The spectrum of hemophagocytic lymphohistiocytosis: a retrospective study comparing adult macrophage activation syndrome to malignancy-associated hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening inflammatory syndrome that can be triggered by autoimmune diseases, malignancy, or infection. In rheumatologic patients, sHLH is referred to as macrophage activation syndrome (MAS). Differentiating between triggers is important for prompt treatment and prognosis. Data comparing subsets of sHLH are limited due to the rarity of this disease. We aim to explore differences in clinical features that may differentiate MAS from malignancy-associated HLH (mHLH) patients. We conducted a single-center retrospective study assessing clinical characteristics, laboratory parameters, treatment regimens and outcomes in 34 patients with sHLH over a 16 year period. We compared patients with MAS to those with mHLH. Hepatomegaly was not present in the MAS group but was present in the mHLH group (0 vs. 25%, p = 0.024). MAS patients had on average nearly double the concentration of platelets at 50.0 (IQR: 31.0-78.0 Kµ/L) vs. 29.0 Kµ/L (IQR: 14.0-37.5 Kµ/L), p = 0.003. Soluble IL-2R concentrations were four times lower in the MAS group with a median soluble IL-2R concentration of 6814.5 kU/L (IQR: 2101-2610 kU/L) vs. 27972.0 kU/L (IQR: 12,820-151,650 kU/L), p = 0.010. The MAS group fared better overall than the mHLH group but was not statistically significant (mortality 22 vs. 44%, p = 0.18). MAS and mHLH patients exhibited different laboratory parameters and clinical features, most notably differences in platelet counts, soluble IL-2R concentration and hepatomegaly, which may help differentiate these conditions early in their course.

Tempo and mode in coevolution of Agave sensu lato (Agavoideae, Asparagaceae) and its bat pollinators, Glossophaginae (Phyllostomidae).

The genus Agave sensu lato contains ca. 211 described species, many of which are considered keystone species because of their ecological dominance and the quantity of resources they provide with their massive, nectar-rich inflorescences. The large diversity of Agave species has been hypothesized as being related to their reproductive strategy (predominantly monocarpic) and diverse pollinators (e.g., bats, hummingbirds, hawkmoths). In particular, Agave species provide resources that a few genera of nectar feeding bats from the subfamily Glosophaginae are dependent upon. To explore a possible coevolutionary relationship between Agave and the bat species that pollinate them, we calibrated molecular phylogenies of both groups and looked for a correlation in their dates of divergence. One coding and two non-coding regions of the chloroplast genome were sequenced from 49 species of the Agavoideae (Asparagaceae), and the mitochondrial gene Cyt-b and nuclear coding gene RAG2 were either sequenced or obtained from gene bank for 120 Phyllostomid bats. Results from the analyses indicate that Agave sensu lato is a young genus (estimated crown age 2.7-8.5/stem age 4.6-12.3 Ma), with an increasing diversification rate, and the highest speciation rate among Agavoideae's clades. The origin of the Glossophaginae bats (stem age 20.3-23.5 Ma) occurred prior to the stem age of Agave sensu lato, while the origin of the current pollinators of Agave species, members of the genera Glossophaga, Leptonycteris, Anoura, Choeronyscus, Musonycteris and Choeronycteris, was estimated to be around 6.3-16.2 Ma, overlapping with the stem age of Agave sensu lato, supporting the hypothesis of diffuse coevolution.

Sugammadex hypersensitivity and underlying mechanisms: a randomised study of healthy non-anaesthetised volunteers.

BACKGROUND: We investigated potential for hypersensitivity reactions after repeated sugammadex administration and explored the mechanism of hypersensitivity. METHODS: In this double-blind, placebo-controlled study (NCT00988065), 448 healthy volunteers were randomised to one of three arms to receive three repeat i.v. administrations of either sugammadex 4 mg kg-1, 16 mg kg-1, or placebo. Primary endpoint was percentage of subjects with hypersensitivity (assessed by an independent adjudication committee). Secondary endpoint of anaphylaxis was classified per Sampson and Brighton criteria. Exploratory endpoints included skin testing, serum tryptase, anti-sugammadex antibodies [immunoglobulin (Ig) E/IgG], and other immunologic parameters. RESULTS: Hypersensitivity was adjudicated for 1/148 (0.7%), 7/150 (4.7%), and 0/150 (0.0%) subjects after sugammadex 4 mg kg-1, 16 mg kg-1, and placebo, respectively. After sugammadex 16 mg kg-1, one subject met Sampson criterion 1 and Brighton level 1 (highest certainty) anaphylaxis criteria; two met Brighton level 2 criteria. After database lock it was determined that certain protocol deviations could have introduced bias in the reporting of hypersensitivity signs/symptoms in a subject subset. Objective laboratory investigations indicated that potential underlying hypersensitivity mechanisms were unlikely to have been activated; the results suggest that most of the observed hypersensitivity reactions were unlikely IgE/IgG-mediated. CONCLUSION: Dose-dependent hypersensitivity or anaphylaxis reactions to sugammadex were observed when administered without prior neuromuscular blocking agent. Laboratory investigations do not suggest prevalent allergen-specific IgE/IgG-mediated immunologic hypersensitivity. Because it could not be fully excluded that estimates of hypersensitivity/anaphylaxis incidence were unbiased, an additional study was conducted to characterise the potential for hypersensitivity reactions and is described in a companion report. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00988065; Protocol number P06042.

Correlation of ICME Magnetic Fields at Radially Aligned Spacecraft.

The magnetic field structures of two interplanetary coronal mass ejections (ICMEs), each observed by a pair of spacecraft close to radial alignment, have been analysed. The ICMEs were observed in situ by MESSENGER and STEREO-B in November 2010 and November 2011, while the spacecraft were separated by more than 0.6 AU in heliocentric distance, less than 4° in heliographic longitude, and less than 7° in heliographic latitude. Both ICMEs took approximately two days to travel between the spacecraft. The ICME magnetic field profiles observed at MESSENGER have been mapped to the heliocentric distance of STEREO-B and compared directly to the profiles observed by STEREO-B. Figures that result from this mapping allow for easy qualitative assessment of similarity in the profiles. Macroscale features in the profiles that varied on timescales of one hour, and which corresponded to the underlying flux rope structure of the ICMEs, were well correlated in the solar east-west and north-south directed components, with Pearson's correlation coefficients of approximately 0.85 and 0.95, respectively; microscale features with timescales of one minute were uncorrelated. Overall correlation values in the profiles of one ICME were increased when an apparent change in the flux rope axis direction between the observing spacecraft was taken into account. The high degree of similarity seen in the magnetic field profiles may be interpreted in two ways. If the spacecraft sampled the same region of each ICME (i.e. if the spacecraft angular separations are neglected), the similarity indicates that there was little evolution in the underlying structure of the sampled region during propagation. Alternatively, if the spacecraft observed different, nearby regions within the ICMEs, it indicates that there was spatial homogeneity across those different regions. The field structure similarity observed in these ICMEs points to the value of placing in situ space weather monitors well upstream of the Earth.

Modeling observations of solar coronal mass ejections with heliospheric imagers verified with the Heliophysics System Observatory.

We present an advance toward accurately predicting the arrivals of coronal mass ejections (CMEs) at the terrestrial planets, including Earth. For the first time, we are able to assess a CME prediction model using data over two thirds of a solar cycle of observations with the Heliophysics System Observatory. We validate modeling results of 1337 CMEs observed with the Solar Terrestrial Relations Observatory (STEREO) heliospheric imagers (HI) (science data) from 8 years of observations by five in situ observing spacecraft. We use the self-similar expansion model for CME fronts assuming 60° longitudinal width, constant speed, and constant propagation direction. With these assumptions we find that 23%-35% of all CMEs that were predicted to hit a certain spacecraft lead to clear in situ signatures, so that for one correct prediction, two to three false alarms would have been issued. In addition, we find that the prediction accuracy does not degrade with the HI longitudinal separation from Earth. Predicted arrival times are on average within 2.6 ± 16.6 h difference of the in situ arrival time, similar to analytical and numerical modeling, and a true skill statistic of 0.21. We also discuss various factors that may improve the accuracy of space weather forecasting using wide-angle heliospheric imager observations. These results form a first-order approximated baseline of the prediction accuracy that is possible with HI and other methods used for data by an operational space weather mission at the Sun-Earth L5 point.

Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial.

PURPOSE: Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting (90)Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5 mm of (90)Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide (213)Bi with a mean tissue range of 81 microm may have a more favourable toxicity profile. Therefore, we evaluated locally injected (213)Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality. METHODS: In a pilot study, we included five patients with critically located gliomas (WHO grades II-IV). After diagnosis by biopsy, (213)Bi-DOTA-substance P was locally injected, followed by serial SPECT/CT and MR imaging and blood sampling. Besides feasibility and toxicity, the functional outcome was evaluated. RESULTS: Targeted radiopeptide therapy using (213)Bi-DOTA-substance P was feasible and tolerated without additional neurological deficit. No local or systemic toxicity was observed. (213)Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis and demarcation of the tumours, which was validated by subsequent resection. CONCLUSION: This study provides proof of concept that targeted local radiotherapy using (213)Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosis.

Psychological characteristics of women who require orthognathic surgery: comparison with untreated controls.

Improvement in appearance is an important motivation for orthodontic treatment and orthognathic surgery, and two possible underlying causes are objective physical abnormalities, or the patient's personality type that leads them to concentrate on their appearance and request unnecessary interventions. Questionnaires that measure personality traits were given to 30 women who required orthognathic operations, and a control group of 30 other women. Traits measured were: satisfaction with the appearance of the face, head, and body; tendency to compare their appearance with that of others; the extent to which they are aware of their appearance and how they thought they should look; sense of self identity; depression; anxiety; and self-esteem. The only difference between patients and controls was that patients were more dissatisfied with their facial appearance than the others. Orthognathic patients were psychologically normal except that they had more dissatisfaction with their facial appearance. As this was the only difference, it is likely that their desire for operation was caused by a genuine physical abnormality rather than a perceived exaggerated aesthetic problem. It seems, therefore, that any patient who seeks orthognathic treatment because they have a personality that causes them to dwell on their appearance (which may lead them to hold unrealistic expectations of intervention) are screened out of the process before they begin treatment.

An evaluation of slot size in orthodontic brackets--are standards as expected?

The slots of five upper left central incisor brackets from 11 commercially available bracket systems (3M Unitek, Monrovia, Calif: Twin Torque Roth, Clarity MBT, and Victory Series MBT; Dentarum, Pforzheim, Germany: Discovery Roth (0.56 mm) and Elegance Plastic Roth; Forestadent, Pforzheim, Germany: Mini Mono MBT; TP LaPorte, Indiana: Nu-Edge Roth and Mxi Advant-Edge Roth; Ormco Corp., Orange, Calif: Damon II SL Roth; Ortho Organizers, San Marcos, Calif: Elite Mini Opti-MIM Roth and Elite Mini Opti-MIM MBT) were measured in the 0.022-inch (0.5588 mm) dimension. Measurements were taken after operator calibration, and a digital readout was produced. Results indicate that all bracket slots are oversized. Three bracket systems slots (Twin Torque, Clarity, and Mini Mono) were within 5% (+/-1.08, 1.655, 1.75) of their stated dimensions with essentially parallel slot walls. The Elegance Plastic slot was parallel sided but oversized by 12% (+/-1.15). The geometry of bracket slots was also variable. The Victory Series slot was slightly divergent with the top oversized by 6% (+/-1.035). The Nu-Edge slot was divergent and slot top oversized by 14% (+/-1.32). The Mxi Advant-Edge, Damon II SL, Elite Mini Opti-MIM Roth, and MBT were all convergent, and the base of the Damon slot was oversized by 17% (+/-1.79). The Discovery bracket was convergent, and the slot base was oversized by 24% (+/-1.255), which was the largest recorded variance. This bracket also had a 7% difference between the widths of the slot top and the base. Inaccurate machining of bracket slot dimensions and the use of undersized archwires may directly and adversely affect three-dimensional tooth positioning.

[A survey on contraceptive knowledge, attitude and behavior among never-married young women who are seeking pregnancy termination in Beijing].

OBJECTIVE: To identify contraceptive knowledge, attitude, behavior and its determinants among never-married young women who have unwanted pregnancy in Beijing. METHODS: A cross-sectional study under adoption of Lawrence "Procede-Proceed" model, was conducted in China in 1999. Three hundred and six unmarried young women aged 18 to 24, requesting for pregnancy termination were interviewed in person. RESULTS: Findings of this study indicated that only one-eighth (13%) of the young women insisted on contraceptive use every time, and almost an equal proportion (26.4%, 26.8% respectively) occasionally or never using contraceptives. Among 224 women who ever used contraceptives during the past 12 months, condom (49%) ranked the first place followed by withdrawal (27.7%) and the rhythm method (15.6%). One of the most important reasons, cited by 73 percent of women who had never used contraceptives, was that they were not aware of the risk of pregnancy when engaging in sexual activities. The results of logistic regression analysis revealed that knowledge about contraception, boyfriend's approval of contraceptive use, perceived the risk of getting pregnancy, perceived availability of contraceptive service and discussion of contraception with boyfriend were important indicators of young women's behavior on contraceptive use. CONCLUSION: These results indicated an urgent need to develop sex education about contraception among young women and men, through enhancing perception about risk of unwanted pregnancy and complications of induced abortion among young women, and to promote men's co-operation and participation in contraceptive use as well as strengthening communication on contraception between young women and their partners.

Patterns of movement and orientation during caching and recovery by Clark's nutcrackers, Nucifraga columbiana.

Clark's nutcrackers regularly store large numbers of pine seeds and remember the locations of the cached seeds. Although they are very accurate, they do make some errors during recovery. In an attempt to determine whether any behaviours during caching predicted the occurrence of errors during recovery, we videotaped Clark's nutcrackers while they cached and recovered seeds under laboratory conditions. We used the videotapes to develop complete, quantitative descriptions of caching and recovery behaviour, with an emphasis on body orientation and directions of movement. During caching, the birds showed the greatest change in their orientation and direction following cache creation. During cache recovery, in contrast, body orientation changed most following successful recovery of a seed. When orientation while making a cache was compared with orientation when recovering the same cache, orientations were similar more often than would be expected by chance. However, this consistency of direction was not related to the accuracy of cache recovery, indicating that such consistency is not necessary for accurate cache recovery. The location in which the birds chose to place their caches was the only variable that predicted the location of probes during recovery. Copyright 1999 The Association for the Study of Animal Behaviour.

Development of novel benzimidazole riboside compounds for treatment of cytomegalovirus disease.

Benzimidazole ribosides are a new class of compounds with novel mechanisms of action against CMV. One compound in this series, BDCRB, inhibits CMV DNA processing by the UL89 gene product (putative terminase), but rapid metabolism to an inactive compound makes it unsuitable for development as a medicine. Another benzimidazole analogue, 1263W94, has many characteristics that make it an attractive candidate for development, including high potency in vitro, selectivity, good oral bioavailability, and lower toxicity than therapies currently available for treatment of CMV disease. Initial clinical trials have provided encouraging results, including good tolerability and linear pharmacokinetics over a wide dose range. Ongoing and planned clinical trials that will study the safety and tolerability of repeated dosing and evaluate the in vivo antiviral activity and ocular penetration of 1263W94, will help to determine the potential of this drug as an improved therapy for CMV disease.

1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89.

The anabolism of 1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, a selective inhibitor of human immunodeficiency virus (HIV), was characterized in human T-lymphoblastoid CD4+ CEM cells. 1592U89 was ultimately anabolized to the triphosphate (TP) of the guanine analog (-)-carbovir (CBV), a potent inhibitor of HIV reverse transcriptase. However, less than 2% of intracellular 1592U89 was converted to CBV, an amount insufficient to account for the CBV-TP levels observed. 1592U89 was anabolized to its 5'-monophosphate (MP) by the recently characterized enzyme adenosine phosphotransferase, but neither its diphosphate (DP) nor its TP was detected. The MP, DP, and TP of CBV were found in cells incubated with either 1592U89 or CBV, with CBV-TP being the major phosphorylated species. We confirmed that CBV is phosphorylated by 5'-nucleotidase and that mycophenolic acid increased the formation of CBV-TP from CBV 75-fold. However, mycophenolic acid did not stimulate 1592U89 anabolism to CBV-TP. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not inhibit CBV-TP formation from CBV or 1592U89, whereas the adenylate deaminase inhibitor 2'-deoxycoformycin selectively inhibited 1592U89 anabolism to CBV-TP and reversed the antiviral activity of 1592U89. 1592U89-MP was not a substrate for adenylate deaminase but was a substrate for a distinct cytosolic deaminase that was inhibited by 2'-deoxycoformycin-5'-MP. Thus, 1592U89 is phosphorylated by adenosine phosphotransferase to 1592U89-MP, which is converted by a novel cytosolic enzyme to CBV-MP. CBV-MP is then further phosphorylated to CBV-TP by cellular kinases. This unique activation pathway enables 1592U89 to overcome the pharmacokinetic and toxicological deficiencies of CBV while maintaining potent and selective anti-HIV activity.

Radiologic placement of metallic esophageal stents: preliminary experience.

OBJECTIVE: To assess the usefulness of covered, self-expanding metallic stents for alleviating stricture associated with malignant esophageal lesions. PATIENTS AND METHODS: Self-expanding metallic stents were placed in 10 patients with dysphagia related to stricture caused by malignant esophageal lesions. The stents were placed fluoroscopically with local anesthesia, and patency of the esophageal lumen was assessed by barium study after the procedure. The patients were then followed clinically. RESULTS: In all 10 cases patency of the lumen was renewed after stent placement. After the procedure 9 of the patients could tolerate a normal or near-normal diet; in the other patient esophageal perforation occurred, and clinical deterioration prevented oral intake of food. In one patient, 2 stents were needed because of the length of the stricture. Two patients experienced reflux after placement of the stent across the gastro-esophageal junction. Another patient had asymptomatic aspiration after stent placement in the proximal esophagus. In 2 patients, symptoms associated with tracheoesophageal fistula were relieved after placement of the stents. Six of the 10 patients died; mean survival after the procedure was 12 (range 1 to 56) weeks. The other 4 patients were alive at the time of writing, having survived for a mean of 7.5 (range 2 to 13) weeks; all of these patients tolerated a near-normal diet. CONCLUSIONS: The placement of covered, self-expanding metallic stents is a quick, effective method of palliating dysphagia related to stricture caused by malignant esophageal lesions.

Use of a psychiatric proforma for accident and emergency officers.

OBJECTIVE: To devise a proforma for clinical documentation of psychiatric illness in an accident and emergency (A&E) department, since A&E senior house officers (SHOs) have little psychiatric experience before starting their jobs. METHODS: History taking and mental state examinations by 16 SHOs were compared before (n = 50) and after (n = 50) the introduction of the proforma. Comments on the proforma were provided by all participants on a questionnaire. RESULTS: There was an improvement in documentation with the use of the proforma (Mann-Whitney U test, P < 0.001). The senior house officers found the proforma useful and supported further development of this initiative. CONCLUSIONS: A standard form for documenting psychiatric history, designed according to local needs, is useful and should be available in A&E departments.

Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase.

The gene encoding cytosine deaminase (CD) has been expressed in the human colorectal carcinoma cell line WiDr. Metabolism studies confirm that tumor cells expressing CD convert the very nontoxic prodrug 5-fluorocytosine (5FCyt) to 5-fluorouracil (5FUra) and 5FUra metabolites. Tumor xenografts composed of CD-expressing cells can selectively generate tumor levels of > 400 microM 5FUra when the host mouse is dosed with nontoxic levels of 5FCyt. The selective metabolic conversion of 5FCyt to 5FUra in CD-expressing tumor cells results in the inhibition of thymidylate synthase and incorporation of 5FUra into RNA. 5FUra is also liberated into the surrounding environment when CD-expressing tumor cells are treated with 5FCyt. The liberated 5FUra is able to kill neighboring, non-CD-expressing tumor cells in vitro and in vivo. Most importantly, when only 2% of the tumor mass contains CD-expressing cells (98% non-CD-expressing cells), significant regressions in all tumors are observed when the host mouse is dosed with nontoxic levels of 5FCyt.

In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase.

A human colorectal carcinoma cell line, WiDr, was genetically engineered to express the nonmammalian enzyme, cytosine deaminase (CD). Expression of CD in WiDr cells (WiDr/CD) did not alter the growth rate of these cells when grown in vitro or as solid tumor xenografts in nude mice. However, expression of CD did increase the sensitivity of these cells to the nontoxic prodrug, 5-fluorocytosine (FCyt), decreasing the 50% inhibitory concentration for FCyt from 26,000 microM in parental WiDr cells to 27 microM in WiDr/CD cells. The increase in sensitivity to FCyt in WiDr/CD cells was the result of the CD-mediated conversion of FCyt to 5-fluorouracil (FUra) and subsequent FUra anabolites. The half-life of the prodrug, FCyt, was determined to be approximately 40 min in nude mice. A single i.p. injection of 500 mg FCyt/kg body weight resulted in a transient FCyt plasma level of approximately 4000 microM while osmotic minipumps or constant tail vein infusions of FCyt achieved continual FCyt plasma levels of 5 microM and 50 microM, respectively, with no overt signs of toxicity. Significant antitumor effects were observed in nude mice bearing tumors derived from WiDr/CD cells when these animals were given 500 mg FCyt/kg i.p. for 10 consecutive days. These antitumor effects were demonstrated by decreases in tumor growth rate, tumor size, tumor weight, and thymidine incorporation into tumor DNA. This antitumor effect was significant but less profound if FCyt was administered by constant tail vein infusion. WiDr and WiDr/CD cells were very sensitive to FUra in vitro (50% inhibitory concentration approximately 5 microM). However, no significant antitumor effects were observed in nude mice bearing tumors derived from either WiDr or WiDr/CD cells when these animals were treated with various doses of FUra. Taken collectively, these data indicate that nontoxic plasma levels of FCyt can be attained which can produce profound antitumor effects on tumors engineered to express CD and that these antitumor effects are significantly better than those that can be achieved using FUra. These positive data support the continued development of a gene therapy approach to colorectal carcinoma involving the selective expression of CD in colorectal tumors with subsequent administration of FCyt.

Influenza--United States, 1989-90 and 1990-91 seasons.

During the 1989-90 influenza season, 98% of all influenza viruses isolated in the United States and reported to CDC were influenza A. Almost all those that were antigenically characterized were similar to influenza A/Shanghai/11/87(H3N2), a component of the 1989-90 influenza vaccine. Regional and widespread influenza activity began to be reported in late December 1989, peaked in mid-January 1990, and declined rapidly through early April 1990. Most of the outbreaks reported to CDC were among nursing-home residents. Considerable influenza-associated mortality was reflected in the percentage of deaths due to pneumonia and influenza (P&I) reported through the CDC 121 Cities Surveillance System from early January through early April. More than 80% of all reported P&I deaths were among persons greater than or equal to 65 years. In contrast to the predominance of influenza A during 1989-90, during the 1990-91 influenza season 86% of all influenza virus isolations reported were influenza B. Widespread influenza activity was reported from mid-January through April 1991, with regional activity extending into May. Outbreaks were reported primarily among schoolchildren, and no evidence of excess influenza-associated mortality was found. Almost all the influenza B isolates tested were related to influenza B/Yamagata/16/88, a component of the 1990-91 influenza vaccine, but were antigenically closer to B/Panama/45/90, a minor variant.

Synthesis and biological evaluation of dinucleoside methylphosphonates of 3'-azido-3'-deoxythymidine and 2', 3'-dideoxycytidine.

The 5'----5' dinucleoside methylphosphonates of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC) were prepared and evaluated for their inhibitory properties against different viruses, including human immunodeficiency virus (HIV). The synthesis of the compounds was achieved by reaction of AZT or N4-(4-monomethoxytrityl)-2',3'-dideoxycytidine with in situ prepared methylphosphonic bis (triazolide), followed in the latter case by an acidic treatment. The two title compounds showed in vitro anti-HIV activity, that was 200- to 450-fold less pronounced that that shown by the corresponding monomeric nucleosides AZT and DDC. The decreased antiviral activity may be ascribed to nuclease resistance of the methylphosphonate linkage.