Effective and safe therapy with coenzyme Q10 for cardiomyopathy

Summary Coenzyme Q₁₀ (CoQ₁₀) is indispensable in mitochondrial bioenergetics and for human life to exist. 88/115 patients completed a trial of therapy with CoQ₁₀ for cardiomyopathy. Patients were selected on the basis of clinical criteria,X-rays, electrocardiograms, echocardiography, and coronary angiography. Responses were monitored by ejection fractions, cardiac output, and improvements in functional classifications (NYHA). Of the 88 patients 75%–85% showed statistically significant increases in two monitored cardiac parameters. Patients with the lowest ejection fractions (approx. 10%–30%) showed the highest increases (115%–210%) and those with higher ejection fractions (50%–80%) showed increases of approx. 10%–25% on therapy. By functional classification, 17/21 in class IV, 52/62 in class III, and 4/5 in class II improved to lower classes. Clinical responses appeared over variable times, and are presumably based on mechanisms of DNA-RNA-protein synthesis of apoenzymes which restore levels of CoQ₁₀ enzymes in a deficiency state. 10/21 (48%) of patients in class IV, 26/62 (42%) in class III, and 2/5 (40%) in class II had exceptionally low control blood levels of CoQ₁₀. Clinical responses on therapy with CoQ₁₀ appear maximal with blood levels of approx. 2.5 µg CoQ₁₀/ml and higher during therapy.Abbreviations CHF Congestive heart failure - CO Cardiac output - CoQ₁₀ Coenzyme Q₁₀ - EF Ejection fraction - IC Impedance cardiography - NYHA New York Heart Association - STI Systolic time interval     

Role of nitric oxide in interleukin 2-induced corticotropin-releasing factor release from incubated hypothalami.

Stimulation of corticotropin-releasing factor (CRF) release from the hypothalamus by interleukin 2 (IL-2) was recently demonstrated. Cytokines induce nitric oxide synthase (NOS), an enzyme that converts L-arginine into L-citrulline and nitric oxide (NO). NO is believed to be responsible for the cytotoxic action of these agents. The constitutive form of NOS occurs in neurons in the central nervous system and NO appears to play a neurotransmitter role in cerebellar and hippocampal function. We explored the probability that IL-2 and synaptic transmitters might release CRF via NO. The effects of L-arginine, the substrate for NOS, and NG-monomethyl-L-arginine (NMMA), a competitive inhibitor of NOS, on IL-2-induced CRF release were studied using mediobasal hypothalami (MBHs) incubated in vitro in Krebs-Ringer bicarbonate buffer. L-Arginine did not alter basal and IL-2-induced CRF release after 30 min of incubation but significantly elevated both basal and IL-2-induced CRF release when MBHs were incubated 30 min longer, presumably because the endogenous substrate had been depleted after the initial 30-min incubation period. In 30-min incubations, both carbachol, an acetylcholineomimetic drug, and norepinephrine stimulated CRF release. There was an additive effect of incubation of the MBHs in the presence of carbachol (10(-7) M) and IL-2 (10(-13) M). On the other hand, coincubation of MBHs with norepinephrine (10(-6) M) and IL-2 (10(-13) M) did not produce any additive effect. Addition of NMMA, an inhibitor of NOS, at 1 or 3 x 10(-4) M completely suppressed IL-2-induced release of CRF as well as that caused by IL-2 plus carbachol. In contrast, the release of CRF induced by norepinephrine was not blocked by 3 x 10(-4) M NMMA. The data indicate that IL-2 can activate constitutive NOS leading to increased NO release, which activates CRF release. It appears that NO is also involved in the release of CRF induced by carbachol but not by norepinephrine.     

Operative field temperature during transnasal endoscopic cranial base procedures

Background

Data regarding the safety of endoscopic skull base exploration are very scarce. With this method, fragile vital structures (cranial nerves, the optic complex, brainstem, hypothalamus or cerebral ventricles) are exposed to direct illumination within a closed space. Also, high-speed drills, cauterization and ultrasonic aspiration deliver a significant load of thermal energy. The aim of this study was to record the temperature close to the structures of the skull base and in the intradural space during the procedures performed using extended endoscopic transnasal approaches.

Methods

The temperature of the skull base was continuously recorded during six transnasal endoscopic procedures. Implantable copper-constantan thermocouples were inserted: one into the esophagus and another through the nostril to reach the operative field at the skull base.

Results

At the beginning of the procedure, the temperature of the operative field was on average 36.8 °C?±?0.80 °C, i.e. only 1 °C higher than the esophageal temperature. Then it grew continuously during the whole procedure, to eventually reach a level of 42–43 °C at the final stage, whereas the esophageal temperature remained stable. Occasionally, the temperature increased up to 45 °C during cauterization and ultrasonic aspiration, and even up to 62 °C during high-speed drilling.

Conclusion

Endoscopic skull base surgery is associated with an incessant increase of the temperature of the intraoperative field. The temperature can peak suddenly to levels which can potentially harm neural structures and influence the rate of postoperative complications.     

Endoscopic lateral orbitotomy

Background

Lateral orbitotomy can be minimalized using contemporary endoscopy.

Methods

Anatomy of the temporal fossa/orbital wall junction is described. The attachment of the temporal fascia is cut off from the orbital rim through a 1.5 cm skin incision in the lateral orbital wrinkle. The temporal muscle is detached from the bone to create a space for the telescope. An appropriate bone opening in the lateral orbital wall is created with the aid of neuronavigation to handle intraorbital pathology.

Conclusion

Endoscopic lateral orbitotomy is an original alternative to the microsurgical Krönlein approach and yields good functional and cosmetic results.     

Tympanic temperature reflects intracranial temperature changes in humans

The purpose of the study was to identify extracranial locations in which temperature changes in humans reflect those of intracranial temperature in a reliable and repeatable way. This was achieved by subjecting 14 non-anaesthetized patients after neurosurgery to face fanning while intracranial and extracranial temperatures were continuously measured. In all patients the cranium was closed and the group included both febrile and non-febrile as well as hyperthermic and normothermic patients. The patients' faces were fanned for 20-30 min, with a small fan at an air speed of 3.25 m s(-1). This gave intracranial temperature changes measured in the subdural space ( T(sd)) that were highly and significantly correlated ( r=0.91, P<0.05, n=14) with changes in tympanic temperatures ( T(ty)). A low, statistically insignificant correlation ( r=0.40, P>0.05, n=12) was found between T(sd) and oesophageal temperatures. In conclusion, intracranial temperature changes, induced by face fanning, were reliably reflected by the changes in T(ty).     

Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from the hypothalamus.

Nitric oxide (NO), formed by conversion of arginine to citrulline and NO by NO synthase, mediates relaxation of vascular smooth muscle. NO synthase has been demonstrated by immunocytochemical methods in neurons in various parts of the central nervous system including the hypothalamus. The latter finding suggested to us that NO might play a role in controlling the release of hypothalamic peptides. We have previously shown that norepinephrine mediates the release of luteinizing hormone-releasing hormone (LHRH) from LHRH terminals in the median eminence into the hypophyseal portal veins, which transport LHRH to the anterior pituitary gland to trigger release of luteinizing hormone from gonadotrophs. LHRH release from these terminals requires increased release of prostaglandin E2 (PGE2). PGE2 activates adenylate cyclase to produce cAMP, and then cAMP induces the exocytosis of LHRH secretory granules. In view of the evidence above and because of the developing evidence for the importance of NO in the central nervous system, it occurred to us that NO might be involved in this process. Consequently, we evaluated the role of NO in the release of PGE2 from medial basal hypothalamic fragments. As previously reported, norepinephrine (10 microM) increased PGE2 release from the hypothalamic fragments. The inhibitor of NO synthase NG-monomethyl-L-arginine (NMMA, 300 microM) blocked the stimulation of PGE2 release induced by norepinephrine but had no effect on the basal release of PGE2. Sodium nitroprusside (100 microM), which liberates NO, also elevated PGE2 release from the hypothalamic fragments. This elevation was not affected by NMMA, presumably because NMMA blocks enzymatic generation of NO but does not alter NO liberated by nitroprusside. When the NO liberated by nitroprusside was inactivated by hemoglobin (2 micrograms/ml), the effect of nitroprusside on PGE2 release was completely inhibited. Neither NMMA nor hemoglobin altered the basal release of PGE2, which indicates that NO is not responsible for basal PGE2 release. Addition of L-arginine (10 microM to 1 mM), the substrate for NO synthase, had no effect on basal PGE2 production. These results indicate that NO synthase is not activated in unstimulated hypothalamic fragments in vitro. The results suggest that norepinephrine activates NO synthase leading to the production of NO, which subsequently activates cyclooxygenase and results in the production of PGE2. PGE2 then activates adenylate cyclase leading to generation of increased cAMP, which induces exocytosis of secretory granules of LHRH and other neuropeptides released by PGE2. The indication that NO is essential to norepinephrine-induced release of PGE2 from hypothalamic fragments provides insight into the mechanism of LHRH release and the results open the possibility that the importance of NO to neuronal functions may be widespread in the nervous system.