Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer

Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF Ab. Of the 2 TF-positive lines, only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, < 5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor-bearing and control mice in an inferior vena cava stenosis model. The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis.     

Comprehensive analytical and structural characteristics of methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate (MDMB-4en-PINACA)

Purpose

The purpose of the study was to evaluate a complete analytical and structural characterization of methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate (MDMB-4en-PINACA), a novel synthetic cannabinoid being the analogue of 5F-ADB.

Methods

The compound was analyzed by gas chromatography–mass spectrometry (GC–MS), high-resolution liquid chromatography–mass spectrometry (LC–MS), X-ray diffraction and spectroscopic methods, such as nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) spectroscopies. To derive MDMB-4en-PINACA molecular geometry and to assign infrared absorption bands, quantum calculations with the employment of density functional theory were also used.

Results

We present a wide range of chromatographic and spectroscopic data supported with theoretical calculations allowing to identify MDMB-4en-PINACA.

Conclusions

To our knowledge, this is the first report presenting a comprehensive analytical and structural characterization of MDMB-4en-PINACA obtained by 1D and 2D NMR, GC–MS, LC–MS(/MS), attenuated total reflection-FTIR spectroscopy, powder X-ray diffraction and quantum chemical calculations. The presented results not only broaden the knowledge about this psychoactive substance but also are useful for forensic and clinical purposes.

     

Generalized purpuric drug exanthem with hemorrhagic plaques following bendamustine chemotherapy in a patient with B-prolymphocytic leukemia

A 72-year-old woman presented with dyspnea and lower extremity edema. Extreme lymphocytosis, cytopenia, and splenomegaly were found, and she was diagnosed with B-prolymphocytic leukemia. Following the first dose of therapy with bendamustine, the patient developed severe generalized maculopapular rash, which subsequently progressed to exuberant, non-blanching palpable purpura with hemorrhagic plaques suspicious for leukocytoclastic vasculitis. These events coincided with severe chemotherapy-induced neutropenia and thrombocytopenia, but there were no clinical symptoms of infection. Skin punch biopsy revealed perivascular and diffuse upper dermal lymphocytic infiltrate with eosinophils and marked erythrocyte extravasation consistent with a purpuric drug exanthem. The patient was treated with steroids, with complete resolution of the findings. This new form of cutaneous toxicity of bendamustine is presented along with a review of previous experience with the drug.     

Severe hypocalcemia after denosumab in a patient with acquired Fanconi syndrome

We report the case of a 48-year-old man with acquired Fanconi syndrome due to IgG-kappa monoclonal gammopathy, who received a single dose of denosumab 60 mg for secondary prevention of skeletal fractures, in conjunction with oral calcium and vitamin D supplementation. The treatment was complicated with a severe, symptomatic hypocalcemia occurring 1 month after the injection and necessitating 4 weeks of intravenous calcium gluconate therapy. Similarly to bisphosphonates, inhibitors of the receptor activator of nuclear factor kappa-B ligand may not be appropriate for the treatment of acquired Fanconi syndrome and other forms of osteomalacia regardless of the degree of renal insufficiency and vitamin D levels. Clinicians should carefully interpret the radiographic and bone densitometry results in light of diverse mechanisms of bone demineralization and potential dependence of calcium homeostasis on high bone turnover.     

Reliability and validity of the Polish version of the Core Outcome Measures Index for the neck

Purpose

Patient reported outcome measures play an increasingly important role in the outcomes research. The Core Outcome Measures Index (COMI) is a short, multidimensional instrument initially developed for the use by patients with low back pain. This study is an evaluation of a Polish version of COMI adapted for neck pain.

Methods

One hundred twenty-three patients complaining of neck pain were enrolled. All of them completed a questionnaire booklet containing COMI-neck, Neck Disability Index and Likert-type questions regarding the frequency of use of pain medications and pain frequency. Ninety-eight patients returned the retest questionnaire. Data quality was also assessed. Assessment of psychometric properties included examination of data quality, construct validity, test–retest reliability and factor analysis.

Results

The quality of data was good with no missing answers and a little floor effect. Exploratory factor analysis revealed a single-factor structure. Reliability expressed as intraclass correlation coefficient was 0.88 (95 % CI 0.84–0.92) for the overall COMI score and was generally good for most of individual core items. The minimum detectable change (MDC_95%) was 1.97.

Conclusion

This version of the COMI-neck is a valid and reliable instrument, with good psychometric properties. It can be recommended for Polish-speaking patients.     

The use of videonystagmography head impulse test (VHIT) in the diagnostics of semicircular canal injuries in patients with vertigo

Objectives

The aim of the study was to assess the function of semicircular canal in videonystagmography head impulse test (VHIT) in the patients with vertigo and balance disorders.

Material and Methods

The study was performed in 135 patients (86 women and 49 men) aged 22–79 years, who were divided into 2 groups: I (study group) — 73 patients with vertigo of peripheral, central or mixed origin, II (control group) — 62 patients without vertigo (healthy individuals). The function of canal was determined on the basis of GAIN and expressed as DG/RH×100% (where DG is deviation of gaze and RH is rotation of head).

Results

In the study group the semicircular canal injuries were found in 37 (50.69%) patients, including 24 (32.87%) patients with 1 injury and 13 (17.8%) patients with 2 or more injuries in semicircular canal. The injured anterior semicircular canal was reported 13 times; the lateral — 9 times and the posterior — 31 times.

Conclusions

In the study group, in the VHIT, injuries in semicircular canals were reported in peripheral vertigo, mixed vertigo with non-compensated and compensated function of the labyrinth in 50.68% cases, whereas in the caloric test dysfunction of the labyrinth was found in 58.49% cases.     

Identification and characterization of novel rapidly mutating Y‐chromosomal short tandem repeat markers

Short tandem repeat polymorphisms on the male‐specific part of the human Y‐chromosome (Y‐STRs) are valuable tools in many areas of human genetics. Although their paternal inheritance and moderate mutation rate (~10^?3 mutations per marker per meiosis) allow detecting paternal relationships, they typically fail to separate male relatives. Previously, we identified 13 Y‐STR markers with untypically high mutation rates (>10^?2), termed rapidly mutating (RM) Y‐STRs, and showed that they improved male relative differentiation over standard Y‐STRs. By applying a newly developed in silico search approach to the Y‐chromosome reference sequence, we identified 27 novel RM Y‐STR candidates. Genotyping them in 1,616 DNA‐confirmed father–son pairs for mutation rate estimation empirically highlighted 12 novel RM Y‐STRs. Their capacity to differentiate males related by 1, 2, and 3 meioses was 27%, 47%, and 61%, respectively, while for all 25 currently known RM Y‐STRs, it was 44%, 69%, and 83%. Of the 647 Y‐STR mutations observed in total, almost all were single repeat changes, repeat gains, and losses were well balanced; allele length and fathers' age were positively correlated with mutation rate. We expect these new RM Y‐STRs, together with the previously known ones, to significantly improving male relative differentiation in future human genetic applications.