Interfacing with the nervous system: a review of current bioelectric technologies.

The aim of this study is to discuss the state of the art with regard to established or promising bioelectric therapies meant to alter or control neurologic function. We present recent reports on bioelectric technologies that interface with the nervous system at three potential sites-(1) the end organ, (2) the peripheral nervous system, and (3) the central nervous system-while exploring practical and clinical considerations. A literature search was executed on PubMed, IEEE, and Web of Science databases. A review of the current literature was conducted to examine functional and histomorphological effects of neuroprosthetic interfaces with a focus on end-organ, peripheral, and central nervous system interfaces. Innovations in bioelectric technologies are providing increasing selectivity in stimulating distinct nerve fiber populations in order to activate discrete muscles. Significant advances in electrode array design focus on increasing selectivity, stability, and functionality of implantable neuroprosthetics. The application of neuroprosthetics to paretic nerves or even directly stimulating or recording from the central nervous system holds great potential in advancing the field of nerve and tissue bioelectric engineering and contributing to clinical care. Although current physiotherapeutic and surgical treatments seek to restore function, structure, or comfort, they bear significant limitations in enabling cosmetic or functional recovery. Instead, the introduction of bioelectric technology may play a role in the restoration of function in patients with neurologic deficits.

Persistence of choking injuries in children.

BACKGROUND: Choking injuries are a significant cause of morbidity and mortality in children and represent a significant public health concern. Evaluating trends and the impact of interventions are essential to highlight whether progress has been made and to target public health efforts. OBJECTIVE: To investigate how rates of nonfatal and fatal choking injuries have changed before and after 2010 when policy recommendations were made by the American Academy of Pediatrics. METHODS: A descriptive study investigating unintentional nonfatal and fatal choking injuries in children aged 0-19 years using national data from 2001 to 2016 through the Centers for Disease Control and Prevention's WISQARS™ and WONDER databases, focusing on the 6 years prior and 6 years after release of the AAP's recommendations. The data was categorized by age, gender, year, and race/ethnicity for descriptive and statistical analyses. RESULTS: From 2001 to 2016, there were a total of 305,814 nonfatal injuries and 2347 choking deaths in children from 0 to 19 years. Children under five years of age accounted for 73% of nonfatal injuries and 75% of choking fatalities. There was a statistically significant increase in the nonfatal injuries rate when comparing 2005-2010 and 2011-2016 (19/100,000 versus 26/100,000, respectively). There was a decrease in the choking fatalities rate in all children (0.18/100,000 versus 0.16/100,000, respectively) but no change in fatalities rate for children under five. White and Black children experience nonfatal choking injuries at a higher rate than Hispanics. Black children had highest rates of choking fatalities over Hispanic, White, Asian, and Alaskan or American Indian ethnicities. The lowest rates of death occurred in Asians. CONCLUSIONS: Overall rate of nonfatal choking injuries increased, while rate of choking fatalities in children decreased after 2010. However, the choking fatalities rate in 0-4 years olds, the highest risk group, did not change. Racial gaps exist with highest rates of injury in Black children. We must continue to educate and raise awareness of choking injuries, with targeted efforts to address racial disparities.

Matrix metalloproteinases and their inhibitors in the foreign body reaction on biomaterials.

Matrix metalloproteinases (MMPs) can degrade structural components within the extracellular matrix and at the cellular surface producing changes in cellular behavior (i.e., adhesion and migration) and subsequent pathological responses (i.e., the foreign body reaction and wound healing). We continue to study the foreign body reaction that occurs following biomaterial implantation by investigating secretory responses of biomaterial-adherent macrophages and foreign body giant cells (FBGCs) as directed by material surface chemistry and further this research by determining whether secreted MMPs play a role in macrophage adhesion and fusion. We have identified numerous MMPs and their tissue inhibitors (TIMPs) in in vitro cell-culture supernatants using antibody arrays and quantified select MMP/TIMPs with ELISAs. MMP-9 concentrations were significantly greater than both TIMP-1 and TIMP-2 on all materials. The ratios of MMP-9/TIMP-1 and MMP-9/TIMP-2 increased with time because of an increase in MMP-9 concentrations over time, while the TIMP concentrations remained constant. Total MMP-9 concentrations in the supernatants were comparable on all materials at each timepoint, while TIMP-1 and TIMP-2 concentrations tended to be greater on hydrophilic/anionic surfaces. Analysis of the MMP/TIMP quantities produced per cell revealed that the hydrophilic/neutral surfaces, which inhibited macrophage adhesion, activated the adherent macrophages/FBGCs to produce a greater quantity of MMP-9, TIMP-1, and TIMP-2 per cell. Pharmacological inhibition of MMP-1,-8,-13, and -18 reduced macrophage fusion without affecting adhesion, while inhibitors of MMP-2,-3,-9, and -12 did not affect adhesion or fusion. These findings demonstrate that material surface chemistry does modulate macrophage/FBGC-derived MMP/TIMP secretion and implicates MMP involvement in macrophage fusion.

A Fully Integrated Quartz MEMS VHF TCXO.

We report on a 32-MHz quartz temperature compensated crystal oscillator (TCXO) fully integrated with commercial CMOS electronics and vacuum packaged at wafer level using a low-temperature MEMS-after quartz process. The novel quartz resonator design provides for stress isolation from the CMOS substrate, thereby yielding classical AT-cut f/T profiles and low hysteresis which can be compensated to < ±0.2 parts per million over temperature using on-chip third-order compensation circuitry. The TCXO operates at low power of 2.5 mW and can be thinned to as part of the wafer-level eutectic encapsulation. Full integration with large state-of-the-art CMOS wafers is possible using carrier wafer techniques.

Proteomic analysis and quantification of cytokines and chemokines from biomaterial surface-adherent macrophages and foreign body giant cells.

Implantation of biomaterial devices results in the well-known foreign body reaction consisting of monocytes, macrophages, and foreign body giant cells (FBGCs) at the material/tissue interface. We continue to address the hypothesis that material surface chemistry modulates the phenotypic expression of these cells. Utilizing our human monocyte culture system, we have used surface-modified polymers displaying hydrophobic, hydrophilic, and/or ionic chemistries to determine the cytokines/chemokines released from biomaterial-adherent macrophages/FBGCs. This study broadens our approach by using proteomic analysis to identify important factors expressed by these cells and further quantifies these molecules with ELISAs. Proteomic profiles changed over time suggesting that the adherent macrophages underwent a phenotypic switch. Macrophage/FBGC-derived proinflammatory cytokines, IL-1beta and IL-6, decreased with time, while the anti-inflammatory cytokine, IL-10, gradually increased with time. Resolution of the inflammatory response was also demonstrated by a decrease in chemoattractant IL-8 and MIP-1beta production with time. Material-dependent macrophage/FBGC activation was analyzed using cytokine/chemokine production and cellular adhesion. Monocyte/macrophage adhesion was similar on all surfaces, except for the hydrophilic/neutral surfaces that showed a significant decrease in cellular density and minimal FBGC formation. Normalizing the ELISA data based on the adherent cell population provided cytokine/chemokine concentrations produced per cell. This analysis showed that although there were fewer cells on the hydrophilic/neutral surface, these adherent cells were further activated to produce significantly greater amounts of each cytokine/chemokine tested than the other surfaces. This study clearly presents evidence that material surface chemistry can differentially affect monocyte/macrophage/FBGC adhesion and cytokine/chemokine profiles derived from activated macrophages/FBGCs adherent to biomaterial surfaces.

Nasal septal perforation in children: Presentation, etiology, and management.

OBJECTIVE: The presentation, etiology, and treatment of nasal septal perforation have been described in the adult literature; however, reports in the pediatric population are limited. In this study, we review our experience with pediatric nasal septal perforations with a focus on presentation, pathogenesis, management, and outcomes of surgical repair. METHODS: A retrospective chart review was performed on pediatric patients diagnosed with nasal septal perforations from 1998 to 2015. Data regarding patient demographics, perforation characteristics, and treatment were extracted and analyzed. RESULTS: Twenty-seven patients met inclusion criteria. Mean age was 10.8 years (range 2 months-17 years). Nasal crusting (n = 19, 73%) and epistaxis (n = 15, 58%) were the most common complaints at presentation. The most common etiologies were trauma (n = 9, 33%), iatrogenic sources (n = 5, 19%), and neoplasm (n = 3, 11%). Septal perforations were primarily located in the anterior septum (n = 17, 81%) and the average size was 0.9 cm (±0.37) in diameter. Four patients were managed with a nasal septal button. Successful closure was achieved in four out of six patients (66.7%) who underwent surgical repair. CONCLUSIONS: In our series, septal perforations in children occurred most frequently due to digital nasal trauma, and crusting was the most common symptom. Factors to consider prior to repair include symptomatology, the etiology of the perforation, co-morbidities, ability to comply with post-operative care/restrictions, availability of adjacent tissue/grafts, and potential effects on nasal growth. Even with careful consideration of these factors, successful closure was limited to two-thirds of patients who were offered repair.

Functional and Histological Effects of Chronic Neural Electrode Implantation.

OBJECTIVES: Permanent injury to the cranial nerves can often result in a substantial reduction in quality of life. Novel and innovative interventions can help restore form and function in nerve paralysis, with bioelectric interfaces among the more promising of these approaches. The foreign body response is an important consideration for any bioelectric device as it influences the function and effectiveness of the implant. The purpose of this review is to describe tissue and functional effects of chronic neural implantation among the different categories of neural implants and highlight advances in peripheral and cranial nerve stimulation. Data Sources: PubMed, IEEE, and Web of Science literature search. Review Methods: A review of the current literature was conducted to examine functional and histologic effects of bioelectric interfaces for neural implants. RESULTS: Bioelectric devices can be characterized as intraneural, epineural, perineural, intranuclear, or cortical depending on their placement relative to nerves and neuronal cell bodies. Such devices include nerve-specific stimulators, neuroprosthetics, brainstem implants, and deep brain stimulators. Regardless of electrode location and interface type, acute and chronic histological, macroscopic and functional changes can occur as a result of both passive and active tissue responses to the bioelectric implant. CONCLUSION: A variety of chronically implantable electrodes have been developed to treat disorders of the peripheral and cranial nerves, to varying degrees of efficacy. Consideration and mitigation of detrimental effects at the neural interface with further optimization of functional nerve stimulation will facilitate the development of these technologies and translation to the clinic. LEVEL OF EVIDENCE: 3.

Comparison of treatment outcomes between intracapsular and total tonsillectomy for pediatric obstructive sleep apnea.

BACKGROUND: Intracapsular tonsillectomy (IT) has been advocated as a treatment for pediatric obstructive sleep apnea (OSA). However, evidence in the literature utilizing polysomnography (PSG) is limited. OBJECTIVE: To examine the experience at a tertiary children's hospital to evaluate the effectiveness and risks of intracapsular tonsillectomy compared to total tonsillectomy (TT) for treating pediatric OSA. METHODS: A retrospective study was undertaken of pediatric tonsillectomy cases performed for OSA at a tertiary children's hospital from 2005 to 2010. Patients with recurrent tonsillitis, craniofacial abnormalities, chromosomal abnormalities, neuromuscular disease, and congenital malformations were excluded. Main outcome measures were apnea-hypopnea index (AHI), minimum oxygen saturation (minO2), and surgical complications. RESULTS: Of the 1583 patients reviewed in this study, there were 75 IT and 93 TT patients with pre- and post-operative PSG results. The IT patients were younger, had lower BMI, larger tonsil size, lower pre-operative (AHI) and lower post-operative AHI (p < 0.05). There was a similar percentage of patients that showed improvement in AHI and minimum oxygen saturation between the IT and TT groups. There were statistically similar average change in AHI and minimum oxygen saturation between the IT and TT groups at 5.6 ± 8.6 and 8.6 ± 12.9, respectively (p = 0.8) as well as similar improvement in minimum oxygen saturation between the two groups at 3.3% ± 4.3% and 3.0% ± 5.2%, respectively (p = 0.66). Of TT patients, 2.9% experienced post-operative bleeding with 1.6% requiring OR for control of hemorrhage. Of IT patients, 2.2% were found to have tonsillar regrowth with 2.0% returning to the OR for secondary tonsillectomy. CONCLUSIONS: Intracapsular tonsillectomy, like total tonsillectomy, is effective in improving polysomnogram results in appropriately selected children. Intracapsular tonsillectomy is a suitable option for the surgical treatment of pediatric OSA consequent to its demonstrated efficacy in relieving OSA and its favorable safety profile.

Protein-engineered hydrogel encapsulation for 3-D culture of murine cochlea.

HYPOTHESIS: Elastin-like protein (ELP) hydrogel helps maintain the three-dimensional (3-D) cochlear structure in culture. BACKGROUND: Whole-organ culture of the cochlea is a useful model system facilitating manipulation and analysis of live sensory cells and surrounding nonsensory cells. The precisely organized 3-D cochlear structure demands a culture method that preserves this delicate architecture; however, current methods have not been optimized to serve such a purpose. METHODS: A protein-engineered ELP hydrogel was used to encapsulate organ of Corti isolated from neonatal mice. Cultured cochleae were immunostained for markers of hair cells and supporting cells. Organ of Corti hair cell and supporting cell density and organ dimensions were compared between the ELP and nonencapsulated systems. These culture systems were then compared with noncultured cochlea. RESULTS: After 3 days in vitro, vital dye uptake and immunostaining for sensory and nonsensory cells show that encapsulated cochlea contain viable cells with an organized architecture. In comparison with nonencapsulated cultured cochlea, ELP-encapsulated cochleae exhibit higher densities of hair cells and supporting cells and taller and narrower organ of Corti dimensions that more closely resemble those of noncultured cochleae. However, we found compromised cell viability when the culture period extended beyond 3 days. CONCLUSION: We conclude that the ELP hydrogel can help preserve the 3-D architecture of neonatal cochlea in short-term culture, which may be applicable to in vitro study of the physiology and pathophysiology of the inner ear.

A child with silent sinus syndrome and spontaneous improvement after sinus surgery.

Silent sinus syndrome is characterized by an asymptomatic hypoplastic maxillary sinus with progressive enophthalmos and hypoglobus. This is a disease rarely affecting children with the majority of reported cases involving adult patients. Treatment is primarily surgical with endoscopic sinus surgery to restore aeration of the sinus along with orbital reconstruction to restore facial symmetry. In this report, we describe a 7 year old child with facial asymmetry and no sinonasal symptoms. CT showed an opacified hypoplastic right maxillary sinus. One year after endoscopic sinus surgery, there was spontaneous improvement of facial asymmetry and relative maxillary sinus size.

Lack of financial barriers to pediatric cochlear implantation: impact of socioeconomic status on access and outcomes.

OBJECTIVES: (1) To analyze if socioeconomic status influences access to cochlear implantation in an environment with adequate Medicaid reimbursement. (2) To determine the impact of socioeconomic status on outcomes after unilateral cochlear implantation. DESIGN: Retrospective cohort study. SETTING: University Hospitals Case Medical Center and Rainbow Babies and Children's Hospital (tertiary referral center), Cleveland, Ohio. PARTICIPANTS: Pediatric patients (age range, newborn to 18 years) who received unilateral cochlear implantation during the period 1996 to 2008. MAIN OUTCOME MEASURES: Access to cochlear implantation after referral to a cochlear implant center, postoperative complications, compliance with follow-up appointments, and access to sequential bilateral cochlear implantation. RESULTS: A total of 133 pediatric patients were included in this study; 64 were Medicaid-insured patients and 69 were privately insured patients. There was no statistical difference in the odds of initial cochlear implantation, age at referral, or age at implantation between the 2 groups. The odds of prelingual Medicaid-insured patients receiving sequential bilateral cochlear implantation was less than half that of the privately insured group (odds ratio [OR], 0.43; P = .03). The odds of complications in Medicaid-insured children were almost 5-fold greater than the odds for privately insured children (OR, 4.6; P = .03). There were 10 complications in 51 Medicaid-insured patients (19.6%) as opposed to 3 in 61 privately insured patients (4.9%). Medicaid-insured patients missed substantially more follow-up appointments overall (35% vs 23%) and more consecutive visits (1.9 vs 1.1) compared with privately insured patients. CONCLUSIONS: In an environment with adequate Medicaid reimbursement, eligible children have equal access to cochlear implantation, regardless of socioeconomic background. However, lower socioeconomic background is associated with higher rates of postoperative complications, worse follow-up compliance, and lower rates of sequential bilateral implantation, observed herein in Medicaid-insured patients. These findings present opportunities for cochlear implant centers to create programs to address such downstream disparities.

Paracrine and juxtacrine lymphocyte enhancement of adherent macrophage and foreign body giant cell activation.

Lymphocytes have been shown to be involved in modulating monocyte and macrophage behavior in the foreign body reaction. Lymphocyte effects on biomaterial-adherent macrophage and foreign body giant cell (FBGC) behavior were further investigated by culturing monocytes alone or together with lymphocytes, either in direct co-cultures or indirectly in transwells, on a series of polyethylene terephthalate-based photograft co-polymerized material surfaces displaying distinct hydrophobic, hydrophilic/neutral, hydrophilic/anionic, and hydrophilic/ cationic chemistries. After periods of 3, 7, and 10 days, cytokine production was quantified by enzyme-linked immunosorbent assay and normalized to adherent macrophage/FBGC density to yield a measure of adherent macrophage/FBGC activation. Interactions with lymphocytes enhanced adherent macrophage and FBGC production of pro-inflammatory IL-1beta, TNF-alpha, IL-6, IL-8, and MIP-1beta on the hydrophobic and hydrophilic/cationic surfaces but had no effect on anti-inflammatory IL-10 production indicating lymphocytes promote a pro-inflammatory response to biomaterials. Lymphocytes also did not significantly influence MMP-9, TIMP-1, and TIMP-2 production. Interactions through indirect (paracrine) signaling showed a significant effect in enhancing adherent macrophage/FBGC activation at early time points whereas interactions via direct (juxtacrine) mechanisms dominated at later time points. Biomaterial surface chemistries differentially affected the observed responses as hydrophilic/neutral and hydrophilic/anionic surfaces, evoked the highest levels of activation relative to the other surfaces but did not facilitate lymphocyte enhancement of adherent macrophage/FBGC activation.

Lymphocyte adhesion and interactions with biomaterial adherent macrophages and foreign body giant cells.

To characterize the effects of adherent macrophages and biomaterial surface chemistries on lymphocyte adhesion and activation, lymphocytes were co-cultured with monocytes alone and together, directly and separated by a porous membrane transwell on hydrophobic, hydrophilic/neutral, hydrophilic/anionic, and hydrophilic/cationic biomaterial surfaces. Surface adherent cells were quantitatively analyzed after 3 days utilizing immunofluorescence and phase contrast imaging. After periods of 3, 7, and 10 days, secreted interferon-gamma (IFN-gamma) was quantified by ELISA. Limited direct biomaterial-adherent lymphocytes were identified regardless of the presence of macrophages or foreign body giant cells (FBGC). The majority of adherent lymphocytes, which were T cells (>95%) rather than natural killer cells, predominantly interacted with adherent macrophages and FBGCs; greater than 90% were interacting on surfaces with higher levels of adherent macrophages and FBGCs and greater than 55% were interacting on surfaces with lower levels of macrophages and FBGCs. The hydrophilic/anionic surface promoted higher levels of macrophage- and FBGC-adherent lymphocytes but was nonselective for lymphocyte subtype interactions. The hydrophilic/neutral surface was selective for CD4+ T lymphocyte interactions while the hydrophobic surface was selective for CD8+ T lymphocyte interactions. IFN-gamma was produced in direct and indirect co-cultures but not in lymphocyte- and monocyte-only cultures suggesting that lymphocytes are activated via macrophage-derived cytokines rather than direct biomaterial contact. Direct lymphocyte interactions with adherent macrophages/FBGCs enhanced IFN-gamma production relative to indirect co-cultures. These results suggest that lymphocytes prefer interactions with adherent macrophages and FBGCs, resulting in lymphocyte activation, and these interactions can be influenced by biomaterial surface chemistries.

Foreign body reaction to biomaterials.

The foreign body reaction composed of macrophages and foreign body giant cells is the end-stage response of the inflammatory and wound healing responses following implantation of a medical device, prosthesis, or biomaterial. A brief, focused overview of events leading to the foreign body reaction is presented. The major focus of this review is on factors that modulate the interaction of macrophages and foreign body giant cells on synthetic surfaces where the chemical, physical, and morphological characteristics of the synthetic surface are considered to play a role in modulating cellular events. These events in the foreign body reaction include protein adsorption, monocyte/macrophage adhesion, macrophage fusion to form foreign body giant cells, consequences of the foreign body response on biomaterials, and cross-talk between macrophages/foreign body giant cells and inflammatory/wound healing cells. Biomaterial surface properties play an important role in modulating the foreign body reaction in the first two to four weeks following implantation of a medical device, even though the foreign body reaction at the tissue/material interface is present for the in vivo lifetime of the medical device. An understanding of the foreign body reaction is important as the foreign body reaction may impact the biocompatibility (safety) of the medical device, prosthesis, or implanted biomaterial and may significantly impact short- and long-term tissue responses with tissue-engineered constructs containing proteins, cells, and other biological components for use in tissue engineering and regenerative medicine. Our perspective has been on the inflammatory and wound healing response to implanted materials, devices, and tissue-engineered constructs. The incorporation of biological components of allogeneic or xenogeneic origin as well as stem cells into tissue-engineered or regenerative approaches opens up a myriad of other challenges. An in depth understanding of how the immune system interacts with these cells and how biomaterials or tissue-engineered constructs influence these interactions may prove pivotal to the safety, biocompatibility, and function of the device or system under consideration.

Lymphocyte/macrophage interactions: biomaterial surface-dependent cytokine, chemokine, and matrix protein production.

The role of lymphocytes in the biological response to synthetic polymers is poorly understood despite the transient appearance of lymphocytes at the biomaterial implant site. To investigate cytokines, chemokines, and extracellular matrix (ECM) proteins produced by lymphocytes and macrophages in response to biomaterial surfaces, human peripheral blood monocytes and lymphocytes were co-cultured on polyethylene terephthalate (PET)-based material surfaces displaying distinct hydrophobic, hydrophilic/neutral, hydrophilic/anionic, and hydrophilic/cationic chemistries. Antibody array screening showed the majority of detected proteins are inflammatory mediators that guide the early inflammatory phases of wound healing. Proteomic ELISA quantification and adherent cell analysis were performed after 3, 7, and 10 days of culture. IL-2 and IFN-gamma were not detected in any co-cultures suggesting lack of lymphocyte activation. The hydrophilic/neutral surfaces increased IL-8 relative to the hydrophobic PET surface (p < 0.05). The hydrophilic/anionic surfaces promoted increased TNF-alpha over hydrophobic and cationic surfaces and increased MIP-1beta compared to hydrophobic surfaces (p < 0.05). Since enhanced macrophage fusion was observed on hydrophilic/anionic surfaces, the production of these cytokines likely plays an important role in the fusion process. The hydrophilic/cationic surface promoted IL-10 production and increased matrix metalloproteinase (MMP)-9/tissue inhibitor of MMP (TIMP) relative to hydrophilic/neutral and anionic surfaces (p < 0.05). These results suggest hydrophilic/neutral and anionic surfaces promote pro-inflammatory responses and reduced degradation of the ECM, whereas the hydrophilic/cationic surfaces induce an anti-inflammatory response and greater MMP-9/TIMP with an enhanced potential for ECM breakdown. The study also underscores the usefulness of protein arrays in assessing the role of soluble mediators in the inflammatory response to biomaterials.

Toward rapid high resolution in vivo intravascular MRI: evaluation of vessel wall conspicuity in a porcine model using multiple imaging protocols.

PURPOSE: To assess magnetic resonance (MR) pulse sequences for high resolution intravascular imaging. MATERIALS AND METHODS: Intravascular imaging of the abdominal aorta and iliac arteries was performed in vivo in a porcine model at 1.5 T using catheter-mounted micro-receive coils. Ten protocols, including spin-echo (SE)-echo planar imaging (SE-EPI), segmented EPI, half-Fourier single-shot turbo spin-echo (HASTE), fast imaging with steady-state free precession (TrueFISP), turbo spin-echo (TSE), and SE acquisition schemes were employed in 13 trials. Images were analyzed by six expert raters with respect to wall-conspicuity, wall-to-lumen/tissue contrast, visible layers of the arterial wall, anticipated clinical usefulness, and overall image quality. Mean differences between sequence-types were evaluated using analysis of variance (ANOVA) between groups with planned comparisons. RESULTS: The vessel wall was delineated in almost all protocols. Motion artifacts from physiological and device motion were reduced in fast techniques. The best contrast between the wall and surrounding tissue was provided by a HASTE protocol. Anatomic layers of the vessel wall were best depicted on dark blood T2-weighted TSE. Overall, TrueFISP was ranked highest on the remaining measures. CONCLUSION: Dedicated catheter-coils combined with fast sequences have potential for in vivo characterization of vessel walls. TrueFISP offered the best overall image quality and acquisition speed, but suffered from the inability to delineate the multiple layers of the wall, which seems associated with dark blood- and T2-weighted contrast. We believe future intra-arterial trials should proceed from this study in normal artery imaging and initially focus on fast T2-weighted dark blood techniques in trials with pathology.

Low molecular weight heparin for venous thromboembolism prophylaxis in urologic oncologic surgery.

OBJECTIVES: This is a prospective study in the use of low molecular weight heparin (LMWH) for venous thromboembolism prophylaxis in the previously unstudied subset of patients undergoing elective urologic cancer surgery. METHODS: Thirty-eight patients undergoing elective urologic surgery were studied. Thirty-six had urologic malignancies. Pre-operative risk factors for venous thromboembolic disease were recorded. All patients received LMWH (dalteparin, Fragmin; Pharmacia, Stockholm, Sweden) subcutaneously on a daily basis beginning 1-2 hr before surgery and lasting for 3-7 days. Postoperative physical examination was used to check for clinical evidence of deep venous thrombosis (DVT). Clinical parameters such as physical examination and radiological testing were used to assess for evidence of DVT. Other data included intraoperative blood loss, transfusion requirements, postoperative bleeding complications, postoperative hematocrit and coagulation profiles, and local complications related to the subcutaneous injection of the LMWH. RESULTS: All patients completed the prophylaxis protocol. None developed DVT. Mean intraoperative blood loss was 735 mL and 12 patients received an average of 1 unit of blood transfusion. No unusual hemorrhagic events were noted intra- or post-operatively. No reactions to the LMWH were noted. Average hematocrit of postoperative day 3 was 30.7 and platelet count and coagulation profiles remained normal postoperatively. CONCLUSIONS: Low molecular weight heparins appear promising for DVT prophylaxis in high-risk urology patients.

Somatic mutations in VHL germline deletion kindred correlate with mild phenotype.

Generally, von Hippel-Lindau (VHL) disease is caused by a germline mutation of the VHL gene (chromosome 3p), and tumorigenesis is initiated from a "second-hit" deletion. A subset of VHL patients have a germline deletion of the VHL gene, and the molecular events leading to tumorigenesis are not fully understood. To determine the molecular pathogenesis of tumor formation in this setting, we analyzed five central nervous system hemangioblastomas from three patients of a single VHL germline deletion kindred, all displaying mild clinical phenotype. Rather than loss of heterozygosity (the "second hit" in VHL germline mutation patients), all tumors from this kindred showed "second-hit" point mutations on the wild-type allele. Moreover, in two patients who each had two hemangioblastomas resected each tumor contained a unique mutation. The specific germline deletion and the overall genetic makeup of the patient did not predict these random "second-hit" point mutations. These results suggest that in patients with germline deletion of a tumor suppressor gene there is a unique genetic mechanism underlying tumorigenesis. This unique genetic mechanism correlates with and may help to understand the mild clinical phenotype seen in these patients.