Intermittent convection-enhanced delivery to the brain through a novel transcutaneous bone-anchored port.

Convection-enhanced delivery (CED) describes a novel method of drug delivery to the brain through intraparenchymal microcatheters. One of the barriers to effective translation of CED to clinical trials is the requirement for intermittent delivery over prolonged periods. This is particularly relevant for delivery of neurotrophins for the treatment of Parkinson's disease where chronic infusion of glial cell-line derived neurotrophic factor (GDNF) with subcutaneously implanted pumps has been associated with poor distribution and local toxicity due to point source accumulation. We have previously described the development of an implantable catheter for CED which facilitates repeated drug administrations at intervals of up to one month. The aim of this study was to determine the feasibility of implanting a transcutaneous bone-anchored port (TBAP) which facilitates chronic intermittent drug delivery to the brain. We describe the design and development of a titanium port which was implanted in Large White and NIH miniature pigs for periods of up to three months. By intermittently accessing the port with a needle administration set it was possible to repeatedly perform CED infusions at one month intervals. This study confirms the safety and feasibility of performing intermittent CED through a transcutaneous bone-anchored port. The use of a transcutaneous port has the potential to facilitate clinical translation of CED of therapeutics requiring intermittent delivery to achieve optimum efficacy whilst negating the need for subcutaneously implanted pumps.

Transperitoneal removal of an intrapelvic acetabular component after total hip replacement and salvage of a destroyed acetabulum.

Intrapelvic migration of the acetabular component of a total hip replacement, with severe acetabular destruction making reconstruction impossible, is very rare. We present a patient in whom the component was removed using a laparotomy and a transperitoneal approach with subsequent salvage using a saddle prosthesis and a total femoral replacement.

Excellent outcomes after emergency groin hernia repair.

PURPOSE: Emergency repair of incarcerated inguinal and femoral hernias has traditionally been regarded as carrying an increased risk of morbidity and mortality in a patient population that tends to be elderly with significant co-morbidities. Excessive waiting times for elective repair and delays in diagnosis and treatment increase the risk of strangulation, bowel resection and overall mortality. This study examined the management of emergency surgery for groin hernias for a 3 year period in a large teaching hospital. METHOD: The notes of all patients undergoing emergency groin hernia repair in our hospital between 1 January 2005 and 31 December 2007 were examined. Patient demographics and details of perioperative course and outcome were analysed. RESULTS: Seventy-nine (50 males) patients had emergency groin hernia repair in the 3 year study period. Inguinal hernias predominated (61 vs 18); 12/79 (15%) had previously been assessed as outpatients prior to emergency presentation-all had inguinal hernias and nine (11.4 %) were on the waiting list for elective repair at the time of emergency surgery (mean wait 59 days). Complications were observed in 24% of patients. Two patients (2.5%) required small bowel resection, both performed without recourse to formal laparotomy, and two patients died within 30 days of surgery (2.5%). CONCLUSIONS: It is possible to achieve excellent complication, bowel resection and 30-day mortality rates in emergency groin hernia repair even in patients who have previously declined surgery due to perceived anaesthetic risks. As NHS waiting times for surgery decrease, the number of hernias repaired emergently whilst awaiting elective surgery will also fall.

Protective attenuated lentivirus immunization induces SIV-specific T cells in the genital tract of rhesus monkeys.

Live attenuated lentivirus immunization is the only vaccine strategy that elicits consistent protection against intravaginal challenge with pathogenic simian immunodeficiency virus (SIV). To determine the mechanism of protection in rhesus monkeys infected with attenuated simian-human immunodeficiency virus (SHIV)89.6, a detailed analysis of SIV Gag-specific T-cell responses in several tissues including the genital tract was performed. Six months after SHIV infection, antiviral T-cell responses were rare in the cervix; however, polyfunctional, cytokine-secreting, and degranulating SIV Gag-specific CD4(+) T cells were consistently found in the vagina of the immunized macaques. SIV-specific CD8(+) T cells were also detected in the vagina, blood, and genital lymph nodes of most of the animals. Thus, an attenuated SHIV vaccine induces persistent antiviral T cells in tissues, including the vagina, where these effector T-cell responses may mediate the consistent protection from vaginal SIV challenge observed in this model.

Delivering images to the operating room: a web-based solution.

As radiology departments become filmless, they are discovering that some areas are particularly difficult to deliver images. Many departments have found that the operating room is one such area. There are space constraints and difficulty in manipulating the images by a sterile surgeon. This report describes one method to overcome this obstacle. The author's institution has been using picture archiving and communication system (PACS) for approximately 3 years, and it has been a filmless department for 1 year. The PACS transfers images to a webserver for distribution throughout the hospital. It is accessed by Internet Explorer without any additional software. The authors recently started a pilot program in which they installed dual panel flat screen monitors in 6 operating rooms. The computers are connected to the hospital backbone by ethernet. Graphic cards installed in the computers allow the use of dual monitors. Because the surgeons were experienced in viewing cases on the enterprise web system, they had little difficulty in adapting to the operating room (OR) system. Initial reception of the system is positive. The use of the web system was found to be superior by the surgeons because of the flexibility and manipulation of the images compared with film. Images can be magnified to facilitate viewing from across the room. The ultimate goal of electronic radiology is to replace hardcopy film in all aspects. One area that PACS has difficulty in accomplishing this goal is in the operating room. Most institutions have continued to print film for the OR. The authors have initiated a project that may allow web viewing in the OR. Because of limited space in the OR, an additional computer was undesirable. The CPU tower, keyboard, and mouse were mounted on a frame on the wall. The images were displayed on 2 flat screen monitors, which simulated the viewboxes traditionally used by the surgeons. Interviews with the surgeons have found both positive and negative aspects of the system. Overall impression is good, but the timeliness of the intraoperative films needs to be improved. The author's pilot project of installing a web-based display system in the operating room still is being evaluated. Their initial results have been positive, and if there are no major problems that arise the project will be expanded. These results show that it is possible to provide image delivery to the OR over the intranet that is acceptable to the surgeons.

Early failure of the porous-coated anatomic cemented unicompartmental knee arthroplasty: A 5- to 9-year follow-up study.

This retrospective study analyzed the results of 26 porous-coated anatomic unicompartmental knee arthroplasties to determine the failure rate, the mode of failure, and the presentation of the failure. The mean follow-up was 6.9 years. All patients were assessed using the American and Oxford knee scores. The revision rate was 42%4, with a mean revision time of 38.4 months. The commonest presentation of failure included pain (100%), decreased mobility (75%), swelling (58%), and giving way (50%). The commonest modes of failure included femoral loosening (55%), polyethylene wear (55%), loosening and polyethylene wear (72%), and fracture-dislocation of the femoral prosthesis (18%). The 42% failure rate of the porous-coated anatomic unicompartmental knee arthroplasty necessitates regular surveillance and prompt revision, if failing, to avoid osteolysis.

Utilization of GIS/GPS-Based Information Technology in Commercial Crop Decision Making in California, Washington, Oregon, Idaho, and Arizona.

Ground-based weather, plant-stage measurements, and remote imagery were geo-referenced in geographic information system (GIS) software using an integrated approach to determine insect and disease risk and crop cultural requirements. Weather forecasts and disease weather forecasts for agricultural areas were constructed with elevation, weather, and satellite data. Models for 6 insect pests and 12 diseases of various crops were calculated and presented daily in georeferenced maps for agricultural areas in northern California and Washington. Grape harvest dates and yields also were predicted with high accuracy. The data generated from the GIS global positioning system (GPS) analyses were used to make management decisions over a large number of acres in California, Washington, Oregon, Idaho, and Arizona. Information was distributed daily over the Internet as regional weather, insect, and disease risk maps as industry-sponsored or subscription-based products. Use of GIS/GPS technology for semi-automated data analysis is discussed.

Altered trafficking of membrane proteins in purkinje cells of SCA1 transgenic mice.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expression of mutant ataxin-1 that contains an expanded polyglutamine tract. Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in a progressive ataxia and Purkinje cell pathology that are very similar to those seen in SCA1 patients. Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles in Purkinje cells seem to originate as large invaginations of the outer cell membrane. The cytoplasmic vacuoles contained proteins from the somatodendritic membrane, including mGluR1, GluRDelta1/Delta2, GluR2/3, and protein kinase C (PKC) gamma. Further examination of PKCgamma revealed that its sequestration into cytoplasmic vacuoles was accompanied by concurrent loss of PKCgamma localization at the Purkinje cell dendritic membrane and decreased detection of PKCgamma by Western blot analysis. In addition, the vacuoles were immunoreactive for components of the ubiquitin/proteasome degradative pathway. These findings present a link between vacuole formation and loss of dendrites in Purkinje cells of SCA1 mice and indicate that altered somatodendritic membrane trafficking and loss of proteins including PKCgamma, are a part of the neuronal dysfunction in SCA1 transgenic mice.

Highly functionalized dimeric tetraethynylethenes and expanded radialenes: strong evidence for macrocyclic cross-conjugation.

A selection of dimeric tetraethynylethenes (TEEs) and perethynylated expanded radialenes, containing different donor/acceptor substitution patterns, have been prepared and fully characterized. The first X-ray crystal structure of an expanded [6]radialene, with twelve peripheral 3,5-di(tert-butyl)phenyl substituents, is presented. This macrocycle, the all-carbon core of which is isomeric with fullerene C60, adopts a non-planar, "chair-like" conformation. Also a TEE dimer, carrying N,N-dimethylaniline donor substituents, has been subjected to an X-ray crystallographic analysis. The electronic properties were studied by UV/Vis spectroscopy and electrochemistry, providing fundamental insight into mechanisms of pi-electron delocalization in the acyclic and macrocyclic chromophores. Donor or donor-acceptor-substituted dimeric TEE derivatives show very strong absorptions extending over the entire UV/Vis region; their longest wavelength absorption bands have high charge-transfer character. Macrocyclic cross-conjugation in the expanded radialenes becomes increasingly efficient with increasing donor-acceptor polarization. A dual, strongly solvent-polarity-dependent fluorescence was observed for a tetrakis(N,N-dimethylaniline)-substituted dimeric TEE; this interesting emission behavior is explained by the twisted intramolecular charge-transfer (TICT) state model. Donor-substituted expanded radialenes display huge resonance-enhanced third-order nonlinear optical coefficients.

Development of a medical nutrition therapy protocol for female collegiate athletes.

Nutrition intervention can improve athletic performance and reduce the risk of nutrition related problems in women athletes. The current healthcare environment demands that dietitians document the outcomes of the medical nutrition therapy (MNT) they provide. This requires the development and validation of MNT protocols so that outcomes can be documented and compared in similar populations across multiple settings. The purpose of this project was to develop a sports nutrition management MNT protocol for collegiate women athletes. A registered dietitian currently working with collegiate women athletes collaborated with four dietitians from the community to develop an MNT protocol. Further testing and validation using this MNT protocol will help dietitians document the outcomes of their interventions in this population.

Identification of genes that modify ataxin-1-induced neurodegeneration.

A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.

The indigenous fisherman divers of Thailand: diving-related mortality and morbidity.

The Urak Lawoi are indigenous fishermen on Thailand's west coast. The population includes an estimated 400 divers who dive using surface-supplied compressed air. In a cross-sectional survey conducted among the 6 major communities of Urak Lawoi, questionnaire-based interviews were administered to active divers, ex-divers, and families or colleagues of divers who had died in the previous 5 years. Six deaths resulting from diving-related accidents were identified, indicating a diving-related mortality rate of approximately 300 per 100,000 person-years, while in the same 5-year period 11 divers had been disabled owing to diving-related events, indicating a diving-related disabling event rate of approximately 550 per 100,000 person-years. Among 342 active divers interviewed, one third reported having suffered from decompression illness, although based on reported current symptoms over 50% were classified as suffering from recurring non-disabling decompression illness. Physical examination conducted on a subset of 98 active divers revealed the presence of spinal injury (clonus, raised muscle tone, and heightened reflexes) and of joint damage (pain in one or more joint, crepitus, or restricted movement) in 24 and 30% respectively. Improved primary prevention and medical treatment are needed to reduce mortality and morbidity among this population.

Cutting edge: In situ tetramer staining of antigen-specific T cells in tissues.

Staining Ag-specific T cells with fluorescently labeled tetrameric MHC/peptide complexes has provided a powerful experimental approach to characterizing the immune response. In this report, we describe an extension of this method to directly visualize Ag-specific T cells in tissues. We successfully stained transgenic T cells with MHC tetramers in spleen sections from both 2C and OT-1 TCR transgenic mice. In addition, with the in situ tetramer staining technique, we detected a very small population of Ag-specific T cells in tissue after adoptive transfer of transgenic TCR T cells to a syngeneic nontransgenic mouse. We also show that the in situ tetramer technique can be applied to lightly fixed as well as frozen tissue, thus extending the method to archived tissue collections. This in situ tetramer staining technique offers a general approach to tracking the Ag-specific T cells in tissues.

Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7.

Spinocerebellar ataxia type 7 (SCA7) belongs to a group of neurological disorders caused by a CAG repeat expansion in the coding region of the associated gene. To gain insight into the pathogenesis of SCA7 and possible functions of ataxin-7, we examined the subcellular localization of ataxin-7 in transfected COS-1 cells using SCA7 cDNA clones with different CAG repeat tract lengths. In addition to a diffuse distribution throughout the nucleus, ataxin-7 associated with the nuclear matrix and the nucleolus. The location of the putative SCA7 nuclear localization sequence (NLS) was confirmed by fusing an ataxin-7 fragment with the normally cytoplasmic protein chicken muscle pyruvate kinase. Mutation of this NLS prevented protein from entering the nucleus. Thus, expanded ataxin-7 may carry out its pathogenic effects in the nucleus by altering a matrix-associated nuclear structure and/or by disrupting nucleolar function.

Outcome after surgical resection for high-grade anal intraepithelial neoplasia (Bowen's disease).

BACKGROUND: High-grade anal intraepithelial neoplasia (Bowen's disease) may predispose to anal carcinoma. Treatment options include surgical resection but effectiveness remains uncertain. This paper reports long-term follow-up of patients with high-grade anal intraepithelial neoplasia treated by surgical resection. METHODS: Between 1989 and 1996, 46 patients were identified with high-grade anal intraepithelial neoplasia. Thirty-four underwent local excision of all macroscopically abnormal disease and the resulting defect was left open, closed primarily or skin grafted. Regular follow-up subsequently included anoscopy and biopsy of any suspicious lesions. RESULTS: Median follow-up was 41 (range 12-104) months. Total excision was difficult; 19 patients had histological evidence of incomplete excision at the time of initial resection. Some 12 of 19 had histo-logically proven recurrent high-grade intraepithelial neoplasia within 1 year. Even with microscopically complete excision two of 15 patients subsequently developed recurrent high-grade intraepithelial neoplasia at 6 and 32 months after operation. No patient developed carcinoma but five had complica-tions of anal stenosis or faecal incontinence. CONCLUSION: Although no definite recommendations can be made for the treatment of high-grade anal intraepithelial neoplasia, these results illustrate some potential drawbacks of surgical excision with a high potential for incomplete excision and persistent disease, even after complete excision in some patients, and a high morbidity rate.

The involvement of genome researchers in high school science education.

The rapid accumulation of genetic information generated by the Human Genome Project and related research has heightened public awareness of genetics issues. Education in genome science is needed at all levels in our society by specific audiences and the general public so that individuals can make well-informed decisions related to public policy and issues such as genetic testing. Many scientists have found that an effective vehicle for reaching a broad sector of society is through high school biology courses. From an educational perspective, genome science offers many ways to meet emerging science learning goals, which are influencing science teaching nationally. To effectively meet the goals of the science and education communities, genome education needs to include several major components-accurate and current information about genomics, hands-on experience with DNA techniques, education in ethical decision-making, and career counseling and preparation. To be most successful, we have found that genome education programs require the collaborative efforts of science teachers, genome researchers, ethicists, genetic counselors, and business partners. This report is intended as a guide for genome researchers with an interest in participating in pre-college education, providing rationale for their involvement and recommendations for ways they can contribute, and highlighting a few exemplary programs. World Wide Web addresses for all of the programs discussed in this report are given in Table 1. We are developing a database of outreach programs offering genetics education () and request that readers submit an entry describing their programs. We invite researchers to contact us for more information about activities in their local area.

Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.

Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1[82] with a mutated NLS were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In a second series of transgenic mice, ataxin-1[77] containing a deletion within the self-association region was expressed within Purkinje cells nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.