Surgical Control Group Research Articles

Weight Gain after Tonsillectomy and Adenotonsillectomy: A Case Control Study

Objectives: (1) Compare height and weight changes of children who underwent tonsillectomy and adenotonsillectomy (T&A) with a control group. (2) Analyze differences in growth based on starting weight class. Methods: A total of 154 children who underwent T&A between December 2010 and March 2011 were included. They were compared with 182 children with similar demographics who were seen in primary care clinics (control). Height and weight were compared at 6-month intervals over a 24-month period. Patients were divided into normal weight, overweight, and obese based on Centers for Disease Control and Prevention criteria. A multilevel regression model was used for analysis. Significance was set at P = .05. Results: There were no differences in average starting weight, age, or sex between surgical and nonsurgical groups. Average starting weight was 47.6 kg (confidence interval [CI] 42.0-53.2) and 48.1 kg (CI 41.8-54.3) for the obese surgical and obese control groups respectively. There was no difference in weight gain at 6 months. However at 12, 18, and 24 months, the obese surgical group had a significant weight increase over and above the obese control group ( P < .001). An average of 14.3 kg weight gain at 24 months was seen in obese children who underwent T&A compared to 10.1 kg for controls (a difference of 4.2 kg (±2.9)). There were no differences in weight changes between the normal and overweight groups or in height for any of the groups. Conclusions: T&A leads to significant increase in weight in obese but not in normal or overweight children. Efforts should be made to provide weight reduction counseling prior to T&A in obese children.

Guinea Pig Model to Establish the Safety of Middle Ear Pellets

Objectives: Effective treatments for otitis media with effusion (OME) remain elusive as many patients have recurrence. Direct drug delivery to the middle ear has the potential to maximize efficacy, minimize side effects, and provide a sustained release treatment, which is particularly important in the treatment of biofilms. Polymer-based pellets are delivery vehicles for antibiotics and pellet placement in the middle ear is a potential future OME treatment. In vivo testing of these pellets in animal models is necessary prior to human application. Methods: Twenty-four adult guinea pigs were divided into 3 (n = 8) treatment groups: biological controls, surgical controls, polylactic glycolic acid (PLGA) pellets inserted in middle ear. The surgical approach involved submandibular incision, dissection, and following digastric up to the middle ear bulla. Perforating the bulla wall facilitated a 2.5-mm diameter pellet insertion. Auditory brainstem responses (ABRs) were recorded at 0, 1, 2, 4, and 16 weeks at 6 frequencies over 8 to 30 kHz. Analysis was performed using a paired t test with significance set at P < .05 (Bonferroni correction). Results: Mean ABR thresholds across the 3 groups ranged between 42 and 49 dB SPL over 4 weeks. There were statistically significant threshold elevations between 4-10db SPL in the surgical control and pellet groups although these were not considered physiologically significant. Conclusions: Using a guinea pig model, PLGA pellet insertion into the middle ear caused ABR threshold elevation of only 4-10 dB SPL, supporting their use as a potential vehicle for middle ear drug delivery.

Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery

IntroductionNeutrophil extracellular traps (NETs) have not been demonstrated after trauma and subsequent surgery. Neutrophil extracellular traps are formed from pure mitochondrial DNA (mtDNA) under certain conditions, which is potently proinflammatory. We hypothesized that injury and orthopedic trauma surgery would induce NET production with mtDNA as a structural component. MethodsNeutrophils were isolated 8 trauma patients requiring orthopedic surgery postinjury and up to 5 days postoperatively. Four healthy volunteers provided positive and negative controls. Total hip replacement patients acted as an uninjured surgical control group. Neutrophil extracellular traps were visualized with DNA (Hoechst 33342TM/Sytox Green/MitoSox/MitoTracker) stains using live cell fluorescence microscopy with downstream quantitative polymerase chain reaction analysis of DNA composition. ResultsNeutrophil extracellular traps were present after injury in all 8 trauma patients. They persisted for 5 days postoperatively. Delayed surgery resulted in NET resolution, but they reformed postoperatively. Total hip replacement patients developed NETs postoperatively, which resolved by day 5. Quantitative polymerase chain reaction analysis of NET-DNA composition revealed that NETs formed after injury and surgery were made of mtDNA with no detectable nuclear DNA component. ConclusionsNeutrophil extracellular traps formed after major trauma and subsequent surgery contain mtDNA and represent a novel marker of heightened innate immune activation. They could be considered when timing surgery after trauma to prevent systemic NET-induced inflammatory complications.

Transplantation of embryonic motor neurons into peripheral nerve combined with functional electrical stimulation restores functional muscle activity in the rat sciatic nerve transection model

Reinnervation of denervated muscle by motor neurons transplanted into the peripheral nerve may provide the potential to excite muscles artificially with functional electrical stimulation (FES). Here we investigated whether transplantation of embryonic motor neurons into peripheral nerve combined with FES restored functional muscle activity in adult Fischer 344 rats after transection of the sciatic nerve. One week after sciatic nerve transection, cell culture medium containing (cell transplantation group, n = 6) or lacking (surgical control group, n = 6) dissociated embryonic spinal neurons was injected into the distal stump of the tibial and peroneal nerves. Electrophysiological and tissue analyses were performed in the cell transplantation and surgical control groups 12 weeks after transplantation, as well as a in naïve control group (n = 6) that received no surgery. In the cell transplantation group, ankle angle was measured during gait, with and without FES of the peroneal nerve. Ankle angle at mid-swing was more flexed during gait with FES (26.6 ± 8.7°) than gait without FES (51.4 ± 12.8°, p = 0.011), indicating that transplantated motor neurons in conjunction with FES restored ankle flexion in gait, even though no neural connection between central nervous system and muscle was present. These results indicate that transplantation of embryonic motor neurons into peripheral nerve combined with FES can provide a novel treatment strategy for paralysed muscles. Copyright © 2013 John Wiley & Sons, Ltd.

Effects of unilateral stereotactic posterior striatotomy on harmaline-induced tremor in rats

Although long known and the most prevalent movement disorder, pathophysiology of essential tremor (ET) remains controversial. The most accepted hypothesis is that it is caused by a dysfunction of the olivocerebellar system. Vilela Filho et al. [2001; Stereotact Funct Neurosurg 77:149-150], however, reported a patient with unilateral hand ET that was completely relieved after a stroke restricted to the contralateral posterior putamen and suggested that ET could be the clinical manifestation of posterior putamen hyperactivity. The present study was designed to evaluate this hypothesis in the most often used model of ET, harmaline-induced tremor in rats. Fifty-four male Wistar rats were randomly distributed into three groups: experimental (EG), surgical control (SCG), and pharmacological control (PCG) groups. EG animals underwent stereotactic unilateral posterior striatotomy. SCG rats underwent sham lesion at the same target. PCG served exclusively as controls for harmaline effects. All animals received, postoperatively, intraperitoneal harmaline, and the induced tremor was video-recorded for later evaluation by a blind observer. Thirteen animals were excluded from the study. Limb tremor was reduced ipsilaterally to the operation in 20 of 21 rats of EG and in two of nine of SCG, being asymmetric in one of 10 of PCG rats. Comparisons between EG × SCG and EG × PCG were statistically significant, but not between SCG × PCG. Limb tremor reduction was greater in anterior than in posterior paws. Lateral lesions yielded better results than medial lesions. These results suggest that the posterior striatum is involved with harmaline-induced tremor in rats and support the hypothesis presented.

Histological Effects of Residual Compression Sustained for 60 Minutes at Different Depths in a Novel Rat Spinal Cord Injury Contusion Model

Spinal cord injuries are frequently accompanied by persisting residual compression of the spinal cord; however, it remains controversial as to what effect the sustained compression has on neurological damage. The objective of this study was to determine the influence of post-traumatic residual spinal cord compression on the extent and progression of tissue damage within a dynamic thoracic contusion rat model. Twenty-nine male Wistar rats were distributed into one of four groups: spinal cord contusion only, contusion with 40% residual compression, contusion with 90% residual compression, and a surgical control group. A moderate injury was performed (1 mm, 700 mm/sec) with our custom University of British Columbia (UBC) multimechanism apparatus, and the residual compression groups had the impactor tip maintained at 40% or 90% of the initial impact depth (1.0 mm) for 60 min post-injury. All animals were killed at 3 h post-injury, when the spinal cord was harvested and stained for hemorrhage, neuronal damage in the gray matter, and axonal disruption in the white matter. The initial contusion injury immediately damaged tissue beneath the impactor as evidenced by rapid relaxation of the reaction force on the spinal cord during the subsequent compression. Importantly, the rostral-caudal extent of intramedullary hemorrhage was 66% larger after 90% residual spinal cord compression compared to the 40% group (p=0.016). Similarly, the extent of neuronal nuclei lost in different gray matter regions was 60-86% greater after 90% residual compression compared with 40% (p<0.001). Thus, a high level of residual compression of the spinal cord following a moderate contusion injury has the potential to adversely increase the extent of tissue damage, whereas a lower level of residual compression may have little to no effect.

Novel Animal Model of Calvarial Defect

Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been shown to be an effective therapy in the acute calvarial defect wound and in calvarial defects complicated by chronic scar. The authors compared the effectiveness of rhBMP-2 with the accepted standard of autologous graft for repair of irradiated calvarial defects. Nineteen adult New Zealand White rabbits underwent subtotal calvariectomy. Four days postoperatively, animals received 15 Gy to their wound. Six weeks postoperatively, scars were débrided and defects reconstructed in one of four groups: empty (n = 3), vehicle (buffer solution/absorbable collagen sponge; n = 3), cryopreserved autograft, (n = 3), or rhBMP-2 repair (rhBMP-2/absorbable collagen sponge, n = 10). Animals underwent computed tomography imaging at 0, 2, 4, and 6 weeks, followed by euthanization and histological analysis. Percent healing was determined and a 4 × 3 mixed model analysis of variance was performed on healing versus treatment group/postoperative time. According to radiopacity, rhBMP-2/sponge and autografts were statistically equivalent, with 99 and 89 percent healing at 6 weeks. Empty and vehicle treatment groups, with 35 and 34 percent healing, were inferior to the rhBMP-2/sponge and autograft groups (p < 0.05). Histologically, bone in the surgical control (autograft) group was less cellular and trabecular than bone formed after rhBMP-2/sponge treatment. rhBMP-2 therapy was as effective in reconstructing calvarial defects in the unfavorable irradiated wound as in the acute, favorable calvarial wound. Compared with cryopreserved autologous graft, rhBMP-2-regenerated bone resulted in equal defect coverage, similar thickness, and greater cellularity. Further studies are necessary to demonstrate the long-term viability and remodeling rhBMP-2/sponge-generated bone.

Hemorrhagic Shock and Surgical Stress Alter Distribution of Labile Zinc Within High- and Low-Molecular-Weight Plasma Fractions

Zinc ions (Zn) are essential for tissue repair following injury or stress. We hypothesize that during such stresses Zn is redistributed to labile pools in plasma components. Here we tested this hypothesis using a novel assay to monitor labile Zn in plasma in hemorrhagic shock. Adult rats in the shock group (S group) underwent hemorrhage and resuscitation. Blood samples were drawn at baseline and at 1, 4, and 24 h. The surgical control group (SC group) was anesthetized and instrumented, but not bled. Albumin, total Zn, and labile Zn levels were assayed in plasma. Binding capacity for Zn was assessed in high- and low-molecular-weight pools. Significant decreases in total Zn were observed by 24 h, in both S and SC groups. Albumin levels were significantly reduced in the S group at 1 and 4 h but restored at 24 h; significant changes were not observed in other groups. In whole plasma, labile Zn levels were stable initially in the S and SC groups, but declined at 24 h. In the high-molecular-weight pool, marked and significant impairment of binding was noted throughout all time periods following the shock period in the S group. Such changes were observed in the SC group of less intensity and duration. These experiments suggest that shock alters affinity of plasma proteins for Zn, promoting delivery to peripheral tissues during periods of increased Zn utilization.

CHANGES IN CILIARY BODY THICKNESS IN PATIENTS WITH DIABETIC MACULAR EDEMA AFTER VITRECTOMY

The purpose of the study to determine whether ciliary body thickness increased in the presence of diabetic macular edema (DME) and whether it changed after pars plana vitrectomy. A DME group consisted of 26 diabetic patients who underwent pars plana vitrectomy for diffuse DME. An epiretinal membrane group, a surgical control group, consisted of 23 nondiabetic patients with epiretinal membrane who underwent pars plana vitrectomy. A healthy control was also included for the comparison of preoperative ciliary body thickness. Ciliary body thickness was measured using ultrasound biomicroscopy, and central macular thickness was determined using optical coherence tomography. The visual acuity, ciliary body thickness, and central macular thickness were compared between groups before and 1, 2, and 4 months after pars plana vitrectomy, and the correlations between the central macular thickness and ciliary body thickness and best-corrected visual acuity were determined. The preoperative ciliary body thickness was increased significantly in the DME group compared with the epiretinal membrane and healthy control groups (both P < 0.001). The ciliary body thickness decreased significantly 1 and 2 months after surgery in the DME group (both P < 0.001) but not in the epiretinal membrane group. In the DME group, the postvitrectomy changes in the ciliary body thickness and central macular thickness showed similar trends and persisted significantly, until 4 months postoperatively (P = 0.027 and P = 0.010, respectively). The correlations between the preoperative central macular thickness and ciliary body thickness and between changes in central macular thickness and ciliary body thickness before and 2 months after surgery were not significant. Ciliary body thickness was increased in patients with DME, and vitrectomy was effective in decreasing ciliary body edema as well as macular edema in those patients during the 4-month follow-up period.

Effects of Different Surgical Techniques on Cephalic Index and Intracranial Volume in Isolated Bilateral Coronal Synostosis Model

Bilateral coronal synostosis (brachycephaly) is the most common single-suture synostosis that may lead to functional deficits such as mental retardation. This increases the importance of volume gain during surgery. This study was designed to understand the differences in volume gain, cranial index (CI), and aesthetic outcomes when additional osteotomies or rotations are applied on the frontoparietal segment. Acrylic brachycephaly models were prepared. Frontoparietal osteotomy was standard in all models. Frontoparietal segment was fixed: to the same position in surgical control model, after 1.2-cm advancement in advancement model, after 180-degree rotation without advancement in rotation model, after 180-degree rotation plus a horizontal osteotomy and 1.2-cm advancement in rotation plus angled advancement model, and after a horizontal osteotomy without rotation and 1.2-cm advancement and in angled advancement model. Intracranial volume changes (in milliliters) and CIs were as follows between groups: control group, 828/94.1; surgical control group, 830/93.8; advancement model, 900/84.5; rotation model, 834/89.1; rotation plus angled advancement model, 897/82.7; angled advancement model, 902/81.8. Advancement of the frontoparietal segment is the keystone of surgery in brachycephaly treatment. Making an additional horizontal osteotomy can angle this segment and may supply additional volume gain. Rotation of the frontoparietal segment does not provide additional volume or CI gain but increase better aesthetic outcomes.

Evaluation of oral health status and salivary flow rate in obese patients after bariatric surgery

The aim of this study was to identify the prevalence of dental caries, periodontal diseases and tooth wear in bariatric patients, and relate the oral health conditions to saliva flow. Fifty-two patients who had undergone bariatric surgery (Roux-en-Y gastric bypass) and 50 severely obese patients indicated for bariatric surgery were submitted to clinical examinations with regard to dental caries (DMFT index), periodontal condition (CPI index), dental wear (DWI index - Dental wear index) and saliva flow. The data were statistically analyzed by the Student's-t, Mann-Whitney, Spearman Correlation and Chi-square (χ(2)) tests at 5% significance level. The DMFT index was 16.11±5.19 in the surgical group and 16.06±6.29 in the control group (P>.05). The mean CPI was 3.05±0.84 for the operated group and 2.66±1.25 for the obese patients with no significant difference between them (P>.05). There was statistically significant difference between the groups for the presence of periodontal pockets (P=.021). All the patients presented some degree of tooth wear, however, with no significant difference between the two groups (P=.82). The mean saliva flow values of the surgical group and control group were 0.64±0.46 mL/min and 0.66±0.49 mL/min, respectively. There was no significant difference in saliva flow and all oral conditions analyzed (P>.05). The prevalence of oral diseases was similar in severely obese patients who were candidates for bariatric surgery and in patients who had been submitted to bariatric surgery. Nevertheless, there was higher prevalence of periodontal pockets in the operated group.

Novel Model of Calvarial Defect in an Infected Unfavorable Wound

Animal models of bone reconstruction have shown recombinant human bone morphogenetic protein 2 (rhBMP-2) to be an effective therapy in the acute calvarial defect wound. The purpose of this study was to compare the effectiveness of rhBMP-2 in a rabbit model of an unfavorable scarred calvarial wound with the criterion standard of autograft. Nineteen adult New Zealand white rabbits underwent subtotal calvariectomy. After 6 weeks of healing and normal scar formation, these animals underwent reoperation for scar debridement and assignment to 1 of 4 therapeutic groups. Animals were assigned to an empty control group (no treatment, n = 3), vehicle control group (neutral buffered solution on an absorbable collagen sponge [ACS], n = 3), surgical control group (cryopreserved autograft, n = 3), or an experimental treatment group (rhBMP-2 on an ACS, n = 10). All animals underwent computed tomography imaging at 0, 2, 4, and 6 weeks after secondary reconstructive surgery. At 6 weeks, all animals were killed, and the defects were examined histologically. Percentage of healing of each defect was determined, and a 4 × 3 mixed-model analysis of variance was performed on healing as a function of time and therapy. Based on measures of defect radiopacity, the treatment group (rhBMP-2/ACS) and surgical control group (autograft) were statistically equivalent with 98% and 83% healing, respectively, at 6 weeks. The empty control and vehicle control groups were inferior to the treatment group (rhBMP-2/ACS) and surgical control (autograft) groups at each timepoint (P < 0.05). Histologically, bone in the surgical control (autograft) group was less trabecular and less cellular than the bone formed in the experimental treatment group (rhBMP-2/ACS). Compared with historical controls, rhBMP-2 therapy was as effective in reconstructing calvarial defects in the unfavorable scarred wound as in the acute favorable calvarial wound. When compared with cryopreserved autograft, rhBMP-2-regenerated bone showed equal defect coverage and similar bone thickness with varying bony architecture.

Modulation of Postoperative Scarring with Tacrolimus and Octreotide in Experimental Glaucoma Filtration Surgery

Purpose: The purposes of this study were to investigate the effects of topically administrated Tacrolimus and Octreotide on modulation of postoperative scarring in experimental glaucoma filtration surgery and to compare the antifibrotic properties of these agents with mitomycin-C (MMC).Material and methods: A total of 28 New Zealand rabbits weighing 2.5–3 kg were randomly divided into a surgical control (SC) group and three experimental groups. Standard filtration surgeries were performed on the right eyes of all the rabbits. The rabbits in the SC group received only vehicle after the surgeries, whereas the rabbits in the three experimental groups were treated either with 0.4 mg/mL MMC during the surgery (MMC group) or with 0.3 mg/mL Tacrolimus drop four times a day (TT group) or with 10 µg/mL Octreotide drop three times a day (OT group) for 14 days. The animals were killed on day 14, eyes were enucleated and histologically and immunohistochemically analyzed.Results: In SC group mean fibroblast, mononuclear cell number and fibroblast growth factor-β (FGF-β), transforming growth factor-β (TGF-β) immunostaining intensity was higher than all treatment groups. In OT group mean fibroblast number was lesser than MMC (p < 0.01) and TT (p < 0.05) group. In TT group mean fibroblast number was lesser than MMC group (p < 0.05). Mean mononuclear cell number was similar between MMC, OT and TT groups (p > 0.05). In MMC, OT and TT groups mean TGF-β and FGF-β immunostaining intensity was similar (p > 0.05).Conclusions: Topically administration of Tacrolimus and Octreotide effectively reduced the subconjuntival scarring response 2 weeks after experimental glaucoma filtration surgery.

Blocking Bone Morphogenetic Protein Function Using In Vivo Noggin Therapy Does Not Rescue Premature Suture Fusion in Rabbits with Delayed-Onset Craniosynostosis

Craniosynostosis is defined as the premature fusion of one or more cranial sutures. Bone morphogenetic proteins (BMPs), regulators of ossification, have been implicated in premature suture fusion. Noggin, an extracellular BMP inhibitor, has been shown experimentally to inhibit resynostosis following surgery. The present study was designed to test the hypothesis that BMP inhibition using noggin therapy may rescue sutures destined to fuse by inhibiting initial ossification. Twenty-six, 10-day old rabbits with familial, delayed-onset, coronal suture synostosis were randomly divided into three groups: (1) the sham surgical control group, (2) the bovine serum albumin-treated group [10 μg/suture (protein/vehicle controls)], and (3) the noggin therapy group (10 μg/suture; experimental group). Sutural growth was monitored by radiopaque markers implanted at 10 days of age. At 25 days, the bovine serum albumin or noggin was combined with a slow-resorbing collagen vehicle and injected subperiosteally above the coronal suture. Somatic and sutural growth data were collected at 10, 25, 42, and 84 days of age. Coronal sutures were harvested at 84 days to histologically assess fusion. Results showed no significant (p > 0.05) differences in suture separation at any age. Suture fusion assessed by histomorphology did not differ among the three groups. Although previous data showed noggin to inhibit postoperative resynostosis in this craniosynostotic rabbit model, here there was no effect on initial suture fusion. These results suggest that in this rabbit model of craniosynostosis, BMPs do not play a role in the pathogenesis of craniosynostosis and only play a role in postoperative bony wound healing.

Sustained impact of electronic alerts on rate of prophylaxis against venous thromboembolism

Advanced electronic alerts (eAlerts) and computerised physician order entry (CPOE) increase adequate thromboprophylaxis orders among hospitalised medical patients. It remains unclear whether eAlerts maintain their efficacy over time, after withdrawal of continuing medical education (CME) on eAlerts and on thromboprophylaxis indications from the study staff. We analysed 5,317 hospital cases from the University Hospital Zurich during 2006-2009: 1,854 cases from a medical ward with eAlerts (interventiongroup) and 3,463 cases from a surgical ward without eAlerts (controlgroup). In the intervention group, an eAlert with hospital-specific venous thromboembolism (VTE) prevention guidelines was issued in the electronic patient chart 6 hours after admission if no pharmacological or mechanical thromboprophylaxis had been ordered. Data were analysed for three phases: pre-implementation (phase 1), eAlert implementation with CME (phase 2), and post-implementation without CME (phase3). The rates of thromboprophylaxis in the intervention group were 43.4% in phase 1 and 66.7% in phase 2 (p<0.001), and increased further to 73.6% in phase3 (p=0.011). Early thromboprophylaxis orders within 12 hours after admission were more often placed in phase 2 and 3 as compared to phase 1 (67.1% vs. 52.1%, p<0.001). In the surgical control group, the thromboprophylaxis rates in the three phases were 88.6%, 90.7%, 90.6% (p=0.16). Advanced eAlerts may provide sustained efficacy over time, with stable rates of thromboprophylaxis orders among hospitalised medical patients.

Morphological and Electromyogram Analysis for the Spinal Accessory Nerve Transfer to the Suprascapular Nerve in Rats

For many years, nerve transfer has been commonly used as a treatment option following peripheral nerve injury, although the precise mechanism underlying successful nerve transfer is not yet clear. We developed an animal model to investigate the mechanism underlying nerve transfer between branches of the spinal accessory nerve (Ac) and suprascapular nerve (Ss) in rats, so that we could observe changes in the number of motor neurons, investigate the 3-dimensional localization of neurons in the anterior horn of the spinal cord, and perform an electromyogram (EMG) of the supraspinatus muscle before and after nerve transfer treatment. The present experiment showed a clear reduction in the number of γ motor neurons. The distributional portion of motor neurons following nerve transfer was mainly within the neuron column innervating the trapezius. Some neurons innervating the supraspinatus muscle also survived post-transfer. Compared with the non-operated group, the EMG restoration rate of the supraspinatus muscle following nerve transfer was 60% in the experimental group and 80% in a surgical control group. Following nerve transfer, there was a distinct reduction in the number of γ motor neurons. Therefore, γ motor neurons may have important effects on the recovery of muscular strength following nerve transfer. Moreover, because the neurons located in regions innervating either the trapezius or supraspinatus muscle were labeled after Ac transfer to Ss, we also suggest that indistinct axon regeneration mechanisms exist in the spinal cord following peripheral nerve transfer.

Predictive or non-predictive, prognostic or non-prognostic: Dilemmas generated through small retrospective studies.

In this issue of the Journal of Gastrointestinal Oncology, Katkoori et al report on the impact of the pro-apoptotic protein Bax and its ratio to the anti-apoptotic portein Bcl2 (Bax/Bcl2) by immunohistochemistry grading on the outcome of patients with colorectal cancer treated with curative intent surgery or curative intent surgery followed by 5-FU-based chemotherapy (1). The chemotherapy group was selected from a patient population treated with curative intent surgery followed by at least 3 months of infusional 5-FU based chemotherapy or 6 months of bolus 5-FU-based chemotherapy between the years 1987-1993. The surgical control group was matched to the chemotherapy group by age, sex, stage, ethnicity, differentiation, and tumor location. The investigators demonstrate a better survival outcome in patients with increased Bax expression vs low Bax expression in the absence of chemotherapy (surgery only). A trend towards a worsened survival outcome is noted in patients with increased Bax expression vs low Bax expression in the presence of chemotherapy. Furthermore, a low Bax/Bcl2 ratio was associated with a better survival outcome in comparison to high Bax/Bcl2 ratio in the presence of 5-FU based chemotherapy. The authors conclude that patients with higher Bax expression may not benefit from adjuvant chemotherapy. One has to recognize that there are several limitations to the Katkoori study. First, the study suffers from a small and heterogeneous population. Twenty-five percent of patients investigated in this study had stage IV disease. Therefore, data extrapolation from this heterogeneous population to adjuvant treatment in stage II-III disease cannot be applied. If the intent of the study is to investigate the impact of Bax on the effectiveness of adjuvant chemotherapy, it would have been advisable to limit the study population to stages II-III disease. Second, it is impossible from the current study design to conduct a meaningful evaluation of the impact of Bax or Bax/Bcl2 or p53 on OS within the surgical and chemotherapy groups. Since patient characteristics among the various biomarker groups had not been matched for other known risk variables of relapse within the surgery and chemotherapy groups, it would be possible that the divergence in outcome was due to an imbalance in other patient characteristics rather than due to Bax of Bax/Bcl2. Third, the study assumes no differences between various arms of 5-FU-based therapy in the chemotherapy arm, a finding refuted by prior randomized studies. Is Bax prognostic? In the surgical group that did not receive chemotherapy, patients with elevated Bax had an improved survival. This would suggest that Bax overexpression is a positive prognostic factor. This could only be hypothesized if the high and low-Bax patients in the surgery-only arm were matched by stage, grade, and other relevant risk factors. This was not the case. Is Bax/bcl-2 predictive of 5-FU response? In the patient undergoing surgery followed by 5-FU, patients with low bax/bcl-2 has a superior outcome than patients with high Bax/Bcl2. This would suggest that high bax/blc-2 is predictive of 5-FU resistance. This can only be hypothesized if the two groups were matched for other risks of recurrence or progression. This was not the case. Stage heterogeneity, small sample size, and the heterogeneity of 5-FU-based therapy, significantly limit the results from this study. In addition, the results do not support findings from a larger series evaluating the impact of Bax and Bcl2 expression on 5-FU-treated colorectal cancer patients (2). In a study of 188 patients treated with 5-FU based chemotherapy, low Bax expression was associated with a worsened outcome and patients with high Bax expression and low Bcl2 had the best outcome (2). How do we move forward? This study illustrates the limitations of analyzing subjectively graded variables in a heterogeneous colorectal cancer population. It is time to recognize the complex interactions between variable prognostic markers of progression and disease resistance. Such interactions can only be tested in large patient populations whose baseline characteristics and outcomes were collected in a prospective controlled manner. A quantitative multi-gene RT-PCR assay for the prediction of recurrence in stage II colon cancer was recently developed by Genome Science using the QUASAR study population (3). While this assay is somewhat successful in categorizing stage II colon cancer into 3 distinct categories of risk of relapse, it failed to predict for benefit or lack off with 5-FU therapy. Oncotype DX profiling is one step in the right direction, but more work is clearly needed.

Neuropsychological Status in Children After Repair of Acyanotic Congenital Heart Disease

The majority of previous studies that described the neuropsychological effects of cardiopulmonary bypass (CPB) in children were performed after surgery in infancy for complex congenital heart disease (CHD). We sought to limit confounding variables and isolate potential independent effects of CPB by describing neuropsychological function in school-aged children after repair of acyanotic CHD. This was a prospective study of patients who were aged 5 to 18 years and undergoing repair of acyanotic CHD. Neuropsychological testing battery included assessment of intelligence, memory, motor, attention, executive function, and behavior before and 6 months after CPB. The independent effects of anesthesia, surgery, and hospitalization on neuropsychological function were assessed by testing a surgical control group of patients who were undergoing repair of pectus deformities. In addition, an outpatient group of children with mild CHD were enrolled to assess the practice effects of serial testing. Patients included CPB (n = 35), surgical control (n = 19), and nonsurgical (n = 12). Groups were comparable in age, gender, and race and demonstrated similar unadjusted group mean scores on baseline and 6-month follow-up neuropsychological testing. When adjusted for practice effects, the CPB group performed similar to the non-CPB groups in all assessed neuropsychological domains, with the exception of 1 of 4 tests of executive function. When controlling for the non-CPB effects of surgery (eg, hospitalization, anesthesia, thoracotomy) and the practice effects of serial testing, there were no consistent independent effects of CPB on neuropsychological status in a cohort of children and adolescents 6 months after repair of acyanotic CHD.

The Influence of Atorvastatin on Tendon Healing: An Experimental Study on Rabbits

Hyperlipidemia is a major risk factor for coronary heart disease. The most commonly used antihyperlipidemic drugs are 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins), of which atorvastatin is one of the most widely used. Little is known about the relationship between tendinopathy and HMG CoA reductase inhibitors (statins) or the effects of atorvastatin use on tendon healing following surgical repair of tendon rupture. We hypothesized that atorvastatin negatively affects this healing process. The Achilles tendons of 16 New Zealand rabbits were ruptured surgically and repaired with sutures. Eight of the rabbits were given oral atorvastatin. The other 8 served as a surgical control group. Six weeks postoperatively, all the rabbits were sacrificed, and the repaired tendons were removed. After standard histological preparation, fibroblastic activity, re-vascularization, collagenization, collagen construction, and inflammatory-cell infiltration were evaluated. On comparing the atorvastatin and surgical control groups, we observed no difference in fibroblastic activity. Although it did not reach statistical significance in our study, a difference was noted in revascularization, collagenization, and inflammatory cell infiltration; and a statistical difference was observed in collagen construction. Doubt remains about the adverse effect of atorvastatin use during tendon healing. Further investigations in animal and human models are needed on the effects of tendon healing when atorvastatin is administered for a longer time frame prior to the injury.

Premature preoperative discontinuation of antiplatelet drug therapy in cardiovascular risk patients: a preliminary study on the role of P2Y12 receptor monitoring

In high-bleeding risk procedures, discontinuation of antiplatelet drug therapy with clopidogrel may be requested by surgeons, usually 7-10 days before the surgical procedure. New platelet function tests, such as the vasodilator-stimulated phosphoprotein phosphorylation assay, may help to assess the perioperative status of the clopidogrel-specific P2Y12 receptor. Using vasodilator-stimulated phosphoprotein phosphorylation assay, the platelet reactivity index (PRI) was measured in 80 individuals, including 20 healthy volunteers, 20 cardiologic patients under full antiplatelet drug therapy with clopidogrel and aspirin, 20 surgical patients without any antiplatelet drugs and 20 patients under clopidogrel, discontinued 7 days before the surgical procedure. The mean PRI (95% confidence interval) in healthy volunteers was 86 (82-89%) and that in the surgical control group was 77% (72-81%). In cardiologic patients under full antiplatelet therapy, mean PRI was 51% (42-60%). In the clopidogrel discontinuation group, PRI increased from 51% (40-62%) on day 0 to 65% (57-74%) on day 3 and to 76% (69-84%) on day 5. On the morning of surgery, mean PRI was 85% (80-91%). The PRI values on the 5th day were equivalent to those of the surgical control group (mean difference -0.4%, 95% confidence interval -8.6% to 7.8%, P = 0.9). Fifty-five percent of the patients in the discontinuation group had a PRI of more than 50% on day 0. The study using vasodilator-stimulated phosphoprotein phosphorylation assay, one of the new platelet function assays for the assessment of inhibition of platelet P2Y12 receptor, demonstrates that the PRI on day 5 after discontinuation of clopidogrel is equivalent to a surgical control group and it questions the rigid practice of delaying surgery for 7-10 days, particularly in patients without a clopidogrel effect.