Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity

Background  

The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAPK5 and analyzed the resulting mice for changes in anxiety-related behaviour.     

Plasma nitrate plus nitrite changes during continuous intravenous infusion interleukin 2.

Nitric oxide (NO), a biologically active mediator generated in many cell types by the enzyme NO synthase, may play an important role in cardiovascular toxicity that is frequently observed in cancer patients during intravenous (i.v.) interleukin 2 (IL-2) therapy. The induction of NO synthase and the production of NO seem to be involved in the pathogenesis of the vascular leakage syndrome, as well as in the regulation of myocardial contractility. In the present study, we evaluated the pattern of plasmatic NO changes during multiple cycles of continuous i.v. infusion (CIVI) of IL-2 in ten advanced cancer patients (five males, five females, median age 59 years, range 33-67 years; eight affected by renal cell cancer and two affected by malignant melanoma). The patients received IL-2 at 18 MIU m-2 day-1 (14 cycles) or 9 MIU m-2 day-1 (seven cycles) for 96 h, repeated every 3 weeks. Interferon alpha (IFN alpha) was also administered subcutaneously (s.c) during the 3 week interval between IL-2 cycles. For each cycle, plasma samples were collected before treatment (t0), 24 h (t1), 48 h (t2), 72 h (t3) and 96 h (t4) after the start of IL-2 infusion, and 24 h after the end of the cycle. NO concentration was determined spectrophotometrically by measuring the accumulation of both nitrite and nitrate (after reduction to nitrite). The following observations may be drawn from data analysis: (1) plasma nitrate + nitrite significantly raised during treatment (P = 0.0226 for t0 vs t3), but statistical significance was retained only when cycles administered with IL-2 18 MIU m-2 day-1 are considered (P = 0.0329 for t0 vs t3; P = 0.0354 for t0 vs t2 vs t4) (dose-dependent pattern); (2) during subsequent cycles a significant trend toward a progressive increase of plasma nitrate + nitrite levels, with increasing cumulative dose of IL-2, was observed (linear regression coefficient r = 0.62, P = 0.0141 for t0; r = 0.80, P = 0.0003 for t1; r = 0.62, P = 0.013 for t2; r = 0.69, P = 0.045 for t3); (3) plasma nitrate + nitrite levels peaked earlier in subsequent cycles than in the first cycle; (4) all patients experienced hypotension. The mean of the systolic blood pressure values was significantly lower at the time of plasma nitrate + nitrite peak than at t0 (P = 0.0004); (5) the two cases of grade III hypotension occurred in patients with the higher mean and peak plasma nitrate + nitrite values. We conclude that determination of plasma nitrate + nitrite levels during CIVI IL-2 can usefully estimate, in a dose-dependent pattern, the degree of peripheral vascular relaxation and capillary leakage associated with cytokine action, clinically manifested as hypotension. However, isolated cardiac toxicity that continues to represent a relevant problem during IL-2 therapy, does not appear to correlate with plasma nitrate + nitrite levels; therefore, further studies are required to understand adequately the mechanisms underlying IL-2-induced cardiac toxicity.     

No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and significant clinical improvement.

BACKGROUND: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown. METHODS: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow. RESULTS: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy. CONCLUSION: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.     

In vivo measurements of fibrin formation and degradation in nephrotic patients

Summary Intraglomerular fibrin deposition has been implicated as an important pathogenetic mechanism in patients with glomerular diseases and the nephrotic syndrome. To investigate fibrin formation and degradation in nephrosis, we measured fibrinopeptide A by radio-immunoassay and D-dimer by enzyme-linked immunosorbent assay in the plasma of 30 consecutive adult patients with the nephrotic syndrome; in 10 the serum creatinine was more than 2 mg/dl. Both fibrinopeptide A and D-dimer were abnormally elevated in the majority of nephrotics (P<0.001 vs. healthy controls), providing evidence of increased fibrin generation and lysis “in vivo.” A positive correlation was found between fibrinopeptide A and D-dimer (correlation coefficient 0.64,P<0.001), suggesting a close relationship between fibrin formation and degradation. Calcium heparin, administered to 12 nephrotics, caused a marked decrease in plasma fibrinopeptide A, due to a reduction of in vivo thrombin activity. As enhanced thrombin activity can favor fibrin deposition within the renal parenchyma, as well as vascular complications, it is reasonable to assume that an antithrombotic treatment aimed at controlling thrombin generation may ameliorate the natural history of nephrosis.     

Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents

Aim  

The aim of the present study was to collect and compare cases of drug-induced PML in order to contribute to the debate about the role of the underlying diseases and/or drug immunosuppression in PML occurrence.     

Localization of parathyroid enlargement: experience with technetium-99m methoxyisobutylisonitrile and thallium-201 scintigraphy,ultrasonography and computed tomography

Technetium-99m methoxyisobutylisonitrile (MIBI), like thallium-201, has recently been introduced as a myocardial perfusion agent and is now also showing very promising results in parathyroid scintigrapy. The results of ²⁰¹Tl/^99mTc-pertechnetate and ^99mTc-MIBI/^99mTc-pertechnetate subtraction scintigraphy, ultrasonography and computed tomography are presented in a series of 43 patients operated on for hyperparathyroidism. All four imaging modalities were confirmed to be reliable, scintigraphy being the most accurate. Sensitivities ranged from 81% to 95%, that of ^99mTc-MIBI being the highest. Moreover this tracer, which has more favourable physical and also biochemical properties, yielded images of superior quality. This allowed localization of the lesion by visual inspection only in as many as 86% of the patients with positive ^99mTc-MIBI/^99mTc-pertechnetate subtraction scintigraphy. We believe that the higher sensitivity, superior image quality and lower cost of ^99mTc-MIBI imaging will make ^99mTc-MIBI the new radiopharmaceutical of choice for parathyroid scintigraphy (when one takes into account the stability of labelling with large activities it is possible to perform three or four cardiac studies together with one parathyroid scintigraphic examination using one lyophililzed vial).     

Cuff pressure in intratracheal tubes. Evaluation of the new Mallinckrodt-Brandt model

Cuff pressure of endotracheal tubes increases to dangerous levels during anesthesia with nitrous oxide. In a small clinical study the Authors conclude that Mallinckrodt-Brandt endotracheal tubes are the only "low pressure" tubes available at the moment.     

X-ray investigation on highly oriented polyacetylene, 3 Crystal structure of the iodine/trans-polyacetylene complex

The crystal structure of iodine/trans-polyacetylene complexes (CHI_y)_x (y = 0,009, 0,035, 0,17 and 0,30) was investigated by X-ray diffraction analysis of highly oriented samples. An iodine-containing phase (PAI) was observed in all cases, accompanied by residual crystallinity due to pristine polyacetylene (PA) for y < 0,17. A structural model is proposed for PAI, consisting of blocks of iodine-saturated PA (PAI_s) and blocks of PA, arranged in a mosaic-like lattice, paracrystalline in character. PAI_s, corresponding to (CHI_0,40)_x, is formed by layers of (CH)_x chains alternating with layers containing polyiodide chains, the latter being characterized by ordered stacking of sequentially disordered (I₃^?-I₅^?-I₃^?) groups. I… C non-bonded interactions are identified in the lattice, which may be responsible for the electron transfer from the polymer to the polyiodide anions. Short-range transverse correlation occurs within the polyiodide layers with a resulting quasi-regular two-dimensional lattice of iodines. The iodine and the polymer lattices are incommensurate along c. The model fits the experimental data from an X-ray fibre diagram. A mathematical expression is derived, which allows to evaluate the intensity scattered by the iodine lattice. An approximate expression of the non-equatorial intensity along the ξ reciprocal direction was obtained, which accounts for the modulation of the streaks observed in the fibre pattern.