Histone deacetylase inhibitors decrease intra-abdominal adhesions with one intraoperative dose by reducing peritoneal fibrin deposition pathways.

Cassidy MR1, Sherburne AC1, Sheldon HK1, Gainsbury ML1, Heydrick S1, Stucchi AF2.

Author information

Abstract

BACKGROUND:

We previously demonstrated that postoperative peritoneal injury and inflammation contribute to adhesiogenesis. Recent evidence suggests that in addition to their role of interfering with the acetylation status of nuclear histone proteins, histone deacetylase inhibitors (HDACIs) including valproic acid (VPA) can target nonhistone proteins to resolve inflammation and modulate immune cells. We hypothesized that HDACIs could reduce adhesions.

METHODS:

Seventy-two rats underwent laparotomy with creation of 6 peritoneal ischemic buttons to induce adhesions. A single intraperitoneal (IP) dose of 50 mg/kg VPA was administered intraoperatively, whereas controls received vehicle. To evaluate the timing, 25 rats underwent ischemic button creation with either an intraoperative or a delayed IP dose of VPA at 1, 3, or 6 hours postoperatively. On postoperative day 7, adhesions were quantified. To investigate mechanisms, ischemic buttons were created in 24 rats and either VPA or saline was administered in 1 intraoperative dose. At 3 or 24 hours later, peritoneal fluid was collected and fibrinolytic activity measured. Alternatively, button tissue was collected 30 minutes postoperatively to measure tissue factor, fibrinogen, and vascular endothelial growth factor (VEGF) by real-time polymerase chain reaction or Western blot.

RESULTS:

A single intraoperative dose of VPA reduced adhesions by 50% relative to controls (P < .001). Delayed dosing did not reduce adhesions. In operated animals, peritoneal fibrinolytic activity was not different between groups. Tissue factor mRNA was downregulated by 50% (P = .02) and protein by 34% (P < .01) in animals administered VPA versus saline. VPA decreased fibrinogen protein by 56% and VEGF protein by 25% compared with saline (P = .03).

CONCLUSION:

These findings suggest that VPA rapidly reduces the extravasation of key adhesiogenic substrates into the peritoneum. A single, intraoperative intervention provides an ideal dosing strategy and indicates an exciting new role for HDACIs in adhesion prevention.

PMID:: 24239397; [PubMed - indexed for MEDLINE]

Wednesday, August 27, 2008

Everything you always wanted to know about menopause but were afraid (or forgot) to ask...

This article features a broad array of information.
Included as issues are bone density to heavy bleeding, even how it effects your teeth.

Also included:
Signs and symptoms of perimenopause
Signs that you are in perimenopause include:
Irregular menstrual periods.
Less frequent, light menstrual periods.
Heavier menstrual periods than you are used to having.

Symptoms of menopause
Symptoms related to menopause are caused by changing or dropping hormone levels and usually end 1 or 2 years after menopause. Some women continue to have symptoms for 5 or more years afterward. Menopause symptoms include:
Hot flashes.
Sleep disturbances (insomnia).
Emotional changes, such as mood swings or irritability.
A change in sexual interest or response.
Problems with concentration and memory that are linked to sleep loss and fluctuating hormones (not a permanent sign of aging).5
Headaches.
Rapid, irregular heartbeats (heart palpitations).
Generalized itching.
Menopause caused by surgery, chemotherapy, or radiation therapy can cause more severe symptoms than usual.6 Preexisting conditions such as depression, anxiety, sleep problems, or irritability can get worse during the perimenopausal transition.

When to Call a Doctor
During perimenopause or postmenopause, call your health professional about:
Menstrual periods that are unusually heavy, irregular, or prolonged (1½ to 2 times longer than normal).
Bleeding between menstrual periods, when periods have been regular.
Renewed bleeding after having no periods for 6 months or more.
Unexplained bleeding while you are taking hormones.
Perimenopause symptoms, such as insomnia, hot flashes, or mood swings, that aren't responding to home treatment and are interfering with your sleep or daily life.
Vaginal pain or dryness that does not improve with home treatment, or you have signs of a urinary tract infection.
If you have concerns about osteoporosis risk and prevention, talk to your health professional during your next office visit.
For more information, see the topics Abnormal Vaginal Bleeding, Dysfunctional Uterine Bleeding, and Osteoporosis.

Click here for even more!