4α-phorbol 12,13-didecanoate activates cultured mouse dorsal root ganglia neurons independently of TRPV4.

BACKGROUND AND PURPOSE: The Ca(2+) -permeable cation channel TRPV4 is activated by mechanical disturbance of the cell membrane and is implicated in mechanical hyperalgesia. Nerve growth factor (NGF) is increased during inflammation and causes mechanical hyperalgesia. 4α-phorbol 12,13-didecanoate (4αPDD) has been described as a selective TRPV4 agonist. We investigated NGF-induced hyperalgesia in TRPV4 wild-type (+/+) and knockout (-/-) mice, and the increases in [Ca(2+) ](i) produced by 4αPDD in cultured mouse dorsal root ganglia neurons following exposure to NGF. EXPERIMENTAL APPROACH: Withdrawal thresholds to heat, von Frey hairs and pressure were measured in mice before and after systemic administration of NGF. Changes in intracellular Ca(2+) concentration were measured by ratiometric imaging with Fura-2 in cultured DRG and trigeminal ganglia (TG) neurons during perfusion of TRPV4 agonists. KEY RESULTS: Administration of NGF caused a significant sensitization to heat and von Frey stimuli in TRPV4 +/+ and -/- mice, but only TRPV4 +/+ mice showed sensitization to noxious pressure. 4αPDD stimulated a dose-dependent increase in [Ca(2+) ](i) in neurons from +/+ and -/- mice, with the proportion of responding neurons and magnitude of increase unaffected by the genotype. In contrast, the selective TRPV4 agonist GSK1016790A failed to stimulate an increase in intracellular Ca(2+) in cultured neurons. Responses to 4αPDD were unaffected by pretreatment with NGF. CONCLUSIONS AND IMPLICATIONS: TRPV4 contributes to mechanosensation in vivo, but there is little evidence for functional TRPV4 in cultured DRG and TG neurons. We conclude that 4αPDD activates these neurons independently of TRPV4, so it is not appropriate to refer to 4αPDD as a selective TRPV4 agonist.

Accuracy of mammography in an Australian community setting.

The records of three surgeons in a Sydney suburban practice have been reviewed to compare the histopathological data from breast biopsies with the clinical assessment, and the mammographic and ultrasound reports, and to assess the extent of the delay before presentation to a surgeon to determine the diagnostic accuracy of the three modalities, and whether mammography contributed to this delay. Two hundred and nineteen breast biopsies that were performed in the years 1984 to 1986 inclusive were reviewed. Of these, 72 were cancerous lesions and 147 were benign lesions. The accuracy (true-positive rate) of mammography for the detection of cancer was 83% with a false-negative rate of 11%. We found no evidence that mammography contributed significantly to the delay before patients presented to specialist surgeons, nor to any delay before they underwent a biopsy.

Splenic trauma from blunt abdominal injury.

Thirty-nine cases of splenic trauma from blunt abdominal injury are presented. Road trauma was the most common aetiological factor, and young adults were predominantly affected. Internal haemorrhage was the main determinant of the clinical picture, and nine cases of delayed haemorrhage following splenic trauma are reported. Associated injuries were present in two-thirds of cases and contributed to the high morbidity and mortality rate of splenic trauma. The operative and non-operative management of splenic trauma is discussed, and the roles of isotope spleen scans are demonstrated.