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The cardiovascular morbidity associated with obstructive sleep apnea (OSA) changes with aging. This review addresses unique aspects of OSA-associated hypertension and cardiovascular disease (CVD) in the elderly. The risk of hypertension and CVD in OSA diminishes with aging. The standard apnea hypopnea index cut-offs for OSA diagnosis and severity do not predict CVD or mortality in the elderly. Further, the impact of continuous positive airway pressure (CPAP) treatment on hypertension and mortality is inconsistent in this population. A therapeutic effect of CPAP is noted in some studies in subsets of elderly with high CPAP adherence. Aging-related physiological changes in upper airway function and ventilatory control function modify the impact of OSA on hypertension and CVD. Future research should identify common endotypes of OSA and optimal OSA severity metrics from polysomnography to inform treatment algorithms for the elderly. Finally, promotion of CPAP adherence in this population may improve CVD outcomes.

Study question Does mode of conception such as in-vitro fertilisation (IVF), ovulation induction (OI), intra-uterine insemination (IUI) affect singleton pregnancy outcomes when compared to spontaneous conception (SC)? Summary answer Singleton pregnancies resulting from OI, IUI, IVF are associated with higher risks of adverse pregnancy outcomes compared to spontaneous pregnancies. What is known already Several meta-analysis have shown singleton pregnancies resulting from IVF have adverse pregnancy outcomes However, these studies had much smaller sample size and did not compare OI or IUI to SC. Additionally, when matched studies were analysed, the pooled events used were not adjust for medical conditions such as polycystic ovaries (PCO) and chronic hypertension which predispose patients to gestational diabetes(GDM) and pre-eclampsia (PET).he lack of consensus on how PET and GDM was defined was also a cause of bias. Our study is the largest meta-analysis to date and aims to provide clinician with the latest evidence when offering fertility treatment. Study design, size, duration Literature search in MEDLINE, COCHRANE Library, and Scopus was performed, up to November 2021. Randomised controlled trials (RCTs), non-randomised studies, cohort and case control studies, reporting on any association between pregnancy outcome, such as pre-eclampsia (PET), gestational diabetes mellitus (GDM), preterm birth, ( Participants/materials, setting, methods 110 studies consisting of 31 cohort studies and 79 case control were included comprising a total of 32,463,058spontaneous singleton conception compared to 1,191,963 singleton pregnancies following OI, IUI and IVF treatment .Matching criteria used for adjustment were also identified For PET and GDM, only studies which defined the condition according to international agreed consensus were included Any inconsistency between studies was quantified through Higgins’ Chi-square (Chi2) and I-squared (I2) using statistical software R. Main results and the role of chance Singleton pregnancies following, OI, IUI, or IVF had a higher odds of PET compared to SC (odds ratio [OR]1.95,, 95% confidence interval [CI]1.61-2.31; I2=97%), OR 1.53, 95%CI 1.36 -1.71,, I2=84% and OR1.62, 95%CI 0.94-2.78, I2=11%).respectively. For GDM, pregnancies following, OI, IUI, or IVF had a higher odds compared to SC (OR1.59, 95%CI 1.59 -1.71, I2=83%, OR 1.62, 95%CI 0.94-2.78, I2=11% and OR1.72, 95% CI 1.49–1.98; I2=13%). Higher odds of TB and vPTB were seen in pregnancies following OI and IVF compared to SC (PTB: OR1.80, 95% CI 1.76–1.85; I2=94% and , (OR 1.47, 95% CI 1.22-1.77 I2=66% and vPTB OR 2.92, 95% CI 2.76-3.09; I2=91%). Only one study reported PTB when comparing IUI to SC (OR 1.88, 95% CI 1.40-2.53) and comparing vPTB in OI vs SC (OR 1.73 95% CI 0.71-4.18). Singleton pregnancies following, OI or IVF had a higher odds of LBW and vLBW compared to SC (OR1.98, 95% CI 1.93–2.04; I2=96%),OR1.72, 95% CI 1.49–1.98 I2=13% and OR4.57, 95% CI 4.34–4.81; I2=98% and OR2.32, 95% CI 1.60–3.37; I2=56% respectively. The rate of SGA was comparable in IVF (OR 0.91, 95% CI 0.90–0.93; I2=99%), OI (OR 0.96, 95% CI 0.95-0.97; I2=100%) and IUI (RR 0.92, 95% CI 0.90–0.94; I2=31%). Limitations, reasons for caution In cases of PE and GDM, published definitions differed in various studies and there was limited information given past medical history which increase the risk of such conditions. This made it impossible to separate the baseline confounders which may increase the risk of PE and consequently PTB, SGA and LBW. Wider implications of the findings Our meta-analysis confirmed that IVF/ICSI pregnancies are at higher odds of adverse pregnancy outcomes. This is the largest systematic review to date analysing pregnancy outcomes and mode of conception comparing OI, IUI and IVF respectively. It provides the latest evidence possible for clinicians to choose the safest fertility treatment, Trial registration number Not applicable

Study question Does COVID-19 vaccination (mRNA or viral vector) in women affect outcomes following IVF treatment? Summary answer There was no difference in both pre-clinical and IVF clinical outcomes in women who received vaccination (1 or 2 doses) compared to those unvaccinated. What is known already The COVID-19 vaccination rollout has been unprecedented and commenced in the UK in December 2020. Compared to the general population, pregnant women have higher risk of morbidity following COVID-19 infection. There is a drive by public health authorities for women of reproductive age to be vaccinated. However, there has been hesitancy in the uptake of vaccination amongst certain patient populations including those who are trying to conceive. Emerging data has shown that follicular function is unaffected by COVID-19 vaccination, although this data is limited. IVF treatment is unique as we can evaluate both pre-clinical embryological outcomes and clinical outcomes. Study design, size, duration We conducted a retrospective analysis of 474 women undergoing IVF treatment between Jan and Dec 2021. COVID-19 vaccination status was recorded including: vaccination type, number of vaccine doses, and whether they had previously contracted COVID-19. We recorded pre-clinical and clinical outcomes: such as number of oocytes retrieved, fertilisation rate and clinical pregnancy. Participants/materials, setting, methods Women were categorised in the three cohorts- unvaccinated (Group 1), defined as the reference group, women who had first dose of COVID-19 vaccine (Group 2) and patients who had two doses of the vaccine (Group 3). Patients whose vaccination status were not known were excluded. Statistical analysis was performed through STATA software. Outcomes were modelled with multivariable logistic and negative binomial regressions and adjusted for the following confounders: age, BMI, parity and past COVID-19 infection. Main results and the role of chance Data from women was analysed, 22.6 % had completed 2 doses, 9.5 % had one vaccine and 9.7% were unvaccinated. Among these women 24.7% had previous COVID-19 infection prior to their IVF cycle. The median number of oocytes retrieved for the entire cohort collected was 10.0 (inter-quartile range (IQR) 6.0, 14.0). There was no significant difference in the number of oocytes retrieved between women who had 1 vaccination dose, 2 doses compared to unvaccinated women (Incidence rate ratios (IRR) 1.18, 95% Confidence Interval (CI) [0.93,1.50] and 0.94, 95% CI [0.76,1.15] respectively). There was no significance difference in the fertilisation rate between women who had one vaccination dose, 2 doses and unvaccinated women (IRR)1.02, 95% CI [0.83, 1.24] and 1.11 95% CI [0.93, 1.31] or failed fertiisation rates (Odds ratio (OR) 0.74, 95% CI [0.09, 6.09] and 0.71, 95% CI [0.12, 4.18]. With regards to clinical outcomes, 51.7% of the cohort had a positive urine pregnancy test. There was no significant difference in clinical pregnancy rate between women who had first vaccination dose and those who had both doses compared to unvaccinated women (OR 3.06, 95% CI [0.37, 3.68] & OR 1.7, 95% CI [ 0.64, 4.52] respectively). Limitations, reasons for caution This is a retrospective study and further accumulated data is warranted to validate the findings. Many patients at the time of analysis were still pregnant, hence we await live birth outcomes. Wider implications of the findings This is the first study to analyse the impact of COVID-19 vaccination on IVF outcomes. These initial findings are reassuring to patients and fertility clinicians on the safety of vaccination. Trial registration number not applicable

Study Objective The study objective was to assess the feasibility of laparoendoscopic single-site surgery (LESS) for the management of nonobstetric, gynecologic disease processes in pregnant patients. Design A retrospective case series of 13 pregnant women aged 21 to 42 years who underwent LESS for various gynecologic pathology. If able to be contacted, the patients were followed up until the delivery of the fetus. Setting The surgeries were performed in a single institution between January 2015 and June 2019. Patients The patients were selected if a laparoscopic intervention was indicated. Interventions The cases included 6 ovarian cystectomies and 2 salpingo-oophorectomies for adnexal masses; 1 myomectomy for a degenerated myoma; 1 salpingectomy for a heterotopic pregnancy; 2 cerclage placements for recurrent pregnancy loss and cervical insufficiency; and 1 paratubal cystectomy. The patients underwent LESS through a 2.5-cm umbilical incision. The masses were exteriorized using a laparoscopic specimen retrieval bag, with the exception of 2 large adnexal masses, which were aspirated at the incision site, exteriorized after content drainage, and cystectomies performed extracorporeally. The fascial incision was repaired with a permanent suture. Measurements and Main Results Various data were collected from patients, including age, surgical and obstetric history, gestational age at surgery, and ultrasonic imaging results. The outcomes measured were operative duration, intraoperative bleeding, postoperative symptoms, fetal monitoring before and after surgery, pathologic findings, conversions, intraoperative complications, and pregnancy outcomes. Eight cases were performed in the first trimester, 4 in the second trimester, and 1 in the third trimester, with the surgeries lasting between 45 minutes and 298 minutes. The blood loss ranged from 5 mL to 300 mL, and postoperative symptoms of mild pelvic or abdominal pain were reported. There were 2 conversions to traditional multiport laparoscopic surgery for the 2 cerclage cases, and there were no open surgery conversions or intraoperative complications. The fetal heart rate ranged between 130 beats per minute and 167 beats per minute postoperatively. Of the 9 patients who were able to be contacted for follow-up, all had successful deliveries. One patient was healthy at 31 weeks and 5 days without complication at the time of her last follow-up. Conclusion LESS may be performed by experienced surgeons on gravid patients in any trimester for adnexal masses, myomas, heterotopic pregnancy, and cervical incompetence. Future multiple-center studies may provide further evidence that LESS is a feasible and safe option for gynecologic surgery during pregnancy.

Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity.Design: Randomised parallel do...

Study Objective To evaluate the safety and feasibility of robot-assisted transvaginal natural orifice transluminal endoscopic surgery (R-vNOTES) hysterectomy when compared with traditional vNOTES (T-vNOTES) hysterectomy. Design Retrospective chart review. Setting Academic tertiary setting. Patients Total of 114 patients with benign gynecologic indication for hysterectomy. Interventions T-vNOTES or R-vNOTES hysterectomy performed by a single minimally invasive gynecologic surgeon in the study period. Measurements and Main Results The primary outcome of this study was surgical equivalence, measured principally by total operative time between T-vNOTES and R-vNOTES hysterectomy. Secondary operative outcomes that were measured included estimated blood loss, length of hospital stay, reported postoperative pain levels, and number of conversions. A total of 79 women underwent T-vNOTES hysterectomy, and 35 women underwent R-vNOTES hysterectomy without differences in operative time (p = .37), estimated blood loss (p = .27), length of hospital stay (p = .06), or reported postoperative pain levels at weeks 1, 2, and 3 after surgery (p = .78, p = .36, p = .38, respectively). A total of 6 patients underwent conversion in the T-vNOTES hysterectomy group compared with 0 in the R-vNOTES hysterectomy group; however, this was not statistically significantly different, and there were no conversions to laparotomy. Conclusion R-vNOTES hysterectomy is a feasible approach to surgery when compared with T-vNOTES hysterectomy and warrants further consideration as a skill set in a gynecologic surgeon's toolbox. Wristed instruments may allow surgeons who are inexperienced in single-site laparoscopy to adopt vNOTES more quickly as a new technique when performing hysterectomy through a comparable minimally invasive approach.

Study Objective Hysterectomy is the most common gynecological surgical procedure, and yet, studies show women have a poor understanding of the procedure. The objective of this study was to assess the feasibility of testing the effectiveness of a video we developed in Spanish, about hysterectomy, in improving knowledge among Spanish speaking women. Design Pre-test, post-test study design using a web-based learning management system (LMS) to fully digitize the study. The knowledge instrument used was previously validated. Setting A women's health clinic at a large teaching hospital in Texas. Patients or Participants Patients were female patients who spoke Spanish and who were being evaluated for conditions for which hysterectomy is a potential treatment. Interventions An empirically developed, focus group tested patient education video on the hysterectomy procedure narrated in Spanish. Measurements and Main Results We had 6 Spanish speaking women participate in this feasibility study. Our study consisted of a demographic survey followed by a pre-test followed by our hysterectomy education video followed by a post-test. All these components were combined in electronic form, using a web-based LMS, as if the study were an online course. Mean time taken to complete the pre-test was 393 seconds (range from 303 to 603 seconds). Mean score on the pre-test was 51.2% with a range from 25.9 to 66.7%. Mean time taken to complete the post-test was 365 seconds (range from 297 to 526 seconds). Mean score on the post-test was 60.5% with a range from 37 to 81.5%. Conclusion This small study demonstrated the feasibility of doing a health literacy study among Spanish speaking women focused on the hysterectomy procedure by using an online learning management system typically used for online courses. Using a learning management system allowed us to fully digitize this study that consisted of both questions to be answered as well as a video to be watched.

Study Objective This video describes and demonstrates various techniques for approaching difficult bladder dissection during laparoscopic hysterectomy. Design N/A Setting The techniques and surgeries demonstrated in this video were performed on patients undergoing laparoscopic hysterectomy in an academic tertiary care center. The patients had surgical histories predisposing them to difficult bladder dissection at the time of laparoscopic hysterectomy. These techniques can be used individually or in combination with each other in order to ensure successful bladder dissection. Patients or Participants N/A Interventions Four techniques for successful bladder dissection are reviewed in this video. The first technique involves backfilling the bladder with lactated ringers in order to help delineate the boundaries of the bladder and avoid inadvertent injury. A second technique involves first approaching the bladder laterally in order to find a surgical plane for adhesiolysis, followed by further dissection cephalad towards the dome of the bladder. Lateralization of the uterine arteries prior to bladder dissection is described in the third technique. Finally, the last technique involves first creating posterior colpotomy and carrying the incision anteriorly in order to help delineate normal anatomical markers. Measurements and Main Results N/A Conclusion Total laparoscopic hysterectomy can be safely completed in the presence of dense bladder adhesions through four techniques described above.

Background The purpose of this study was to test if oral D-methionine (D-met) reduced mucositis during chemoradiotherapy. Methods We conducted a placebo-controlled double-blind randomized phase II trial of D-met (100 mg/kg p.o. b.i.d.) testing the rate of severe (grades 3-4) mucositis. Results Sixty patients were randomized. Grade 2 + oral pain was higher with placebo (79% vs 45%; P = .0165), whereas grade 2 + body odor was greater with D-met (3% vs 41%; P = .0015). Mucositis was decreased with D-met by the physician (World Health Organization [WHO], P = .007; Radiation Therapy Oncology Group [RTOG], P = .009) and patient functional scales (RTOG, P = .0023). The primary end point of grades 3 to 4 mucositis on the composite scale demonstrated a decrease with D-met (48% vs 24%; P = .058), which was borderline in significance. A planned secondary analysis of a semiquantitative scoring system noted decreased oral ulceration (2.2 vs 1.5; P = .023) and erythema (1.6 vs 1.1; P = .048) with D-met. Conclusion Although not meeting the primary end point, results of multiple assessments suggest that D-met decreased mucositis.

Sao Paulo State Univ UNESP, Ctr Human Reprod Prof Franco Jr, Paulista Ctr Diag Res & Training, Dept Gynecol & Obstet,Botucatu Med Sch, Ribeirao Preto, Brazil

(E)-2′-deoxy-2′-(fluoromethylene)cytidine (FMdC), was evaluated as a potential treatment for malignant gliomas using the rat 9L brain tumor model. FMdC was shown to be an effective inhibitor of cell proliferation in cultured 9L cells with an EC50 of 40 ng/ml. In vitro studies also revealed that this compound significantly inhibited incorporation of [3H]thymidine in 9L cells. In vivo therapeutic efficacy of FMdC was evaluated in rats harboring intracerebral 9L tumors which were treated daily with 15 mg/kg, i.p. Treatment response was quantified from changes in tumor growth rates as assessed from sequential magnetic resonance imaging (MRI) tumor volume measurements. In vivo tumor cell kill in individual animals was calculated by fitting tumor volume data with an iterative computer routine. It was estimated that therapeutically responsive rats treated with FMdC daily produced a ≥ 0.1 log kill per therapeutic dose which resulted in a significant reduction in tumor growth rate. In addition, localized 1H-MRS of intracerebral 9L tumors revealed changes in metabolite levels which correlated with therapeutic response. These results provide evidence supporting the use of FMdC in clinical trials for the treatment of malignant gliomas and reveals that MR can play an important role in the pre-clinical evaluation of novel compounds using orthotopic tumor models. Copyright © 2003 John Wiley & Sons, Ltd.

High-resolution 3D bone-tissue structure measurements may provide information critical to the understanding of the bone regeneration processes and to the bone strength assessment. Tissue engineering studies rely on such nondestructive measurements to monitor bone graft regeneration area. In this study, we measured bone yield, fractal dimension and trabecular thickness through micro-CT slices for different grafts and controls. Eight canines underwent surgery to remove a bone volume (defect) in the canine's jaw at a total of 44 different locations. We kept 11 defects empty for control and filled the remaining ones with three regenerative materials; NanoGen (NG), a FDA-approved material (n=11), a novel NanoCalcium Sulfate (NCS) material (n=11) and NCS alginate (NCS+alg) material (n=11). After a minimum of four and eight weeks, the canines were sacrificed and the jaw samples were extracted. We used a custom-built micro-CT system to acquire the data volume and developed software to measure the bone yield, fractal dimension and trabecular thickness. The software used a segmentation algorithm based on histograms derived from volumes of interest indicated by the operator. Using bone yield and fractal dimension as indices we are able to differentiate between the control and regenerative material (p

The synthesis and evaluation of farnesyl-derived inhibitors of ras farnesyl transferase are presented. Evaluation of inhibitors of farnesyl transferase and comparison with the previously described inhibitor was accomplished using purified enzyme and Amersham′s Farnesyl:Transferase enzyme assay kit. These results show an order of magnitude increase in inhibitory activity for β-ketophosphonic acid over β-hydroxyphosphonic acid. Incorporation of fluorines in α-position, led to an increase in inhibitory activity over the nonfluorinated analogues.

Solid pseudopapillary tumour (SPT) is an uncommon cystic exocrine pancreatic neoplasm. The typical patient is a female in the third decade of life presenting with pain and/or palpable mass. Classic imaging characteristics include large size, mixed solid and cystic nature, encapsulation and haemorrhage. A pancreatic mass with these features in a young adult female should raise suspicion for an SPT. Although typically a non-aggressive neoplasm with surgery curative in most cases, SPT may exhibit more aggressive features such as local invasion, metastases or recurrence in up to 20% of cases.

A series of chalcones was evaluated as antimitotic agents. One of these, (E)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methyl-2-pr open- 1-one) (73), was found to be an effective antimitotic agent at a concentration of 4 nM in an in vitro HeLa cell test system. When evaluated in experimental tumor models in vivo, this compound exhibited antitumor activity against L1210 leukemia and B16 melanoma.

The design and synthesis of (E)- and (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (6 and 13, respectively), a new class of mechanism-based inhibitors of S-adenosyl-L-homocysteine (SAH) hydrolase, is described. A number of analogues of 6 and 13 were synthesized in order to determine the structure-activity relationship necessary for inhibition of the enzyme. Substitution of chlorine for fluorine in 6 (i.e. 44), addition of an extra chlorine to the 5'-vinyl position (i.e. 51 and 52), modification of the 2'-hydroxyl group to the deoxy (34 and 35) and arabino (36 and 37) nucleosides provided competitive inhibitors of SAH hydrolase. Nucleosides 6 and 13, as well as 5'-deoxy-5',5'-difluoroadenosine (14) proved to be time-dependent inhibitors of SAH hydrolase. All three compounds are postulated to inhibit through the potent electrophile derived from oxidation of the 3'-hydroxyl of 6 or 13 to the ketone (i.e. 3 and/or the E-isomer). Consistent with the proposed mechanism of inactivation of SAH hydrolase by 6, 13, and 14 was the observation that incubation of purified rat liver SAH hydrolase with 6 resulted in release of 1 equiv of fluoride ion (by 19F NMR) and incubation with 14 resulted in release of 2 equiv of fluoride ion. The general synthetic route developed for the synthesis of the title nucleosides utilized the fluoro Pummerer reaction for the introduction of fluorine into the requisite precursors. Preliminary antiretroviral data from Moloney leukemia virus (MoLV) is presented and correlates with SAH hydrolase inhibition. Antiviral activity (IC50 against MoLV) ranged from 0.05 to 10 micrograms/mL.

Polyhydroxylated indolizidine 6a and quinolizidine 6b were synthesized from a common precursor, iminoheptitol 8 . The target compounds are potent inhibitors of the glycoprotein trimming enzyme--α-glucosidase I.

Purpose: A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically. Experimental Design: The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly. Results: Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis. Conclusions: There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature. Clin Cancer Res; 16(9); 2666–76. ©2010 AACR.

A program was established in which the parents of children with cancer were trained to administer intravenous chemotherapy to the children in their homes. The main objectives of this program (Home Intravenous Chemotherapy by Parents [HICP]) were to improve the quality of life for children with cancer and their parents and to decrease the cost of medical care for these children by decreasing the number of clinic visits and hospital stays intended solely for the administration of chemotherapy. Twenty-four months of experience with this program indicates that with a close communication network and a good working relationship among a home care organization (HCO), the parents of the patient, a pediatric oncology nurse, and an attending pediatric oncologist, many chemotherapeutic agents can be safely administered to these children by their parents in their homes. The patients and their parents are enthusiastic about this program because of the valuable time saved and the increased participation in care. In addition, this program greatly decreased the cost of medical care for these children.

Polyhydroxylated indolizidine 6a and quinolizidine 6b were synthesized from a common precursor, iminoheptitol 8 . The target compounds are potent inhibitors of the glycoprotein trimming enzyme--α-glucosidase I.

The antiviral activity of 6-0-butanoylcastanospermine (MDL 28,574) [50% inhibitory concentration (IC50: 1.1 microM)] in JM cells infected with a recent isolate of HIV-1 (GB8), was compared with other inhibitors of glycoprotein-processing enzymes. N-butyldeoxynojirimycin (BuDNJ), deoxynojirimycin (DNJ), castanospermine (CAST) or the reverse transcriptase inhibitor 2'3'-dideoxycytidine (ddC) had activities of 56, 560, 29 and 0.1 microM, respectively. MDL 28,574 was at least 50 times more active than BuDNJ and less active but better tolerated in cell culture than ddC, two compounds currently undergoing clinical trials. The CAST derivative showed good protection in H9 cells infected with HIV-1 (RF; IIIB; U455), and HIV-2 (ROD), although the potency was less than that seen in the JM/GB8 system. HIV-1 glycoproteins, gp160 and gp120, synthesized in H9 cells chronically infected with HIV-1 (RF) and treated with MDL 28,574, were characterized by an increase in relative molecular weight of approximately 7-8000 kD. The ratio of gp120 to gp160 was markedly reduced in treated cells and provided further evidence that cleavage of the gp160 precursor molecule is a major consequence of the inhibition of glycoprotein processing. The intracellular target for MDL 28,574 was verified as alpha-glucosidase-I of the processing enzymes by the analysis of high-glucose glycopeptides recovered from treated mouse cells. This activity correlated with the antiviral effect observed against the growth of a mouse retrovirus, Moloney murine leukemia virus (MOLV), in mouse cells.

Purpose: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. d-Methionine (d-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults. Experimental Design: We evaluated if d-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice. Results: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P < 0.05) whereas it did not confer a similar protection on transformed tumor cells. d-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6 ± 0.15). d-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by d-Met treatment. Pharmacokinetics following administration of a liquid suspension of d-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral d-Met doses between 200 and 500 mg/kg (P < 0.0003). Conclusions: d-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of d-Met to protect from oral mucositis are warranted.

A series of chalcones was evaluated as antimitotic agents. One of these, (E)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methyl-2-pr open- 1-one) (73), was found to be an effective antimitotic agent at a concentration of 4 nM in an in vitro HeLa cell test system. When evaluated in experimental tumor models in vivo, this compound exhibited antitumor activity against L1210 leukemia and B16 melanoma.

Module optimization modeling with discrete event simulation is described. The models allow the organization of tools and chambers and visualization of the modules in different configurations as well as the analysis of the expected performance relative to parameters. Representative results for a Dep/Etch/Dep module are presented.

New wide bandgap semiconductors are needed for the development of a large number of novel devices having a wide range of applications. All semiconducting materials, particularly those with bandgaps in range 2.2 to 2.7 eV offer excellent opportunities to enhance the frontiers of technology. Reliable and robust new materials with this bandgap will greatly impact many areas of technology including high temperature integrated circuits, high power electronic devices, radiation immune solar cells, short wavelength light emitting diodes, and solid state lasers. Currently the technology based on wide bandgap semiconductors is driven by II‐VI compounds, III‐V compounds, and SiC. But the success has been marginal because of the difficulties in growing bulk single crystals and epitaxial thin films of these materials at a reasonable cost. Members of the iron‐titanate family appear to be extremely attractive candidates for development of efficient and reliable devices both for terrestrial and space power applications (Pandey 1986). The stable members of the iron‐titanate series, namely ilmenite (FeTiO3), pseudobrookite (FeTi2O5), and ulvospinel (Fe2TiO4) are of interest for fundamental studies and applications. But ilmenite (moon rock) is of particular interest because of its unique mechanical and semiconducting properties. This paper will focus on the crystal growth of ilmenite. A strategy to model and control the growth process to optimize the properties and grow large crystals is proposed. Some space related applications are of special interest because of the high probability of fabricating ilmenite based devices which could meet the stringent requirements of space applications.

The ribonucleotide reductase inhibitor MDL 101,731 was examined for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro and in combination with acyclovir in the murine zosteriform model of HSV-1 infection. The in vitro antiviral activity (IC50) for both serotypes of HSV was similar and in the range 23-98 nM for Vero cells. Comparable activities were obtained against acyclovir-resistant viruses. In the zosteriform model, topical combination therapy of MDL 101,731 with acyclovir (5%:5% w/w) applied 48 h after infection was more effective than acyclovir alone and even appeared to promote lesion resolution.

Daily oral or intravenous administration of the ribonucleoside diphosphate reductase inhibitor, (E)-2'-deoxy-2'-(fluoromethylene)cytidine (MDL 101,731), to nude mice caused rapid regression of colon and prostate xenografts. Studies were performed to optimize dosing schedule and route of administration. MDL 101,731 was tested against colon (HT-29) and prostate (PC-3) xenografts using twice weekly oral and intravenous administration. PC-3 tumors regressed almost completely with doses of 20 mg/kg. HT-29 xenografts regressed during intravenous administration of 100 mg/kg MDL 101,731, whereas oral administration was less effective. Based on these data it seems that MDL 101,731 is effective when administered intravenously, twice weekly and is an excellent candidate for clinical development against solid tumors.

We have used a simple and efficient procedure for the synthesis of N-5-carboxypentyl-1-deoxynojirimycin, an affinity ligand for alpha-glucosidase I (Bernotas, R. C. and Ganem, B., Biochem. J., 270, 539-540, 1990). The affinity gel was used to purify alpha-glucosidase I in one step from crude extract. In subsequent steps, partially purified alpha-glucosidase II was obtained. We have synthesized several analogues of castanospermine and studied their inhibition of alpha-glucosidase I in vitro using purified alpha-glucosidase I and in vivo in cultured B16F10 cells. Although the castanospermine analogues were significantly less active against the purified enzyme (IC50 approximately 1-23 micrograms/ml) as compared to castanospermine (IC50 = 0.02 microgram/ml), several compounds had up to 30-fold higher activity than castanospermine against alpha-glucosidase I in B16F10 cells, based on the accumulation of G3M7-9N2 oligosaccharide-containing glycoproteins. These results suggest that these analogues with lipophilic side chains cross the membrane barrier more efficiently than castanospermine. Once inside the cell, they may be converted to their active metabolite, castanospermine, by cellular esterases to give enzyme inhibition.

Mineralized tissues in oral and craniofacial science: biological principles and clinical correlates

The 6-O-butanoyl derivative of castanospermine (MDL 28,574) was previously shown to be approximately 30-fold more potent than the naturally occurring molecule at inhibiting the replication of human immunodeficiency virus (HIV) (D. L. Taylor, P. S. Sunkara, P. S. Liu, M. S. Kang, T. L. Bowlin, and A. S. Tyms, AIDS 5:693-698, 1991). We now report that consistent with its improved anti-HIV activity, MDL 28,574 is more effective (50% inhibitory concentration [IC50], 20 microM) than the parent molecule (IC50, 254 microM) at causing the accumulation of glucosylated oligosaccharides in HIV-infected cells by inhibition of glycoprotein processing. These were predominantly of the glucose 3 type, as determined by P4 Bio-Gel analysis after digestion with purified alpha-glucosidase I, indicating that, intracellularly, this enzyme is the major target for inhibition. MDL 28,574, however, was less active (IC50, 1.27 microM) than castanospermine (IC50, 0.12 microM) against the mutual target enzyme, cellular alpha-glucosidase I, in a cell-free assay system. The increased effects of MDL 28,574 against alpha-glucosidase I in cell culture were attributed to the improved cellular uptake of the more lipophilic derivative. Inhibition of this enzyme activity in HIV-infected H9 cells impaired viral glycoprotein processing and resulted in the expression of abnormally configured gp120. This did not affect virus production, but the virions had decreased infectivity which was partially related to a reduced ability to bind to CD4+ T cells.

A program was established in which the parents of children with cancer were trained to administer intravenous chemotherapy to the children in their homes. The main objectives of this program (Home Intravenous Chemotherapy by Parents [HICP]) were to improve the quality of life for children with cancer and their parents and to decrease the cost of medical care for these children by decreasing the number of clinic visits and hospital stays intended solely for the administration of chemotherapy. Twenty-four months of experience with this program indicates that with a close communication network and a good working relationship among a home care organization (HCO), the parents of the patient, a pediatric oncology nurse, and an attending pediatric oncologist, many chemotherapeutic agents can be safely administered to these children by their parents in their homes. The patients and their parents are enthusiastic about this program because of the valuable time saved and the increased participation in care. In addition, this program greatly decreased the cost of medical care for these children.

The design and synthesis of (E)- and (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (6 and 13, respectively), a new class of mechanism-based inhibitors of S-adenosyl-L-homocysteine (SAH) hydrolase, is described. A number of analogues of 6 and 13 were synthesized in order to determine the structure-activity relationship necessary for inhibition of the enzyme. Substitution of chlorine for fluorine in 6 (i.e. 44), addition of an extra chlorine to the 5'-vinyl position (i.e. 51 and 52), modification of the 2'-hydroxyl group to the deoxy (34 and 35) and arabino (36 and 37) nucleosides provided competitive inhibitors of SAH hydrolase. Nucleosides 6 and 13, as well as 5'-deoxy-5',5'-difluoroadenosine (14) proved to be time-dependent inhibitors of SAH hydrolase. All three compounds are postulated to inhibit through the potent electrophile derived from oxidation of the 3'-hydroxyl of 6 or 13 to the ketone (i.e. 3 and/or the E-isomer). Consistent with the proposed mechanism of inactivation of SAH hydrolase by 6, 13, and 14 was the observation that incubation of purified rat liver SAH hydrolase with 6 resulted in release of 1 equiv of fluoride ion (by 19F NMR) and incubation with 14 resulted in release of 2 equiv of fluoride ion. The general synthetic route developed for the synthesis of the title nucleosides utilized the fluoro Pummerer reaction for the introduction of fluorine into the requisite precursors. Preliminary antiretroviral data from Moloney leukemia virus (MoLV) is presented and correlates with SAH hydrolase inhibition. Antiviral activity (IC50 against MoLV) ranged from 0.05 to 10 micrograms/mL.

A yellow amorphous compound, wassumycin, was isolated from an unidentified strain of Streptomyces. Wassumycin inhibited the growth of several species of human and animal pathogenic bacteria especially Clostridia. Wassumycin also inhibited the growth of HeLa cells, and showed good antitumour activity against experimental mouse tumours such as L1210, P388 leukaemias, and B16 melanoma. On the basis of the chemical and antimicrobial properties, the antibiotic appeared similar to the chromomycins and olivomycins, but its ultraviolet, infrared, and proton magnetic resonance spectra differed from theirs significantly.

The requirement of the natural polyamines, putrescine, spermidine and spermine, for cell growth suggests that appropriate structural analogues of these compounds could serve as potential antiproliferative agents acting via polyamine antagonism. In this investigation, the antiproliferative activity of N, N'-Bis[3-(ethylamino)-propyl]-1-7-heptane diamine (BEPH), a synthetic polyamine analogue, was investigated employing HeLa cells in culture and L1210 leukemia in mice. BEPH inhibited the growth of HeLa cells with an IC50 of 0.25 microM during a four day culture period. This concentration of the compound was cytotoxic to the cells as evidenced by an 80% reduction in cloning efficiency. Only marginal changes in intracellular polyamine concentrations were observed during incubation with 0.25 microM BEPH. In both HeLa cells and L1210 cells in culture, incorporation of radioactive precursors into DNA, RNA and protein were reduced by BEPH. Inhibition of protein synthesis was discernible prior to inhibition of RNA and DNA in these cells. In mice inoculated i.p. with 10(5) L1210 cells on day 0, i.p. administration of 10.0 mg/kg of BEPH qd(X5) beginning on day 1 prolonged the survival time by 84% compared to controls. The same dose of the compound, in combination with 10.0 mg/kg of N,N'-bis-2-3-butadienylputrescine, an inhibitor of the polyamine catabolizing enzyme polyamine oxidase (PAO), produced a 100% cure rate. Similar results were obtained when BEPH was combined with N-methyl-N'-2-3-butadienylputrescine, another PAO inhibitor. Furthermore, animals cured of the leukemia by the combination chemotherapy were resistant to a subsequent challenge with L1210 cells, indicating the development of tumor "immunity". The striking antitumor activity along with the development of tumor immunity indicate that synthetic polyamine analogues have potential for development as antineoplastic agents.