Inhibition of tau-derived hexapeptide aggregation and toxicity by a self-assembled cyclic d,l-α-peptide conformational inhibitor.

Aggregation and accumulation of amyloid ß and tau proteins to plaques and neurofibrillary tangles are the key pathogenic events in Alzheimer's disease. Here, we studied the capability of the cyclic d,l-α-peptide CP-2 as a conformational inhibitor of different amyloids to cross-interact with tau-derived AcPHF6 peptide and inhibit its aggregation, membrane perturbation and toxicity.

The use of a fibrin tissue sealant during laparoscopic partial nephrectomy.

OBJECTIVE: To assess the feasibility and efficacy of commercially available fibrin tissue sealant as a haemostatic agent and collecting-system sealant during hand-assisted laparoscopic partial nephrectomy (LPN). PATIENTS AND METHODS: Fifteen consecutive patients underwent LPN for enhancing renal masses suspicious for renal cell carcinoma via a transperitoneal approach and with the use of a hand-assistance device. Monopolar electrocauterization and argon-beam coagulation were initially used to slow bleeding from the resection site. Through a laparoscopic applicator, Tisseel(TM) fibrin sealant (Baxter Inc., Deerfield, IL) was applied to the transected partial nephrectomy bed while the surgeon's hand maintained adequate compression and partial haemostasis. No further haemostatic measures were required in any patient; the patients were evaluated for acute and delayed bleeding or urinary extravasation. RESULTS: In all cases electrocauterization and argon-beam coagulation followed by the application of Tisseel was successful in obtaining strict haemostasis of the surgical bed, with no evidence of bleeding during or after surgery on immediate and extended follow-up. In addition, there was no evidence during or after surgery of any urinary leak. There were no immediate or delayed complications in any of the patients; a short-term outpatient follow-up (12-60 weeks) revealed no additional problems. CONCLUSIONS: Conventional haemostatic measures of electrocauteriztion and argon-beam coagulation combined with commercial fibrin sealant allows successful haemostasis during LPN. In addition to haemostatic properties, fibrin sealants appear to have sealing properties that may help to prevent complications of urinary leakage by helping to seal or close the small defects in the urinary collecting system. The use of this compound may facilitate the ability of the urological laparoscopist during LPN.

Isolated cavernous sinus extramedullary relapse of chronic myelogenous leukemia following allogeneic stem cell transplant.

Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. A case is reported of a patient who developed a granulocytic sarcoma of the cavernous sinus 7 months after allogeneic transplant for CML. He presented with neurologic deficits, and a mass lesion was found on imaging. No evidence of hematologic relapse was identified by bone marrow histology or cytogenetics. A premortem diagnosis was not possible, and the patient died 2 months later of an intracerebral hemorrhage after receiving various therapies directed against a presumed infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic transplant for CML, even if there is no evidence of medullary disease.

Characterization of a minimal screening set of 172 microsatellite markers for genome-wide screens of the canine genome.

We have characterized a subset of 172 microsatellite markers from the canine map, termed 'Minimal Screening Set 1' (Canine MSS-1), which we propose be used for initial genome-wide genetic linkage studies. Three hierarchical criteria were used to select markers from the current meiotic linkage and radiation hybrid maps for MSS-1. Markers were selected that (1) provided as complete coverage as possible of the canine genome, (2) were highly informative, and (3) have been ordered in linkage groups with a high degree of statistical support. This resulting screening set spans all reported meiotic linkage and RH groups, leaving only 10 known gaps > or = 20 cM. The average polymorphic information content (PIC) value of markers tested is 0.74. Coverage estimates suggest 42% of the genome is within 5 cM of at least one marker in the minimal screening set, 77% of the genome is within 10 cM. This minimal mapping set therefore provides an efficient and cost effective way to begin screening pedigrees of interest for genetic linkage.

Complex emergencies in Indonesia.

Recently, Indonesia has experienced six major provincial, civil, armed conflicts. Underlying causes include the transmigration policy, sectarian disputes, the Asian economic crisis, fall of authoritarian rule, and a backlash against civil and military abuses. The public health impact involves the displacement nationwide of > 1.2 million persons. Violence in the Malukus, Timor, and Kalimantan has sparked the greatest population movements such that five provinces in Indonesia each now harbor > 100,000 internally displaced persons. With a background of government instability, hyperinflation, macroeconomic collapse, and elusive political solutions, these civil armed conflicts are ripe for persistence as complex emergencies. Indonesia has made substantial progress in domestic disaster management with the establishment of central administrative authority, strategic planning, and training programs. Nevertheless, the Indonesian experience reveals recurrent issues in international humanitarian health assistance. Clinical care remains complicated by absences of treatment protocols, inappropriate drug use, high procedural complication rates, and variable referral practices. Epidemiological surveillance remains complicated by unsettled clinical case definitions, non-standardized case management of diseases with epidemic potential, variable outbreak management protocols, and inadequate epidemiological analytic capacity. International donor support has been semi-selective, insufficient, and late. The militia murders of three UN staff in West Timor prompted the withdrawal of UN international staff from West Timor for nearly a year to date. Re-establishing rules of engagement for humanitarian health workers must address security, public health, and clinical threats.

Injury control in Honduras: a survey of injury mortality.

STUDY OBJECTIVE: We sought to evaluate the methods and accuracy of mortality data collection and summarize the injury mortality rate in one sector of the State of Olancho, Honduras, with the intent to establish a baseline of injury mortality that will identify potential areas of intervention and serve as a comparison after subsequent interventions. METHODS: Mortality data were collected from a rural, regional, health center database containing age, sex, and cause of death for one geographic sector in the State of Olancho, Honduras. Causes of death were classified as medical or intentional versus nonintentional injury. RESULTS: Accurate mortality data were difficult to obtain for several reasons: (1) deaths are often recorded by untrained health care workers, (2) causes of death are not coded in a standard manner, and (3) infant mortality is underreported. We found 132 recorded noninfant deaths. A disproportionate number of these resulted from injury, especially from intentional injury, particularly among male subjects aged 12 to 49 years. Eighty-two percent of male subjects aged 12 to 49 years who died did so from injuries, and 52% died from intentional injuries. Overall, 48% of all male deaths were injury related. The estimated male mortality rate (age 12 to 49 years) from injuries was 4.5 times that of the United States. CONCLUSION: Injury, particularly intentional injury, is an important cause of mortality in rural Honduras, particularly among male subjects aged 12 to 49 years. This suggests a fertile opportunity for intervention. More reliable data collection will be necessary to accurately target which specific causes of injury death are most amenable to interventions and to monitor the effect of injury control programs.

Partnership for excellence in asthma care: evidence-based disease management.

Partnership for Excellence in Asthma Care, a practical example of evidence-based disease management, was launched by Egleston Scottish Rite Children's Health Care System. The process of development and implementation of evidence-based practice guidelines for the outpatient management of asthma is described. Methods to influence physician practice patterns and the preparation of feedback reports are discussed. The method for measuring outcomes and preliminary outcome data are shared.

An integrated linkage-radiation hybrid map of the canine genome.

Purebred dogs are a unique resource for dissecting the molecular basis of simple and complex genetic diseases and traits. As a result of strong selection for physical and behavioral characteristics among the 300 established breeds, modern dogs are characterized by high levels of interbreed variation, complemented by significant intrabreed homogeneity. A high-resolution map of the canine genome is necessary to exploit the mapping power of this unusual resource. We describe here the integration of an expanded canine radiation hybrid map, comprised of 600 markers, with the latest linkage map of 341 markers, to generate a map of 724 markers-the densest map of the canine genome described to date. Through the inclusion of 217 markers on both the linkage and RH maps, the 77 RH groups are reduced to 44 syntenic groups, thus providing comprehensive coverage of most of the canine genome.

Partnership for excellence in asthma care: evidence-based disease management.

Our experience with developing and implementing the outpatient component of an evidence-based disease management initiative has been a positive one. Involvement of respected practicing physicians in the planning phase, recommendation of evidence-based guidelines, and the supportive relationship between the hospital and participating practices have been essential to the successful launching of an asthma disease management program by a children's healthcare system. As the implementation phase continues to progress, we are preparing for the 6 month data collection stage, including outcomes measurement and practice pattern feedback. After 1 year of implementation we will analyze the data and report on the effects of the Partnership. We expect that physicians will continue to use the guidelines, and therefore sustain the improved health status of children with asthma. We will continue to invite pediatricians' participation in the Partnership so that more children in our community can benefit from high-quality cost-effective care that results in superior health outcomes.

Olfactory marker protein (OMP) gene deletion causes altered physiological activity of olfactory sensory neurons.

Olfactory marker protein (OMP) is an abundant, phylogentically conserved, cytoplasmic protein of unknown function expressed almost exclusively in mature olfactory sensory neurons. To address its function, we generated OMP-deficient mice by gene targeting in embryonic stem cells. We report that these OMP-null mice are compromised in their ability to respond to odor stimull, providing insight to OMP function. The maximal electroolfactogram response of the olfactory neuroepithelium to several odorants was 20-40% smaller in the mutants compared with controls. In addition, the onset and recovery kinetics following isoamyl acetate stimulation are prolonged in the null mice. Furthermore, the ability of the mutants to respond to the second odor pulse of a pair is impaired, over a range of concentrations, compared with controls. These results imply that neural activity directed toward the olfactory bulb is also reduced. The bulbar phenotype observed in the OMP-null mouse is consistent with this hypothesis. Bulbar activity of tyrosine hydroxylase, the rate limiting enzyme of catecholamine biosynthesis, and content of the neuropeptide cholecystokinin are reduced by 65% and 50%, respectively. This similarity to postsynaptic changes in gene expression induced by peripheral olfactory deafferentation or naris blockade confirms that functional neural activity is reduced in both the olfactory neuroepithelium and the olfactory nerve projection to the bulb in the OMP-null mouse. These observations provide strong support for the conclusion that OMP is a novel modulatory component of the odor detection/signal transduction cascade.

Inferior vena caval blood flow and cardiac hemodynamics during carbon dioxide pneumoperitoneum.

BACKGROUND: The effects of carbon dioxide pneumoperitoneum on venous return and cardiac hemodynamics during laparoscopic surgery were studied. METHODS: Twelve adult pigs underwent placement of an electromagnetic flow meter across the infrarenal vena cava (IVC) as well as placement of Swan Ganz and arterial monitoring catheters. Measurements of the flow through infrarenal IVC, cardiac output (CO), pulmonary capillary wedge pressure (PCWP), mean arterial pressure (MAP), and heart rate were recorded at baseline, 5 and 60 min following insufflation to 15 mmHg with CO2, and 5 min following desufflation. Stroke volumes and systemic vascular resistance (SVR) were calculated as well. RESULTS: Flow through the IVC dropped by 24 and 31% at 5 and 60 min (p = 0.03 and 0.02, respectively). Paradoxically, cardiac output rose by 14 and 28% at 5 and 60 min (p = 0.03 at 60 min). Central venous and pulmonary capillary wedge pressures rose transiently by 35 and 36% at 5 min before returning to baseline (p < 0.01). Mean arterial pressure and heart rate remained relatively constant during insufflation. Systemic vascular resistance diminished from 938 dynes/cm/s prior to insufflation to its nadir at 60 min of 650 dynes/cm/s (p < 0.01). CONCLUSIONS: These observations suggest potentially complex interactions between the mechanical and systemic effects of the CO2 pneumoperitoneum on venous return. Transient elevations in cardiac filling pressures occur by an unknown mechanism, and a generalized enhanced inotropic state mediated via increased sympathetic outflow is observed in this hypercapnic anesthetized animal model.

Mother and adolescent knowledge of sexual development: the effects of gender, age, and sexual experience.

As part of a larger study on the impact of personal and family characteristics on adolescents' HIV risk and risk-reduction behavior, 90 adolescents and 73 mothers were asked to define in their own words seven terms related to sexual development: ejaculation, hormones, menstruation, ovulation, puberty, semen, and wet dreams. Mother and adolescent knowledge of sexual development terms and the effects of age and sexual experience on that knowledge were examined. Results suggest that the mothers were not able to adequately define the sexual development terms and thus may be ill-prepared to teach their children about sex or reinforce information they learn in school. Since adolescent knowledge did not significantly increase with age and sexual experience, the researchers suggest that continuing sex education about normal sexual development is needed.

Hemodialysis graft salvage with endoluminal stents.

The most common cause of failure of hemodialysis access sites is stenosis within the site. The stenoses have traditionally been corrected surgically, but endovascular techniques may be an alternative method to treat these flow-limiting lesions and maintain graft patency. Over a recent 17-month period, endoluminal stents to relieve stenoses resistant to balloon dilatation alone were placed in 14 access sites. All sites were located on the upper extremity (13 PTFE bridge grafts and 1 A-V fistula). A total of 20 stents were placed: seven at the venous anastomosis, 12 in the venous outflow tract (including 3 in the subclavian vein), and one within the graft. Nine patients had placement of a single stent, four patients had two stents placed, and one patient had three. An additional eight stenotic lesions within these 14 sites were successfully dilated without need of a stent. After stent placement, these 14 sites have remained functional for a mean of 6.2 months. Four were functioning without further intervention at a mean of 8.5 months. Nine sites occluded at a mean of 4.7 months. The remaining site remained functional until death of the patient 10 months after stent placement. Of the nine failed sites, four developed restenosis at the site of stent placement, four developed stenoses at other sites, and the other site was abandoned. Three stents were placed in subclavian vein stenoses, and none of these has failed. Further study is necessary to determine whether endovascular stenting of dialysis access site stenoses will prove to be a durable, cost-effective alternative to surgical revision.

Identifying the low-risk patient with penetrating colonic injury for selective use of primary repair.

As the mortality rate for penetrating colonic injuries approaches zero, emphasis has shifted toward reducing associated morbidity. This study was done to identify patients at low risk for colon-related extensive morbidity after primary repair of a penetrating colonic injury. The records of 100 consecutive patients admitted to the District of Columbia General Hospital (DCGH) between 1984 to 1990, surviving more than 24 hours after full-thickness penetrating colonic injuries, were retrospectively reviewed. Data collection included mechanism, management and anatomic location of the colonic injury. Severity of injury was evaluated by the Trauma Score (TS), Penetrating Abdominal Trauma Index (PATI), Flint Colon Injury Score (FCIS), time in the operating room, blood transfused during the first 24 hours and presence of preoperative shock (systolic blood pressure less than 90 millimeters of mercury). Mechanism of injury included 97 gunshot wounds and three stab wounds. Fifty-seven patients had primary repair (17 having resection and anastomosis) and 43 had colostomy. The anatomic location of injury was right colon in 37, transverse colon in 27, left colon in 35 and multiple sites (two) in one patient. In this series, only two patients had colon-related extensive morbidity--a parastomal hernia and wound dehiscence, both requiring operative intervention. There were no instances of intraperitoneal abscess formation. One patient died from overwhelming pneumonia after segmental resection of the colon with primary anastomosis. The literature reports a 12 to 42 percent colon-related morbidity rate in patients sustaining penetrating colonic injuries. This series from DCGH represents the lowest colon-related extensive morbidity and mortality rates reported to date in any substantial series of penetrating abdominal trauma. We attribute the 2 percent extensive morbidity rate to high TS (mean of 15.7), low PATI (mean of 24.2), low FCIS (mean of 1.9) and few associated intra-abdominal injuries (59 percent of patients with less than two). We have identified a group of patients with full-thickness penetrating injuries to the colon, few associated intra-abdominal injuries, high TS, low PATI and low FCIS who can be managed safely and judiciously by primary repair without undue morbidity and mortality.

Mapping of the two mouse engrailed-like genes: close linkage of En-1 to dominant hemimelia (Dh) on chromosome 1 and of En-2 to hemimelic extra-toes (Hx) on chromosome 5.

The mouse genome contains two genes, En-1 and En-2, with sequence similarity to the engrailed gene of Drosophila. Using conventional linkage crosses, we have shown that En-1 maps approximately 0.28 cM distal to the dominant hemimelia (Dh) gene on chromosome 1 and that En-2 maps approximately 1.1 cM proximal to the hemimelic extra-toes (Hx) gene on chromosome 5. We have also shown by Northern blot analysis that En-1 transcripts in Dh homozygotes and En-2 transcripts in Hx homozygotes are of normal size and abundance. These data, in conjunction with previously published studies of the patterns of En-1 and En-2 expression in developing mouse embryos, suggest that Dh and Hx are very unlikely to be mutant alleles of En-1 or En-2, respectively. Instead, we suggest that En-1-Dh and En-2-Hx represent paralogous linkage groups that evolved following duplication of a common ancestral chromosome segment.

Lack of host cellular immune response in eruptive molluscum contagiosum.

A lack of cellular immunity on the part of the host has been incriminated as the cause of the persistence of the cutaneous lesions of molluscum contagiosum. We present a patient in the eruptive phase of the disease, confirming the absence of T-lymphocyte and natural killer cell subsets in the base of these typical lesions, using a panel of monoclonal antibodies. We also report the observation of lipid material ultrastructurally (confirmed by osmium staining on fresh-frozen tissue), as well as cross-reactivity immunocytochemically of the antigens on these molluscum bodies with antigens normally present on macrophages, as defined by DAKO-macrophage monoclonal antibodies. We have considered the possible role of these findings in the lack of host cellular responsiveness in the eruptive phase of the disease.