Altered plasma melatonin concentrations after administration of propofol in continuous infusion

OBJECTIVE: To determine possible variations in plasma levels of melatonin in patients sedated with propofol administered in continuous infusion. PATIENTS AND METHODS: Healthy patients receiving spinal anesthesia for lower limb orthopedic surgery were randomized to 2 groups in this prospective study: group A patients were sedated with intravenous propofol infused at a rate of 3 to 4 mg kg(-1) h(-1) and group B underwent surgery without sedation. Data from these groups were compared with data from 2 other groups. Group C data, from healthy volunteers who did not undergo surgery or sedation, were compared with baseline values. Group D data were theoretical reference values for plasma melatonin levels taken from the literature, for comparisons at baseline and in the range of hypnosis. Hormone levels were determined by enzyme-linked immunosorbent assay at baseline, at 10 and 60 minutes after the start of sedation, and 90 minutes after withdrawal of sedation. RESULTS: Twenty patients were enrolled. No significant between-group differences were detected at baseline (P>.269), 60 minutes after starting sedation or 90 minutes after withdrawing it (P>.347 and P>.057 respectively). Values were significantly different between group B and groups A and D 10 minutes after starting sedation with propofol (P<.001). CONCLUSIONS: Plasma levels of melatonin increased during administration of propofol in continuous perfusion.     

Analytical detection of immunoglobulin heavy chain gene rearrangements in gastric lymphoid infiltrates by peak area analysis of the melting curve in the LightCycler System

Because it is difficult to differentiate gastric mucosa-associated lymphoid tissue (MALT) lymphoma from chronic gastritis in gastric lymphoid infiltrates, molecular detection of monoclonality through immunoglobulin heavy chain (IgH) gene rearrangements is commonly performed. However, heterogeneity in the performance and results obtained from IgH gene rearrangements has been reported. To improve the accuracy in the diagnosis of gastric lymphoid infiltrates, we developed an analytical approach based on one-peak area analysis of the melting curve in the LightCycler System. Using a training-testing approach, the likelihood ratio method was selected to find a discriminative function of 4.64 in the training set (10 gastric MALT lymphomas and 10 chronic gastritis cases). This discriminative function was validated in the testing set (five gastric MALT lymphomas, six abnormal lymphocytic infiltrates with subsequently demonstrated gastric MALT lymphomas, and six cases of chronic gastritis). All but one case of gastric MALT lymphoma, as well as abnormal lymphocytic infiltrates, clustered under 4.64, and all chronic gastritis cases clustered above 4.64. These results were validated by conventional electrophoreses confirming one or two sharp bands in cases of gastric MALT lymphomas and a smear of multiple bands in cases of chronic gastritis. Analytical detection of IgH gene rearrangement in gastric lymphoid infiltrates by one-peak area analysis correctly distinguishes gastric MALT lymphomas from chronic gastritis, even in cases with diagnosis of abnormal lymphocytic infiltrates.     

Store-operated calcium entry mediates intracellular alkalinization, ERK1/2, and Akt/PKB phosphorylation in bovine neutrophils

Neutrophil's responses to G protein-coupled chemoattractants are highly dependent on store-operated calcium (Ca(2+)) entry (SOCE). Platelet-activating factor (PAF), a primary chemoattractant, simultaneously increases cytosolic-free Ca(2+), intracellular pH (pH(i)), ERK1/2, and Akt/protein kinase B (PKB) phosphorylation. In this study, we looked at the efficacy of several putative SOCE inhibitors and whether SOCE mediates intracellular alkalinization, ERK1/2, and Akt/PKB phosphorylation in bovine neutrophils. We demonstrated that the absence of external Ca(2+) and the presence of EGTA reduced the intracellular alkalinization and ERK1/2 phosphorylation induced by PAF, apparently via SOCE influx inhibition. Next, we tested the efficacy of several putative SOCE inhibitors such as 2-aminoethoxydiphenyl borate (2-APB), capsaicin, flufenamic acid, 1-{beta-[3-(4-methoxy-phenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride (SK&F 96365), and N-(4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP2) on Ca(2+) entry induced by PAF or thapsigargin. 2-APB was the most potent SOCE inhibitor, followed by capsaicin and flufenamic acid. Conversely, SK&F 96365 reduced an intracellular calcium ([Ca(2+)](i)) peak but SOCE partially. BTP2 did not show an inhibitory effect on [Ca(2+)](i) following PAF stimuli. 2-APB strongly reduced the pH(i) recovery, whereas the effect of flufenamic acid and SK&F 96365 was partial. Capsaicin and BTP2 did not affect the pH(i) changes induced by PAF. Finally, we observed that 2-APB reduced the ERK1/2 and Akt phosphorylation completely, whereas the inhibition with flufenamic acid was partial. The results suggest that 2-APB is the most potent SOCE inhibitor and support a key role of SOCE in pH alkalinization and PI-3K-ERK1/2 pathway control. Finally, 2-APB could be an important tool to characterize Ca(2+) signaling in neutrophils.     

Regulation of carbohydrate metabolism by 2,5-anhydro-D-mannitol.

In hepatocytes isolated from fasted rats, 2,5-anhydromannitol inhibits gluconeogenesis from lactate plus pyruvate and from substrates that enter the gluconeogenic pathway as triose phosphate. This fructose analog has no effect, however, on gluconeogenesis from xylitol, a substrate that enters the pathway primarily as fructose 6-phosphate. The sensitivity of gluconeogenesis to 2,5-anhydromannitol depends on the substrate metabolized; concentrations of 2,5-anhydromannitol required for 50% inhibition increase in the order lactate plus pyruvate less than dihydroxyacetone less than glycerol less than sorbitol less than fructose. The inhibition by 2,5-anhydromannitol of gluconeogenesis from dihydroxyacetone is accompanied by an increase in lactate formation and by two distinct crossovers in gluconeogenic-glycolytic metabolite patterns-i.e., increases in pyruvate concentrations with decreases in phosphoenolpyruvate and increases in fructose-1,6-bisphosphate concentrations with little change in fructose 6-phosphate. In addition, 2,5-anhydromannitol blocks the ability of glucagon to stimulate gluconeogenesis and inhibit lactate production from dihydroxyacetone. 2,5-Anhydromannitol decreases cellular fructose 2,6-bisphosphate content in hepatocytes; therefore the effects of the fructose analog are not mediated by fructose 2,6-bisphosphate, a naturally occurring allosteric regulator. 2,5-Anhydromannitol also inhibits gluconeogenesis in hepatocytes isolated from fasted diabetic rats, but higher concentrations of the analog are required.     

Efficacy of a comprehensive geriatric intervention in older patients hospitalized for hip fracture: a randomized, controlled trial

OBJECTIVES: To evaluate whether an early multidisciplinary geriatric intervention in elderly patients with hip fracture reduced length of stay, morbidity, and mortality and improved functional evolution. DESIGN: Randomized, controlled intervention trial. SETTING: Orthopedic ward in a university hospital. PARTICIPANTS: Three hundred nineteen patients aged 65 and older hospitalized for hip fracture surgery. INTERVENTION: Participants were randomly assigned to a daily multidisciplinary geriatric intervention (n=155) or usual care (n=164) during hospitalization in the acute phase of hip fracture. MEASUREMENTS: Primary endpoints were in-hospital length of stay and incidence of death or major medical complications. Secondary endpoints were the rate of recovery of previous activities of daily living and ambulation ability at 3, 6, and 12 months. RESULTS: Median length of stay was 16 days in the geriatric intervention group and 18 days in the usual care group (P=.06). Patients assigned to the geriatric intervention showed a lower in-hospital mortality (0.6% vs 5.8%, P=.03) and major medical complications rate (45.2% vs 61.7%, P=.003). After adjustment for confounding variables, geriatric intervention was associated with a 45% lower probability of death or major complications (95% confidence interval=7-68%). More patients in the geriatric intervention group achieved a partial recovery at 3 months (57% vs 44%, P=.03), but there were no differences between the groups at 6 and 12 months. CONCLUSION: Early multidisciplinary daily geriatric care reduces in-hospital mortality and medical complications in elderly patients with hip fracture, but there is not a significant effect on length of hospital stay or long-term functional recovery.     

Clinical management of patients receiving cell‐based immunoregulatory therapy

Administering immunoregulatory cells as medicinal agents is a revolutionary approach to the treatment of immunologically mediated diseases. Isolating, propagating, and modifying cells before applying them to patients allows complementation of specific cellular functions, which opens astonishing new possibilities for gain‐of‐function antigen‐specific treatments in autoimmunity, chronic inflammatory disorders, and transplantation. This critical review presents a systematic assessment of the potential clinical risks posed by cell‐based immunotherapy, focusing on treatment of renal transplant recipients with regulatory macrophages as a concrete example.     

IFN-γ-induced iNOS Expression in Mouse Regulatory Macrophages Prolongs Allograft Survival in Fully Immunocompetent Recipients

Mouse monocytes exposed to macrophage colony-stimulating factor (M-CSF) and interferon-γ (IFN-γ) were driven to a novel suppressor phenotype. These regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarized macrophages and monocyte-derived dendritic cells (DCs). M regs completely suppressed polyclonal T cell proliferation through an inducible nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs eliminated cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5 × 10⁶ donor-strain M regs before transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c (32.6 ± 4.5 versus 8.7 ± 0.2 days) and B6-to-BALB/c (31.1 ± 12 versus 9.7 ± 0.4 days) strain combinations. Nos2-deficient M regs did not prolong allograft survival, proving that M reg function in vivo is iNOS-dependent and mediated by living cells. M regs were detectable for at least 2 weeks postinfusion in allogeneic recipients. In their origin, development, phenotypic relationship with other in vitro-derived macrophages and functions, there are solid grounds to assert a near-equivalence of mouse and human M regs. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of suppressor macrophages. Clinical applications of M reg therapy as an adjunct immunosuppressive therapy are currently being investigated within The ONE Study.     

El osteoma en la mastoides, ¿un hallazgo incidental?

Osteoma in the mastoid is a rare benign osteogenic tumour that has been described in literature in only 137 cases. It usually appears in asymptomatic patients, although a few cases are described associated with clinical manifestations. We report three cases of mastoid osteoma: a pedunculated osteoma in the aditus ad antrum (associated with a cholesteatoma), a superficial osteoma of the mastoid surface and a sessile osteoma that progressed to the temporal lobe (associated with vertigo). A brief review of this rare entity is presented and a possible association between mastoid osteoma, cholesteatoma otitis and vertigo is posed.