Transcranial Surgery for Pituitary Tumors: A "Community Neurosurgery Experience".

Background: Despite the evolution of endoscopic techniques, large pituitary adenomas with unfavorable characteristics and irregular anatomical configurations continue to pose a challenge for the dexterity, skills, and patience of endoscopic surgeons. Transcranial surgery retains a significant role in these situations where the tumor access, hemostasis, and dissection around adjoining neurovascular tissues can be controlled efficaciously. Objective: In this report, we describe our experience with transcranial surgery for pituitary adenomas highlighting its safety and versatility in peripheral centers. Methods: We accessed the case files and imaging records of pituitary tumors operated between 2001 and 2019 at a private hospital in a major Indian city. The records were analyzed with emphasis on postoperative clinical course, visual, and endocrinological outcomes. The data was analyzed with respect to differences between transcranial and transsphenoidal procedures. Categorical variables were compared with Chi-square test/Fischer's exact test and difference in means evaluated with Welch's t-test. Results: A total of 178 procedures were performed in 173 patients with pituitary adenoma, who were the subjects of this study. Ninety-eight (56.7%) patients were treated by transsphenoidal excision whereas 80 (46.2%) underwent transcranial procedures (75 primary and five secondary). In the patients operated transcranially, we observed three deaths and nine patients suffered from significant morbidity. Visual outcomes were similar to the group operated transsphenoidally. However, incidence of panhypopituitarism was significantly higher in transcranial procedures; the extent of resection was poorer than transsphenoidal surgeries owing to more extensive nature of tumors. Conclusions: In low-volume centers, the endoscopic skills required for transsphenoidal resection of large and complex pituitary adenomas may be scarce. Transcranial surgery, dependent on familiar microsurgical techniques and equipment, may still be viable, safe, and an effective option.

Effects of Pharmacological Inhibitors of NADPH Oxidase on Myogenic Contractility and Evoked Vasoactive Responses in Rat Resistance Arteries.

Reactive oxygen species (ROS), such as superoxide anions and hydrogen peroxide, are reported to contribute to the dynamic regulation of contractility in various arterial preparations, however, the situation in pressurized, myogenically active resistance arteries is much less clear. In the present study, we have utilized established pharmacological inhibitors of NADPH oxidase activity to examine the potential contribution of ROS to intrinsic myogenic contractility in adult Sprague-Dawley rat resistance arteries and responses to vasoactive agents acting via the endothelium (i.e., acetylcholine, SKA-31) or smooth muscle (i.e., sodium nitroprusside, phenylephrine). In cannulated and pressurized cremaster skeletal muscle and middle cerebral arteries, the NOX inhibitors 2-acetylphenothiazine (2-APT) and VAS2870, selective for NOX1 and NOX2, respectively, evoked concentration-dependent inhibition of basal myogenic tone in a reversible and irreversible manner, respectively, whereas the non-selective inhibitor apocynin augmented myogenic contractility. The vasodilatory actions of 2-APT and VAS2870 occurred primarily via the vascular endothelium and smooth muscle, respectively. Functional responses to established endothelium-dependent and -independent vasoactive agents were largely unaltered in the presence of either 2-APT or apocynin. In cremaster arteries from Type 2 Diabetic (T2D) Goto-Kakizaki rats with endothelial dysfunction, treatment with either 2-APT or apocynin did not modify stimulus-evoked vasoactive responses, but did affect basal myogenic tone. These same NOX inhibitors produced robust inhibition of total NADPH oxidase activity in aortic tissue homogenates from control and T2D rats, and NOX isozymes 1, 2 and 4, along with superoxide dismutase 1, were detected by qPCR in cremaster arteries and aorta from both species. Based on the diverse effects that we observed for established, chemically distinct NOX inhibitors, the functional contribution of vascular NADPH oxidase activity to stimulus-evoked vasoactive signaling in myogenically active, small resistance arteries remains unclear.

KCa channel activation normalizes endothelial function in Type 2 Diabetic resistance arteries by improving intracellular Ca2+ mobilization.

BACKGROUND: Endothelial dysfunction is an early pathogenic event in the progression of cardiovascular disease in patients with Type 2 Diabetes (T2D). Endothelial KCa2.3 and KCa3.1 K+ channels are important regulators of arterial diameter, and we thus hypothesized that SKA-31, a small molecule activator of KCa2.3 and KCa3.1, would positively influence agonist-evoked dilation in myogenically active resistance arteries in T2D. METHODOLOGY: Arterial pressure myography was utilized to investigate endothelium-dependent vasodilation in isolated cremaster skeletal muscle resistance arteries from 22 to 24 week old T2D Goto-Kakizaki rats, age-matched Wistar controls, and small human intra-thoracic resistance arteries from T2D subjects. Agonist stimulated changes in cytosolic free Ca2+ in acutely isolated, single endothelial cells from Wistar and T2D Goto-Kakizaki cremaster and cerebral arteries were examined using Fura-2 fluorescence imaging. MAIN FINDINGS: Endothelium-dependent vasodilation in response to acetylcholine (ACh) or bradykinin (BK) was significantly impaired in isolated cremaster arteries from T2D Goto-Kakizaki rats compared with Wistar controls, and similar results were observed in human intra-thoracic arteries. In contrast, inhibition of myogenic tone by sodium nitroprusside, a direct smooth muscle relaxant, was unaltered in both rat and human T2D arteries. Treatment with a threshold concentration of SKA-31 (0.3 µM) significantly enhanced vasodilatory responses to ACh and BK in arteries from T2D Goto-Kakizaki rats and human subjects, whereas only modest effects were observed in non-diabetic arteries of both species. Mechanistically, SKA-31 enhancement of evoked dilation was independent of vascular NO synthase and COX activities. Remarkably, SKA-31 treatment improved agonist-stimulated Ca2+ elevation in acutely isolated endothelial cells from T2D Goto-Kakizaki cremaster and cerebral arteries, but not from Wistar control vessels. In contrast, SKA-31 treatment did not affect intracellular Ca2+ release by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid. CONCLUSIONS: Collectively, our data demonstrate that KCa channel modulation can acutely restore endothelium-dependent vasodilatory responses in T2D resistance arteries from rats and humans, which appears to involve improved endothelial Ca2+ mobilization.

SKA-31, an activator of Ca2+-activated K+ channels, improves cardiovascular function in aging.

Aging represents an independent risk factor for the development of cardiovascular disease, and is associated with complex structural and functional alterations in the vasculature, such as endothelial dysfunction. Small- and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacological activators of these channels induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of such compounds are unknown. In our study, we hypothesized that such treatment would ameliorate aging-related cardiovascular deficits. Aged (∼18 months) male Sprague Dawley rats were treated daily with either vehicle or the KCa channel activator SKA-31 (10 mg/kg, intraperitoneal injection; n = 6/group) for 8 weeks, followed by echocardiography, arterial pressure myography, immune cell and plasma cytokine characterization, and tissue histology. Our results show that SKA-31 administration improved endothelium-dependent vasodilation, reduced agonist-induced vascular contractility, and prevented the aging-associated declines in cardiac ejection fraction, stroke volume and fractional shortening, and further improved the expression of endothelial KCa channels and associated cell signalling components to levels similar to those observed in young male rats (∼5 months at end of study). SKA-31 administration did not promote pro-inflammatory changes in either T cell populations or plasma cytokines/chemokines, and we observed no overt tissue histopathology in heart, kidney, aorta, brain, liver and spleen. SKA-31 treatment in young rats had little to no effect on vascular reactivity, select protein expression, tissue histology, plasma cytokines/chemokines or immune cell properties. Collectively, these data demonstrate that administration of the KCa channel activator SKA-31 improved aging-related cardiovascular function, without adversely affecting the immune system or promoting tissue toxicity.

Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat.

Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2-0.3 µM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.

Alpha1 -adrenergic stimulation selectively enhances endothelium-mediated vasodilation in rat cremaster arteries.

We have systematically investigated how vascular smooth muscle α1 -adrenoceptor activation impacts endothelium-mediated vasodilation in isolated, myogenically active, rat cremaster muscle 1A arteries. Cannulated cremaster arteries were pressurized intraluminally to 70 mmHg to induce myogenic tone, and exposed to vasoactive agents via bath superfusion at 34°C. Smooth muscle membrane potential was measured via sharp microelectrode recordings in pressurized, myogenic arteries. The α1 -adrenergic agonist phenylephrine (25-100 nmol/L) produced further constriction of myogenic arteries, but did not alter the vasorelaxant responses to acetylcholine (0.3 µmol/L), SKA-31 (an activator of endothelial Ca2+ -dependent K+ channels) (3 µmol/L) or sodium nitroprusside (10 µmol/L). Exposure to 0.25-1 µmol/L phenylephrine or 1 µmol/L norepinephrine generated more robust constrictions, and also enhanced the vasodilations evoked by acetylcholine and SKA-31, but not by sodium nitroprusside. In contrast, the thromboxane receptor agonist U46619 (250 nmol/L) dampened responses to all three vasodilators. Phenylephrine exposure depolarized myogenic arteries, and mimicking this effect with 4-aminopyridine (1 mmol/L) was sufficient to augment the SKA-31-evoked vasodilation. Inhibition of L-type Ca2+ channels by 1 µmol/L nifedipine decreased myogenic tone, phenylephrine-induced constriction and prevented α1 -adrenergic enhancement of endothelium-evoked vasodilation; these latter deficits were overcome by exposure to 3 and 10 µmol/L phenylephrine. Mechanistically, augmentation of ACh-evoked dilation by phenylephrine was dampened by eNOS inhibition and abolished by blockade of endothelial KCa channels. Collectively, these data suggest that increasing α1 -adrenoceptor activation beyond a threshold level augments endothelium-evoked vasodilation, likely by triggering transcellular signaling between smooth muscle and the endothelium. Physiologically, this negative feedback process may serve as a "brake" to limit the extent of vasoconstriction in the skeletal microcirculation evoked by the elevated sympathetic tone.

Pharmacologic targeting of endothelial Ca2+-activated K+ channels: A strategy to improve cardiovascular function.

Endothelial small and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) play an important role in the regulation of vascular function and systemic blood pressure. Growing evidence indicates that they are intimately involved in agonist-evoked vasodilation of small resistance arteries throughout the circulation. Small molecule activators of KCa2.x and 3.1 channels, such as SKA-31, can acutely inhibit myogenic tone in isolated resistance arteries, induce effective vasodilation in intact vascular beds, such as the coronary circulation, and acutely decrease systemic blood pressure in vivo. The blood pressure-lowering effect of SKA-31, and early indications of improvement in endothelial dysfunction suggest that endothelial KCa channel activators could eventually be developed into a new class of endothelial targeted agents to combat hypertension or atherosclerosis. This review summarises recent insights into the activation of endothelial Ca2+ activated K+ channels in various vascular beds, and how tools, such as SKA-31, may be beneficial in disease-related conditions.

The augmentation of BK channel activity by nitric oxide signaling in rat cerebral arteries involves co-localized regulatory elements.

Large conductance, Ca2+-activated K+ (BK) channels control cerebrovascular tone; however, the regulatory processes influencing these channels remain poorly understood. Here, we investigate the cellular mechanisms underlying the enhancement of BK current in rat cerebral arteries by nitric oxide (NO) signaling. In isolated cerebral myocytes, BK current magnitude was reversibly increased by sodium nitroprusside (SNP, 100 µM) and sensitive to the BK channel inhibitor, penitrem-A (100 nM). Fostriecin (30 nM), a protein phosphatase type 2A (PP2A) inhibitor, significantly prolonged the SNP-induced augmentation of BK current and a similar effect was produced by sildenafil (30 nM), a phosphodiesterase 5 (PDE5) inhibitor. Using proximity ligation assay (PLA)-based co-immunostaining, BK channels were observed to co-localize with PP2A, PDE5, and cGMP-dependent protein kinase (cGKI) (spatial restriction < 40 nm); cGKI co-localization increased following SNP exposure. SNP (10 µM) reversibly inhibited myogenic tone in cannulated cerebral arteries, which was augmented by either fostriecin or sildenafil and inhibited by penitrem-A. Collectively, these data suggest that (1) cGKI, PDE5, and PP2A are compartmentalized with cerebrovascular BK channels and determine the extent of BK current augmentation by NO/cGMP signaling, and (2) the dynamic regulation of BK activity by co-localized signaling enzymes modulates NO-evoked dilation of cerebral resistance arteries.

A pharmacologic activator of endothelial KCa channels increases systemic conductance and reduces arterial pressure in an anesthetized pig model.

SKA-31, an activator of endothelial KCa2.3 and KCa3.1 channels, reduces systemic blood pressure in mice and dogs, however, its effects in larger mammals are not well known. We therefore examined the hemodynamic effects of SKA-31, along with sodium nitroprusside (SNP), in anesthetized, juvenile male domestic pigs. Experimentally, continuous measurements of left ventricular (LV), aortic and inferior vena cava (IVC) pressures, along with flows in the ascending aorta, carotid artery, left anterior descending coronary artery and renal artery, were performed during acute administration of SKA-31 (0.1, 0.3, 1.0, 3.0 and 5.0mg/ml/kg) and a single dose of SNP (5.0 µg/ml/kg). SKA-31 dose-dependently reduced mean aortic pressure (mPAO), with the highest dose decreasing mPAO to a similar extent as SNP (-23 ± 3 and -28 ± 4 mmHg, respectively). IVC pressure did not change. Systemic conductance and conductance in coronary and carotid arteries increased in response to SKA-31 and SNP, but renal artery conductance was unaffected. There was no change in either LV stroke volume (SV) or heart rate (versus the preceding control) for any infusion. With no change in SV, drug-evoked decreases in LV stroke work (SW) were attributed to reductions in mPAO (SW vs. mPAO, r(2)=0.82, P<0.001). In summary, SKA-31 dose-dependently reduced mPAO by increasing systemic and arterial conductances. Primary reductions in mPAO by SKA-31 largely account for associated decreases in SW, implying that SKA-31 does not directly impair cardiac contractility.

Inhibition of Myogenic Tone in Rat Cremaster and Cerebral Arteries by SKA-31, an Activator of Endothelial KCa2.3 and KCa3.1 Channels.

Endothelial KCa2.3 and KCa3.1 channels contribute to the regulation of myogenic tone in resistance arteries by Ca(2+)-mobilizing vasodilatory hormones. To define further the functional role of these channels in distinct vascular beds, we have examined the vasodilatory actions of the KCa channel activator SKA-31 in myogenically active rat cremaster and middle cerebral arteries. Vessels pressurized to 70 mm Hg constricted by 80-100 µm (ie, 25%-45% of maximal diameter). SKA-31 (10 µM) inhibited myogenic tone by 80% in cremaster and ∼65% in middle cerebral arteries, with IC50 values of ∼2 µM in both vessels. These vasodilatory effects were largely prevented by the KCa2.3 blocker UCL1684 and the KCa3.1 blocker TRAM-34 and abolished by endothelial denudation. Preincubation with N(G) nitro L-arginine methyl ester (L-NAME, 0.1 mM) did not affect the inhibitory response to SKA-31, but attenuated the ACh-evoked dilation by ∼45%. Penitrem-A, a blocker of BK(Ca) channels, did not alter SKA-31 evoked vasodilation but did reduce the inhibition of myogenic tone by ACh, the BKCa channel activator NS1619, and sodium nitroprusside. Collectively, these data demonstrate that SKA-31 produces robust inhibition of myogenic tone in resistance arteries isolated from distinct vascular beds in an endothelium-dependent manner.

The cognitive and technical skills impact of the Congress of Neurological Surgeons simulation curriculum on neurosurgical trainees at the 2013 Neurological Society of India meeting.

OBJECTIVE: To assess the impact of a simulation-based educational curriculum of 4 modules on neurosurgical trainees at the Neurological Societies of India annual meeting, which was held in Mumbai, India, in December 2013. METHODS: We developed a microanastomosis, anterior cervical discectomy and fusion (ACDF), posterior cervical fusion (PCF), and durotomy repair and their corresponding objective assessment scales. Each module was divided into 3 components: 1) a before didactic cognitive knowledge and technical skills testing, 2) a didactic lecture, and 3) an after didactic cognitive knowledge and technical skills testing. We compared the trainees' cognitive and technical scores from the before and after testing phases. Wilcoxon sum rank test was used to test statistical significance. The incorporation of a simulation-based educational program into neurosurgical education curriculum has faced a number of barriers. It is essential to develop and assess the success and feasibility of simulation-based modules on neurosurgical residents. RESULTS: The knowledge test median scores increased from 60%, 69% to 72%, and 60% to 80%, 85%, 90%, and 75% on the microanastomosis, ACDF, PCF, and durotomy modules, respectively (P < 0.05). The practical hands-on scores increased from 45%, 45% to 60%, and 65% to 62%, 68%, 81%, and 70% on the microanastomosis, ACDF, PCF, and durotomy modules, respectively (P < 0.05). CONCLUSIONS: Our course suggests that a simulation-based neurosurgery curriculum has the potential to enhance resident knowledge and technical proficiency.

Coffin-Siris syndrome with the rarest constellation of congenital cardiac defects: A case report with review of literature.

We report a case of type-A Coffin-Siris syndrome (CSS) with a unique constellation of congenital heart defects. A 17-year-old Indian boy was referred to our hospital for central cyanosis with features of right heart failure. The cardiac abnormalities included biventricular outflow tract obstruction, small atrial septal defect (ASD), subaortic ventricular septal defect, drainage of left superior venacava to left atrial appendage, and aortic arch anomaly. Patient underwent successful right ventricular infundibular resection, subaortic membrane resection, closure of atrial and ventricular septal defect, rerouting left superior vena cava to left pulmonary artery and aortic valve replacement.

A pharmacologic activator of endothelial KCa channels enhances coronary flow in the hearts of type 2 diabetic rats.

Endothelial dysfunction is a common early pathogenic event in patients with type 2 diabetes (T2D) who exhibit cardiovascular disease. In the present study, we have examined the effect of SKA-31, a positive modulator of endothelial Ca(2+)-activated K(+) (KCa) channels, on total coronary flow in isolated hearts from Goto-Kakizaki rats, a non-obese model of T2D exhibiting metabolic syndrome. Total coronary flow and left ventricular developed pressure were monitored simultaneously in isolated, spontaneously beating Langendorff-perfused hearts. Acute administrations of bradykinin (BK) or adenosine (ADO) increased coronary flow, but responses were significantly blunted in diabetic hearts at 10-12 and 18-20weeks of age compared with age-matched Wistar controls, consistent with the presence of endothelial dysfunction. In contrast, SKA-31 dose-dependently (0.01-5µg) increased total coronary flow to comparable levels in both control and diabetic rat hearts at both ages. Flow responses to sodium nitroprusside were not different between control and diabetic hearts, suggesting normal arterial smooth muscle function. Importantly, exposure to a sub-threshold concentration of SKA-31 (i.e. 0.3µM) rescued the impaired BK and ADO-evoked vasodilatory responses in diabetic hearts. Endothelial KCa channel activators may thus help to preserve coronary flow in diabetic myocardium.

SKA-31, a novel activator of SK(Ca) and IK(Ca) channels, increases coronary flow in male and female rat hearts.

AIMS: Endothelial SK(Ca) and IK(Ca) channels play an important role in the regulation of vascular function and systemic blood pressure. Based on our previous findings that small molecule activators of SK(Ca) and IK(Ca) channels (i.e. NS309 and SKA-31) can inhibit myogenic tone in isolated resistance arteries, we hypothesized that this class of compounds may induce effective vasodilation in an intact vascular bed, such as the coronary circulation. METHODS AND RESULTS: In a Langendorff-perfused, beating rat heart preparation, acute bolus administrations of SKA-31 (0.01-5 µg) dose-dependently increased total coronary flow (25-30%) in both male and female hearts; these responses were associated with modest, secondary increases in left ventricular (LV) systolic pressure and heart rate. SKA-31 evoked responses in coronary flow, LV pressure, and heart rate were qualitatively comparable to acute responses evoked by bradykinin (1 µg) and adenosine (10 µg). In the presence of apamin and TRAM-34, selective blockers of SK(Ca) and IK(Ca) channels, respectively, SKA-31 and bradykinin-induced responses were largely inhibited, whereas the adenosine-induced changes were blocked by ∼40%; TRAM-34 alone produced less inhibition. Sodium nitroprusside (SNP, 0.2 µg bolus dose) evoked changes in coronary flow, LV pressure, and heart rate were similar to those induced by SKA-31, but were unaffected by apamin + TRAM-34. The NOS inhibitor L-NNA reduced bradykinin- and adenosine-evoked changes, but did not affect responses to either SKA-31 or SNP. CONCLUSION: Our study demonstrates that SKA-31 can rapidly and reversibly induce dilation of the coronary circulation in intact functioning hearts under basal flow and contractility conditions.

The transylvian trans-insular approach to lateral thalamic lesions.

BACKGROUND: Thalamic tumors are rare intracranial tumors. The most common approaches to the thalamus have been directed through the ventricular system, which surrounds it. The transsylvian trans-insular approach to the lateral thalamus has been infrequently described probably because of the vulnerability of the internal capsule, which skirts this part of the thalamus. AIMS: To describe the approach emphasizing its anatomical basis and also to evaluate its safety and efficacy. SETTINGS AND DESIGN: Retrospective study conducted at a tertiary hospital. MATERIALS AND METHODS: Patient population included all the patients who underwent surgery for the lesions in lateral thalamus using the transylvian trans-insular approach between 2005 and 2011. A trephine craniotomy was made, centered over posterior sylvian fissure and the surgical corridor was developed through the insular cortex. RESULTS: During the study period 10 patients (7 tumors and inflammatory lesions and 3 hypertensive bleeds) were treated using this approach. One peri-operative mortality was noted. In patients with lesions other than hypertensive thalamic hemorrhage, there was no postoperative worsening of neurological deficit as comparative to preoperative deficits. Total excision/evacuation of the lesion could be accomplished in all the patients. CONCLUSIONS: The transylvian trans-insular approach is safe, effective, anatomical procedure, and can be performed at a peripheral center without the need for navigation and intra-operative monitoring.

Retrospective evidence for clinical validity of expanded genetic model in warfarin dose optimization in a South Indian population.

AIM: To optimize warfarin dose in patients at risk for thrombotic events, we have recently developed a pharmacogenomic algorithm, which explained 44.9% of the variability in warfarin dose requirements using age, gender, BMI, vitamin K intake, CYP2C9 (*2 and *3) and VKORC1 (*3, *4 and -1639 G>A) as predictors. The aim of the current study is to develop an expanded genetic model that can explain greater percentage of warfarin variability and that has clinical validity. PATIENTS & METHODS: CYP2C9*8, CYP4F2 V433M, GGCX G8016A and thyroid status were added to an expanded genetic model (n = 243). RESULTS: The expanded genetic model explained 61% of the variability in warfarin dose requirements, has a prediction accuracy of ±11 mg/week and can differentiate warfarin sensitive and warfarin resistant groups efficiently (areas under receiver operating characteristic curves: 0.93 and 0.998, respectively; p < 0.0001). Higher percentage of International Normalized Ratios in therapeutic range (52.68 ± 4.21 vs 43.80 ± 2.27; p = 0.04) and prolonged time in therapeutic range (61.74 ± 3.18 vs 47.75 ± 5.77; p = 0.03) were observed in subjects with a prediction accuracy of <1 mg/day compared with subjects with prediction accuracy >1 mg/day. In the warfarin-resistant group, primary hypothyroidism was found to induce more resistance while in the warfarin-sensitive group, hyperthyroidism was found to increase sensitivity. CONCLUSION: The expanded genetic model explains greater variability in warfarin dose requirements and it prolongs time in therapeutic range and minimizes out-of-range International Normalized Ratios. Thyroid status also influences warfarin dose adjustments.

A tetrad of bicuspid aortic valve association: A single-stage repair.

We report a 27 years old male who presented with a combination of both congenital and acquired cardiac defects. This syndrome complex includes congenital bicuspid aortic valve, Seller's grade II aortic regurgitation, juxta- subclavian coarctation, stenosis of ostium of left subclavian artery and ruptured sinus of Valsalva aneurysm without any evidence of infective endocarditis. This type of constellation is extremely rare. Neither coarctation of aorta with left subclavian artery stenosis nor the rupture of sinus Valsalva had a favorable pathology for percutaneus intervention. Taking account into morbidity associated with repeated surgery and anesthesia patient underwent a single stage surgical repair of both the defects by two surgical incisions. The approaches include median sternotomy for rupture of sinus of Valsalva and lateral thoracotomy for coarctation with left subclavian artery stenosis. The surgery was uneventful. After three months follow up echocardiography showed mild residual gradient across the repaired coarctation segment, mild aortic regurgitation and no residual left to right shunt. This patient is under follow up. This is an extremely rare case of single stage successful repair of coarctation and rupture of sinus of Valsalva associated with congenital bicuspid aortic valve.