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Return of a heartbeat doesn't mean that cerebral bloodflow is adequate. [ABSTRACT FROM AUTHOR]

Introduction: Whole blood (WB) resuscitation has reemerged as a resuscitation strategy for injured patients. However, the effect of WB-based resuscitation on outcomes has not been established. The primary objective of this guideline was to develop evidence-based recommendations on whether WB should be considered in civilian trauma patients receiving blood transfusions., Methods: An Eastern Association for the Surgery of Trauma working group performed a systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation methodology. One Population, Intervention, Comparison, and Outcomes question was developed to analyze the effect of WB resuscitation in the acute phase on mortality, transfusion requirements, infectious complications, and intensive care unit length of stay. English language studies including adult civilian trauma patients comparing in-hospital WB to component therapy were included. Medline, Embase, Cochrane CENTRAL, CINAHL Plus, and Web of Science were queried. GRADEpro (McMaster University; Evidence Prime, Inc.; Ontario) was used to assess quality of evidence and risk of bias. The study was registered on International Prospective Register of Systematic Reviews (CRD42023451143)., Results: A total of 21 studies were included. Most patients were severely injured and required blood transfusion, massive transfusion protocol activation, and/or a hemorrhage control procedure in the early phase of resuscitation. Mortality was assessed separately at the following intervals: early (i.e., emergency department, 3 hours, or 6 hours), 24 hours, late (i.e., 28 days or 30 days), and in-hospital. On meta-analysis, WB was not associated with decreased mortality. Whole blood was associated with decreased 4-hour red blood cell (mean difference, -1.82; 95% confidence interval [CI], -3.12 to -0.52), 4-hour plasma (mean difference, -1.47; 95% CI, -2.94 to 0), and 24-hour red blood cell transfusions (mean difference, -1.22; 95% CI, -2.24 to -0.19) compared with component therapy. There were no differences in infectious complications or intensive care unit length of stay between groups., Conclusion: We conditionally recommend WB resuscitation in adult civilian trauma patients receiving blood transfusions, recognizing that data are limited for certain populations, including women of childbearing age, and therefore this guideline may not apply to these populations., Level of Evidence: Systematic Review/Meta-Analysis; Level III., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: As medical advances have significantly increased the life expectancy among older adults, the number of older patients requiring trauma care has risen proportionately. Nevertheless, it is unclear among this growing population which sociodemographic and economic factors are associated with decisions to triage and transfer to level I/II centers. This study aims to assess for any association between patient sociodemographic characteristics, triage decisions, and outcomes during acute trauma care presentations., Methods: The National Trauma Data Bank was queried for patients aged 65 and older with an injury severity score > 15 between the years 2007 to 2017. Factors associated with subsequent levels of triage on presentation were assessed using multivariate logistic regression, and associations of levels of triage with outcomes of mortality, morbidity, and hospital length of stay are examined using logistic and linear regression models., Results: Triage of 210,310 older adult trauma patients showed significant findings. American Indian patients had higher odds of being transferred to level I/II centers, while Asian, Black, and Native Hawaiian patients had lower odds of being transferred to level I/II centers when compared to Caucasian patients (P < 0.001). Regarding insurance, self-pay (uninsured) patients were less likely to be transferred to a higher level of care; however, this was also demonstrated in private insurance holders (P < 0.001). Caucasian patients had significantly higher odds of mortality, with Black patients (odds ratio [OR] 0.80 [0.75, 0.85]) and American Indian patients (OR 0.87 [0.72, 1.04]) having significantly lower odds (P < 0.001). Compared to government insurance, private insurance holders (OR 0.82 [0.80, 0.85]) also had significantly lower odds of mortality, while higher odds among self-pay were observed (OR 1.75 [1.62, 1.90]), (P < 0.001)., Conclusions: Access to insurance is associated with triage decisions involving older adults sustaining trauma, with lower access increasing mortality risk. Factors such as race and gender were less likely to be associated with triage decisions. However, due to this study's retrospective design, further prospective analysis is necessary to fully assess the decisions that influence trauma triage decisions in this patient population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Intimate partner violence (IPV) is a serious public health issue with a substantial burden on society. Screening and intervention practices vary widely and there are no standard guidelines. Our objective was to review research on current practices for IPV prevention in emergency departments and trauma centers in the USA and provide evidenced-based recommendations., Methods: An evidence-based systematic review of the literature was conducted to address screening and intervention for IPV in adult trauma and emergency department patients. The Grading of Recommendations, Assessment, Development and Evaluations methodology was used to determine the quality of evidence. Studies were included if they addressed our prespecified population, intervention, control, and outcomes questions. Case reports, editorials, and abstracts were excluded from review., Results: Seven studies met inclusion criteria. All seven were centered around screening for IPV; none addressed interventions when abuse was identified. Screening instruments varied across studies. Although it is unclear if one tool is more accurate than others, significantly more victims were identified when screening protocols were implemented compared with non-standardized approaches to identifying IPV victims., Conclusion: Overall, there were very limited data addressing the topic of IPV screening and intervention in emergency medical settings, and the quality of the evidence was low. With likely low risk and a significant potential benefit, we conditionally recommend implementation of a screening protocol to identify victims of IPV in adults treated in the emergency department and trauma centers. Although the purpose of screening would ultimately be to provide resources for victims, no studies that assessed distinct interventions met our inclusion criteria. Therefore, we cannot make specific recommendations related to IPV interventions., Prospero Registration Number: CRD42020219517., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Fracture is a common injury after a traumatic event. The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) to treat acute pain related to fractures is not well established., Methods: Clinically relevant questions were determined regarding NSAID use in the setting of trauma-induced fractures with clearly defined patient populations, interventions, comparisons and appropriately selected outcomes (PICO). These questions centered around efficacy (pain control, reduction in opioid use) and safety (non-union, kidney injury). A systematic review including literature search and meta-analysis was performed, and the quality of evidence was graded per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The working group reached consensus on the final evidence-based recommendations., Results: A total of 19 studies were identified for analysis. Not all outcomes identified as critically important were reported in all studies, and the outcome of pain control was too heterogenous to perform a meta-analysis. Nine studies reported on non-union (three randomized control trials), six of which reported no association with NSAIDs. The overall incidence of non-union in patients receiving NSAIDs compared with patients not receiving NSAIDs was 2.99% and 2.19% (p=0.04), respectively. Of studies reporting on pain control and reduction of opioids, the use of NSAIDs reduced pain and the need for opioids after traumatic fracture. One study reported on the outcome of acute kidney injury and found no association with NSAID use., Conclusions: In patients with traumatic fractures, NSAIDs appear to reduce post-trauma pain, reduce the need for opioids and have a small effect on non-union. We conditionally recommend the use of NSAIDs in patients suffering from traumatic fractures as the benefit appears to outweigh the small potential risks., Competing Interests: Competing interests: ERH reports research funding from The Patient-Centered Outcomes Research Institute, the Agency for Healthcare Research and Quality, the National Institutes of Health/National Heart, Lung, and Blood Institute, the Department of Defense/Army Medical Research Acquisition Activity and the Henry M. Jackson Foundation for the Advancement of Military Medicine. ERH is a volunteer past president of the Eastern Association for the Surgery of Trauma (EAST) and past chair of the EAST guidelines committee., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Angioembolization is an important adjunct in the non-operative management of adult trauma patients with splenic injury. Multiple studies have shown that angioembolization may increase the non-operative splenic salvage rate for patients with high-grade splenic injuries. We performed a systematic review and developed evidence-based recommendations regarding the need for post-splenectomy vaccinations after splenic embolization in trauma patients., Methods: A systematic review and meta-analysis of currently available evidence were performed utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology., Results: Nine studies were identified and analyzed. A total of 240 embolization patients were compared to 443 control patients who neither underwent splenectomy nor were embolized. There was no statistical difference between the splenic immune function of embolized and control patients. In addition, a total of 3974 splenectomy patients was compared with 686 embolization patients. Embolization patients had fewer infectious complications and a greater degree of preserved splenic immune function., Conclusion: In adult trauma patients who have undergone splenic angioembolization, we conditionally recommend against routine post-splenectomy vaccinations., Study Type: systematic review/meta-analysis Level of evidence: level III., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Antibiotic prophylaxis is routinely administered for most operative procedures, but their utility for certain bedside procedures remains controversial. We performed a systematic review and meta-analysis and developed evidence-based recommendations on whether trauma patients receiving tube thoracostomy (TT) for traumatic hemothorax or pneumothorax should receive antibiotic prophylaxis., Methods: Published literature was searched through MEDLINE (via PubMed), Embase (via Elsevier), Cochrane Central Register of Controlled Trials (via Wiley), Web of Science and ClinicalTrials.gov databases by a professional librarian. The date ranges for our literature search were January 1900 to March 2020. A systematic review and meta-analysis of currently available evidence were performed using the Grading of Recommendations Assessment, Development and Evaluation methodology., Results: Fourteen relevant studies were identified and analyzed. All but one were prospective, with eight being prospective randomized control studies. Antibiotic prophylaxis protocols ranged from a single dose at insertion to 48 hours post-TT removal. The pooled data showed that patients who received antibiotic prophylaxis were significantly less likely to develop empyema (OR 0.47, 95% CI 0.25 to 0.86, p=0.01). The benefit was greater in patients with penetrating injuries (penetrating OR 0.25, 95% CI 0.10 to 0.59, p=0.002, vs blunt OR 0.25, 95% CI 0.06 to 1.12, p=0.07). Administration of antibiotic prophylaxis did not significantly affect pneumonia incidence or mortality., Discussion: In adult trauma patients who require TT insertion, we conditionally recommend antibiotic prophylaxis be given at the time of insertion to reduce incidence of empyema., Prospero Registration Number: CRD42018088759., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Quantitative, three-dimensional (3D) spatially resolved magnetic resonance flow imaging (flow MRI) methods are presented to characterize structure-flow correlations in a 4-mm-diameter plug of Ketton limestone rock using undersampled k- and q-space data acquisition methods combined with compressed sensing (CS) data reconstruction techniques. The acquired MRI data are coregistered with an X-ray microcomputed tomography (μCT) image of the same rock sample, allowing direct correlation of the structural features of the rock with local fluid transport characteristics. First, 3D velocity maps acquired at 35 μm isotropic spatial resolution showed that the flow was highly heterogeneous, with ∼10% of the pores carrying more than 50% of the flow. Structure-flow correlations were found between the local flow velocities through pores and the size and topology (coordination number) associated with these pores. These data show consistent trends with analogous data acquired for flow through a packing of 4-mm-diameter spheres, which may be due to the microstructure of Ketton rock being a consolidation of approximately spherical grains. Using two-dimensional and 3D visualization of coregistered μCT images and velocity maps, complex pore-scale flow patterns were identified. Second, 3D spatially resolved propagators were acquired at 94 μm isotropic spatial resolution. Flow dispersion within the rock was examined by analyzing each of the 331 776 local propagators as a function of observation time. Again, the heterogeneity of flow within the rock was shown. Quantification of the mean and standard deviation of each of the local propagators showed enhanced mixing occurring within the pore space at longer observation times. These spatially resolved measurements also enable investigation of the length scale of a representative elementary volume. It is shown that for a 4-mm-diameter plug this length scale is not reached.

Background: Assessment of the immediate need for specific blood product transfusions in acutely bleeding patients is challenging. Clinical assessment and commonly used coagulation tests are inaccurate and time-consuming. The goal of this practice management guideline was to evaluate the role of the viscoelasticity tests, which are thromboelastography (TEG) and rotational thromboelastometry (ROTEM), in the management of acutely bleeding trauma, surgical, and critically ill patients., Methods: Systematic review and meta-analyses of manuscripts comparing TEG/ROTEM with non-TEG/ROTEM-guided blood products transfusions strategies were performed. The Grading of Recommendations Assessment, Development and Evaluation methodology was applied to assess the level of evidence and create recommendations for TEG/ROTEM-guided blood product transfusions in adult trauma, surgical, and critically ill patients., Results: Using TEG/ROTEM-guided blood transfusions in acutely bleeding trauma, surgical, and critically ill patients was associated with a tendency to fewer blood product transfusions in all populations. Thromboelastography/ROTEM-guided transfusions were associated with a reduced number of additional invasive hemostatic interventions (angioembolic, endoscopic, or surgical) in surgical patients. Thromboelastography/ROTEM-guided transfusions were associated with a reduction in mortality in trauma patients., Conclusion: In patients with ongoing hemorrhage and concern for coagulopathy, we conditionally recommend using TEG/ROTEM-guided transfusions, compared with traditional coagulation parameters, to guide blood component transfusions in each of the following three groups: adult trauma patients, adult surgical patients, and adult patients with critical illness., Level of Evidence: Systematic Review/Meta-Analysis, level III.

Background: Unaddressed alcohol use among injured patients may result in recurrent injury or death. Many trauma centers incorporate alcohol screening, brief intervention, and referral to treatment for injured patients with alcohol use disorders, but systematic reviews evaluating the impact of these interventions are lacking., Methods: An evidence-based systematic review was performed to answer the following population, intervention, comparator, outcomes question: Among adult patients presenting for acute injury, should emergency department, trauma center, or hospital-based alcohol screening with brief intervention and/or referral to treatment be instituted compared with usual care to prevent or decrease reinjury, hospital readmission, alcohol-related offenses, and/or alcohol consumption? A librarian-initiated query of PubMed, MEDLINE, and the Cochrane Library was performed. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of the evidence and create recommendations. The study was registered with PROSPERO (registration number CRD42019122333)., Results: Eleven studies met criteria for inclusion, with a total of 1,897 patients who underwent hospital-based alcohol screening, brief intervention, and/or referral to treatment for appropriate patients. There was a relative paucity of data, and studies varied considerably in terms of design, interventions, and outcomes of interest. Overall evidence was assessed as low quality, but a large effect size of intervention was present., Conclusion: In adult trauma patients, we conditionally recommend emergency department, trauma center, or hospital-based alcohol screening with brief intervention and referral to treatment for appropriate patients in order to reduce alcohol-related reinjury., Level of Evidence: Systematic review, Level III.

Introduction: Non-powder guns (NPG) are viewed as toys for children by the general public. Literature on firearm injuries in the pediatric population is increasing, however there are still large gaps in the published literature regarding NPG. We intended to identify and compare the epidemiology, circumstances of injury and outcomes of children with NPG versus powder-gun injuries (GSW)., Patients and Methods: We performed a 6-year retrospective analysis of children 0-14 years old treated for NPG and GSW injuries at our level one pediatric trauma center. Mann-Whitney U test and Pearson's X 2 were used to compare continuous and categorical variables, respectively., Results: There were 43 NPG and 112 GSWs. Patients were predominantly male (36 children; 84%) NPG vs. 92 children; 82% GSW) with a median age in both groups of 11 years. Analysis of residential zip codes showed that 74% (32 children) NPG injuries and 85% (95 children) GSW lived in regions with higher poverty than the national level. Children with NPG injuries were more likely to be Caucasian (24 children; 56%) and to have suffered an unintentional injury (36 children; 84%), while children with GSW were African-American (80 children; 71%; p=0.0002) and victims of assault (50 children; 45%; p<0.0001). When compared with NPG, children with GSW had more severe injuries, longer hospital stays, and higher overall mortality. There were no significant differences in rate of emergent OR intervention and ED mortality between the two groups., Conclusion: Our results highlight two important findings. First, NPG injuries were accidental and thus preventable with improved legislation and public education. Second, health disparities related to gun violence among African-Americans are prevalent even in early childhood and prevention efforts should include this younger population., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Residual aromatic extracts (RAE) are petroleum substances with variable composition predominantly containing aromatic hydrocarbons with carbon numbers greater than C25. Because of the high boiling nature of RAEs, the aromatics present are high molecular weight, with most above the range of carcinogenic polycyclic aromatic hydrocarbons (PAHs). However, refinery distillations are imperfect; some PAHs and their heteroatom-containing analogs (collectively referred to as polycyclic aromatic content or PAC) may remain in the parent stream and be extracted into the RAE, and overall PAC content is related to the carcinogenic potential of an RAE. We describe here a real-time analytical chemistry-based tool to assess the carcinogenic hazard of RAE via the development of a functional relationship between carcinogenicity and boiling point. Samples representative of steps along the RAE manufacturing process were obtained from five refineries to evaluate relationships between mutagenicity index (MI), PAC ring content and gas chromatographic distillation (GCD) curves. As expected, a positive linear relationship between MI and PAC ring content occurred, most specifically for 3-6 ring PAC (R 2 =0.68). A negative correlation was found between MI and temperature at 5% vaporization by GCD (R 2 =0.72), indicating that samples with greater amounts of lower boiling constituents were more likely to be carcinogenic. The inverse relationship between boiling range and carcinogenicity was further demonstrated by fractionation of select RAE samples (MI=0.50+0.07; PAC=1.70+0.51wt%; n=5) into low and high boiling fractions, where lower boiling fractions were both more carcinogenic than the higher boiling fractions (MI=2.36±0.55 and 0.17±0.11, respectively) and enriched in 3-6 ring PACs (5.20+0.70wt% and 0.97+0.35wt%, respectively). The criteria defining carcinogenicity was established as 479°C for the 5% vaporization points by GCD, with an approximate 95% probability of a future sample having an MI below the recommended limit of 0.4 for RAEs. Overall, these results provide a cost-efficient and real-time tool by which the carcinogenic potential of RAEs can be assessed at the refinery level, ultimately providing a means to readily monitor and minimize the carcinogenic potential of RAEs., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Purpose: Previous methods of distraction enterogenesis have relied upon blind-ending intestinal segments or transmural device fixation, requiring multiple operations and potential bowel injury. We hypothesized that using a novel attachment would allow reversible device coupling to the luminal bowel surface, achieving effective endoluminal distraction., Methods: A telescopic hydraulic device was designed with latex balloon attachments covered with high-friction mesh and a dilating fenestrated elastic mask (DFM attachment), allowing mesh-to-mucosa contact only with inflation. Yorkshire pigs underwent jejunal Roux-en-Y limb creation and device placement via jejunostomy. Devices underwent 3 cycles of balloon inflation and hydraulic extension/retraction per day for 7 days and then explanted and studied for efficacy., Results: DFM attachment allowed reversible, high-strength endoluminal coupling without tissue injury or reduction in bowel perfusion. After 7 day implant, distracted bowel achieved a 44 ± 2% increase in length vs. fed, nondistracted bowel, corresponding to a gain of 7.1 ± 0.3 cm. Distracted bowel demonstrated increased epithelial cell proliferation vs. control bowel. Attachment sites demonstrated villus flattening, increased crypt depth, thicker muscularis mucosa, and unchanged muscularis propria thickness vs., Conclusion: Novel high-strength, reversible attachments enabled fully endoluminal distraction enterogenesis, achieving length gains comparable to open surgical techniques. This approach may allow development of clinically applicable technology for SBS treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Short bowel syndrome (SBS) is characterized by poor nutrient absorption due to a deficit of healthy intestine. Current treatment practices rely on providing supportive medical therapy with parenteral nutrition; while life saving, such interventions are not curative and are still associated with significant co-morbidities. As approaches to lengthen remaining intestinal tissue have been met with only limited success and intestinal transplants have poor survival outcomes, new approaches to treating SBS are necessary. Human intestine derived from embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs), called human intestinal organoids (HIOs), have the potential to offer a personalized and scalable source of intestine for regenerative therapies. However, given that HIOs are small three-dimensional structures grown in vitro, methods to generate usable HIO-derived constructs are needed. We investigated the ability of hESCs or HIOs to populate acellular porcine intestinal matrices and artificial polyglycolic/poly L lactic acid (PGA/PLLA) scaffolds, and examined the ability of matrix/scaffolds to thrive when transplanted in vivo. Our results demonstrate that the acellular matrix alone is not sufficient to instruct hESC differentiation towards an endodermal or intestinal fate. We observed that while HIOs reseed acellular porcine matrices in vitro, the HIO-reseeded matrices do not thrive when transplanted in vivo. In contrast, HIO-seeded PGA/PLLA scaffolds thrive in vivo and develop into tissue that looks nearly identical to adult human intestinal tissue. Our results suggest that HIO-seeded PGA/PLLA scaffolds are a promising avenue for developing the mucosal component of tissue engineered human small intestine, which need to be explored further to develop them into fully functional tissue., (© 2015. Published by The Company of Biologists Ltd.)

Background: Distraction enterogenesis may provide a novel therapy for short bowel syndrome. Previously described methods have relied on isolated intestinal segments or transmural fixation because of ineffective endoluminal attachment. We hypothesized that a novel approach of geometric coupling between a tapering device and the mesenteric curvature would allow trans-stomal distraction enterogenesis., Methods: A catheter device was designed with tapering stiffness, consisting of a stiff catheter with a taper to a flexible latex tip to prevent perforation. Yorkshire pigs underwent creation of a jejunal Roux limb with device placed via jejunostomy. Intestinal attachment was achieved without a substantial decrease in bowel perfusion as measured by laser Doppler. An external clamp was secured at the stoma to provide external fixation of the device. The catheter was advanced 1 cm/day for either 7 or 14 days before explant., Results: After 7 days, the distracted segment achieved a mean ± SD increase in length of 37 ± 6% versus fed, nondistracted bowel, corresponding to an absolute gain of 10.6 ± 1.7 cm (1.5 cm/day). After 14 days, the Roux limb achieved an 80 ± 2% increase in length versus fed control bowel, corresponding to an absolute gain of 16.8 ± 3.0 cm (1.2 cm/day). No perforation or stoma-related complication occurred., Conclusion: We describe a novel catheter device with tapering stiffness allowing for endoluminal distraction enterogenesis via geometric coupling. This approach may allow development of clinically applicable technology for the treatment of patients with short bowel syndrome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Recent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO-TPN mice and prevents mucosal atrophy. C57Bl/6 and strain-matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF-α decreased in TLR4KO-TPN versus wild-type (WT)-TPN mice. Apoptotic positive crypt cells were 15-fold higher in WT-TPN versus TLR4KO-TPN mice. Bcl-2 was significantly increased in TLR4KO-TPN mice, while Bax decreased 10-fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO-sTPN mice. TLR4 blockade significantly prevented TPN-associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF-α abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN-associated atrophy., (© FASEB.)

Human intestinal organoids (HIOs) are a tissue culture model in which small intestine-like tissue is generated from pluripotent stem cells. By carrying out unsupervised hierarchical clustering of RNA-sequencing data, we demonstrate that HIOs most closely resemble human fetal intestine. We observed that genes involved in digestive tract development are enriched in both fetal intestine and HIOs compared to adult tissue, whereas genes related to digestive function and Paneth cell host defense are expressed at higher levels in adult intestine. Our study also revealed that the intestinal stem cell marker OLFM4 is expressed at very low levels in fetal intestine and in HIOs, but is robust in adult crypts. We validated our findings using in vivo transplantation to show that HIOs become more adult-like after transplantation. Our study emphasizes important maturation events that occur in the intestine during human development and demonstrates that HIOs can be used to model fetal-to-adult maturation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Catheter associated blood stream infections (CABSIs) are morbid and expensive for all ages, including neonates. Thus far, the impact of CABSI prevention protocols, such as insertion and maintenance bundles, in the neonatal intensive care unit (NICU) is largely unknown. We hypothesized that lines placed in the operating room (OR) would have a lower infection rate due to established insertion protocols and a more sterile environment., Methods: A retrospective chart review of NICU patients who received a percutaneous or tunneled central venous catheter between 2005 and 2012 was performed. ECMO cannulas, PICC and umbilical catheters were excluded. Variables of interest included demographics, anatomical site, hospital location, line days, and line infection. Line infection was defined as a positive blood culture drawn through the catheter., Results: A total of 368 catheters were placed in 285 NICU patients. Majority of catheters (65.5%) were placed in OR. Saphenous and femoral veins were most common anatomical sites (50.8%). Twenty-eight catheters were infected (7.6%). After adjusting for preoperative antibiotics, anatomical site, and SNAPPE-II scores, lines placed in OR were three times less likely to become infected (Odds Ratio=0.32, p=0.038). Although implementation of CABSI prevention protocols resulted in statistically significant reductions in infection (Odds Ratio=0.4, p=0.043), lines placed in the OR remained less likely to become infected., Conclusions: NICU line infection rates decreased with implementation of CABSI prevention protocols. Despite this implementation, catheters placed in the NICU continued to have higher infection rates. As a result, when patient status allows it, we recommend that central lines in newborns be placed in the operating room., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To report a previously poorly recognized process of secondary formation of inflammatory bowel disease (IBD)-like process, specifically Crohn's-like changes in pediatric surgery patients who underwent major small bowel and colorectal surgery. We describe potential etiologies, presenting symptoms and treatment approaches., Methods: Retrospective chart review of patients with history of either chronic, partial gastrointestinal (GI) obstruction or Hirschsprung disease (HD) and subsequent histopathologic findings similar to IBD. Pathology and case histories were reviewed and treatments were compared., Results: Over the last 20 years, a total of nine patients were identified that had the diagnoses of either HD (n = 3) or chronic GI partial obstruction (n = 6) with subsequent development of histopathologic changes similar to those seen in IBD. Overall meantime to diagnosis of IBD-like changes after intestinal resection was 7.70 ± 5.6 years. Half of the patients were also being managed for short bowel syndrome (SBS), and associated GI symptoms may have prolonged the time to identifying these IBD-like changes. When SBS patients were excluded, mean time to IBD changes after pull through for HD was 2.4 ± 0.24 years and after chronic GI partial obstruction was 6.3 ± 2.1 years. Two of the nine patients who underwent a resection of this IBD-like lesion developed a recurrence of this lesion. Anti-TNF-α treatment was used in three of the GI partial obstruction cases: two with complete relief and one with partial response that was supplemented with steroids. Two HD patients were treated with anti-TNF-α and both had marked improvement of symptoms., Conclusion: We describe IBD-like intestinal changes following intestinal resection in the pediatric age group. We also present the novel finding that these lesions are responsive to anti-IBD treatment, including anti-TNF-α, and recommend it as part of the medical treatment regiment offered for such patients.

Objective: Distraction enterogenesis may provide a novel therapy for short bowel syndrome (SBS). Previously described methods have relied upon isolated intestinal segments or transmural fixation. Our objective was to develop a novel, fully endoluminal device, permitting placement and removal through an enteral stoma or orifice., Methods: A flexible device was designed consisting of two latex balloons mounted on coaxial catheters. The inner catheter allowed longitudinal force transmission from an external spring. Yorkshire pigs underwent jejunal Roux limb creation with device placement via jejunostomy. Balloons were inflated to 52 mmHg without significant reduction in bowel perfusion as measured by laser Doppler. The device was explanted after 7 days., Results: Distracted bowel achieved an increase in length of 26.1 ± 6.1 % vs nondistracted fed bowel. As the device resided in unfed bowel, a 66.7 ± 14.5% increase vs unfed bowel was noted. These corresponded to a gain of 6.3 ± 2.3 cm (0.9 ± 0.3 cm/day) and 12.9 ± 7.6 cm (1.8 ± 1.1 cm/day), respectively. Attachment sites demonstrated occasional epithelial sloughing with no balloon-associated perforation., Conclusion: A novel double-balloon catheter device allows for fully endoluminal distraction enterogenesis. This approach may allow development of clinically applicable technology for the treatment of patients with SBS.

Introduction: This study presents our surgical experience for redo-pullthrough (RedoPT) for Hirschsprung disease (HD). It reviews the patient's clinical outcomes and assesses stooling patterns after RedoPT., Methods: A retrospective review of our institution's RedoPTs as well as one author's overseas cases was performed. Stooling scores were tabulated using an established survey tool and compared to primary PT matched patients., Results: Between 1974 and 2012, 46 individuals (52% males) underwent RedoPT, representing 3 percent of all HD pullthroughs. Median age at primary PT and RedoPT was 1year (range 1week-18years) and 3.5years (range 8weeks-41years), respectively. Indications for RedoPT were predominately for aganglionosis/transition zone pathology (71%); followed by stricture or an obstructing Duhamel pouch (19%), tight cuff (8%) and a twisted PT (4%). None were performed for an isolated clinical diagnosis of repeated bouts of enterocolitis. RedoPT surgical approach depended upon the initial pullthrough technique and any previous complications. Stooling scores were significantly (P<0.05) worse in the RedoPT patients compared to the historically-matched group of children undergoing a primary PT for HD (5.5±1.2 vs. 12.2±1.4, primary PT versus RedoPT, respectively). When breaking down this total score into individual parameters, stooling pattern scores (1.0±0.2 vs. 4.1±0.4, P=0.001) and enterocolitis scores (2.0±0.4 vs. 4.2±0.4, P=0.001) were statistically worse in the RedoPT group. Patients in both groups had similar overall continence rates., Conclusion: Appropriately selected children undergoing a RedoPT can achieve good results, with comparable continence rates to those undergoing a primary PT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: A major research gap is determining the best age to perform an appendicostomy or cecostomy. This study hypothesizes that performance of appendicostomy/cecostomy prior to starting school (<6 years) would improve functional stooling and quality of life (QOL)., Methods: Patients who underwent appendicostomy/cecostomy for bowel management between 2003 and 2013 were retrospectively identified. Families were prospectively surveyed regarding current stooling habits (17 items) and a (7 item) pediatric QOL survey. Lower stooling survey scores represent better bowel control. Higher QOL scores indicated better quality. The primary outcome was to correlate age of appendicostomy/cecostomy to QOL score. Statistics were performed using paired, unpaired t tests, and Chi-square. p Values ≤0.05 were considered significant., Results: 35 patients underwent placement of appendicostomy/cecostomy. Fourteen (40%) patients/families were prospectively contacted (<6, n = 6; >6, n = 8). Stooling scores (15.17 ± 1.35 vs. 22.25 ± 1.70; for <6 vs. >6 years old, p = 0.009) and continence scores (6.33 ± 1.45 vs. 11.13 ± 1.64; p = 0.06), at time of contacting families, were significantly better in those undergoing appendicostomy/cecostomy in the <6 group. Pre-procedure QOL scores for the two groups were similar (p = 0.89). Post-procedure QOL significantly increased to the good subcategory for both age groups; however improvement was significantly better in the <6 age group vs. ≥6 group: 6.33 ± 0.92 vs. 3.13 ± 0.91 points (p = 0.03). A secondary parent survey showed significantly more families wished an appendicostomy/cecostomy were done earlier in the >6 vs. <6 group (87.5 vs. 33%; p = 0.04)., Conclusion: Early placement of cecostomy or appendicostomy as part of a bowel management program may contribute to improved QOL and functional stooling.

Background/purpose: Although physician-reported complications following circumcision are very low, parental satisfaction is not well documented. This study examined parental opinions and compared these with those of the medical professional., Methods: Physicians independently assessed complications and cosmetic outcome following the circumcision. Six weeks post-circumcision, parental report of complications, cosmetic outcome, and overall satisfaction were assessed., Results: Newborn infants (n = 710) were prospectively recruited and underwent either a Gomco [n = 552 (78 %)] or Plastibell(®) [n = 158 (22 %)] circumcision. Physician assessed complication rates were equivalent (Gomco 4.3 % versus Plastibell 5.1 %; p = 0.67), however, parental assessment found a much lower complication rate for Gomco 5.6 % versus Plastibell 12.0 % (p < 0.001). There was no difference between who performed the procedure nor between the techniques in regards to parental rating of overall satisfaction (excellent/good: Gomco 96.9 % versus Plastibell 95.6 %, p = 0.45). However, perceived post-operative pain as scored by parents was significantly higher in patients undergoing Plastibell procedure (6.4 % too much pain) versus Gomco (2.7 %; p = 0.05). Gomco accounted for 72.7 % of parental cosmetically unsatisfactory cases., Conclusions: Clinicians and parents differed considerably in terms of opinion of cosmetic outcome and occurrence of post-operative complications. This study emphasizes the need for clinicians to better understand and address parental concerns before and after circumcision.

The process streams refined from petroleum crude oil for use in petroleum products are among those designated by USEPA as UVCB substances (unknown or variable composition, complex reaction products and biological materials). They are identified on global chemical inventories with unique Chemical Abstract Services (CAS) numbers and names. The chemical complexity of most petroleum substances presents challenges when evaluating their hazards and can result in differing evaluations due to the varying level of hazardous constituents and differences in national chemical control regulations. Global efforts to harmonize the identification of chemical hazards are aimed at promoting the use of consistent hazard evaluation criteria. This paper discusses a systematic approach for the health hazard evaluation of petroleum substances using chemical categories and the United Nations (UN) Globally Harmonized System (GHS) of classification and labeling. Also described are historical efforts to characterize the hazard of these substances and how they led to the development of categories, the identification of potentially hazardous constituents which should be considered, and a summary of the toxicology of the major petroleum product groups. The use of these categories can increase the utility of existing data, provide better informed hazard evaluations, and reduce the amount of animal testing required., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This article describes an unusual case of a vesicocutaneous fistula in a patient with a history of radiation therapy and recent abdominal surgery., Case: A 61-year-old woman was transferred to our acute care facility from a rehabilitation facility, with poor nutritional intake and a concern for urine draining from her wound. A nephrostomy tube was placed (she had only 1 functioning kidney) and negative-pressure wound therapy was used to close the fistula., Conclusion: Urinary diversion via a nephrostomy tube and negative-pressure wound therapy were used to successfully and safely close this vesicocutaneous fistula.

Background and Purpose: There is a paucity of information present in the current literature with regard to the role of SPMI performance in academic radiology centers. Our aim was to evaluate the current practice patterns for the performance of SPMIs in academic radiology departments., Materials and Methods: A survey of 186 academic radiology departments in the United States was conducted between March 2009 and May 2009. The survey included questions on departmental demographics, recent trends in departmental SPMI performance, type of physicians who refer to radiology for SPMI performance, types of SPMIs offered, the fraction of total institutional SPMI volume performed by radiologists, and the current state of resident and fellow SPMI training proficiency., Results: Forty-five of the 186 (21.4%) surveys were completed and returned. Twenty-eight of the 45 responding departments stated that they performed SPMIs; the other 17 stated that they did not. Among the 28 responding departments that perform SPMIs, 6 (21.4%), 5 (17.9%), and 8 (28.6%) stated that the number of departmental SPMIs had, respectively, increased, decreased, or remained stable during the past 5 years. SPMI referrals to radiology were made by orthopedic surgeons, neurologic surgeons, neurologists, psychiatrists, anesthesiologists, and internal medicine physicians. CESIs, SNRBs, facet injections, and synovial cyst aspirations are the most frequently performed injections. Fellows and residents become proficient in 88.5% and 51.9%, respectively, of SPMI-performing departments. Most departments perform <50% of the SPMI volume of their respective institutions., Conclusions: Most responding academic radiology departments perform SPMIs. Most fellows and just more than half of residents at SPMI-performing departments achieve SPMI proficiency. For the most part, the number of SPMIs performed in responding departments has been stable during the past 5 years.

Female F344 rats were fed diets containing 0.02%, 0.2%, or 2.0% white mineral oil for 90 days. There were no gross or microscopic differences in target organs at the 0.02% level. In the higher-dose groups, relative liver and mesenteric lymph node (MLN) weights were increased, and MLN inflammation was observed. At the 2% level, there was very limited evidence of microgranuloma formation in the liver but at a lower incidence and at lesser severity than has been reported in studies of C₂₂-C₂₅ oils. Analysis of liver extracts from treated rats revealed that C₁₅-C₂₀ constituents were underrepresented by comparison to their corresponding concentrations in the test oil. These results provide evidence that although hydrocarbons with carbon numbers < C₂₀ are absorbed, they are not preferentially retained and do not contribute to inflammatory processes in liver.

Clark et al. (accepted for publication) reported that a sample of field-matched fume condensate from a Type III built-up roofing asphalt (BURA) resulted in a carcinogenic response in a mouse skin bioassay, with relatively few tumor-bearing animals, long tumor latency and chronic skin irritation. This mouse skin initiation/promotion study was conducted to assess possible mechanisms, i.e., genotoxic initiation vs. tumor promotion subsequent to repeated skin injury and repair. The same Type III BURA fume condensate sample was evaluated in groups of 30 male Crl:CD1® mice by skin application twice per week (total dose of 50 mg/week) for 2 weeks during the initiation phase and for 26 weeks during the promotion phase. Positive control substances were 7,12-dimethylbenz(a)anthracene (DMBA, 50 μg applied once) as an initiator and 12-O-tetradecanoyl-13-acetate (TPA, 5 μg, applied twice weekly) during the promotion phase. During the 6 months of study with the asphalt fume condensate, eight skin masses were observed when tested for initiation, five of which were confirmed microscopically to be benign squamous cell papillomas. Only two papillomas were observed when tested for promotion. There was no apparent relationship between skin irritation and tumor development in this study. These results are more indicative of genotoxicity rather than a non-genotoxic mode of action., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Asphalt (bitumen) fume condensates collected from the headspace above paving and Type III built up roofing asphalt (BURA) tanks were evaluated in two-year dermal carcinogenicity assays in male C3H/HeNCrl mice. A third sample was generated from the BURA using a NIOSH laboratory generation method. Similar to earlier NIOSH studies, the BURA fume condensates were applied dermally in mineral oil twice per week; the paving sample was applied 7 days/week for a total weekly dose of 50 mg/wk in both studies. A single benign papilloma was observed in a group of 80 mice exposed to paving fume condensate at the end of the two-year study and only mild skin irritation was observed. The lab generated BURA fume condensate resulted in statistically significant (P<0.0001) increases in squamous cell carcinomas (35 animals or 55% of animals at risk). The field-matched BURA condensate showed a weaker but significant (P=0.0063) increase (8 carcinomas or 13% of animals) and a longer average latency (90 weeks vs. 76 for the lab fume). Significant irritation was observed in both BURA condensates. It is concluded that the paving fume condensate was not carcinogenic under the test conditions and that the field-matched BURA fume condensate produced a weak tumor response compared to the lab generated sample., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A paving asphalt and a vacuum residuum (derived from crude oil by atmospheric and subsequent vacuum distillation and used as a blend stock for asphalt) were tested in skin carcinogenesis assays in mice and in optimized Ames assays for mutagenic activity. In the skin cancer tests, each substance was applied twice weekly for 104 weeks to the clipped backs of groups of 50 male C3H mice. Neither the paving asphalt nor the vacuum residuum (30% weight/volume and 75% weight/weight in US Pharmacopeia mineral oil, respectively) produced any tumors. The positive control benzo[a]pyrene (0.05% w/v in toluene) induced tumors in 46 of 50 mice, demonstrating the effectiveness of the test method. Salmonella typhimurium tester strain TA98 was used in the optimized Ames assay to evaluate mutagenic potential. Dimethylsulfoxide (DMSO) extractions of the substances were not mutagenic when tested up to toxic limits. Thus, under the conditions of these studies, neither the paving asphalt nor the vacuum residuum was carcinogenic or mutagenic.

Otoconia are biomineral particles of microscopic size essential for perception of gravity and maintenance of balance. Millions of older Americans are affected in their mobility, quality of life and in their health by progressive demineralization of otoconia. Currently, no effective means to prevent or counteract this process are available. Because of prohibitive anatomical and biological constraints, otoconial research is lagging far behind other systems such as bone and teeth. We have overcome these obstacles by generating otoconial matrix proteins by recombinant techniques. In the present study, we evaluated the effects of recombinant Otoconin 90 (OC90), the principal soluble matrix protein upon calcite crystal growth patterns in vitro. Our findings highlight multiple effects, including facilitation of nucleation, and inhibition of crystal growth in a concentration-dependent manner. Moreover, OC90 induces morphologic changes characteristic of native otoconia. OC90 is considerably less acidic than the prototypical invertebrate CaCO(3) -associated protein, but is nevertheless an effective modulator of calcite crystal growth. Based on homology modeling of the sPLA2-like domains of OC90, we propose that the lower density of acidic residues of the primary sequence is compensated by formation of major anionic surface clusters upon folding into tertiary conformation., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

This experimental study investigated how the dynamics of the crystallization of the evaporite mineral halite could affect the accumulation and preservation of organic macromolecules present in the crystallizing solution. Halite was grown under controlled conditions in the presence of polymer nanoparticles that acted as an analog to protocellular material. Optical microscopy, atomic force microscopy, and laser scanning confocal fluorescence microscopy were used to trace the localization of the nanoparticles during and after growth of halite crystals. The present study revealed that the organic nanoparticles were not regularly incorporated within the halite, but were very concentrated on its surfaces. Their distribution was controlled dominantly by the morphologic surface features of the mineral rather than by specific molecular interactions with an atomic plane of the mineral. This means that the distribution of organic molecules was controlled by surfaces like those of halite's evaporitic growth forms. The experiments with halite also demonstrated that a mineral need not continuously incorporate organic molecules during its crystallization to preserve those molecules: After rejection by (non-incorporation into) the crystallizing halite, the organic nanoparticles increased in concentration in the evaporating brine. They ultimately either adsorbed in rectilinear patterns onto the hopper-enhanced surfaces and along discontinuities within the crystals, or they were encapsulated within fluid inclusions. Of additional importance in origin-of-life considerations is the fact that halite in the natural environment rapidly can change its role from that of a protective repository (in the absence of water) to that of a source of organic particles (as soon as water is present) when the mineral dissolves.

The Mars Express Observatoire pour la Minéralogie, l'Eau, les Glaces, et l'Activité (OMEGA) hyperspectral image data covering eastern Terra Meridiani indicate the ubiquitous presence of molecular water in etched terrain materials that disconformably overlie heavily cratered terrains and underlie the hematite-bearing plains explored by the Opportunity rover. Identification of crystalline water in kieserite (MgSO4.H2O) is linked to materials exposed in a valley and plateau to the north of hematite-bearing plains. The mineralogical similarities between the etched terrain deposits examined with OMEGA data and the layered rocks examined by Opportunity imply that the ancient aqueous environments inferred from analyses of the rover data extend over regional scales.

Two-year dietary studies were conducted to determine the chronic toxicity and its reversibility, and the carcinogenicity of P70(H) and P100(H) white mineral oils in Fischer-344 rats (F-344). The studies were identical in design and followed the Organization for Economic Cooperation and Development, Guidelines for Testing Chemicals, Guideline 453, 1981. Additional endpoints evaluated were: (1) extent of mineral hydrocarbon deposition in liver, kidneys, mesenteric lymph nodes, and spleen of female rats at 3, 6, 12, 18 and 24 months, and (2) reversibility of effects following cessation of exposure. Dietary concentration were 60, 120, 240, and 1,200 mg/kg/day, adjusted periodically to account for bodyweight changes. Study results were consistent with preceding subchronic studies. No treatment-related mortality, neoplastic lesions, or changes in clinical health, hematology, serum chemistry, or urine chemistry were evident in any group administered either white oil. Statistically significant higher food consumption was noted in the 1,200 mg/kg group males and females exposed to either white oil and statistically significant higher body weights were noted in the 1,200-mg/kg males during the latter portion of the P100(H) study. Higher mesenteric lymph node weights were accompanied by increased severity of infiltrating histiocytes. This occurred to a greater extent with the P70(H) than the P100(H) oil. No other histopathology of significance was observed. Mineral hydrocarbons were detected in the liver following exposure to either oil. Maximal concentrations of mineral hydrocarbons in the liver were similar with both oils but occurred more rapidly with the P70(H) oil. Liver mineral hydrocarbon content returned to near-background levels during the reversibility phase. In conclusion, lifetime exposer of F344 rats to P70(H) and P100(H) white oils resulted in only minimal findings and with no consequence to clinical health. Thus, under the conditions of these studies, the No Observable Adverse Effect Level (NOAEL) for these studies was considered to be 1,200 mg/kg/day.

Using laser Raman microprobe spectroscopy, we have characterized the degree of hydroxylation and the state of atomic order of several natural and synthetic calcium phosphate phases, including apatite of biological (human bone, heated human bone, mouse bone, human and boar dentin, and human and boar enamel), geological, and synthetic origin. Common belief holds that all the studied phases are hydroxylapatite, i.e., an OH-containing mineral with the composition Ca10(PO4)6(OH)2. We observe, however, that OH-incorporation into the apatite crystal lattice is reduced for nanocrystalline samples. Among the biological samples, no OH-band was detected in the Raman spectrum of bone (the most nanocrystalline biological apatite), whereas a weak OH-band occurs in dentin and a strong OH-band in tooth enamel. We agree with others, who used NMR, IR spectroscopy, and inelastic neutron scattering, that-contrary to the general medical nomenclature-bone apatite is not hydroxylated and therefore not hydroxylapatite. Crystallographically, this observation is unexpected; it therefore remains unclear what atom(s) occupy the OH-site and how charge balance is maintained within the crystal. For non-bone apatites that do show an OH-band in their Raman spectra, there is a strong correlation between the concentration of hydroxyl groups (based on the ratio of the areas of the 3572 deltacm(-1) OH-peak to the 960 deltacm(-1) P-O phosphate peak) and the crystallographic degree of atomic order (based on the relative width of the 960 deltacm(-1) P-O phosphate peak) of the samples. We hypothesize that the body biochemically imposes a specific state of atomic order and crystallinity (and, thus, concentration of hydroxyl) on its different apatite precipitates (bone, dentin, enamel) in order to enhance their ability to carry out tissue-specific functions.

We report on experiments to characterize internal magnetic field gradients that are caused by magnetic susceptibility differences between the solid phase and the fluids filling the pore space. Our measurements focus on low-field relaxometry of brine and oil in sandstones from various reservoirs around the world. Our results show the need to understand the dependence of internal field gradients on diffusion length, pore size- and fluid distribution in order to predict the impact of internal gradients on the interpretation of NMR experiments.

Laser Raman microprobe spectroscopy, which characterizes the molecular structure of a mineral, was used to analyze microscopically small regions of bioapatite in mouse femora in order to study the effect of mouse age and in vitro fluoride treatment on the bone mineral (i.e., mineral identity and degree of crystallinity). Both femora that had and those that had not undergone in vitro NaF treatment underwent point analysis of 1 micron spots in the center of the compact bone's cross-section. The Raman spectra of bones treated with fluoride showed a peak up-shift of the PO4 vibration mode from 961 to 964 delta cm-1 indicating a conversion from a carbonated hydroxylapatitic to a carbonated fluorapatitic mineral phase. The spectral band width of the 961 delta cm-1 PO4 vibration in femora of 4-, 10-, and 24-week-old mice showed that aging, as well as in vitro treatment with 1.5 M NaF for 12 hours, significantly increases the degree of crystallinity of the bioapatite. In vitro fluoridation of 10-week-old mouse femora increased the bioapatite's degree of crystallinity to about the same degree as did aging to 24 weeks. Four-point bending tests indicated that the age-related increase in crystallinity of untreated bones was associated with decreased deformation to failure, i.e., increased brittleness. In contrast, the increased crystallinity following fluoridation of 10-week-old bones was associated with increased deformation, i.e., increased ductility, perhaps due to the altered mineral composition. This study shows that the laser Raman microprobe readily detects the conversion of carbonated hydroxylapatite to carbonated fluorapatite, as well as changes in crystallinity of either mineral phase, in microscopically small regions of a bone sample.

Di-isodecyl phthalate (DIDP) is a commercial plasticizer with low toxicity in many animal studies. The effects of dietary DIDP administration on fertility and developmental parameters were assessed in Sprague-Dawley rats utilizing two generation reproductive toxicity studies generally consistent with current regulatory guidelines. Dietary levels ranged from 0.02 to 0.8% (or approximately 15 to 600 mg/kg/day). In the reproductive studies, there were no effects on fertility, but there were decreases in adult body weight along with corresponding increases in liver and kidney weights and histopathologic changes indicative of peroxisomal proliferation. There were no effects on live birth index, but reduced offspring survival was observed at postnatal days 1 to 4. This reduced survival was more pronounced in the F2 generation in which statistical significance was achieved at levels of 0.2% DIDP and greater. There were also transient decreases in offspring body weights prior to weaning, corresponding to rapid offspring growth, and high levels of food consumption. There were no notable alterations in developmental landmarks. Overall, these studies provided experimentally defined No-Observed-Adverse-Effect Levels (NOAELs) of 0.06% (approximately 50 mg/kg/day) for F2 offspring survival and 0.8% (approximately 600 mg/kg/day) for fertility, other measures of reproductive function, and developmental landmarks. Statistical evaluation of the data from both studies identified 108 mg/kg/day with a 95% lower bound value of 86 mg/kg/day as a theoretical NOAEL for reduced F2 offspring survival.

The first two recognized cases of rapidly fatal hantavirus pulmonary syndrome in Pennsylvania occurred within an 8-month period in 1997. Illness in the two patients was confirmed by immunohistochemical techniques on autopsy material. Reverse transcription-polymerase chain reaction analysis of tissue from one patient and environmentally associated Peromyscus leucopus (white-footed mouse) identified the Monongahela virus variant. Physicians should be vigilant for such Monongahela virus-associated cases in the eastern United States and Canada, particularly in the Appalachian region.

The potential reproductive toxicity of di-isononyl phthalate (DINP: CAS RN 68515-48-0) was assessed in one- and two-generation reproductive toxicity studies. Groups of 30 male and female CRL : CD(SD)BR rats were given DINP via dietary administration at levels of either 0.0, 0.5, 1, or 1.5% (one-generation study) or 0.0, 0.2, 0. 4, or 0.8% (two-generation study). There were no changes in any of the classic reproductive parameters, i.e. mating, male or female fertility, fecundity, gestational index, or length of gestation in either study. The overall NOAELs for these effects were the highest Dietary Level (%)s tested, approximately 500 mg/kg/day in the two-generation study and 1000 mg/kg/day in the one-generation study. There were no testicular effects in parental animals exposed as juveniles and young adults at 960 mg/kg/day in the one-generation study. In the two-generation study, there were no testicular effects in either the P(1) males, exposed as juveniles and young adults or the P(2) (F(1)) offspring exposed in utero, through lactation, and continuously to terminal sacrifice. The NOAEL was 470 mg/kg/day. Offspring survival was reduced at the 1.5% level ( approximately 1100 mg/kg/day) but unaffected at the 1% level ( approximately 760 mg/kg/day). There were decreased offspring body weights both at postnatal day (PND) 0 and during lactation; however, the PND 0 effects were only clearly related to treatment at the 1.5% level. Weights of offspring during lactation were significantly reduced but within the historical control range at Dietary Level (%)s below 1%. As there was rapid recovery at the lower levels, even though treatment continued, the toxicologic significance is unclear. Adult survival was unaffected at any level in either study, but weight gain was significantly reduced at the 1% level ( approximately 600 mg/kg/day). Liver and kidney weights were elevated at Dietary Level (%)s above approximately 110 mg/kg/day, consistent with evidence from other studies of peroxisomal proliferation at these levels. This study showed that DINP treatment does not affect fertility or male reproductive development at doses of up to approximately 1000 mg/kg/day.