Diabetic nephropathy: Clinical and histological study in 22 patients

Summary Twenty-two patients with insulin-dependent diabetes mellitus and renal involvement were submitted to renal biopsy. Mean age was 42 years; 10 were males, 12 females. The mean interval between clinical manifestation of nephropathy and biopsy was about 2 years. At the time of biopsy, 4 groups were distinguished according to clinical conditions, depending on the presence or absence of nephrotic syndrome and renal failure. Renal lesions were semiquantitatively evaluated, a separate score being considered for glomerular and vascular lesions. Immunofluorescence most frequently showed a pattern of faint linear IgG deposits along glomerular basement membranes: Severity of histological lesions and pattern of urinary abnormalities were not correlated with the duration of diabetes or the patients’ age. Both glomerular and vascular lesions were correlated with the presence of renal failure, while no relationship with the pattern of urinary abnormalities was found. Fourteen patients were followed for more than one year after biopsy: 5 had normal renal function, 4 were in chronic renal insufficiency and 5 in end-stage renal failure (3 were in dialysis, 2 died). There was no correlation between the 3 above-mentioned types of evolution and glomerular histological findings. Nevertheless a higher score of vascular impairment at biopsy was observed among patients who subsequently were found to have a more unfavorable prognosis. Therefore renal biopsy, by providing information on the degree of renal vascular damage, may have some value in predicting the clinical course of diabetic nephropathy.     

Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling

In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population. The available data indicate that IL-8, expressed by tumour cells and induced by chemotherapeutic treatment, is a key regulator of the survival and self-renewal of the population of CXCR1-expressing CSC. Consequently, this investigation on the mechanism of action of the reparixin/paclitaxel combination, was based on the observation that reparixin treatment contained the formation of metastases in several experimental models. However, specific data on the formation of breast cancer brain metastases, which carry remarkable morbidity and mortality to a substantial proportion of advanced breast cancer patients, have not been generated. The obtained data indicate a beneficial use of the drug combination reparixin and paclitaxel to counteract brain tumour metastasis due to CSC, probably due to the combined effects of the two drugs, the pro-apoptotic action of paclitaxel and the cytostatic and anti-migratory effects of reparixin.     

A peroxiredoxin‐based proteinaceous scaffold for the growth and differentiation of neuronal cells and tumour stem cells in the absence of prodifferentiation agents

The use of nanoscale materials in the design of scaffolds for CNS tissue is increasing, due to their ability to promote cell adhesion, to mimic an extracellular matrix microenvironment and to interact with neuronal membranes. In this framework, one of the major challenges when using undifferentiated neural cells is how to control the differentiation process. Here we report the characterization of a scaffold based on the self‐assembled nanotubes of a mutant of the protein peroxiredoxin (from Schistosoma mansoni or Bos taurus), which allows the growth and differentiation of a model neuronal cell line (SHSY5Y). The results obtained demonstrate that SHSY5Y cells grow without any sign of toxicity and develop a neuronal phenotype, as shown by the expression of neuronal differentiation markers, without the use of any differentiation supplement, even in the presence of serum. The prodifferentiation effect is demonstrated to be dependent on the formation of the protein nanotube, since a wild‐type (WT) form of the peroxiredoxin from Schistosoma mansoni does not induce any differentiation. The protein scaffold was also able to induce the spread of glioblastoma cancer stem cells growing in neurospheres and allowing the acquisition of a neuron‐like morphology, as well as of immature rat cortical neurons. This protein used here as coating agent may be suggested for the development of scaffolds for tissue regeneration or anti‐tumour devices. Copyright © 2016 John Wiley & Sons, Ltd.     

Introducing chirality in halogenated 3-arylsydnones and their corresponding 1-arylpyrazoles obtained by 1,3-dipolar cycloaddition

New 1-arylpyrazoles substituted with halogen atoms (Br, I) were synthesized from the corresponding sydnones by 1,3-dipolar cycloaddition. By introduction of a prochiral group such as isopropyl, in the ortho position of the benzene ring, in the starting phenylglycine 1 the rotamers caused by the hindered rotation between the phenyl and the heterocyclic ring were detected by NMR spectroscopy for 1-arylpyrazoles and for the first time for 3-arylsydnones. The N-nitrosophenylglycines present E–Z stereoisomerism due to the partial C–N double bond character. All the new compounds were structurally characterized by NMR spectroscopy and confirmed by X-ray crystallography. The crystal structures of N-nitrosophenylglycine 2c and of the sydnone 3c present similar Br⋯Br type II halogen contacts.

New 1-arylpyrazoles substituted with halogen atoms (Br, I) were synthesized from the corresponding sydnones by 1,3-dipolar cycloaddition.     

A novel congenital dysprothrombinemia leading to defective prothrombin maturation

Introduction

Prothrombin deficiency is a very rare disorder caused by mutations in the F2 gene that generate hypoprothrombinemia or dysprothrombinemia and is characterized by bleeding manifestations that can vary from clinically irrelevant to life-threatening.

Aim

Here we characterize a patient with a novel missense mutation in F2, c.1090 T/A (p.Val322Glu), that causes severe dysprothrombinemia.

Methods

Coagulation assays, prothrombin Western Blotting, FII activation by Ecarin, fibrinogen degradation products quantification and thrombin generation assay were carried out to assess prothrombin expression and function. PCR followed by direct sequencing was carried out to characterize the mutation. In silico analysis for missense variant and molecular modeling were applied to predict the mechanism that leads to dysprothrombinemia.

Results and conclusions

The homozygous patient had a markedly prolonged prothrombin time, strongly reduced FII activity (0.82%) but normal antigen levels. In the thrombin generation assay the lag time and the peak height were unmeasurable, suggesting that the Val322Glu mutation results in the inability of the mutant prothrombin to be fully activated to thrombin. In fact, prothrombin activation by ecarin was defective, with a massive accumulation of the meizothrombin intermediate. Molecular modeling and dynamic simulation studies showed that the Val322Glu mutation interferes with protein flexibility at Arg271 and Arg320. This impairs the switch of the protein from zymogen to proteinase, thus preventing the formation of thrombin. Accumulated meizothrombin, however, maintains some fibrinogen-degrading activity, as shown by the formation of FDPs, and this probably explains the patient’s mild bleeding phenotype.     

Mechanical Properties of the Flexor Digitorum Profundus Tendon Attachment

The current study was performed to determine the strength and rigidity of the intact flexor digitorum profundus (FDP) tendon attachment and compare the rigidity at the attachment site to the rigidity within a more proximal part of the tendon. Eight cadaveric index fingers were tested to failure of the FDP tendon. Lines were drawn on each tendon with India ink stain at the position of the attachment to bone and 5 mm and 10 mm proximally. Each test was recorded using a high resolution video camera. A minimum of six images per test were used for analysis of tissue deformation. The centroid of each line was computationally identified to characterize the deformation of the tendon between the lines. Force vs. deformation curves were generated for the 5 mm region representing the tendon attachment and the 5 mm region adjacent to the attachment. Stiffness measurements were generated for each curve, and normalized by the initial length to determine the rigidity. The failure strength ranged from 263 N to 548 N, with rigidity values ranging from 2201 N/(mm/mm) to 8714 N/(mm/mm) and from 3459 N/(mm/mm) to 6414 N/(mm/mm) for the attachment and the tendon proximal to the attachment, respectively. The rigidity did not vary significantly between the attachment and proximal tendon based on a Wilcoxon signed rank test (p = 0.2). The measured strength and rigidity establish biomechanical properties for the FDP tendon attachment to bone.     

Uterine rupture in a nulliparous woman with septate uterus of the second trimester pregnancy and review in literature

INTRODUCTIONUterine rupture (UR) in early pregnancy in nulliparous women is a rare and unpredictable occurrence with high maternal morbidity and fatal fetal outcomes. Intrauterine anomalies could be the primum movens of this dangerous condition and underestimated in the literature.PRESENTATION OF CASEAn uncommon case of uterine rupture at the 23rd week of gestation in a nulliparous woman, who became pregnant before the resection of an uterine septum. To provide more insight into the possible risk factors, a literature review was performed.DISCUSSIONLoss of pregnancy is common, despite prompt uterine repair. In all cases reviewed abdominal pain characterized by indistinct vague symptoms constitutes the initial symptom of this obstetrical life threatening condition.CONCLUSIONThe current case highlights the association of curettage and septate uterus as a risk factor for UR in the second trimester of pregnancy. It's reasonable that obstetricians must take into account that common gastrointestinal tract problems might be an indicator of the initial weakness of uterine wall leading to the rupture, which is unpredictable all of cases reviewed.