antibiotics in hospitals. The growing challenges of C. difficile infections and antimicrobial resistance can both be addressed, at least in part, through so called ''antimicrobial stewardship'' efforts. Data suggest that when the right antibiotics are prescribed at the right dose for the right durations patient outcomes are improved and healthcare dollars are saved. That improving antibiotic use is a win-win-win is not in question; what remains to be determined is how best to ensure that these efforts are implemented in all hospitals. I believe that hospitalists must play an important role in advancing antimicrobial stewardship.

Experimental Gerontology, 1991

Although mean mitogen-induced lymphoproliferation decreases with increased age, the response of i... more Although mean mitogen-induced lymphoproliferation decreases with increased age, the response of individual subjects demonstrates great heterogeneity. Results of this study clearly illustrate that individual variation is apparent not only in the level of proliferation, but also in the amount of interleuldn-2 (IL-2) detectable after mitogen stimulation. Further, addition of exogenous IL-2 significantly increases proliferation in only about one third of elderly subjects. Data from inbred strains of rats housed under identical environmental conditions indicate that although genetic factors greatly influence both the level of proliferation and the rate of decline with age, variation occurs even within one inbred strain of rat.

Experimental Cell Research, 1992

Cellular Immunology, 1993