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Biomedical subjects

G Famularo

Publications and source records attributed to G Famularo.

At least 37 records · Page 2Linked to original sources
PubMed2000

Apoptosis and surgical trauma: dysregulated expression of death and survival factors on peripheral lymphocytes.

BACKGROUND: Surgery and anesthesia cause depression of cell-mediated immunity in the postoperative period, including a reduction in the numbers of circulating lymphocytes. It has been claimed that this immunosuppression is associated with an increased incidence of postoperative infections. HYPOTHESIS: Lymphocytopenia following surgical trauma depends on a dysregulated expression of death/and survival factors associated with apoptosis that, in turn, interferes with the occurrence of postsurgical infections. DESIGN: Fifteen subjects undergoing elective surgery under general anesthesia entered the study. The data of the patients who had infections during the postoperative outcome were compared with the data of those who did not. The data were collected prospectively. MAIN OUTCOME MEASURES: Peripheral blood samples were drawn before the operation, and 24 hours and 96 hours after the operation. Lymphocytes were isolated and examined for quantification and phenotypic analysis of apoptosis using the 7-amino-actinomycin D method, as well as for Fas and Fas ligand, interleukin 1-converting enzyme p20/caspase-1, Bcl-2, and p35 expression. The rate of apoptotic cells was correlated with the incidence of postoperative infections. SETTING: University hospital. RESULTS: Twenty-four hours after surgery, CD4(+) and CD8(+) cells exhibited a significantly higher frequency of apoptosis as well as of Fas and Fas ligand and interleukin 1-converting enzyme p20/caspase-1 expressions than preoperatively. This increase was paralleled by a significant down-regulation of antiapoptotic factors such as Bcl-2. However, the expression of the proapoptotic factor p35 was reduced. In addition, we found a relationship between the rate of the apoptotic CD8(+) subset and the occurrence of infectious complications during the postoperative course. At 96 hours after surgery, the variables studied returned to the baseline levels. CONCLUSIONS: In the early postoperative period, surgical trauma under general anesthesia induces an intracellular perturbation on peripheral lymphocytes, resulting in both up-regulation of death-signaling factors and down-regulation of survival-signaling factors. The increased apoptosis of CD8(+) lymphocytes, but not of CD4(+) cells, seemed to be associated with a greater risk of postsurgical infections.

Analysis of Variance↗
PubMed2000

Apoptosis and apoptosis-associated perturbations of peripheral blood lymphocytes during HIV infection: comparison between AIDS patients and asymptomatic long-term non-progressors.

This study was designed to compare the degree of lymphocyte apoptosis and Fas-Fas ligand (FasL) expression in AIDS patients and long-term non-progressors (LTNPs) and correlate these parameters with apoptosis-associated perturbations in lymphocyte function. LTNPs had a lower frequency of apoptotic CD4+ and CD8+ T cells compared with subjects with AIDS. This correlated with a lower frequency of cells expressing Fas and FasL. The frequency of selected lymphocyte populations exhibiting a disrupted mitochondrial transmembrane potential (DeltaPsim) and increased superoxide generation was lower in LTNPs than in patients with AIDS; these abnormalities were associated with lower levels of caspase-1 activation in LTNPs. The results indicate a significantly reduced level of apoptosis and apoptosis-associated parameters in LTNPs than in patients developing AIDS. Based on these findings, a crucial role for mitochondria can be predicted in the process of lymphocyte apoptosis during the evolution of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Acquired transient stuttering during a migraine attack.

Stuttering is an abnormality in the fluency of speech, which is characterized by interruption of the normal rhythm due to involuntary repetition and prolongation, or arrest, of uttered letters or syllables. The aphasic syndrome and dysarthria can be associated with classic migraine, but, to our knowledge, no study has so far described stuttering as the only neurological symptom accompanying an attack.

Adult↗
PubMed2000

Fulminant purpuric rash.

We report on a fatal case of purpura fulminans caused by severe meningococcaemia. Despite early and aggressive treatment with the use of a specific algorithm and the maintenance of a stable haemodynamic status in the first hour since admission, purpura fulminans developed impressively over a few minutes. Necropsy showed microvascular thrombosis in the dermis but not in visceral organs, suggesting the diagnosis of meningococcal septic shock with purpura fulminans limited to the skin. Acquired deficiency of protein C, which exerts anticoagulant and antiinflammatory functions, is the central mechanism ultimately responsible for purpura fulminans. The disorder predicts a poor outcome of meningococcaemia and early and aggressive resuscitation is recommended in the emergency department with antibiotics, volume expansion, inotropic drugs, and protein C replacement. An attitude of scepticism is appropriate in the management of these patients even when early resuscitation is successful and haemodynamic parameters remain stable.

Adolescent↗
PubMed2000

Clinical errors in emergency medicine: experience at the emergency department of an Italian teaching hospital.

The level of commitment in the analysis of clinical errors made in the emergency department (ED) is currently focused on organization and processes rather than on individual action. Four major cases of clinical errors made in the ED of a teaching hospital were investigated. Analysis suggested that the process of clinical decision making and the overreliance on the use of patterns during the cognitive process had a major role in causing the errors, rather than factors related to procedures or organization. It appears hard to design system changes and tactics to significantly reduce the probability of making errors associated with the cognitive process involved in clinical decision making. The authors have initiated a systematic analysis of errors made during the diagnostic workup in their ED, and the rate of clinically significant errors is tracked. A file is being created with the purpose to use it for teaching and orientation of all new staff.

Aged↗
PubMed2000

Symptomatic crystalluria associated with indinavir.

OBJECTIVE: To report a case of severe and recurrent crystalluria resulting from the use of indinavir and to review the literature describing this adverse effect. CASE SUMMARY: A 26-year-old HIV-positive white woman had recurrent episodes of left-sided flank pain accompanied by dilation of the left renal collecting system while undergoing treatment with a triple-drug regimen including indinavir 1200 mg every 12 hours (full dosage). Typical indinavir crystalluria was observed, with no evidence of stones. Acute episodes were treated with intravenous fluids, diclofenac, and ciprofloxacin. Crystalluria and clinical symptoms eventually resolved with withdrawal of indinavir and substitution with a different protease inhibitor. Renal function remained normal. DISCUSSION: A wide spectrum of disorders of the urinary tract can occur in subjects taking indinavir, with potentially severe complications caused by crystalluria and stones. Indinavir is excreted in the urine; the low solubility of those crystals is the critical factor accounting for the risk of stone formation. An elevated pH with a reduced excretion of citric acid contributes to the low urinary solubility of indinavir. Pharmacokinetic interactions with other drugs, leading to elevated plasma concentrations of indinavir, and dehydration could also increase the risk of stone formation. The impact on renal function can be unfavorable over the long-term period. Cornerstones of treatment and prevention are increased fluid intake and possibly urinary acidification. Emergency drainage may be required for patients with severe obstruction. Reducing the dosage of indinavir has been proposed, but this carries the risk of viral mutations with development of resistance. CONCLUSIONS: Treatment with indinavir can result in crystalluria with potentially severe obstruction. All patients taking indinavir, not only those with documented crystalluria or renal effects from the drug, should greatly increase their fluid intake and have renal function checked at baseline and then monitored regularly. Urinalysis also should be performed regularly for appropriate monitoring and prevention.

Adult↗
PubMed1999

Fas/Fas ligand on the road: an apoptotic pathway common to AIDS, autoimmunity, lymphoproliferation and transplantation.

There is considerable interest in the role of Fas protein as it induces apoptotic cell death when ligated by its natural ligand (FasL). Interaction between Fas and FasL is a crucial mechanism for clonal deletion and immune tolerance and privilege, control of T cell expansion during immune responses and killing by cytotoxic T lymphocytes. Loss of function of the system can block lymphocyte apoptosis and cause lymphoproliferation and autoimmunity but, when the system overfunctions, it can end to tissue injury and destruction. Recent studies have demonstrated that the Fas/FasL system is implicated in the pathogenesis of several human diseases ranging from AIDS to autoimmunity and lymphoproliferation, hepatitis, multiple sclerosis and transplant rejection. It is conceivable that modulating the activity of the Fas/fasL pathway would have clinical applications for the treatment of these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Ceramide concentrations in septic patients: a possible marker of multiple organ dysfunction syndrome.

OBJECTIVES: To investigate the concentrations of mononuclear cell-associated ceramide and serum tumor necrosis factor-alpha (TNF-alpha) in patients with sepsis and to assess their predictive value for the development of multiple organ dysfunction syndrome (MODS). DESIGN: Prospective, cohort study. SETTING: Intensive care unit and two research laboratories at a university hospital. PATIENTS: Twenty-three adult patients admitted to an intensive care unit meeting the criteria for diagnosis of sepsis. INTERVENTIONS: Blood samples were collected at the time when diagnosis of sepsis was made. MEASUREMENTS AND MAIN RESULTS: Mononuclear cell-associated ceramide and serum TNF-alpha were significantly elevated in the samples from the septic patients compared with the control individuals (318.01+/-270.15 pmol/10(6) cells vs. 99.90+/-52.75 pmol/10(6) cells; p<.001, and 28.52+/-18.77 pg/mL vs. 10.43+/-3.37 pg/mL; p<.0001, respectively), and a direct correlation linked ceramide and TNF-alpha concentrations (r2 = .90, p<.00001). In the septic patients who went on to develop MODS, ceramide and TNF-alpha were significantly higher compared with the no MODS patients (489.22+/-264.93 pmol/10(6) cells vs. 131.23+/-99.02 pmol/10(6) cells; p<.0001, and 40.96+/-18 pg/mL vs. 14.95+/-5.60 pg/mL; p<.001, respectively). The receiver operating characteristic curves demonstrated that both TNF-alpha and ceramide were prognostic of MODS, but ceramide concentrations were more efficient predictors. CONCLUSIONS: These observations suggest that mononuclear cells of peripheral blood from patients with sepsis are committed to undergo apoptosis, because there is evidence that ceramide acts as an endogenous mediator of apoptosis. The strong correlation we found between cell-associated ceramide and serum TNF-alpha supports the hypothesis that this cytokine plays an important role in activating the sphingomyelin pathway and ceramide generation in patients with sepsis. In addition, this study provides evidence that consistent concentrations of mononuclear cell-associated ceramide may predict progression toward MODS in septic patients.

Adult↗
PubMed1999

Systemic sclerosis from autoimmunity to alloimmunity.

BACKGROUND: The biologic significance of microchimerism from pregnancy in systemic sclerosis and other autoimmune diseases is not fully characterized. METHODS: We based this brief review on a systematic search of the MEDLINE database for all relevant articles published between 1980 and July 1998, indexing systemic sclerosis, microchimerism, and pregnancy as key words. We also searched textbooks, meeting proceedings, and reference lists. RESULTS: Fetal microchimerism and class II human leukocyte antigen (HLA) compatibility between mother and fetus are common among women with systemic sclerosis. Alternative sources of microchimerism include the engraftment of donor cells after a blood transfusion, from a dizygotic twin, or possibly from the mother. CONCLUSIONS: Systemic sclerosis could be a form of chronic graft-versus-host disease caused by fetal or maternal cells, which have crossed the placenta and have remained unrecognized by the host due to class II HLA compatibility.

Autoimmune Diseases↗
PubMed1999

The puzzle of neuronal death and life: is mannitol the right drug for the treatment of brain oedema associated with ischaemic stroke?

Brain oedema is a major factor contributing to the poor outcome of subjects with acute ischaemic stroke but the use of mannitol and other hyperosmolar agents in this setting is controversial and hardly debated. Recent data have demonstrated that mannitol at concentrations which may be achieved in clinical conditions and hyperosmotic stress itself can activate the process of apoptotic cell death. This could have important clinical implications as apoptosis is involved in the more gradual loss of neurons in the penumbra zone surrounding the core of ischaemic stroke where neurons die immediately from oxygen starvation. Mannitol has the potential to activate inflammatory mediators, induce oxidant stress and produce rebound cell swelling and, through these mechanisms, can further aggravate the neuronal injury due to ischaemia. Furthermore, apoptosis in ischaemic areas closely parallels the timing of brain oedema and this suggests that a cause-effect relationship links the two phenomena rather than simply a temporal correlation. On this basis, it is crucial that emergency-physicians critically rethink the management strategy of brain oedema associated with ischaemic stroke.

Apoptosis↗
PubMed1999

Reduction of glutamate levels in HIV-infected subjects treated with acetylcarnitine.

The excitotoxic amino acid glutamate, which is elevated in blood and cerebrospinal fluid from subjects with AIDS dementia complex, is crucially implicated in the neurotoxicity of HIV infection. We describe a subject with AIDS dementia complex who showed a significant motor and cognitive improvement after a course of intravenous acetylcarnitine therapy. The clinical improvement was paralleled by a significant reduction of glutamate concentrations in both blood and cerebrospinal fluid. A prospective pilot study confirmed that acetylcarnitine administration resulted indeed to reduce the blood levels of glutamate in AIDS patients treated with acetylcarnitine therapy in order to prevent the neurotoxicity of nucleoside analogs. Even though the mechanisms responsible for the reduction of glutamate concentrations remain to be established, we suggest that acetylcarnitine should be added to the list of drugs under investigation for the treatment of AIDS dementia complex. The anti-apoptotic activity of carnitines and their safety profile further support this view.

AIDS Arteritis, Central Nervous System↗
PubMed1999

Combined antiviral therapy reduces HIV-1 plasma load and improves CD4 counts but does not interfere with ongoing lymphocyte apoptosis.

The progression of HIV-1 disease appears associated with an unregulated Fas-mediated apoptosis of lymphocytes that involves the activation of ICE protease and ceramide generation and antiviral therapy may not be fully effective in the absence of a relevant impact on apoptosis. Six drug-naive HIV-1-infected symptomless patients with advanced immunodeficiency were treated with combined AZT and ddl for 4 months; plasma HIV-1 RNA levels, the counts of CD4 cells, CD4 and CD8 apoptotic lymphocytes, Fas-positive cells and ICE-positive cells, and intracellular ceramide levels were measured at base-line and after 7, 45 and 120 days of treatment. There was a prompt reduction in plasma viremia and a secondary increase in CD4 counts, but the treatment had no impact on apoptotic CD4 and CD8 lymphocytes, Fas-positive cells and ICE-positive cells, and on the intracellular levels of ceramide. A discrepancy exists between the positive impact of combined AZT and ddl treatment on plasma viral load and CD4 counts and the lack of any effect on the process of lymphocyte apoptosis. We suggest to use the measurement of apoptotic lymphocytes as a surrogate marker to predict, in combination with viral load and CD4 counts, a large proportion of the clinical effect of antiviral therapy.

Adult↗