Prevalence and Spatial Distribution of Gastroschisis in an Industrial Watershed.

The relationship between the congenital defect of gastroschisis and environmental toxins is poorly understood. We examined gastroschisis incidence, risk factors, and spatial association in a geographic region with known environmental pollution and hazardous waste sites. An observational study of fetal and neonatal gastroschisis diagnosed from 1/1/2006 to 12/31/2020 was conducted in a southern West Virginia (WV) tertiary care hospital. Emerging hot spot analysis and Ripley's K-Function examined the spatial relationship between gastroschisis cases and Environmental Protection Agency (EPA) Federal Registry Sites (FRS). A total of 63 gastroschisis cases provided a prevalence rate of 14.6 per 10000 live births. Gastroschisis was associated with younger maternal age, decreased pre-pregnancy BMI, and increased maternal tobacco use. Relative to FRS sites, spatial clusters were identified with emerging hot spot analysis. Observed Ripley K was higher at all measured bands. Results suggest a potential geographic association between gastroschisis cases and EPA-designated hazardous waste sites.

Toe Pressures are Superior to Duplex Parameters in Predicting Wound Healing following Toe and Foot Amputations.

BACKGROUND: No criteria, including preamputation vascular diagnostic thresholds, have been established to reliably predict healing versus nonhealing following minor lower extremity amputations. Thus, the goal of our study was to identify clinical factors, including noninvasive vascular laboratory measures, associated with wound healing following toe, forefoot, and midfoot amputations. METHODS: We retrospectively examined records of patients receiving elective toe, forefoot, or midfoot amputation at our institution over a 5-year span (2010-2015). A total of 333 amputations received noninvasive vascular assessment of the lower extremity preamputation and follow-up at 90 days postamputation. Multivariate binomial logistic regression was used to identify variables predicting wound healing as defined as the absence of reamputation due to wound breakdown. RESULTS: Wound healing occurred in 81% of amputations. A total of 23 (7%) patients required revisions of the foot while 39 (12%) patients required major amputations by 90 days. Chi-squared analysis found that toe pressure at or above the value of 47 mm Hg (P = 0.04), bi/triphasic anterior tibial (P = 0.01), and posterior tibial artery (P = 0.01) waveforms were associated with wound healing. When these diagnostic parameters were examined in the presence of confounders (increasing age, chronic kidney disease, and concomitant revascularization), only toe pressure ≥ 47 mm Hg predicted amputation site healing (odds ratio: 3.1 [95% CI: 1.0-9.4], P = 0.04). CONCLUSION: Preamputation toe pressures of 47 mm Hg and above are associated with wound healing. No other noninvasive vascular studies predicted wound healing in the presence of confounders. Thus, toe pressures may assist in clinical decision-making and should be routinely obtained preamputation.

Factors Affecting Choice of Treatment for Early-Stage Breast Cancer in West Virginia: A 10-Year Experience from a Rural Tertiary Care Center.

Recent literature shows changing trends in use of breast conservation surgery (BCS), mastectomy, and contralateral prophylactic mastectomy (CPM) in women with early-stage breast cancer (ESBC). We analyzed factors associated with selection of these treatment modalities in a rural West Virginia tertiary care hospital. We conducted a 10-year analysis of women treated for ESBC at our institution from the institutional cancer registry. Variables were compared between patients choosing BCS versus mastectomy. In women who chose mastectomy, predictors for choice of CPM were also examined. Variables with P < 0.05 on univariate analysis were entered into a multivariate logistic regression model to define independent predictors of treatment choice. The mastectomy rate increased from 18.0 per cent in 2006 to 40.2 per cent in 2013. On multivariate analysis, insurance status (P < 0.001), comorbidities (P = 0.001), and surgeon graduation after 1987-a surrogate for surgeon age-(P = 0.010) predicted receipt of mastectomy. Of those receiving mastectomy, 106 (25.1%) elected CPM. CPM rates increased from 8.0 per cent in 2006 to 45.0 per cent in 2013. Younger age at diagnosis (P < 0.001) and use of preoperative MRI (P = 0.012) independently predicted use of CPM versus unilateral mastectomy. Rates of mastectomy and CPM in ESBC have increased in West Virginia over time. Independent predictors of selecting mastectomy over BCS included insurance status, surgeon age, and associated comorbidities. Younger patients and patients receiving preoperative MRI were more likely to choose CPM. Awareness of these factors will aid in counseling women with ESBC and allow clinicians to address potential biases or disparities that may affect treatment choices. Further prospective study of these findings is warranted.

Disparities in Rural Breast Cancer Care: Factors Affecting Choice of Breast Reconstruction in a West Virginia Tertiary Care Hospital.

The decision to pursue immediate postmastectomy breast reconstruction (IBR) is not uniform across all groups of women in the United States. We sought to investigate if the challenges of caring for a socioeconomically and geographically challenged rural population affected the incidence of IBR and to identify predictive factors of IBR in this population. Using our institution's cancer registry, we conducted a 10-year review of women with early-stage, unilateral breast cancer who received mastectomy. Demographics, insurance status, comorbidities, and surgeon graduation year were compared for patients receiving IBR versus no reconstruction. Variables with P < 0.05 on univariate analysis were included into a multivariate logistic regression model to determine independent predictors of IBR. From 2006 to 2015, 53/423 (12.5%) patients underwent IBR. On multivariate analysis, three factors independently predicted the decision to undergo IBR: age (P = 0.004), insurance type (P = 0.034), and use of contralateral prophylactic mastectomy (CPM, P < 0.001). Our data indicate that age, insurance type, and utilization of CPM influence the decision to pursue reconstruction. Additionally, the rate of IBR was found to be much lower in our West Virginia population than reported nationally, suggesting disparities in the care of women with early-stage, unilateral breast cancer in a rural population, even in a tertiary care environment.

Trends and Outcomes in the Operative Management of Traumatic Vascular Injuries: A Comparison of Open versus Endovascular Approaches.

Controversy exists in vascular trauma regarding the best method of treatment-open versus endovascular techniques. Little has been published on this complex topic. Patients from 2005 to 2013 at a Level I trauma center with vascular injuries were identified via a prospectively trauma registry. Patient data, injury type/severity, treatment, and 30-day outcomes were obtained from the trauma registry and the chart review. Adverse events (limb loss, major disability, and death) were outcomes of interest. Univariate analysis and multivariate logistic regression were used to identify predictors of adverse events. In all, 346 patients were included (median age 34, range 1-93 years). Median Injury Severity Score (ISS) was 10 (1-59). Endovascular repairs (n = 52) increased from 0 per cent (2005) to 32 per cent (2013), and demonstrated equivalent outcomes to open approaches (P = 0.24). On multivariate analysis, higher ISS (P = 0.001), increasing age (P = 0.01), and lower extremity injuries (P = 0.001) were associated with adverse outcomes across the entire series. Endovascular approaches were most commonly used in vascular injuries of the chest/abdomen (39 of 52, 75% of all endovascular procedures in the series, P < 0.001), older patients (P = 0.003), blunt injury mechanism (P < 0.001), and patients with a higher ISS at presentation (P < 0.001). In conclusion, this large series, the use of endovascular procedures increased over time, and was associated with equivalent outcomes to open approaches, despite their higher usage in older patients, those with chest/abdominal injuries, and those with a higher ISS at presentation. Although these retrospective results are encouraging, further prospective study into the role of endovascular therapies in the treatment of vascular injuries.

The Impact of Biochemical Markers on Major Adverse Cardiovascular Events and Contralateral Carotid Artery Stenosis Progression Following Carotid Interventions.

BACKGROUD: To determine if elevated preintervention high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) levels associate with major adverse cardiovascular events (MACE) or disease progression after carotid revascularization. METHODS: We retrospectively examined patients receiving elective carotid endarterectomy (CEA) or carotid artery stenting (CAS) at our institution from 2007 to 2014. All included patients had preintervention hsCRP and BNP levels. Examined outcomes of interest included contralateral carotid disease progression (increased stenosis or need for revascularization) and MACE (composite of death, stroke, myocardial infarction, need for coronary artery bypass graft or percutaneous coronary intervention) at 3 years after procedure. The relationship between baseline hsCRP and BNP levels and time to event was examined by univariate and multivariate Cox proportional hazard regression analyses. RESULTS: A total of 248 patients were included in the analysis (mean age: 68 ± 10 years), with 14% receiving CAS and 86% CEA. A total of 61 patients (25%) had 1 or more MACE by 3 years. Elevated hsCRP (>3 mg/L) trended toward associating with MACE but failed to reach significance (hazard ratio [HR]: 1.6 [1.0-2.7], P = 0.07). Multivariate analysis found that elevated BNP (>100pg/mL, HR: 2.2 [1.3-3.7], P = 0.002) and diabetes mellitus (HR: 1.9 [1.2-3.2], P = 0.01) predicted MACE. Having elevated preprocedural levels of both hsCRP and BNP significantly increased patients' likelihood of experiencing MACE (HR: 3.4 [1.6-7.1], P = 0.001). About 175 patients received contralateral carotid imaging postprocedure and of those patients, 31 (18%) experienced stenosis progression and/or revascularization within 3 years. However, neither elevated hsCRP (HR: 1.2 [0.6-2.3], P = 0.68) nor BNP (HR: 1.1 [0.5-2.5], P = 0.88) associated with disease progression. CONCLUSIONS: BNP elevation at the time of carotid intervention is associated with MACE in long-term follow-up. hsCRP does not appear to correlate with either disease progression of the contralateral artery or MACE.

Management of Iatrogenic Pseudoaneurysms in Patients Undergoing Coronary Artery Bypass Grafting.

OBJECTIVE: A plethora of papers have been written regarding postcatheterization femoral pseudoaneurysms. However, literature is lacking on pseudoaneurysmal management in patients undergoing coronary artery bypass grafting (CABG). Thus, we examined if pseudoaneurysms with subsequent CABG can be managed with the same strategies as those not exposed to the intense anticoagulation accompanying CABGs. METHODS: During a 14-year study period, we retrospectively examined femoral iatrogenic pseudoaneurysms (IPSAs) diagnosed postheart catheterization in patients having a subsequent CABG. Patient information was obtained from electronic medical records and included pseudoaneurysm characteristics, treatment, and resolution. Outcomes of interest included the occurrence of IPSA treatment failures and complications. RESULTS: In the 66 patients (mean age, 66 ± 11 years, 46% male) meeting inclusion criteria, mean dose of heparin received during the CABG procedure was 34 000 ± 23 000 units. The IPSA size distribution was the following: 17% of IPSAs measured <1 cm, 55% between 1 and 3 cm, and 21% measured >3 cm. Pseudoaneurysms were managed with compression, duplex-guided thrombin injection, and surgical repair (1%, 27%, and 26% of cases, respectively). Thrombin injection and surgical repair were 100% effective at treating pseudoaneurysms, with 1 patient experiencing a surgical site infection postsurgical repair. Observation-only management was employed in 30 (45%) patients. Nine of 30 patients with no intervention beyond observation had duplex documented resolution/thrombosis during follow-up. One patient initially managed by observation required readmission and surgical repair of an enlarging pseudoaneurysm (6 cm growth) following CABG. CONCLUSION: Management of pseudoaneurysms in patients prior to CABG should be similar to those patients not undergoing intense anticoagulation. In appropriate cases, small aneurysms can be safely observed, while thrombin injections are effective and safe as well. Thus, routine open surgical repair is not routinely required in patients with femoral pseudoaneurysms at time of CABG.

Ten-Year Experience of Vascular Surgeon Management of Iatrogenic Pseudoaneurysms: Do Anticoagulant and/or Antiplatelet Medications Matter?

BACKGROUND: Previous studies examining the natural history of femoral pseudoaneurysms (PSAs) were performed before the current era of anticoagulant and/or antiplatelet therapy. The purpose of our study was to elucidate in a vascular surgeon directed approach to PSAs, the association between medication use and the failure of conservative, observation-only management. METHODS: We retrospectively examined 308 femoral iatrogenic PSAs diagnosed via duplex imaging at our institution during a 10-year time period (2004-2013). Information on PSA characteristics, treatment, and antiplatelet and/or anticoagulant medication usage was obtained. We identified patients who failed observation-only conservation management, with failure defined as the need for delayed treatment because of PSAs triggered by either expansion (≥ 1 cm increase or size enlarging to ≥ 3 cm) and/or persistence (≥ 15 days). RESULTS: Immediate and/or acute treatments of PSAs included 1 ultrasound-guided compression, 14 surgical repairs, and 126 thrombin injections. Of the 167 PSAs initially managed by observation only, 70 (42%) were found by ultrasound imaging to thrombosis spontaneously. An additional 70 (42%) patients had the diagnosis of PSA <3 cm and were managed conservatively with only clinical follow-up. Twenty-seven PSAs (16%) originally managed conservatively required additional treatment because of expansion and/or persistence. Patients receiving dual-antiplatelet therapy had higher rates of failed conservative management (44%) than patients not on dual therapy (9%, P < 0.01). The number of antiplatelet and/or anticoagulant medications used during observation was larger in patients failing conservative management (2.0 ± 0.7) versus patients not requiring additional intervention (1.5 ± 0.7, P < 0.01). CONCLUSIONS: Most of the PSAs initially managed with observation-only did not require additional intervention. However, anticoagulant and/or antiplatelet agents use associated with PSAs required further intervention after failing observation-only management. When observation is the chosen strategy for PSA management, especially in the setting of aggressive antithrombotic and dual-antiplatelet therapy, surveillance is required to ensure proper resolution.

Biochemical markers in patients with open reconstructions with peripheral arterial disease.

The purpose of our study was to determine outcome differences as a function of baseline high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) levels in patients receiving lower extremity open reconstructions for the treatment of peripheral arterial occlusive disease. We retrospectively examined patients who underwent surgical reconstructions performed by a single operator during a seven-year time span who received preoperative hsCRP and BNP testing and post-procedure imaging. Outcomes of interest included major adverse limb events, a composite end point of target vessel revascularization, limb amputation, and disease progression, and major adverse cardiovascular events comprised of stroke, myocardial infarction, and death. A total of 89 limbs in 82 patients were included in analysis. Multivariate analysis demonstrated that higher hsCRP levels (>3.0 mg/L) trended toward, but failed to significantly associate with major adverse limb events at 24 months (hazard ratio: 2.2 [1.0-5.2], p = 0.06), however the use of a vein bypass conduit (vs. prosthetic reconstruction) significantly predicted major adverse limb events (hazard ratio: 3.2 [1.5-6.9], p < 0.01). Elevated BNP levels (>100 pg/ml), but not hsCRP, associated with major adverse cardiovascular events (hazard ratio: 3.5 [1.2-10.3], p = 0.03). Preoperative biochemical markers may assist in clinical decision making and stratifying patients regarding adverse events following open reconstructions.

Early results with LifeStent implantation in RESILIENT and non-RESILIENT inclusion criteria patients.

The purpose of our study was to determine outcomes of patients receiving the LifeStent (Bard Peripheral Vascular, Tempe, AZ) for femoropopliteal peripheral arterial disease in real-world academic practice outside the limitations of an industry supported trial. All patients from 2009 to 2012 at our institution who received a LifeStent during endovascular interventions and had follow-up were included. Outcomes evaluated included patency and freedom from limb loss. A total of 166 limbs in 151 patients had the LifeStent implanted in de novo vessels (54% male; 68 ± 12 years). Eighty-percent of limbs did not meet RESILIENT criteria due to Rutherford category >3 (51%), TransAtlantic Inter-Society Consensus II classifications C/ D (51%), zero runoff vessels (6%), or stent location (17%). Primary patency rates were 81% at 6 months and 58% at 12 months with predictors for primary patency loss at 1 year including Rutherford category >3 (HR: 1.8 (95% CI: 1.0-3.1), p = 0.04), tobacco use (HR: 1.8 (95% CI: 1.0-3.3), p = 0.04), and no clopidogrel at discharge (HR: 3.2 (95% CI: 1.6-6.7), p < 0.01). A preintervention Rutherford category >3 predicted 24-month limb loss (HR, 16.0 (95% CI: 2.0-122.0), p < 0.01). The LifeStent is a viable option regardless of the TransAtlantic Inter-Society Consensus II classification; however, critical limb ischemia, current tobacco use, and absence of clopidogrel on discharge predict decreased patency on follow-up.

C-reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization.

BACKGROUND: High-sensitivity C-reactive protein (hsCRP) and brain natriuretic peptide (BNP) have been shown to be independent predictors of adverse cardiovascular outcomes and increased risk of secondary interventions or limb loss in patients with peripheral arterial disease (PAD). To assist clinicians in decision-making about treatment approaches and predicting postprocedure mortality and morbidity, we retrospectively examined patients with preprocedure hsCRP and BNP levels who underwent elective angioplasty or stent placement for lower extremity PAD. METHODS: The study period was from January 1, 2007, to December 31, 2012, and patients were included who had angioplasty or stenting for PAD. Minimal required follow-up for study inclusion was at least one postoperative ankle-brachial index, contrast angiography, or duplex imaging of the treated limb. Events of interest included major adverse limb events (MALE), defined as target vessel revascularization, amputation, or disease progression by 1 year, and major adverse cardiovascular events (MACE; stroke, myocardial infarction, or death) by 2 years. Elevated/abnormal values for our biomarkers of interest were established by the upper limits of our institution's clinical laboratory reference range (hsCRP, >0.80 mg/dL; BNP, >100 pg/mL). RESULTS: A total of 159 limbs in 118 patients were included in analysis (42% men; median age [range], 64 [42-87] years). All limbs were symptomatic (Rutherford classification: 1-6). Iliac artery revascularization without other adjunct lower extremity intervention was performed in 60% of the limbs. High hsCRP levels (>0.80 mg/dL) were present in 32 patients (27%) and high BNP values (>100 pg/mL) in 24 patients (20%). Kaplan-Meier analysis with log-rank comparison demonstrated that elevated hsCRP levels were associated with MALE but only in limbs receiving interventions distal to the iliac arteries (P = .005). High BNP levels did not affect MALE rates (P = .821). Conversely, both elevated BNP levels (hazard ratio, 5.6; 95% confidence interval [CI], 2.0-5.8; P = .001) and hsCRP levels (hazard ratio, 2.9; 95% CI, 1.1-7.6; P = .034) predicted MACE at 2 years in the presence of confounders in Cox proportional hazards multivariate analysis. Patients with high preintervention values of hsCRP and BNP were 10.6 times (95% CI, 2.6-42.9; P = .001) more likely to experience MACE than were patients with normal hsCRP and BNP values. CONCLUSIONS: After lower extremity endovascular interventions, elevated preprocedural hsCRP levels are associated with MALE (femoral-popliteal interventions), and elevated levels of hsCRP and BNP are associated with late cardiovascular events.

Evolving treatment of popliteal artery aneurysms.

BACKGROUND: Over the past decade, the treatment of popliteal aneurysms has evolved at our institution from sole operative intervention during the initial part of the study period, to combined surgical and endovascular treatment, and finally to endovascular-centered management in more recent years. METHODS: This is a retrospective review of all patients with popliteal aneurysms treated at our institution from 2001 to 2011. Data collection included the indication for intervention, treatment details, interventional patency, limb salvage, perioperative outcome, and midterm survival. RESULTS: Eighty-eight aneurysms (72 patients) were treated during this period. Indications for intervention included symptomatic presentations in 53% (n = 47) and asymptomatic in 47% (n = 41). Treatment included endovascular exclusion in 24, surgical repair in 63 (14 posterior approach and 49 medial approach with bypass and exclusion), and primary amputation in one patient. Nine aneurysms (10.2%) received catheter-directed thrombolysis. Demographics were similar between the two treatment cohorts, except for age with endovascular stenting patients being significantly older (76.0 vs 66.0 years; P = .002). The mean length of stay was 3.9 days vs 9.5 days (P < .001), favoring endovascular treatment. There were no perioperative (30-day) deaths in the endovascular group and one in the surgical cohort. The mean patency follow-up was 21.2 vs 28.3 months. Primary patency did not differ between endovascular and surgically treated patients at 1 year (92.9% vs 83.3%; P = .26) and 3 years (63.7% vs 77.8%; P = .93). No limbs were lost in the endovascular group during the follow-up period of 22.4 months, and one late limb loss occurred in the surgical cohort (mean follow-up, 29.2 months). Endovascular patients had a midterm survival rate of 65% (mean follow-up, 33.9 months), whereas surgical patients experienced a survival rate of 80.8% (mean follow-up, 42.9 months; P = .22). CONCLUSIONS: Endovascular treatment of popliteal aneurysms provides similar short-term patency to that of the traditional gold standard approach with surgical bypass, with shorter hospitalizations in both symptomatic and asymptomatic patients. Further long-term follow-up is required to compare these two treatment modalities for durability to determine the optimal popliteal aneurysm management.

Pharmacological analysis of the cortical neuronal cytoskeletal protective efficacy of the calpain inhibitor SNJ-1945 in a mouse traumatic brain injury model.

The efficacy of the amphipathic ketoamide calpain inhibitor SNJ-1945 in attenuating calpain-mediated degradation of the neuronal cytoskeletal protein α-spectrin was examined in the controlled cortical impact (CCI) traumatic brain injury (TBI) model in male CF-1 mice. Using a single early (15 min after CCI-TBI) i.p. bolus administration of SNJ-1945 (6.25, 12.5, 25, or 50-mg/kg), we identified the most effective dose on α-spectrin degradation in the cortical tissue of mice at its 24 h peak after severe CCI-TBI. We then investigated the effects of a pharmacokinetically optimized regimen by examining multiple treatment paradigms that varied in dose and duration of treatment. Finally, using the most effective treatment regimen, the therapeutic window of α-spectrin degradation attenuation was assessed by delaying treatment from 15 min to 1 or 3 h post-injury. The effect of SNJ-1945 on α-spectrin degradation exhibited a U-shaped dose-response curve when treatment was initiated 15 min post-TBI. The most effective 12.5 mg/kg dose of SNJ-1945 significantly reduced α-spectrin degradation by ~60% in cortical tissue. Repeated dosing of SNJ-1945 beginning with a 12.5 mg/kg dose did not achieve a more robust effect compared with a single bolus treatment, and the required treatment initiation was less than 1 h. Although calpain has been firmly established to play a major role in post-traumatic secondary neurodegeneration, these data suggest that even brain and cell-permeable calpain inhibitors, when administered alone, do not show sufficient cytoskeletal protective efficacy or a practical therapeutic window in a mouse model of severe TBI. Such conclusions need to be verified in the human clinical situation.

Occurrence of vitamin D deficiency in pediatric patients at high risk in West Virginia.

OBJECTIVES: Vitamin D deficiency is prevalent and is increasingly associated with the development of medical conditions both related and unrelated to bone metabolism. The purpose of this study was to examine vitamin D deficiency in patients of a pediatrics subspecialty practice. METHODS: The study consisted of a retrospective chart review of patients aged 2 to 18 years who were referred to the West Virginia University Physicians of Charleston pediatrics subspecialty group with a diagnosis of obesity, chronic kidney disease, diabetes, hypertension, or cystic fibrosis. All of the patients had 25-hydroxyvitamin D levels measured from 2007-2009. Seventy-six patients met inclusion criteria. RESULTS: A total of 23.7% of patients were vitamin D deficient (≤ 20 ng/mL). Children with vitamin D deficiency were older and had higher rates of obesity than those with nondeficient vitamin D levels. The comorbidities of cystic fibrosis, diabetes, hypertension, and chronic kidney disease did not associate with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is common in children in West Virginia and is associated with increasing age and obesity. Vitamin D screening and supplementation should be considered in all children with chronic illness, particularly those who are overweight.

Medication discrepancies identified at time of hospital discharge in a geriatric population.

BACKGROUND: It has been reported that 14.1% of geriatric patients experience ≥1 medication discrepancies after hospitalization. OBJECTIVE: The goal of this study was to identify and characterize discharge medication list discrepancies among geriatric patients and to describe characteristics associated with discrepancies. METHODS: An institutional review board-approved retrospective review was conducted of patients aged ≥65 years discharged from hospitalist and internal medicine services at a large tertiary care hospital from August 2008 to December 2009. A random cohort of 200 patients was selected and categorized by age, gender, attending medical service, and the absence or presence of a pharmacist on the service. Medication lists were obtained from physician discharge summaries, discharge orders, and nursing discharge lists. RESULTS: A total of 1923 medication discrepancies were identified, consisting of 402 related to the absence or presence of a medication, 298 related to the dosage administered at one time, 223 related to the number of daily doses, and 1000 related to the route of administration. Physician discharge summaries contained the most medication discrepancies. There was no relationship between patient age and the number of medication discrepancies (r(2) = 0.006; P = 0.279), whereas there was a linear relationship between the number of medications and the number of discrepancies (r(2) = 0.249; P < 0.001). The internal medicine team with a pharmacist had a lower average number of discrepancies per patient compared with other medicine services that did not have a pharmacist present. CONCLUSIONS: Medication discrepancies at the time of hospital discharge are a common occurrence for geriatric patients. Physician summaries might be the least reliable source of discharge medication lists. The number of discrepancies appears to not be associated with patient age, but rather with the number of medications at discharge. Discrepancies among medication lists are common, and the presence of a pharmacist may reduce the number that occur.

A pharmacological analysis of the neuroprotective efficacy of the brain- and cell-permeable calpain inhibitor MDL-28170 in the mouse controlled cortical impact traumatic brain injury model.

The cytoskeletal and neuronal protective effects of early treatment with the blood-brain barrier- and cell-permeable calpain inhibitor MDL-28170 was examined in the controlled cortical impact (CCI) traumatic brain injury (TBI) model in male CF-1 mice. This was preceded by a dose-response and pharmacodynamic evaluation of IV or IP doses of MDL-28170 with regard to ex vivo inhibition of calpain 2 activity in harvested brain homogenates. From these data, we tested the effects of an optimized MDL-28170 dosing regimen on calpain-mediated degradation of the neuronal cytoskeletal protein α-spectrin in cortical or hippocampal tissue of mice 24 h after CCI-TBI (1.0 mm depth, 3.5 m/sec velocity). With treatment initiated at 15 min post-TBI, α-spectrin degradation was significantly reduced by 40% in hippocampus and 44% in cortex. This effect was still observed with a 1-h but not a 3-h post-TBI delay. The cytoskeletal protection is most likely taking place in neurons surrounding the area of mainly necrotic degeneration, since MDL-28170 did not reduce hemispheric lesion volume as measured by the aminocupric silver staining method. This lack of effect on lesion volume has been seen with other calpain inhibitors, which suggests that pharmacological calpain inhibition by itself, while able to reduce axonal injury, may not be able to produce a measurable reduction in lesion volume. This is in contrast to certain other neuroprotective mechanistic approaches such as the mitochondrial protectant cyclosporine A, which produces at least a partial decrease in lesion volume in the same model. Accordingly, the combination of a calpain inhibitor with a compound such as cyclosporine A may be needed to achieve the optimal degree of post-TBI neuroprotection.

Regulation of the polymeric immunoglobulin receptor in intestinal epithelial cells by Enterobacteriaceae: implications for mucosal homeostasis.

The commensal microbiota of the human colon profoundly impacts host gene expression and mucosal homeostasis. Secretory IgA antibodies, which influence the composition of the intestinal microbiota and provide immunity against pathogens, are transported across intestinal epithelial cells (IEC) by the polymeric immunoglobulin receptor (pIgR). To compare the effects of different colonic bacteria on pIgR expression, the human IEC line HT-29 was stimulated with various species representing the 4 major phyla of colonic bacteria. Only bacteria from the family Enterobacteriaceae (phylum Proteobacteria) induced expression of pIgR and other target genes of bacterial pattern recognition receptors. HT-29 cells responded to purified ligands for Toll-like receptor (TLR)4 but not TLR2. Expression of pIgR and transport of IgA were significantly reduced in colons of mice deficient in the TLR adaptor MyD88, consistent with a role for TLR signaling in the regulation of pIgR by colonic bacteria. Induction of pIgR expression in HT-29 cells required NF-kappaB signaling but not MAPK signaling, in contrast to the requirement for both NF-kappaB and MAPK signaling for induction of pro-inflammatory genes. These results suggest that commensal Enterobacteriaceae may promote intestinal homeostasis by enhancing pIgR expression in IEC.

Identification and characterization of PEBP as a calpain substrate.

Calpains are calcium- and thiol-dependent proteases whose dysregulation has been implicated in a number of diseases and conditions such as cardiovascular dysfunction, ischemic stroke, and Alzheimer's disease (AD). While the effects of calpain activity are evident, the precise mechanism(s) by which dysregulated calpain activity results in cellular degeneration are less clear. In order to determine the impact of calpain activity, there is a need to identify the range of specific calpain substrates. Using an in vitro proteomics approach we confirmed that phosphatidylethanolamine-binding protein (PEBP) as a novel in vitro and in situ calpain substrate. We also observed PEBP proteolysis in a model of brain injury in which calpain is clearly activated. In addition, with evidence of calpain dysregulation in AD, we quantitated protein levels of PEBP in postmortem brain samples from the hippocampus of AD and age-matched controls and found that PEBP levels were approximately 20% greater in AD. Finally, with previous evidence that PEBP may act as a serine protease inhibitor, we tested PEBP as an inhibitor of the proteasome and found that PEBP inhibited the chymostrypsin-like activity of the proteasome by approximately 30%. Together these data identify PEBP as a potential in vivo calpain substrate and indicate that increased PEBP levels may contribute to impaired proteasome function.

Relationship of calpain-mediated proteolysis to the expression of axonal and synaptic plasticity markers following traumatic brain injury in mice.

The role of neuronal plasticity and repair on the final functional outcome following traumatic brain injury (TBI) remains poorly understood. Moreover, the relationship of the magnitude of post-traumatic secondary injury and neurodegeneration to the potential for neuronal repair has not been explored. To address these questions, we employed Western immunoblotting techniques to examine how injury severity affects the spatial and temporal expression of markers of axonal growth (growth-associated protein GAP-43) and synaptogenesis (pre-synaptic vesicular protein synaptophysin) following either moderate (0.5 mm, 3.5 M/s) or severe (1.0 mm, 3.5 M/s) lateral controlled cortical impact traumatic brain injury (CCI-TBI) in young adult male CF-1 mice. Moderate CCI increased GAP-43 levels at 24 and 48 h post-insult in the ipsilateral hippocampus relative to sham, non-injured animals. This increase in axonal plasticity occurred prior to maximal hippocampal neurodegeneration, as revealed by de Olmos silver staining, at 72 h. However, moderate CCI-TBI did not elevate GAP-43 expression in the ipsilateral cortex where neurodegeneration was extensive by 6 h post-TBI. In contrast to moderate injury, severe CCI-TBI failed to increase hippocampal GAP-43 levels and instead resulted in depressed GAP-43 expression in the ipsilateral hippocampus and cortex at 48 h post-insult. In regards to injury-induced changes in synaptogenesis, we found that moderate CCI-TBI elevated synaptophysin levels in the ipsilateral hippocampus at 24, 48, 72 h and 21 days, but this effect was not present after severe injury. Together, these data highlights the adult brain's ability for axonal and synaptic plasticity following a focal cortical injury, but that severe injuries may diminish these endogenous repair mechanisms. The differential effects of moderate versus severe TBI on the post-traumatic plasticity response may be related to the calpain-mediated proteolytic activity occurring after a severe injury preventing increased expression of proteins required for plasticity. Supporting this hypothesis is the fact that GAP-43 is a substrate for calpain along with our data demonstrating that calpain-mediated degradation of the cytoskeletal protein, alpha-spectrin, is approximately 10 times greater in ipsilateral hippocampal tissue following severe compared to moderate CCI-TBI. Thus, TBI severity has a differential effect on the injury-induced neurorestorative response with calpain activation being one putative factor contributing to neuroregenerative failure following severe CCI-TBI. If true, then calpain inhibition may lead to both neuroprotective effects and an enhancement of neuronal plasticity/repair mechanisms post-TBI.