Randomized Trial of Trimethoprim-Sulfamethoxazole versus Pyrimethamine-Sulfadiazine for Therapy of Toxoplasmic Encephalitis in Patients with AIDS

The aim of the present pilot study was to compare the efficacy and safety of trimethoprim (TMP) and sulfamethoxazole (SMX) with those of the standard therapy pyrimethamine (P)-sulfadiazine (S) for the treatment of toxoplasmic encephalitis in patients with AIDS. This was a pilot, multicenter, randomized, and prospective study. Patients were randomly assigned to receive TMP (10 mg/kg of body weight/day) and SMX (50 mg/kg/day) or P (50 mg daily) and S (60 mg/kg/day) as acute therapy (for 4 weeks) and then as maintenance therapy for 3 months at half of the original dosage. Seventy-seven patients were enrolled and randomized to the study: 40 patients were treated with TMP-SMX and 37 were treated with P-S. There was no statistically significant difference in clinical efficacy during acute therapy. In contrast, patients randomized to TMP-SMX appeared more likely to achieve a complete radiologic response after acute therapy. Adverse reactions were significantly more frequent in patients treated with P-S, and skin rash was the most common adverse event noted in these patients. In conclusion, the results of the study suggest that TMP-SMX appears to be a valuable alternative to P-S, in particular in patients with opportunistic bacterial infections.     

Prevalence of intra-abdominal hypertension in critically ill patients: a multicentre epidemiological study

Objective Although intra-abdominal hypertension (IAH) can cause dysfunction of several organs and raise mortality, little information is available on the incidence and risk factors for IAH in critically ill patients. This study assessed the prevalence of IAH and its risk factors in a mixed population of intensive care patients.Design A multicentre, prospective 1-day point-prevalence epidemiological study conducted in 13 ICUs of six countries.Interventions None.Patients Ninety-seven patients admitted for more than 24 h to one of the ICUs during the 1-day study period.Methods Intra-abdominal pressure (IAP) was measured four times (every 6 h) by the bladder pressure method. Data included the demographics, medical or surgical type of admission, SOFA score, etiological factors such as abdominal surgery, haemoperitoneum, abdominal infection, massive fluid resuscitation, and ileus and predisposing conditions such as hypothermia, acidosis, polytransfusion, coagulopathy, sepsis, liver dysfunction, pneumonia and bacteraemia.Results We enrolled 97 patients, mean age 64±15 years, 57 (59%) medical and 40 (41%) surgical admission, SOFA score of 6.5±4.0. Mean IAP was 9.8±4.7 mmHg. The prevalence of IAH (defined as IAP 12 mmHg or more) was 50.5 and 8.2% had abdominal compartment syndrome (defined as IAP 20 mmHg or more). The only risk factor significantly associated with IAH was the body mass index, while massive fluid resuscitation, renal and coagulation impairment were at limit of significance.Conclusion Although we found a quite high prevalence of IAH, no risk factors were reliably associated with IAH; consequently, to get valid information about IAH, IAP needs to be measured.     

A simple method for the measurement of intrinsic positive end-expiratory pressure during controlled and assisted modes of mechanical ventilation.

OBJECTIVE: To evaluate a new and simple method for the measurement of intrinsic positive end-expiratory pressure during controlled and assisted modes of mechanical ventilation. DESIGN: Prospective study. SETTING: Three university hospital medical ICUs. PATIENTS: A total of 13 intubated, mechanically ventilated patients with severe airway obstruction. INTERVENTIONS: Airway occlusions reproducibly timed to occur coincidently with end-expiration were obtained by: a) manipulation of a three-way manual valve placed in the inspiratory limb of the external ventilator circuit (manual valve method) and b) activation of the expiratory pause hold function of the mechanical ventilator (Siemens 900C). MEASUREMENTS AND MAIN RESULTS: Airway pressure, flow, and volume were recorded during controlled and assisted modes of mechanical ventilation. Intrinsic positive end-expiratory pressure was determined from the plateau in airway pressure, which was developed during end-expiratory occlusions. For controlled mechanical ventilation, intrinsic positive end-expiratory pressure averaged 11.42 +/- 0.77 (SEM) cm H2O with the manual valve method, compared with 11.38 +/- 0.70 cm H2O, using the ventilator expiratory pause hold function. There was close correlation between results over the wide range of intrinsic positive end-expiratory pressure observed, which varied from approximately 5 to 22 cm H2O (y = 1.08x - 0.92; r2 = .99). Values of intrinsic positive end-expiratory pressure were comparable for the two methods during assist-control ventilation, pressure support ventilation, and spontaneous breathing through the ventilator circuit. The manual valve method was also effective when tested with different mechanical ventilators using a mechanical lung model. CONCLUSIONS: The manual valve method can be used to determine intrinsic positive end-expiratory pressure during controlled and assisted modes of ventilatory support with current ventilators. The availability of such an approach should facilitate the routine monitoring of intrinsic positive end-expiratory pressure in mechanically ventilated patients, thereby aiding clinical decision-making and management in these critically ill individuals.     

Amino acid loss in acute renal failure: comparative effects of peritoneal dialysis and haemodialysis

The concentration of free amino acids has been determined in plasma and erythrocytes of 10 patients with acute renal failure treated by peritoneal dialysis and haemodialysis, and of 10 healthy subjects as controls. The variations observed have been compared in an attempt to evaluate the effects of two different methods of dialysis on the amino acid pools. The effects of peritoneal dialysis on changes in the plasma valine, glycine, glutamic acid and taurine have been interpreted.     

Cellular redox potential and hemoglobin S-glutathionylation in human and rat erythrocytes: A comparative study

The rat is commonly used to evaluate responses of red blood cells (RBCs) to oxidative stress. How closely the rat RBC model predicts the human RBC human response has not been well characterized. The objective of this study was to compare human and rat RBC responses to the thiol-specific oxidant tert-butylhydroperoxide by monitoring the intraerythrocyte glutathione redox potential and its correlation with hemoglobin S-glutathionylation. Changes in redox potential did not differ significantly between rat and human RBCs under the considered conditions, and both human and rat hemoglobins were apparently S-glutathionylated by a thiol–disulfide exchange mechanism with glutathione disulfide, though the extent of S-glutathionylation in rat erythrocytes was more than 10-fold higher than in human ones. On the contrary, human and rat hemoglobin S-glutathionylation differently correlated with redox potential for the glutathione redox couple, suggesting that the formation of S-glutathionylated hemoglobin was not simply a function of glutathione disulfide concentration or glutathione/glutathione disulfide ratio and that the content of reactive cysteines in hemoglobin β globin can strongly influence intraerythrocyte glutathione metabolism and distribution between free and hemoglobin-bound forms. This study reveals fundamental physiological differences in rat and human RBCs because of differences in rat and human β globin cysteine and reactivity, which can have important implications for the study of rat biology as a whole and for the use of rats as models for human beings under physiological and pathological circumstances and, therefore, highlights the need for caution when extrapolating rat responses to humans.     

mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.     

Amniotic liquid derived stem cells as reservoir of secreted angiogenic factors capable of stimulating neo-arteriogenesis in an ischemic model

Most urgent health problems are related to a blood vessel formation failure. The use of stem cells from different sources or species for both in vitro and in vivo engineering of endothelium does not necessarily imply their direct commitment towards a vascular phenotype. In the present study, we used human amniotic fluid stem cells (AFSC) to evoke a strong angiogenic response in murine recipients, in terms of host guided-regeneration of new vessels, and we demonstrated that the AFSC secretome is responsible for the vascularising properties of these cells. We indentified in AFSC conditioned media (ACM) pro-angiogenic soluble factors, such as MCP-1, IL-8, SDF-1, VEGF. Our in vitro results suggest that ACM are cytoprotective, pro-differentiative and chemoattractive for endothelial cells. We also tested ACM on a pre-clinical model of hind-limb ischemic mouse, concluding that ACM contain mediators that promote the neo-arteriogenesis, as remodelling of pre-existing collateral arteries to conductance vessels, thus preventing the capillary loss and the tissue necrosis of distal muscles. In line with the current regenerative medicine trend, in the present study we assert the concept that stem cell-secreted mediators can guide the tissue repair by stimulating or recruiting host reparative cells.     

No major progranulin genetic variability contribution to disease etiopathogenesis in an ALS Italian cohort

To analyze the contribution of progranulin (PGRN) to the etiopathogenesis of amyotrophic lateral sclerosis (ALS), we performed a PGRN gene screening in 146 Italian patients (12 familial cases) and evaluated the association of two common variants with risk of developing ALS in 239 sporadic cases (SALS). Progranulin mRNA and protein levels were measured in peripheral blood mononuclear cells and serum of a subset of these patients and controls. PGRN sequence analysis revealed a heterozygous change (p.S120Y), previously observed in an independent sporadic ALS-FTD patient. Haplotype analysis showed a conserved PGRN region among these two subjects consistent with possible common ancestor allele. Two non-coding polymorphisms were not associated to increased risk to develop ALS; mRNA and serum levels were not significantly different between cases and controls. Overall, our data argue against the hypothesis of progranulin as a major risk factor for motor neuron dysfunction, at least in Italian population. The p.S120Y variant may characterize rare patients with SALS, although its pathogenetic mechanism remains to be elucidated.