Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-kappaB activation and alleviates myocardial ischemia/reperfusion injury.

Acute myocardial infarction (AMI) remains the leading cause of death in developed countries. Although reperfusion of coronary arteries reduces mortality, it is associated with tissue injury. Endothelial P-selectin-mediated infiltration of neutrophils plays a key role in reperfusion injury. However, the mechanism of the P-selectin induction is not known. Here we show that infarct size after ischemia/reperfusion was significantly smaller in mice lacking guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. The decrease was accompanied by decreases in neutrophil infiltration in coronary endothelial P-selectin expression. Pretreatment with HS-142-1, a GC-A antagonist, also decreased infarct size and P-selectin induction in wild-type mice. In cultured endothelial cells, activation of GC-A augmented H2O2-induced P-selectin expression. Furthermore, ischemia/reperfusion-induced activation of NF-kappaB, a transcription factor that is known to promote P-selectin expression, is suppressed in GC-A-deficient mice. These results suggest that inhibition of GC-A alleviates ischemia/reperfusion injury through suppression of NF-kappaB-mediated P-selectin induction. This novel, GC-A-mediated mechanism of ischemia/reperfusion injury may provide the basis for applying GC-A blockade in the clinical treatment of reperfusion injury.

The neuron-restrictive silencer element-neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes.

Induction of the atrial natriuretic peptide (ANP) gene is a common feature of ventricular hypertrophy. A number of cis-acting enhancer elements for several transcriptional activators have been shown to play central roles in the regulation of ANP gene expression, but much less is known about contributions made by transcriptional repressors. The neuron-restrictive silencer element (NRSE), also known as repressor element 1, mediates repression of neuronal gene expression in nonneuronal cells. We found that NRSE, which is located in the 3' untranslated region of the ANP gene, mediated repression of ANP promoter activity in ventricular myocytes and was also involved in the endothelin 1-induced increase in ANP gene transcription. The repression was conferred by a repressor protein, neuron-restrictive silencer factor (NRSF). NRSF associated with the transcriptional corepressor mSin3 and formed a complex with histone deacetylase (HDAC) in ventricular myocytes. Trichostatin A (TSA), a specific HDAC inhibitor, relieved NRSE-mediated repression of ANP promoter activity, and chromatin immunoprecipitation assays revealed the involvement of histone deacetylation in NRSE-mediated repression of ANP gene expression. Furthermore, in myocytes infected with recombinant adenovirus expressing a dominant-negative form of NRSF, the basal level of endogenous ANP gene expression was increased and a TSA-induced increase in ANP gene expression was apparently attenuated, compared with those in myocytes infected with control adenovirus. Our findings show that an NRSE-NRSF system plays a key role in the regulation of ANP gene expression by HDAC in ventricular myocytes and provide a new insight into the role of the NRSE-NRSF system outside the nervous system.

Two cases of endoscopic management of carpal tunnel syndrome in macrodactyly patients.

Some cases of carpal tunnel syndrome in macrodactyly patients have been reported. We performed endoscopic carpal canal release on two unilateral macrodactyly patients suffering from bilateral carpal tunnel syndrome. We measured carpal canal pressure before performing endoscopic surgery using the Universal Subcutaneous Endoscope system to confirm median nerve compression. We diagnosed median nerve compression in each patient due to the high preoperative carpal canal pressure. Carpal canal pressure immediately decreased to within normal range following release of both the flexor retinaculum and the distal holdfast fibres of the flexor retinaculum. One patient recovered to within normal in terms of sensory disturbances and abductor pollicis brevis muscle strength. The other patient showed improvement in terms of sensory disturbance, however, muscle power did not recover because this patient had suffered from carpal tunnel syndrome for ten years. Endoscopic carpal canal release and decompression surgery was effective for carpal tunnel syndrome in both macrodactyly patients.

Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo.

CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines. Intravenous injection of 20 microgram/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-1 injection was not observed. Forced expression of JAB or CIS3, but not other CISs, directly blocked CT-1-induced STAT3 activation in 293 cells. These results suggest that JAB and CIS3 serve as endogenous inhibitors of CT-1-mediated JAK-STAT signaling in the cardiovascular system in vivo.

Carpal tunnel syndrome accompanying radial dysplasia due to thalidomide embryopathy.

We performed endoscopic carpal tunnel release in four hands in three patients suffering from radial dysplasia due to thalidomide embryopathy. Carpal canal pressure measurements results confirmed the diagnoses. All operations were successfully performed and resulted in no complications. Tingling sensation and sensory disturbances of the hands subsided.

Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte interactions during hypertrophy of rat cardiac myocytes in vitro.

BACKGROUND: The mechanism responsible for cardiac hypertrophy is currently conceptualized as having 2 components, mediated by cardiac myocytes and nonmyocytes, respectively. The interaction between myocytes and nonmyocytes via growth factors and/or cytokines plays an important role in the development of cardiac hypertrophy. We found that cardiac myocytes showed hypertrophic changes when cocultured with cardiac nonmyocytes. Cardiotrophin-1 (CT-1), a new member of the interleukin-6 family of cytokines, was identified by its ability to induce hypertrophic response in cardiac myocytes. In this study, we used the in vitro coculture system to examine how CT-1 is involved in the interaction between cardiac myocytes and nonmyocytes during the hypertrophy process. METHODS AND RESULTS: RNase protection assay revealed that CT-1 mRNA levels were 3. 5 times higher in cultured cardiac nonmyocytes than in cultured cardiac myocytes. We developed anti-CT-1 antibodies and found that they significantly inhibited the increased atrial and brain natriuretic peptide secretion and protein synthesis characteristic of hypertrophic changes of myocytes in the coculture. In addition, non-myocyte-conditioned medium rapidly elicited tyrosine phosphorylation of STAT3 and induced an increase in natriuretic peptide secretion and protein synthesis in cultured cardiac myocytes; these effects were partially suppressed by anti-CT-1 antibodies. Finally, the hypertrophic effects of CT-1 and endothelin-1, which we had previously implicated in the hypertrophic activity in the coculture, were additive in cardiac myocytes. CONCLUSIONS: These results show that CT-1 secreted from cardiac nonmyocytes is significantly involved in the hypertrophic changes of cardiac myocytes in the coculture and suggest that CT-1 is an important local regulator in the process of cardiac hypertrophy.

Initial effects of the left ventricular repair by plication may not last long in a rat ischemic cardiomyopathy model.

BACKGROUND: Long term effects of left ventricle (LV) repair surgery (LVR) for ischemic cardiomyopathy are not well understood. METHODS AND RESULTS: Sixty-nine rats developed ischemic cardiomyopathy with large akinetic LV area 4 weeks after the left anterior descending artery was ligated. In a second surgery 4 weeks later, 33 rats underwent LVR by plication of the akinetic LV area (LVR group), and 36 underwent rethoracotomy alone (sham group). No medication was used in either group. All rats survived the second surgery. LV end-diastolic dimension as measured by echocardiography, LV fractional shortening, and the maximal end-systolic pressure-volume relationship (E(max)) as calculated from the data by catheter-tipped manometer and echocardiography improved in the LVR group after the second surgery, but LV end-diastolic dimension and E(max) gradually deteriorated as time passed. LV end-diastolic pressure improved 1 week after LVR but rose significantly 4 weeks after LVR. Brain natriuretic peptide mRNA was lower in the LVR group than in the sham group 1 week after LVR but not 4 weeks postoperatively. CONCLUSIONS: Initial improvement in LV function and neurohormonal status after LVR did not last for 4 weeks in this rat model when untreated medically. The mechanism of deterioration should be elucidated to improve long-term results of LVR.

Endothelial nitric oxide synthase gene is positively associated with essential hypertension.

Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n=458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.

The effects of the selective ROCK inhibitor, Y27632, on ET-1-induced hypertrophic response in neonatal rat cardiac myocytes--possible involvement of Rho/ROCK pathway in cardiac muscle cell hypertrophy.

A small GTPase, Rho, participates in agonist-induced cytoskeletal organization and gene expression in many cell types including cardiac myocytes. However, little is known about the functions of Rho's downstream targets in cardiac myocytes. We examined the role of ROCK, a downstream target of Rho, in ET-1-induced hypertrophic response. Y27632, a selective ROCK inhibitor, inhibited ET-1-induced increases in natriuretic peptide production, cell size, protein synthesis, and myofibrillar organization. In addition, a dominant-negative mutant of p160ROCK suppressed ET-1-induced transcription of the BNP gene. These findings suggest that the Rho/ROCK pathway is an important component of ET-1-induced hypertrophic signals in cardiac myocytes.

A heart-specific increase in cardiotrophin-1 gene expression precedes the establishment of ventricular hypertrophy in genetically hypertensive rats.

OBJECTIVE: Cardiotrophin-1 is a cytokine, a novel member of the interleukin-6 superfamily, which is isolated from mouse embryoid bodies. It is known to bind a gp130/ leukemia inhibitory factor (LIF) receptor heterodimer and to induce myocyte hypertrophy. Accumulating evidence indicates that a gp130 signaling pathway is involved in cardiac development and ventricular hypertrophy. METHODS: In order to elucidate the pathophysiologic significance of cardiotrophin-1 in ventricular hypertrophy associated with hypertension, we examined the level of cardiotrophin-1 mRNA in the ventricle of spontaneously hypertensive rats/Izm stroke-prone (SHRSP/Izm) in neonates, and at 4-, 12- and 20-weeks of age by Northern blot analysis. We also examined the gene expression of LIF by Northern blot and reverse transcription-polymerase chain reaction analyses. RESULTS: No significant difference was observed in the level of cardiotrophin-1 mRNA in the ventricle between SHRSP/ Izm and Wistar-Kyoto/Izm (WKY/Izm) neonates. However, the level of cardiotrophin-1 mRNA in the ventricle was significantly augmented in 4-week-old SHRSP/Izm, which did not yet show overt ventricular hypertrophy, and its augmented expression lasted for the duration of the experimental period. The difference in the level of cardiotrophin-1 mRNA between the two strains was most prominent at the age of 4 weeks. This augmented expression of the cardiotrophin-1 gene was not related to the severity of left ventricular hypertrophy. The level of cardiotrophin-1 mRNA in other organs, including the kidney and lung, showed no significant change with aging and was not different between the two strains. After long-term treatment with lisinopril, levels of cardiotrophin-1 mRNA were not changed, although it morphologically prevented the development of left ventricular hypertrophy. LIF mRNA was not detected in any ventricles examined by Northern blot analysis. CONCLUSIONS: The present study demonstrates that the expression of cardiotrophin-1 mRNA is increased in the early stage of ventricular hypertrophy in SHRSP/Izm and it remains elevated after hypertrophy has been established. However, it is unlikely that cardiotrophin-1 plays a mechanistic role in the development and maintenance of left ventricular hypertrophy in SHRSP/Izm. The present study also suggests that cardiotrophin-1, but not LIF, is a possible candidate for natural ligand of a gp130 signaling pathway in the heart.

Measurement of pressure in the carpal canal before and after endoscopic management of carpal tunnel syndrome.

In forty-six patients who had carpal tunnel syndrome, a technique of continuous infusion, given under local anesthesia and without a pneumatic tourniquet, was used to measure pressures in the carpal canal before and after endoscopic release of the transverse carpal ligament (retinaculum flexorum manus). Pressures were similarly measured in sixteen subjects in a control group. The mean preoperative pressures were significantly higher in the patients who had carpal tunnel syndrome than in the patients in the control group when the pressures were measured under four conditions: with the wrist in the resting position, with active grip, and with maximum passive extension and flexion of the wrist. The mean pressures improved significantly postoperatively and were in the range of values that were found under each condition for the control group. Measurement of pressure in the carpal canal before and after operation may be useful in diagnosing carpal tunnel syndrome and in determining the effectiveness of endoscopic management.

Intraneural median nerve pressure in carpal tunnel syndrome.

In order to determine whether endoscopic carpal tunnel release decompresses the median nerve, we measured the intraneural median nerve pressure pre- and postoperatively in 55 hands. The median nerve pressure was significantly reduced postoperatively.

Complete endoscopic carpal tunnel release in long-term haemodialysis patients.

The roof of the carpal tunnel (or canal) consists of the distal portion of the flexor retinaculum, the flexor retinaculum (or the transverse carpal ligament) and the proximal portion of the flexor retinaculum. We tried to determine which anatomical structures were relevant to complete endoscopic carpal tunnel decompression in long-term haemodialysis patients with carpal tunnel syndrome. Carpal tunnel pressure was measured using the continuous infusion technique before and after endoscopic release of the flexor retinaculum, distal portion of the flexor retinaculum and the proximal portion of the flexor retinaculum respectively in 257 hands. We concluded that release of the distal portion of the flexor retinaculum, in addition to the flexor retinaculum, is essential for complete carpal tunnel decompression in long-term haemodialysis patients.

Complete endoscopic carpal canal decompression.

We made a model of the endoscopic decompression of the carpal canal in clinical cases. The model entailed the release of the transverse carpal ligament, ie, the flexor retinaculum, first; then the transverse fibers: deep layer of the midpalmar fascia or distal portion of the flexor retinaculum; and, finally, release of the forearm fascia. Carpal canal pressure was measured using the continuous infusion technique, and the carpal canal was observed endoscopically at each step. Carpal canal pressure data were analyzed by using the Wilcoxon matched pairs signed-rank test. When the transverse carpal ligament and the transverse fibers were divided, carpal canal pressure was significantly statistically lower than that with release of the transverse carpal ligament alone. We conclude that release of both the transverse carpal ligament and the transverse fibers are essential for complete decompression of the carpal canal in endoscopic surgery.

A new diagnostic provocation test for carpal tunnel syndrome: Okutsu test.

Many authors have reported various clinical provocation tests for diagnosis of carpal tunnel syndrome, however, some tests cannot be administered correctly on patients who suffer from restricted wrist joint movement. We compiled positive rates from a new diagnostic provocation test (Okutsu test) carried out on 3474 hands, and compared them and their success rates with results from other provocation tests performed on these same hands. The Okutsu test positive rate was 72.4%. There were statistical differences between Phalen test (69.8%) and wrist-extension test (60.2%) results. The Okutsu test success rate was 99.9% and there were statistical differences between Phalen test (52.8%) and wrist-extension test (56.8%) results. There were no statistical differences between percussion test at the wrist results in positive rate (71.1%) and in success rate (99.7%). The Okutsu test positive rate is high and it serves as a reliable screening test for clinical diagnosis of carpal tunnel syndrome.

Endoscopic anatomical nerve observation and minimally invasive management of cubital tunnel syndrome.

Experience with the use of the Universal Subcutaneous Endoscope (USE) system in surgical treatment of cubital tunnel syndrome in 35 patients is reported. Patients included in the study had pre- and postoperative clinical and electrophysiological data, and had undergone a minimum follow-up period of 13 months. Mean patient age was 59.5 years and the mean follow-up period was 25.9 months. The operation was performed under local anaesthesia without pneumatic tourniquet and on an out-patient basis. A 1.5 cm portal is made at the cubital tunnel and the USE system is inserted next to the ulnar nerve, first distally and then proximally. The nerve is endoscopically assessed and only the tissue that compresses the nerve is released, in keeping with the principles of minimally invasive treatment. Preoperative tingling sensations disappeared postoperatively in 63% of cases. Pain and sensory disturbance recovered to normal in 92% and 89% of cases, respectively. Abnormal motor nerve conduction velocities improved in 77%. Abductor digiti minimi weakness MMT 0, 1, 2 in 16 hands recovered to MMT 4 or 5 in eight. First-dorsal interosseous weakness in 18 hands recovered to MMT 4 or 5 in seven. There were no complications in this series. The endoscopic approach facilitates inspection of the ulnar nerve so that selective release of the tissue that compresses the nerve can readily be performed. The technique has proven effective in the treatment of cubital tunnel syndrome.

Pre- and postoperative Guyon's canal pressure change in endoscopic carpal tunnel release: correlation with transient postoperative Guyon's canal syndrome.

Perioperative Guyon's canal and carpal canal pressure in one-forearm portal endoscopic carpal tunnel release surgery were measured in resting position and during active power gripping in 66 hands. This was done using the continuous infusion technique with a local anaesthetic and without pneumatic tourniquet. Immediate mean postoperative Guyon's canal and carpal canal pressure decreased in both measurements. During active power gripping, postoperative Guyon's canal pressure was less than 40 mmHg in 61 hands, however, this increased to over 40 mmHg in five hands. In these five hands, Guyon's canal syndrome did not develop. Guyon's canal and carpal canal pressures were only correlated during postoperative active power gripping. It remains unclear whether immediate postoperative Guyon's canal pressure correlates with higher pressures a few days later as reported in cases of transient postoperative Guyon's canal syndrome.

Is complete release of all volar carpal canal structures necessary for complete decompression in endoscopic carpal tunnel release?

This study investigated the need to completely divide the flexor retinaculum to achieve full decompression of the median nerve in the carpal canal, using carpal canal pressure measurements at the mid-point and/or the proximal one-third of the flexor retinaculum to analyse the degree of decompression after release of successive lengths of the flexor retinaculum from the distal hold-fast fibres to its proximal margin. Pressure measurements were taken at each operative step in the resting hand position and during active power gripping. The pressure measurements indicated that decompression of the carpal canal was achieved both at rest and on active gripping after complete division of the flexor retinaculum. However, pressure measurements indicated that complete decompression had not been achieved during active power gripping with the proximal one-third of the flexor retinaculum intact. These results demonstrate the need for complete release of the full length of the flexor retinaculum, including the distal hold-fast fibres.

Results of endoscopic management of carpal-tunnel syndrome in long-term haemodialysis versus idiopathic patients.

The purpose of this paper is to compare the results of our endoscopic management of carpal-tunnel syndrome caused by long-term haemodialysis to that with no apparent cause (idiopathic). We have operated on 551 hands in 370 patients using the Universal Subcutaneous Endoscope system under local anaesthesia without a pneumatic tourniquet on an out-patient basis since 1986. Ninety-six hands in 64 patients who suffered from carpal-tunnel syndrome from long-term haemodialysis and 85 hands in 52 patients who suffered from carpal-tunnel syndrome for no apparent cause were statistically analysed using complete pre- and postoperative electrophysiological and clinical studies for periods of time ranging from over 6 months to 4.8 years (mean 16.9 months). Electrophysiological and clinical results showed that our endoscopic management in long-term haemodialysis patients is effective, safe and yields the same results as in patients who suffered from carpal-tunnel syndrome for no apparent cause.

Endoscopic management of shoulder pain in long-term haemodialysis patients.

In 48 shoulders of 29 patients receiving long-term haemodialysis and complaining of intolerable shoulder pain, endoscopic resection of the coracoacromial ligament was performed under local anaesthesia on an outpatient basis, using the Universal Subcutaneous Endoscope system. Predominant endoscopic findings were proliferation of the subacromial bursae and popping between the coracoacromial ligament and the rotator cuff. Amyloid originating from beta 2 microglobulin (beta 2-M) was demonstrated in 87% of the resected coracoacromial ligaments and 86% of the subacromial bursae. Resection of the coracoacromial ligament relieved the shoulder pain in all patients.