Cerebellar tumour presenting with pathological laughter and gelastic syncope.

There is no report of patients in whom pathological laughter, a rare condition characterized by uncontrollable episodes of laughter usually triggered by unrelated stimuli, was ever closely associated with a loss of consciousness overtly linked with the onset of such uncontrollable laughter, also referred to as a gelastic syncope. A 53-year-old man presented with a 4-month history of syncope following intense and uncoordinated laughter. Physical and neurological examination was normal and the patient had no other typical cerebellar signs. We found a mass in the cerebellar vermis abutting the floor of the fourth ventricle, which upon histological examination after surgery proved to be an ependymoma. We emphasize that pathological laughter and gelastic syncope could represent unique and sole features of a cerebellar disorder.

Prolonged remission of neuro-Behcet disease following autologous transplantation.

Two young male patients with severe progressive Behcet's disease with neurological involvement (N-BD) were treated by high-dose immunosuppressive chemotherapy (HIC) followed by autologous CD34+ selected peripheral blood stem cell transplantation (APBSCT). Neurological impairment and disability were quantified by means of Expanded Disability Status Scale (EDSS). Neuroimaging included spine and brain MRI and brain SPECT by radiolabeling technetium (Tc99m) Ethyl Cisteynate Dimer (ECD). Disease progression halted after treatment in both patients. At 48 months of follow-up they were therapy-free and one showed neurological status and disability improvement. Brain MRI findings were unchanged in both patients, but SPECT-ECD showed an increase of blood flow in the hypoperfused cerebral areas in the ameliorated patient. Immune ablation followed by APBSCT can modify the course of severe N-BD. Because of the high risk and the transplant-related mortality, these cases have to be carefully selected.

Use of probiotics for prevention of radiation-induced diarrhea.

AIM: To investigate the efficacy of a high-potency probiotic preparation on prevention of radiation-induced diarrhea in cancer patients. METHODS: This was a double-blind, placebo-controlled trial. Four hundred and ninety patients who underwent adjuvant postoperative radiation therapy after surgery for sigmoid, rectal, or cervical cancer were assigned to either the high-potency probiotic preparation VSL#3 (one sachet t.i.d.,) or placebo starting from the first day of radiation therapy. Efficacy endpoints were incidence and severity of radiation-induced diarrhea, daily number of bowel movements, and the time from the start of the study to the use of loperamide as rescue medication. RESULTS: More placebo patients had radiation-induced diarrhea than VSL#3 patients (124 of 239 patients, 51.8%, and 77 of 243 patients, 31.6%; P<0.001) and more patients given placebo suffered grade 3 or 4 diarrhea compared with VSL#3 recipients (55.4% and 1.4%, P<0.001). Daily bowel movements were 14.7 +/- 6 and 5.1 +/- 3 among placebo and VSL#3 recipients (P<0.05), and the mean time to the use of loperamide was 86 +/- 6 h for placebo patients and 122 +/- 8 h for VSL#3 patients (P<0.001). CONCLUSION: Probiotic lactic acid-producing bacteria are an easy, safe, and feasible approach to protect cancer patients against the risk of radiation-induced diarrhea.

Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine.

OBJECTIVE: Reduced levels of serum carnitines (3-hydroxy-4-N-trimethyl-ammonio-butanoate) are found in most patients treated with zidovudine. However, since serum carnitines do not strictly reflect cellular concentrations we examined whether a carnitine depletion could be found in peripheral blood mononuclear cells (PBMC) from AIDS patients with normal serum carnitine levels. In addition, we explored whether it was possible to relate the host's immunoreactivity to the content of carnitine in PBMC and whether carnitine levels can be corrected by oral supplementation of L-carnitine. DESIGN: Immunopharmacologic study. METHODS: Twenty male patients with advanced AIDS (Centers for Disease Control and Prevention stage IVCI) and normal serum levels of carnitines were enrolled. Patients were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At baseline and at the end of the trial, we measured carnitines in both sera and PBMC, serum triglycerides, CD4 cell counts, and the frequency of cells entering the S and G2-M phases of cell cycle following mitogen stimulation. RESULTS: Concentrations of total carnitine in PBMC from AIDS patients was lower than in healthy controls. A significant trend towards the restoration of appropriate intracellular carnitine levels was found in patients treated with high-dose L-carnitine and was associated with an increased frequency of S and G2-M cells following mitogen stimulation. Furthermore, at the end of the trial we found a strong reduction in serum triglycerides in the L-carnitine group compared with baseline levels. CONCLUSIONS: Our data indicate that carnitine deficiency occurs in PBMC from patients with advanced AIDS, despite normal serum concentrations. The increase in cellular carnitine content strongly improved lymphocyte proliferative responsiveness to mitogens. Because carnitine status is an important contributing factor to immune function in patients with advanced AIDS, we therefore believe that L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals.

Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues.

OBJECTIVE: A severe dose limiting axonal peripheral neuropathy may develop in subjects on treatment with the nucleoside analogues didanosine (ddl), zalcitabine (ddC), and stavudine (d4T). The impairment of mitrochondrial DNA synthesis is crucial to the pathogenesis of this disorder although other mechanisms have not been ruled out. The depletion of acetyl-carnitine, which regulates the metabolism and function of peripheral nerves could contribute to the neurotoxicity of these compounds. DESIGN: Non-randomized, cross-sectional study of selected patients. METHODS: We measured the serum levels of acetyl- and total carnitine in 12 subjects with axonal peripheral neuropathy developed on treatment with different regimens of neurotoxic nucleoside analogues (ddl, ddC, d4T). Subjects who did not develop peripheral neuropathy while staying on treatment with ddl (n = 10) or zidovudine (n = 11) served as the control groups. HIV-negative subjects with axonal on demyelinating autoimmune neuropathies (n = 10) and healthy individuals (n = 13) were additional control groups. RESULTS: Subjects experiencing axonal peripheral neuropathy on treatment with ddl, ddC and d4T had significantly reduced levels of acetyl-carnitine in comparison to the control groups. No difference was observed in the levels of total carnitine between study subjects and the control groups. CONCLUSIONS: Our results demonstrate that subjects who developed peripheral neuropathy while staying on treatment with ddl, ddC and d4T had acetyl-carnitine deficiency. The normal levels of total carnitine in the study group appear to indicate the specificity of the defect and rule out coexisting relevant nutritional problems. The critical role of acetyl-carnitine for the metabolism and function of the peripheral nerves supports the view that the acetyl-carnitine deficiency found in these subjects may contribute to the neurotoxicity of ddl, ddC and d4T, even though the interference with mitochondrial DNA synthesis is regarded as the main cause of their toxicity.

Mitochondrial perturbations and oxidant stress in lymphocytes from patients undergoing surgery and general anesthesia.

BACKGROUND: Previous studies have shown that a profound suppression of immune function transiently occurs in patients who undergo surgery under general anesthesia. The decline in the absolute counts of peripheral blood lymphocytes constitutes a major factor accounting for this immune defect, and recent evidence indicates that apoptosis plays a crucial role in determining postsurgical lymphocytopenia. HYPOTHESIS: An altered oxidation-reduction status of mitochondria may contribute through apoptosis to the loss of lymphocytes following surgical trauma and general anesthesia. DESIGN: We studied 16 patients with American Society of Anesthesiologists' physical status I or II who underwent elective surgery under general anesthesia. The data were collected prospectively. SETTING: University hospital. MAIN OUTCOME MEASURES: Samples of peripheral blood were drawn on the day before surgery and at 24 and 96 hours after the operation. Following lymphocyte isolation, the mitochondrial transmembrane potential was assessed by flow cytometry using 3,3'-dihexylocarbo-cyanine iodide, and stains with hydroethidine and 2'-7'-dichlorofluorescein diacetate were used to determine the generation of reactive oxygen species. The labeling of lymphocytes with monobromobimane was used to assess the presence of reduced glutathione. RESULTS: At 24 hours after surgery, we detected a significantly elevated frequency of peripheral blood lymphocytes (P =.002), which incorporated low levels of 3,3'-dihexylocarbo-cyanine iodide, compared with the preoperative period. At this same time point, the frequency of lymphocytes with the hydroethidine- and 2'-7'-dichlorofluorescein diacetate-positive phenotype was elevated compared with baseline levels. Conversely, at 24 hours after surgery, the frequency of cells that stained positive for glutathione was strongly decreased compared with preoperative values. Overall measurements returned to the baseline levels at 96 hours after surgery. CONCLUSION: The strict association we observed between the overproduction of reactive oxygen species and the disruption of the mitochondrial transmembrane potential supports the view that alterations in mitochondrial energy metabolism, paralleled by the presence of a pro-oxidant oxidation-reduction status, could be involved in the accelerated apoptotic loss of lymphocytes following surgical trauma and general anesthesia.

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.

Traditional and high potency probiotic preparations for oral bacteriotherapy.

Current research continues to improve the treatment options available to clinicians for oral bacteriotherapy. Recently, a greater understanding of the role of endogenous digestive microflora has generated renewed interest in the potential of oral bacteriotherapy for the management of a wide spectrum of gastrointestinal and systemic disorders. Several treatment strategies for oral bacteriotherapy have already entered clinical trials and it is hoped that some of these strategies will become widely available in the near future. This review summarises the current status of oral probiotic preparations for bacteriotherapy and discusses any obstacles to their successful clinical development. Newer probiotic preparations include high potency preparations that are greatly enriched in lactic acid bacteria, both in terms of bacterial concentrations and the number of bacterial strains. These preparations have a greater potential for clinical effectiveness than traditional preparations and are entering clinical evaluation especially in patients with inflammatory bowel disease and pouchitis, irritable bowel syndrome, or cryptosporidiosis. The pitfalls of previous clinical investigations of traditional probiotic preparations and the perils of future clinical trials with high potency preparations are discussed in the context of unmet needs and realistic expectations of success. Although considerable progress has been made in oral bacteriotherapy, focused efforts by basic scientists and clinical investigators and continued support from pharmaceutical companies is required to successfully develop probiotics for use in clinical medicine. Newer high potency probiotic preparations appear to have a great advantage over traditional preparations and should be the area of most active biomedical research in the field.

Severe thrombophilia with antiphospholipid syndrome and hyperhomocysteinemia in a patient with Schnitzler's syndrome.

Schnitzler's syndrome is a rare condition with chronic urticaria, intermittent fever, bone pain, and a monoclonal IgM gammopathy. Most patients have a chronic and indolent course, but a small number ultimately progress to a lymphoplasmacytic malignancy. We describe a patient with Schnitzler's syndrome who entered an accelerated phase of clinical deterioration with repeated thromboses of the cerebral and coronary arteries that ultimately led to a fatal outcome. We found that the he fulfilled the Sapporo criteria for definite antiphospholipid syndrome and had elevated blood levels of homocysteine during the active clotting phase of the disease. We suggest that the association with immune-mediated or metabolic disorders, such as the antiphospholipid syndrome and hyperhomocysteinemia, may unfavorably affect the otherwise chronic and stable course of patients with Schnitzler's syndrome. The systemic clotting disorder, the association with the antiphospholipid syndrome and hyperhomocysteinemia, and the biclonal rather than monoclonal IgM gammopathy were striking features of this atypical case of Schnitzler's syndrome.

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.

Heat shock protein (HSP70) expression in septic patients.

PURPOSE: This study investigates heat shock protein 70 (HSP70) expression by peripheral blood mononuclear cells (PBMCs) of septic patients admitted to an intensive care unit and examines the possibility of a correlation between HSP70 levels and plasma tumor necrosis factor alpha (TNF-alpha) concentrations. Additionally, we evaluated whether the HSP70 production could be regarded as a prognostic factor for the development of septic shock as well as for patient survival. MATERIALS AND METHODS: Blood samples of 29 patients were taken 24 hours after the diagnosis of sepsis. HSP70 expression and TNF-alpha level were measured using indirect immunofluorescent analysis and a commercially available enzyme-linked immunosorbent assay method, respectively. RESULTS: PBMCs expressed significantly high levels of HSP70 (11.9 +/- 5.6 [sd]) compared with those of the healthy control group (3.2 +/- 2.1% positive cells). Such enhanced levels were correlated to plasma TNF-alpha concentrations (r = .99, P < .01). This study failed to demonstrate a relationship between HSP70 production and clinical outcome. CONCLUSION: These findings give further evidence that also in humans, heat shock response is activated during sepsis. The correlation observed between HSP70 overproduction and TNF-alpha plasma concentrations suggests that HSP70 exerts a possible protective effect against TNF-alpha cytotoxicity. Such hypothesis has not been confirmed by our clinical data.

AIDS patients with bacterial lower respiratory tract infections: treatment with ofloxacin versus sulbactam-ampicillin.

In this open-label, randomized, parallel-groups study the Authors compare the parenteral administration of a beta-lactamase inhibitor associated with a semisynthetic penicillin (sulbactam-ampicillin) with the oral administration of a 3rd-generation quinolone (ofloxacin), in 20 HIV-infected subjects suffering from lower respiratory tract (LRT) infections. 12 patients were classified as AIDS, 6 as ARC (AIDS related complex) and 2 as asymptomatic seropositives. The risk of becoming HIV-infected and the work load for the health staff were also evaluated. The clinical and microbiological results indicate that oral ofloxacin is as effective as parenteral sulbactam-ampicillin for the treatment of LRT infections in HIV-positive individuals. In addition, the members of the health staff reported significantly less difficulty in administering ofloxacin in respect to sulbactam-ampicillin.

Apoptosis: mechanisms and relation to AIDS.

Infection with the human immunodeficiency virus (HIV) is considered to lead to the acquired immunodeficiency syndrome (AIDS) via the progressive loss of immune competence in the infected host. Recent research has highlighted that HIV may indirectly trigger an active cell suicide process, referred to as programmed cell death or apoptosis, that contributes to the decline in lymphocyte counts throughout the course of HIV infection. We review here the main host- and HIV-related factors actively involved in inducing lymphocyte apoptosis. Among them, the relationships linking HIV, the oxidant/antioxidant balance in the cellular redox system, tumor necrosis factor (TNF) and lymphocyte-associated ceramide generated through the activation of sphingomyelin pathway are receiving growing consideration. Recognizing the importance of apoptosis in AIDS pathogenesis may have a great impact on the design of new strategies for the treatment of the disease. Available data indicate that antioxidant compounds exert antiapoptotic activity. These compounds, in our opinion, should be used in combination regimens with antiretroviral drugs in the treatment of HIV-infected subjects.

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.

Microecology, bacterial vaginosis and probiotics: perspectives for bacteriotherapy.

Probiotics enriched in lactobacilli have been proposed as an effective and alternative tool to antibiotics for the treatment of bacterial vaginosis. The protective role of H(2)O(2)-producing lactobacilli has been strongly emphasized, but no clear-cut correlation appears to link the metabolic characteristics of administered lactobacilli with the clinical impact of probiotic therapy. On account of our review of basic mechanisms involved in bacterial vaginosis, we suggest that lactobacilli with an elevated arginine deiminase activity could have a greater therapeutic potential than strains producing only H(2)O(2). Preliminary results from our laboratory have demonstrated that treatment with probiotics containing arginine deiminase-positive lactobacilli improves clinical symptoms and is paralleled by a significant decline of polyamine levels in vaginal microenvironment. This is of outstanding interest due to the central role of polyamines in the pathogenesis of bacterial vaginosis. We should critically rethink, against this perspective, the use of probiotics for the treatment of affected women.

Drug interaction between cyclosporin A and nizatidine in Sprague-Dawley rats.

The H2-receptor antagonists seem to be effective in prevention and treatment of stress ulcer in transplant recipients. In a previous study on rats, an increase was observed in cyclosporinaemia and hepatotoxicity after administration of cimetidine or ranitidine in association with cyclosporin A (CyA). On the contrary, famotidine does not influence the blood CyA levels. The aim of the study was to detect the possible synergistic nephro- and hepatotoxicity of nizatidine administered in association with CyA, assaying the serum creatinine, the ALT and AST levels, and histological features of thirty young male Sprague-Dawley rats, divided into 6 groups of five animals each. After 10 days, all the rats were sacrificed, their blood was collected to assay serum creatinine, ALT, AST and serum CyA levels: kidneys and livers were processed for light microscopy. The results obtained demonstrated that, while the level of creatinine was normal in each group, the average level of transaminase and the serum levels of CyA were significantly higher in the animals receiving the association of CyA and nizatidine. Furthermore, this group demonstrated a mild infiltrate of the liver characterized in some cases with eosinophilic polymorphonuclear cells. In light of the results obtained, it is probable that the increase of cyclosporinaemia is the consequence of an enhanced hepatotoxicity due to administration of CyA in association with nizatidine.

Evidence of drug interaction between cyclosporin A and H2-receptor antagonists (cimetidine, ranitidine and famotidine) in Sprague-Dawley rats.

H2-receptor antagonists, such as cimetidine (C), ranitidine (R) and famotidine (F) seem to be effective in the prevention and treatment of stress ulcer in transplant recipients receiving cyclosporin A (CyA). The aim of this study was to detect the possible synergistic nephro- and hepato-toxicity of these drugs, assaying the serum creatinine (SC), ALT, AST levels, and the histological features of 45 young male Sprague-Dawley rats, divided into nine groups of five rats each. After 10 days of treatment the results showed: (i) serum CyA levels were increased in the group receiving daily CyA (5 mg/kg) + R(5 mg/kg) (2430 +/- 403 ng/ml; p less than 0.05 vs. controls) and in the group receiving daily CyA (5 mg/kg) +/- C (10 mg/kg) (2440 +/- 265 ng/ml; p less than 0.01 vs. controls); (ii) ALT and AST levels were increased in this latter group (ALT 223 +/- 133 UL, AST 114.67 +/- 39 UL; p less than 0.01 vs. controls); (iii) SC levels were normal; and (iv) steatosis of the liver was observed in these two groups. These findings suggest that C and R, but not F, may inhibit the hepatic cytochromes P-450 which are involved in the oxidative metabolism of the drugs. Furthermore, the high serum CyA levels seem to play a major role in the appearance of biochemical and histological damage to the liver.

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.