Cardiac cycle length variability in ponies at rest and during exercise.

We evaluated cardiac cycle length variability in ponies at rest and during strenuous exercise with and without premedication with atropine. In the absence of premedication, cardiac cycle length at rest was 1,112 +/- 53 ms, the individual cardiac cycle length standard deviation (SDCL) was 75 +/- 23 ms, and the individual cycle length coefficient of variation (CVCL) was 6.32 +/- 1.62. Exercise significantly decreased (P < 0.05) all three indexes (290 +/- 9 ms, 5 +/- 1 ms, and 1.65 +/- 0.20, respectively). Atropine premedication significantly reduced resting cardiac cycle length (685 +/- 46 ms), SDCL (10 +/- 2 ms), and CVCL (1.45 +/- 0.19) compared with nonpremedicated values. Cardiac cycle length was significantly decreased by exercise after atropine premedication, but no statistically significant changes occurred in SDCL or CVCL. Thus, although considerable cardiac cycle length variability exists in nonpremedicated ponies at rest, it is nearly completely abolished by strenuous exercise. The absence of significant differences between the indexes of variability during exercise without premedication, at rest after atropine, and during exercise after atropine indicates that cardiac cycle length variability in the pony is mediated primarily through activity of the parasympathetic system.     

The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype–phenotype correlation

The aim of this study was to assess the natural history of the SCO2 deficiency in relation to the genotype in a cohort of 62 patients with SCO2 mutations (36 this study, 26 previous reports).A novel, milder phenotype (disease onset delayed until one year after birth, nonspecific encephalomyopathy, and 2–4 year survival period) associated with compound heterozygosity of the common p.E140K and a novel p.M177T mutations extends the range of symptoms of the SCO2 deficiency.The prevalence of SCO2 deficiency in Poland is relatively high. A search for SCO2 mutations in patients with histology resembling SMA appears to efficiently improve the detection rate.     

Effect of Anesthesia on Postoperative Pain in Patients after Septoplasty

Doklady Biochemistry and Biophysics - The aim of the study was to assess acute pain syndrome in patients after septoplasty using different tactics of general anesthesia. All patients received local...     

Investigating the cardiac pathology of SCO2‐mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell–derived cardiomyocytes

Mutations in SCO2 are among the most common causes of COX deficiency, resulting in reduced mitochondrial oxidative ATP production capacity, often leading to hypertrophic cardiomyopathy (HCM). To date, none of the recent pertaining reports provide deep understanding of the SCO2 disease pathophysiology. To investigate the cardiac pathology of the disease, we were the first to generate induced pluripotent stem cell (iPSC)‐derived cardiomyocytes (iPSC‐CMs) from SCO2‐mutated patients. For iPSC generation, we reprogrammed skin fibroblasts from two SCO2 patients and healthy controls. The first patient was a compound heterozygote to the common E140K mutation, and the second was homozygote for the less common G193S mutation. iPSC were differentiated into cardiomyocytes through embryoid body (EB) formation. To test the hypothesis that the SCO2 mutation is associated with mitochondrial abnormalities, and intracellular Ca²⁺‐overload resulting in functional derangements and arrhythmias, we investigated in SCO2‐mutated iPSC‐CMs (compared to control cardiomyocytes): (i) the ultrastructural changes; (ii) the inotropic responsiveness to β‐adrenergic stimulation, increased [Ca²⁺]_o and angiotensin‐II (AT‐II); and (iii) the Beat Rate Variability (BRV) characteristics. In support of the hypothesis, we found in the mutated iPSC‐CMs major ultrastructural abnormalities and markedly attenuated response to the inotropic interventions and caffeine, as well as delayed afterdepolarizations (DADs) and increased BRV, suggesting impaired SR Ca²⁺ handling due to attenuated SERCA activity caused by ATP shortage. Our novel results show that iPSC‐CMs are useful for investigating the pathophysiological mechanisms underlying the SCO2 mutation syndrome.     

Localization of follicle-stimulating hormone (FSH) immunoreactivity and hormone receptor mRNA in testicular tissue of infertile men

Testicular biopsies from 82 oligo-or azoospermic male patients were subjected to immunostaining using anti-human FSH antibodies. Histological evaluation showed normal spermatogenesis (nspg) in 7 (FSH: 2.7±0.7), mixed atrophy (ma) in 63 (FSH:5.3±0.5), and bilateral or unilateral Sertoli Cell Only syndrome (SCO) in 12 (FSH:21.7±3.5) patients. For the relationship between FSH values and testicular histology, see Bergmann et al. (1994). FSH immunoreactivity was found exclusively in Sertoli cells and in some interstitial cells. Seminiferous epithelium showing normal or impaired spermatogenesis displayed only weak immunoreactivity compared to intense immunoreaction, i.e. large and numerous vesicles in Sertoli cells of SCO tubules in biopsies showing mixed atrophy or SCO. In addition, h-FSH receptor mRNA was demonstrated by in situ hydridization using biotinylated cDNA antisense oligonucleotides. Hybridization signals were found within the seminiferous epithelium exclusively in Sertoli cell cytoplasm associated with normal spermatogenesis and in epithelia showing different signs of impairment, including SCO. It is concluded that: (1) Sertoli cells are the only cells within the seminiferous epithelium expressing FSH receptors; (2) the accumulation of FSH immunoreactivity in Sertoli cells of SCO tubules appears to be a sign of impaired Sertoli cell function.     

The characteristics of the opioid regulation of the afferent reactions of the stomach and duodenum to the early stages of their acute damage]

Acute cat experiments were conducted to study the effect of naloxone, moradol and dalargin on the formation of afferent reactions of gastroduodenal complex components by registration of cortical and subcortical evoked potentials during electrostimulation of the stomach and duodenum at an early stage of their acute lesion. It is found that agonists and antagonists of opiate receptors prevent the depression of afferentation of gastroduodenal complex components early after acute lesion. It is suggested that the main mechanism underlying the depression of gastric and duodenal afferent reactions at early post-alteration period may be related to activation of intraorganic opioid systems.     

Oral premedication for operations on the face under local anesthesia: a placebo-controlled double-blind trial.

Modern strategies for preventing or controlling pain and anxiety demand a premedication for operations using local anesthesia and for those using sedation or general anesthesia. For optimal patient care, the premedication should be given orally and, with respect to the outpatient basis of the operations, should have a short recovery period. Midazolam, one of the most favored premedications for general anesthesia, has been recommended as a premedication for operations using local anesthesia as well. However, midazolam has only sedative-anxiolytic effects and does not reduce pain sensation, which should be mandatory for operations using local anesthesia. A further requirement is the maintenance of stable hemodynamics for the prevention of postoperative hematomas, especially in the face. For these reasons, another premedication meeting all requirements (anxiolysis, analgesia, and stable hemodynamics) was researched. A randomized, double-blind prospective study was performed from March of 1997 to June of 1998. Five groups totalling 150 patients were included in the study; each group contained 30 patients who had operations performed solely on the face. In the first four groups, the effect of midazolam (0.15 mg/kg(-1)), morphine (0.3 mg/kg(-1)), and clonidine (1.5 microg/kg(-1)) administered orally was compared with a placebo. The fifth group was the control group and received no premedication. To evaluate the effects of the premedications, a corresponding questionnaire was completed independently by the patient and surgeon. With regard to the anxiolytic or analgesic properties of the premedication, 61 percent of the patients preferred pain reduction to anxiety control, and 24 percent of patients preferred reduction of anxiety. The remainder insisted on a reduction of both properties (8 percent) or had no preference (7 percent). Reduction of anxiety was largest in the midazolam and the clonidine groups, but the difference was not significant. The least pain during the application of local anesthesia was experienced by the morphine group (37 percent) and the clonidine group (33 percent), in contrast to the midazolam group (60 percent) (p = 0.04). Morphine and clonidine met the requirements of pain reduction equally well. Nevertheless, considering the rate and intensity of adverse effects with respect to hemodynamic compromises, nausea, and emesis, clonidine is even better suited as an oral premedication for operations on the face using local anesthesia.     

Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency

At least three proteins, COX17p, SCO1p, and its homologue SCO2p are thought to be involved in mitochondrial copper transport to cytochrome-c-oxidase (COX), the terminal enzyme of the respiratory chain. Recently, we and others have shown that mutations in SCO2 are associated with a lethal infantile hypertrophic cardiomyopathy (HCMP) with COX-deficiency. The majority of patients with a similar phenotype were, however, negative for SCO2 mutations, suggesting the other genes as candidates for this disorder. Here we report on the genomic organization of SCO1 and COX17 on human chromosomes 17 and 3 respectively, and the complete sequence analysis of COX17 and SCO1 in 30 patients with COX deficiency. Using a panel of human:mouse-monochromosomal hybrids, the expression of COX17 was specifically restricted to chromosome 3, indicating that the previously reported sequence on chromosome 13 represents a pseudogene. DNA sequence analysis of SCO1 and COX17 in nine patients with severe COX deficiency and fatal HCMP, and in 21 patients with other COX deficiency disorders, did not reveal any pathogenic mutations or polymorphisms. We conclude that neither SCO1 nor COX17 are common causes of COX deficiency disorders.     

Randomised controlled trial and economic evaluation of a chest pain observation unit compared with routine care

Objectives To measure the effectiveness and cost effectiveness of providing care in a chest pain observation unit compared with routine care for patients with acute, undifferentiated chest pain.Design Cluster randomised controlled trial, with 442 days randomised to the chest pain observation unit or routine care, and cost effectiveness analysis from a health service costing perspective.Setting The emergency department at the Northern General Hospital, Sheffield, United Kingdom.Participants 972 patients with acute, undifferentiated chest pain (479 attending on days when care was delivered in the chest pain observation unit, 493 on days of routine care) followed up until six months after initial attendance.Main outcome measures The proportion of participants admitted to hospital, the proportion with acute coronary syndrome sent home inappropriately, major adverse cardiac events over six months, health utility, hospital reattendance and readmission, and costs per patient to the health service.Results Use of a chest pain observation unit reduced the proportion of patients admitted from 54% to 37% (difference 17%, odds ratio 0.50, 95% confidence interval 0.39 to 0.65, P < 0.001) and the proportion discharged with acute coronary syndrome from 14% to 6% (8%, -7% to 23%, P = 0.264). Rates of cardiac event were unchanged. Care in the chest pain observation unit was associated with improved health utility during follow up (0.0137 quality adjusted life years gained, 95% confidence interval 0.0030 to 0.0254, P = 0.022) and a saving of £78 per patient (-£56 to £210, P = 0.252).Conclusions Care in a chest pain observation unit can improve outcomes and may reduce costs to the health service. It seems to be more effective and more cost effective than routine care.     

Effect of nor-trimebutine on neuronal activation induced by a noxious stimulus or an acute colonic inflammation in the rat

Nor-trimebutine is the main metabolite of trimebutine that is used in the treatment of patients with irritable bowel syndrome. Nor-trimebutine has a blocking activity on sodium channels and a potent local anesthetic effect. These properties were used to investigate the effect of nor-trimebutine on spinal neuronal activation induced by models of noxious somato-visceral stimulus and acute colonic inflammation. Nor-trimebutine was administered in rats either subcutaneously 30 min before intraperitoneal administration of acetic acid or intracolonically 30 min before intracolonic infusion of trinitrobenzenesulfonic acid. Abdominal contractions were counted for 1 h as a marker of abdominal pain. c-fos expression was used as a marker of neuronal activation and revealed by immunohistochemistry 1h after intraperitoneal acetic acid injection and 2 h after colonic inflammation. Nor-trimebutine decreased Fos expression in the thoraco-lumbar (peritoneal irritation) and lumbo-sacral (colonic inflammation) spinal cord in laminae I, IIo V, VII and X. This effect was also observed in the sacral parasympathetic nucleus after colonic inflammation. Nor-trimebutine induced a significant decrease of abdominal contractions following intraperitoneal acetic acid injection. These data may explain the effectiveness of trimebutine in the therapy of abdominal pain in the irritable bowel syndrome.     

Acute hand compartment syndromes after closed crush: a reappraisal

Severe crush to the hand is associated with a poor prognosis. The authors investigated the hypothesis that compartment syndrome complicates such injuries. From 1996 to 2000, the authors retrospectively identified 11 patients who, after sustaining a closed crush injury, developed acute hand compartment syndrome. Diagnosis was made on clinical grounds in two patients (the intracompartmental pressure was not measured) and after clinical examination plus measurement of intracompartmental pressure in nine patients. In all cases, the muscle burst out once the fascia was released from the affected compartment. Clinical clues to elicit the diagnoses were massive hand swelling and tenseness to palpation. Classic symptoms, such as excruciating pain, were absent or their intensity was attributed to the trauma event (in six patients). Classic signs such as intrinsic muscle minus position and pain on stretching were absent in six and three patients, respectively. In addition, the latter stretch test could not be properly judged in five more patients because of interference by the associated injuries. None of the patients developed contracture or sequela that could be attributed to compartment syndrome. On the basis of this experience, it was concluded that crush injury does not in itself carry a poor functional prognosis, provided that attention is paid to the often-concomitant compartment syndrome. Elevated subfascial pressure may be present despite the absence of classic signs and symptoms.     

Primary percutaneous coronary angioplasty in patients with acute coronary syndrome and concomitant cancer

The paper gives the results of X-ray surgical treatment in patients with acute coronary syndrome who have been ascertained to have concomitant cancer during their examination. Cancer was found in 11 patients in their medical history and diagnosed in 2 patients during examination after surgical treatment and 1 patient one year after his hospital discharge. The results of combination treatment showed the high efficiency of X-ray surgical treatment for acute coronary syndrome. Recovery of TIMI-III blood flow through the infarct-related coronary artery was achieved in 100% of cases; immediate clinical efficiency was 97.4%. In the concomitant cancer group, the therapeutic efficacy was 100%; there were no complications during X-ray surgery. All the patients from this group were discharged from hospital in a satisfactory state to be followed up by a cardiologist and oncologist for further treatment. The study performed suggests that concomitant cancer is not a contraindication to primary coronary angioplasty in patients with acute coronary syndrome. Primary coronary angioplasty with stenting is a safe effective treatment for acute coronary syndrome in this category of patients.     

Insignificant role of the N-terminal cobalt-binding site of albumin in the assessment of acute coronary syndrome: discrepancy between the albumin cobalt-binding assay and N-terminal-targeted immunoassay

The aim of this study was to evaluate whether the N-terminus of human serum albumin (HSA) has a role in the cobalt binding detected using albumin cobalt-binding (ACB) assay. We compared the results obtained using an enzyme-linked immunosorbent assay (ELISA) for N-terminal-modified HSA with those of a conventional ACB assay in two groups: acute coronary syndrome (n?=?43) and non-ischemic chest pain (n = 39). ACB and cardiac troponin-I levels were higher in the acute coronary syndrome group. No significant correlation between ACB assay and ELISA results was observed in either of the two patient groups. In acute chest pain patients, the N-terminal site of HSA has a negligible or limited role in cobalt binding in the ACB assay.     

The primary structure of the constant part of mu-chain-disease protein BOT

The complete primary structure of the constant part of the mu-chain-disease protein, BOT, was established. It includes the whole CH2, CH3 and CH4 domains. two amino acid changes were found, at positions 309 (Ser leads to Gly) and 333 (Val leads to Gly) (GAL numbering). In two additional monoclonal mu chains (SCO and CO), the same positions showed an amino acid variability. From these data it may be concluded that four types of mu chains exist in the human: (1) GAL type with Ser-309 and Val-333; (2) OU type with Gly-309 and Val-333; (3) SCO type with Ser-309 and Gly-333; (4) BOT/CO type with Gly-309 and Gly-333. The meaning of this molecular polymorphism is discussed.     

Analysis of reported SCO2 gene mutations affecting cytochrome c oxidase activity in various diseases

A large number of mutations have been reported in SCO2 (synthesis of cytochrome c oxidase) gene in association with COX deficiency reported in different diseases such as cardioencephalomyopathy, cardiomyopathy and Leigh syndrome. However, very few of these mutations have been functionally analyzed.SCO2 gene encodes for an essential assembly factor for the formation of cytochrome c oxidase (COX). It is a nuclear encoded protein that helps in transfer of copper ions to COX. This study is an attempt to understand the possible effect of these mutations on the structure and function of SCO2 protein, by using different in silico tools. As per Human Gene Mutation Database, total 11 non synonymous variations have been reported in SCO2 gene. Among these 11 variations, only E140K and R171W are functionally proven to cause COX deficiency. They have been used as controls in this study. The remaining variations were further analyzed using ClustalW, SIFT, PolyPhen-2, GOR4, MuPro and Panther softwares. As compared to the results of the controls, most of these variations were predicted to affect the structure of SCO2 protein and hence, may cause COX dysfunction. Thus, we hypothesize that these variations have the potential to result in a disease phenotype and should be investigated by subsequent functional analyses. This will help in an appropriate diagnosis and management of the wide spectrum of COX deficiency diseases.     

COX19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux

SCO1 and SCO2 are metallochaperones whose principal function is to add two copper ions to the catalytic core of cytochrome c oxidase (COX). However, affected tissues of SCO1 and SCO2 patients exhibit a combined deficiency in COX activity and total copper content, suggesting additional roles for these proteins in the regulation of cellular copper homeostasis. Here we show that both the redox state of the copper-binding cysteines of SCO1 and the abundance of SCO2 correlate with cellular copper content and that these relationships are perturbed by mutations in SCO1 or SCO2, producing a state of apparent copper overload. The copper deficiency in SCO patient fibroblasts is rescued by knockdown of ATP7A, a trans-Golgi, copper-transporting ATPase that traffics to the plasma membrane during copper overload to promote efflux. To investigate how a signal from SCO1 could be relayed to ATP7A, we examined the abundance and subcellular distribution of several soluble COX assembly factors. We found that COX19 partitions between mitochondria and the cytosol in a copper-dependent manner and that its knockdown partially rescues the copper deficiency in patient cells. These results demonstrate that COX19 is necessary for the transduction of a SCO1-dependent mitochondrial redox signal that regulates ATP7A-mediated cellular copper efflux.     

High androgen receptor immunoexpression in human "Sertoli cell only" testis

Our purpose was to evaluate cellular androgen receptor (AR) distribution and intensity of immunostaining in the human azoospermic testis. Thirty six biopsy specimens from azoospermic men were immunostained, using a monoclonal antibody of human AR. The localization and the intensity of AR immunostaining was evaluated in Sertoli Cell Only (SCO) testis (G1, n = 21), in spermatogenesis arrest testis (G2, n = 11) and in histologically normal testis (G3, n = 4). We found an AR immunostaining in Sertoli, peritubular myoid and Leydig cells, but not in germ cells. The intensity of the immunostaining varied substantially between biopsy specimens of different patients. Sertoli and Leydig cells AR immunostaining (score and intensity) in SCO group was higher than in the other groups. For Sertoli cells, the score means of AR immunoreactivity were 20 +/- 2.36, 10.18 +/- 1.0 and 1 +/- 1, for G1, G2 and G3 groups, respectively. For Leydig cells, the score means were 10.24 +/- 1.37, 6 +/- 0.71 and 0, for G1, G2 and G3 groups, respectively. We found significant differences between G1 and G2 (p = 0.0008), between G1 and G3 (p = 1.54 10-7) and G2 and G3 (p = 0.00032). These results suggest that in the testis AR is located exclusively in somatic cells and its expression is higher in SCO syndrome than in normal and in arrest spermatogenesis testes.