Behavioural and somatic effects of bradykinin injected into the cerebral ventricles of unanaesthetized rabbits

1. The effects of bradykinin (1-5 μg) injected into the cannulated lateral cerebral ventricles were studied in unanaesthetized rabbits before and after intravenous atropine, diphemanil and morphine.

2. The intraventricular injections of bradykinin produced a short-lasting phase of behavioural excitation with vocalization followed by sedation. The behavioural excitation was associated with desynchronization in the electrocorticogram (e.co.g.), bradycardia and hypotension followed by tachycardia and hypertension. Tachypnoea was also observed. The subsequent phase of sedation was more prolonged and associated with synchronization of the e.co.g. and signs of catalepsy. Intense miosis was present during both phases.

3. With repeated intraventricular injections of bradykinin, excitation, miosis, cardiovascular responses and tachypnoea diminished and eventually disappeared but the sedation did not exhibit tachyphylaxis.

4. Atropine abolished the e.co.g. desynchronization, vocalization and bradycardia, reduced the duration of the excitatory and sedatory phase, diminished the tachycardia and hypotension, enhanced the hypertension, but did not affect the miosis and tachypnoea.

5. Diphemanil affected only the cardiovascular effects produced by intraventricular bradykinin. They were affected in the same way as by atropine.

6. Morphine did not affect the excitatory phase, but enhanced the cardiovascular effects produced by intraventricular bradykinin.

7. The intraventricular injection of bradykinin (50 μg) caused a reduction in the amount of noradrenaline but not of 5-hydroxytryptamine (5-HT) in the brain stem; the amount of dopamine in the caudate nuclei was not affected.

8. It is suggested that central cholinergic and adrenergic systems are activated by intraventricular bradykinin.

     

A Ca2+-linked increase in coupled cAMP synthesis and hydrolysis is an early event in cholinergic and beta-adrenergic stimulation of parotid secretion.

The dynamics and compartmental characteristics of cAMP metabolism were examined by 18O labeling of cellular adenine nucleotide alpha phosphoryls in rat parotid gland stimulated to secrete with beta-adrenergic and cholinergic agents. The secretory response occurred in association with a rapidly increased rate of cAMP hydrolysis apparently coordinated with an equivalent increase in the rate of cAMP synthesis, since the cellular concentration of cAMP remained unchanged. The magnitude of this metabolic response was equivalent to the metabolism of 10-75 times the cellular content of cAMP within the first minute of stimulation. This increased metabolic rate occurred only during the early (1-3 min) period of stimulation, in what appeared to be an exclusive cellular compartment distinguished by a unique distribution of 18O among adenine nucleotide alpha phosphoryls. This 18O distribution contrasted with that produced by forskolin, which increased cellular cAMP concentration and elicited only a delayed response missing the early secretory component. The early acceleration of cAMP metabolism appeared linked to a stimulus-induced increase in intracellular Ca2+ concentration, since the Ca2+ ionophore ionomycin produced the same metabolic response in association with secretion. These observations suggest that cAMP metabolism is involved in stimulus-secretion coupling by a Ca2+-linked mechanism different from that in which cAMP plays the role of a second messenger.     

Does age matter in palliative care?

PURPOSE: To assess whether age has an impact on symptoms, problems and needs of hospitalized advanced cancer patients. PATIENTS AND METHODS: A prospective analysis of 181 patients referred to a Palliative Care Team was done using a standardized list of symptoms, problems and needs. Differences between 3 age groups (<60; 60-70; > or =70) were analyzed. RESULTS: Patients > or =70 years had a significantly different prevalence of depressed mood (48% versus 13% of patients 60-70 years and 24% of patients <60 years, p=0.002), urinary tract problems (20% versus 3% versus 8%, p=0.024) and drowsiness (18% versus 42% versus 25%, p=0.039). They expressed more problems with a shortage of informal caregivers (45% versus 42% versus 17%, p<0.001) and less need for support in coping (40% versus 61% versus 63%, p=0.043), relational support (3% versus 8% versus 14%, p=0.019) and support in communication (0% versus 8% versus 11%, p=0.013). CONCLUSION: Fewer differences than expected were found. Elderly cancer patients admitted to a hospital have more or less the same symptoms, problems and needs as their younger counterparts. Despite these findings, age-specific assessment of symptoms, problems and needs ought to be part of optimal symptom management.     

Antisense inhibition of urokinase reduces spread of human ovarian cancer in mice

Urokinase-type plasminogen activator (uPA) is a protease involved in the process of tissue remodelling and cell migration in vitro. To explore whether uPA is a prerequisite for human ovarian cancer spread in vivo the expression of uPA was suppressed in human ovarian cancer cells by antisense phosphorothioate oligonucleotides (PS-ODN). The suppression of uPA expression was dependent on PS-ODN concentration and only observed in the presence of liposomes. This phenomenon seemed to be due to the fact that PS-ODNs were taken up by the cancer cells only in concert with liposomes as studied by fluorescently-labeled PS-ODNs using flow cytofluorometry and laser scanning microscopy. uPA-deprived cancer cells exhibited a significantly reduced invasive capacity in vitro compared with untreated cancer cells or cells treated with control PS-ODNs (P = 0.003). The intraperitoneal spread of the cancer cells in vivo was significantly diminished when nude mice were treated with uPA antisense PS-ODNs in comparison with control mice (P = 0.009). These results suggest that uPA expression may be required for spread of human ovarian cancer and that its inhibition could provide a therapeutic approach.     

Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3‐kinase δ (PI3K δ ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain‐of‐function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype.