Adolescent growth: genes, hormones and the peer group. Proceedings of the 20th Aschauer Soiree, held at Glücksburg castle, Germany, 15th to 17th November 2013.

The association between poverty, malnutrition, illness and poor socioeconomic conditions on the one side, and poor growth and short adult stature on the other side, is well recognized. Yet, the simple assumption by implication that poor growth and short stature result from poor living conditions, should be questioned. Recent evidence on the impact of the social network on adolescent growth and adult height further challenges the traditional concept of growth being a mirror of health. Twenty-nine scientists met at Glücksburg castle, Northern Germany, November 15th - 17th 2013, to discuss genetic, endocrine, mathematical and psychological aspects and related issues, of child and adolescent growth and final height.

Electronic excited states of a strongly correlated organic radical 1,3,5-trithia-2,4,6-triazapentalenyl (TTTA) adsorbed on a Si(001) surface.

Electronic excited states of a strongly correlated organic radical, 1,3,5-trithia-2,4,6-triazapentalenyl (TTTA), adsorbed on a Si(001) surface were investigated by means of two-photon photoemission spectroscopy (2PPE) to elucidate the functional organic thin-film formation on a typical semiconductor substrate. The spectra were interpreted with the aid of density functional theoretical calculations. The unpaired electron of TTTA forms a covalent bond with the dangling bond of the Si-dimer initially, and there are resonant states of TTTA to Si near the surface. The molecules adsorbed at room temperature form dimers having diamagnetic properties at thicknesses of a few monolayers, while the paramagnetic phase appears at multilayer thickness. From the change in the work function, the orientation of the adsorbed TTTA molecules was determined to change depending on the thickness of the adsorbed layer.

Clinical benefits of precision medicine in treating solid cancers: European Society of Medical Oncology-Magnitude of Clinical Benefit Scale score-based analysis.

BACKGROUND: Precision and matched cancer medicine has the potential to complement the existing biomarker approaches in cancer treatment. However, despite their promising potential, certain negative results have highlighted their limitations in molecular biology-driven treatment strategies. This study aimed to evaluate the clinical benefits of precision therapies. MATERIALS AND METHODS: Three reviewers independently identified and assessed precision and matched cancer treatment studies published between January 2015 and December 2020. Clinical benefits of the treatments included in our cohort were assessed using two established frameworks; the European Society of Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) and the American Society of Clinical Oncology Value Framework. RESULTS: Of the 290 eligible studies, 130 were for lung cancer, 51 for solid tumors, 24 for melanoma, and 24 for breast cancer. The common targets were: epidermal growth factor receptor (N = 66), serine/threonine-protein kinase B-Raf (N = 40), anaplastic lymphoma kinase (ALK) (N = 34), breast cancer protein (N = 26), phosphatidylinositol-3 kinase/protein kinase B/phosphatase and tensin homolog (PI3K/AKT/PTEN) pathway (N = 19), receptor tyrosine-protein kinase erbB-2 (HER2) (N = 19), mitogen-activated protein kinase (RAS/RAF/MAPK) pathway (N = 18), programmed death-ligand 1 (N = 12), fibroblast growth factor receptor (N = 8), and others (N = 43). The ESMO-MCBS scales ranged from 0 to 4. Based on the clinical benefit values, tumor mutational burden/mismatch repair-deficient/microsatellite instability-high for immunotherapy, anaplastic lymphoma kinase, and neurotrophic receptor tyrosine kinase therapeutic targets were considered high, whereas RAS/RAF/MAPK and PI3K/AKT/PTEN were considered low. Additionally, we found a significant difference between each average score (P < 0.001). CONCLUSIONS: This study showed that precision and matched cancer therapies require further improvement. This is consistent with the views of the tumor board and of clinicians that precision strategies need to be revised to improve their therapeutic effects.

Steady state characteristics of acclimated hydrogenotrophic methanogens on inorganic substrate in continuous chemostat reactors.

A Monod model has been used to describe the steady state characteristics of the acclimated mesophilic hydrogenotrophic methanogens in experimental chemostat reactors. The bacteria were fed with mineral salts and specific trace metals and a H(2)/CO(2) supply was used as a single limited substrate. Under steady state conditions, the growth yield (Y(CH4)) reached 11.66 g cells per mmol of H(2)/CO(2) consumed. The daily cells generation average was 5.67 x 10(11), 5.25 x 10(11), 4.2 x 10(11) and 2.1 x 10(11) cells/l-culture for the dilutions 0.071/d, 0.083/d, 0.1/d and 0.125/d, respectively. The maximum specific growth rate (mu(max)) and the Monod half-saturation coefficient (K(S)) were 0.15/d and 0.82 g/L, respectively. Using these results, the reactor performance was simulated. During the steady state, the simulation predicts the dependence of the H(2)/CO(2) concentration (S) and the cell concentration (X) on the dilution rate. The model fitted the experimental data well and was able to yield a maximum methanogenic activity of 0.24 L CH(4)/g VSS.d. The dilution rate was estimated to be 0.1/d. At the dilution rate of 0.14/d, the exponential cells washout was achieved.

Role of phospholipase in the genesis of doxorubicin-induced cardiomyopathy in rats.

The role of phospholipase on the mechanism of doxorubicin-induced cardiomyopathy was investigated in the heart mitochondria of Wistar rats. In the in vivo study, rats were divided into 3 groups: 1, the control group, untreated; 2, the doxorubicin 1-day group, in which doxorubicin (4 mg/kg) was injected s.c. once; and 3, the doxorubicin 4-day group, in which doxorubicin (4 mg/kg) was injected once a day for 4 consecutive days. In each group, the level of lipid peroxides and the phospholipase activity, the phospholipid content, and the enzymic activities in the respiratory chain were measured. The doxorubicin 4-day group showed significant increases of lipid peroxide level and phospholipase activity and an inhibition of mitochondrial respiratory function compared with the control group, while the doxorubicin 1-day group showed no significant difference. In the in vitro study, Experiment 1, intact rat heart mitochondria were incubated with 0.1 unit of phospholipase A2. After the incubation, the enzymic activities of the respiratory chain were disturbed in the same manner as in the in vivo experiment. In Experiment 2, rat heart mitochondria were incubated with ascorbate and ferrous sulfate. The experiment demonstrated the elevation of phospholipase activity associated with lipid peroxidation. These results suggested that the enhanced phospholipase activity caused by lipid peroxidation is responsible for the mechanism of doxorubicin-induced cardiomyopathy.

Donor site selection and clinical outcomes of nipple-areola skin-sparing mastectomy with immediate autologous free flap reconstruction: A single-institution experience.

BACKGROUND: The objective of this study was to examine the clinical outcomes of immediate breast reconstruction using perforator flaps from different donor sites, and to characterize the trends among these flaps. METHODS: We retrospectively reviewed 136 consecutive patients who underwent immediate breast reconstruction using free flaps after skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM). The whole breast was pathologically analyzed in 5-mm sections. Breast reconstruction was performed using the deep inferior epigastric perforator (DIEP) flap, gluteal artery perforator (GAP) flap, and posterior medial thigh perforator (PMTP) flap. Patient characteristics were compared among donor sites. RESULTS: NSM was converted to SSM because of intraoperative subareolar tumor positivity in 7 of 107 patients. Eleven patients had positive margins in permanent sections. All but one patient had a positive horizontal margin in the peripheral direction. The 5-year recurrence-free survival rate was 91.9%. The locoregional recurrence rate was 5.1% with a mean follow-up observation period of 75 months. DEIP, GAP, and PMTP flaps were used in 64 (47.1%), 38 (27.9%), and 34 (25.0%) patients, retrospectively. DIEP flaps were used in older patients and those with a higher body mass index. GAP flaps were used in younger patients. DIEP and GAP flaps were used for larger breasts, and PMTP flaps for smaller breasts. CONCLUSION: NSM or SSM with immediate perforator flap breast reconstruction is an oncologically acceptable surgical option. We believe that age, desire to have children, body mass index, and excised breast volume are valuable factors for selecting the optimal donor site.

Alteration of 1,2-diacylglycerol content in myocardium from diabetic rats.

1,2-Diacylglycerol has been proposed to be a secondary messenger; therefore, in this study we evaluated the amount of 1,2-diacylglycerol in heart tissue from streptozocin-induced diabetic rats and examined the effect of insulin treatment on 1,2-diacylglycerol content. Diabetic rats had lower body and ventricular weights and higher ratios of ventricular to body weight, all of which shifted toward normal values after 4 wk of untreated diabetes followed by 4 wk of insulin treatment. The contents of major phospholipids were significantly depressed in the diabetic rat hearts. In contrast, the triglyceride and cholesterol contents in the myocardium were increased by streptozocin injection and completely normalized by insulin treatment, and glucose levels returned to normal. The 1,2-diacylglycerol content in the myocardium was also significantly elevated in the diabetic rats compared with age-matched controls. Moreover, the 1,2-diacylglycerol content was significantly higher in rats with 4 wk of diabetes than in those with 8 wk of diabetes. Insulin treatment in the diabetic rats, however, did not produce any decrease in 1,2-diacylglycerol content. The results of this study suggest that the development of cardiomyopathy induced by streptozocin injection is associated with a high 1,2-diacylglycerol level, which may result in the activation of protein kinase C. Insulin is one of the agonists that generates 1,2-diacylglycerol in myocytes; however, the relationship between the sustained 1,2-diacylglycerol level and the normalization of diabetes by insulin administration is unclear.

Altered acetylcholine and norepinephrine concentrations in diabetic rat hearts. Role of parasympathetic nervous system in diabetic cardiomyopathy.

The concentrations of acetylcholine (ACh) as a parasympathetic marker and norepinephrine (NE) as a sympathetic marker were investigated in the hearts of rats 2, 4, and 8 wk after the induction of diabetes by an injection of streptozocin (STZ; 65 mg/kg i.v.). ACh and NE were measured by high-performance liquid chromatography with electrochemical detection. Diabetic rats showed low body weight and heart weight at 2, 4, and 8 wk and higher heart-to-body weight ratio and bradycardia at 8 wk, almost all of which were normalized after insulin treatment. Myocardial ACh and NE concentrations in the diabetic rats at 2 and 4 wk were not significantly different from those in age-matched control rats. However, ACh and NE concentrations in the diabetic rats at 8 wk significantly increased compared with the control rats. Diabetic rats at 8 wk also had increased myocardial choline concentration and choline acetyltransferase activity and decreased acetylcholinesterase activity. Insulin treatment normalized all of these changes in the diabetic rats. Thus, in STZ-induced diabetes (STZ-D), the concentrations of both cholinergic and noradrenergic neurotransmitters in the myocardium increased. The results of this study confirm a previously reported increase in sympathetic activity to the heart and also indicate that there is an increase in the synthesis and a decrease in the metabolism of ACh in STZ-D and that adequate insulin treatment normalizes these changes.

Mechanism of cardiac arrhythmias induced by epinephrine in dogs with hypokalemia.

To investigate the mechanism of ventricular arrhythmias induced by epinephrine in dogs with hypokalemia, 30 adult mongrel dogs were separated into a control group (n = 13) and a hypokalemia group (n = 17). In the hypokalemia group, sodium polystyrene sulfonate (5 g/kg body weight) was infused into the colon. In both groups, the serum concentrations of sodium, potassium and calcium were measured every 15 minutes for 60 minutes. The mean (+/- standard deviation) serum potassium level of the hypokalemia group decreased significantly from 3.81 +/- 0.21 to 2.92 +/- 0.36 mEq/liter; there were no significant changes in other electrolytes. After 60 minutes, epinephrine (10 micrograms/kg) was injected intravenously in the hypokalemia and control groups, and the arrhythmia ratio (the number of ventricular ectopic beats divided by the total heart rate) was calculated for 5 minutes. Each group was further classified into subgroups of dogs with an arrhythmia ratio higher or lower than 10%. An arrhythmia ratio over 10% was observed in 7.7% of the control group and 53% of the hypokalemia group. Immediately after 5 minutes of epinephrine injection, myocardial mitochondria and plasma membrane fraction were prepared from each group. Mitochondrial calcium content and phospholipase activity of plasma membrane fraction were determined. Significant increases in both mitochondrial calcium content and phospholipase activity were observed in the dogs with hypokalemia and an arrhythmia ratio greater than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac alpha 1 and beta adrenoceptors in rabbits: effects of dietary sodium and cholesterol.

To investigate the effects of dietary sodium and cholesterol on alpha 1 and beta adrenoceptors in hearts, male Japanese white rabbits were treated with either deoxycorticosterone acetate (DOCA) (50 mg/week sc) plus 1% saline in drinking water, frusemide (10 mg/2 days im), or cholesterol enriched diet (2%, w/w) for eight weeks. Using myocardial membrane preparations, characteristics of alpha 1 and beta adrenoceptors were assessed by a radioligand binding assay using 3H-prazosin and 125I-iodocyanopindolol (125I-CYP) as radioactive ligands respectively. Although the treatment with DOCA and salt induced a small but significant increase in the mean arterial blood pressure, other treatments did not affect blood pressure. None of these interventions affected body weight, ventricular weight, ratio of ventricular weight to body weight, or protein yield of membrane preparations. Neither the number nor the affinity of cardiac alpha 1 adrenoceptors (Bmax 15.1(1.7) fmol X mg protein-1, KD 0.63(0.13) nmol X litre-1 for controls) was affected by any of the treatments given. In contrast to alpha 1 adrenoceptors, the number of beta adrenoceptors (Bmax) decreased significantly from 109.9(9.6) fmol X mg protein-1 for controls to 54.8(5.2) and 52.7(6.9) for rabbits treated with DOCA salt and cholesterol respectively. KD values of beta adrenoceptors for 125I-CYP decreased significantly with cholesterol treatment from 22.5(2.5) to 13.6(2.7) pmol X litre-1. Salt depletion produced by frusemide administration did not affect either the number or the affinity of beta adrenoceptors. These results suggest that changes in the sensitivity of tissues to catecholamines induced by the administration of DOCA salt and cholesterol enriched diet are due to alterations in beta adrenoceptors in the heart.

Mechanism of isoproterenol induced myocardial damage.

To study the harmful effects of isoproterenol on myocardium rats were injected with isoproterenol 10 or 0.1 mg.kg-1 or with isoproterenol 10 mg.kg-1 after an injection of propranolol 20 mg.kg-1. Endogenous phospholipase activity in heart homogenate and tissue adenosine triphosphate concentrations were determined 1, 7, and 15 h after isoproterenol injection. The activities of three segments (NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) of the electron transport chain in heart mitochondria were also measured in the same manner. In the group given isoproterenol 0.1 mg.kg-1 the tissue adenosine triphosphate concentration was decreased after 1 h but returned to control value after 15 h. No significant change in phospholipase activity or in the activities of the three segments in mitochondria was observed throughout the study. In the group given isoproterenol 10 mg.kg-1 the tissue adenosine triphosphate concentration was significantly decreased after 1 h and did not return to control values after 15 h. Phospholipase activity was increased and the activities of NADH-cytochrome c reductase and cytochrome c oxidase were significantly decreased after 15 h. The activity of succinate-cytochrome c reductase was not affected. In the propranolol group, pretreatment with propranolol protected against a reduction in adenosine triphosphate after isoproterenol 10 mg.kg-1. Propranolol also prevented activation of phospholipase and maintained the activities of the three segments of mitochondria throughout the study. In an in vitro study mitochondria prepared from intact rat hearts were incubated with 0.1 unit phospholipase A2.(ABSTRACT TRUNCATED AT 250 WORDS)

Time dependent conversion of creatine kinase MM isoforms in man.

Subforms of creatine kinase MM isoenzyme (isoforms, pI: MMA = 7.95, MMB = 7.76, MMC = 7.54) in human myocardium and serum were quantified by chromatofocusing. Creatine kinase MMA was a dominant isoform (greater than 94% of MM) in normal (n = 3) and in both infarcted and non-infarcted myocardium (n = 2). To investigate isoform conversion in vitro partially purified MMA was incubated with human plasma at 37 degrees C for 24 h (n = 5). Creatine kinase MMB (0%, 47%, 44% of MM at 0, 12, 24 h respectively) and MMC (0%, 22%, 42%) sequentially appeared in incubation media whereas MMA (100%, 31%, 14%) disappeared rapidly with a mean disappearance rate of -0.00169(0.00021)(SD) min-1. Individual differences in conversion velocity were small (SD less than 5%). To investigate isoform conversion in vivo serum isoforms were analysed in patients with acute myocardial infarction (n = 7). MMA was first dominant (A:B:C = 54:34:12%) in the early stage (6-9 h after the onset of chest pain) followed by MMB dominant (19:42:39%) in the middle stage (24-35 h), and MMC dominant (6:22:72%) in the late stage (54-60 h). Changes in isoform proportion were time dependent regardless of serum creatine kinase activity. These findings are consistent with canine isoform conversion reported previously except that in man the velocity of conversion was slower than in the dog. Thus analysis of serum creatine kinase MM isoforms may allow the onset of acute myocardial infarction to be precisely dated. Moreover, determination of MMA, the isoform native to myocardium with a short serum half life, may be useful in the prompt diagnosis of myocardial infarction.

Isoenzyme profiles of creatine kinase, lactate dehydrogenase, and aspartate aminotransferase in the diabetic heart: comparison with hereditary and catecholamine cardiomyopathies.

STUDY OBJECTIVE: The aim was to investigate the redistribution of isoenzymes, clinically important markers of myocardial necrosis, in the diabetic heart and compare it with that investigated in other types of cardiomyopathies. DESIGN: Myocardial isoenzyme activity of creatine kinase (CK), lactate dehydrogenase (LD) and aspartate aminotransferase (AST) was measured in animals with diabetic, hereditary, and catecholamine cardiomyopathies. SUBJECTS: Diabetic rats (4 and 8 weeks after intravenous streptozotocin, n = 21), Bio 14.6 hamsters (30, 90, 160 and 240 days old, n = 29), and rats injected with isoprenaline (0.25, 0.5 and 1.0 mg.kg-1.d-1 for 3 weeks, n = 20) were used. Controls were age matched intact animals (n = 8-11). MEASUREMENTS AND MAIN RESULTS: Total CK and CK MM activity decreased in all groups. CK MB and BB decreased by 62 and 52% in diabetic rats, but increased by 40 and 33% in Bio hamsters and by 9 and 96% in isoprenaline treated rats. Thus the CK-B subunit decreased by 61% in diabetics and increased by 33 and 38% in Bio and isoprenaline groups, while the CK-M subunit decreased in all groups. Mitochondrial CK decreased in diabetic and isoprenaline groups. Total LD activity increased in diabetics and decreased in Bio. LD-H subunit increased by 21% in diabetics and decreased by 19 and 18% in Bio and isoprenaline groups. Accordingly the proportion of LD-M subunit, an index of anaerobic metabolism, decreased in diabetics and increased in Bio and isoprenaline groups. Changes in CK-M and CK-B subunits and the LD-M proportion in diabetic heart were normalised by insulin. Total AST activity decreased in diabetics because of the reduction in mitochondrial AST. CONCLUSIONS: Increased LD-M proportion and CK-B observed in Bio and isoprenaline groups may be a metabolic "compensation" to decreased myocardial perfusion and substrate. Decreased LD-M proportion and CK-B in the diabetic heart was insulin dependent and may indicate either lack of "compensation" to myocardial ischaemia or absence of ischaemia per se. Decreased myocardial CK and CK MB activity possibly causes underestimation of enzymatically assessed infarct size in the diabetic heart.

Prostaglandin I2 analogue and propranolol prevent ischaemia induced mitochondrial dysfunction through the stabilisation of lysosomal membranes.

Leakage of lysosomal enzymes is associated with irreversible cellular damage. To determine the effect of prostaglandin I2 analogue and propranolol on the ischaemic myocardium in relation to changes in lysosomal integrity 26 anaesthetised mongrel dogs were divided into three treatment groups and subjected to 2 h coronary occlusion. In the control group (n = 12) physiological saline was infused throughout the experiment. In the prostaglandin I2 analogue group (n = 7) the prostaglandin I2 analogue, OP-41483-alpha-CD;5(E)-6-Deoxa-6,9 alpha-methylene-15-cyclopentyl-16,17,18,19,20-pentanor-PGI2. alpha-cyclodextrin clathrate (5 ng.kg-1.min-1) was infused from 25 min before occlusion until the end of the experiment. In the propranolol group (n = 7) propranolol (0.3 mg.kg-1) was injected for 10 min 25 min before occlusion. Two hours after occlusion mitochondria were prepared from both ischaemic and non-ischaemic areas in each group and their function measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both non-ischaemic and ischaemic areas was performed and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase; beta-glucuronidase) were measured. In the control group, mitochondrial function in the ischaemic area was reduced compared with that from the non-ischaemic area. The activities of both lysosomal enzymes were increased significantly in the supernatant fraction obtained from the ischaemic area compared with those for the supernatant from the non-ischaemic area. The administration of prostaglandin I2 analogue or propranolol not only prevented the leakage of lysosomal enzymes but also maintained mitochondrial function.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of leukotoxin (9, 10-epoxy-12-octadecenoate) and free fatty acids in dogs.

Leukotoxin (9,10-epoxy-12-octadecenoate) biosynthesised from linoleate by neutrophils is highly toxic to cellular function. Its cardiovascular effects were studied in dogs together with the effects of various fatty acids. Aortic flow, left ventricular peak dP.dt-1, and aortic pressure were measured in 60 anaesthetised dogs, which were divided into 10 groups of six animals each--namely, control group (10 ml of physiological saline), three leukotoxin groups (5, 10, and 50 mg.kg-1), two linoleic acid groups (10 and 50 mg.kg-1), two oleic acid groups (10 and 50 mg.kg-1), and two stearic acid groups (10 and 50 mg.kg-1). Leukotoxin injected intravenously depressed cardiac function in a dose dependent manner. Administration of leukotoxin 5 mg.kg-1 showed no significant cardiotoxic effect. However, 10 mg.kg-1 of leukotoxin significantly decreased aortic flow from 0.74(0.04) to 0.40(0.07) litre.min-1 (mean(SEM], left ventricular peak dP.dt-1 from 2040(205) to 1140(217) mmHg.s-1, and aortic pressure from 106(7.1)/67(6.3) to 75(9.2)/48(6.5) mmHg 5 min after injection. Dogs given leukotoxin 50 mg.kg-1 showed more pronounced cardiodepressive effects; aortic flow was decreased to 0.19(0.06), left ventricular dP.dt-1 to 560(134), and aortic pressure to 72(15.1)/41(10.6) 5 min after injection. All dogs in this group were dead within 45 min. Administration of 10 mg.kg-1 of linoleic acid, oleic acid, or stearic acid caused no significant haemodynamic changes. Administration of linoleic acid 50 mg.kg-1 had cardiotoxic effects, but the effect was less than that of leukotoxin. Since leukotoxin appears to be a potent cardiodepressive agent it may be an important factor in the development of heart failure observed in patients with severe burns.

Disappearance and appearance of isoenzymes of creatine kinase, lactate dehydrogenase and aspartate aminotransferase in the myocardium undergoing infarction.

Recent investigations have shown that cardiac isoenzymes change with mechanical overload and possibly with myocardial ischaemia. This complicates the interpretation of serum enzyme changes in acute myocardial infarction. We have therefore investigated the rate of release of isoenzymes from necrosing myocardium and the effect of ischaemia per se. Discrete myocardial infarction was produced in 35 male Wistar rats by ligation of left coronary artery. Six (n = 7), 12 (n = 6), 24 (n = 9), 72 (n = 7) h and 3 weeks (n = 6) after surgery, total and isoenzyme activities of creatine kinase (CK), lactate dehydrogenase (LD) and aspartate aminotransferase (AST) were measured in the infarcted myocardium. Untreated rats (n = 12) were used as the control (time 0). Sham operation was performed in 36 rats. During the early period (0 to 12 or 24 h) of infarction, each (iso)enzyme disappeared monoexponentially from the myocardium (mean r = 0.88) with different disappearance rates. Cytosolic isoenzyme fractions decreased more rapidly than mitochondrial fractions. CK MB and the LD-H subunit decreased faster than CK MM and the LD-M subunit. Such differences in the disappearance rate may be related to subcellular localisation of each isoenzyme. In the late period (72 h and 3 weeks), CK BB and the LD-M subunit showed significant reaccumulation in the infarcted myocardium. Although inflammatory cells can be responsible for the reaccumulation of LD-M subunit, the origin of CK BB is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical and morphological changes in myocardium during coronary occlusion and reperfusion in canine hearts: effects of propranolol on myocardial damage.

To clarify the mechanism of irreversible myocardial damage, we studied the relationship between ischaemic mitochondrial dysfunction and leakage of lysosomal enzymes, and the effects of propranolol on myocardial damage. Open chest anaesthetised dogs were divided into six groups: 30 min occlusion of the left anterior coronary artery (LAD); 2 h LAD occlusion; 2 h LAD occlusion after premedication with 0.3 mg.kg-1 propranolol; 30 min LAD occlusion/l h reperfusion; 2 h LAD occlusion/l h reperfusion; and 2 h LAD occlusion/l h reperfusion after propranolol premedication. After occlusion or reperfusion, heart mitochondria were prepared from normal and occluded or reperfused areas, and mitochondrial function (rate of oxygen consumption in State III, and respiratory control index) was measured polarographically. Myocardial tissue was fractionated and activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase and beta-glucuronidase) were measured. Electron microscopic studies were performed. Thirty min occlusion induced mitochondrial dysfunction without leakage of lysosomal enzymes. Reperfusion for 1 h reversed these changes. However occlusion for 2 h induced mitochondrial dysfunction associated with the leakage of lysosomal enzymes, and mitochondrial dysfunction was not reversed by 1 h reperfusion. Propranolol reduced mitochondrial dysfunction after 2 h occlusion and prevented leakage of lysosomal enzymes. Mitochondrial function was fairly well maintained after 1 h reperfusion in dogs premedicated with propranolol. Structural changes in mitochondria were observed in the 2 h occlusion/l h reperfusion group, and were reduced by premedication with propranolol. These results suggest that irreversible injury of ischaemic mitochondria is closely linked with instability of lysosomal membranes, and that propranolol prevented irreversible myocardial mitochondrial dysfunction.

Outcomes of immediate perforator flap reconstruction after skin-sparing mastectomy following neoadjuvant chemotherapy.

BACKGROUND: The impact of neoadjuvant chemotherapy (NACT) on immediate free flap breast reconstruction remains controversial. Furthermore, the oncological outcomes of immediate free flap breast reconstruction after skin-sparing mastectomy (SSM) following NACT remain unclear. This study aimed to investigate the surgical complications and oncological outcomes of immediate perforator flap reconstruction after SSM following NACT. METHODS: A total of 201 consecutive patients with indications for immediate perforator flap reconstruction after SSM were included between 2004 and 2012. Surgical and oncological outcomes were compared between patients with and without NACT. RESULTS: There were 38 patients in the NACT group and 163 in the non-NACT control group. The median age of the NACT group was 39.5 years, which was significantly younger than the control group (43.0 years; P < 0.05). Patients in the NACT group also had more advanced and aggressive disease (P < 0.05). There was no significant difference in the frequency of surgical complications between the groups, no difference in the type of complications, and no significant difference in the frequencies of major and minor complications. No patients in the NACT group had delayed adjuvant therapy. Eight patients (4%) developed recurrences, with a median follow-up time of 3.0 years. Local recurrences occurred in three control patients but no patients in the NACT group. CONCLUSION: NACT does not affect short-term or interim outcomes after immediate perforator flap reconstruction and may thus represent a safe and practical treatment option for the multidisciplinary treatment of breast cancer.

Central nervous system-mediated glucagon secretion is enhanced by alpha 2-adrenoreceptor activation.

We assessed the response of the adrenergic receptor in pancreatic glucagon secretion to central nervous system stimulation. Injection of neostigmine (5 x 10(-8) mol) into the third cerebral ventricle in intact rats resulted in increased epinephrine and norepinephrine secretion associated with glucagon secretion. This glucagon secretion was still observed in bilateral adrenalectomized (ADX) rats, although its concentration was significantly lower than that in the intact rats. This glucagon rise was significantly inhibited by ip treatment of ganglionic blocker with hexamethonium. Intraperitoneal injection of alpha-adrenergic receptor antagonist phentolamine (5 x 10(-7) mol), but not of beta-adrenergic receptor antagonist propranolol (1 x 10(-6) mol), reduced the hyperglucagonemic effect of a subsequent neostigmine injection in intact and ADX rats, although these antagonists did not influence epinephrine or norepinephrine secretion in intact rats. In addition, ip injection of the selective alpha 2-receptor antagonist yohimbine (5 x 10(-7) mol), but not of the selective alpha 1-receptor antagonist prazosin (1 x 10(-6) mol), inhibited the neostigmine-induced glucagon secretion in intact and ADX rats. From this evidence it is suggested that central nervous system-mediated glucagon release is enhanced by alpha 2-adrenoreceptor stimulation by either catecholamines or the autonomic nervous system.

Prostaglandin H2 may be the endothelium-derived contracting factor released by acetylcholine in the aorta of the rat.

The present experiment was performed to identify endothelium-derived contracting factor produced by acetylcholine stimulation in the aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The rings of the thoracic aorta were obtained from age-matched SHR and WKY rats, and changes in isometric tension were recorded. The relaxant responses to acetylcholine in the aortic rings from SHR were significantly weaker than those from WKY rats. The relaxant responses to acetylcholine were significantly enhanced by pretreatment with a cyclooxygenase inhibitor (indomethacin) or thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708) in aortic rings from both SHR and WKY rats. A thromboxane A2 synthetase inhibitor (OKY-046) did not affect the acetylcholine-induced relaxation in the aortic rings from SHR or WKY rats. In the organ bath solution, after acetylcholine stimulation, prostaglandin E2 and 6-keto-prostaglandin F1 alpha concentrations increased but not prostaglandin F2 alpha and thromboxane B2 concentrations. Exogenous prostaglandin H2, a stable analogue of thromboxane A2, and prostaglandin F2 alpha induced contractions of the SHR rings at a lower concentration than prostaglandin E2, prostaglandin D2, and prostaglandin I2. These contractile responses to various prostaglandins were markedly inhibited by pretreatment with ONO-3708. A prostacyclin synthetase inhibitor did not affect the relaxant responses to acetylcholine in the SHR rings. These results show that endothelium-derived contracting factor is produced and released by acetylcholine stimulation not only in the aorta of SHR but also in those of WKY rats and suggest that prostaglandin H2, a precursor of the released prostaglandins, is a strong candidate for endothelium-derived contracting factor produced by acetylcholine stimulation.