Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma

Human herpesvirus 8 (HHV-8, also called KSHV) is linked to the etiopathogenesis of Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). The universal presence of HHV-8 in early KS has not yet been shown. We used a mAb (LN53) against latent nuclear antigen-1 (LNA-1) of HHV-8 encoded by ORF73 to study the distribution of the cell types latently infected by HHV-8 in patch, plaque, and nodular KS, MCD, and PEL. In early KS, HHV-8 is present in <10% of cells forming the walls of ectatic vessels. In nodular KS, HHV-8 is present in cells surrounding slit-like vessels and in >90% of spindle cells, but not in normal vascular endothelium. In addition, HHV-8 colocalizes with vascular endothelial growth factor receptor-3 (VEGFR-3), a marker of lymphatic and precursor endothelium. In early KS lesions, VEGFR-3 is more extensively expressed than LNA-1, indicating that HHV-8 is not inducing the proliferation of VEGFR-3-positive endothelium directly. In MCD, HHV-8 is present in mantle zone large immunoblastic B cells. No staining for LNA-1 is seen in samples from multiple myeloma, prostate cancer, and angiosarcoma, supporting the absence of any etiological link between these diseases and HHV-8.     

Practices and opinions regarding HPV vaccination among French general practitioners: evaluation through two cross-sectional studies in 2007 and 2010

Objectives

To use both quantitative and qualitative methods to investigate the evolution of practices and opinions regarding human papillomavirus (HPV) vaccination among French general practitioners.

Methods

A cross-sectional study (self-questionnaires) was performed in 2007 and repeated in 2010 among 271 general practitioners. Semi-structured interviews were conducted on 27 voluntary participants by a sociologist and analyzed according to content analysis.

Results

Acceptability of HPV vaccination had increased from 2007 to 2010 (79.9 vs. 87.1 %, respectively), just as the practice of HPV vaccination among 14-year-old girls (19.0 vs. 49.1 %, respectively). Though about 60 % reported complications associated with HPV vaccination, irrespective of year, the types of difficulties have varied: difficulties related to “questions asked by patients” had decreased, though concerns about side effects had remained stable. During interviews, difficulties related to “the reason for medical consultation” and “the target age” were often associated with addressing the issue of sexuality, especially when the parents were present.

Conclusions

Although the high level of acceptability of HPV vaccination among general practitioners, which increased from 2007 to 2010, there remain difficulties in addressing this practice.     

Intravenous Immunoglobulin and Rituximab for Cerebellar Ataxia with Glutamic Acid Decarboxylase Autoantibodies

Cerebellar ataxia associated with glutamic acid decarboxylase autoantibodies (GAD-ab) is a rare and usually slow progressive disease with moderate to severe gait and limb ataxia, dysarthria, and nystagmus. The treatment for this condition is still being discussed. We report the cases of three patients with GAD-ab cerebellar ataxia treated successively with intravenous immunoglobulin (IVIg) and rituximab. Symptoms improved in one case after rituximab therapy and were stabilized in another after a combined therapy of IVIg and rituximab. The third patient continued to worsen despite these treatments. We conclude that IVIg and rituximab therapy could improve or stabilize GAD-ab cerebellar ataxia. Early treatment, the lack of cerebellar atrophy on magnetic resonance imaging, and a subacute onset of the symptoms could be decisive prognostic factors.     

Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.     

A chasing dead-end case report: a fatal lead intoxication following an attempted homicide

Forensic Toxicology - In developed countries, lead intoxication is decreasing in adults as sources of contamination were considerably reduced. Hence, cases of lead encephalopathy have become...     

Zinc Deficiency in a Parenteral Nutrition–Dependent Patient During a Parenteral Trace Element Product Shortage

Parenteral nutrition product shortages are common and place vulnerable patients at risk for nutrient deficiencies. This case report describes a parenteral nutrition–dependent patient who was found to have zinc deficiency during a parenteral nutrition product shortage. The management of the patient's zinc deficiency is described.     

Accuracy of preoperative automatic measurement of the liver volume by CT-scan combined to a 3D virtual surgical planning software (3DVSP)

Background

Liver volumetry is a critical component of safe hepatic surgery, in order to minimize the risk of postoperative liver failure. Liver volumes can be calculated routinely using the time-consuming gold standard method of manual volumetry. The current work sought to evaluate an alternative automatic technique based on a novel 3D virtual planning software, and to compare it to the manual technique.

Methods

A prospective study of patients undergoing liver resection was conducted. Every patient had a pre and 2-day postoperative CT-scan. For each patient, total, remnant and resected volumes were calculated manually and automatically. Planes of resection were verified by a hepatobiliary surgeon and compared with postoperative volumes. Paired t-tests and correlation coefficients were calculated.

Results

A major hepatectomy was carried out in 36/43 patients. The automatic TLV (1,759 mL) and the manual TLV (1,832 mL) were significantly different (p < 0.001), but extremely highly correlated (r = 0.989). The percentages of preoperative RLV (manual 58.5 %, automatic 58.9 %) were similar, with an excellent correlation of 0.917. The preoperative RLV were matched with the 2-day postoperative RLV showing a significant difference (p = 0.0301). The resected volumes using both techniques (871 and 832 mL) were compared with the resected specimen volume (670 mL), showing a significant difference (p < 0.001) but a high degree of correlation (r = 0.874).

Conclusion

The 3D virtual surgical planning software is accurate and reliable in determining the total liver and future remnant liver volumes. This technique demonstrates a good correlation with the manual technique. Future work will be required to confirm these findings and to evaluate the clinical value of the three-dimensional planning platform.     

Monitoring glycosidase activity for clustered sugar substrates,a study on β-glucuronidase

Determination of glycosidase hydrolysis kinetics for a monovalent sugar substrate is relatively straightforward and classically achieved by monitoring the fluorescence signal released from the sugar-conjugated probe after enzymatic hydrolysis. Naturally occuring sugar epitopes are, however, often clustered on biopolymers or at biological surfaces, and previous reports have shown that glycosidase hydrolytic rates can differ greatly with multivalent presentation of the sugar epitopes. New probes are needed to make it easier to interpret the importance of substrate clustering towards a specific enzyme activity. In this work, we developed multivalent glucuronide substrates attached to fluorescent amino-coumarines through self-immolative linkers to enable real time-monitoring of the hydrolysing activity of E.coli β-glucuronidases (GUS) towards clustered substrates. GUS are exoglycosidases of considerable therapeutic interest cleaving β-d-glucuronides and are found in the lysosomes, in the tumoral microenvironment, and are expressed by gut microbiota. GUS showed a much lower catalytic efficiency in hydrolysing clustered glucuronides due to a significantly lower enzymatic velocity and affinity for the substrates. GUS was 52-fold less efficient in hydrolysing GlcA substrates presented on an octameric silsequioxane (COSS) compared with a monovalent GlcA of similar chemical structure. Thus, kinetic and thermodynamic data of GUS hydrolysis towards multivalent glucuronides were easily obtained with these new types of enzymatically-triggered probes. More generally, adapting the substrate nature and valency of these new probes, should improve understanding of the impact of multivalency for a specific enzyme.

Enzymatically-triggered probes to determine glucuronidase hydrolysis kinetics for clustered substrates.