Amphiphilic polypeptides with prolonged enzymatic stability for the preparation of self-assembled nanobiomaterials

Due to their excellent biocompatibility and biodegradability, polypeptides have emerged as versatile bio-inspired scaffolds for the preparation of artificial biomaterials. In order to create self-assembled polypeptide nanoparticles with enhanced stability towards enzymatic degradation, we synthesized a series of random and block polypeptides based on lysine and α-aminoisobutyric acid (Aib) by the ring-opening polymerization of N-carboxyanhydrides (ROP NCA) of the corresponding amino acids. A conformational analysis carried out by means of FT-IR absorption and CD spectroscopies revealed a noticeable difference between random and block copolymers. In turn, the spatial organization of the polypeptide chains induced the formation of nanostructures of different types. The block copolymers self-assembled in vesicle-like structures, whereas polypeptides with randomly distributed monomers formed micelles. In contrast with the polymers with only natural amino acids, all nanoparticles based on Aib/Lys polypeptides showed strong resistance to proteolytic cleavage. The cytotoxicity and the kinetics of the cellular uptake of the prepared nanostructures were also studied. The results obtained could not only contribute to the understanding of long Aib polypeptide folding and self-assembling, but also pave the way to the design of nanomaterials with finely tuned properties in the fields of drug delivery and tissue engineering.

Aib residue distribution in Lys/Aib polymers influences the morphology of forming nanoparticles and the rate of their enzymatic degradation.     

Lack of bone lesions at diagnosis is associated with inferior outcome in multisystem langerhans cell histiocytosis of childhood

Skeletal involvement is generally, but not universally, characteristic of Langerhans cell histiocytosis (LCH). We investigated whether the presence of bone lesions at diagnosis is a prognostic factor for survival in LCH. Nine hundred and thirty‐eight children with multisystem (MS) LCH, both high (386 RO+) and low (RO?) risk, were evaluated for bone lesions at diagnosis. Risk organ (RO+) involvement was defined as: haematopoietic system (haemoglobin <100 g/l, and/or white blood cell count <4·0 × 10⁹/l and/or platelet count <100 × 10⁹/l), spleen (>2 cm below the costal margin), liver (>3 cm and/or hypoproteinaemia, hypoalbuminaemia, hyperbilirubinaemia, and/or increased aspartate transaminase/alanine transaminase). Given the general view that prognosis in LCH worsens with increasing extent of disease, the surprising finding was that in MS+RO+ LCH the probability of survival with bone involvement 74 ± 3% (n = 230, 56 events) was reduced to 62 ± 4% (n = 156, 55 events) if this was absent (P = 0·007). An even greater difference was seen in the subgroup of patients with both liver and either haematopoiesis or spleen involvement: 61 ± 5% survival (n = 105; 52 events) if patients had bony lesions, versus 47 ± 5% (n = 111; 39 events) if they did not (P = 0·014). This difference was retained in multivariate analysis (P = 0·048). Although as yet unexplained, we conclude that bone involvement at diagnosis is a previously unrecognized favourable prognostic factor in MS+RO+ LCH.     

Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans

Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans, can have pro-longevity effects. This apparent paradox indicates that cellular adaptation to partial mitochondrial stress can induce beneficial responses, but how this is achieved is largely unknown. Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich's ataxia, is lethal in C. elegans, while its partial deficiency extends animal lifespan in a p53 dependent manner.     

Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology

The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age-adjusted incidence rates (IRs) of CLL and SLL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age-standardized to the 2000 US population, overall IRs were 3.83 per 100 000 person-years for CLL (n = 15 676) and 1.31 for SLL (n = 5382) during 1993-2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1.98) than for SLL (1.67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal trends must be interpreted cautiously. CLL and SLL IRs increased exponentially with age among all gender/race groups, with CLL IRs increasing more steeply with advancing age than SLL. Avenues of future research include assessment of delayed- and under-reporting to cancer registries and exploration of race, gender, and age effects in epidemiological studies.     

Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors

CONTEXT: Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumors (GISTs) and pulmonary chondromas. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC, and SDHD are found in PGLs, gain-of-function mutations of c-kit (KIT), and platelet-derived growth factor receptor A (PDGFRA) in GISTs. OBJECTIVE: Our objective was to investigate the possibility that patients with CT and/or their tumors may harbor mutations of the SDHB, SDHC, SDHD, KIT, and PDGFRA genes and identify any other genetic alterations in CT tumors. DESIGN: Three males and 34 females with CT were studied retrospectively. We sequenced the stated genes and performed comparative genomic hybridization on a total of 41 tumors. RESULTS: No patient had coding sequence mutations of the investigated genes. Comparative genomic hybridization revealed a number of DNA copy number changes: losses dominated among benign lesions, there were an equal number of gains and losses in malignant lesions, and the average number of alterations in malignant tumors was higher compared with benign lesions. The most frequent and greatest contiguous change was 1q12-q21 deletion, a region that harbors the SDHC gene. Another frequent change was loss of 1p. Allelic losses of 1p and 1q were confirmed by fluorescent in situ hybridization and loss-of-heterozygosity studies. CONCLUSIONS: We conclude that CT is not due to SDH-inactivating or KIT- and PDGFRA-activating mutations. GISTs and PGLs in CT are associated with chromosome 1 and other changes that appear to participate in tumor progression and point to their common genetic cause.     

Electroencephalographic characterization of spike-wave discharges in cortex and thalamus in WAG/Rij rats

PURPOSE: The waveform of spontaneous spike-wave discharges (SWD) in the electroencephalogram (EEG) was delineated in the WAG/Rij rat model of absence epilepsy according to the definitions of clinical electroencephalography. We defined four elements in SWD based on the schema of Weir (1965): Spike 1 and 2, Positive Transient (PT), and Wave. The EEG patterns of generalized type I and local type II SWD in cortical and thalamic areas were analyzed. METHODS: EEGs were recorded in freely moving rats epidurally from different cortical regions and with deep electrodes from the specific and reticular thalamic nuclei. Grand average SWD waveforms were computed to assess spatiotemporal patterns of seizures. RESULTS: SWD I in the frontal cortex comprised of a large Spike 2 + Wave, and in the thalamus PT + Wave. Small transient spikes were associated with SWD I in the anterior-middle part of the cortex. SWD II were found in the occipital cortex as a sequence of (occasional) Spike 1 + PT + Wave. CONCLUSIONS: The EEG structure of SWD in WAG/Rij rats was comparable with that of epileptic patients, suggesting face validity of the WAG/Rij model. Fast transients spikes are an integrative part of SWD I. Time-amplitude linkage between cortical and thalamic counterparts of SWD I suggests a complex spatiotemporal organization of SWD I. The thalamus sustained SWD I, but not SWD II.     

Pregnancy Outcome in Patients Following Different Types of Bariatric Surgeries

Background  The objective of this study was to investigate pregnancy outcome of patients following different types of bariatric surgery. Methods  A population-based study includes all pregnancies of patients with bariatric surgeries delivered during 1988–2008. Pregnancy outcome was compared between the different types of surgeries. Results  This retrospective study included 449 deliveries: 394 deliveries following pure restrictive operations—laparoscopic gastric banding (LAGB; n = 202), silastic ring vertical gastroplasty (SRVG; n = 136), and vertical-banded gastroplasty (VBG; n = 56)—and 55 deliveries following restrictive and malabsorptive Roux-en-Y gastric bypass (RGB). While no significant differences were noted between the groups regarding body mass index (BMI) before the bariatric operations or prepregnancy BMI, patients following LAGB had significantly higher BMI before delivery (36.8 ± 5.9 kg compared to the SRVG 33.4 ± 6.0, VBG 34.2 ± 5.4, and RGB 34.9 ± 6.8 groups; p < 0.001). Following LAGB, patients had higher weight gain during pregnancy (13.1 ± 9.6 kg) compared to the SRVG (8.8 ± 7.4), VBG (8.5 ± 8.0), and RGB (11.6 ± 9.6; p < 0.001) groups. The interval between operation and pregnancy was shorter in the LAGB group (22.8 months) compared to the SRVG (41.0) and the VBG (42.1) groups and was significantly higher in the RGB group (57.4; p < 0.001). Birth weight was significantly higher among newborns of patients following RBG (3,332.8 ± 475.5 g) compared to the restrictive procedures (3,104.3 ± 578.7 in the LAGB, 3,086.7 ± 533.1 in the SRVG, and 3,199.2 ± 427.2 in the VBG groups). No significant differences in low birth weight (<2,500 g) or macrosomia (>4,000 g), or low Apgar scores or perinatal mortality were noted between the groups. Conclusion  There is no difference in the affect on pregnancy outcome among the different forms of bariatric surgeries; all procedures have basically comparable perinatal outcome. Précis  Pregnancy outcome is not negatively affected by any specific bariatric operation; all procedures have basically comparable perinatal outcome.     

Bortezomib is an effective agent for MDS/MPD syndrome with 5q- anomaly and thrombocytosis

Thrombocytosis is not a frequent event in myelodysplasia (MDS) and is observed mainly in 5q- syndrome and MDS/myeloproliferative (MPD) overlap syndromes. The pathogenetic mechanism of thrombocytosis in 5q- has not been fully elucidated to-date. Bortezomib is a proteasome inhibitor which seems to be effective in MDS. We present here the first case in the literature with MDS/MPD syndrome, sole 5q- anomaly and thrombocytosis in which bortezomib administration normalized platelet count, produced a major erythroid response, and reduced levels of interleukin-6 (IL-6) and TNF-alpha while increased levels of IL-4 in the bone marrow plasma. The study of such cases will reveal the exact role of bortezomib in the management of MDS/MPD.     

Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328)

Background  

Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks.