Temporally Distinct Roles for the Zinc Finger Transcription Factor Sp8 in the Generation and Migration of Dorsal Lateral Ganglionic Eminence (dLGE)-Derived Neuronal Subtypes in the Mouse.

Progenitors in the dorsal lateral ganglionic eminence (dLGE) are known to give rise to olfactory bulb (OB) interneurons and intercalated cells (ITCs) of the amygdala. The dLGE enriched transcription factor Sp8 is required for the normal generation of ITCs as well as OB interneurons, particularly the calretinin (CR)-expressing subtype. In this study, we used a genetic gain-of-function approach in mice to examine the roles Sp8 plays in controlling the development of dLGE-derived neuronal subtypes. Misexpression of Sp8 throughout the ventral telencephalic subventricular zone (SVZ) from early embryonic stages, led to an increased generation of ITCs which was dependent on Tshz1 gene dosage. Additionally, Sp8 misexpression impaired rostral migration of OB interneurons with clusters of CR interneurons seen in the SVZ along with decreased differentiation of calbindin OB interneurons. Sp8 misexpression throughout the ventral telencephalon also reduced ventral LGE neuronal subtypes including striatal projection neurons. Delaying Sp8 misexpression until E14-15 rescued the striatal and amygdala phenotypes but only partially rescued OB interneuron reductions, consistent with an early window of striatal and amygdala neurogenesis and ongoing OB interneuron generation at this late stage. Our results demonstrate critical roles for the timing and neuronal cell-type specificity of Sp8 expression in mouse LGE neurogenesis.

Treatment Effects and Lip Profile Changes Following Surgical Mandibular Advancement Versus Premolar Extractions in Class II Div 1 Malocclusion: A Randomized Controlled Trial.

ABSTRACT: No randomized controlled trial has compared the treatment outcome between surgical mandibular advancement and premolar extractions in class II malocclusion. This 2-arm parallel randomized controlled trial evaluated the treatment effects and lip profile changes in skeletal class II adult patients subjected to bilateral sagittal split ramus osteotomy for mandibular advancement and those treated with premolar extractions. Seventy skeletal class II patients were accessed and forty-six subjects who fulfilled inclusion criteria were distributed randomly into Group CG (patients: 23, mean age: 21.28 ±â€Š2.69 years) and Group SG (patients: 23, mean age: 21.15 ±â€Š2.64 years). Group CG was subjected to extraction of maxillary first premolars and mandibular second premolars followed by implant supported space closure and Group SG was managed by surgical mandibular advancement. Skeletal, dental, and soft-tissue changes were analyzed. The study was single-blinded (statistical analyzer). Groups were closely matched for baseline parameters. In the present trial there was no loss to follow-up. Though overjet and overbite were optimized in both the groups but significant improvement was seen in surgical cases. Group CG demonstrated statistically significant point "A" remodeling, dentoalveolar changes, and increase in nasolabial angle. Group SG exhibited significant sagittal and vertical skeletal improvement and lip position change. Surgical mandibular advancement was found to be a better treatment modality compared to premolars extraction for managing skeletal class II div 1 malocclusion as it permits greater improvement of the profile and skeletal relationship.

Foxo1 is a downstream effector of Isl1 in direct pathway striatal projection neuron development within the embryonic mouse telencephalon.

Recent studies have shown that the LIM-homeodomain transcription factor Isl1 is required for the survival and differentiation of direct pathway striatonigral neurons during embryonic development. The downstream effectors of Isl1 in these processes are presently unknown. We show here that Foxo1, a transcription factor that has been implicated in cell survival, is expressed in striatal projection neurons (SPNs) that derive from the Isl1 lineage (i.e. direct pathway SPNs). Moreover, Isl1 conditional knockouts (cKOs) show a severe loss of Foxo1 expression at E15.5 with a modest recovery by E18.5. Although Foxo1 is enriched in the direct pathway SPNs at embryonic stages, it is expressed in both direct and indirect pathway SPNs at postnatal time points as evidenced by co-localization with EGFP in both Drd1-EGFP and Drd2-EGFP BAC transgenic mice. Foxo1 was not detected in striatal interneurons as marked by the transcription factor Nkx2.1. Conditional knockout of Foxo1 using Dlx5/6-CIE mice results in reduced expression of the SPN marker Darpp-32, as well as in the direct pathway SPN markers Ebf1 and Zfp521 within the embryonic striatum at E15.5. However, this phenotype improves in the conditional mutants by E18.5. Interestingly, the Foxo family members, Foxo3 and Foxo6, remain expressed at late embryonic stages in the Foxo1 cKOs unlike the Isl1 cKOs where Foxo1/3/6 as well as the Foxo1/3 target Bach2 are all reduced. Taken together, these findings suggest that Foxo-regulated pathways are downstream of Isl1 in the survival and/or differentiation of direct pathway SPNs.

The neglected role of relative humidity in the interannual variability of urban malaria in Indian cities.

The rapid pace of urbanization makes it imperative that we better understand the influence of climate forcing on urban malaria transmission. Despite extensive study of temperature effects in vector-borne infections in general, consideration of relative humidity remains limited. With process-based dynamical models informed by almost two decades of monthly surveillance data, we address the role of relative humidity in the interannual variability of epidemic malaria in two semi-arid cities of India. We show a strong and significant effect of humidity during the pre-transmission season on malaria burden in coastal Surat and more arid inland Ahmedabad. Simulations of the climate-driven transmission model with the MLE (Maximum Likelihood Estimates) of the parameters retrospectively capture the observed variability of disease incidence, and also prospectively predict that of 'out-of-fit' cases in more recent years, with high accuracy. Our findings indicate that relative humidity is a critical factor in the spread of urban malaria and potentially other vector-borne epidemics, and that climate change and lack of hydrological planning in cities might jeopardize malaria elimination efforts.

Successful management of primary nontuberculous mycobacterial infection of hepatic allograft following orthotopic liver transplantation for hepatitis C.

Nontuberculous mycobacteria are a rare cause of disease in solid organ and hematopoietic stem cell transplant recipients. The impact of mycobacterial infections in transplant recipients necessitates prompt diagnosis and early initiation of therapy. However, diagnosis remains difficult and there is a lack of specific recommendations for the choice of anti-mycobacterial drugs, duration of therapy, and monitoring of graft function as well as immunosuppression in these patients. Issues involved in the management are illustrated by an index case of hepatic allograft infection due to Mycobacterium avium complex.

Biological properties and growth in SCID mice of a new myelogenous leukemia cell line (KBM-5) derived from chronic myelogenous leukemia cells in the blastic phase.

The establishment and the biological properties of a new leukemic cell line (KBM-5) derived from a patient in the blastic phase of chronic myelogenous leukemia are described. The cells exhibited multiple copies of the Philadelphia chromosome, and a high level of p210Bcr-Abl kinase activity was detected with rabbit anti-Abl and anti-Bcr (exon 3) peptide antisera. Use of specific primers and polymerase chain reaction followed by Southern blotting revealed that KBM-5 cells carried a bcr3-ABLII splice junction. While a normal BCR message was detected, no normal ABL message was found. The cells were phenotypically myeloid with monocytic differentiation. The high cloning efficiency in semisolid media was independent of the presence of exogenous colony-stimulating factors. In vitro exposure to induces of differentiation, such as retinoic acid, dimethyl sulfoxide, or hemin, failed to influence the growth rate of the cells and their level of differentiation. KBM-5 cells are highly resistant to the antiproliferative action of recombinant alpha- and gamma-interferons. Although sensitive to recombinant tumor necrosis factor alpha, they were completely resistant to natural killer cell action. KBM-5 cells constitutively expressed mRNA for tumor necrosis factor alpha but not for gamma-interferon, other interleukins, or hematopoietic growth factors. The KBM-5 cells that were transplanted into SCID mice manifested metastatic potential and tissue invasiveness similar to the way leukemic cells in humans do. This new KBM-5 cell line represents a helpful model for examining in vitro and in vivo modulation of the growth and properties of leukemic cells by using biological and chemotherapeutic agents.

Effect of surgical mandibular advancement on pharyngeal airway dimensions: a three-dimensional computed tomography study.

The aim of this study was to quantify the changes in pharyngeal airway space (PAS) in patients with a skeletal class II malocclusion managed by bilateral sagittal split ramus osteotomy for mandibular advancement, using three-dimensional (3D) registration. The sample comprised 16 patients (mean age 21.69±2.80 years). Preoperative (T0) and postoperative (T1) computed tomography scans were recorded. Linear, cross-sectional area (CSA), and volumetric parameters of the velopharynx, oropharynx, and hypopharynx were evaluated. Parameters were compared with paired samples t-tests. Highly significant changes in dimension were measured in both sagittal and transverse planes (P<0.001). CSA measurements increased significantly between T0 and T1 (P<0.001). A significant increase in PAS volume was found at T1 compared with T0 (P<0.001). The changes in PAS were quantified using 3D reconstruction. Along the sagittal and transverse planes, the greatest increase was seen in the oropharynx (12.16% and 11.50%, respectively), followed by hypopharynx (11.00% and 9.07%) and velopharynx (8.97% and 6.73%). CSA increased by 41.69%, 34.56%, and 28.81% in the oropharynx, hypopharynx, and velopharynx, respectively. The volumetric increase was greatest in the oropharynx (49.79%) and least in the velopharynx (38.92%). These established quantifications may act as a useful guide for clinicians in the field of dental sleep medicine.

Fusion of restriction termini using synthetic adaptor oligonucleotides.

A method is proposed for linking a DNA fragment possessing a 5' single-stranded extension to one carrying a 3' extension. Synthetic oligonucleotide adaptors can be used to (i) change the site specificity at the termini of a fragment generated by restriction enzyme cleavage and (ii) simultaneously dephosphorylate the extremities of a DNA molecule to prevent recircularisation and allow positive selection for recombinant DNA molecules.

Calpain inhibition prevents sinusoidal endothelial cell apoptosis in the cold ischemic rat liver.

BACKGROUND: Cold preservation of the liver followed by reperfusion results in sinusoidal endothelial cell (SEC) apoptosis. Calpain-like activity is dramatically increased during reperfusion and inhibition of calpains results in lower graft injury and longer survival. Recently, calpains have been implicated in inducing apoptosis. Our aim was to determine the effect of calpain inhibition on SEC apoptosis. METHODS: Livers were stored in the University of Wisconsin solution for 24 hr (survival conditions) and 40 hr (nonsurvival conditions) and ex vivo reperfused for 1 hr at 37 degrees C. Calpain-like activity was inhibited in some experiments using an i.p. injection of a selective inhibitor 2 hr before explantation. Apoptosis was quantified using the terminal deoxynucleotidyl trans. ferase-mediated dUTP nick end-labeling assay. Cross-inhibition by the inhibitor was determined for caspases 1 and 3. RESULTS: Apoptosis of exclusively the SEC was a key feature of reperfusion injury after both storage periods in University of Wisconsin solution after 1 hr normothermic reperfusion. Inhibition of calpain activity with Cbz-Val-Phe methyl ester resulted in a 50% reduction of apoptotic SEC in the 40-hr preserved liver, and an almost complete abrogation of SEC apoptosis after 24 hr preservation. Only minimal cross-inhibition of caspases was determined at high concentrations in vitro by the calpain inhibitor. CONCLUSION: Apoptosis of exclusively SEC is a key feature of reperfusion injury partially mediated through calpain-dependent processes. Calpain inhibition reduces the number of apoptotic SEC. Based on these data and our previous work, calpain inhibition may prove to be useful in clinical transplantation.

Endothelial cell and hepatocyte deaths occur by apoptosis after ischemia-reperfusion injury in the rat liver.

BACKGROUND: Ischemic injury of the liver is generally considered to result in necrosis, but it has recently been recognized that mediators of apoptosis are activated during ischemia/reperfusion. This study was designed to characterize the extent and the type of cells within the liver that undergo apoptosis at different periods of ischemia and reperfusion. METHODS: Male Wistar rats were subjected to 30 or 60 min of normothermic ischemia. Liver sections were evaluated at the end of ischemia and at 1, 6, 24, and 72 hr after reperfusion. Apoptosis was determined by DNA fragmentation as evaluated by laddering on gel electrophoresis, in situ staining for apoptotic cells using TdT-mediated dUTP-digoxigenin nick-end labeling (TUNEL), and morphology on electron microscopy. RESULTS: In situ staining of liver biopsy specimens using TUNEL showed significant apoptosis after reperfusion. Sinusoidal endothelial cells (SEC) showed evidence of apoptosis earlier than hepatocytes. For example, at 1 hr of reperfusion after 60 min of ischemia, 22+/-4% of the SEC stained TUNEL positive compared with 2+/-1% of the hepatocytes (P<0.001). With a longer duration of ischemia, a greater number of SEC and hepatocytes became TUNEL positive. An increase in TUNEL-positive cells was also noted with an increasing duration of reperfusion. The presence of apoptotic SEC and hepatocytes was supported by DNA laddering on gel electrophoresis and cell morphology on electron microscopy. Several Kupffer cells were seen containing apoptotic bodies but did not show evidence of apoptosis. Only rare hepatocytes showed features of necrosis after 60 min of ischemia and 6 hr of reperfusion. CONCLUSION: These results suggest that apoptosis of endothelial cells followed by hepatocytes is an important mechanism of cell death after ischemia/reperfusion injury in the liver.

Similar time-dependent recovery property of fast and slow atrioventricular nodal pathways.

The purpose of this study was to determine whether fast and slow atrioventricular (AV) nodal pathways have the same recovery property. AV nodal recovery property is studied by delivering atrial extrastimuli coupled to atrial beats and plotting nodal coupling intervals against nodal conduction time. In patients with dual pathways the resultant curves will include a fast to fast (F-F) and a fast to slow (F-S) pathway coupled curves. Although fast pathway recovery property can be represented by the former, slow pathway recovery property requires further assessment by studying slow to slow (S-S) pathways coupled curve. In 9 patients with dual pathways F-F, F-S, S-F, and S-S curves were obtained by pacing protocols. In 8 patients (control) without dual pathways, F-F curve and atrial extrastimuli coupled to a preceding slowly conducted fast pathway beat (also designated as S-F curve) were obtained. (1) The S-S curve had a similar time constant as the F-F curve. (2) Although the S-S curve was markedly shifted upward and leftward from the F-F curve, the degree of leftward and upward shifts of the S-S curve from the F-F curve were both close to the difference of the basic fast and slow pathway conduction time (a constant). (3) Although the effective refractory period of the fast pathway in dual pathway patients was longer than that of the control patients, the slow pathway effective refractory period when corrected was close to that of fast pathway in control patients. These results suggest that the fast and slow AV nodal pathways have a similar time-dependent recovery property.

Comparison of frequency-distance relationship and Gaussian-diffusion-based methods of compensation for distance-dependent spatial resolution in SPECT imaging.

The goal of this investigation was to compare resolution recovery versus noise level of two methods for compensation of distance-dependent resolution (DDR) in SPECT imaging. The two methods of compensation were restoration filtering based on the frequency-distance relationship (FDR) prior to iterative reconstruction, and modelling DDR in the projector/backprojector pair employed in iterative reconstruction. FDR restoration filtering was computationally faster than modelling the detector response in iterative reconstruction. Using Gaussian diffusion to model the detector response in iterative reconstruction sped up the process by a factor of 2.5 over frequency domain filtering in the projector/backprojector pair. Gaussian diffusion modelling resulted in a better resolution versus noise tradeoff than either FDR restoration filtering or solely modelling attenuation in the projector/backprojector pair of iterative reconstruction. For the pixel size investigated herein (0.317 cm), accounting for DDR in the projector/backprojector pair by Gaussian diffusion, or by applying a blurring function based on the distance from the face of the collimator at each distance, resulted in very similar resolution recovery and slice noise level.

Influence of OSEM, elliptical orbits and background activity on SPECT 3D resolution recovery.

In maximum-likelihood expectation-maximization (MLEM) reconstruction of SPECT images, if both attenuation correction (AC) and detector response correction (DRC) are included, the reconstruction can be too time consuming to be clinically useful. With use of the ordered-subset expectation-maximization (OSEM) reconstruction, it has been reported that the reconstruction time can be substantially reduced. We investigated the reconstruction of point sources in a non-uniform attenuation medium in terms of the normalized FWHM of these sources. We compared MLEM versus OSEM reconstructions; circular versus elliptical orbits; and the presence versus the absence of background activity in the object. We found: (i) that OSEM does speed up the reconstruction by a factor of 10 over MLEM; (ii) that the resolution recovery does not depend on the type of orbit if both AC and DRC are included in the reconstruction; however, when there is background activity, a significant number of iterations are required to alleviate the effect of orbit; (iii) that background activity significantly slows down the resolution recovery of the point sources; and (iv) that if reconstruction only includes AC, and not DRC, changing orbit can change isotropy of recovered resolution, whereas introducing background activity may degrade the recovered resolution and also changes the isotropy.

GATE: a simulation toolkit for PET and SPECT.

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

Cardioprotective effects of diltiazem infusion in the perioperative period.

OBJECTIVE: To evaluate the perioperative effects of intravenous diltiazem infusion on left ventricular functions, hemodynamics and as an anti-ischemic and antiarrhythmic agent in patients undergoing coronary artery bypass grafting (CABG). METHODS: A double blind, randomised study was performed on 71 patients undergoing elective CABG. Infusion of diltiazem (0.1 mg/kg per h, n = 34) or nitroglycerin (1 microgram/kg per min, n = 37) was given for 24 h starting from onset of cardiopulmonary bypass. Holter monitoring, electrocardiogram and serum cardiac enzymes levels were used to diagnose myocardial ischemia. Myocardial function was assessed by perioperative transesophageal echocardiography. RESULTS: The two groups did not differ with respect to preoperative and operative data. Diltiazem had no influence on hemodynamic parameters except for significant reduction in post operative heart rate and pulse pressure rate. Transient ischemic events (dilitiazem 10.2% versus nitroglycerin 33.3%, P = 0.15) and transient coronary spasm (diltiazem-6.8% versus nitroglycerin 25.9%, P = 0.15) were reduced in the diltiazem group as compared with the nitroglycerin group. The postoperative incidence of atrial fibrillation (diltiazem 3% versus nitroglycerin 22%, P = 0.03), supra ventricular tachycardia (diltiazem-3% versus nitroglycerin-22%, P = 0.03) and average ventricular premature contraction per h (diltiazem-40.2 +/- 10.2 versus nitroglycerin 53.8 +/- 12.3, P < 0.01) were significantly lower in the diltiazem group. Transesophageal echocardiography showed no significant difference in left ventricular functions and better preservation of left ventricular diastolic functions in post cardiopulmonary bypass period in diltiazem group. In addition mean deceleration time for the E wave on a 12 h post cardiopulmonary bypass period was significantly lower in the diltiazem group as compared with nitroglycerin (diltiazem 131 +/- 6 versus nitroglycerin 171 +/- 6, P < 0.01). CONCLUSION: The present study demonstrates that diltiazem infusion provides superior anti-ischemic protection and control of supraventricular arrhythmias as compared to nitroglycerin and does not produce any negative inotropic effect, as demonstrated by transesophageal echocardiography.

Significantly reduced incidence of stroke during coronary artery bypass grafting using transesophageal echocardiography.

OBJECTIVE: Protruding atheromas of thoracic aorta have been identified as a source of systemic emboli and a major cause of stroke following cardiac surgery. This prospective study used transesophageal echocardiography (TEE) to identify atherosclerosis of thoracic aorta intraoperatively. The influence of risk factors was studied. Finally the impact of modifying surgical technique on the outcome was evaluated. METHODS: Seven-hundred and ninety-two patients undergoing coronary artery bypass grafting (CABG) were evaluated with TEE. Depending on the location and extent of thoracic aortic disease various surgical modifications were carried out, e.g. hypothermic circulatory arrest with aortic arch atherectomy, CABG on beating heart and others. The stroke rate in this group of patients was determined and analysed. RESULTS: Of the 114 patients with grade II and III atheromas of aortic arch and ascending aorta in whom surgical modifications were done, none had stroke. The overall stroke rate in the study group was 0.76%, six patients had stroke. Stepwise logistic regression identified age, diabetes, serum triglycerides and VLDL as important risk factors. Associated carotid artery disease and calcium on chest X-ray (CXR) were identified as important predictors of disease. CONCLUSIONS: Intraoperative TEE is an invaluable modality for evaluating the thoracic aorta. There is significant reduction in stroke rate following identification of atheromas and modification of surgical technique.

Coronary artery bypass surgery without cardiopulmonary bypass: short- and mid-term results.

From March 1994 to April 1997, 433 patients had undergone coronary artery bypass grafting without cardiopulmonary bypass in our institute. Sixty-eight patients had various organ dysfunctions and/or aortic atheroma or calcification and were regarded as high risk for cardiopulmonary bypass. In 277 patients surgery was performed through midline sternotomy, while in 156 minithoracotomy approach was used. In 361 patients single coronary artery bypass grafting was done, and in 72 two-coronary arteries were bypassed. In 63 patients who had graftable vessels in anterior wall and diffusely diseased ungraftable vessels in posterolateral and/or inferior wall, transmyocardial laser revascularisation was also done along with coronary artery bypass grafting to achieve complete myocardial revascularisation. Nine patients in this series were also subjected to simultaneous carotid endarterectomy along with myocardial revascularisation. In two patients complementary percutaneous transluminal coronary angioplasty of left circumflex coronary artery was done five days after minithoracotomy and left internal mammary artery to left anterior descending coronary artery bypass grafting. Forty-two cases were extubated in operating room. Average blood loss was 260 ml. Six patients were reexplored for postoperative bleeding. Seven patients had perioperative myocardial infarction. One developed neurological complication. Hospital mortality was 2.3 percent (10/433 cases) and four deaths were due to malignant ventricular arrhythmias. Nine patients developed chest wound complications. Average hospital stay after operation was six days, 423 patients were discharged from hospital and all of them were asymptomatic. During three years follow-up (range 3 to 38 months) there were three known cardiac deaths. Ninety percent (391) patients reported to the follow-up clinic and 91 percent of them were angina-free. In patients who were subjected to transmyocardial laser revascularisation along with coronary artery bypass grafting, myocardial perfusion scan showed a step-wise improvement in reversible ischemia. The perfusion index increased from 52 percent at three months to 90 percent at 12 months. We conclude that coronary artery bypass grafting without cardiopulmonary bypass can be done with relatively low mortality, more so in a group of patients in whom cardiopulmonary bypass poses a high risk. Transmyocardial laser revascularisation is a suitable means to provide complete myocardial revascularisation along with coronary artery bypass surgery in patients who have graftable vessels in anterior wall and ungraftable vessels in posterolateral and inferior walls.

Transmyocardial laser revascularisation as an adjunct to CABG.

Transmyocardial laser revascularisation (TMLR), a new technique in which the ischaemic myocardium is perfused via laser-created transmural channels, was performed in 116 patients at the Escorts Heart Institute. TMLR was combined with CABG in 104 of these patients. The main indication for the combined procedure was the presence of one or more bypassable vessels along with diffuse disease in the other vessels. The age of the patients ranged from 37 to 73 years. Preoperatively, 53.84 percent of patients had Canadian Cardiovascular Society (CCS) class III angina while 24 percent had class IV angina. The mean LVEF was 46 percent; however, 19 percent of the patients had LVEF < 35 percent. Thirteen patients were operated upon a beating heart without cardiopulmonary bypass. The early mortality was 2.88 percent, 7.69 percent of patients showed elevation in CPK-MB, while 5.76 percent had a rise in Troponin 'T' and 2 percent of patients showed ECG changes. The mean follow-up was 7.6 months. Myocardial perfusion scan showed a step-wise improvement in reversible ischaemia, the perfusion index increasing from 52 percent at 3 months to 91 percent at 12 months. At 12 months, 91.6 percent of patients were angina-free. The Karnofsky score of 46 percent at baseline also increased to 86 percent at 12 months.

Discrete subvalvular aortic stenosis.

Discrete Subaortic Stenosis is one of the many lesions responsible for left ventricular outflow tract (LVOT) obstruction. It may present as in an isolated from as membranous or fibromuscular ring below the aortic valve or in association with other congenital anamolies such as VSD, PDA, coarctation of aorta, hypoplastic aortic annulus, double chamber right ventricle among others. The condition is rarely diagnosed antenataly or in infancy but often manifests in the first decade of life with features of progressive LVOT obstruction, LV hypertrophy and dysfunction aortic regurgitation due to damage to the aortic cusps because of the jet from the subaortic narrowing which may also render the aortic valve prone to infective endocarditis. Interaction of genetic predisposition and morphologically deformed long and narrow LVOT cause rheological abnormalities and increased shear stress in the region of subaortic stenosis and seem to be the main etiological factor alongwith poorly defined role of more extensive but subtle changes in the LV endocardium. Condition can be easily diagnosed by cross-sectional and Doppler echocardiography and confirmed by demonstrating a pressure gradient below aortic valve on cardiac catheterisation and LV angiography. Surgical membranectomy alongwith myotomy or myomectomy remain the mainstay of treatment but long term results are not satisfactory as there is a high rate of recurrences requiring reoperations. A close follow up with serial echocardiographic examinations is very helpful in early detection of subaortic obstruction in patients who have so called functional murmurs in the childhood.

Discrete subvalvular aortic stenosis in adults.

Discrete subvalvular aortic stenosis is a relatively rare condition in adults. It is often diagnosed during first decade of life especially in association with other congenital malformations. Isolated form of discrete subvalvular aortic stenosis may however silently progress from innocent murmurs of childhood and adolescence to symptomatic left ventricular outflow tract obstruction in adults. Certain overt and subtle morphological abnormalities may underlie the initial expression as well as high recurrence rates after surgical resection of sub aortic membrane. Though surgical resection is the only treatment available, debate on the surgical technique and appropriate timing of surgery continues. Close followup with serial echocardiographic examinations in patients detected to have functional murmurs during childhood may be helpful in early detection of subvalvular aortic stertosis.