Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus-United States, May 2013-August 2016.

November 11, 2016/65(44);1234-1237. What is already known about this topic? Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing.

Outbreak of type A foodborne botulism at a boarding school, Uganda, 2008.

Botulism has rarely been reported in Africa. In October 2008, botulism was reported in three Ugandan boarding-school students. All were hospitalized and one died. A cohort study was performed to assess food exposures among students, and clinical specimens and available food samples were tested for botulinum toxin. Three case-patients were identified; a homemade, oil-based condiment was eaten by all three. In the cohort study, no foods were significantly associated with illness. Botulinum toxin type A was confirmed in clinical samples. This is the first confirmed outbreak of foodborne botulism in Uganda. A homemade, oil-based condiment was the probable source. Consumption of homemade oil-based condiments is widespread in Ugandan schools, putting children at risk. Clinicians and public health authorities in Uganda should consider botulism when clusters of acute flaccid paralysis are seen. Additionally, schools should be warned of the hazard of homemade oil-based condiments, and take steps to prevent their use.

RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis.

The RAS protooncogene has a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor-suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is overexpressed in numerous human cancers. Here we provide new evidence that the pleiotropic regulator of G protein signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts from wild-type and RGS6(-/-) mice, we found that oncogenic Ras induced upregulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by downregulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GTPase-activating protein activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments.

A numerical coarse-grained description of a binary alloy.

We employ Monte Carlo simulation in the semi-grand canonical ensemble to obtain the coarse-grained free energy corresponding to an embedded-atom method description of a binary alloy. In particular, the Ginzburg-Landau free energy for a Cu-Ni alloy was determined from a tabulated histogram of the joint probability density of composition, energy, and volume. Using histogram reweighting techniques, the free energy is extrapolated to a range of points in parameter space from a small number of simulations. The results are interpreted by comparing the free energy with that corresponding to a regular solution model of an alloy. In addition, we obtain expressions for thermodynamic quantities in terms of the joint cumulants of the probability density at a given temperature and chemical potential difference. These expressions may then be likewise extrapolated to obtain the dependence of the composition on the temperature and the chemical potential difference over a wide range of parameter space.

Multistate outbreak of Listeria monocytogenes associated with Mexican-style cheese made from pasteurized milk among pregnant, Hispanic women.

Listeriosis is a severe infection caused by Listeria monocytogenes. Since 2004, the Centers for Disease Control and Prevention has requested that listeriosis patients be interviewed using a standardized Listeria Initiative (LI) questionnaire. In January 2009, states and the Centers for Disease Control and Prevention began investigating a multistate outbreak of listeriosis among pregnant, Hispanic women. We defined a case as an illness occurring between October 2008 and March 2009 with an L. monocytogenes isolate indistinguishable from the outbreak strain by pulsed-field gel electrophoresis. We conducted a multistate case-control study using controls that were selected from L. monocytogenes illnesses in non-outbreak-related pregnant, Hispanic women that were reported to the LI during 2004 to 2008. Eight cases in five states were identified. Seven of these were pregnant, Hispanic females aged 21 to 43 years, and one was a 3-year-old Hispanic girl, who was excluded from the study. Seven (100%) cases but only 26 (60%) of 43 controls had consumed Mexican-style cheese in the month before illness (odds ratio, 5.89; 95% confidence interval, 1.07 to ∞; P = 0.04). Cultures of asadero cheese made from pasteurized milk collected at a manufacturing facility during routine sampling by the Michigan Department of Agriculture on 23 February 2009 yielded the outbreak strain, leading to a recall of cheeses produced in the plant. Recalled product was traced to stores where at least three of the women had purchased cheese. This investigation highlights the usefulness of routine product sampling for identifying contaminated foods, of pulsed-field gel electrophoresis analysis to detect multistate outbreaks, and of the LI for providing timely exposure information for case-control analyses. Recalls of contaminated cheeses likely prevented additional illnesses.

Progress toward tuberculosis control and determinants of treatment outcomes--Kazakhstan, 2000-2002.

INTRODUCTION: In Kazakhstan, during 1995-2002, the annual notification rate per 100,000 population for new cases of tuberculosis (TB) increased from 67.1 to 165.1. Beginning in 1998, public health authorities have used the national case management strategy (DOTS) promulgated by the World Health Organization (WHO) to control TB. Intended goals of DOTS include achieving a cure rate of >85% for persons with newly detected pulmonary TB sputum-smear-positive (PTB+) cases and having PTB+ represent >65% of all PTB cases among adults. Surveillance data collected during 2000-2002 were analyzed to evaluate progress toward achieving these goals and identify factors associated with specific treatment outcomes. METHODS: Surveillance data included the following nonidentifiable information on persons with newly reported cases of PTB: dates of disease onset and treatment initiation; methods of diagnosis; treatment outcomes; HIV status; and selected demographic, socioeconomic, and behavioral characteristics. Cure rates and proportions of PTB+ cases were calculated on the basis of the TB case definition and treatment outcome classification format outlined in DOTS guidelines issued by WHO. Denominator data to calculate rates were obtained from the National Census Office of Kazakhstan. Logistic regression was employed to investigate factors associated with treatment outcomes using Epi Info version 3.2. RESULTS: During 2000-2002, a total of 65,011 new cases of PTB were detected in Kazakhstan. The average annual countrywide notification rate per 100,000 population was 146.0; provincial notification rates varied (range: 65.1-274.0). The countrywide cure rate for newly detected PTB+ was 72.2%; provincial rates varied (range: 65%-81%). Of 59,905 cases of PTB among adults during 2000-2002, a total of 26,804 (44.7%) were PTB+. Unfavorable treatment outcome of new PTB+ cases was associated with alcohol abuse, homelessness, and previous incarceration. CONCLUSION: The cure rate for new PTB+ cases and the proportion of cases of PTB+ among all adults with PTB were below targeted goals. This might, in part, be explained by the 1998 adoption of DOTS. Improving program indicators requires evaluation of detection efforts, laboratory diagnostic capabilities, and adherence to treatment regimens, especially in provinces in which rates are high and among persons at high risk for unfavorable treatment outcomes.

Nicastrin, a presenilin-interacting protein, contains an aminopeptidase/transferrin receptor superfamily domain.

Nicastrin, a protein implicated in Alzheimer's disease, has a domain that is found in the aminopeptidase/transferrin receptor superfamily. In nicastrin, this domain might possess catalytic activity (as observed with aminopeptidases) or it could serve merely as a binding domain (with analogy to the transferrin receptors) for the beta-amyloid precursor protein.

The epidemiology of invasive pneumococcal disease in children in Far North Queensland.

OBJECTIVES: To describe the epidemiology of invasive pneumococcal disease in children under 5 years of age in Far North Queensland and to examine the potential impact of a seven- and 11-valent conjugate pneumococcal vaccine. METHODS: A review of all cases of invasive pneumococcal disease in children under 5 years of age in Far North Queensland over a 9 year period (1992-2000). The distribution of the serotypes of isolates causing invasive pneumococcal disease was compared with the serotypes contained in the two vaccines. RESULTS: The annual incidence in indigenous and non-indigenous children under 5 years of age was 163 (95% confidence interval (CI) 122-213) and 42 (95% CI 31-55) cases per 100 000 children, respectively. For children under 2 years of age, these figures were 297 (95% CI 208-411) and 71 (95% CI 49-100), respectively. There was a greater variety of serotypes isolated from indigenous children (n=17) than from non-indigenous children (n=9; P < 0.01). The serotypes within the seven-valent vaccine accounted for 62% (95% CI 46-75%) and 88% (95% CI 76-95%) of the isolates from indigenous and non-indigenous children, respectively (P < 0.01). Serotypes within the 11-valent vaccine accounted for 72% (95% CI 57-84%) of the isolates from indigenous children under 5 years of age, but did not account for any extra isolates from non-indigenous children. CONCLUSION: Although the seven- and 11-valent conjugate pneumococcal vaccines cover only approximately 60 and 70%, respectively, of the isolates that cause invasive disease in indigenous children in Far North Queensland, they nevertheless have the potential to prevent much morbidity in and hospitalization of these children. It will be essential to maintain surveillance following the introduction of conjugate pneumococcal vaccines so as to monitor changes in the incidence of invasive pneumococcal disease, particularly in high-risk children.

Bioinformatics, target discovery and the pharmaceutical/biotechnology industry.

With the first draft of the human genome now available a directed genome-wide mining strategy is being implemented by many pharmaceutical and biotechnology companies in order to identify novel members of the most therapeutically relevant target families. At the same time there is an increasing amount of annotation relevant to the human genome sequence entering into the public domain. The ability to identify protein families on a genome-wide scale can only be done at speed by using high-throughput computational approaches. This review describes many of the latest algorithmic developments in this field and shows how they can be best put to use for target identification and prioritization.

Chiasmal herniation as a complication of bromocriptine therapy.

INTRODUCTION: Medical treatment of macroprolactinomas with dopamine agonists decreases tumor mass and improves visual defects. We report an unusual complication of a macroprolactinoma responding to bromocriptine: a visual field defect caused by downward herniation of the optic chiasm. MATERIALS AND METHODS: A 64-year-old woman was found to have a 4.5 cm macroprolactinoma with superior displacement of the optic chiasm, bitemporal hemianopia, and serum prolactin concentration (P) of 17,060 micrograms/L. Bromocriptine was initiated at 2.5 mg/day and increased to 7.5 mg/day over 2 months. RESULTS: After 2 months, visual fields improved significantly and tumor height decreased to 3 cm with resolution of the optic chiasm displacement. P decreased to 1,180 micrograms/L. After 5 months of therapy, visual fields were normal, and P was 8 micrograms/L. After 8 months of therapy, new bilateral visual defects were observed. Magnetic resonance imaging (MRI) revealed further decrease of the tumor height to 1.5 cm, and inferior and leftward traction of the optic chiasm as the probable mechanism for the new visual field deficit. P was < 1 microgram/L. Bromocriptine was decreased to 5 mg/day to allow reduced traction on the optic chiasm and its blood supply. Over the next 4 months, visual field abnormalities resolved. CONCLUSIONS: We report the development of a visual field abnormally that is explained by chiasmal herniation caused by a shrinking macroprolactinoma. This complication resolved with a decrease in the bromocriptine dose. We suggest that patients undergoing bromocriptine therapy for macroprolactinomas be followed for this potential complication.

Pressure sore management in the independent sector: 2.

This is the second of two articles looking at pressure sore prevention and treatment in the independent sector of a large northern city. Part one presented background information, details of data collection and analysis, baseline data on current practice and initial conclusions which included an assessment of the extent of evidence-based practice, equipment use, educational needs, patient and informal carer involvement and quality of care maintenance. Part two considers these findings in greater depth. Both positive and negative aspects of pressure sore management in the independent sector are explored. Factors such as the number and types of pressure-relieving equipment used and the lack of independent evidence regarding product efficacy are considered. The survey highlights gaps in educational provision, and the lack of research evidence on certain aspects of care. The article concludes with a detailed series of recommendations with regard to practice, education and research.

Pressure sore management in the independent sector: 1.

Little is known about pressure sore prevention and treatment in the independent sector. With a rapidly increasing number of care settings taking over responsibility for continuing care, particularly for elderly people, it is important that essential nursing care is provided at nationally agreed standards. This is the first of two articles which explore current practice in the independent sector of a large northern city. Background information on the study, details of data collection and analysis and baseline data on current practice are presented. This study investigates the extent of evidence-based practice, equipment use, educational needs, patient and informal carer involvement and maintenance of quality of care. Initial conclusions indicate that pressure sore management in the independent sector is evidence-based. However, in many areas of practice, personal observations and experience continue to take precedence over research evidence.

Arthroscopic treatment of acute complete thumb metacarpophalangeal ulnar collateral ligament tears.

An arthroscopic technique was used to reduce Stener lesions associated with acute ulnar collateral ligament ruptures of the thumb. We operated on eight thumbs, seven dominant and one nondominant. The average follow-up period was 39 months (range, 30-48). At follow-up examination, no patient reported pain or functional limitation or had joint contracture. In most cases, key pinch, tip pinch, grip strength, and range of motion were equal to or greater than in the thumb on the unaffected side. The only complication, a pin track infection, resolved after wire removal and treatment with oral antibiotics. Results indicate that arthroscopic reduction of a Stener lesion allows healing of the ulnar collateral ligament without the need for open repair.

Health of the Nation targets: where school nurses find constraints on achievement.

A qualitative research methodology was used to investigate 73 school nurses' perceptions of their contributions towards Health of the Nation targets (1). The inquiry aimed to identify areas in which the school nurses felt that educational assistance was required. The study demonstrated that school nurses function well and have an enormous potential to affect positively the health of the nation's children. Four main areas of constraint, however, were identified by the nurses. These areas, pinpointed as the major obstacles for target achievement, are education, joint planning, resources and perceived value. The author highlights recommendations for the future role of the school nurse.

Phosphorylation of E2F-1 modulates its interaction with the retinoblastoma gene product and the adenoviral E4 19 kDa protein.

The transcription factor E2F is regulated through its cyclical interaction with a spectrum of cellular proteins. One such protein is the product of the retinoblastoma gene (Rb); association of E2F with Rb inhibits its transactivation potential. However, in adenovirus-infected cells, E2F is complexed to the 19 kDa product of the adenovirus E4 gene. We have studied the interaction of E2F-1 with the Rb and adenovirus E4 proteins and show that phosphorylation of E2F-1 on serine residues 332 and 337 prevented its interaction with Rb but was a prerequisite for interaction with E4. These residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. Upon stimulation of serum-starved cells, phosphorylation was induced in the late G1 phase of the cell cycle. These observations suggest that phosphorylation of E2F-1 is important in the regulation of its activity during the cell cycle and during infection of cells by adenovirus.

Translational control of ornithine-delta-aminotransferase (OAT) by estrogen.

Ornithine-delta-aminotransferase (OAT) catalyzes the reversible transamination of ornithine to glutamate semialdehyde. OAT is abundant in liver, kidney and retina; hereditary deficiency of the enzyme leads to chorioretinal degeneration. Studies of OAT regulation in retinoblastomas have revealed an alternatively spliced OAT mRNA, which contains an additional exon (exon 2) in the 5' untranslated region. Estrogen and thyroid hormone were previously shown to increase OAT mRNA levels approximately 3-fold and 5-fold, respectively, in these cells. To determine the mechanism of hormonal action in retinoblastomas, we performed nuclear transcription assays and analyzed the distribution of OAT mRNAs in individual fractions of a polysome gradient. Thyroid hormone increased the rate of transcription of the OAT mRNA in these cells. Estrogen did not stimulate transcription; it was associated with increased translation, since it resulted in a shift of the major (spliced) OAT mRNA species into denser fractions of the polysome gradient. Cycloheximide treatment suggested that the latter effect was due to increased initiation of translation. The unspliced OAT mRNA, which is inefficiently compared to the spliced mRNA, was insensitive to estrogen in these experiments.

Translational control of ornithine aminotransferase. Modulation by initiation factor eIF-4E.

Ornithine aminotransferase (OAT) is a mitochondrial enzyme expressed at high levels in liver, kidney, and retina. To characterize OAT regulation in retinal lines, we have been studying OAT synthesis in retinoblastomas RB355 and Y79. Our previous data (Fagan, R.J., Sheffield, W.P., and Rozen, R. (1989) J. Biol. Chem. 264, 20513-20517) indicated similar OAT mRNA levels in the two strains with 3-fold greater immunoreactive OAT protein and enzyme activity in Y79. To examine the regulatory mechanisms in these cell lines, we performed nuclear runoff experiments and characterized polysome-associated OAT mRNAs. The nuclear runoff data did not reveal any differences in transcription between the two strains. However, OAT mRNA of the RB355 strain was present in the lighter polysome fractions as compared with Y79. Treatment with cycloheximide, which slows the rate of elongation, indicated that initiation was decreased in RB355. Eukaryotic initiation factor eIF-4E mRNA and protein were reduced in RB355, suggesting that eIF-4E might be rate-limiting for OAT translation. Overexpression of a wild-type eIF-4E in RB355 shifted the OAT mRNA into denser fractions of the gradient and increased the amount of OAT protein to the level observed in Y79; overexpression of a mutant eIF-4E had no such effect. We previously identified an alternatively spliced OAT mRNA (containing exon 2) in these cells. This mRNA appeared in the lightest fractions of the gradient in both strains and was not affected by eIF-4E overexpression.

Expression of transforming growth factor-alpha and epidermal growth factor receptor in human fetal kidneys.

Beginning at the fifth week of fetal life, successive generations of individual nephrons are induced by contact between metanephric mesenchyme and ureteric bud. Following phenotypic transformation, cells of each primitive renal vesicle undergo a phase of rapid cell division. In order to identify genes which might regulate nephron development in man, we screened adult and fetal kidney RNA for expression of a panel of growth-related genes. Among the genes which were expressed at higher levels in fetal kidney was the epidermal growth factor (EGF) receptor. There is controversy as to the most likely physiologic EGF receptor ligand in fetal kidney; we were able to identify a transcript for transforming growth factor-alpha (TGF-alpha) but not EGF on Northern blots of fetal kidney RNA. Since the abundance of TGF-alpha mRNA is low, we confirmed its presence by polymerase chain reaction amplification. Using specific radioimmunoassays, we also provide direct evidence for TGF-alpha but not EGF peptide in extracts of fetal kidney and mid-gestational amniotic fluid. We suggest that TGF-alpha/EGF receptor interactions may serve an important function in development of human fetal kidney.

Regulation of ornithine aminotransferase in retinoblastomas.

Ornithine-delta-aminotransferase (OAT) is a nuclear-encoded, mitochondrial enzyme that converts ornithine to glutamate semialdehyde. Although OAT is expressed in most tissues of the rat, liver, kidney, and retina have the highest levels of OAT activity. Studies of OAT regulation in liver and kidney have indicated transcriptional and translational controls for the enzyme in a tissue-specific manner. Little is known about OAT modulation in retinal tissue, although chorio-retinal degeneration is the predominant feature in a hereditary disorder of OAT deficiency, gyrate atrophy. To characterize OAT regulation in retinal lines, we studied its synthesis in two retinoblastoma strains, Y79 and RB355. Baseline OAT mRNA levels were similar in the two cell lines, yet Y79 expressed 3-fold more immunoreactive OAT protein and enzyme activity than RB355; this finding suggested the presence of a post-transcriptional mechanism for the regulation of steady-state OAT levels. Treatment of the two strains with estradiol or thyroid hormone for 24 h resulted in approximately 5-fold increases in OAT protein and activity. Since similar increases in OAT mRNA levels were observed in both strains after Northern blotting, it is likely that these hormones exert their effects at the transcriptional level. Finally, primer extension analysis revealed two OAT mRNA species in both strains, due to the presence of an additional exon (exon 2) in one of the transcripts. The absence of this exon in other tissues reflects the unique mechanisms which govern OAT in retinoblastomas.

Reasons for alcohol use in maritally violent men.

This study compared the contexts and reasons for drinking of a maritally violent group as compared to three nonviolent comparison groups. We found that the maritally violent group reported higher levels of alcohol consumption in all of the drinking context items with the most significant differences being on drinking at home after work, at home while playing with the kids, at recreational activities, at home by oneself, on the job, at workday lunch, and with people after work. While we did find significant differences, the mean level of consumption in all contexts was relatively low. We found that the maritally violent men tended to drink to forget worries, pains, and stresses in their lives more so than the nonviolent groups. At least half the maritally violent men reported that drinking accompanied abusive events at least occasionally, while about one-third reported it often or very often accompanied their abuse. We concluded that while our findings indicate that alcohol use may facilitate marital violence, they also suggest that alcohol use and mental abuse may be symptoms of other individual, structural, or cultural norm factors. Therapy should not focus exclusively on alcohol use, but on underlying causes of both alcohol use and spouse abuse.