HIV-positiver Patient mit multiplen Ulzerationen

Ohne Zusammenfassung     

A new approach for the treatment of malignant melanoma: enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2

The progression of malignant melanoma is characterized by overexpression of a number of matrix metalloproteinases (MMPs), especially MMP-2, which play a critical role in the degradation of basement membranes and the extracellular matrix. Consequently, we assessed a drug targeting strategy in which the protease activity of MMP-2 is exploited to release an anticancer agent from a macromolecular carrier, i.e., circulating albumin. For this purpose, a water-soluble maleimide derivative of doxorubicin (1) incorporating a MMP-2 specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln) was developed that binds rapidly and selectively to the cysteine-34 position of circulating albumin. The albumin-bound form of 1 was efficiently and specifically cleaved by MMP-2 liberating a doxorubicin tetrapeptide (Ile-Ala-Gly-Gln-DOXO) and subsequently doxorubicin. In vivo, 1 was superior to the parent compound doxorubicin in the A375 human melanoma xenograft, which is characterized by a high expression of MMP-2.     

Memory T cells and vaccines

T lymphocytes play a central role in the generation of a protective immune response in many microbial infections. After immunization, dendritic cells take up microbial antigens and traffic to draining lymph nodes where they present processed antigens to na?ve T cells. These na?ve T cells are stimulated to proliferate and differentiate into effector and memory T cells. Activated, effector and memory T cells provide B cell help in the lymph nodes and traffic to sites of infection where they secrete anti-microbial cytokines and kill infected cells. At least two types of memory cells have been defined in humans based on their functional and migratory properties. T central-memory (T(CM)) cells are found predominantly in lymphoid organs and can not be immediately activated, whereas T effector-memory (T(EM)) cells are found predominantly in peripheral tissue and sites of inflammation and exhibit rapid effector function. Most currently licensed vaccines induce antibody responses capable of mediating long-term protection against lytic viruses such as influenza and small pox. In contrast, vaccines against chronic pathogens that require cell-mediated immune responses to control, such as malaria, Mycobacterium tuberculosis (TB), human immunodeficiency virus (HIV) and hepatitis C virus (HCV), are currently not available or are ineffective. Understanding the mechanisms by which long-lived cellular immune responses are generated following vaccination should facilitate the development of safe and effective vaccines against these emerging diseases. Here, we review the current literature with respect to memory T cells and their implications to vaccine development.     

Impact of smoking on the response to treatment of thyroid associated ophthalmopathy

BACKGROUND: In patients with Graves' disease, smoking considerably increases the incidence and severity of thyroid associated ophthalmopathy (TAO). The authors sought to determine if smoking also influences the course of TAO during treatment, and the efficacy of therapy. METHODS: 41 smokers and 19 non-smokers with moderate untreated TAO were included in this prospective study. All patients were treated with steroids and, 6 weeks after the beginning of drug therapy, with orbital irradiation. Follow up was performed 1.5, 4.5, 7.5, and 12 months after the beginning of the study. Proptosis, clinical activity score (CAS), and motility were evaluated. The extent of smoking was derived from the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV), a parameter of long term smoking. RESULTS: There was no difference in the clinical manifestations of TAO between smokers and non-smokers at the beginning of treatment. However, CAS decreased (p<0.05) and motility improved (p<0.02) significantly faster and to a greater extent in non-smokers than smokers. Inverse correlations between the CAS decrease and the HEV levels observed 4.5 and 7.5 months after the beginning of treatment and between the improvement of motility and the HEV levels after 1.5, 4.5, and 7.5 months indicated a dose dependence. Mean HEV levels did not vary much during the follow up period and were significantly different in smokers (mean 5.4 (SD 2.7) micro g/l) and non-smokers (mean 1.8 (1.3) micro g/l; p<0.01). CONCLUSION: Smoking influences the course of TAO during treatment in a dose dependent manner. The response to treatment is delayed and considerably poorer in smokers.     

Spatial point analysis based on dengue surveys at household level in central Brazil

Background  

Dengue virus (DENV) affects nonimunne human populations in tropical and subtropical regions. In the Americas, dengue has drastically increased in the last two decades and Brazil is considered one of the most affected countries. The high frequency of asymptomatic infection makes difficult to estimate prevalence of infection using registered cases and to locate high risk intra-urban area at population level. The goal of this spatial point analysis was to identify potential high-risk intra-urban areas of dengue, using data collected at household level from surveys.     

Communication plays key role in OB patient expectations

Obstetrics is a medical specialty with high profe sional liability exposure. Every aspect of an adverse OB outcome has become an opportunity for a legal review. Common root causes in adverse outcomes include communication failure, poor teamwork, and system failures. Indeed, poor communication is a significant factor in OB‐related malpractice claims. This excerpt from the booklet Risk Management Pearls for Obstetrics highlights those causes (particularly poor communications) and provides strategies to address them.     

The needle in the haystack: Application of breast fine‐needle aspirate samples to quantitative protein microarray technology

BACKGROUND.

There is an unmet clinical need for economic, minimally invasive procedures that use a limited number of cells for the molecular profiling of tumors in individual patients. Reverse‐phase protein microarray (RPPM) technology has been applied successfully to the quantitative analysis of breast, ovarian, prostate, and colorectal cancers using frozen surgical specimens.

METHODS.

For this report, the authors investigated the novel use of RPPM technology for the analysis of both archival cytology aspirate smears and frozen fine‐needle aspiration (FNA) samples. RPPMs were printed with 63 breast FNA samples that were obtained before, during, and after treatment from 21 patients who were enrolled in a Phase II trial of neoadjuvant capecitabine and docetaxel therapy for breast cancer.

RESULTS.

Based on an MCF7 cell line model of breast adenocarcinoma, the sensitivity of the RPPM detection method was in the femtomolar range with a coefficient of variance <13.5% for the most dilute sample. Assay linearity was noted from 1.0 μg/μL to 7.8 ng/μL total protein/array spot (R² = 0.9887) for a membrane receptor protein (epidermal growth factor receptor; R² = 0.9935).

CONCLUSIONS.

The results from this study indicated that low‐abundance analytes and phosphorylated and nonphosphorylated proteins in specimens that consist of a few thousand cells obtained through FNA can be quantified with RPPM technology. The ability to monitor the in vivo state of cell‐signaling proteins before and after treatment potentially will augment the ability to design individualized therapy regimens through the mapping of aberrant cell‐signaling phenotypes. The mapping of these protein pathways will further the development of rational drug targets. Cancer (Cancer Cytopathol) 2007. Published 2007 by the American Cancer Society.     

Randomised clinical trial of a group parent education programme for Australian Indigenous families

Aim:   Parenting programmes have been shown to improve children's adjustment and reduce problem behaviour; however, little research has addressed outcomes for Indigenous families. The aim of this project was to assess the impact and cultural appropriateness of a parenting programme tailored for Indigenous families, an adaptation of the evidence-based Group Triple P – Positive Parenting Program.
Methods:   A repeated measures randomised group design methodology was used, comparing the intervention with a waitlist control condition pre- and post-intervention, with a 6-month follow-up of the intervention group.
Results:   Parents attending Group Triple P reported a significant decrease in rates of problem child behaviour and less reliance on some dysfunctional parenting practices following the intervention in comparison to waitlist families. The programme also led to greater movement from the clinical range to the non-clinic range for mean child behaviour scores on all measures. Effects were primarily maintained at 6-month follow-up. Qualitative data showed generally positive responses to the programme resources, content and process. However, only a small number of waitlist families subsequently attended groups, signalling the importance of engaging families when they first make contact, helping families deal with competing demands, and offering flexible service delivery so families can resume contact when circumstances permit.
Conclusions:   This study provides empirical support for the effectiveness and acceptability of a culturally tailored approach to Group Triple P conducted by Child Health and Indigenous Health workers in a community setting. The outcomes of this trial may be seen as a significant step in increasing appropriate service provision for Indigenous families and reducing barriers to accessing available services in the community.     

Auditory responses from the frontal cortex in the short-tailed fruit bat Carollia perspicillata

Based on neuroanatomical findings it was hypothesized that an area in the bat frontal cortex is part of a sensorimotor feedback loop and probably important to goal-directed behaviors guided by auditory information. The present report describes the basic stimulus preferences and response properties of neurons from this area in the short-tailed fruit bat Carollia perspicillata. Responses to acoustic stimuli mimicking biosonar pulse-echo (i.e. FM-FM) combinations were found to be facilitated throughout but only rarely exhibited tuning to pulse-echo delay. As opposed to the often sharply delay-tuned FM-FM neurons in the species' auditory cortex, frontal cortical FM-FM neurons seem to be suited for indicating the presence of an insonified object irrespective of its distance and hence are likely to function as novelty detectors and to trigger changes in the bats' orientation behavior.     

Effect of green tea on p53 mutation distribution in ultraviolet B radiation-induced mouse skin tumors

In the present study, administration of green tea to SKH-1 mice, via the drinking fluid, was found to significantly reduce the incidence and volume of ultraviolet B (UVB) radiation-induced skin tumors. Thirty-six skin tumors induced by UVB and 32 skin tumors induced by UVB, in mice treated with green tea in their drinking water, were collected and examined for the presence of mutations in the p53 gene. Polymerase chain reaction products from p53 exons 5-8 were screened by single- strand conformation polymorphism and direct sequence analyses. Eight of 36 UVB-induced tumors contained nine p53 mutations, with four in exon 5 and five in exon 8. In contrast, nine of 32 UVB-induced tumors in mice treated with green tea contained 11 p53 mutations, with two in exon 5, five in exon 6 and four in exon 8. All of the p53 mutations occurred at dipyrimidine sequences. These results were further corroborated by p53 immunohistochemistry. The most frequent mutations were C-->T or T-->C transitions, which are consistent with the genetic alterations caused by UVB exposure. Interestingly, mutations found in exon 6 of the p53 gene occurred only in tumors from the UVB/green tea group. Thus, the tumors observed in UVB/green-tea-treated mice have a different exon distribution of p53 mutations than tumors obtained from mice treated with UVB alone.