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BACKGROUND Apheresis technology to collect platelet (PLT) components differs among devices. We evaluated the relationship of the plateletpheresis device with bacterial contamination and reported septic transfusion reactions. STUDY DESIGN AND METHODS Plateletpheresis was performed using Amicus (Fenwal, a Fresenius Kabi Company) or Trima (Trima Accel, TerumoBCT) from 2010 to 2014. All donations used inlet-line sample diversion and were tested by quality control (QC; Day 1) aerobic culture. Rates of bacterial contamination and septic reactions to PLTs were calculated for both devices. RESULTS During the 5-year study period, plateletpheresis collections using Amicus and Trima devices totaled 1,486,888 and 671,955 donations, respectively. The rate of confirmed-positive bacterial cultures of apheresis PLT donations was significantly higher with Amicus than with Trima (252 vs. 112 per 106 donations [odds ratio {OR}, 2.3; 95% confidence interval {CI}, 1.8-2.9]). Septic transfusion reactions were caused by 30 apheresis PLT units from 25 contaminated Amicus procedures and three apheresis PLT units from three contaminated Trima procedures. The overall rate of septic reactions was significantly higher with apheresis PLT components collected with Amicus than with Trima (16.8 vs. 4.5 per 106 donations [OR, 3.8; 95% CI, 1.1-12.5]). All apheresis PLT components implicated in septic transfusion reactions had negative QC culture results incubated through Day 5 (i.e., false negatives). CONCLUSION Apheresis technology affects bacterial contamination of plateletpheresis collections. The device-specific, higher rate of confirmed-positive bacterial culture results also correlated with a significantly higher rate of reported septic transfusion reactions to apheresis PLTs.

BACKGROUND Transfusion-transmitted West Nile virus (WNV) infection is infrequent as a result of minipool (MP) and individual-donation (ID) nucleic acid testing (NAT) of blood donations. ID-NAT is triggered on the basis of local WNV activity identified by MP-NAT. STUDY DESIGN AND METHODS A 78-year-old male patient who was treated for cardiac disease received 14 blood components from 30 donors in August 2016. He was discharged 7 days after aortic valve replacement and coronary bypass surgery, but was re-admitted on Day 12 with symptoms of viral infection, and eventually was diagnosed with aseptic meningitis. The patent died on Day 51. RESULTS The patient was positive for WNV-immunoglobulin M (IgM) antibodies in his cerebrospinal fluid on Day 14 and was positive for WNV-IgM (on Days 14 and 16) and WNV-IgG antibodies (on Day 16) in his serum. All associated donations were nonreactive by MP-NAT or ID-NAT. However, one MP-NAT was noted to have an elevated (but negative) signal-to-cutoff ratio, and one donor from that MP was subsequently found positive for WNV-IgM and IgG antibodies; the donor was diagnosed with a WNV-like viral syndrome that had an onset 3 to 5 days postdonation. The donor's plasma was transfused 12 days before the patient's onset of WNV-meningoencephalitis. Conversion to ID-NAT was triggered for the region 7 days after the implicated donation, which was associated with the region's first human WNV case. CONCLUSION Despite the possibility of mosquito-borne transmission, this was considered to be a case of transfusion-transmitted WNV infection from an MP-NAT–nonreactive donation collected just before triggering conversion to ID-NAT; a rare event recognized once in 84 million donations.

BACKGROUND Blood donation screening for human immunodeficiency virus Type 2 (HIV-2) has been in place in the United States since 1992. However, only three HIV-2 antibody–positive donors have been reported to date, all detected via HIV-1 cross-reactivity. STUDY DESIGN AND METHODS Here we identify two additional HIV-2–positive donors by routine anti-HIV-1 and anti-HIV-2 screening, including a first-time male donor living in Georgia having recently immigrated to the United States from West Africa (from a 1998 donation) and a Taiwanese female repeat donor (nurse) living in California with no travel outside of Taiwan or apparent connections to West Africa (from a 2015 donation). Neither donor acknowledged any risk factors, and both remained asymptomatic through follow-up. The second donor was further investigated by serologic, molecular, and genomic assays because of her unusual demographics. She was documented to harbor HIV-2 RNA, albeit sporadically by HIV-2–specific nucleic acid tests (35%-100% of replicates) and at very low levels (

BACKGROUND: Almost all of the reported US tick-borne and transfusion-associated Babesia cases have been caused by Babesia microti, which is endemic in the Northeast and upper Midwest. We investigated a case caused by B. duncani (formerly, the WA1-type parasite), in a 59-year-old California resident with sickle cell disease (HbSS) whose only risk factor for infection was receipt of red blood cell transfusions. CASE REPORT: The patient's case was diagnosed in September 2008: intraerythrocytic parasites were noted on a blood smear, after a several-month history of increasing transfusion requirements. Molecular and indirect fluorescent antibody (IFA) analyses were negative for B. microti but were positive for B. duncani (IFA titer, 1:1024). The complete 18S ribosomal RNA gene of the parasite was amplified from a blood specimen; the DNA sequence was identical to the sequence for the index WA1 parasite isolated in 1991. The patient's case prompted a transfusion investigation: 34 of 38 pertinent blood donors were evaluated, none of whom tested positive by B. microti IFA. The implicated donora 67-year-old California residenthad a B. duncani titer of 1:4096; B. duncani also was isolated by inoculating jirds (Mongolian gerbils) with a blood specimen from March 2009, more than 10 months after his index donation in April 2008. The patient's case was diagnosed more than 4 months after the implicated transfusion in May 2008. CONCLUSIONS: This patient had the third documented transfusion case caused by B. duncani. His case underscores the fact that babesiosis can be caused by agents not detected by molecular or serologic analyses for B. microti.

We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Tyr663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonsense mutation is predicted to destroy the inhibitory action of AXIN2 on WNT signaling. Previous authors have described an unrelated family with autosomal dominant oligodontia and a variable colorectal phenotype segregating with a nonsense mutation of AXIN2, as well as a frameshift AXIN2 mutation in an unrelated individual with oligodontia. Our report provides additional evidence supporting an autosomal dominant AXIN2-associated ectodermal dysplasia and neoplastic syndrome.

Type 2 diabetes mellitus affects more than 170 million people worldwide. Because this disease is strongly linked to obesity, the term "diabesity" has been coined to describe the confluence of the 2 disease processes. Bariatric surgery has been performed for many years to achieve sustained weight loss in the morbidly obese population. As a secondary effect, a remarkable improvement in glycemic control is commonly achieved postoperatively. This has led to substantial interest in the use of bariatric procedures to treat type 2 diabetes mellitus. Surgical procedures in common use include the adjustable gastric band, the Roux-en-Y gastric bypass, the biliopancreatic diversion with duodenal switch, and the sleeve gastrectomy. Additionally, several investigational procedures including the ileal interposition and duodenal-jejunal bypass have been proposed as primary interventions for type 2 diabetes mellitus. These operations achieve their metabolic effects through a combination of volume restriction, intestinal bypass, and hormonal changes. As more data become available on the positive effect of bariatric procedures on type 2 diabetes mellitus, the use of such operations may grow. Bariatric surgery may ultimately become a major tool in the long-term treatment of type 2 diabetes mellitus. This manuscript presents an extensive review of the literature supporting these concepts.

BACKGROUND: Plasma components from female donors were responsible for most cases of transfusion-related acute lung injury (TRALI) reported to the American Red Cross (ARC) between 2003 and 2005. Consequently, we began preferentially distributing plasma from male donors for transfusion in 2006 and evaluated the effect on reported TRALI cases in the ensuing 2 years. STUDY DESIGN AND METHODS: Suspected TRALI cases reported to the ARC Hemovigilance Program in calendar years (CY) 2006, 2007, and 2008 are described. Any case involving a fatality was also independently reviewed by three ARC physicians and classified as probable TRALI or not TRALI. RESULTS: The percentage of plasma collected from male donors and distributed for transfusion increased each year from 55% in CY2006 to 79% in CY2007 and 95% in CY2008. Independent medical review of the 77 reported TRALI cases involving a fatality identified 38 cases as probable TRALI. Plasma was the only component transfused in six of these cases in 2006, five in 2007, and zero in 2008. Overall, the analysis of reported fatalities and nonfatal cases demonstrates that TRALI involving only plasma transfusion was significantly reduced in 2008 compared to 2006 (32 vs. 7 cases; odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08-0.45), to a level that was no longer different from the rate of TRALI observed for RBC transfusion (4.0 vs. 2.3 per 106 distributed components; OR = 1.78; 95% CI = 0.67-4.36). CONCLUSIONS: Reported TRALI cases from plasma transfusion decreased in 2008 compared to the prior 2 years simultaneously with the conversion to male-predominant plasma for transfusion.

Diabetes is one of the most common diseases in the United States, with 1.5 million new cases reported in 2005 and a projected 48.3 million diabetics in the year 2050. Despite the disease's remarkably high prevalence and the substantial efforts focused on pharmacological treatment of the disease, current dietary, behavioral, and medical therapies have achieved only limited success. For over 2 decades, bariatric surgeons have recognized that gastric bypass surgery causes a remarkable, durable improvement in type 2 diabetes mellitus. Remarkably, this normalization of glucose metabolism occurs within several weeks of surgery, long before substantial weight loss takes place. As early as in 1987, data have been available demonstrating that 83% of patients with diabetes and 99% of those with impaired glucose tolerance become euglycemic after gastric bypass surgery. Despite the availability of this effective treatment for diabetes, the primary therapy for type 2 diabetes mellitus has remained medical. In this article, we review some of the hypotheses about how bariatric operations affect glucose metabolism and diabetes as well as the research that has been done to elucidate these mechanisms. Additionally, we discuss how surgery may one day represent an important management option for type 2 diabetes mellitus. Mt Sinai J Med 76:281–293, 2009. © 2009 Mount Sinai School of Medicine

Summary 1. Linking microbial activity with ecosystem function is a continuing goal among ecologists focusing their efforts below ground in terrestrial ecosystems. 2. Genomic approaches, using DNA and RNA extracted from soil to characterize types of microbes present and genes expressed in soil, are promising, but, the required destructive harvest confounds spatial and temporal information. 3. Microbiosensors offer a gene-based way to examine microbial perception of, and response to, the soil environment non-destructively, with high spatial and temporal resolution. 4. In this mini-review, we explore the promise, challenges and tradeoffs associated with the design and deployment of microbiosensors in soil, as well as the interpretation of information derived from them live from the soil grain'. Both the promises and challenges are caused by the facts that: microbiosensors are living organisms with specific traits; they come from a phylogenetically diverse but restricted subsample of enormous soil microbial diversity; they are responsive to internal and external influences on multiple cellular processes (not just promoter induction); and they become part of food chains in non-sterile soils. We examine each of these characteristics, and associated blessings and curses, in the context of using microbiosensors to explore microbial soil ecology.

Effective management of introduced species requires the early identification of species that pose a significant threat of becoming invasive. To better understand the invasive ecology of species in New England, USA, we compiled a character data set with which to compare non-native species that are known invaders to non-native species that are not currently known to be invasive. In contrast to previous biological trait-based models, we employed a Bayesian hierarchical analysis to identify sets of plant traits associated with invasiveness for each of three growth forms (vines, shrubs, and trees). The resulting models identify a suite of ‘invasive traits’ highlighting the ecology associated with invasiveness for each of three growth forms. The most effective predictors of invasiveness that emerged from our model were ‘invasive elsewhere’, ‘fast growth rate’, ‘native latitudinal range’, and ‘growth form’. The contrast among growth forms was pronounced. For example, ‘wind dispersal’ was positively correlated with invasiveness in trees, but negatively correlated in shrubs and vines. The predictive model was able to correctly classify invasive plants 67% of the time (22/33), and non-invasive plants 95% of the time (204/215). A number of potential future invasive species in New England that deserve management consideration were identified.

BACKGROUND: American Red Cross surveillance data on transfusion-related acute lung injury (TRALI) fatalities were analyzed to evaluate the association with components from donors with white blood cell (WBC) antibodies and to examine the potential impact of the selective transfusion of plasma from male donors. STUDY DESIGN AND METHODS: Suspected TRALI reports in 2003 through 2005 were identified and all fatalities were reviewed and classified by three physicians as “probable TRALI” or of “unrelated etiology,” with independent review of the associated serologic investigation. Hospital investigational and reporting biases could not be fully controlled in this retrospective study. RESULTS: A total of 550 reports of suspected TRALI, including 72 fatalities, were investigated. The number of reports increased each year and the rate varied by geographic region. Retrospective review of fatalities revealed 38 cases of probable TRALI, the majority (24 of 38 [63%]) after plasma transfusion. A female, WBC antibody–positive donor was involved in 71 percent (27 of 38) of cases and in 75 percent (18 of 24) of cases involving plasma transfusion. Female antibody-positive donors were more likely to be associated with probable TRALI than with unrelated cases (p = 0.0001; odds ratio [OR], 9.5; 95% confidence interval [CI], 2.9-31.1]. The rate of probable TRALI among recipient fatalities was higher for plasma components (1:202,673; OR, 12.5; 95% CI, 5.4-28.9) and apheresis platelets (PLTs; 1:320,572; OR, 7.9; 95% CI, 2.5-24.8) compared to red cells (1:2,527,437). Male donors contributed 64.5 and 52.0 percent of distributed apheresis PLTs and plasma components, respectively, in 2005. CONCLUSION: Plasma components linked to female donors with WBC antibodies were responsible for the majority of probable TRALI fatalities. Prudent measures to limit transfusion of WBC antibody–containing plasma components may prevent as many as six fatalities per year in the Red Cross system.

The authors assessed the potential for a pharmacokinetic/pharmacodynamic interaction between desloratadine and fluoxetine. This randomized, placebo-controlled, open-label study was conducted in 54 healthy volunteers. Subjects received 1 of 3 treatments: desloratadine 5 mg plus fluoxetine 20 mg, desloratadine 5 mg plus placebo, or fluoxetine 20 mg plus placebo. Serial electrocardiograms (ECGs) were performed at baseline and day 35. Treatment effects on C(max) and AUC were assessed. During coadministration of desloratadine with fluoxetine, the ratio of the mean log-transformed C(max) and AUC values for desloratadine following concomitant fluoxetine therapy revealed a small increase in C(max) values of 15% (90% confidence interval [CI], 95%-139%) but no increase for AUC values (90% CI, 82%-123%). Corresponding values for 3-OH desloratadine demonstrated small increases in mean log-transformed C(max) and AUC ratios: 17% (90% CI, 100%-136%) and 13% (90% CI, 96%-132%), respectively. Statistical evaluation of the ratio of the mean C(max) and AUC values for fluoxetine following concomitant desloratadine therapy revealed small decreases of 9% (90% CI, 72%-115%) and 11% (90% CI, 69%-113%), respectively. Corresponding values for norfluoxetine demonstrated modest increases in mean log-transformed C(max) and AUC ratios: 22% (90% CI, 100%-139%) and 18% (90% CI, 101%-136%), respectively. Coadministration of desloratadine with a potent inhibitor of CYP2D6 did not result in clinically relevant changes in its pharmacokinetic parameters. Desloratadine administration was not associated with clinically important changes in the pharmacokinetics of fluoxetine, a drug metabolized by CYP2D6. The most common adverse event in all groups was headache (65%). Desloratadine plus fluoxetine caused no significant changes in ECGs or ventricular rate.

A tandem reduction-reductive amination reaction has been applied to the synthesis of 3,4-dihydro-2H-1,4-benzoxazines and 1-acetyl-1,2,3,4-tetrahydroquinoxalines. The nitroketones required for the benzoxazine ring closures were prepared by (A) alkylation of the anion derived from 2-nitrophenol with an allylic halide or (B) nucleophilic aromatic substitution of an allylic alkoxide on 2-fluoro-1-nitrobenzene followed by ozonolysis. Precursors for the quinoxalines were prepared by alkylation of the anion of 2-nitroacetanilide with an allylic halide followed by ozonolysis. Catalytic hydrogenation of the nitroketones using 5% palladium-on-carbon in methanol then gave the target heterocycles by a reduction-reductive amination sequence. The N-methyl derivatives for both ring systems were easily prepared by adding 5-10 equivalents of aqueous formaldehyde prior to the reduction. The dihydrobenzoxazines were isolated in high yield following purification by chromatographic methods; tetrahydroquinoxalines were isolated in a similar manner and possessed differentiated functionality on the two nitrogens.

N-Phenyl-substituted pyrrolidines and piperidines have been synthesized by catalytic reduction of nitrobenzene in the presence of 4- and 5-oxoaldehydes, respectively. The process involves reduction of the aromatic nitro group to give the N-phenylhydroxylamine or aniline followed by reductive amination with the two carbonyl functional groups. Monocyclic systems are generally formed in high yield and are easily purified. The method has also been extended to the synthesis of fused N-phenylazabicyclics from 2-(3-oxo-propyl)cycloalkanones. A high degree of diastereoselectivity for the trans-fused product is observed in substrates having an ester group α to the cycloalkanone carbonyl. Bicyclic precursors lacking this ester group give mixtures of cis and trans products. Finally, contrary to previous reports, we have demonstrated that aniline can be substituted for nitrobenzene in these reactions.

BACKGROUND: Trypanosoma cruzi, the agent of Chagas' disease, continues to be a concern for blood safety, as demonstrated by recent transfusion-transmitted cases in the United States and Canada. The chronic nature of Chagas', coupled with increasing numbers of immigrants from T. cruzi-endemic countries, suggests that Chagas' is a long-term public health problem. Herein, we report on a multiyear epidemiologic study of T. cruzi in Los Angeles and Miami blood donors. STUDY DESIGN AND METHODS: From May 1994 to September 1998, blood donors in Los Angeles and Miami were queried regarding birth or time spent in an endemic country. Donations of “yes” respondents were tested by EIA, confirmed by radioimmunoprecipitation assay, and if confirmed as seropositive, enrolled in look-back investigations. RESULTS: A total of 1,104,030 Los Angeles and 181,139 Miami donors were queried regarding risk; 7.3 and 14.3 percent, respectively, responded yes. Seropositive rates were 1 in 7,500 Los Angeles and 1 in 9,000 Miami donors. In Los Angeles, seroprevalence rates increased significantly from 1996 to 1998 and were significantly higher for directed donors than nondirected donors. Look back identified 18 recipients, all of whom were seronegative for T. cruzi. CONCLUSION: Significant numbers of T. cruzi-seropositive donors contribute to the U.S. blood supply. The incidence of seropositivity is enhanced by minority recruitment efforts necessitated by donor demographic shifts. Similarly, high rates among directed donations in Los Angeles are attributable to a disproportionate number of at-risk directed donors. Current look-back data likely underestimate the frequency of transfusion- transmitted T. cruzi. These results indicate that con- tinued evaluation of transfusion as a mode of T. cruzi transmission in the United States is needed.

In cystic fibrosis the bronchiectatic conducting airways have large numbers of neutrophils in their walls and in their luminal contents. The neutrophil's primary granule enzyme activities of elastase and peroxidase are increased in the sputum of these patients. It has been postulated that these enzymes--together or individually--act to damage the airway epithelium. However, only peroxidase activity has consistently correlated with the degree of structural and functional airway disease in these patients with leakage of plasma protein into the airway lumen (Regelmann et al., Pediatr Pulmonol, 1995; 19:1-9). The present study was designed to test whether human neutrophil-derived myeloperoxidase can independently produce bronchial epithelial damage without the presence of proteases, as measured by increased permeability of the airway epithelium. Human peripheral blood neutrophils were purified, their primary granules isolated, and their peroxidase purified using affinity and ion exchange column chromatography. Activity of the proteinase-free peroxidase was measured using a chromogenic substrate. The effect of this peroxidase on the permeability of excised rat tracheas was measured using radioactive and fluorescent-labeled non-ionic molecules of varying molecular weight. Rat tracheas exposed to 15 minute treatments with either 130 U of peroxidase or hydrogen peroxide (10(-5) M) did not show a significant increase in the permeability of the epithelium to [3H]inulin, [14C]sucrose, and fluorescein isothiocyanate dextran 20 compared with control tracheas. However, those tracheas exposed to 130 U peroxidase followed by 10(-5) M hydrogen peroxide showed an increased permeability to each of the three test solutes. We conclude that proteinase-free myeloperoxidase, in the presence of non-toxic concentrations of its substrates, hydrogen peroxide and halide, produced increases in permeability to non-ionic molecules in the rat trachea within 15 minutes.

BACKGROUND: Patients with sickle cell anemia may develop serious, life-threatening hemolytic transfusion reactions (HTRs). More severe anemia may develop after the HTR than was present before transfusion, which suggests the possibility of an increased rate of hemolysis of autologous red cells. STUDY DESIGN AND METHODS: The signs and symptoms occurring during eight severe HTRs that occurred in five patients with sickle cell anemia were reviewed, as were published reports by other investigators. Calculations of red cell production and destruction incorporating known correction factors for reticulocyte maturation were performed to determine the most probable mechanism for the striking drop in hematocrit observed in several instances. RESULTS: A characteristic constellation of findings was recognized in some severe HTRs in patients with sickle cell anemia. Calculations of daily red cell production and senescence indicated that a marked drop in hematocrit occurs when erythropoiesis is suppressed in a patient with a short red cell life span and that this could account for severe posttransfusion anemia when donor red cells are hemolyzed during an HTR. CONCLUSION: A sickle cell HTR syndrome was defined. A rapid increase in the severity of anemia occurs in patients with sickle cell anemia when all donor red cells are hemolyzed during an HTR and when there is suppression of erythropoiesis, as commonly occurs as a result of transfusion or concomitant illness. Although an increased rate of hemolysis of autologous red cells may also occur, more definitive data are required to document that in these patients.

Patients with cystic fibrosis (CF) of the same age differ significantly in their degree of pulmonary disease. Based on preliminary observations, we postulated that the activity of my-eloperoxidase would be significantly increased in patients with greater structural lung damage than in those with less lung damage. Acid extracts of weighed sputum samples were assayed for lactoferrin concentrations by ELISA. Activities of peroxidase, cathepsin G, and elastase (with and without proteinase 3) were determined by kinetic analysis using chromogenic substrates. The patients were divided into quartiles based on their Brasfield chest-radiograph score. Patients in the first quartile (least amount of structural lung abnormality) were compared to those in the fourth quartile. The concentration of lactoferrin, a specific (secondary) granule protein of neutrophils, did not differ between the two patient groups. However, the activities of the neutrophil primary granule proteins, peroxidase, elastase, and elastase plus proteinase 3, were significantly elevated in the group with the most structural lung abnormality. Sputum albumin concentration was used to estimate leakages of plasma proteins into the airways. Peroxidase activity, but not the activity of cathepsin G, of elastase, or of elastase plus proteinase 3, correlated significantly with albuminig sputum in both quartile groups. To confirm the association of sputum peroxidase activity with differences in lung structure and to test its correlation with lung function, spirometry was performed in a second group of patients during the week prior to the time of sputum sampling. In this second group, increased sputum peroxidase activity was associated with worse Brasfield scores and with decreased percent-predicted forced expiratory volume in 1 sec. Lactoferrin concentration again did not differ between the groups. Bacterial factors also did not differ. The results indicate that the degree of lung damage in patients with CF was more closely related to sputum peroxidase activity than to age, gender, CFTR genotype, or sputum bacterial parameters. Further study is required to determine whether or not peroxidase activity in the airway causes this lung damage. © 1995 Wiley-Liss, Inc.

A diastereoselective synthesis of 1-methyl-2-alkyl- and 2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic esters has been developed from methyl (2-nitrophenyl)acetate (1). The method involves alkylation of 1 with an allylic halide, ozonolysis of the double bond, and catalytic hydrogenation. The final hydrogenation initiates a tandem sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the aniline or hydroxylamine8 nitrogen with the side chain carbonyl, (3) reduction of the resulting nitrogen intermediate, and (4) reductive amination of the tetrahydroquinoline with formaldehyde produced in the ozonolysis to give a methyl (±)-1-methyl-2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylate. Removal of the formaldehyde prior to hydrogenation gives the simple (±)-2-alkyl derivatives. The products are isolated in high yield as single diastereomers having the C-2 alkyl group cis to the C-4 carboxylic ester. The reaction has been extended to the synthesis of tricyclic structures with simila...

N-Phenyl-substituted pyrrolidines and piperidines have been synthesized by catalytic reduction of nitrobenzene in the presence of 4- and 5-oxoaldehydes, respectively. The process involves reduction of the aromatic nitro group to give the N-phenylhydroxylamine or aniline followed by reductive amination with the two carbonyl functional groups. Monocyclic systems are generally formed in high yield and are easily purified. The method has also been extended to the synthesis of fused N-phenylazabicyclics from 2-(3-oxo-propyl)cycloalkanones. A high degree of diastereoselectivity for the trans-fused product is observed in substrates having an ester group α to the cycloalkanone carbonyl. Bicyclic precursors lacking this ester group give mixtures of cis and trans products. Finally, contrary to previous reports, we have demonstrated that aniline can be substituted for nitrobenzene in these reactions.

A two-step diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles has been developed from cyclic β-ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2-oxo-cycloalkanecarboxylates with 2-nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxyl-amine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated in high yield as single diastereomers having the trans-fused ring junction. The observed selectivity is rationalized in terms of a steric effect imposed by the ester group in the final reductive amination step which directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference for the cis-fused heterocycle.

Purpose: A narrow‐field, low energy, stereotactic radiosurgery(SRS)device (the “IRay”) designed specifically for the treatment of wet age‐related macular degeneration is being evaluated in a European clinical trial. Because of precise targeting requirements for ophthalmological SRS, a new QA method has been designed to automate the evaluation of system alignment, targeting, and kerma consistency. This poster describes that method. Method and Materials: The IRay delivers up to 24 Gy in three lOOkVp, 4mm‐diameter beams that converge on the retina with a source‐axis distance of 150mm. The beams are delivered inferiorly in a fashion that avoids the patients lens and optic nerve, requiring submillimeter targeting precision. The eye is stabilized with a suction‐enabled lens assembly (the “I‐Guide”) that has retroreflective fiducials used by the imaging system for targeting and eye motion assessment. A self‐test fixture has been designed that incorporates similar fiducials for automatic alignment, a scintillant strip for direct imaging of the X‐ray beam, and an ion chamber for kerma measurements. Results and Discussion Using the retroreflective fiducials, the IRay is able to repeatably and accurately target the fixture. This is critical not only for targeting assessment, but also for accurate kerma measurements which are difficult in a narrow field with a finite‐sized detector. Once targeted, software automatically evaluates and enforces several critical parameters including X‐ray to targeting laser coaxiality (< 100 microns), robotic motion, imaging system alignment (better than 100 microns), X‐ray targeting (within 300 microns), and air kerma consistency (within 3%). Other system tests are performed, including lighting, communication, and dose‐timer checks. Conclusion: Performing comprehensive QA on a narrow‐field, low‐energy SRS unit requiring submillimeter precision is non‐trivial. An automated method of evaluating alignment, targeting, and kerma consistency allows regular (even daily) assessment to provide confidence that all systems are performing within specification. Research sponsored by Oraya Therapeutics.

Purpose: Age‐related Macular Degeneration (AMD) is the leading cause of blindness in people over 65 in the U.S. It is a neovascular disease that can result in profound and rapid loss of central vision and has been shown to be susceptible to radiotherapy. A 100kVp tabletop stereotactic radiosurgical (SRS)device has recently been developed to treat AMD. Here we evaluate a new set of anthropomorphic eye phantoms for verifying the targeting and dosimetric accuracy of the device.Method and Materials: A series of eye phantoms were developed to match human eyes in size and shape. The phantoms are made of Solid Water, have a post at the cornea to attach to the clinical fixation assembly, and at the retina have a cutout with fiducial posts that support the precise mounting of laser‐cut pieces of radiochromic film. After irradiation of the phantom, a flatbed scanner and image analysis software are used to assess the accuracy of beam targeting using the fiducial holes in the film. Multiple “treatments” were repeated on stationary phantoms to assess system precision and accuracy. A dynamic eye was also created by attaching set of stepper motors to a phantom. While irradiating the phantom, the motors were driven with clinically‐measured human eye motions to simulate actual treatment and test the automatic beam shut‐off of the system when motion exceeded an established threshold. Results: Phantom measurement precision of 0.1mm was achieved. Static repeated delivery of the therapy showed a system precision of 0.2mm and an accuracy of 0.4mm. Analysis of films irradiated while the eye phantom was being driven with clinically‐measured human motion verified the gating algorithm was capable of protecting radiosensitive structures. Conclusion: The eye phantoms demonstrate that a specialized ophthalmic SRSdevice can accurately target the back of the eye. Research Supported by Oraya Therapeutics

Studies in which the rate of local cerebral blood flow is determined by xenon-enhanced computerized tomography require measurement of end-tidal gas. A mass spectrometer and a thermoconductivity detector were compared in measuring the concentration of xenon in end-tidal gas both in humans and in a clinically simulated ("breathing bag") system. The experiments showed that the two instruments provided virtually identical results up to a rate of 18 breaths/min, at which rate recorded concentrations showed marginal degradation with the thermoconductivity detector. Given the absence of a significant difference in the ability of the mass spectrometer and the thermoconductivity detector to measure end-tidal xenon concentration, the thermoconductivity detector appears to be a satisfactory alternative in studies measuring the rate of local cerebral blood flow by enhanced computerized tomography.

Errors in the determination of xenon concentrations in arterial blood during inhalation of xenon-oxygen mixtures are used to assess errors in the derivation of regional cerebral blood flow by the xenon-enhanced computed tomography (CT) method. The results of this study indicate that approximating the arterial buildup by a single exponential introduces relatively small errors in estimated flow values. The most significant systematic error is introduced by errors in estimation of the xenon arrival time to the brain in relationship to sequential (CT) scanning times.

The antihypertensive activity of a sustained-release preparation of diltiazem (given each 12 hours) was assessed in 96 patients with supine diastolic blood pressure (BP) between 95 and 110 mm Hg in a multicenter, randomized, double-blind, placebo run-in, parallel-group trial comparing optimally titrated doses of diltiazem and placebo. The aim was to assess the onset of action as well as the extent and variability of BP control of this formulation during the 12-hour interval. Diltiazem was titrated from 120 mg bid to 180 mg bid as necessary to lower BP. At baseline, on the first day of titration, and at the end of 8 weeks, BP was evaluated at 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The onset of action was within 2 hours, and the effect was maintained throughout the 12-hour period. Mean BP for the diltiazem group at baseline was 154/101 mm Hg. At week 8, BP was 148/93 mm Hg at hour "0" (P less than .02 and P = .0001 for systolic and diastolic BP vs. placebo), 139/84 mm Hg at the nadir at hour 5 (P = .0001), and 149/91 mm Hg at the end of the 12-hour period (P less than .02 and P = .0001 for systolic and diastolic BP). Diltiazem was significantly more effective than placebo (P = .0001) with 50% of patients controlled to a diastolic pressure of less than 90 mm Hg at 7 of the 10 evaluation points, including the evaluation point of 12 hours post-dose.(ABSTRACT TRUNCATED AT 250 WORDS)

During seedling to crown root stages daily dry matter production was 30 to 50 pounds per acre and N uptake about 1 pound; both were increased only slightly by N fertilizer. During crown root through flowering stages increased growth and N uptake rates were further increased by irrigation and N fertilization, ranging from 240 to 340 pounds and from 4 to 6 pounds, respectively. Maximum production and N uptake occurred between soft and hard dough stages.

Each ton of high quality manure was equivalent to 22 lb of nitrogen from ammonium nitrate as measured by equivalent grain sorghum (Sorghum vulgare Pers.) yields over a 4-year period. Phosphorus level of the soil by the Bray and Kurtz no. 1 procedure was increased by 1 ppm for each ton of applied manure. Commercial phosphorus fertilizer did not increase grain yields. Total N content of the surface soil was increased by all manure treatments. Nitrogen uptake by grain was correlated with relative yield of grain. The forage portion of sorghum appeared to take up N in excess of needs for maximum grain yield.

A simple, easy to use, quality assurance and performance test phantom was developed for the xenon/computed tomography (CT) cerebral blood flow method. The phantom combines an inhalation system which allows for the simulation of xenon buildup or washout in the arterial blood as well as a multisection translatable cylinder in which several sections can be scanned during a preselected protocol to simulate the CT enhancement in brain tissue during a study. The phantom and scanning protocol are described and their use is demonstrated. The results compare favorably to the theoretically expected fast, intermediate, and slow ‘‘flow’’ values designed into the phantom.