Are biomarkers associated with sensitivity to physical activity?

BACKGROUND: Activity-based treatments play an integral role in managing musculoskeletal conditions including low back pain. However, while therapeutic exercise has been shown to reduce pain in such conditions, certain individuals experience a paradoxical pain increase in response to exercise. The physiological processes underlying this sensitivity to physical activity (SPA) are not fully understood, however stress and inflammation have been shown to contribute to SPA. The present cross-sectional study investigated whether physiological indicators of stress (cortisol) and inflammation (IL-6) help explain SPA. METHODS: Twenty-seven patients with chronic low back pain and 21 healthy controls completed a 1-h exercise session of standardized physical tasks. SPA was calculated from the difference between post- and pre-exercise pain levels. Participant's saliva was collected at several timepoints for cortisol and IL-6 levels quantification. Their waking cortisol response was calculated to reflect their cortisol regulation. Reactivity of IL-6 and cortisol was calculated to reflect changes in these measures during exercise. RESULTS: IL-6 reactivity was significantly and positively correlated with SPA among participants with low back pain. In contrast, neither cortisol waking response nor cortisol reactivity was significantly correlated within the low back pain group. No significant differences in IL-6 reactivity, cortisol reactivity or cortisol waking response were observed. CONCLUSION: These findings are the first to link SPA to an objective biomarker among people with low back pain. These findings help describe the physiological mechanisms of SPA and can support new clinical research that targets the inflammatory response of patients with chronic low-back pain and elevated SPA. SIGNIFICANCE: This study reveals a correlation between SPA and an objective salivary biomarker of IL-6 in people with low back pain, improving our understanding of this clinically relevant subjective experience.

[Stereotactic body radiation therapy for primary kidney cancer]. / Radiothérapie stéréotaxique des carcinomes rénaux primitifs.

The incidence of primary renal cancer is increasing, particularly in elderly patients who may have comorbidities and/or a surgical contraindications. Stereotactic body radiotherapy has primarily been evaluated retrospectively to date. The most commonly used dose schedules are 40Gy in five fractions, 42Gy in three fractions, and 26Gy in one fraction. The results in terms of local control and toxicity are very encouraging. The advantages of stereotactic body radiotherapy compared to thermal ablative treatments are its non-invasive nature, absence of general anesthesia, ability to treat larger lesions, and those close to the renal hilum. Prospective evaluations are still necessary.

TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy.

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.

Prevalence and genotype distribution of JC polyomavirus in urine from patients with hematological malignancies in Vietnam.

JC virus (JCV) causes progressive multifocal leukoencephalopathy in immunocompromised patients. The prevalence and genotype patterns of JCV vary between different geographical regions. This study was done to investigate the prevalence and genotype distribution of JCV in patients with hematological malignancies in Vietnam. A total of 48 urine samples were collected from patients with hematological malignancies. DNA was extracted and detection of JCV was by nested-polymerase chain reaction. Sequence analysis was obtained and a phylogenetic tree was constructed for genotyping of JCV. Twenty-seven (56.25%) urine samples tested positive for JCV. JCV genotype 7 was only observed in this study. Subtype analysis showed that JCV subtype 7A was the most commonly prevalent, followed by 7B1 and 7C1. Other subtypes were not detected in this population. There were no significant differences associated with age, gender, and biochemical parameters between patients with JCV and without JCV excretion in urine. The present study showed a high prevalence of JCV in the urine of patients with hematologic malignancies. The most common genotype found in this population was JCV subtype 7A.

Applications of dual energy computed tomography in abdominal imaging.

Dual energy computed tomography (CT) is an imaging technique based on data acquisition at two different energy settings. Recent advances in CT have allowed data acquisition and almost simultaneously analysis of two spectra of X-rays at different energy levels resulting in novel developments in the field of abdominal imaging. This technique is widely used in cardiovascular imaging, especially for pulmonary embolism work-up but is now also increasingly developed in the field of abdominal imaging. With dual-energy CT it is possible to obtain virtual unenhanced images from monochromatic reconstructions as well as attenuation maps of different elements, thereby improving detection and characterization of a variety of renal, adrenal, hepatic and pancreatic abnormalities. Also, dual-energy CT can provide information regarding urinary calculi composition. This article reviews and illustrates the different applications of dual-energy CT in routine abdominal imaging.

Narrow band imaging: clinical applications in oral and oropharyngeal cancer.

Narrow Band Imaging (NBI) is an endoscopic optical imaging enhancement technology that improves the contrast of mucosal surface texture, and enhances visualisation of mucosal and submucosal vasculature. White light is filtered to emit two 30-nm narrow bands of blue (415 nm) and green light (540 nm) light simultaneously, the former corresponding to the main peak absorption spectrum of haemoglobin, and the latter allowing visualisation of blood vessels in the deeper mucosal and submucosal layers. NBI has been used to better assess oral potentially malignant disorders (OPMD), identify oral and oropharyngeal squamous cell carcinoma (SCC), and to define surgical margins of head and neck malignancies. NBI shows great potential in improving detection rates of OPMD, facilitating better assessment of oral and oropharyngeal SCC, and reducing the risk of recurrence for oral SCC. Although further research is required to better understand and define intrapapillary capillary loop (IPCL) patterns and to relate these with clinical, histopathological and molecular parameters especially for early mucosal changes, there is building evidence to recommend its use as the new gold standard for endoscopic assessment in head and neck oncology.

Polyoxygenated steroids from the gorgonian Menella woodin with capabilities to modulate ROS levels in macrophages at response to LPS.

Four new polyoxygenated sterol derivatives (1-4) along with the compounds (5-7) previously known from other biological sources were isolated from the gorgonian Menella woodin, collected from the Vietnamese waters. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses as well as comparison with those reported in literature data. Compounds 1, 4, and 6 decrease the production of reactive oxygen species (ROS) by the murine macrophages of RAW 264.7 line at induction by endotoxic lipopolysaccharide (LPS) from Escherichia coli.

Diagnostic accuracy of Narrow Band Imaging for the detection of oral potentially malignant disorders.

OBJECTIVE: To determine the clinical diagnostic accuracy of Narrow Band Imaging(™) for the detection of oral potentially malignant disorders in a prospective series of patients. MATERIALS AND METHODS: New and existing patients referred to an oral medicine and pathology specialist clinic for assessment of at least one white, red or red-white oral mucosal lesion underwent conventional oral examination, followed by examination with the white light mode and then narrow band imaging mode of a Narrow Band Imaging(™) system. The clinical presentation, microvascular architecture and relevant histopathology of all lesions were recorded. RESULTS: A total of 272 lesions from 95 patients were observed. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for the detection of oral potentially malignant disorders or worse by Narrow Band Imaging(™) were 100%, 74.63%, 92.38%, 100% and 93.77%, respectively, when compared with conventional oral examination. Narrow Band Imaging(™) aided the detection of 24 lesions undetected by conventional oral examination and 13 lesions undetected by white light endoscopy. CONCLUSION: Narrow Band Imaging(™) demonstrates great utility as a visualisation adjunct for detecting and monitoring oral potentially malignant diseases, particularly lesions not identified by conventional oral examination or white light examination alone.

Multiple components of the spliceosome regulate Mcl1 activity in neuroblastoma.

Cancer treatments induce cell stress to trigger apoptosis in tumor cells. Many cancers repress these apoptotic signals through alterations in the Bcl2 proteins that regulate this process. Therapeutics that target these specific survival biases are in development, and drugs that inhibit Bcl2 activities have shown clinical activity for some cancers. Mcl1 is a survival factor for which no effective antagonists have been developed, so it remains a principal mediator of therapy resistance, including to Bcl2 inhibitors. We used a synthetic-lethal screening strategy to identify genes that regulate Mcl1 survival activity using the pediatric tumor neuroblastoma (NB) as a model, as a large subset are functionally verified to be Mcl1 dependent and Bcl2 inhibitor resistant. A targeted siRNA screen identified genes whose knockdown restores sensitivity of Mcl1-dependent NBs to ABT-737, a small molecule inhibitor of Bcl2, BclXL and BclW. Three target genes that shifted the ABT-737 IC50 >1 log were identified and validated: PSMD14, UBL5 and PRPF8. The latter two are members of a recently characterized subcomplex of the spliceosome that along with SART1 is responsible for non-canonical 5'-splice sequence recognition in yeast. We showed that SART1 knockdown similarly sensitized Mcl1-dependent NB to ABT-737 and that triple knockdown of UBL5/PRPF8/SART1 phenocopied direct MCL1 knockdown, whereas having no effect on Bcl2-dependent NBs. Both genetic spliceosome knockdown or treatment with SF3b-interacting spliceosome inhibitors like spliceostatin A led to preferential pro-apoptotic Mcl1-S splicing and reduced translation and abundance of Mcl1 protein. In contrast, BN82865, which inhibits the second transesterification step in terminal spliceosome processing, did not have this effect. These findings demonstrate a prominent role for the spliceosome in mediating Mcl1 activity and suggest that drugs that target either the specific UBL5/PRPF8/SART1 subcomplex or SF3b functions may have a role as cancer therapeutics by attenuating the Mcl1 survival bias present in numerous cancers.

[Papillomatous and nevus of the caruncle]. / Association naevus et papillome de la caroncule. A propos d'un cas observation anatomo-clinique.

A 63-year-old male patient was operated of a single conjunctival papillomatous lesion located on the left caruncle. The curative tumoral excision was followed by its histological analysis. Histologically, the tumor associated an epithelial squamous papilloma with a subepithelial nevus, confirming a combination of two different lesions.

Herpes zoster in seven disparate dermatomes (zoster multiplex): report of a case and review of the literature.

Noncontiguous multidermatomal herpes zoster is very rare in both immunocompetent and immunocompromised persons. Most of the reported cases have been limited to 2 noncontiguous dermatomes. This unique presentation has been referred to as zoster duplex unilateralis or bilateralis, depending on whether one or both halves of the body are involved. Granulomatous dermatitis at sites of herpes zoster scars, a rare isotopic response, has only been reported in persons with contiguous dermatomes of zoster. We describe an immunocompromised patient who developed herpes zoster in 7 disparate dermatomes. Three months after resolution of the zoster, the patient developed a granulomatous dermatitis in a zosteriform distribution at the sites of previous infection.

Possible role of disturbed Na+ homeostasis in mouse vas deferens contractile hyperreactivity after immunological sensitization.

In the present study we have investigated the involvement of sensitized mice immunoglobulins and some electrophysiological alterations that participate to the antigenic sensitization-induced hyperreactivity of isolated mouse vas deferens. Active sensitization was performed by subcutaneous injection of egg albumen. Contractile responses to noradrenaline were isometrically recorded in the isolated vas deferens. Low external Na(+)-induced contractions and rapid cooling contractures were evaluated. Resting membrane potential (Er) and intracellular Na activity were measured in control and actively sensitized vas deferens by using conventional KCl-filled and Na(+)-sensitive microelectrodes respectively. Active sensitization-induced hyperreactivity to noradrenaline was reproduced by in vitro passive sensitization of control vas deferens with sensitized mice immunoglobulins. The inhibition of the nitric oxide synthesis by N-nitro-L-arginine methyl ester (L-NAME) did not change control vas deferens reactivity in vitro to noradrenaline and acetylcholine. Rapid cooling contractures, performed after lowering external Na+ concentration, were not altered by active sensitization. However, sensitization increased significantly the strength of the low external Na+-induced contractions. In control vas deferens Er was a mean of -49.2+/-0.3 mV (mean+/-SEM). Sensitization resulted in reduction of Er by 14 mV. In sensitized preparations, relative insensitivity of Er to ouabain, external K+ removal and cooling were observed. The intracellular Na+ activity was increased by about 40% in sensitized vas deferens. It is concluded that sensitization-induced hyperreactivity is mediated by immunoglobulins and produced smooth muscle cells depolarisation. The low Er of sensitized muscle may be partly the result of an increase in membrane permeability to Na+ which could interfere with intracellular Ca2+ homeostasis.

Effect of moderate cooling on contractile responses in mouse vas deferens and its relation to calcium.

Isolated mouse vas deferens preparations were used to study the effect of temperature on noradrenaline-induced contractions. Preparations were suspended in the organ bath containing Krebs-Henseleit solution for isometric tension recording. Contractile responses to noradrenaline were investigated in the mouse vas deferens after moderate cooling from 37 to 26 or 22 degrees C. A significant increase of the phasic contractions to noradrenaline was observed at 26 or 22 degrees C compared with responses obtained at 37 degrees C (about 12.3 and 35.6% increase at 26 and 22 degrees C, respectively). The secondary noradrenaline-induced sustained contraction was also significantly enhanced after moderate cooling to 26 degrees C. The potentiation of noradrenaline-induced contraction at 26 degrees C remained in a Ca(2+)-free EGTA (1 mM)-containing solution. However, sustained contraction was suppressed after removal of the calcium from the medium at 37 and 26 degrees C. Contraction to caffeine was significantly enhanced at 22 degrees C compared with 37 degrees C. By contrast, barium chloride-induced contraction of the vas deferens was markedly decreased after moderate cooling to 22 degrees C. In the presence of ouabain (0.1 mM), the noradrenaline-induced peak contraction was significantly increased at 37 degrees C. However, potentiation of the noradrenaline response at 22 degrees C was unaffected by the Na+/K+ pump inhibitor. Noradrenaline-induced peak contractions were depressed in the presence of vanadate (1 mM) and cyclopiazonic acid (10 microM), two Ca(2+)-ATPase inhibitors, at 37 degrees C and also at 22 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant porcine prorelaxin produced in Chinese hamster ovary cells is biologically active.

Although prorelaxin has a similar structure as proinsulin, the posttranslational processing of prorelaxin seems to be quite different from that of proinsulin. There are no pairs of basic residues flanking the relaxin moiety in most prorelaxins studied so far. Instead, the prorelaxins of many species contains a tetrabasic sequence (Arg-Lys-Lys-Arg) between the connecting peptide and the A-chain. This is the recognition sequence of furin. In order to study this possible processing by furin, we express the recombinant porcine prorelaxin in Chinese hamster ovary cells. The expected 19 kDa recombinant porcine prorelaxin was found to be constitutively secreted into the medium at a level of approximately 250 ng/ml. No conversion of the 19 kDa prorelaxin into the 6 kDa relaxin was observed. Unlike most prohormones which are biologically inactive, the recombinant prorelaxin was found to be biologically active in an in vitro bioassay.

Treatment of cutaneous T cell lymphoma with 2'-deoxycoformycin (pentostatin).

2'-Deoxycoformycin, a potent inhibitor of adenosine deaminase, was administered to three patients with cutaneous T cell lymphoma refractory to multiple treatment modalities. Patient 1, who received 5 mg/m2/day for 3 days at 35- to 71-day intervals, has achieved a complete remission greater than 16 months in duration. Patient 2 had progressive disease despite two courses of 2'-deoxycoformycin at a dose of 5 mg/m2/day for 3 days at 28-day intervals. The third patient, who was treated with 4 mg/m2 2'-deoxycoformycin weekly to biweekly, had an initial response, but the disease progressed after eight treatments. Only one patient had any side effects: Patient 1 developed reversible episcleritis, mild elevation of liver enzymes, and persistent nausea and vomiting. In red blood cells of all patients, there was near complete inhibition of adenosine deaminase (91% to 96%) and S-adenosylhomocysteine hydrolase (89% to 95%) activities with treatment. In peripheral blood lymphocytes, adenosine deaminase was inhibited by 85% to 98% and S-adenosylhomocysteine hydrolase by 51% to 88%. The deoxyadenosine triphosphate level, reflected by the total cellular adenine deoxyribonucleotide measurement in erythrocytes, was noted to be modestly elevated during treatment, with the highest level in the patient who demonstrated the only complete response and the only toxic effects. Low-dose 2'-deoxycoformycin appears to be safe but may be an insufficiently intensive regimen to treat refractory cutaneous T cell lymphoma. With proper biochemical monitoring, higher doses may be both safe and more effective.

The principal protein antigens of isolates of Mycoplasma pneumoniae as measured by levels of immunoglobulin G in human serum are stable in strains collected over a 10-year period.

To determine whether antigenic variation in protein antigens of Mycoplasma pneumoniae occurred over time, 12 isolates obtained from pneumonia patients over a 10-year period (1964 to 1974) were compared by immunoblotting (Western blotting) against acute and convalescent human serum samples obtained from the same patients. The strains selected were isolated from patients who had low anti-lipid complement-fixing antibody titers in their acute-phase serum samples and high titers in their convalescent-phase serum samples. The polypeptide composition of the strains was closely similar by protein staining even when compared with prototype FH-Liu. On immunoblotting, all strains showed five bands (170, 130, 90, 45, and 35 kilodaltons [kDa]) which were stained more intensely by convalescent-phase than by acute-phase specimens. A sixth band (62 kDa) was detected by the conjugate alone. In FH-Liu, one band (110 kDa) was prominently stained by convalescent-phase specimens; this band was much less apparent in all of the clinical isolates. Two isolates possessed an additional band (92 kDa) which was stained more prominently by some but not all convalescent-phase specimens. Because of its known antigenic relationships and culture similarities, Mycoplasma genitalium was used for comparison. More polypeptides of M. genitalium than of M. pneumoniae were recognized by acute-phase serum samples, and 4 of 12 convalescent-phase serum samples showed increases in antibodies to certain M. genitalium polypeptides. However, these reactive polypeptides did not correspond in molecular mass to polypeptides recognized in M. pneumoniae; thus the signature profile of human convalescent-phase specimens with M. pneumoniae was distinct. These five polypeptides, individually or in combination, are especially promising for use in detection of human serum antibodies by enzyme-linked immunosorbent assay because they were found in all M. pneumoniae isolates tested.

Functional alterations of macrophages in autoimmune MRL-lpr/lpr mice.

To assess the role of macrophages (MAC) in the pathogenesis of systemic lupus erythematosus, we investigated functional aspects of peritoneal MAC obtained from autoimmune MRL/MpJ-lpr/lpr (MRL-lpr) mice. MRL-lpr and control C3H/HeN MAC were obtained from untreated mice or mice injected i.p. with 1 ml of 10% sterile peptone 3 days before cell harvest. MRL-lpr mice had significantly more peritoneal cells (MAC and lymphocytes) than did control mice. In endotoxin-free conditions, MRL-lpr MAC were similar to C3H/HeN MAC in their baseline, and IFN-gamma and/or LPS enhanced cytolysis of 3T12 fibrosarcoma tumor cells. Compared with C3H/HeN MAC, MRL-lpr MAC had a significant increase in antibody-dependent cellular cytotoxicity activity against sheep erythrocytes. This enhanced activity was not accompanied by a similar increase in adherence and/or phagocytosis of the same targets. Finally, in response to phorbol myristate acetate stimulation, both resident and peptone-induced MAC from MRL-lpr mice produced significantly more hydrogen peroxide than did those from control mice. These results indicate that MAC from MRL-lpr mice display features of selective "activation", and suggest that MAC or their products may play a role in the pathogenesis of inflammatory disorders seen in autoimmune diseases.