Skin closure with 2-octyl cyanoacrylate and polyester mesh after primary total knee arthroplasty offers superior cosmetic outcomes and patient satisfaction compared to staples: a prospective trial

European Journal of Orthopaedic Surgery & Traumatology - The goals of this study were to compare patient satisfaction and wound-related complications in patients receiving 2-octyl cyanoacrylate...     

Local anesthetics: lipophilicity, charge, diffusion and site of action in isolated neuron

Sodium channel blocking activity was measured in a series of newly synthesized tertiary amine compounds and their quaternary derivatives applied externally on internally in the rat sensory neuron. The large difference in effectiveness of the quaternary compounds on external and or internal application became smaller and even disappeared with increasing lipophilicity of the compounds. No such difference was observed in the tertiary analogs. It was concluded that lipophilicity played an important role in determining the channel blocking activity of externally applied quaternary compounds. The results suggest that, in addition to the neutral form, highly lipophilic amine local anesthetics may penetrate into and/or pass across the neuronal membrane probably as electroneutral ion pair complexes consisting of the cationic form and an appropriate anion. The present results support our hypothesis which stresses, in addition to dissociability, the role of lipophilicity of amine local anesthetics in the pH dependence of their effect.     

In vitro physiological evidence of enhanced antioxidant and neuroprotective action of 2,3-dihydromelatonin, a melatonin analogue.

As the capacity of the endogenous antioxidative system is limited, pharmacological treatment with antioxidants may help to protect neuronal tissue against increased amount of reactive oxygen species produced during oxidative stress. We attempted to improve resistance of rat hippocampal slices exposed to ischaemia in vitro (hypoxia (HYP) accompanied with decreased glucose concentration followed by reoxygenation (ROX)) and thus to diminish the impairment of synaptic transmission after HYP/ROX. We compared the protective features of the melatonin analogue 2,3-dihydromelatonin (2,3-DHM) with melatonin itself. In preliminary experiments, the compound 2,3-DHM compared to melatonin revealed enhanced antilipoperoxidation action in rat brain homogenates exposed to Fe/ascorbate system (-logIC(50) = 4.76 +/- 0.01 versus -logIC(50) = 2.51 +/- 0.02, respectively). In this study, 2,3-DHM (from 0.3 to 10 micromol l(-1)) applied at 30 min before the beginning of HYP and remaining all over the 6-min HYP as well as 20-min ROX, exerted a protective effect demonstrated by improvement of the population spike amplitude (PoS) recovery during ROX, with the maximum effect at 3 micromol l(-1). In accordance with this, the ratio of irreversibly damaged slices after HYP/ROX was decreased in the groups treated with 2,3-DHM. Moreover, a significant delay of PoS decay during HYP (expressed as half time, t(0.5)) was revealed at 2,3-DHM concentration 1 and 3 micromol l(-1)). An equipotent effect of melatonin and 2,3-DHM was achieved by a 100-times lower concentration of the latter (0.3 and 1 micromol l(-1)) compared to that of melatonin (30 and 100 micromol l(-1)). Further, compared to the highest effect of 2,3-DHM in the concentration 3 micromol l(-1) on the percentage of irreversibly damaged slices (only 20%), melatonin did not exert such pronounced effect, either in the concentration 30 or 100 micromol l(-1) (67 and 50%, respectively). We conclude that hydrogenation of the melatonin molecule significantly improved its antihypoxic effect in our model of rat hippocampal slices exposed to ischaemic conditions in vitro, similarly as it enhanced the antilipoperoxidation action of 2,3-DHM in our previous studies. These findings suggest that 2,3-DHM deserves more attention concerning its neuroprotective effect in oxidative stress-associated tissue damage.     

Sympathetic reinnervation after heart transplantation, assessed by iodine-123 metaiodobenzylguanidine imaging, and heart rate variability.

OBJECTIVE: Complete allograft denervation occurs during heart transplantation. Partial ventricular sympathetic reinnervation may develop one year or later after transplantation and can be measured with iodine-123-meta-iodobenziylguanidine (MIBG) uptake. Aim of this study was to assess sinus node sympathetic reinnervation measured with heart rate variability and ventricular sympathetic reinnervation evaluated with MIBG. METHODS: Twelve patients and 14 healthy controls were included. In patients, MIBG scintigraphy with early and late imaging was performed. Heart to mediastinum ratio (HMR) was calculated and patients were divided in groups with (HMR>1.3) and without left ventricular reinnervation (HMR<1.3). Bipolar ECG with high sampling rate and resolution was recorded over 8.5 min in supine position and in upright position after 10 min interval. R-R intervals in time domain and heart rate variability in frequency domain through spectral power analysis of R-R intervals were analysed to evaluate sinus node reinnervation. Spectral power in low frequency range (0.04-0.15 Hz) above 4.5 ms(2) was considered as sinus node sympathetic reinnervation. RESULTS: Six (50%) patients had evidence of left ventricular sympathetic reinnervation on scintigraphy. Sinus node sympathetic reinnervation based on heart rate variability was detected in 6 (50%) patients in supine, and in 4 (33%) patients in upright body position. Four patients groups were discerned: (1) with ventricular and sinus node sympathetic reinnervation, (2) with sinus node sympathetic reinnervation, (3) with ventricular sympathetic reinnervation and (4) without atrial or ventricular sympathetic reinnervation. Ventricular reinnervation process was time dependent and sinus node reinnervation was not. CONCLUSIONS: Simultaneous ventricular sympathetic reinnervation assessed by MIBG and sinus node sympathetic reinnervation assessed by heart rate variability in supine as in upright position were detected only in two patients (17%). The results of our study show that eventual sinus node sympathetic reinnervation and left ventricular sympathetic reinnervation do not occur simultaneously.     

pH dependence of the blocking activity of carbisocaine and its derivatives

The blocking activity and pH dependence of carbanilate local anaesthetics, carbisocaine and its homologues, were tested on isolated rat sciatic nerves at pH 6.0, 7.2 and 8.4. Carbisocaine blocked the compound action potential more strongly than the derivatives with shorter alkoxysubstituents. The blocking potency of shorter derivatives increased with the rise of external medium pH, whereas the activity of carbisocaine increased with decreasing external pH. Quaternary compounds applied in the external medium were able to block the action potential, but in higher concentrations and with a longer half-time than their tertiary analogues. The blocking potency of quaternary derivatives correlated well with the length of the alkoxysubstituent and thus also with their lipophilicity. Extracellular pH did not consistently change the inhibitory effect of quaternized derivatives. These observations support the view that the lipophilicity of local anaesthetics is one of the possible factors determining their anaesthetic activity and the pH dependence of their effect.     

An HLA-DRB α-helix motif shared by DR11 and DR8 alleles is implicated in the pluriallelic restriction of peptide-specific T-cell lines

The T-cell recognition of HLA-DR-peptide complexes is generally restricted by the polymorphism of the DRB molecules but pluriallelic restriction has been described. The molecular basis of restriction and promiscuity of such peptide-specific responses is poorly understood. We isolated a panel of T-cell lines specific for the tetanus toxin peptide p2 (TT830-843) exhibiting pluriallelic restriction by DR11 and DR8 alleles. Fine restriction specificity of the T-cell lines was examined in functional assays against DR oligotyped APCs expressing different variants of DR11 and DR8 alleles. Our results show that (a) polymorphisms between serologically related alleles are relevant in terms of restriction of the peptide-specific T-cell response; in some instances, a single amino acid substitution can determine the restriction of a T-cell line; (b) different patterns of restriction are not the result of specific differences in DR-p2 binding as p2 peptide binds to all DR11 and DR8 alleles tested (DRB1^* 1101, -1102, -1103, -1104, 110X, -0801, -0802, -0803, and -0806); and (c) pluriallelic restriction of the peptide-specific T-cell responses correlates with the presence of a DRB1 α-helix motif (67-71-86) shared by some DR11 and DR8 alleles. Possible implications of pluriallelic restriction of peptide-specific T-cell response in autoimmune disorders associated with DR11 and DR8 are discussed.     

GABAergic control of the ascending input from the median raphe nucleus to the limbic system

The median raphe nucleus (MRN) is the primary source of serotonergic afferents to the limbic system that are generally considered to suppress hippocampal theta oscillations. GABA receptors are expressed in the MRN by serotonergic and nonserotonergic cells, including GABAergic and glutamatergic neurons. This study investigated the mechanisms by which the fluctuating GABA tone in the MRN leads to induction or suppression of hippocampal theta rhythm. We found that MRN application of the GABA(A) agonist muscimol (0.05-1.0 mM) or GABA(B) agonist baclofen (0.2 mM) by reverse microdialysis had strong theta promoting effects. The GABA(A) antagonist bicuculline infused in low concentrations (0.1, 0.2 mM) eliminated theta rhythm. A short period of theta activity of higher than normal frequency preceded hippocampal desynchronization in 46% of rats. Bicuculline in larger concentrations (0.5, 1.0, 2.0 mM) resulted in a biphasic response of an initial short (<10 min) hippocampal desynchronization followed by stable theta rhythm that lasted as long as the infusion continued. The frequency and amplitude of theta waves were higher than in control recordings and the oscillations showed a conspicuous intermittent character. Hippocampal theta rhythm elicited by MRN administration of bicuculline could be completely (0.5 mM bicuculline) or partially (1.0 mM bicuculline) blocked by simultaneous infusion of the GABA(B) antagonist CGP35348. Our findings suggest that the GABAergic network may have two opposing functions in the MRN: relieving the theta-generators from serotonergic inhibition and regulating the activity of a theta-promoting circuitry by the fluctuating GABA tone. The two mechanisms may be involved in different functions.     

Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease

It is unresolved whether elevated homocysteine in coronary artery disease (CAD) is the cause of arteriosclerosis or its consequence. In contrast, genetic variants of enzymes that metabolize homocysteine cannot be altered by arteriosclerosis. Consequently, their association with CAD would permit to imply causality. We modeled by regression analysis the effect of 11 variants in the methionine cycle upon CAD manifestation in 591 controls and 278 CAD patients. Among the examined variants only the carriership for the c.844ins68 in the cystathionine beta-synthase (CBS) gene was associated with a significantly lowered risk of CAD (OR=0.56; 95% CI=0.35-0.90 in the univariable, and OR=0.41, 95% CI=0.19-0.89 for obese people in the multivariable analysis, respectively). Healthy carriers of the c.844ins68 variant exhibited, compared to the wild type controls, significantly higher postload ratios of blood S-adenosylmethionine to S-adenosylhomocysteine (61.4 vs. 54.9, p=0.001) and of plasma total cysteine to homocysteine (8.6 vs. 7.3, p=0.004). The changes in these metabolites are compatible with an improved methylation status and with enhanced activity of homocysteine transsulfuration. In conclusion, the coincidence of clinical and biochemical effects of a common c.844ins68 CBS variant supports the hypothesis that compounds relating to homocysteine metabolism may play role in the development and/or progression of CAD.