Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites

Normalization of the increased vascular nitric oxide (NO) generation with low doses of NG-nitro-L-arginine methyl ester (L-NAME) corrects the hemodynamic abnormalities of cirrhotic rats with ascites. We have undertaken this study to investigate the effect of the normalization of vascular NO production, as estimated by aortic cyclic guanosine monophosphate (cGMP) concentration and endothelial nitric oxide synthase (eNOS) protein expression in the aorta and mesenteric artery, on sodium and water excretion. Rats with carbon tetrachloride-induced cirrhosis and ascites were investigated using balance studies. The cirrhotic rats were separated into two groups, one receiving 0.5 mg/kg per day of L-NAME (CIR-NAME) during 7 d, whereas the other group (CIR) was administrated the same volume of vehicle. Two other groups of rats were used as controls, one group treated with L-NAME and another group receiving the same volume of vehicle. Sodium and water excretion was measured on days 0 and 7. On day 8, blood samples were collected for electrolyte and hormone measurements, and aorta and mesenteric arteries were harvested for cGMP determination and nitric oxide synthase (NOS) immunoblotting. Aortic cGMP and eNOS protein expression in the aorta and mesenteric artery were increased in CIR as compared with CIR-NAME. Both cirrhotic groups had a similar decrease in sodium excretion on day 0 (0.7 versus 0.6 mmol per day, NS) and a positive sodium balance (+0.9 versus +1.2 mmol per day, NS). On day 7, CIR-NAME rats had an increase in sodium excretion as compared with the CIR rats (sodium excretion: 2.4 versus 0.7 mmol per day, P < 0.001) and a negative sodium balance (-0.5 versus +0.8 mmol per day, P < 0.001). The excretion of a water load was also increased after L-NAME administration (from 28+/-5% to 65+/-7, P < 0.05). Plasma renin activity, aldosterone and arginine vasopressin were also significantly decreased in the CIR-NAME, as compared with the CIR rats. The results thus indicate that normalization of aortic cGMP and eNOS protein expression in vascular tissue is associated with increased sodium and water excretion in cirrhotic rats with ascites.

mTOR Inhibition and the Tumor Vasculature

Abstract: Blocking tumor growth by targeting the tumor vasculature is a promising approach in cancer therapy. Both, disrupting tumor vessels as well as normalization of tumor vessel abnormalities have shown anti-cancer efficacy. A plethora of agents that act on the tumor vasculature have been developed; however, so far few have shown clinical benefits. Among the successful agents, inhibitors of the mammalian target of rapamycin (mTOR) are able to reduce tumor growth by targeting tumor vessels. mTOR inhibition exerts at least three different effects on the tumor vasculature. First, it reduces tumor angiogenesis. Second it normalizes the tumor vasculature and third, it promotes the formation of thrombosis in tumor vessels. The characterization of the molecular functions regulated by mTOR and of relevance to the tumor vasculature is therefore important in order to further identify biological mechanisms involved in the tumor vascular network as well as to improve the efficacy of these inhibitors. Here, we will first enumerate the evidences for the anti-angiogenic activities of mTOR inhibitors and describe the molecular mechanisms involved. We will further analyze the effects of mTOR inhibition on vascular normalization and also describe how mTOR inhibition promotes thrombosis formation specifically in tumor vessels. Finally, we will describe a new generation of mTOR inhibitors and examine their effects on the tumor vasculature

Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway.

Tissue protein hypercatabolism (TPH) is a most important feature in cancer cachexia, particularly with regard to the skeletal muscle. The rat ascites hepatoma Yoshida AH-130 is a very suitable model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle waste mainly due to TPH (Tessitore, L., G. Bonelli, and F. M. Baccino. 1987. Biochem. J. 241:153-159). Detectable plasma levels of tumor necrosis factor-alpha associated with marked perturbations in the hormonal homeostasis have been shown to concur in forcing metabolism into a catabolic setting (Tessitore, L., P. Costelli, and F. M. Baccino. 1993. Br. J. Cancer. 67:15-23). The present study was directed to investigate if beta 2-adrenergic agonists, which are known to favor skeletal muscle hypertrophy, could effectively antagonize the enhanced muscle protein breakdown in this cancer cachexia model. One such agent, i.e., clenbuterol, indeed largely prevented skeletal muscle waste in AH-130-bearing rats by restoring protein degradative rates close to control values. This normalization of protein breakdown rates was achieved through a decrease of the hyperactivation of the ATP-ubiquitin-dependent proteolytic pathway, as previously demonstrated in our laboratory (Llovera, M., C. García-Martínez, N. Agell, M. Marzábal, F. J. López-Soriano, and J. M. Argilés. 1994. FEBS (Fed. Eur. Biochem. Soc.) Lett. 338:311-318). By contrast, the drug did not exert any measurable effect on various parenchymal organs, nor did it modify the plasma level of corticosterone and insulin, which were increased and decreased, respectively, in the tumor hosts. The present data give new insights into the mechanisms by which clenbuterol exerts its preventive effect on muscle protein waste and seem to warrant the implementation of experimental protocols involving the use of clenbuterol or alike drugs in the treatment of pathological states involving TPH, particularly in skeletal muscle and heart, such as in the present model of cancer cachexia.

Proof of concept for microarray-based detection of DNA-binding oncogenes in cell extracts.

The function of DNA-binding proteins is controlled not just by their abundance, but mainly at the level of their activity in terms of their interactions with DNA and protein targets. Moreover, the affinity of such transcription factors to their target sequences is often controlled by co-factors and/or modifications that are not easily assessed from biological samples. Here, we describe a scalable method for monitoring protein-DNA interactions on a microarray surface. This approach was designed to determine the DNA-binding activity of proteins in crude cell extracts, complementing conventional expression profiling arrays. Enzymatic labeling of DNA enables direct normalization of the protein binding to the microarray, allowing the estimation of relative binding affinities. Using DNA sequences covering a range of affinities, we show that the new microarray-based method yields binding strength estimates similar to low-throughput gel mobility-shift assays. The microarray is also of high sensitivity, as it allows the detection of a rare DNA-binding protein from breast cancer cells, the human tumor suppressor AP-2. This approach thus mediates precise and robust assessment of the activity of DNA-binding proteins and takes present DNA-binding assays to a high throughput level.

Probe-specific mixed-model approach to detect copy number differences using multiplex ligation-dependent probe amplification (MLPA)

Background: MLPA method is a potentially useful semi-quantitative method to detect copy number alterations in targeted regions. In this paper, we propose a method for the normalization procedure based on a non-linear mixed-model, as well as a new approach for determining the statistical significance of altered probes based on linear mixed-model. This method establishes a threshold by using different tolerance intervals that accommodates the specific random error variability observed in each test sample.Results: Through simulation studies we have shown that our proposed method outperforms two existing methods that are based on simple threshold rules or iterative regression. We have illustrated the method using a controlled MLPA assay in which targeted regions are variable in copy number in individuals suffering from different disorders such as Prader-Willi, DiGeorge or Autism showing the best performace.Conclusion: Using the proposed mixed-model, we are able to determine thresholds to decide whether a region is altered. These threholds are specific for each individual, incorporating experimental variability, resulting in improved sensitivity and specificity as the examples with real data have revealed.

Evaluating bone marrow metastasis of neuroblastoma with iodine-123-MIBG scintigraphy and MRI.

Of 10 patients with neuroblastoma who had both 123I-MIBG scintigraphy and MRI at diagnosis, four presented with bone marrow metastasis that was diagnosed by both imaging modalities and confirmed by bone marrow biopsy and smears. This report focuses on the follow up of the four patients with bone marrow metastasis. MIBG scintigraphy and MRI were concordant in two patients, a case of normalization and a case of relapse in the seventh dorsal vertebra confirmed by surgical biopsy. The last two patients presented a normalized MIBG scan for marrow infiltration after chemotherapy but persistent abnormal MRI signal of several vertebrae, suggesting marrow infiltration, up to 27 mo after the end of chemotherapy in one case. In the second patient, MRI bone marrow aspect returned to normal 4 mo after the end of chemotherapy. Bone marrow biopsy remained negative in these two MIBG-negative patients. These cases suggest that in presence of complete normalization of the MIBG scan after chemotherapy, the persistence of a hypointense signal on bone marrow on T1WI does not necessarily indicate persistence of disease but may be due to delayed normalization. Therefore, attention must be paid to the delay of signal normalization on MRI (which can be as long as more than 2 yr after the end of chemotherapy) in order to avoid false-positive interpretation.

Infective Endocarditis in a Finnish Teaching Hospital. 25 Years of Experience of Adult Patients

Infektiivinen endokardiitti yliopistollisessa keskussairaalassa vuosina 1980-2004 hoidetuilla aikuispotilailla Tausta: Infektiivinen endokardiitti on edelleen vakava sairaus. Huolimatta siitä, että taudin diagnostiikka ja hoito ovat kehittyneet, siihen liittyy edelleen merkittävää sairastuvuutta ja kuolleisuutta. Endokardiitin taudinkuvassa on viime vuosina tapahtunut muutoksia monissa maissa. Tavoitteet: Tutkia endokardiitin kliinista kuvaa ja ennustetta suomalaisessa yliopistosairaalassa vuosina 1980-2004 endokardiitin vuoksi hoidetuilla aikuispotilailla. Aineisto: Osatyössä I endokardiitin todennäköisyyttä analysoitiin 222:lla vuosina 1980-1995 endokardiittiepäilyn vuoksi hoidetulla potilaalla käyttäen apuna sekä Duken että von Reyn diagnostisia kriteereitä. Osatyössä II tutkittiin endokardiittiin liittyviä neurologisia komplikaatioita 218 varmassa tai mahdollisessa endokardiittiepisodissa. Osatyössä III tutkittiin seerumin C-reaktiivisen proteiinin (CRP) käyttökelpoisuutta hoitovasteen arvioinnissa 134:ssä varmaksi luokitellussa endokardiittiepisodissa. Osatyössä IV tutkittiin yleisbakteeri-PCRmenetelmän käyttökelpoisuutta etiologisessa diagnostiikassa 56:lla endokardiittiepäilyn vuoksi leikatulla potilaalla. Osatöissä V ja VI analysoitiin kaikki vuosina 1980-2004 hoidetut 303 endokardiittipotilasta lyhytaikais- ja 1-vuotisennusteen suhteen sekä tutkittiin endokardiitin taudinkuvassa tapahtuneita muutoksia sairaalassamme. Tulokset: Duken kriteerit osoittautuivat von Reyn kriteereitä herkemmiksi endokardiitin diagnostiikassa: 243 tutkitusta episodista 114 luokiteltiin varmoiksi endokardiiteiksi Duken kriteereillä, kun vastaavasti ainoastaan 64 luoteltiin varmoiksi von Reyn kriteereillä (p<0.001). Lisäksi peräti 115 episodissa endokardiitin diagnoosi hylättiin von Reyn kriteereillä, kun diagnoosi hylättiin Duken kriteereillä ainoastaan 37 episodissa (p<0.001). Neurologinen komplikaatio ilmeni ennen mikrobilääkehoidon aloittamista 76 %:ssa episodeja ollen ensimmäinen oire 47 %:ssa. Kuolema oli merkitsevästi yhteydessä neurologisiin komplikaatioihin. Hoitovastetta seurattaessa seerumin CRP:n lasku oli merkitsevästi nopeampaa komplikaatioitta toipuvilla potilailla kuin niillä, joille kehittyi komplikaatioita tai jotka menehtyivät tautiinsa. PCR-tutkimus poistetusta läpästä antoi ainoana menetelmänä etiologisen diagnoosin neljässä tapauksessa (2 stafylokokkilajia, 1 Streptococcus bovis,1 Bartonella quintana), joissa kaikissa mikrobilääkehoito oli ollut käytössä ennen näytteiden ottamista. Koko aineistossa kahden läpän infektio tai neurologisten komplikaatioiden, perifeeristen embolioiden tai sydämen vajaatoiminnan kehittyminen ennustivat sekä sairaalakuolleisuutta että 1-vuotiskuolleisuutta, kun taas ≥65 vuoden ikä ja sydämen ultraäänitutkimuksessa todettu vegetaatio tai Duken luokittelun mukainen pääkriteeri ennustivat kuolemaa vuoden sisällä. Korkea CRP-taso sairaalaan tullessa ennusti sekä sairaalakuolleisuutta että 1-vuotiskuolleisuutta. Huumeiden käyttäjien endokardiitit lisääntyivät tutkimusaikana merkitsevästi (p<0.001). Päätelmät: Tässä työssä vahvistetaan Duken kriteerien käyttökelpoisuus endokardiitin diagnostiikassa. Lisäksi vahvistui käsitys, että nopea diagnoosi ja mikrobilääkehoidon aloittaminen ovat parhaat keinot ehkäistä neurologisia komplikaatioita ja parantaa endokardiittipotilaiden ennustetta. CRP:n normalisoituminen on endokardiittipotilailla hyvän ennusteen merkki. Suoraan läppäkudoksesta tehty PCR-tutkimus on hyödyllinen, kun taudin aiheuttaja on kasvuominaisuuksiltaan vaativa tai potilas on saanut mikrobilääkehoitoa ennen viljelynäytteiden ottamista. Muutamat aiemmissa tutkimuksissa todetut huonon ennusteen merkit ennustavat huonoa ennustetta myös tämän tutkimuksen potilailla. Uutena löydöksenä ilmeni, että korkea CRP-arvo sairaalaan tullessa merkitsee sekä huonoa lyhyt- että pitkäaikaisennustetta. Huumeiden käyttäjien endokardiittien ilmaantuminen on tärkein epidemiologinen muutos 25 vuoden tutkimusaikana.

Canakinumab (Acz885) Relieves Pain And Controls Inflammation Rapidly In Patients With Difficult-To-Treat Gouty Arthritis : Comparison With Triamcinolone Acetonide

Background : Monosodium urate (MSU) crystals stimulate the productionof interleukin-1b (IL-1b), a potent inflammatory cytokine. Targeted IL-1b blockade with canakinumab, a fully human monoclonal anti-IL-1b antibody, is a novel treatment for gouty arthritis. Its effects on pain and inflammation in acute gouty arthritis flares were compared with triamcinolone acetonide (TA). TA has been shown to be effective in the treatment of acute gouty arthritis flares.Methods : This was an 8-week, dose-ranging, multicenter, blinded, active-controlled trial. Patients _18 to _80 years with an acute gouty arthritis flare, refractory to or contraindicated to NSAIDs and/or colchicine were randomized to one subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n¼143) or one intramuscular dose of TA (40 mg; n¼57). Primary outcome was pain intensity at 72 hours post dose on VAS scale (0-100 mm). Secondary outcomes included Creactive protein (CRP), serum amyloid A (SAA), and physician's assessment of tenderness, swelling and erythema of target joint at 72 hours, 7 days, 4 and 8-weeks post dose.Results : 191/200 patients completed the study. Canakinumab showed a statistically significant dose response at 72 hours. The 150mg dose group reached superior pain relief compared to TA group starting from 24 hours as previously reported. At 72 hours post dose, 78% of canakinumab 150mg treated patients achieved _75% and 96% achieved _50% reduction in pain from baseline. In contrast, 45% and 61% of patients treated with TA achieved _75% and _50% pain reduction, respectively. Median CRP/SAA levels were normalized by Day 7 for all canakinumab doses above 10mg and remained below the upper limit of normal [(ULN): CRP 3.0 mg/L; SAA 6.7 mg/L)] for rest of the study. In TA group, median CRP levels remained above the ULN throughout the study while median SAA levels decreased below ULN only 28 days after first dose. At 72 hours post dose, canakinumab 150mg group was 3.2 (95% CI, 1.27-7.89) times more likely to have less joint tenderness and 2.7 (95% CI, 1.09-6.5) times more likely to have less joint swelling than TA group (p<0.05). At 72 hours post dose, erythema disappeared in 74.1% of patients receiving canakinumab150mg and 69.6% of patients receiving TA. At 7 days post dose, erythema was absent in 96.3% of canakinumab 150mg treated patients vs. 83.9% of patients receiving TA. The overall incidence of AEs was similar for canakinumab (41%) and triamcinolone acetonide (42%). Serious AEs (canakinumab treatment groups n¼4, TA n¼1) were not considered treatment-related by investigators. No discontinuationsdue to AEs occurred.Conclusions : Canakinumab 150mg provided superior pain relief compared to TA for acute flares in difficult-to-treat gouty arthritis patients. Canakinumab provided rapid normalization of markers of inflammation accompanied by reduction of clinical signs and symptoms of inflammation.Disclosure statement : U.A., V.M., D.R. and P.S. are shareholders and employees of Novartis Pharma AG. A.P. has received research support from Novartis Pharma AG. N.S. has received research support from and acts as a consultant for Novartis Pharmaceuticals Corporation, has served on advisory boards for Novartis, Takeda, Savient, URL Pharma and Enzyme Rx, and is/has been a member of a speakers' bureau for Takeda. A.S. has received consultancy fees from Novartis Pharma AG, Abbott, Wyeth, UCB, Roche, MSD, Pfizer, Essex and Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Hippocampal atrophy predicts conversion to dementia after STN-DBS in Parkinson's disease.

BACKGROUND: Hippocampal atrophy (HA) is a known predictor of dementia in Alzheimer's disease. HA has been found in advanced Parkinson's disease (PD), but no predicting value has been demonstrated yet. The identification of such a predictor in candidates for subthalamic deep brain stimulation (STN-DBS) would be of value. Our objective was to compare preoperative hippocampal volumes (HV) between PD patients who subsequently converted to dementia (PDD) after STN-DBS and those who did not (PDnD). METHODS: From a cohort of 70 consecutive STN-DBS treated PD patients, 14 converted to dementia over 25.6+/-20.2 months (PDD). They were compared to 14 matched controls (PDnD) who did not convert to dementia after 43.9+/-11.7 months. On the preoperative 3D MPRAGE MRI images, HV and total brain volumes (TBV) were measured by a blinded investigator using manual and automatic segmentation respectively. RESULTS: PDD had smaller preoperative HV than PDnD (1.95+/-0.29 ml; 2.28+/-0.33 ml; p<0.01). This difference reinforced after normalization for TBV (3.28+/-0.48, 3.93+/-0.60; p<0.01). Every 0.1 ml decrease of HV increased the likelihood to develop dementia by 24.6%. A large overlap was found between PD and PDnD HVs, precluding the identification of a cut-off score. CONCLUSIONS: As in Alzheimer's disease, HA may be a predictor of the conversion to dementia in PD. This preoperative predictor suggests that the development of dementia after STN-DBS is related to the disease progression, rather then the procedure. Further studies are needed to define a cut-off score for HA, in order to affine its predictive value for an individual patient.

Iridocyclectomy for neovascular glaucoma caused by proton-beam radiotherapy of pigmented ciliary adenocarcinoma.

PURPOSE: To report neovascular glaucoma after proton-beam radiotherapy of an adenocarcinoma of the pigmented ciliary epithelium and its successful treatment by iridocyclectomy. PATIENT AND METHODS: A 65-year-old man developed neovascular glaucoma 10 months after proton-beam radiotherapy of a small pigmented iridociliary tumour with a clinical differential diagnosis of uveal melanoma or adenocarcinoma. The diagnosis of 'toxic tumour syndrome' was made, and iridocyclectomy performed. RESULTS: Histopathology and immunohistochemistry of the specimen diagnosed an adenocarcinoma of the pigmented ciliary epithelium, with the presence of mitoses suggesting residual viable tumour cells. The rubeosis regressed, with normalization of the intraocular pressure. Phacoemulsification for radiation-induced cataract restored VA to 6/9, which was better than that recorded at initial referral, the patient having longstanding cellophane maculopathy. CONCLUSIONS: Neovascular glaucoma after radiotherapy of a small, pigmented, ciliary body tumour raises the possibility of adenocarcinoma. This 'toxic tumour syndrome' may respond to iridocyclectomy of the irradiated tumour.

Isolated disturbance of written language-acquisition as an initial symptom of epileptic aphasia in a 7-year-old child - a 3-year follow-up-study

A 7-year-old right-handed girl developed partial complex seizures with a left-sided onset. A brief period of post-ictal aphasia of the conduction type was documented before seizure control and complete normalization of oral language were obtained. We also found that she had a history of previous unexplained difficulty with written language acquisition that had occurred prior to the clinically recognized epilepsy and a subsequent loss of this ability. This rapidly improved with control of the epilepsy. The evolution of written language were been followed for 3 years, and continued improvement has occurred with fluctuations related to her epilepsy. This observation adds support to the growing body of data indicating that specific cognitive disturbances can be due to epilepsy in young children. It shows the vulnerability of skills which are in a period of active development, and the possibility that oral/written language can be differentially involved by cerebral dysfunction in the young child.

Pulmonary hypertension complicating isolated atrial septal defect.

Atrial septal defect (ASD) typically is asymptomatic in infancy and early childhood and elective defect closure usually is performed at an age between 4 - 6 years. Severe pulmonary hypertension (PHT) complicating an ASD is seen in adulthood and has only occasionally been reported in small children. A retrospective study was undertaken to evaluate the incidence of severe PHT complicating an isolated ASD and requiring early surgical correction in the fi rst year of life. 355 pediatric patients underwent treatment for an isolated ASD either surgically or by catheter intervention during a 10 year period (1996 - 2006) at two tertiary referral centers. 297 patients had secundum ASD and 58 primum ASD with mild to moderate mitral regurgitation. 8 infants were found with isolated ASD (six with secundum and two with primum ASD) associated with signifi cant PHT, accounting for 2.2% of all ASD patients in our centers. These 8 infants had invasively measured pulmonary artery pressures between 50 and 100% of systemic pressure. Median size of the ASD at the time of surgery was 14mm (7 - 20). They were operated in the fi rst year of life and had complicated postoperative courses requiring specifi c treatment for PHT for up to 16 weeks (median 12) postoperatively. Compared to ASD patients without PHT these infants had prolonged postoperative ICU stay of 5 - 9 days (median 8) and prolonged perioperative overall hospital stay of 8 - 32 days (median 15). Ultimate outcome in all 8 infants was good with persistent normalization of pulmonary pressures during mid-term follow-up of between 8 to 60 months (median 28). All other ASD patients had normal pulmonary pressures and mean age at defect closure was higher being 6.2 years for secundum ASD and 3.2 years for primum ASD. In conclusion, ASD is rarely associated with signifi cant PHT in infancy but then requires early surgery to normalize the prognosis of the patients.

Ambulatory assessment of 3D ground reaction force using plantar pressure distribution.

This study aimed to use the plantar pressure insole for estimating the three-dimensional ground reaction force (GRF) as well as the frictional torque (T(F)) during walking. Eleven subjects, six healthy and five patients with ankle disease participated in the study while wearing pressure insoles during several walking trials on a force-plate. The plantar pressure distribution was analyzed and 10 principal components of 24 regional pressure values with the stance time percentage (STP) were considered for GRF and T(F) estimation. Both linear and non-linear approximators were used for estimating the GRF and T(F) based on two learning strategies using intra-subject and inter-subjects data. The RMS error and the correlation coefficient between the approximators and the actual patterns obtained from force-plate were calculated. Our results showed better performance for non-linear approximation especially when the STP was considered as input. The least errors were observed for vertical force (4%) and anterior-posterior force (7.3%), while the medial-lateral force (11.3%) and frictional torque (14.7%) had higher errors. The result obtained for the patients showed higher error; nevertheless, when the data of the same patient were used for learning, the results were improved and in general slight differences with healthy subjects were observed. In conclusion, this study showed that ambulatory pressure insole with data normalization, an optimal choice of inputs and a well-trained nonlinear mapping function can estimate efficiently the three-dimensional ground reaction force and frictional torque in consecutive gait cycle without requiring a force-plate.

Frequency of severe pulmonary hypertension complicating "isolated" atrial septal defect in infancy.

Atrial septal defects (ASDs) are typically asymptomatic in infancy and early childhood, and elective defect closure is usually performed at ages of 4 to 6 years. Severe pulmonary hypertension (PH) complicating an ASD is seen in adulthood and has only occasionally been reported in small children. A retrospective study was undertaken to evaluate the incidence of severe PH complicating an isolated ASD and requiring early surgical correction. During a 10-year period (1996 to 2006), 355 pediatric patients underwent treatment for isolated ASDs either surgically or by catheter intervention at 2 tertiary referral centers. Two hundred ninety-seven patients had secundum ASDs, and 58 had primum ASDs with mild to moderate mitral regurgitation. Eight infants were found with isolated ASDs (6 with secundum ASDs and 2 with primum ASDs) associated with significant PH, accounting for 2.2% of all patients with ASDs at the centers. These 8 infants had invasively measured pulmonary artery pressures of 50% to 100% of systemic pressure. They were operated in the first year of life and had complicated postoperative courses requiring specific treatment for PH for up to 16 weeks postoperatively. The ultimate outcomes in all 8 infants were good, with persistent normalization of pulmonary pressures during midterm follow-up of up to 60 months (median 28). All other patients with ASDs had normal pulmonary pressures, and the mean age at defect closure was significantly older, at 6.2 years for secundum ASDs and 3.2 years for primum ASDs. In conclusion, ASDs were rarely associated with significant PH in infancy but then required early surgery and were associated with excellent midterm outcomes in these patients.

Stimulus-response curve of human motor nerves: multicenter assessment of various indexes.

The value of various indexes to characterize the stimulus-response curve of human motor nerves was assessed in 40 healthy subjects recruited from four European centers of investigation (Créteil, Lausanne, Liège, Marseille). Stimulus-response curves were established by stimulating the right median and ulnar motor nerves at the wrist, with stimulus durations of 0.05 and 0.5 ms. The following parameters were studied: the threshold intensity of stimulation to obtain 10% (I 10), 50% (I 50), and 90% (I 90) of the maximal compound muscle action potential, the ratios I 10/I 50, I 90/I 50, (I 90 - I 10)/I 10, (I 90-I 50)/I 50, and (I 50 - I 10)/I 10, and the slopes of the stimulus-response curves with or without normalization to I 50. For each parameter, within-center variability and reproducibility (in a test-retest study) were assessed and between-center comparisons were made. For most of the parameters, the results varied significantly within and between the centers. Within the centers, only the ratios I 10/I 50 and I 90/I 50 were found constant and reproducible. Between the centers, the absolute intensity thresholds (I 10, I 50, I 90) and the ratio I 90/I 50 did not show significant differences at stimulus duration of 0.5 ms, whatever the stimulated nerve. The reduced variability and good reproducibility of the ratios I 10/I 50 and I 90/I 50 open perspectives in neurophysiological practice for the use of these indexes of the stimulus-response curve, a rapid and noninvasive test.