Ipilimumab-induced hypophysitis: MR imaging findings.

Ipilimumab is a promising new immunotherapeutic antineoplastic agent with clinical activity in the treatment of metastatic melanoma and renal cell carcinoma. With advances in immunotherapy, however, a host of new side effects related to the mechanism of action of these drugs has appeared. At our institution, 3 patients presented with hypophysitis, which was attributed to an autoimmune process based on the documented relationship of the drug to other autoimmune phenomena and significant and rapid improvement with discontinuation of the drug and addition of steroids. We present the imaging findings in 3 patients with presumed ipilimumab-induced hypophysitis.

Focal interstitial CC chemokine receptor 7 (CCR7) expression in idiopathic interstitial pneumonia.

BACKGROUND/AIMS: Idiopathic interstitial pneumonias (IIPs) are a diverse grouping of chronic pulmonary diseases characterised by varying degrees of pulmonary fibrosis. The triggers of the fibroproliferative process in IIP remain enigmatic but recent attention has been directed towards chemokine involvement in this process. METHODS: The expression of two chemokine receptors, CCR7 and CXCR4, and their respective ligands, CCL19, CCL21, and CXCL12, were examined in surgical lung biopsies (SLBs) from patients with IIP. Transcript and protein expression of these receptors and their ligands was compared with that detected in histologically normal margin SLBs. RESULTS: CCR7 and CXCR4 were detected by gene array and real time polymerase chain reaction analysis and CCR7, but not CXCR4, expression was significantly raised in usual interstitial pneumonia (UIP) relative to biopsies from patients diagnosed with non-specific interstitial pneumonia (NSIP) or respiratory bronchiolitis/interstitial lung disease (RBILD). CCR7 protein was expressed in interstitial areas of all upper and lower lobe UIP SLBs analysed. CCR7 expression was present in 50% of NSIP SLBs, and CCR7 was restricted to blood vessels and mononuclear cells in 75% of RBILD SLBs. Immune cell specific CXCR4 expression was seen in IIP and normal margin biopsies. CCR7 positive areas in UIP biopsies were concomitantly positive for CD45 (the leucocyte common antigen) but CCR7 positive areas in all IIP SLBs lacked the haemopoietic stem cell antigen CD34, collagen 1, and alpha smooth muscle actin. CONCLUSION: This molecular and immunohistochemical analysis showed that IIPs are associated with abnormal CCR7 transcript and protein expression.

Aspergillus and asthma--any link?

The innate immune and acquired immune responses are not separate, parallel systems but form interdependent components of a single integrated immune response. This is nicely highlighted by an expanding database demonstrating that the innate immune response provides the acquired immune response with information about the origin of the antigen and the type of response required via pattern recognition receptors (PRRs). Aspergillus is among a growing list of allergens that can aggravate asthmatic responses. Significant pulmonary pathology is associated with Aspergillus-induced allergic and asthmatic lung disease characterized by increased Th2 cytokine generation, IgE and IgG, eosinophilia, airway hyper-responsiveness and airway remodeling. Experimental data from a model of chronic fungal asthma demonstrate that thymus associated and regulated chemokine (TARC/CCL17) and macrophage derived chemokine (MDC/CCL22), working via CCR4, directly impair the innate anti-fungal immune response, thereby promoting the maintenance of acquired Th2-mediated asthmatic disease. Both chemokines appear to accomplish this by regulating the expression of PRRs such as toll like receptors (TLRs) and triggering receptor expressed on myeloid cells (TREM-1) by immune cells. Thus, the link between Aspergillus and asthma appears to reside in the magnitude and appropriateness of the host innate immune response, and ongoing research is revealing promising targets for therapy.

Catastrophic phase inversion in region II of an ionomeric polymer-water system.

Previous work has identified distinct regions, on a phase inversion map, for dispersions of polyurethane ionomer (PUI) and water. In this study, events that occur, before, during, and after catastrophic phase inversion (provoked by adding water to polyurethane ionomer (PUI) in the RII regions of the phase inversion map) have been studied in order to characterise the inversion mechanism. Before phase inversion, initial water addition leads to the hydration of ionic groups and eventually water drops start to form in the hydrophobic portions of the polymer matrix. At the phase inversion point, the PUI-water interface restructures and the ionomer disintegrates into a dispersion of spherical particles enclosed by a continuous aqueous phase. It is suggested that pseudo-drop structures are formed simultaneously during the production of the small polymer-in-water drops. After phase inversion, water addition dilutes the emulsion and destroys the apparent ionic-centre-rich environment surrounding any isolated ionic groups on a particle surface. The larger water-in-polymer drops are likely to have participated in the phase inversion and the smaller water drops form the primary water drops in the multiple emulsions. The resultant emulsions are stable over a period of a few months but very few multiple drops remain after 1(1/4) years.

Solution crystallisation via a submerged liquid-liquid phase boundary: oiling out.

In many situations the process of crystallisation from solution is known to occur via metastable crystalline states (polymorphs or solvates). Here we present what we believe to be a novel example of small molecule crystallisation in which the initial separation of a solute rich liquid phase precedes the crystallisation event. We believe this occurs because a submerged liquid-liquid phase boundary is accessible within the metastable zone of the crystal nucleation process.

Different dispersion regions during the phase inversion of an ionomeric polymer-water system.

Catastrophic phase inversion is induced by changing the phase ratio in a liquid-liquid dispersion and is widely used during the dispersion stage in the production of aqueous polyurethane ionomer (PUI) colloids. In the work reported here, water was added to polyurethane ionomer prepolymer (PUIp) until the water became the continuous phase. Three different dispersion regions have been discovered by changing the ionic group content. Stable emulsions containing small polymer drops were produced in Region I. Stable coarse emulsions containing a mixture of drop structures were produced in Region II, but only temporary dispersions could be produced in Region III. Conductivity measurements could not always be used to detect the phase inversion points effectively because the PUIp was swollen by water. Therefore, torque change measurements have been used in conjunction with the conductivity measurements to detect the phase inversion points for all three dispersion regions. Scanning electron microscopy (SEM) and optical microscopy were used to obtain images of these dispersions in the different regions. A catastrophic phase inversion map is used to represent the changes that occur in the PUIp-W dispersions. This map is plotted using the ionic group content as the ordinate and water content (at the phase inversion points) as the abscissa.

Amino acids are still as exciting as ever.

Glutamate is probably the most important excitatory transmitter in the vertebrate central nervous system. Its multiple functional roles in the brain and spinal cord make therapeutic manipulation of these systems fraught with difficulties. There has, however, been recent progress in pharmacological manipulations of NMDA receptor subtypes and non-NMDA receptors, and understanding of the roles of NAAG, that promise rapid advances in pain control.

Peripheral administration of low pH solutions causes activation and sensitisation of convergent dorsal horn neurones in the anaesthetised rat.

This is the first study to examine the effects of peripheral administration of acid on the activity of dorsal horn neurones in vivo. Extracellular recordings from convergent neurones revealed increases in neuronal activity evoked by administration of low pH solutions into the peripheral receptive field. Threshold for activity ranged from pH 5.85 to 2.5. The magnitude of responses increased with decreasing pH; maximum effects were achieved with pH 2.5 (648+/-181 action potentials/60 s, as compared to control-evoked activity of 86.3+/-29 action potentials/60 s). Activity lasted for up to 60 s, likely to represent the time for which the solutions were able to surmount the buffering capacity of the intact hindpaw. Significant sensitisation of the neurones to both innocuous (von Frey filament 9 g) and noxious (30 g) mechanical punctate stimuli was also observed.

Neuronal inhibitory effects of methadone are predominantly opioid receptor mediated in the rat spinal cord in vivo.

This study aims to assess whether the antinociceptive actions of methadone are mediated solely through opioid mechanisms, or whether its reported affinity for NMDA receptors has physiological relevance in vivo. Methadone is a mu-opioid receptor agonist reported to relieve pain unresponsive to other opioids. It is a racemic mixture comprising d- and l-optical isomers; the d-isomer has a lower affinity for opioid receptors, and both also exhibit NMDA receptor binding, likely to indicate antagonist activity. d -Methadone is antinociceptive in behavioural studies via non-opioid mechanisms, which could include functional NMDA receptor-blocking activity. Here we investigate the ability of d - and dl -methadone to inhibit noxious and innocuous electrically-evoked responses of dorsal horn neurones in the anaesthetized rat. Racemic methadone (5, 25, 50, 250 microg) applied spinally, dose-relatedly inhibited the C-fibre evoked response, input and wind-up of the neurones, with a profile resembling that of morphine. d-Methadone (5, 25, 50, 250, 500 microg) was also inhibitory, although less potent by a factor of between 13 and 48 depending on the neuronal measure; its profile of inhibition resembled that of the racemic mixture rather than an NMDA receptor antagonist. Both compounds had minimal effects on Abeta-fibre-evoked activity. The inhibitory effects of both d - and dl -methadone on noxious-evoked activity were naloxone reversible. The naloxone reversibility of d -methadone inhibitions is best interpreted as indicative of a purely opioid mechanism of action. However, the ability of naloxone to reverse the effects of d -methadone may also reflect a degree of synergy between weak NMDA antagonist and opioid agonist activity.

Forgotten mysteries in the early history of vitamin D.

In the early 1920s, workers in both England and the US had discovered that rats on a rachitic diet would remain healthy if irradiated with ultraviolet light. However, they also found, to their surprise, that "control" rats too would recover if either their jar was irradiated without the rat in it or if a cage-mate was removed for irradiation and then returned. The ideas that either air or material objects that had been irradiated continued themselves to convey healthful secondary radiations were investigated but not confirmed. There was then the commercially important finding that with irradiation, some rachitic diets would become anti-rachitic. However, this effect did not explain all the previous findings. Consumption of either small irradiated fecal particles or of feces from irradiated rats was the likely explanation for the recovery of nonirradiated rats, but this was not tested by direct experiment, and it now appears unlikely that feces from irradiated rats would show significant antirachitic activity. It is suggested that an alternative possibility--activity of grease from irradiated fur--deserves investigation.

Evidence that [Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, a peripheral ORL-1 receptor antagonist, acts as an agonist in the rat spinal cord.

[Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, a pseudopeptide analogue of nociceptin is an antagonist in peripheral assays. Here, using in vivo electrophysiological recordings of dorsal horn neurones, [Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2 appears to have agonist activity after spinal administration. The noxious evoked activity of the neurones was inhibited by [Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, which was as potent as nociceptin itself.

Early ideas on the nutritional significance of lipids.

By 1824, Chevreul had demonstrated that fats were esters of glycerol and fatty acids of differing chain length. At the time, it was thought that fats could be synthesized only by the plant kingdom. However, by 1850, it had been found from balance studies that animals also could synthesize fats from carbohydrates. The caloric value of fat was determined in the 1860s and shown to be more than double that of carbohydrate. In 1907, it was shown that this was also true when fat was used as a source of energy for physical work. The special value of cod liver oil for the prevention and treatment of rickets was well known by 1850 but was not to be explained until much later.