Cancer of prostate with osseous metastases prolonged pain relief with very high-dose epidural morphine

Summary Osseous metastases may cause severe unremitting pain that may be difficult to control. We report a case of severe pain due to metastases of prostate cancer into the vertebral column, which was well controlled for 93 days with b.i.d. bolus epidural morphine injections. The starting dose was 80 mg/day, which was increased during the 93-day period to 540 mg/day without producing any side effects.     

Which young physicians are satisfied with their work? A prospective nationwide study in Norway

Background  

Few studies have investigated personality and medical school variables in regard to job satisfaction after graduation. It is of great importance to investigate these factors because this information may be used in the recruitment/admittance process to medical schools, and possibly to improve medical education.     

Cyclic AMP-dependent protein kinase (cAK) in human B cells: co-localization of type I cAK (RIα2C2) with the antigen receptor during anti-immunoglobulin-induced B cell activation

Cyclic AMP (cAMP) inhibits antigen-stimulated B cell proliferation through activation of cAMP-dependent protein kinases (cAK). We have examined the molecular composition and cellular localization of cAK in human B cells. We find that human B cells contain substantial amounts of mRNA for RIα, RIIα, Cα and Cβ, barely detectable levels of RIβ mRNA, and no detectable RIIβ or Cγ mRNA. At the protein level, using Western blotting and subunit-specific antibodies against the different R subunits, we find RIα and RIIα, but no RIβ or RIIβ. The presence of catalytic subunits was demonstrated using a nonselective anti-C antiserum. By photoaffinity labeling of R subunits with 8-azido-[³²P]cAMP, followed by immunoprecipitation with subunit-specific antibodies, we were also able to demonstrate low levels of RIβ. Immunofluorescence staining of RIα and RIIα demonstrates a rather homogeneous intracellular (but extranuclear) distribution of RIα, whereas the RIIα subunits of cAK are localized to distinct perinuclear structures, previously identified as centrosomes in other cell types. Upon anti-Ig-mediated capping of B cells, RIα subunits redistribute to the cap, co-localizing with the antigen-receptors, whereas the intracellular localization of RIIα subunits remains unchanged.     

One‐step synthesis of [18F]cabozantinib for use in positron emission tomography imaging of c‐Met

Cabozantinib is an FDA‐approved kinase inhibitor for the treatment of medullary thyroid cancer and advanced renal cell carcinoma, which exerts its therapeutic effect by inhibiting, among others, the tyrosine kinase c‐Met. Noninvasive imaging techniques are becoming increasingly important clinically to ensure drug efficacy, staging, monitoring, and patient stratification. PET isotope labelled tyrosine kinase inhibitors have, for the same reason, potential as PET tracers for imaging of various cancers. On the basis of cabozantinib, we synthesized the novel boronic acid pinacol ester 4 as a labelling precursor, where the boronic ester moiety replaces the fluorine native to this kinase inhibitor. By this, we wanted to explore whether recently developed Cu‐mediated fluorination methods are adaptable to more complex substrates and thereby provide easy access to [¹⁸F]cabozantinib directly. Hydrolysis was implemented before preparative purification due to challenges with on‐column hydrolysis of the precursor 4 , and [¹⁸F]cabozantinib was obtained in ≥99% radiochemical purity and in 2.8 ± 0.05% (n = 4) isolated decay corrected yield in a synthesis time of 90 minutes. The molar activity of representative batches was determined to be 17 ± 8 GBq/μmol.     

The diagnostic accuracy of pocket-size cardiac ultrasound performed by unselected residents with minimal training

Pocket-size imaging devices may represent a tool for fast initial cardiac screening in the emergency setting. Pocket-size cardiac ultrasound (PCU) examinations performed by experienced echocardiographers yield acceptable diagnostic accuracy compared to standard echocardiogram (SE). However, the success of this method when used by unselected non-cardiologists remains unexplored. The current study studies the diagnostic accuracy of PCU when used by unselected internal medicine residents with minimal training. All residents were given a 2-hour introductory course in PCU (Vscan) and reported PCU results for up to 15 predefined cardiac landmarks. These were arbitrarily divided into 3 priority groups, such that left ventricle (LV) and pericardium were of first priority. Diagnostic accuracy [sensitivity/specificity and negative/positive predictive values (PPV/NPV)] and agreement were evaluated using a subsequent SE as reference. During a 9.2 months period a total of 303 patients were included in the study, the majority on the basis of presenting with chest pain or suspected heart failure. In the pooled LV and pericardial (1st priority) data, sensitivity/specificity/PPV/NPV were 61/92/70/89 % respectively. Similar specificities and NPVs were observed for the 11 remaining indices, as were lower sensitivities and PPVs. The best PCU sensitivity (76 %) was attained for the assessment of LV wall motion abnormalities. Overall agreement was k = 0.50. PCU examination performed by internal medicine residents with minimal training could provide a suitable means of ruling out cardiac pathology, as reflected in the high specificities and NPVs. It is not, however, a satisfactory tool for identifying patients with various cardiac disorders.     

Molecular scaffolds underpinning macroglial polarization: An analysis of retinal Müller cells and brain astrocytes in mouse

Key roles of macroglia are inextricably coupled to specialized membrane domains. The perivascular endfoot membrane has drawn particular attention, as this domain contains a unique complement of aquaporin‐4 (AQP4) and other channel proteins that distinguishes it from perisynaptic membranes. Recent studies indicate that the polarization of macroglia is lost in a number of diseases, including temporal lobe epilepsy and Alzheimer's disease. A better understanding is required of the molecular underpinning of astroglial polarization, particularly when it comes to the significance of the dystrophin associated protein complex (DAPC). Here, we employ immunofluorescence and immunogold cytochemistry to analyze the molecular scaffolding in perivascular endfeet in macroglia of retina and three regions of brain (cortex, dentate gyrus, and cerebellum), using AQP4 as a marker. Compared with brain astrocytes, Müller cells (a class of retinal macroglia) exhibit lower densities of the scaffold proteins dystrophin and α‐syntrophin (a DAPC protein), but higher levels of AQP4. In agreement, depletion of dystrophin or α‐syntrophin—while causing a dramatic loss of AQP4 from endfoot membranes of brain astrocytes—had only modest or insignificant effect, respectively, on the AQP4 pool in endfoot membranes of Müller cells. In addition, while polarization of brain macroglia was less affected by dystrophin depletion than by targeted deletion of α‐syntrophin, the reverse was true for retinal macroglia. These data indicate that the molecular scaffolding in perivascular endfeet is more complex than previously assumed and that macroglia are heterogeneous with respect to the mechanisms that dictate their polarization. © 2012 Wiley Periodicals, Inc.     

In vivo NADH fluorescence imaging indicates effect of aquaporin-4 deletion on oxygen microdistribution in cortical spreading depression

Using in vivo two-photon imaging, we show that mice deficient in aquaporin-4 (AQP4) display increased fluorescence of nicotinamide adenine dinucleotide (NADH) when subjected to cortical spreading depression. The increased NADH signal, a proxy of tissue hypoxia, was restricted to microwatershed areas remote from the vasculature. Aqp4 deletion had no effects on the hyperemia response, but slowed [K⁺]_o recovery. These observations suggest that K⁺ uptake is suppressed in Aqp4^−/− mice as a consequence of decreased oxygen delivery to tissue located furthest away from the vascular source of oxygen, although increased oxygen consumption may also contribute to our observations.