Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian Registry Investigative Neuro AIDS (IRINA)

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.     

The structure of Schwann cells in unmyelinated fibres. A qualitative and quantitative electron microscope study

The structure, size and distribution of many cytoplasmic components of Schwann cells associated with unmyelinated axons in lizard thoracic spinal roots were analysed under the electron microscope. The percentages of Schwann cell cytoplasmic area occupied by the following cytoplasmic components were determined: mitochondria, Golgi apparatus, granular endoplasmic reticulum, multivesicular bodies, smooth endoplasmic reticulum, lipofuscin granules, peroxisome-like bodies, autophagic vacuoles, dense bodies and lipid droplets. A linear correlation was found between the sectional areas of the mitochondria and granular endoplasmic reticulum of the Schwann cell and both length of Schwann cell plasma membrane profile and size of the related axoplasm. The structure of Schwann cells associated with unmyelinated axons and that of Schwann cells associated with myelinated axons were compared in the same species and in the same region of the peripheral nervous system using the same fixative and the same preparation technique. Some differences were detected in the organization of the granular endoplasmic reticulum, in the presence of cilia and in the percentages of cytoplasm occupied by various components. The hypothesis that Schwann cell mitochondria and granular endoplasmic reticulum are involved in the production and storage of proteins for the plasma membrane of this cell as well as the hypothesis that these organelles are involved in the production and storage of protein metabolites which are subsequently transferred to the related axons seem applicable not only to Schwann cells associated with myelinated axons (Pannese et al., in press), but also to those associated with unmyelinated ones.     

Intracerebral mass lesions in patients affected by AIDS

Summary Toxoplasma gondii cerebral abscess is a common opportunistic infection in patients affected by AIDS. Making a reliable diagnosis of acute cerebral toxoplasmosis is difficult in AIDS patients because of the lack of specificity of serological data and neuroradiological findings. Brain biopsy is the only procedure which enables a reliable diagnosis to be made a trial of specific medical therapy for toxoplasmosis in patients affected by AIDS and intracranial mass lesion can be advisable before performing brain biopsy. The authors report the cases of three patients affected by AIDS and cerebral toxoplasmosis.Tissue diagnosis was made in the first patient from autopsy material while a presumptive diagnosis was made in the other two cases since specific medical therapy resulted in a dramatic improvement of the neurological status.Despite the good possibilities in the treatment of this complication AIDS, however, carries a poor prognosis.     

Cytological aspects of the nasal respiratory epithelium in reproductive-age women taking oral contraceptives.

OBJECTIVE: To determine the effects of monophasic oral contraceptives on the nasal respiratory epithelium in premenopausal women. DESIGN: Prospective open clinical trial. SETTING: Outpatient Family Planning Centre. PATIENT(S): Eighty-eight premenopausal women, with ovulatory cycle, who were planning to take oral contraceptives. INTERVENTION(S): Baseline endovaginal ultrasound examination and blood test to measure serum progesterone to confirm ovulatory cycle. Thirty-eight women on pill containing 30 microg ethinylestradiol (EE) plus 75 microg gestodene, and 35 women on pill containing 15 microg ethinylestradiol plus 60 microg gestodene. MAIN OUTCOMES/MEASURE(S): Cytological changes on the nasal respiratory epithelium evaluated with the maturation index performed during the follicular, periovular, and luteal phases of the menstrual cycle, and on the sixth cycle of pill intake. RESULT(S): Hematoxylin-eosin staining for the maturation index showed similar trophic cytological aspects between the nasal and vaginal epithelium during the menstrual cycle and pill usage. Both the nasal and vaginal cytological samples showed higher maturation indexes during both the follicular and the periovular phases than during the luteal phase. Women on pill containing 15 microg EE showed lower trophic aspects in the nasal cytological samples compared with those on pill with 30 microg EE. CONCLUSION(S): Along with the vaginal cells, the nasal respiratory epithelium is an ovarian steroid target. The maturation index of the nasal respiratory epithelium seems to depend on the variation of the ovarian steroids during the menstrual cycle and on the iatrogenic effects of oral contraceptives.     

Vitamin D Treatment Prevents Uremia-Induced Reductions in Aortic microRNA-145 Attenuating Osteogenic Differentiation despite Hyperphosphatemia

In chronic kidney disease, systemic inflammation and high serum phosphate (P) promote the de-differentiation of vascular smooth muscle cells (VSMC) to osteoblast-like cells, increasing the propensity for medial calcification and cardiovascular mortality. Vascular microRNA-145 (miR-145) content is essential to maintain VSMC contractile phenotype. Because vitamin D induces aortic miR-145, uremia and high serum P reduce it and miR-145 directly targets osteogenic osterix in osteoblasts, this study evaluated a potential causal link between vascular miR-145 reductions and osterix-driven osteogenic differentiation and its counter-regulation by vitamin D. Studies in aortic rings from normal rats and in the rat aortic VSMC line A7r5 exposed to calcifying conditions corroborated that miR-145 reductions were associated with decreases in contractile markers and increases in osteogenic differentiation and calcium (Ca) deposition. Furthermore, miR-145 silencing enhanced Ca deposition in A7r5 cells exposed to calcifying conditions, while miR-145 overexpression attenuated it, partly through increasing α-actin levels and reducing osterix-driven osteogenic differentiation. In mice, 14 weeks after the induction of renal mass reduction, both aortic miR-145 and α-actin mRNA decreased by 80% without significant elevations in osterix or Ca deposition. Vitamin D treatment from week 8 to 14 fully prevented the reductions in aortic miR-145 and attenuated by 50% the decreases in α-actin, despite uremia-induced hyperphosphatemia. In conclusion, vitamin D was able to prevent the reductions in aortic miR-145 and α-actin content induced by uremia, reducing the alterations in vascular contractility and osteogenic differentiation despite hyperphosphatemia.     

Proposal for a New Pathologic Prognostic Index After Neoadjuvant Chemotherapy in Pancreatic Ductal Adenocarcinoma (PINC)

Background

Limited information is available on the relevant prognostic variables after surgery for patients with pancreatic ductal adenocarcinoma (PDAC) subjected to neoadjuvant chemotherapy (NACT). NACT is known to induce a spectrum of histological changes in PDAC. Different grading regression systems are currently available; unfortunately, they lack precision and accuracy. We aimed to identify a new quantitative prognostic index based on tumor morphology.

Patients and Methods

The study population was composed of 69 patients with resectable or borderline resectable PDAC treated with preoperative NACT (neoadjuvant group) and 36 patients submitted to upfront surgery (upfront-surgery group). A comprehensive histological assessment on hematoxylin and eosin (H&E) stained sections evaluated 20 morphological parameters. The association between patient survival and morphological variables was evaluated to generate a prognostic index.

Results

The distribution of morphological parameters evaluated was significantly different between upfront-surgery and neoadjuvant groups, demonstrating the effect of NACT on tumor morphology. On multivariate analysis for patients that received NACT, the predictors of shorter overall survival (OS) and disease-free survival (DFS) were perineural invasion and lymph node ratio. Conversely, high stroma to neoplasia ratio predicted longer OS and DFS. These variables were combined to generate a semiquantitative prognostic index based on both OS and DFS, which significantly distinguished patients with poor outcomes from those with a good outcome. Bootstrap analysis confirmed the reproducibility of the model.

Conclusions

The pathologic prognostic index proposed is mostly quantitative in nature, easy to use, and may represent a reliable tumor regression grading system to predict patient outcomes after NACT followed by surgery for PDAC.