Use of the collagen-binding assay for von Willebrand factor in the analysis of type 2M von Willebrand disease: a comparison with the ristocetin cofactor assay

This study compares the utility of two functional assays for von Willebrand factor (VWF), the ristocetin cofactor assay (VWF:RCo) and the collagen-binding assay (VWF:CBA). We analysed a group of 32 patients with type 2 von Willebrand disease (VWD) (25 patients with type 2M, six with type 2A and one with type 2B) and 22 normal control subjects. VWF:RCo/VWF antigen (VWF:Ag) ratios and VWF:CBA/VWF:Ag ratios were compared between the patient and control groups. In the six patients with type 2A VWD, both VWF:RCo/VWF:Ag ratios and VWF:CBA/VWF:Ag ratios were discordant (< or = 0.7). In the 25 type 2M VWD patients, the VWF:CBA/VWF:Ag ratios were concordant (> 0.7), but the VWF:RCo/VWF:CBA ratios were discordant (< or = 0.7) (P = 0.001) compared with control subjects. Thus, VWF:RCo/VWF:Ag ratios were discordant in both type 2M and 2A VWD patient groups indicating a functional abnormality. However, VWF:CBA/VWF:Ag ratios were discordant in the type 2A VWD group but not in the type 2M VWD group. Our study showed that VWF:CBA is sensitive to functional variants associated with the loss of high-molecular-weight multimers, i.e. type 2A and 2B in VWD, but the assay was unable to discriminate defective platelet-binding VWD variants with normal multimeric patterns such as type 2M VWD. It was concluded that the VWF:CBA assay should be used in association with rather than as a replacement for the VWF:RCo assay.     

A Meta-Analysis on the Impact of Platinum-Based Adjuvant Treatment on the Outcome of Borderline Ovarian Tumors With Invasive Implants

Background.

Treatment of borderline ovarian tumors (BOTs) remains contentious, and there is no consensus regarding therapy for BOTs with invasive implants (BOTi). The benefits of platinum-based adjuvant treatment were evaluated in patients with BOTi at primary diagnosis.

Methods.

The PubMed database was systematically searched for articles using the following terms: ((borderline) OR (low malignant potential) AND (ovarian)) AND ((tumor) OR (cancer)) AND (invasive implants) AND ((follow-up) OR (survival) OR (treatment) OR (chemotherapy) OR (adjuvant treatment) OR (surgery) OR (surgical treatment)).

Results.

We identified 27 articles including 3,124 patients, 181 with invasive implants. All studies provided information regarding mortality or recurrence rates. Central pathological examination was performed in 19 studies. Eight studies included more than 75% stage I patients; 7 included only advanced-stage patients, and 14 included only serous BOT. The pooled recurrence estimates for both treatment groups (adjuvant treatment: 44.0%, upfront surgery: 21.3%) did not differ significantly (p = .114). A meta-analysis of the 6 studies providing separate mortality data for both treatment groups favored surgical treatment only, but this difference did not reach statistical significance (.05 < p < .1; odds ratio: 0.33; 95% confidence interval: 0.09–1.71; p = .086). We were unable to pool the results of the included studies because not all studies registered events in both treatment groups. Egger’s regression indicated low asymmetry of the studies (p = .39), and no heterogeneity was found (I² = 0%).

Conclusion.

We did not find evidence supporting platinum-based adjuvant therapy for BOT with invasive implants.     

Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma

The complex regulation of tumor suppressive gene and its pseudogenes play key roles in the pathogenesis of hepatocellular cancer (HCC). However, the roles played by pseudogenes in the pathogenesis of HCC are still incompletely elucidated. This study identifies the putative tumor suppressor INTS6 and its pseudogene INTS6P1 in HCC through the whole genome microarray expression. Furthermore, the functional studies – include growth curves, cell death, migration assays and in vivo studies – verify the tumor suppressive roles of INTS6 and INTS6P1 in HCC. Finally, the mechanistic experiments indicate that INTS6 and INTS6P1 are reciprocally regulated through competition for oncomiR-17-5p. Taken together, these findings demonstrate INTS6P1 and INTS6 exert the tumor suppressive roles through competing for oncomiR-17-5p. Our investigation of this regulatory circuit reveals novel insights into the underlying mechanisms of hepatocarcinogenesis.     

Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects

Background

Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU^®-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate.

Methods

63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 ≥ 350 cells/mm³ and pHIV-RNA ≥ 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5 mg/dose) or intramuscularly (IM) (1 mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1 mg/dose (ID) and 2 mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts.

Results

Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p = 0.012) and increases in CD4+ T cell counts (p = 0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation.

Conclusions

The GTU^®-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801haplotypes.     

Left atrium remodeling after acute myocardial infarction (results of the GISSI-3 Echo Substudy)

To evaluate the existence, timing, and determinants of post-infarction left atrial remodeling, we studied a subgroup of 514 patients from the Third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Echo Substudy who underwent 4 serial 2-dimensional echocardiograms up to 6 months after acute myocardial infarction. This study is the first to demonstrate, in a large series of patients, the existence of early and late left atrial remodeling after low-risk acute myocardial infarction and the relation of left atrial remodeling to left ventricular remodeling.     

In vivo MRI visualization of mesh shrinkage using surgical implants loaded with superparamagnetic iron oxides

Background  

Prosthetic mesh implants are widely used in hernia surgery. To show long-term mesh-related complications such as shrinkage or adhesions, a precise visualization of meshes and their vicinity in vivo is important. By supplementing mesh fibers with ferro particles, magnetic resonance imaging (MRI) can help to delineate the mesh itself. This study aimed to demonstrate and quantify time-dependent mesh shrinkage in vivo by MRI.     

Control of prolactin-secreting macroadenomas with parenteral, long-acting bromocriptine in 30 patients treated for up to 3 years

OBJECTIVE We investigated the effect of intramuscular injections of long-acting bromocriptine in patients with macroadenomas. STUDY DESIGN AND PATIENTS Thirty patients with PRL-secreting pituitary macroadenomas were treated with repeated 4-weekly intramuscular injections of 50 or 100 mg of a long-acting, repeatable bromocriptine formulation for six to 37 injections, amounting to a total of 473 injections. Twenty patients received parenteral bromocriptine as primary therapy, ten had persisting hyperprolactinemia after previous therapies including pituitary surgery (n= 7), oral bromocriptine (7), and pituitary Irradiation (2). MEASUREMENTS A PRL day profile was obtained and the patients' clinical status and history were documented, at intervals. Detailed clinical, laboratory, and radiological (pituitary nuclear magnetic resonance or computed tomography scan) evaluations were performed at baseline, after 1 injection and every 6th injection therafter. RESULTS In all patients PRL was suppressed from a mean ± SEM pretreatment level of 32 620 ± 8680 to 4480 ± 1140 mU/l on the third day after the first injection. In 12 patients PRL levels normalized (< 400 mU/l) with the first to fourth injection, in three additional patients PRL levels normalized after 8–15 months. In 19 patients PRL was suppressed to less than 1000 mU/l. In three patients PRL did not decrease to less than 50% of pretreatment; in two of them on oral bromocriptine prior to this study there had been a comparable low efficacy. Of 28 patients with macroadenomas (median height 22 mm) tumour shrinkage was evident in 15 by nuclear magnetic resonance or computed tomography scan 28 days after the first injection, and in three additional patients after 6 months. There was further regression in seven cases after 12, 18 or 24 injections. Adenoma size (mean SEM) decreased to 66 ± 7% of the pretreatment value. The 40 adverse events noted in 20 of 30 patients during 24 hours after the first injection were similar to known side-effects of oral bromocriptine, nausea and postural hypotension being the most frequent. With repeated injections, on average 0 6 adverse events were noted per injection (mostly mild asthenia). There were no local adverse reactions at the injection site. CONCLUSION We conclude that long-acting repeatable bromocriptine in patients with macroprolactinomas offers a safe and efficacious primary treatment that ensures compliance and gives long-term control. Adverse reactions are comparable to oral bromocriptine but subside with repeated injections.     

Treatment with Neurokinin-1 Receptor Antagonist Reduces Severity of Inflammatory Bowel Disease Induced by Cryptosporidium parvum

Inflammatory bowel disease (IBD) is a chronic, debilitating disorder of uncertain and perhaps multiple etiologies. It is believed to be due in part to disregulation of the immune system. Neuroimmune interactions may be involved in induction or maintenance of IBD. In the present study, we examined the potential role of a neurotransmitter, substance P, in a mouse model of IBD. We found that binding sites for substance P, and more specifically, neurokinin-1 receptors, were upregulated in intestinal tissue of mice with IBD-like syndrome. Dosing of mice with LY303870, a neurokinin-1 receptor antagonist, reduced the severity of IBD, and treatment of mice with preexisting IBD allowed partial healing of lesions. We hypothesize that blocking the binding of substance P to the neurokinin-1 receptor interrupts the inflammatory cascade that triggers and maintains intestinal lesions of IBD.