How to Investigate the Origins of Novelty: Insights Gained from Genetic, Behavioral, and Fitness Perspectives.

Biologists are drawn to the most extraordinary adaptations in the natural world, often referred to as evolutionary novelties, yet rarely do we understand the microevolutionary context underlying the origins of novel traits, behaviors, or ecological niches. Here we discuss insights gained into the origins of novelty from a research program spanning biological levels of organization from genotype to fitness in Caribbean pupfishes. We focus on a case study of the origins of novel trophic specialists on San Salvador Island, Bahamas and place this radiation in the context of other rapid radiations. We highlight questions that can be addressed about the origins of novelty at different biological levels, such as measuring the isolation of novel phenotypes on the fitness landscape, locating the spatial and temporal origins of adaptive variation contributing to novelty, detecting dysfunctional gene regulation due to adaptive divergence, and connecting behaviors with novel traits. Evolutionary novelties are rare, almost by definition, and we conclude that integrative case studies can provide insights into this rarity relative to the dynamics of adaptation to more common ecological niches and repeated parallel speciation, such as the relative isolation of novel phenotypes on fitness landscapes and the transient availability of ecological, genetic, and behavioral opportunities.

Como Investigar as Origens da Novidade: Ideias Obtidas a Partir de Perspectivas da Genética, do Comportamento e de Fitness (How to Investigate the Origins of Novelty: Insights Gained from Genetic, Behavioral, and Fitness Perspectives) Biólogos são atraídos pelas adaptações mais extraordinárias do mundo natural, muitas vezes chamdas de novidades evolutivas, mas raramente entendemos o contexto microevolutivo subjacente às origens de novas características, novos comportamentos ou nichos ecológicos. Aqui discutimos ideias obtidas sobre as origens da novidade evolutiva a partir de um programa de pesquisa abrangendo níveis biológicos de organização de genótipo para fitness em pupas do Caribe. Nós nos concentramos em um estudo de caso sobre as origens de novos especialistas tróficos na ilha de São Salvador, Bahamas, e colocamos essa radiação no contexto de outras radiações rápidas. Destacamos questões que podem ser abordadas sobre as origens da novidade evolutiva em diferentes níveis biológicos, como medir o isolamento de novos fenótipos no cenário adaptativo, localizando as origens espaciais e temporais da variação adaptativa que contribuem para a novidade evolutiva, detectando a regulação gênica disfuncional devido à divergência adaptativa, e conectando comportamentos com novas características. As novidades evolutivas são raras, quase por definição, e concluímos que estudos de caso integrativos podem fornecer ideias sobre essa raridade em relação à dinâmica de adaptação a nichos ecológicos mais comuns e especiação paralela repetitiva, como o relativo isolamento de novos fenótipos em cenários adaptativos e a disponibilidade transitória de oportunidades ecológicas, genéticas, e comportamentais. Translated to Portuguese by G. Sobral (gabisobral@gmail.com).

An examination of the elastic properties of tissue-mimicking phantoms using vibro-acoustography and a muscle motor system.

Tissue hardness, often quantified in terms of elasticity, is an important differentiating criterion for pathological identity and is extensively used by surgeons for tumor localization. Delineation of malignant regions from benign regions is typically performed by visual inspection and palpation. Although practical, this method is highly subjective and does not provide quantitative metrics. We have previously reported on Vibro-Acoustography (VA) for tumor delineation. VA is unique in that it uses the specific, non-linear properties of tumor tissue in response to an amplitude modulated ultrasound beam to generate spatially resolved, high contrast maps of tissue. Although the lateral and axial resolutions (sub-millimeter and sub-centimeter, respectively) of VA have been extensively characterized, the relationship between static stiffness assessment (palpation) and dynamic stiffness characterization (VA) has not been explicitly established. Here we perform a correlative exploration of the static and dynamic properties of tissue-mimicking phantoms, specifically elasticity, using VA and a muscle motor system. Muscle motor systems, commonly used to probe the mechanical properties of materials, provide absolute, quantitative point measurements of the elastic modulus, analogous to Young's modulus, of a target. For phantoms of varying percent-by-weight concentrations, parallel VA and muscle motor studies conducted on 18 phantoms reveal a negative correlation (p < - 0.85) between mean signal amplitude levels observed with VA and calculated elastic modulus values from force vs. indentation depth curves. Comparison of these elasticity measurements may provide additional information to improve tissue modeling, system characterization, as well as offer valuable insights for in vivo applications, specifically surgical extirpation of tumors.

Outcome of HIV-infected Pregnant Women and Their Offspring in Barbados: A Five-year Study.

OBJECTIVES: To describe the outcome of HIV-infected pregnant women and their offspring during a five-year period. METHODS: The medical records of HIV-infected pregnant women who delivered between January 2007 and December 2011 and their HIV-exposed infants were reviewed. Demographics, outcome of pregnancy and infants, and clinic attendance were analysed. Data were entered on a Microsoft Excel spreadsheet. RESULTS: One hundred and forty-three women, aged 17-45 years (mean 27.3 years), were included in the study with 143 pregnancies and 142 pregnancy outcomes being recorded. One woman migrated before delivery. There were 122 live births and 18 (13%) terminations: 13 (9%) elective and five (4%) spontaneous. There was one ectopic pregnancy and one stillbirth. One hundred and twenty-two (85%) women were unmarried. Women were prescribed highly active antiretroviral therapy for prevention of mother-to-child transmission from the time of booking, apart from those opting for terminations or those who had spontaneous abortions. For clinic follow-up, 105 (73%) had regular attendance, 30 (21%) defaulted and could not be located despite intense tracking, four attended irregularly, and one refused to attend clinic. Four (3%) migrated after delivery. Two (1%) mothers died during the period of study. Two successive DNA polymerase chain reaction tests done within four months of age did not substantiate any cases of infant infection. CONCLUSION: This study revealed that there was a good outcome and compliance with follow-up of HIV-infected pregnant women and their offspring.

Diagnostic value of sentinel lymph node biopsy in head and neck cancer: a meta-analysis.

This study aimed to evaluate the diagnostic reliability of sentinel lymph node biopsy in patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx by reviewing the published literature. A systematic literature review was performed using MEDLINE from 1970 to 2011. With Boolean search strings, search terms included sentinel node, supraglottic, supraglottis, tongue, head and neck, oral, pharynx, laryngeal, and larynx. Additional studies were identified through article references. Duplicate data and articles were excluded based on treating institution and study inclusion time period. Additional studies were excluded if the head and neck subsite or tumor stage was not specifically identified or if the sentinel lymph node biopsy occurred in previously treated necks. All patients had sentinel lymph node biopsy performed followed by a concurrent neck dissection. Twenty-six studies met our inclusion criteria (n = 766 patients). The pooled sensitivity and negative predictive value of SLNB for all head and neck tumors was 95 % (95 % CI 91-99 %) and 96 % (95 %CI 94-99 %), respectively. The overall sensitivity and negative predictive value of SLNB in the subset of oral cavity tumors (n = 631) was 94 % (95 % CI 89-98 %) and 96 % (95 % CI 93-99 %), respectively. One-hundred percent of oropharyngeal (n = 72), hypopharyngeal (n = 5), and laryngeal (n = 58) tumor sentinel lymph biopsy results correlated with subsequent neck dissections giving a negative predictive value of 100 %, showing that, sentinel lymph node biopsy is a valid diagnostic technique to correctly stage regional metastases in patients with head and neck squamous cell carcinoma.

Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies.

BACKGROUND: Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors. METHODS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. RESULTS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells. CONCLUSION: In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC.

Follicular adenoma presenting as lateral aberrant thyroid.

INTRODUCTION: True benign thyroid masses very rarely present as a solitary lateral neck mass. Different aetiological mechanisms have been proposed for such masses. CASE REPORT: We report a case of thyroid follicular adenoma that presented as a lateral neck mass. DISCUSSION: Ectopic thyroid tissue and metastases from primary thyroid carcinoma should always be considered in the differential diagnosis of lateral neck masses. Complete investigation should include complete blood tests to characterise the orthotopic thyroid gland.

Correlates of spontaneous viral control among long-term survivors of perinatal HIV-1 infection expressing human leukocyte antigen-B57.

OBJECTIVE: We sought to identify immunologic and virologic correlates of spontaneous viral control among long-term survivors of perinatal HIV infection expressing the protective human leukocyte antigen (HLA)-B57 allele. DESIGN: The frequency, epitope specificity, and functional attributes of HIV-specific T cells and sequence variation within B57-restricted epitopes were compared between 'spontaneous controllers' who maintained normal CD4 percentages and viral loads less than 3000 copies/ml without antiretroviral therapy, and 'treated progressors' who had initiated HAART. METHODS: Recognition of HIV optimal epitopes was assessed by interferon gamma (IFNgamma) enzyme-linked immunosorbent spot. Functional characterization of CD8 cells targeting B57 epitopes was performed by staining for cytokine production (intracellular IFNgamma, interleukin-2, tumor necrosis factor alpha) and degranulation. Sequencing of autologous RNA was performed to determine the prevalence of viral escape mutations within B57-restricted epitopes and associated compensatory mutations. RESULTS: HLA-B57 remained immunodominant during chronic infection in both controllers and progressors, but controllers recognized fewer epitopes and targeted epitopes within Gag and reverse transcriptase only, whereas progressors demonstrated a broader response targeting additional proteins. No individual epitope was targeted more frequently by spontaneous controllers. CD8 cytokine production patterns were heterogeneous among individuals and even among different epitopes in the same individual and did not correlate with spontaneous viral control. Extensive sequence variation within B57 epitopes was observed in both groups, but only progressors displayed additional capsid mutations that are known to offset the viral fitness cost of B57-driven immune escape. CONCLUSION: Among HLA-B57-positive long-term survivors, spontaneous control of viremia is not associated with a qualitatively or quantitatively superior T-cell response, but with uncompensated fitness-attenuating mutations in the viral capsid.

Maternal transmission of human immunodeficiency virus escape mutations subverts HLA-B57 immunodominance but facilitates viral control in the haploidentical infant.

Expression of HLA-B57 is associated with restricted replication of human immunodeficiency virus (HIV), but the mechanism for its protective effect remains unknown. If this advantage depends upon CD8 T-cell recognition of B57-restricted epitopes, mother-to-child transmission of escape mutations within these epitopes could nullify its protective effect. However, if the B57 advantage is largely mediated by selection for fitness-attenuating viral mutations within B57-restricted epitopes, such as T242N in TW10-Gag, then the transmission of such mutations could facilitate viral control in the haploidentical infant. We assessed the consequences of B57-associated mutations on replication capacity, viral control, and clinical outcome after vertical transmission in 13 mother-child pairs. We found that expression of HLA-B57 was associated with exceptional control of HIV during infancy, even when mutations within TW10 and most other B57-restricted epitopes were transmitted, subverting the natural immunodominance of HLA-B57. In contrast, most B57-negative infants born to B57-positive mothers progressed rapidly to AIDS. The presence of T242N led to a reproducible reduction in viral fitness, as demonstrated by in vitro assays using NL4-3 constructs encoding p24 sequences from individual mothers and infants. Associated compensatory mutations within p24-Gag were observed to reverse this impairment and to influence the propensity of T242N to revert after transmission to B57-negative hosts. Moreover, primary failure to control viremia was observed in one infant to whom multiple compensatory mutations were transmitted along with T242N. These parallel in vivo and in vitro data suggest that HLA-B57 confers its advantage primarily by driving and maintaining a fitness-attenuating mutation in p24-Gag.

Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes.

Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.

A descriptive study of HIV-infected long-term surviving children in Barbados--a preliminary report.

OBJECTIVES: To describe the clinical and immunologic characteristics of human immunodeficiency virus type-1 (HIV-1)-infected children surviving to more than eight-years of age (long-survivors) before the introduction of antiretroviral therapy. METHODS: This report is based on all the long-term survivors from a prospective cohort of HIV-infected children born to HIV-positive women in Barbados during 1986-1995. Infants born to HIV-infected women were enrolled into this cohort at birth or at the time of diagnosis of HIV exposure in the postnatal period and followed-up at regular intervals. RESULTS: From a cohort of 44 HIV-infected children, 17 (38.6%) children survived to the age of eight years and beyond and were classified as long-term survivors. Median age of the sixteen long-term surviving children alive at the time of this report was 12 years (age range 8 - 16.7 years). At the age of 8 years, 17.6% of these children remained asymptomatic. Nine (52.9%) children had no immunodeficiency (CD4 counts >500 cells x 10(6)/L). Of the 16 long-term surviving children who were alive and had a median follow-up of 4.1 years (range 0.1 year to 8.5 years) after their eighth birthday, 37.5% had a CD4 cell count greater than 500 cells x 10(6)/L and had either no symptoms or only mild symptoms of HIV infection and were therefore categorized as the long-term non-progressors. CONCLUSIONS: In a small cohort of HIV-infected children, in the absence of antiretroviral therapy, only about one-third survived beyond eight years of age. On further follow-up of these long-term surviving children, over one-third had a slow rate of disease progression.

HLA-B63 presents HLA-B57/B58-restricted cytotoxic T-lymphocyte epitopes and is associated with low human immunodeficiency virus load.

Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection.

HIV-1 viral escape in infancy followed by emergence of a variant-specific CTL response.

Mutational escape from the CTL response represents a major driving force for viral diversification in HIV-1-infected adults, but escape during infancy has not been described previously. We studied the immune response of perinatally infected children to an epitope (B57-TW10) that is targeted early during acute HIV-1 infection in adults expressing HLA-B57 and rapidly mutates under this selection pressure. Viral sequencing revealed the universal presence of escape mutations within TW10 among B57- and B5801-positive children. Mutations in TW10 and other B57-restricted epitopes arose early following perinatal infection of B57-positive children born to B57-negative mothers. Surprisingly, the majority of B57/5801-positive children exhibited a robust response to the TW10 escape variant while recognizing the wild-type epitope weakly or not at all. These data demonstrate that children, even during the first years of life, are able to mount functional immune responses of sufficient potency to drive immune escape. Moreover, our data suggest that the consequences of immune escape may differ during infancy because most children mount a strong variant-specific immune response following escape, which is rarely seen in adults. Taken together, these findings indicate that the developing immune system of children may exhibit greater plasticity in responding to a continually evolving chronic viral infection.

A descriptive study of HIV-infected long-term surviving children in Barbados--a preliminary report / Estudio Descriptivo de Niños Infectados por el VIH Sobrevivientes a Largo Plazo en Barbados Un Informe Preliminar

OBJECTIVES: To describe the clinical and immunologic characteristics of human immunodeficiency virus type-1 (HIV-1)-infected children surviving to more than eight-years of age (long-survivors) before the introduction of antiretroviral therapy. METHODS: This report is based on all the long-term survivors from a prospective cohort of HIV-infected children born to HIV-positive women in Barbados during 1986-1995. Infants born to HIV-infected women were enrolled into this cohort at birth or at the time of diagnosis of HIV exposure in the postnatal period and followed-up at regular intervals. RESULTS: From a cohort of 44 HIV-infected children, 17 (38.6%) children survived to the age of eight years and beyond and were classified as long-term survivors. Median age of the sixteen long-term surviving children alive at the time of this report was 12 years (age range 8 - 16.7 years). At the age of 8 years, 17.6% of these children remained asymptomatic. Nine (52.9%) children had no immunodeficiency (CD4 counts >500 cells x 10(6)/L). Of the 16 long-term surviving children who were alive and had a median follow-up of 4.1 years (range 0.1 year to 8.5 years) after their eighth birthday, 37.5% had a CD4 cell count greater than 500 cells x 10(6)/L and had either no symptoms or only mild symptoms of HIV infection and were therefore categorized as the long-term non-progressors. CONCLUSIONS: In a small cohort of HIV-infected children, in the absence of antiretroviral therapy, only about one-third survived beyond eight years of age. On further follow-up of these long-term surviving children, over one-third had a slow rate of disease progression

OBJETIVOS: Describir las características clínicas e inmunológicas de niños infectados por el VIH-1, que lograron sobrevivir hasta más de ocho años de edad (sobrevivientes a lago plazo) antes de la introducción de terapia antiretroviral. MÉTODOS: Este informe se basa en todos los sobrevivientes a largo plazo de una cohorte prospectiva de niños infectados por el VIH nacidos de mujeres VIH positivas en Barbados, durante los años 1986-1995. Los niños nacidos de mujeres infectadas por el VIH fueron enrolados en esta cohorte al nacer o en el momento de diagnóstico de exposición al VIH en el periodo postnatal, y seguidos a intervalos regulares. RESULTADOS: De una cohorte de 44 niños infectados por el VIH, 17 niños (38.6%) sobrevivieron hasta los ocho años de edad y más, clasificándoseles por ende como sobrevivientes a largo plazo. La edad media de los 16 niños sobrevivientes a largo plazo, aún vivos en el momento en que se hace este informe, fue de 12 años (rango de edad 8 ­ 16.7 años). A la edad de 8 años, el 17.6% de estos niños permanecían asintomáticos. Nueve de los niños (52.9%) no tenían inmunodeficiencia (conteos CD4 >500 células x 106/L). De los 16 niños sobrevivientes a largo plazo que estaban vivos y tuvieron un seguimiento de 4.1 años (en un rango de 0.1 año a 8.5 años) después de su octavo cumpleaños, 37.5% tuvo un conteo CD4 mayor de 500 células x 106/L, y bien no presentaban síntoma alguno de infección de VIH o se trataba sólo de síntomas leves, por lo cual fueron categorizados como no progresores de largo plazo. CONCLUSIONES: En una pequeña cohorte de niños infectados por el VIH, en ausencia de la terapia del antiretroviral, sólo aproximadamente un tercio logró sobrevivir más allá de ocho años de edad. Un seguimiento posterior de estos últimos niños sobrevivientes a largo plazo, mostró que más de un tercio presentaba un ritmo lento de progresión de la enfermedad

RNA profiling of cell-free saliva using microarray technology.

Saliva, like other bodily fluids, has been used to monitor human health and disease. This study tests the hypothesis that informative human mRNA exists in cell-free saliva. If present, salivary mRNA may provide potential biomarkers to identify populations and patients at high risk for oral and systemic diseases. Unstimulated saliva was collected from ten normal subjects. RNA was isolated from the cell-free saliva supernatant and linearly amplified. High-density oligonucleotide microarrays were used to profile salivary mRNA. The results demonstrated that there are thousands of human mRNAs in cell-free saliva. Quantitative PCR (Q-PCR) analysis confirmed the present of mRNA identified by our microarray study. A reference database was generated based on the mRNA profiles in normal saliva. Our finding proposes a novel clinical approach to salivary diagnostics, Salivary Transcriptome Diagnostics (STD), for potential applications in disease diagnostics as well as normal health surveillance.

Mortality among HIV-infected paediatric patients in Barbados.

Since the onset of the HIV epidemic, AIDS has become the leading cause of mortality in the paediatric age group in many developing countries. The main objective of this study was to review the mortality in HIV-infected paediatric patients in Barbados. It is a retrospective analysis of the hospitalization course of HIV-infected paediatric patients aged < 16 years who died during a 15-year period of surveillance. Using a specific database, information pertaining to number and duration of hospitalizations, and cause of death were analyzed. There were 39 (65%) deaths among 60 HIV-infected patients diagnosed during the period of study. Twenty-one (54%) were male and 18 (46%) were female. Twenty-seven (69%) case records were retrieved for analysis. The highest mortality (56%) was among patients aged < 1 year and between 1989 and 1995. Hospitalizations averaged three per patient. No patient received anti-retroviral therapy. Nineteen (70%) patients died during hospitalization on the paediatric ward. Lower respiratory tract infections suspected to be Pneumocystis carinii, gastroenteritis and septicaemia were the most frequent diagnoses at the time of death. The annual mortality ranged between 0 and 1.7 (mean 0.7) per 1000 live births. The overall mortality rate was high among HIV-infected paediatric patients, with lower respiratory tract infections being implicated as a major contributing cause of death. Results of this study definitely indicate a need for improved resources in the management of paediatric HIV/AIDS cases, especially focussing on the availability and administration of anti-retroviral therapy.

The use of 2D and 3D displays for shape-understanding versus relative-position tasks.

Research on when and how to use three-dimensional (3D) perspective views on flat screens for operational tasks such as air traffic control is complex. We propose a functional distinction between tasks: those that require shape understanding versus those that require precise judgments of relative position. The distortions inherent in 3D displays hamper judging relative positions, whereas the integration of dimensions in 3D displays facilitates shape understanding. We confirmed these hypotheses with two initial experiments involving simple block shapes. The shape-understanding tasks were identification or mental rotation. The relative-position tasks were locating shadows and determining directions and distances between objects. We then extended the results to four experiments involving complex natural terrain. We compare our distinction with the integral/separable task distinction of Haskel and Wickens (1993). Applications for this research include displays for air traffic control, geoplots for military command and control, and potentially, any display of 3D information.

Effect of sulfosulfuron on the urine and urothelium of male rats.

Sulfosulfuron, developed as a herbicide, caused increased microcrystalluria and the formation of urinary tract calculi when fed to male and female rats in a chronic 2-year study at doses of 5,000 ppm and 20,000 ppm. Hyperplasia was also seen in urinary bladders at 5,000 ppm and 20,000 ppm, almost exclusively in the presence of observable calculi/microcalculi. Urinary bladder tumors were found in 2 females in the 5000 ppm group, both in the presence of calculi. No increased microcrystalluria, calculi, or tumors were found at doses of 500 ppm and lower. In the current study, 5 groups of male Sprague-Dawley rats were fed sulfosulfuron at doses of 50, 500, 5,000, and 20,000 ppm for 10 weeks. Ten animals were co-administered 5,000 ppm sulfosulfuron with 12,300 ppm NH4Cl to determine if inhibition of the formation of calculi would prevent any urothelial effects of treatment with sulfosulfuron. Ten animals in the control group and in the high-dose sulfosulfuron group were fed only basal diet for an additional 10 weeks to determine if the effects of sulfosulfuron on the bladder epithelium were reversible. There was an increased incidence of microcrystalluria observed at 5,000 and 20,000 ppm. There was no increase in microcrystalluria observed in the urine of rats co-administered sulfosulfuron and NH4Cl. Urinary bladder calculi were found in the bladder of 1 animal fed 20,000 ppm. Examination by light microscopy showed diffuse papillary/nodular hyperplasia of the bladder epithelium in this animal. No increased microcrystalluria was observed after withdrawal of the chemical from the diet and the bladder epithelium was normal by light microscopy. The hyperplastic effects associated with the feeding of high doses of sulfosulfuron occur only with the appearance of urinary tract calculi. Based on these results and anatomical differences between rats and humans, it may be concluded that the hyperplastic and carcinogenic effects of sulfosulfuron in rats are high-dose, threshold phenomena that are not likely to occur in humans under environmentally relevant exposures.

Dietary effects of ortho-phenylphenol and sodium ortho-phenylphenate on rat urothelium.

Ortho-phenylphenol (OPP) and sodium ortho-phenylphenate (NaOPP) are pesticides used commercially in the food industry that have been shown to be carcinogenic to rat urothelium. Dietary administration of 1.25% OPP or 2.0% NaOPP caused increased incidences of urothelial hyperplasia and eventually caused tumors in male F344 rats, with NaOPP apparently having a more potent effect. In other studies, various sodium salts such as saccharin and ascorbate enhanced bladder carcinogenesis, although the acid forms of these salts did not. In studies with high dietary doses of these sodium salts, an amorphous precipitate was produced in the urine; precipitate formation was pH dependent. In previous experiments in which high doses of OPP were fed for up to 17 weeks, severe hyperplasia of the urothelium was produced, but without the formation of an urinary amorphous precipitate, calculi, or abnormal microcrystalluria. In addition, we found no evidence of OPP-DNA adduct formation in the urothelium. The present study was conducted to determine if feeding NaOPP * 4 H(2)0 to male F344 rats as 2.0% of the diet resulted in the formation of an amorphous precipitate in the urine, and if NaOPP caused an increased mineral concentration in the urine and/or kidneys. NaOPP administration produced a higher urinary pH than did OPP fed as 1.25% of the diet. Neither amorphous precipitate nor other solids were observed in the urine of the OPP or NaOPP-treated rats, and urinary calcium concentrations in the treated groups were similar to control. OPP and NaOPP had similar proliferative effects on rat urothelium after 10 weeks of treatment by light microscopy, scanning electron microscopy (SEM), and bromodeoxyuridine (BrdU) labeling indices. The results of this study indicate that formation of abnormal urinary solids is not part of the mechanism by which OPP or NaOPP exert their effects on the rat bladder epithelium.

Leptospirosis occurring in two children after fresh water immersion

Leptospirosis is relatively uncommon in children. Two cases of severe leptospirosis occurred in teenaged boys who shared a common exposure via immersion in fresh water. While both patients had laboratory-confirmed leptospirosis, their symptoms differed in many respects.