Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria

It is known that a global decrease in food ingestion (dietary restriction, DR) lowers mitochondrial ROS generation (mitROS) and oxidative stress in young immature rats. This seems to be caused by the decreased methionine ingestion of DR animals. This is interesting since isocaloric methionine restriction in the diet (MetR) also increases, like DR, rodent maximum longevity. However, it is not known if old rats maintain the capacity to lower mitROS generation and oxidative stress in response to MetR similarly to young immature animals, and whether MetR implemented at old age can reverse aging-related variations in oxidative stress. In this investigation the effects of aging and 7 weeks of MetR were investigated in liver mitochondria of Wistar rats. MetR implemented at old age decreased mitROS generation, percent free radical leak at the respiratory chain and mtDNA oxidative damage without changing oxygen consumption. Protein oxidation, lipoxidation and glycoxidation increased with age, and MetR in old rats partially or totally reversed these age-related increases. Aging increased the amount of SIRT1, and MetR decreased SIRT1 and TFAM and increased complex IV. No changes were observed in the protein amounts of PGC1, Nrf2, MnSOD, AIF, complexes I, II and III, and in the extent of genomic DNA methylation. In conclusion, treating old rats with isocaloric short-term MetR lowers mitROS production and free radical leak and oxidative damage to mtDNA, and reverses aging-related increases in protein modification. Aged rats maintain the capacity to lower mitochondrial ROS generation and oxidative stress in response to a short-term exposure to restriction of a single dietary substance: methionine.     

Mirabegron for Male Lower Urinary Tract Symptoms

Benign prostatic hyperplasia (BPH) is a common cause of lower urinary tract symptoms (LUTS) in men. Patients with BPH often present with a combination of obstructive and overactive bladder (OAB) symptoms. It is postulated that bladder outlet obstruction (BOO) from BPH results in concomitant OAB symptoms through ischemic induced variations in the response to neurotransmitters of both the detrusor and the urothelium. This altered response leads to the pathologic activation of the micturition reflex, generating sensory dysfunction and involuntary bladder contractions. Alpha-1 adrenoceptor antagonists (alpha-blockers) and 5-alpha reductase inhibitors (5-ARIs) are commonly used to treat the BOO caused by BPH. Anticholinergic agents are frequently used to treat concurrently OAB symptoms caused by the BOO. Unfortunately, anticholinergic medications demonstrate bothersome side effects and a theoretical risk of urinary retention. Basic science and clinical research has led to the development of a new class of pharmaceuticals for the treatment of overactive bladder with diminished risk of urinary retention and lacking many anticholinergic side effects. This novel compound, mirabegron (Mybertriq, Astellas Pharma US, Inc.), is a β₃-adrenoceptor agonist and represents a promising new class of oral agents designed for the treatment of OAB symptoms, with minimal effect on voiding.     

Outcomes following Microvascular Free Tissue Transfer in Reconstructing Skull Base Defects

Objective Successful resection of complex tumors involving the skull base (SB) depends on the ability to reconstruct the resulting defects. The objective of this study was to assess the outcomes of patients undergoing reconstruction after resection of SB tumors with free flaps.Methods From 1995 to 2010 a retrospective review of cases was undertaken. Demographics, histology, surgical management, complications, locoregional control, and survival were analyzed.Results We performed 62 flaps in 57 patients. There was a preponderance of sinonasal malignancies (45%), and most lesions involved the anterior SB (81%). A total of 94% of patients underwent radiotherapy. Reconstruction was undertaken mainly with anterolateral thigh (37%) or radial forearm (34%) flaps. Complications occurred in 17% of patients, and the flap''s success rate was 94%.Conclusion Free flaps are versatile and highly reliable for reconstructing defects resulting from resections of the SB. They should be considered for SB reconstruction of large three-dimensional defects as well as defects involving an irradiated field. Successful reconstruction of the SB can be performed using a small number of highly dependable flaps.     

Perinatal infection and hypoxic-ischemic encephalopathy: a pilot study

Recent studies suggest a synergic effect of infection and hypoxia-ischemia in the causation of perinatal brain damage. We conducted a prospective pilot study on the presence of infection in hypoxic-ischemic encephalopathy (HIE), focusing on neurotropic viruses. Sixteen newborns with HIE were included in the study. There were no confirmed cases of viral infection. There was a case of bacterial early onset sepsis and four cases of suspected sepsis due to clinical and/or analytical signs, but with negative cultures. Our results do not support universal screening for viral infection in cases of HIE.     

Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension

OBJECTIVES: To review the literature on the use of hypertonic saline (HS) in treating cerebral edema and intracranial hypertension. DATA SOURCES: Review of scientific and clinical literature retrieved from a computerized MEDLINE search from January 1965 through November 1999. STUDY SELECTION: Pertinent literature is referenced, including clinical and laboratory investigations, to demonstrate principles and efficacy of treatment with HS in patients with intracranial space-occupying pathology. DATA EXTRACTION: The literature was reviewed to summarize the mechanisms of action, efficacy, adverse effects, systemic effects, and comparisons with standard treatments in both clinical and laboratory settings. DATA SYNTHESIS: HS has an osmotic effect on the brain because of its high tonicity and ability to effectively remain outside the bloodbrain barrier. Numerous animal studies have suggested that fluid resuscitation with HS bolus after hemorrhagic shock prevents the intracranial pressure (ICP) increase that follows resuscitation with standard fluids. There may be a minimal benefit in restoring cerebral blood flow, which is thought to be mitigated through local effects of HS on cerebral microvasculature. In animal models with cerebral injury, the maximum benefit is observed in animals with focal injury associated with vasogenic edema (cryogenic injury). The ICP reduction is seen for < or =2 hrs and may be maintained for longer periods by using a continuous infusion of HS. The ICP reduction is thought to be caused by a reduction in water content in areas of the brain with intact blood-brain barrier such as the nonlesioned hemisphere and cerebellum. Most comparisons with mannitol suggest almost equal efficacy in reducing ICP, but there is a suggestion that mannitol may have a longer duration of action. Human studies published to date reporting on the use of HS in treating cerebral edema and elevated ICP include case reports, case series, and small controlled trials. Results from studies directly comparing HS with standard treatment in regard to safety and efficacy are inconclusive. However, the low frequency of side effects and a definite reduction of ICP observed with use of HS in these studies are very promising. Systemic effects include transient volume expansion, natriuresis, hemodilution, immunomodulation, and improved pulmonary gas exchange. Adverse effects include electrolyte abnormalities, cardiac failure, bleeding diathesis, and phlebitis. Although unproven, a potential for central pontine myelinolysis and rebound intracranial hypertension exists with uncontrolled administration. CONCLUSIONS: HS demonstrates a favorable effect on both systemic hemodynamics and intracranial pressure in both laboratory and clinical settings. Preliminary evidence supports the need for controlled clinical trials evaluating its use as resuscitative fluid in brain-injured patients with hemorrhagic shock, as therapy for intracranial hypertension resistant to standard therapy, as firstline therapy for intracranial hypertension in certain intracranial pathologies, as small volume fluid resuscitation during spinal shock, and as maintenance intravenous fluid in neurocritical care units.