Severe acute respiratory syndrome (SARS) is a recently described illness of humans that has spread widely over the past 6 months. With the use of detailed epidemiologic data from Singapore and epidemic curves from other settings, we estimated the reproductive number for SARS in the absence of interventions and in the presence of control efforts. We estimate that a single infectious case of SARS will infect about three secondary cases in a population that has not yet instituted control measures. Public-health efforts to reduce transmission are expected to have a substantial impact on reducing the size of the epidemic.

Rapid diagnostics, vaccines and therapeutics are important interventions for the management of the 2019 novel coronavirus (2019-nCoV) outbreak.It is timely to systematically review the potential of these interventions, including those for Middle East respiratory syndrome-Coronavirus (MERS-CoV) and severe acute respiratory syndrome (SARS)-CoV, to guide policymakers globally on their prioritization of resources for research and development. A systematic search was carried out in three major electronic databases (PubMed, Embase and Cochrane Library) to identify published studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Supplementary strategies through Google Search and personal communications were used. A total of 27 studies fulfilled the criteria for review. Several laboratory protocols for confirmation of suspected 2019-nCoV cases using real-time reverse transcription polymerase chain reaction (RT-PCR) have been published. A commercial RT-PCR kit developed by the Beijing Genomic Institute is currently widely used in China and likely in Asia. However, serological assays as well as point-of-care testing kits have not been developed but are likely in the near future. Several vaccine candidates are in the pipeline. The likely earliest Phase 1 vaccine trial is a synthetic DNA-based candidate. A number of novel compounds as well as therapeutics licensed for other conditions appear to have in vitro efficacy against the 2019-nCoV. Some are being tested in clinical trials against MERS-CoV and SARS-CoV, while others have been listed for clinical trials against 2019-nCoV. However, there are currently no effective specific antivirals or drug combinations supported by high-level evidence.

Regulation of erythropoietin production by the kidneys is central to the control of erythropoiesis. Uncertainty about the identity of the renal cells involved has been a major obstacle to understanding this mechanism. We have used sequence from the mouse erythropoietin locus to direct expression of a marker gene, SV40 T antigen, to these cells in transgenic mice. The transgenic constructs contained an oligonucleotide marker (Epo-M) or SV40 sequence (Epo-TAg) in the 5' untranslated region of the mouse erythropoietin gene, flanked on each side by 9 and 7.5 kb of DNA from the mouse erythropoietin locus. Anemia-inducible expression of Epo-M and Epo-TAg was observed in the kidney. In one of thirteen lines, homologous integration of Epo-TAg into the mouse erythropoietin locus occurred. In transgenic mice bearing Epo-TAg at homologous and heterologous insertion sites, renal expression was restricted to a population of cells in the interstitium of the cortex and outer medulla. Immunohistochemical characterization by light and electron microscopy shows that these are the fibroblast-like type I interstitial cells.

China informed the World Health Organization of a novel viral pneumonia in the city of Wuhan, in Hubei Province. Singapore is an independent city-state 3400 km (2125 miles) from Wuhan, but as a major air hub had an average of 330 000 visitor arrivals from China each month in 2019. 1 On January 2, 2020, Singapore's Ministry of Health alerted all physicians to identify any patient with pneumonia and a recent travel history to Wuhan. On January 3, Singapore started temperature screening at its airport of all travelers arriving from Wuhan. Researchers in China identified a novel coronavirus as the causative agent on January 9, 2 the genetic sequence was released on January 12, 3 and human transmission to health care workers was confirmed on January 20. 4 Singapore promptly shifted its public health response level to "enhanced preparedness" and diagnosed its first case, a tourist from Wuhan, on January 23. The range of public health measures that were instituted and rapidly escalated included aggressive contact tracing and quarantine of close contacts of confirmed cases (namely persons who had spent a prolonged period within 2 m of a confirmed case), travel advisories and then entry restrictions on people traveling from Hubei, and on January 31, entry restrictions on people who had traveled to China in the preceding 14 days. Approximately 700 recent travelers from Hubei were quarantined, and Singaporeans, permanent residents, and longterm visa holders returning from China were placed under a 14-day compulsory leave of absence from work.As of February 19, Singapore has 84 cases of coronavirus disease 2019 (COVID-19) infection with positive results by real-time reverse transcriptasepolymerase chain reaction (RT-PCR) tests targeting the N, S, and ORF1ab genes. Of these cases, 23 were imported cases comprising 17 visitors from China and 6 Singaporeans who had been evacuated from Wuhan. Of the 61 locally transmitted cases, 5 clusters with local transmission involving 43 patients have been identified, a further 10 patients were related, and 8 are as yet not linked to any clear exposure. All 84 confirmed case patients were hospitalized, and of these, 34 have been discharged, 4 are currently in intensive care, and to date there have been no deaths. 5 The approach taken by Singapore, learning from its experience with the severe acute respiratory syndrome (SARS), is that all confirmed cases are isolated until 2 consecutive respiratory samples for RT-PCR (sputum or nasal/throat/nasopharyngeal swabs) become negative over 2 days. Close contacts are identified and those individuals without symptoms are quarantined for 14 days from last exposure. As of February 19, a total of 2593 close contacts have been identified.

Erythropoietin (EPO) mRNA levels were measured by ribonuclease (RNase) protection in organs from unstimulated rats and from animals after normobaric hypoxia or hemorrhagic anemia. Both liver and kidney responded to stimulation with large increases in EPO mRNA, but the response characteristic to graded stimulation was different. The liver responded poorly to mild normobaric hypoxia, accounting for only 2 +/- 1% of total EPO mRNA at 11% O2, but hepatic EPO mRNA levels increased steeply with more severe hypoxia so that at 7.5% O2 the liver contributed to 33 +/- 7% of the total. After hemorrhagic anemia, the liver also responded more strongly to more severe stimulation, but at all points it accounted for a significant proportion of total EPO mRNA, contributing 18 +/- 6% after removal of 2.5 ml (hematocrit 37.2 +/- 1.3%), increasing to 37 +/- 14% after venesection of 10.5 ml (hematocrit 15.8 +/- 0.8%). Studies of EPO mRNA in other organs confirmed that EPO production outside the liver and kidney were quantitatively insignificant in stimulated animals. However, the hypoxia-induced increases in EPO mRNA in brain, testis, and spleen suggest the existence of an oxygen-sensing mechanism at other sites.

An outbreak of severe acute respiratory syndrome (SARS) was detected in Singapore at the beginning of March 2003. The outbreak, initiated by a traveler to Hong Kong in late February 2003, led to sequential spread of SARS to three major acute care hospitals in Singapore. The critical factor in containing this outbreak was early detection and complete assessment of movements and follow-up of patients, healthcare workers, and visitors who were contacts. Visitor records were important in helping identify exposed persons who could carry the infection into the community. In the three hospital outbreaks, three different containment strategies were used to contain spread of infection: closing an entire hospital, removing all potentially infected persons to a dedicated SARS hospital, and managing exposed persons in place. On the basis of this experience, if a nosocomial outbreak is detected late, a hospital may need to be closed in order to contain spread of the disease. Outbreaks detected early can be managed by either removing all exposed persons to a designated location or isolating and managing them in place.

In acute promyelocytic leukemia (APL), the typical t(15;17) and the rare t(11;17) translocations express, respectively, the PML͞RAR␣ and PLZF͞RAR␣ fusion proteins (where RAR␣ is retinoic acid receptor ␣). Herein, we demonstrate that the PLZF and PML proteins interact with each other and colocalize onto nuclear bodies (NBs). Furthermore, induction of PML expression by interferons leads to a recruitment of PLZF onto NBs without increase in the levels of the PLZF protein. PML͞RAR␣ and PLZF͞RAR␣ localize to the same microspeckled nuclear domains that appear to be common targets for the two fusion proteins in APL. Although PLZF͞RAR␣ does not affect the localization of PML, PML͞ RAR␣ delocalizes the endogenous PLZF protein in t(15;17)-positive NB4 cells, pointing to a hierarchy in the nuclear targeting of these proteins. Thus, our results unify the molecular pathogenesis of APL with at least two different RAR␣ gene translocations and stress the importance of alterations of PLZF and RAR␣ nuclear localizations in this disease.Acute promyelocytic leukemia (APL) represents approximately 10% of all adult acute myeloid leukemias (1). The molecular pathogenesis of APL is, at least in part, associated with the disruption of the retinoic acid receptor ␣ (RAR␣) gene through its fusion to one of four different loci (2-7). These translocations result in the expression of chimeric RAR␣ fusion proteins that retain the DNA and ligand binding domains of the receptor and gain a dimerization domain from the fusion partner. Paradoxically, APL is the first human malignancy that may undergo complete remission in response to differentiation therapy with all-trans-retinoic acid (RA). The molecular basis of these remissions is still disputed.The majority of APL cases, and all cases that consistently respond to RA treatment, possess the t(15;17) translocation that fuses the PML and RAR␣ genes (3,(8)(9)(10)(11)(12). PML is a member of a functionally diverse gene family that encodes proteins characterized by the presence of a N-terminal C 3 HC 4 RING-finger motif (13), followed by one or two cysteine-rich regions (B boxes) and a coiled-coil protein dimerization interface. The function of PML is unknown, but up-regulation of its expression by interferons (IFNs) (14-16) and its negative effect on cell growth and cellular transformation by cooperating oncogenes (17-19) suggest a role in growth control. The product of the wild-type PML gene is a phosphoprotein (20) that localizes both in the nucleoplasm and in the specific multiprotein structures called PML nuclear bodies (NBs) (20-24). The PML͞RAR␣ fusion protein, which is expressed in APL cells as a result of t(15;17), contains all predicted PML structural motifs and is able to delocalize the wild-type PML and other NB components onto discrete microspeckled nuclear structures (21-24). It is still unclear which role, if any, disruption of NBs and͞or establishment of microspeckled structures play in cellular transformation. Nevertheless, complete restoration of NBs upon RA treatment in NB4 ...

Using RNAse protection, we have made quantitative measurements of erythropoietin (EPO) mRNA in liver and kidneys of developing rats (days 1-54), to determine the relative contribution of both organs to the total EPO mRNA, to monitor changes which occur with development, and to compare the hypoxia-induced accumulation of EPO mRNA with the changes in serum EPO concentrations. To determine whether developmental and organ-specific responsiveness is related to the type of hypoxic stimulus, normobaric hypoxia was compared with exposure to carbon monoxide (functional anemia).Under both stimuli EPO mRNA concentration in liver was maximal on day 7 and declined during development. In contrast, EPO mRNA concentration in kidney increased during development from day 1 when it was 30-65% the hepatic concentration to day 54 when it was 12-fold higher than in liver.When organ weight was considered the liver was found to contain the majority of EPO mRNA in the first three to four weeks of life, and although, in stimulated animals, the hepatic proportion declined from 85-91% on day 1, it remained -33% at day 54 and was similar for the two types of stimuli. When normalized for body weight the sum of renal and hepatic EPO mRNA in animals of a particular age was related linearly to serum hormone concentrations. However, the slope of this regression increased progressively with development, suggesting age-dependent alterations in translational efficiency or EPO metabolism. (J. Clin. Invest. 1992. 89:753-760.)