The effects of the selective and non‐peptide CXCR2 receptor antagonist SB225002 on acute and long‐lasting models of nociception in mice

This study evaluated the antinociceptive effects of the selective and non‐peptide CXCR2 antagonist SB225002 in mouse models of pain. As assessed in different tests of spontaneous nociception, intraperitoneal (i.p.) administration of SB225002 caused consistent and dose‐related reduction of acetic acid‐induced abdominal constrictions, whereas it did not significantly affect the nociception evoked by formalin, capsaicin, glutamate or phorbol ester acetate (PMA). Systemic treatment with SB225002 strikingly reduced the spontaneous nociception induced by 8‐bromo‐cAMP (8‐Br‐cAMP), or mechanical hypernociception induced by prostaglandin E₂ (PGE₂), epinephrine, or the keratinocyte‐derived chemokine (KC). In the carrageenan model, SB225002 markedly reduced mechanical hypernociception when administered by i.p., intrathecal (i.t.) or intracerebroventricular (i.c.v.) routes, or even when co‐administered with carrageenan into the mouse paw, indicating peripheral and central sites of action for SB225002. In addition, i.p. treatment with SB225002 significantly attenuated the increase in MPO activity or the elevation of IL‐1β, TNFα or KC levels following carrageenan injection. In the persistent models of pain evoked by complete Freund's adjuvant (CFA) or by the partial ligation of the sciatic nerve (PLSN), the repeated administration of SB225002 displayed prominent and long‐lasting antinociceptive effects. Notably, SB225002 did not evoke unspecific central effects, as evaluated in the open‐field and rota‐rod tests, or even in the latency responses for thermal stimuli. Our data confirm the previous notion on the critical role exerted by chemokines in pain, indicating that selective CXCR2 antagonists, such as SB225002, might well represent interesting and innovative alternatives for the management of both acute and chronic pain.     

A web-based simulation of a longitudinal clinic used in a 4-week ambulatory rotation: a cohort study

Background  

Residency training takes place primarily on inpatient wards. In the absence of a resident continuity clinic, internal medicine residents rely on block rotations to learn about continuity of care. Alternate methods to introduce continuity of care are needed.     

Sinn und Inhalt von Behandlungspfaden in der Orthopädie und Unfallchirurgie

The aim of the study was to find the best possible methodology to evaluate the perioperative processes in the main diagnosis-related groups in an orthopaedic and trauma centre. A model in five phases was followed to develop the care pathways. Optimization potentials were derived from estimated problems and their origin. Cases of missing objectives led to re-organization and the necessary quality in treatment could be prepared as a new work flow management. The cost-effectiveness of treatment procedures and the costs of processes conditionally led to a change in management. The advantages of the study were increased knowledge of the processes involved in diagnosis and therapy with regard to the evoked costs. So the limited budget became more calculable.     

Serologic response to oncogenic human papillomavirus types in male and female university students in Busan, South Korea.

In the absence of genital samples, human papillomavirus (HPV) serology may be useful to assess HPV infection in young men and women. HPV seroprevalence and determinants of seropositivity were assessed in 817 female and 518 male university students in Busan, South Korea, of whom 74% and 44%, respectively, reported never having had penetrative sexual intercourse. Type-specific HPV DNA status, assessed by a short PCR fragment primer set, was available from genital samples. Seropositivity to L1 proteins of HPV types 16, 18, 31, 33, 45, 52, and 58 were assessed using multiplex HPV serology. Among women, HPV seroprevalence was significantly higher among sexually active (26.1%) than nonsexually active students [11.1%, odds ratio (OR) = 2.9; 95% confidence interval (95% CI), 1.8-4.7], although the association was weaker than that for HPV DNA prevalence (OR, 14; 95% CI, 4.7-42). Furthermore, HPV seroprevalence was higher among HPV DNA-positive (24%) than HPV DNA-negative women (13%), and there was a positive correlation of type-specific seroprevalence with the presence of HPV DNA of the same type. In contrast, HPV seropositivity among men was not associated with sexual behavior or the presence of HPV DNA. Seroprevalence correlates with genital HPV exposure in young women, but its meaning in young men is unclear.     

The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1.

The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-alpha) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-alpha, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-alpha-expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-alpha gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-alpha and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-alpha-positive HES.     

Permissive and suppressive effects of dexamethasone on enzyme induction in hepatocyte co-cultures

1. Steroids are known to act as permissive factors in hepatocytes. This study shows that dexamethasone (DEX) is a permissive factor for induction of CYP2B1/2, CYP3A1, CYP2A1 and probably also CYP2C11 in cultures with primary rat hepatocytes. 2. The induction factor of phenobarbital (PB)-induced formation of 16beta-hydroxytestosterone (OHT), a testosterone biotransformation product predominantly formed by CYP2B1, is increased 18-fold by the addition of 32 nM DEX to the culture medium. Interestingly, higher concentrations of DEX up to 1000 nM led to a concentration-dependent maximally 5-fold decrease (p = 0.002) of phenobarbital-induced 16beta-OHT formation compared with the effect observed with 32 nM DEX. Thus, DEX shows permissive and suppressive effects on enzyme induction depending on the concentration of the glucocorticoid. 3. Qualitatively similar but smaller permissive and suppressive effects of DEX were observed for PB-induced CYP3A1 activity as evidenced by formation of 2beta-, 6beta- and 15beta-OHT. 4. DEX is a permissive factor for induction of CYP2A1 activity by 3-methylcholanthrene (3MC), as evidenced by the formation of 7alpha-OHT. Without addition of DEX, 3MC did not induce formation of 7alpha-OHT, whereas an almost 3-fold induction occurred in the presence of DEX. In contrast to CYP2B and CYP3A, concentrations up to 1000 nM DEX were not suppressive for the induction of CYP2A1. 5. We described recently a technique that allows preparation of cultures from cryopreserved hepatocytes. An almost identical influence of dexamethasone on enzyme induction was observed here in cultures from cryopreserved compared with freshly isolated hepatocytes. 6. Cultures with primary hepatocyte cultures represent a well-established technique for the study of drug-drug interactions. However, a large interlaboratory variation is known. Our study provides evidence that differences in glucocorticoid concentration in the culture medium contribute to this variation.     

Is there a place for otorhinolaryngology in primary care? Analysis of different areas

Otolaryngological disorders do have a high incidence, and prevalence and require specific physical examinations amongst general population. As a result, it is believed that it would be efficient to have otorhinolaryngologists within the primary care system. The main aim of this study was to assess the differences in hospital referrals comparing primary care units with and without ENT specialists. The study was carried out in Osona County (Catalonia, Spain). We studied the referrals to the hospital from two different primary care units, one with otorhinolaryngology services and the other without them. We analysed the morbidity, follow up and demographic variables of first visits in the hospital ENT department referred by these two primary care units. The primary care organisation without ENT specialist tends to refer more patients (3.96 first visits more per 1000 inhabitants a year, CI 95% 2.84-5.09) with ENT problems than the primary care one with ENT specialist. The difference is mainly due to an higher number of referrals that do not require hospital treatment (i.e. acute otitis, patients without an ENT clear diagnosis). In the area with ENT specialist, GP's also tend to refer patients directly to the hospital, hampering the organisation efficiency. The referrral pattern of GPs from the two organisations is quite similar, and they refer a high percentage of patients that do not need ENT hospital care. The study shows that ENT specialists in primary care units refer less patients with ENT disorders that can be successfully diagnosed and treated outside the hospital.     

Longitudinal impedance is independent of outflow resistance

BACKGROUND: Many investigators have measured outflow resistance (R) following peripheral bypass procedures, but correlations with graft patency have been weak. This is because the primary determinants of graft patency are the size and quality of the conduit, not its outflow bed. Efforts at separating conduit resistance from outflow resistance have been unsuccessful. Recently, the concept of longitudinal impedance ( integral Z(L)) has been suggested as a measure of conduit resistance independent of outflow resistance. The purpose of this in vitro experiment was to test the hypothesis that integral Z(L) is independent of R within physiologically relevant ranges. METHODS: Rigid polyethylene tubing of known internal diameter and length (4.3 mm, 375 cm) was perfused with a glycerin/saline mixture mimicking the viscosity of blood (4.1 cp), utilizing a variable pulsatile pump and Windkessel, with outflow into multiply branched tubes of decreasing diameter simulating the hemodynamic conditions of arterial bypass. Flow and pressure were measured using ultrasonic transit time and catheter transduction, respectively, and waveforms digitized at 200 Hz. Flow was varied while maintaining "systemic" pressure and resistance. After Fourier transformation, integral Z(L) was calculated as deltaP/Q at each harmonic and integrated over 4 Hz. RESULTS: integral Z(L) calculations were remarkably reproducible within the same day with a coefficient of variation (CV) = 4.0% (at 100 dyne. s/cm(5); n = 4) or over 4 successive days (CV = 4.3%). Furthermore, integral Z(L) was largely independent of R over the physiologic range tested, with integral Z(L) remaining relatively constant as R was increased sixfold. CONCLUSION: integral Z(L) is a consistent and reproducible measure of conduit resistance independent of R over a wide physiologic range. It may be useful for measuring the adequacy of bypass graft conduits.     

Bone patterning is altered in the regenerating zebrafish caudal fin after ectopic expression of sonic hedgehog and bmp2b or exposure to cyclopamine

Amputation of the zebrafish caudal fin stimulates regeneration of the dermal skeleton and reexpression of sonic hedgehog (shh)-signaling pathway genes. Expression patterns suggest a role for shh signaling in the secretion and patterning of the regenerating dermal bone, but a direct role has not been demonstrated. We established an in vivo method of gene transfection to express ectopically genes in the blastema of regenerating fins. Ectopic expression of shh or bmp2 in the blastema-induced excess bone deposition and altered patterning of the regenerate. The effects of shh ectopic expression could be antagonized by ectopic expression of chordin, an inhibitor of bone morphogenetic protein (bmp) signaling. We disrupted shh signaling in the regenerating fin by exposure to cyclopamine and found a dose-dependent inhibition of fin outgrowth, accumulation of melanocytes in the distal region of each fin ray, loss of actinotrichia, and reduction in cell proliferation in the mesenchyme. Morphological changes were accompanied by an expansion, followed by a reduction, in domains of shh expression and a rapid abolition of ptc1 expression. These results implicate shh and bmp2b signaling in the proliferation and/or differentiation of specialized bone-secreting cells in the blastema and suggest shh expression may be controlled by regulatory feedback mechanisms that define the region of bone secretion in the outgrowing fin.     

The rise of the plasma lipid concentration elicited by dietary sodium chloride restriction in Wistar rats is due to an impairment of the plasma triacylglycerol removal rate

Studies in humans have indicated that dietary salt restriction raises plasma levels of total cholesterol (TC) and triacylglycerols (TAG). In order to explain the mechanisms involved, a rat experimental model was developed consisting of chronic feeding ad libitum isocaloric diets with variable sodium chloride contents. Rates of synthesis of plasma TAG were measured either as the increase of plasma TAG after blocking its removal from plasma by the intra-arterial pulse infusion of Triton-WR 1339, or as the plasma rate of incorporation of [(14)C]-oleic acid [(14)C]-TAG. Plasma TAG removal rate was determined by the intra-arterial pulse infusion of a lipid emulsion. Severe salt restriction increased the plasma concentrations of TAG (71%) and of TC (10%). This result was not due to modification of the rate of synthesis of plasma TAG but was attributed to a 55% slower rate of removal of the TAG-containing lipoproteins. An increased plasma non-esterified fatty acid concentration, probably due to a salt restriction-related insulin resistance, may have impaired the activity of the enzyme lipoprotein lipase.