Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder.

Patients with PEX3 mutations usually present with a severe form of Zellweger spectrum disorder with death in the first year of life. Whole exome sequencing in adult siblings with intellectual disability revealed a homozygous variant in PEX3 that abolishes the normal splice site. A cryptic acceptor splice site is activated and an in-frame transcript with a deletion is produced. This transcript translates into a protein with residual activity explaining the relatively mild peroxisomal abnormalities and clinical phenotype.

Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer.

Breast cancer consists of at least five main molecular "intrinsic" subtypes that are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA, and DNA copy-number profiles from a total of 59 in situ lesions and 85 invasive tumors in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression.

[Inflammation as part of cerebral amyloid angiopathy disguised as a tumour].

A male with probable cerebral amyloid angiopathy (CAA)-related inflammation presented with headache and subacute hemi-paresis. After admission he developed a disturbance of consciousness and a CT brain scan showed oedema with significant midline shift. He was treated with corticosteroids with prompt clinical improvement. A MR brain scan after treatment showed confluent T2-weighted lesions, microbleeds and regression of oedema. The patient was discharged in habitual status. During withdrawal of corticosteroids he showed clinical and radiological signs of relapsing CAA-related inflammation.

No release of interstitial glutamate in experimental human model of muscle pain.

Glutamate may be released from muscle nociceptors and thereby contribute to mechanisms underlying acute and chronic muscle pain. In vivo concentration of glutamate during muscle pain has not previously been studied in either animals or humans. In the present study, we aimed to study the in vivo concentration of glutamate before, during and after acute pain of trapezius muscle in humans using the microdialysis technique. In addition, we examined the nutritive skeletal muscle blood flow and the interstitial concentrations of lactate, glucose, glycerol, pyruvate and urea. Experimental pain and tenderness were induced by intramuscular infusion of a chemical mixture consisting of bradykinin, prostaglandin E(2), histamine and serotonin. One EMG-needle and one microdialysis catheter were inserted into non-dominant and dominant trapezius muscles on a standard anatomical point in 19 healthy subjects. Dialysates were collected at rest, during infusion and 60 and 120 min after stop of infusion. Local tenderness was recorded at baseline and at the end of experiment. Local pain was recorded during infusion. The infusion of chemical mixture was more painful than infusion of placebo (p < 0.05) and resulted in significantly higher local tenderness score than placebo (p = 0.007). There was no difference in change in interstitial concentrations of glutamate, lactate, glucose, glycerol, pyruvate and urea from baseline to infusion and post-infusion periods between chemical mixture and placebo (p > 0.05). Muscle blood flow increased significantly over time in response to infusion of chemical mixture and placebo (p = 0.001). However, we found no difference in changes in muscle blood flow between chemical mixture and placebo (p > 0.05). In conclusion, the present study demonstrates no signs of increased release of glutamate from myofascial nociceptors during and after acute experimentally induced muscle pain and tenderness.

Experimental muscle pain and tenderness following infusion of endogenous substances in humans.

Several human models of myofascial pain exist, but none are similar to clinical pain. The aim of the present study was to develop a clinically relevant model of prolonged human myofascial pain using infusion of the naturally occurring endogenous substances. Initially, bradykinin (Bk), serotonin (5-hydroxytryptamine (5-HT)), histamine (His), prostaglandin E(2) (PGE(2)), adenosine-tri-phosphate (ATP), and their combinations were infused into the trapezius muscle of 36 healthy subjects in a total of 67 sessions to identify substances, which could induce a moderate muscle pain. PGE(2), ATP, and a combination of Bk, 5-HT, His, and PGE(2) produced the intended moderate pain. These substances were further examined in a randomised, blinded, placebo-controlled dose-finding design in 15 healthy subjects in 68 sessions. PGE(2) (3, 6, and 12 nmol/ml) induced mild pain and tenderness not different from placebo. ATP (9000, 18,000, and 36,000 nmol/ml) induced pain of moderate to strong intensity (P=0.04) and the dose of 18,000 nmol/ml furthermore produced moderate local tenderness (P=0.04). Because of unacceptable side effects in subsequent examinations, further studies of ATP in humans were suspended. Infusion of the combination of Bk (92 nmol), 5-HT (156 nmol), His (140 nmol), and PGE(2) (1.95 nmol) produced a moderate pain intensity (P=0.04) and mild tenderness (P=0.04) without inducing unacceptable side effects. Intramuscular infusion of a combination of Bk, 5-HT, His, and PGE(2) induced a prolonged moderate pain and tenderness in healthy humans, and this model may be a valuable tool in future studies of the pathophysiological mechanisms of myofascial pain.

Does nociceptin play a role in pain disorders in man?

Nociceptin-immunoreactive cellbodies were detected in the human trigeminal ganglion, while no such fibers were identified in the temporal artery or in dermal tissue from the neck region. In four healthy subjects receiving nociceptin into the temporal muscle in an open labeled design no pain was detected. In 10 healthy subjects who received 200pmol of nociceptin into tender non-dominant trapezius muscles in a placebo-controlled, randomized, balanced, and double-blinded design local tenderness increased (P=0.025) while no pain was noted. Thus, the action of nociceptin should be searched for in the trigeminal ganglion and/or in the central nervous system (CNS).