Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam

The aim of this study was to gain insight into the feasibility of using microparticles (MPs) constituted by the biodegradable poly (DL-lactide-co-glycolide) (PLGA) and a number of cyclodextrins (CDs) as an orally sustained delivery system of the hypnotic agent etizolam (ETZ). A further aim of the work was to investigate the effects of different CDs on the morphology, loading, and release properties of the MPs prepared. For these purposes, ETZ alone, and ETZ/CD-PLGA loaded MPs were prepared by the W/O/W emulsion-solvent evaporation method. It was found that the release of ETZ in vitro was more prolonged over three days with a kinetic constant proportional to t(1/2). It was also demonstrated that the CDs in these MPs are able to modulate several properties such as morphology, drug loading, and release properties. In fact, marked differences in shape, surface, and encapsulation efficiencies were noted depending on the presence, hydrophilicity, and charge of the CD employed. The obtained results induce us to consider the present ETZ-containing formulations as new valuable tools for the treatment of different insomnia categories.     

Microalbuminuria predicts overt proteinuria among patients with HIV infection

Background

This study examines the association between microalbuminuria and the development of proteinuria among HIV‐infected persons.

Methods

A total of 948 subjects provided urine samples for albumin, protein and creatinine measurements semiannually. Microalbuminuria was defined as an albumin‐to‐creatinine ratio of >30 mg/g. Proteinuria was defined as a protein‐to‐creatinine ratio of ≥0.350 mg/mg. The progression from microalbuminuria to proteinuria was described.

Results

At baseline, 69.4% of the subjects had no detectable proteinuria, 20.2% had microalbuminuria, and 10.4% had proteinuria. Subjects with microalbuminuria and proteinuria were more likely to be black (P=0.02), have lower CD4 cell counts (P=0.02 comparing subjects without abnormal urine protein excretion to subjects with microalbuminuria; P=0.0001 comparing subjects with microalbuminuria to subjects with proteinuria), and have a higher HIV RNA level (P=0.08 and 0.04, respectively). Among 658 subjects with normal urine protein, 82.7% continued to have no abnormality, 14.3% developed microalbuminuria, and 3.0% developed proteinuria. Subjects without baseline proteinuria (i.e. either normal protein excretion or microalbuminuria) who developed proteinuria were more likely to have microalbuminuria (P=0.001), a lower CD4 cell count (P=0.06), and a higher plasma HIV RNA (P=0.03) than those who did not progress to proteinuria. In multivariate analysis, only microalbuminuria remained associated with the development of proteinuria (odds ratio 2.9; 95% confidence interval 1.5, 5.5; P=0.001).

Conclusion

Microalbuminuria predicts the development of proteinuria among HIV‐infected persons. Because proteinuria has been linked to poorer outcomes, strategies to affect microalbuminuria should be tested.

     

Use of T2-weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure

Introduction  

The dural sheath surrounding the optic nerve communicates with the subarachnoid space, and distends when intracranial pressure is elevated. Magnetic resonance imaging (MRI) is often performed in patients at risk for raised intracranial pressure (ICP) and can be used to measure precisely the diameter of optic nerve and its sheath. The objective of this study was to assess the relationship between optic nerve sheath diameter (ONSD), as measured using MRI, and ICP.     

Magnesium and its transporters in cancer: a novel paradigm in tumour development

The relationship between magnesium and cancer is not as simple as could be assumed from the well-established requirement of magnesium for cell proliferation. Basic and pre-clinical studies indicate that magnesium deficiency can have both anti- and pro-tumour effects. In the present review, we briefly outline the new findings on the role of magnesium in angiogenesis and metastatization, and focus on the relationship between tumour cell proliferation and metabolic reprogramming, discussing how magnesium and its transporters are involved in these processes. The role of magnesium in cancer is also critically examined with regard to mitochondrial function, apoptosis and resistance to treatment. Finally, we bring together the latest experimental evidence indicating that alteration in the expression and/or activity of magnesium channels is a frequent finding in cancer cells and human tumour tissues examined to date, and we discuss the potential implications for developing novel diagnostic and therapeutic strategies.     

DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families

ABSTRACT: BACKGROUND: The neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males. METHODS: We examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility. RESULTS: There was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children(P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing. CONCLUSION: Our findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families.     

Burden of childhood-onset arthritis

Juvenile arthritis comprises a variety of chronic inflammatory diseases causing erosive arthritis in children, often progressing to disability. These children experience functional impairment due to joint and back pain, heel pain, swelling of joints and morning stiffness, contractures, pain, and anterior uveitis leading to blindness. As children who have juvenile arthritis reach adulthood, they face possible continuing disease activity, medication-associated morbidity, and life-long disability and risk for emotional and social dysfunction. In this article we will review the burden of juvenile arthritis for the patient and society and focus on the following areas: patient disability; visual outcome; other medical complications; physical activity; impact on HRQOL; emotional impact; pain and coping; ambulatory visits, hospitalizations and mortality; economic impact; burden on caregivers; transition issues; educational occupational outcomes, and sexuality.     

Biomimetic hydroxyapatite paste for molar–incisor hypomineralization: A randomized clinical trial

Objectives

The aim of this randomized clinical trial was to evaluate the desensitizing and remineralizing effect of a new zinc-hydroxyapatite-based paste in sites affected by molar–incisor hypomineralization (MIH), by assessing dental sensitivity, tooth wear, and periodontal indexes.

Materials and Methods

Twenty-five patients with presence of 1 enamel demineralization of permanent molars and incisors in two different quadrants were recruited. After professional dental hygiene, a domiciliary hydroxyapatite-based paste was assigned and recommended to be applied on 2 MIH teeth in one random quadrant (test group), while the 2 contralateral MIH teeth did not undergo paste application (control group). The following primary outcomes were assessed: Plaque Control Record (PCR), Bleeding Index (BI), MIH Treatment Need Index (MIH-TNI), and Schiff Air Index (SAI).

Results

No significant inter- and intragroup differences were found for PI and BI, except for both intragroup T0–T1. For MIH-TNI, significant intergroup differences were detectable in the test group after 9 months of treatment. For SAI values, no significant differences were found in the control group, while in the test group, significant lower values were found after 1 and 3 months since baseline, respectively.

Conclusions and Clinical Relevance

Biomimetic zinc-hydroxyapatite showed a desensitizing effect when used to treat MIH.     

Evidence for a multistep pathogenesis of chronic myelogenous leukemia

To study the relationship of the Philadelphia chromosome (Ph1) to the pathogenesis of chronic myelogenous leukemia, multiple B-lymphoid cell lines were established from a patient with Ph1-positive leukemia who was heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase. Both A and B types of enzyme were found in a 1:1 proportion in normal tissues, but 45 of 63 (71%) Ph1-negative B- lymphoid cells lines derived from this patient showed only the single glucose-6-phosphate dehydrogenase (type B) found in the Ph1-positive leukemic clone. Furthermore, 8 of 33 analyzable lines with B-type enzyme had chromosomal aberrations compared to 0 of 14 lines with A- type glucose-6-phosphate dehydrogenase. These results provide evidence for the suggestion that some cells of the abnormal clone do not express the Ph1 abnormality. Thus, acquisition of Ph1 may not be a sufficient cause for the disease. It is possible that at least two steps are involved in the pathogenesis of Ph1-positive chronic myelogenous leukemia, one causing abnormal proliferation of a clone of pluripotent hematopoietic stem cells and the other inducing Ph1 in descendants of these progenitors.