Mammary intraepithelial neoplasia outgrowths (MINO): MINO and human ductal carcinoma <Emphasis Type="Italic">in situ</Emphasis>

Germ-line mutations in the BRCA1 tumour suppressor gene contribute to familial breast tumour formation, but there is no evidence for direct mutation of the BRCA1 gene in the sporadic form of the disease. In contrast, decreased expression of the BRCA1 gene has been shown to be common in sporadic tumours, and the magnitude of the decrease correlates with disease progression. BRCA1 expression is also tightly regulated during normal breast development. Determining how these developmental regulators of BRCA1 expression are co-opted during breast tumourigenesis could lead to a better understanding of sporadic breast cancer aetiology and the generation of novel therapeutic strategies aimed at preventing sporadic breast tumour progression.     

Screening for treatable left ventricular abnormalities in diabetic patients

Cardiovascular disease is the leading cause of death in patients with diabetes mellitus. Attempts to improve this statistic tend to focus primarily on the prevention of coronary artery disease. However, coronary artery disease is not the sole cause of cardiac death in diabetic patients; left ventricular dysfunction (LVD) and left ventricular hypertrophy (LVH) are also implicated and, unlike coronary artery disease, are ideal targets for screening. The treatment of left ventricular abnormalities, even when these are asymptomatic, is associated with prognostic benefit. Prescreening diabetic patients with plasma B-type natriuretic peptide (BNP) may permit identification of those who are likely to have left ventricular abnormalities, so that they may be put forward for echocardiography and receive targeted therapy.     

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

Background and Purpose

The Ca²⁺-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 [Ca²⁺]_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 Ca²⁺ 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 [Ca²⁺]_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 Ca²⁺ 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.     

The effect of angiotensin II on endogenous noradrenaline release in man.

1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and forearm isometric exercise. 3. The presence of the angiotensin II infusion had no effect on the systolic blood pressure, diastolic blood pressure, heart rate or plasma noradrenaline responses to stimulation of the sympathetic nervous system. 4. We have therefore found no evidence to support the enhancement of noradrenaline release by this low dose of angiotensin II in man.     

Furosemide responsiveness, non-adherence and resistance during the chronic treatment of heart failure: a longitudinal study

BACKGROUND AND METHODS: Loop diuretic therapy is an essential part of chronic systolic heart failure (CH)F management, yet response to treatment can be variable. We analysed diuretic responsiveness in 39 stable patients with CHF in the community over 2 years. We measured serum ACE as a marker of adherence to ACE inhibitor therapy and urinary furosemide as a marker of diuretic adherence and action. Patients' clinical outcome was stable and not hospitalized (Group 0); alive but hospitalized (Group 1); or dead during follow up (Group 2). RESULTS: Prescribed furosemide dose was variable (range 20-370 mg generally once daily) and progressive dose increments were common. Failed furosemide adherence (defined as < 10% of a dose excreted in 24 h urine where normal average excretion = 50% of an oral dose) during static prescribed dosing was infrequent relative to all days of therapy; yet was equally common across all outcome groups. Furosemide non-adherence appeared to be independent of non-adherence with ACE inhibitor (as marked by serum ACE activity > 20 U l(-1)) treatment. Furosemide responsiveness (mm of sodium excreted per mg furosemide in urine) showed no relationship to prescribed dose and paradoxically tended to rise in patients with higher basal aldosterone concentrations. Furosemide responsiveness fell by outcome class despite increased dose. Within-patient responsiveness remained relatively constant although highly variable between individuals. CONCLUSIONS: Furosemide responsiveness varied greatly between individuals but was constant within an individual. Non-adherence with furosemide was less common among those who died and appeared to occur at different time points from non-adherence with ACE inhibitor treatment, which was slightly more common in all outcome groups. Patients who died were prescribed higher furosemide doses and had greater furosemide excretion yet had similar sodium excretion. The main factor in response to chronic furosemide therapy was intrarenal diuretic resistance. Gross non-adherence was less important.     

THE ARTISTRY AND ABILITY OF TRADITIONAL WOMEN HEALERS

In a phenomenological research study with a purposeful sample, 6 Ojibwa and Cree indigenous women healers from Canada and the United States shared their experience of being a traditional healer. Using stories obtained during open-ended, unstructured interviews, in this article I depict the lives, backgrounds, and traditional healing practices of women who, in the past, have not been afforded an opportunity to dialogue about their healing art and abilities. The methods of these women healers, their arts and their gifts, are different from those of Western conventional medicine because of dissimilar world views related to health and illness. An increased awareness of health care providers related to the ancient art of traditional healing currently practiced in communities by gifted women who provide culturally specific holistic healing and health care is essential.