mTOR inhibitors (rapamycin and its derivatives) and nitrogen containing bisphosphonates: bi-functional compounds for the treatment of bone tumours

N-BP, rapamycin and its derivatives have been originally developed respectively as anti-resorptive and anti-fungal agents. In fact, in vitro and in vivo experiments demonstrated that these compounds are multi-functional molecules exerting their effects on tumour cell growth and bone remodelling. The major challenge in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumour cells. Whether nitrogen containing bisphosphonates (N-BP) are potent bone inhibitors, they also inhibit tumour cell proliferation and increase atypical apoptosis of bone tumour cells regardless of the p53 and Rb status. N-BP may be then considered as effective therapeutic agents in clinical trials of bone tumours. Rapamycin and its derivatives inhibit mTOR dependent mRNA translation both in osteoclasts and tumour cells. Cellular physiological mechanisms regulated by mTOR integrate many environmental parameters including growth factors, hormones, cytokines, amino acids, energy availability and cellular stresses that are coupled with cell cycle progression and cell growth. Rapamycin and its derivatives as well as N-BP must be considered as bi-(multi) functional molecules affecting simultaneously bone and tumour metabolisms. The present survey describes these two molecular families and discusses their therapeutic interests for primary bone tumours and bone metastases.     

Sensitivity and specificity of immunoglobulin G titer for the diagnosis of mumps virus in infected patients depending on vaccination status

The aim of the study was to evaluate the usefulness of serological detection of mumps IgM and titration of IgG in patients with acute parotitis according to their vaccination status. The detection of mumps virus RNA in saliva by RT-PCR was used as reference. 116 patients (109 of them previously vaccinated) with mumps RT-PCR-negative results and 21 (19 vaccinated) with mumps RT-PCR-positive results were studied. Mumps-specific IgM and IgG were assayed by EIA (Enzygnost, Dade Behring, Germany). IgM results were expressed as positive or negative. For IgG, several cut-offs were calculated using receiver operating characteristic (ROC) curves. Seven RT-PCR-positive and five RT-PCR-negative patients showed IgM-positive results (sensitivity 33.3% and specificity 95.7%). Among vaccinated patients, the sensitivity and specificity of IgM were 26.3% (5/19) and 99.1% (108/109). For IgG, a titer of 5,000 in all the patients showed a sensitivity of 76.2% (16/21) and a specificity of 83.6% (97/116). In vaccinated patients, the corresponding figures for this cut-off were 84.2% (16/19) and 83.5% (91/109), respectively. Although IgM detection against mumps is highly specific, its sensitivity is very low in immunized subjects. In this group, the titration of IgG could serve as an additional diagnostic tool.     

Acute meningitis due to Toscana virus infection among patients from both the Spanish Mediterranean region and the region of Madrid.

Toscana virus (TOSV) is a member of the genus Phlebovirus that is transmitted to humans by two different species of sand fly and causes acute aseptic meningitis (AAM) and meningoencephalitis in Central Italy. Fifteen cases of AAM due to TOSV have been found at the Spanish province of Granada, but no data regarding the presence of TOSV-related disease in other regions of Spain have been still reported. A collection of 88 serum and 53 cerebrospinal fluid (CSF) samples taken from 81 selected patients with AAM of unknown aetiology, residing at Madrid or at the southern Mediterranean coast of Spain, was retrospectively studied for presence of TOSV-specific antibodies from both IgG and IgM classes. Anti-TOSV IgG was also investigated in 457 serum samples from healthy individuals, aged 2-60 years, residing at the south of the Region of Madrid. Specific IgM in serum and/or intrathecally produced anti-TOSV IgG were detected in seven patients, three residents from the Mediterranean region and the remainder four from the Region of Madrid. The overall prevalence of anti-TOSV among the healthy population studied was 5%. These results confirm the role of TOSV as an agent causing AAM in the Spanish Mediterranean coast, extend these findings to the central region of the country and suggest that TOSV might be producing infection and neurological disease in every area of Spain harbouring significant populations of the viral vectors.     

Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1(-/-) survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.     

Predictors of body mass index among low-income community-dwelling older adults

This study investigated demographic, behavioral, and functional predictors of overweight and obesity, using secondary data from 705 community-dwelling individuals aged 65 years and older receiving or seeking Medicaid personal care services. Half of the participants were obese, while an additional 28% were overweight. The relationships between body mass index (BMI) levels and selected independent variables were analyzed. Females were more likely to be obese, while those who were older (75 years or older), more cognitively impaired, and smoked were less likely to obese. Comparing obesity with being overweight, being female and reporting more pain symptoms increased the odds of being obese, whereas being older (75 years or older) and being more cognitively impaired decreased the odds. The especially high rates of obesity in Texas have a profound impact on personal health and may result in increased health care costs that threaten public programs as well.     

Detection of varicella-zoster virus-specific DNA sequences in cerebrospinal fluid from patients with acute aseptic meningitis and no cutaneous lesions

Acute aseptic meningitis (AAM) is considered as an uncommon manifestation of varicella-zoster virus (VZV) recrudescence and is usually regarded as a complication of the cutaneous infection in patients with impaired cellular immunity. Indirect evidence suggests, however, that VZV-associated AAM may also respond to direct spread of the virus to the leptomeninges from the cells supporting the latency. The polymerase chain reaction (PCR) was used to amplify VZV-specific DNA sequences in serial cerebrospinal fluid (CSF) samples from 21 patients with AAM, who presented laboratory evidence of intrathe-cal production of VZV-specific antibody on follow-up. Eleven of these patients never showed cutaneous zosteriform lesions. VZV-DNA sequences were detected in the CSF from all patients with cutaneous zoster, as well as from six patients (55%) lacking skin lesions. Viral DNA sequences were present in six cases before the rise in specific antibody was seen in CSF, disappearing during follow-up in the seven positive cases. These results support the proposed involvement of VZV in the etiology of AAM seen among normal young adults and strongly suggest that the virus can reach directly and infect the CNS from the latently infected spinal ganglia. © 1994 Wiley-Liss, Inc.     

A single amino acid distinguishes the high-responder from the low-responder form of Fc receptor II on human monocytes.

The low-affinity Fc receptor on human peripheral blood monocytes (Fc gamma RIIA) is polymorphic with respect to its ability to bind murine IgG1. The two allelic forms of the receptor, high responder (HR) and low responder (LR), yield characteristic patterns after isoelectric focusing and react differently with the anti-Fc gamma RII monoclonal antibody (mAb), 41H16. We recently cloned cDNA encoding the extracellular domains of Fc gamma RIIA on monocytes from one HR and two LR donors, and found that they differed at only a single base. The cDNA isolated from the HR donor had a G at position 519 and would be expected to encode an aginine at residue 133 in the mature protein, while the cDNA isolated from both LR donors had an A at position 519 and would be expected to encode a histidine at the same residue. To determine whether this single amino acid substitution actually accounts for the functional polymorphism involving Fc gamma RIIA, we transfected COS cells with full-length HR and LR Fc gamma RIIA cDNA, and examined them for their ability to react with anti-Fc gamma RIIA mAb and to bind red blood cells (RBC) coated with either murine IgG2b or murine IgG1. Whereas COS cells transfected with either the HR cDNA or the LR cDNA reacted with the anti-Fc gamma RII mAb, IV.3, and bound murine IgG2b-coated RBC, only COS cells transfected with the HR cDNA formed rosettes with murine IgG1-coated RBC and reacted strongly with mAb 41H16. A total of nine LR donors were identified, and all were homozygous for the A substitution at position 519. We conclude that at an A at position 519 in the cDNA encoding Fc gamma RIIA is the primary molecular basis for the LR form of the receptor, and that the amino acid at residue 133 determines whether Fc gamma RIIA efficiently binds murine IgG1.