Jagajan Karmacharya

Craniosynostosis and altered patterns of fetal TGF-β expression induced by intrauterine constraint. Discussion

Recent work has demonstrated that fusion of the calvarial sutures is mediated by locally elaborated soluble growth factors, including the transforming growth factor-betas (TGF-betas), leading some to speculate that external biomechanical forces play little role in suture development. Clinical evidence has long suggested, however, that fetal head constraint may play a critical role in the pathogenesis of many cases of nonsyndromic craniosynostosis. The purpose of these experiments was to test the hypothesis that intrauterine constraint leads to an alteration in normal patterns of TGF-beta expression and that these alterations are associated with craniosynostosis. Fetal constraint was induced by allowing C57Bl/6 murine fetuses to grow for 2.5 days beyond the normal 20-day gestation by performing uterine cerclage on the eighteenth day. Cranial suture morphology was examined in hematoxylin and eosin-stained sections and in cleared whole-mount specimens, double stained with alizarin red S and Alcian blue. Expression patterns of TGF-beta1 and TGF-beta3 were examined by immunohistochemical techniques. Gross and microscopic examination of the cranial sutures of 17 constrained fetuses revealed changes that ranged from narrowing to complete osseous obliteration of the coronal and squamosal sutures. All sutures of 14 nonconstrained control pups remained patent. Fetal head constraint was associated with increased TGF-beta1 immunoreactivity within the new bone and the underlying dura when compared with nonconstrained age-matched controls. TGF-beta3 immunoreactivity was associated with the dura underlying patent, nonconstrained sutures, whereas constraint-induced synostosis was characterized by down-regulation of dural TGF-beta3 expression. These experiments confirm the ability of intrauterine constraint to induce premature fusion of the cranial sutures and provide evidence that intrauterine head constraint induces the expression of osteogenic growth factors in fetal calvarial bone and the underlying dura.

Endovascular Therapy of Symptomatic Innominate-Subclavian Arterial Occlusive Lesions

The purpose of this study was to determine the safety and efficacy of angioplasty and stenting for symptomatic innominate-subclavian lesions by review of records of symptomatic patients undergoing angioplasty and stenting of high-grade lesions (>80%) of the innominate and subclavian arteries. Follow-up consisted of history (symptoms) and physical examination (pulses and blood pressures) at 1, 3, 6, and then every 12 months plus an annual duplex ultrasound examination. Between 1998 to 2003, 25 patients (27 lesions) were treated. Ages ranged from 48 to 89 years. Symptoms included vertebrobasilar/steal (15), claudication (6), ischemia (4), and coronary artery bypass grafting/left internal mammary artery (2). There were 7 occlusions and 20 high-grade stenoses. Access was attempted via brachial cutdown (19) or percutaneous puncture of the brachial (2) or femoral arteries (10). Twenty-two lesions were stented with either self-expanding (13) or balloon-expandable (9) stents. Technical success was 89%; 3 occluded lesions could not be crossed owing to complete occlusion. The remaining 4 occlusions were all crossed via a retrograde approach. The mean difference in systolic blood pressure between upper limbs decreased from 36 mm Hg (preprocedure) to 10 mm Hg (postprocedure). There were no procedure-related complications. Mean follow-up was 18 months (range 1–62 months). One patient died 4 months after the procedure secondary to complications from pulmonary surgery unrelated to the percutaneous transluminal angioplasty/stent. Of the 4 successfully treated occlusions, 2 were followed up to 3 years with continued patency. Three patients developed recurrent stenoses documented by duplex examination. However, these patients remained asymptomatic and were not treated. Endovascular management of high-grade lesions of the subclavian or innominate arteries is safe and efficacious and may be considered as a first line of therapy. Continued follow-up is needed to assess long-term patency.

Carotid artery stenting: identification of risk factors for poor outcomes.

OBJECTIVES Age greater than 80 has been identified as a risk factor for complications, including stroke and death, in patients undergoing carotid artery angioplasty and stenting (CAS). This study evaluates other potential predictors of perioperative complications in patients undergoing CAS. METHODS All cerebrovascular endovascular procedures performed by the vascular surgery division at our university hospital between July 2003 and December 2005 were retrospectively examined. During the course of 212 admissions, 198 patients underwent 215 procedures. Patient age, comorbidities, and admission status were analyzed as independent (predictor) variables. Complication rate, discharge disposition, and length of hospital stay were considered dependent (outcome) variables. Logistic regression and Fisher exact test or Student t test were performed, as appropriate. RESULTS Complications included major and minor stroke, myocardial infarction, femoral artery pseudoaneurysm, and death. The rates of perioperative major and minor stroke were 0.5% and 2.8%, respectively. Chronic renal insufficiency was a predictor of perioperative complications, including stroke: patients with serum creatinine greater than 1.3 mg/dL had a 37% complication rate and a 11.1% stroke rate, while those with normal renal function had a 13% complication rate (P = .003) and a 0.6% stroke rate (P =.001). Similar association was seen between creatinine clearance and both stroke and complications. Obesity was a risk factor for complications, but not stroke: obese patients had a complication rate of 28%, while others had a 16% complication rate (P = .024). Emergency admission predicted both extended hospital stay (P < .001) and requirement for further inpatient care in a rehabilitation or nursing facility (P = .007). There was no significant difference in complication rate or stroke rate between octogenarians and others. CONCLUSION This experience demonstrates that chronic renal insufficiency, obesity, and emergent clinical setting are risk factors for patients undergoing CAS.

Immunolocalization of androgen receptor in the developing craniofacial skeleton.

Male predominance in metopic and sagittal craniosynostosis and in nonsynostotic plagiocephaly suggests a role for circulating androgens in early craniofacial development. Androgens have been documented to play an important role in postnatal skeletal growth, and the androgen receptor has been recently demonstrated in human and rat osteoblast-like cell lines and in human long bones. The purpose of this study was to describe the expression of androgen receptor in the fetal craniofacial skeleton. The heads of E18 fetal CD-1 male and female mice were fixed in 10% formalin, decalcified, and embedded in paraffin. Four- to 6-μm coronal and sagittal sections were stained with a monoclonal antibody specific to androgen receptor, which was detected by an avidinbiotin conjugate and peroxidase system. The sections were then examined for androgen receptor expression patterns. Strong androgen receptor immunoreactivity was observed in the dura mater of developing fetuses. Androgen receptor expression was also noted in cells lining the osteogenic fronts and in calvarial osteoblasts. Similar androgen receptor expression patterns were found in male and female mice. Androgen receptor is abundantly expressed in fetal dura mater and calvarial bone. This study confirms the presence of androgen receptor in the murine fetal craniofacial skeleton, suggesting a potential role for the anabolic effects of androgens in the developing craniofacial skeleton.

Synthetic hybrid grafts for craniofacial reconstruction: sustained gene delivery using a calcium phosphate bone mineral substitute.

These experiments were performed to evaluate the efficacy of a biocompatible bone cement, Norian CRS, engineered as a hybrid graft for simultaneous bone matrix reconstruction and sustained, site-directed gene transfer using an adenoviral vector. Norian CRS was cured ex vivo by mixing a calcium source powder with a phosphate source solution to form a paste. To 1.0 ml of the cement was added 50 &mgr;l of a solution containing 1 × 108 plaque-forming units of a replication-deficient adenoviral vector containing a bacterial &bgr;-galactosidase reporter gene (AdLacZ). In vitro, fragments of the hybrid Norian-AdLacZ construct were placed into 12-&mgr;m-pore culture plate inserts and cocultured with human fibroblasts. The same insert was transferred to a new well of fibroblasts every 48 hours for 30 days, and, after allowing 72 hours for gene expression, fibroblasts were examined for transgene expression by 5 bromo-4-chloro-3-indoyl-&bgr;-D-galactosidase (X-gal) staining. In vivo, the Norian-AdLacZ hybrid was implanted into 10-mm frontal bone defects in 3-week-old piglets. The implant sites were harvested after 5 days and were examined for transgene expression by X-gal staining. X-gal staining of fibroblasts incubated with the hybrid Norian-AdLacZ construct was observed throughout the 30-day period. Transgene expression was also observed about the periphery of the calvarial defects treated with hybrid Norian-AdLacZ constructs. Thus, adenoviral vectors may be incorporated successfully into a synthetic calcium phosphate bone mineral substitute to provide effective, sustained local gene delivery.

Thoracic Aortic Transection Treated by Thoracic Endovascular Aortic Repair: Predictors of Survival

Background: We reviewed all patients presenting to our institution with a traumatic thoracic aortic injury (TTAI) between January 2006 and May 2007. Age, gender, injury severity score (ISS), location of injuries, surgical intervention, and length of stay were assessed to determine what characteristics might be predictive of survival. Of the 56 patients who were identified, 23 (41%) were dead on arrival, 15 (20%) died on that admission, and 18 (32%) survived to discharge. Injury severity score was elevated in mortalities (57) compared to survivors (34). Penetrating and blunt aortic injuries had 89% and 58% mortality rates, respectively. Female gender was associated with increased survival (P = .032), as was receiving surgical intervention (P = .03). Patients with a prolonged ICU stay demonstrated increased survival. All eight patients who received thoracic endovascular aortic repair survived to discharge. Injury severity score, mechanism, thoracic endovascular aortic repair (TEVAR), female gender, and surgical treatment were associated with survival after TTAI.

Differential Effects of Carotid Artery Stenting versus Carotid Endarterectomy on External Carotid Artery Patency

PURPOSE To determine the effect of stent coverage of the external carotid artery (ECA) after carotid artery stenting (CAS) compared to eversion endarterectomy of the ECA after carotid endarterectomy (CEA). METHODS The records of 101 CAS and 165 CEA procedures performed over 2 years were reviewed. Duplex velocities and history and physical examinations were taken prior to the procedure, at 1 month, and at 6-month intervals subsequently. CAS was performed by extending the stent across the internal carotid artery (ICA) lesion into the common carotid artery (CCA) thereby covering the ECA. CEA was performed with eversion endarterectomy of the ECA. RESULTS The mean peak systolic velocities (PSV) in the ICA pre-CAS and pre-CEA were 361 and 352 cm/s, respectively. In terms of CAS, there was a significant increase in ECA velocities versus baseline at 12 (p = 0.009), 18 (p = 0.00001), and 24 (p = 0.005) months. In the CEA group, there was a significant decrease in ECA velocities versus baseline at 1 (p = 0.01) and 6 (p = 0.004) months. There were 2 occluded ECAs in follow-up in the CAS group and none in the CEA group. No significant differences were noted when comparing preprocedural ICA or ECA velocities. However, at the 1-, 6-, and 12-month intervals, the ECA velocities in the CAS group were significantly higher than in the CEA group (p = 0.03, p = 0.001, and p = 0.0004, respectively). There were no neurological symptoms in any patients during the study period. CONCLUSION Although progressive stenosis of the ECA is noted during CAS, the ECA usually does not occlude. Furthermore, there are no associated neurological symptoms. Thus, apprehension for progressive ECA occlusion should not be a contraindication to CAS. In addition, concern for ECA coverage should not deter stent extension from the ICA to the CCA during CAS.