Attenuation of microglial and neuronal activation in the brain by ICV minocycline following myocardial infarction.

Following myocardial infarction, microglia, the immune cells in the central nervous system, become activated in the hypothalamic paraventricular nucleus (PVN) suggesting inflammation in this nucleus. Little is known about other brain nuclei. In the present study, we investigated whether the rostral ventrolateral medulla (RVLM), the nucleus tractus solitarius (NTS) and the periaqueductal grey (PAG), regions known to have important cardiovascular regulatory functions, also show increased microglial activation and whether this coincides with increased neuronal activity. We also investigated whether minocycline inhibited microglial activation and whether this also affected neuronal activity and cardiac function. Compared to controls there was a significant increase in the proportion of activated microglia and neuronal activation in the PVN, RVLM, NTS and PAG, 12weeks following myocardial infarction (P<0.001). Intracebroventricular infusion of minocycline (beginning one week prior to infarction) significantly attenuated the increase in microglial activation by at least 50% in the PVN, RVLM, PAG and NTS, and neuronal activation was significantly reduced by 50% in the PVN and virtually abolished in the PAG, RVLM and NTS. Cardiac function (percent fractional shortening) was significantly reduced by 55% following myocardial infarction but this was not ameliorated by minocycline treatment. The results suggest that following myocardial infarction, inflammation occurs in brain nuclei that play key roles in cardiovascular regulation and that attenuation of this inflammation may not be sufficient to ameliorate cardiac function.

Sustained activation of microglia in the hypothalamic PVN following myocardial infarction.

Microglia are the immune cells in the central nervous system and can produce cytokines when they are activated by an insult or injury. In the present study, we investigated in detail the time frame of the activation of microglia in the hypothalamic paraventricular nucleus (PVN) following myocardial infarction in rats. Morphological changes and immunohistochemistry to detect CD11b (clone OX-42) were used to identify activated microglia. Compared to rats that had undergone sham surgical procedures, there was a significant increase of between 40 and 50% in the proportion of activated microglia in the PVN 4-16 weeks following myocardial infarction (P<0.001, One way ANOVA). At 24h or 1 week post myocardial infarction, however, there was no significant increase in the proportion of activated microglia. Echocardiography and haemodynamic parameters after myocardial infarction indicated significantly reduced left ventricular function. In conclusion, following myocardial infarction, activation of microglia in the PVN does not occur immediately but once manifested, activation is sustained. Thus, activated microglia may contribute to the chronic elevation in cytokine levels observed following myocardial infarction. Since cytokines elicit sympatho-excitatory effects when locally microinjected into the PVN, activated microglia may contribute to the mechanisms mediating the chronic increase in sympathetic nerve activity in animals with reduced left ventricular function induced following myocardial infarction.

Role of the hypothalamic PVN in the reflex reduction in mesenteric blood flow elicited by hyperthermia.

The hypothalamic paraventricular nucleus (PVN) is an important integrative center in the brain. In the present study, we investigated whether the PVN is a key region in the mesenteric vasoconstriction that normally accompanies an increase in core body temperature. Anesthetized rats were monitored for blood pressure, heart rate, mesenteric blood flow, and vascular conductance. In control rats, elevation of core body temperature to 41 degrees C had no significant effect on blood pressure, increased heart rate, and reduced mesenteric blood flow by 21%. In a separate group of rats, muscimol was microinjected bilaterally (1 nmol/side) into the PVN. Compared with the control group, there was no significant difference in the blood pressure and heart rate responses elicited by the increase in core body temperature. In contrast to control animals, however, mesenteric blood flow did not fall in the muscimol-treated rats in response to the elevation in core body temperature. In a separate group, in which muscimol was microinjected into regions outside the PVN, elevating core body temperature elicited the normal reduction in mesenteric blood flow. The results suggest that the PVN may play a key role in the reflex decrease in mesenteric blood flow elicited by hyperthermia.

Managing elders with comorbidities.

Carle's Medicare Coordinated Care Demonstration care/disease management interventional components, based on the chronic care model, are described for elderly patients in 13 counties in Illinois. Patients enrolled in the program are diagnosed with chronic obstructive pulmonary disease, coronary artery disease, diabetes, atrial fibrillation, or congestive heart failure. Primary care teams are made up of a primary care physician, an advanced practice nurse, a nurse case manager, and a case assistant. The patient/family is the cornerstone of the intervention, which is evaluated using a prospective, longitudinal randomized treatment-control design.