Multiscale modelling of heterogeneous fillers in polymer composites: the case of polyisoprene and carbon black.

The dispersion of inorganic particles within polymeric materials is an extensively used method to enhance their mechanical properties. One of the major challenges in the simulation of polymer composites is to model the uneven surface of the fillers which strongly affects the dynamics of the adsorbed polymers and consequently the macroscopic mechanical properties of the final composite. Here we propose a new multiscale approach that, using experimental adsorption data, constructs the filler surface to statistically reproduce the surface defects. We use this approach to analyse the structure and dynamics of highly entangled polyisoprene melt in contact with different realistic carbon black samples. We show that the presence of the heterogeneous surface has a negligible influence on the structure of the polymer chains but a major effect on their dynamics and the surface wettability.

Computational characterisation of dried and hydrated graphene oxide membranes.

A multi-step molecular dynamics procedure was developed to construct fully flexible atomistic models of graphene oxide (GO) membranes. The method of preparation replicates the experimental synthesis of the material; i.e. the flow-directed self-assembly of individual flakes onto a substrate or filter. A total of 180 GO membrane models were prepared with water contents varying between 0 and 20%, providing an insight into changes in the membrane's interlayer distance with swelling. Membranes with 15% water content have an average interlayer distance (0.80 nm), bulk density (1.77 g cm-3) and tensile modulus (18.1 GPa) in excellent agreement with the experimental literature, demonstrating that air-dried membranes have 15% water content. The models reveal the intrinsic structural heterogeneity and complex morphology of GO membranes. This feature has previously been unaccounted for in both experimental interpretations and GO nanopore models, which often use pre-defined and idealised 2D geometries. Completely dried membranes have considerable free pore volume. This observation explains the modest change in interlayer distance (0.02 nm) as the membrane's water content is increased from 0% to 10% compared to a much more significant change (0.12 nm) as the water content is increased from 10% to 20%. Combined with this new understanding of membrane swelling, the availability of such representative models opens the possibility of the molecular-level design of GO membranes for a variety of applications, such as gaseous and aqueous separations.

Local and global dynamics of multi-resolved polymer chains: Effects of the interactions atoms-beads on the dynamic of the chains.

We present a thorough analysis of the dynamic behaviour of hybrid atomistic/coarse-grained (CG) models of polymer melts. While structural properties are well preserved in a dual-resolved model, we show how the dynamic of the chains can be influenced by the simultaneous presence of atoms and beads. We show that although the polymer chains are long enough to exhibit reptation, the corresponding CG model is unable to capture the expected subdiffusive regimes and seems to still follow the Rouse dynamics. The introduction of atoms in the chain restores the correct dynamic regime, and the dynamics of hybrid systems becomes comparable to that of the atomistic dynamics as the atoms/beads ratio is increased.

Van der Waals pressure and its effect on trapped interlayer molecules.

Van der Waals assembly of two-dimensional crystals continue attract intense interest due to the prospect of designing novel materials with on-demand properties. One of the unique features of this technology is the possibility of trapping molecules between two-dimensional crystals. The trapped molecules are predicted to experience pressures as high as 1 GPa. Here we report measurements of this interfacial pressure by capturing pressure-sensitive molecules and studying their structural and conformational changes. Pressures of 1.2±0.3 GPa are found using Raman spectrometry for molecular layers of 1-nm in thickness. We further show that this pressure can induce chemical reactions, and several trapped salts are found to react with water at room temperature, leading to two-dimensional crystals of the corresponding oxides. This pressure and its effect should be taken into account in studies of van der Waals heterostructures and can also be exploited to modify materials confined at the atomic interfaces.

Precise and ultrafast molecular sieving through graphene oxide membranes.

Graphene-based materials can have well-defined nanometer pores and can exhibit low frictional water flow inside them, making their properties of interest for filtration and separation. We investigate permeation through micrometer-thick laminates prepared by means of vacuum filtration of graphene oxide suspensions. The laminates are vacuum-tight in the dry state but, if immersed in water, act as molecular sieves, blocking all solutes with hydrated radii larger than 4.5 angstroms. Smaller ions permeate through the membranes at rates thousands of times faster than what is expected for simple diffusion. We believe that this behavior is caused by a network of nanocapillaries that open up in the hydrated state and accept only species that fit in. The anomalously fast permeation is attributed to a capillary-like high pressure acting on ions inside graphene capillaries.

[Folic acid and congenital malformation: scientific evidence and public health strategies]. / Acido folico e difetti congeniti: evidenze scientifiche e strategie di sanità pubblica.

In Italy at least 3% of babies are born with some congenital malformation. The intake of folic acid (FA) prior to conception and during the early stages of pregnancy plays an important role in preventing neural tube defects, severe anomalies of brain embryogenesis, and other malformations such as cardiac and urinary tract anomalies, oro-facial clefts and limb reduction defects. The Italian Network for Folic Acid Promotion, coordinated by the National Center on Rare Diseases of the Italian National Institute of Health, has elaborated and diffused a recommendation for the periconceptional FA supplementation: "Women of child-bearing age, are recommended to consume 0,4 mg/day of FA, to reduce the risk of congenital defects. The intake of folic acid should start at least one month before the conception and should continue for the first quarter of pregnancy". This paper discusses various strategies in order to promote FA intake during periconceptional period. Food fortification, adopted in several countries such as USA, has raised concerns about the risk of an excessive FA intake which may lead to adverse effect such as tumour promotion. Currently, periconceptional supplementation and healthy dietary habits promotion appear to be the most effective strategies.

The possible role of endocrine disrupting chemicals in the aetiology of cryptorchidism and hypospadias: a population-based case-control study in rural Sicily.

Abstract This was an open case-control study of the possible association between parental occupational and domestic exposures to potential endocrine disrupting chemicals (EDC) assessed by questionnaire and cryptorchidism and hypospadias in their offspring in the agricultural area of Ragusa. Cases of infants born between 1998 and 2002 with either of these two malformations (n=90), and controls (n=203), were recruited through the paediatric services (for cases) and a random sample of healthy infants attending the same services born in the same period of time (for controls). Data on occupational and environmental exposures of parents prior to and during the index case (or control), were collected through interviews with both parents. Concerning occupational exposures, we did not find a statistically significant increase in risk among parents directly involved in agricultural work. We did find a non-statistically significant increase in risk for cryptorchidism in mothers employed in agriculture [adjusted odds ratios (OR) 2.97; 95% confidence interval (CI) 0.77-11.47] and with probable exposure to pesticides (adjusted OR 2.74; 95% CI 0.72-10.42). Fathers who had indirect contact with agricultural products (transport and retail) had an increased risk (not statistically significant) for cryptorchidism (adjusted OR 2.45; 95% CI 0.63-9.59) and hypospadias and cryptorchidism combined (adjusted OR 2.24; 95% CI 0.67-7.48). Increases in risk of the two malformations pooled were also observed in relation to the mother's age below 25 (adjusted OR 1.99; 95% CI 0.97-4.09), to the presence of genital disease of the father (adjusted OR 2.41; 95%C I0.94-6.17), and the mother (adjusted OR 3.47;95% CI 1.34-8.99), to low birth weight of the infant (adjusted OR 4.49; 95% CI 1.23-16.31). Increased risk was also observed for mothers consuming alcohol during pregnancy (adjusted OR 3.09; 95% CI 0.98-9.66), and for couples who conceived while using condoms (adjusted OR 2.12; 95% CI 1.02-4.41). The study therefore provides only limited support to the hypothesis of a possible association between the risk of cryptorchidism and hypospadias and the occupational exposure to EDC and agricultural work.

Cryptorchidism and hypospadias in the Sicilian district of Ragusa and the use of pesticides.

The aim of the study was to explore the role of environmental exposures to pesticides in the birth prevalence of hypospadias and cryptorchidism, in the 12 agricultural municipalities of Ragusa Sicily. Data on the birth prevalence of the two birth defects were obtained from the local pediatric services for the period 1998-2002. Municipalities were ranked according to the degree of "pesticide impact" on the basis of three quantitative criteria of intensity of agricultural activities of the population. We found a significantly higher birth prevalence of hypospadias with increasing "pesticide impact" (trend test, P=0.003). The association with cryptorchidism was not statistically significant, but when the two birth defects were pooled together, the linear trend was significant (trend test, P=0.001).

[Study of reproductive health risks in Sicily. Congenital malformations and exposure to EDCs: a case-control study (study methodology)]. / Indagine siciliana sui rischi per la salute riproduttiva. Malformazioni congenite ed esposizione ad EDCs: uno studio caso-controllo (metodologia di studio).

INTRODUCTION: The incidence of Congenital Malformations may represent an early biological indicator for human toxicity to environmental and occupational contaminants. SCIENTIFIC OBJECTIVE: We are in the process of exploring the relation between various potential sources of parental periconceptional pregnancy exposures to Endocrine Disrupting Chemicals (EDCs) and selected Congenital Malformations in offspring. MATERIALS AND METHODS: The low incidence of Congenital Malformations leads to an epidemiological "Case-Control" study. The areas of the study are the Ragusa Municipalities and the south-east Siracusa Municipalities. We are conducting personal interviews with parents of about 100 cases with orafacial clefts or male genital malformations and 200 nonmalformed controls. The infants for the study were selected from those born during 1998-2002 in these areas. The more important variables considered are: 1--parental occupation and workplace exposures. 2--relevant confounders and recall bias. The analysis of the data will use the classical approach of case-control study (matching procedure), comparing risk factor frequency between cases and controls. CONCLUSIONS: The results of the study will allow to clarify the relationship between parental exposure to EDCs compounds and human reproduction.

Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282.

BACKGROUND: A phase II study of dacarbazine (DTIC), was conducted to determine the response rate, duration of response, toxicity and overall survival of patients with advanced pancreatic islet cell tumors. PATIENTS AND METHODS: Fifty patients with advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease were entered on this study. DTIC was given by IV infusion at a dose of 850 mg/m2, over 60-90 minutes, repeated every four weeks. RESULTS: The response rate was 33% in 42 patients who had measurable tumor, and 34% in the 50 patients (90% confidence interval (90% CI): 23%-47%). The majority of the responses were seen in patients without prior chemotherapy. Median overall survival was 19.3 months. There were two lethal toxicities on the study, one septic shock and one myocardial infarction. Grade 4 toxicities were, hematological (5 patients), sepsis, neurological (depression and paranoid behavior) and bleeding (1 patient each). The most common toxicity was vomiting, grade 3 in 13% of patients. CONCLUSIONS: DTIC has activity in advanced previously untreated pancreatic islet cell tumors.

Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants.

Individuals who receive life-saving organ transplants and the required immunosuppression often develop secondary cancers. One of the most common secondary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to prevent these cancers have not been successful. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experimental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 organ transplant recipients, randomized to 1.0 and 0.5 g of DFMO or a placebo, designed to look at short-term toxicities over 28 days as well as the impact of DFMO on two biological parameters, skin polyamines and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity. Blood levels of DFMO were also measured. The results indicate that DFMO was well tolerated over the 28-day period. The TPA-induced ODC activity in 3-mm skin biopsies was significantly lowered by 80 and 67% at the two dose levels. Polyamine levels were not affected significantly except for putrescine at the 0.5-g level. Blood levels of DFMO were about two times higher than expected, based on our prior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this population as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.

Phase II evaluation of menogaril in advanced prostate cancer: Eastern Cooperative Oncology Group EST P-A885.

Menogaril is a semisynthetic anthracycline that is less cardiotoxic than doxorubicin in a preclinical model. We conducted a phase II trial to determine the activity of menogaril in hormone-refractory prostate cancer. Between October 1985 and November 1987, 32 eligible patients were enrolled and were divided into good- and poor-risk categories, the latter being defined by prior radiotherapy to less than one third of the marrow-containing skeleton. Good-risk patients received a starting dose of 200 mg/m2 by 60-minute IV infusion, whereas the poor-risk patients received 160 mg/m2. Treatment was repeated every 3 weeks until disease progression. Menogaril caused leukopenia in 90% of patients, of whom 47% had grade III or IV toxicity. Thrombocytopenia was uncommon and mild, with only three patients (9%) experiencing grade II toxicity. Nonhematologic toxicity included mucositis (9%), and mild weight loss in 33% of patients. Nine patients (28%) had stable disease of 3 or more months' duration. There were no objective partial or complete responses. The median time to progression for the entire group was 10 weeks, and the median survival time for all patients was 24 weeks. Because of appreciable toxicity and limited antitumor activity, further study of menogaril cannot be recommended in hormone-refractory prostate cancer.

Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease.

Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by greatly altered somatic cholesterol metabolism. The NPC1 gene has recently been cloned and shown to have sequence homology to other sterol-sensing proteins. We have used a mouse model with a disrupted npc1 gene to study the effects of the cholesterol-mobilizing compound, 2-hydroxypropyl-beta-cyclodextrins (HPBCD), on the clinical course of this disorder. Treatment with two HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol storage while a third HPBCD was without effect. The ameliorating effect was not improved by longer exposure times (commencement of exposure in utero), however, it is not known if there is transplacental transfer of HPBCDs. The combination of HPBCD with probucol or nifedipine (which have previously been shown to lower liver cholesterol in this animal model) markedly decreased liver storage of unesterified cholesterol without altering the depressed levels of esterified cholesterol. The slight effects of the HPBCDs on neurological symptoms may be partially due to their apparent non-permeation of the blood-brain barrier (BBB). This non-permeation was assayed with radioactive tracers and was also present in the mdr1a knockout mice which have greatly increased BBB permeability for many drugs. Intrathecal delivery of HPBCD by an Alzet osmotic minipump did not improve its efficacy in ameliorating neurological symptoms.

Bioavailability study of oral liquid and tablet forms of alpha-difluoromethylornithine.

The purpose of this study was to assess the bioavailability of two oral preparations of difluoromethylornithine (DFMO). The current preparation of DFMO is a liquid with a concentration of 0.2 gram/ml that must be drawn up into a syringe and dispensed into a small medicine glass. This form of DFMO causes wastage of the medication. The liquid form also makes compliance and blinding difficult. Recently, a new coated tablet preparation has become available from Ilex Oncology Services (San Antonio, TX). The coated tablets are 0.25 gram and are scored. The tablet form should increase compliance by making it much easier for the subject to take the medication. This report compares the bioavailability of both preparations with the goal of demonstrating equivalence of the preparations. Ten normal subjects entered the cross-over study in which the order in which they would receive the liquid or tablet preparation of DFMO was randomized. The study was designed with the objective of establishing the bioequivalence of a tablet preparation of DFMO at daily dose 0.5 gram/m2 and a liquid preparation of DFMO at the same daily dose. The mean area under the time-by-concentration curves (microM x hours) for the liquid and tablet preparations was 368.2 and 370.4, respectively. The peak concentrations for the liquid and tablet preparations were 47.3 and 48.2 microM, respectively. No statistically significant differences were seen in these parameters, in time to peak concentration, or in serum half-life.

Advances in the systemic treatment of cancers in the elderly.

Cancer is a disease of the elderly. More than 50% of all cancers and deaths occur in people over 65 years. Older cancer patients are less likely to be referred to centers or to be given adequate chemotherapy. The elderly are under-represented in Phase I and II trials. Some of this hesitancy to give chemotherapy is related to the increased presence of co-morbid conditions in the elderly. Toxicity is another concern. This review summarizes data from literature on the effectiveness, outcome, and toxicity of chemotherapy in selected tumors. Information is presented on age related effects. In addition, a summary of new agents and biologics is presented that needs to be looked at for age related effects. Some comments are made on the pharmacokinetic impact of physiologic changes in the elderly on chemotherapy drugs. As the world's population ages, we need to include the elderly in trials to get data on age related effects. Most of the information presented shows that effective chemotherapy can be given safely to the elderly and the outcomes and toxicity are equivalent for many of the common solid tumors.

Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine.

A two-step Phase I study of piroxicam (PXM) and a-difluoromethylornithine (DFMO) alone and in combination was initiated to assess toxicity and the impact of these drugs on several biological markers. In step 1, 12 subjects with a history of skin cancers were assigned to receive PXM 10 mg every day (q.d.) or 10 mg every other day (q.o.d.). The dosage of PXM 10 mg q.o.d. was tolerated. No changes were seen in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) or urinary polyamine levels. Steady-state serum levels of PXM were consistent with the oral dose level. In step 2, 31 subjects with stage 0 or I nonmelanoma skin cancers, stage A or B prostate or colon cancer, or stage I breast cancer or who had a family history of cancer were randomized to receive DFMO 0.5 g/m2, PXM 10 mg q.o.d., or the combination of DFMO and PXM. In addition to the biological markers of TPA-induced ODC activity in skin biopsies and urinary polyamine levels, we measured urinary 11-dehydrothromboxane B2, a specific metabolite of thromboxane A2. Of the 12 subjects on DFMO/PXM, 2 dropped out for non-drug-related reasons. Three developed grade-2 drug-related toxicities. One subject developed dyspnea that resolved and was able to continue on the study for 6 months. One subject who developed diarrhea that resolved after 5 days was also able to restart the drug without a recurrence. A third subject described intermittent episodes of tinnitus starting 4 h after taking PXM that lasted only 5 s and did not progress on treatment. Comparing the 6-month measurements with pretreatment, DFMO/PXM or DFMO significantly reduced TPA-induced ODC levels (Ps, 0.03 and 0.05). Urinary polyamine levels of spermidine decreased slightly with the DFMO/PXM or DFMO alone, whereas putrescine decreased with PXM alone. Levels of 11-dehydrothromboxane B2 were depressed by PXM and PXM/DFMO. The doses of DFMO/PXM determined in step 2 are potential starting dosages for Phase IIa and IIb chemoprevention trials.

PALA versus streptozotocin, doxorubicin, and MeCCNU in the treatment of patients with advanced pancreatic carcinoma.

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

Palliative medicine in the elderly.

Cancer is primarily a disease of the elderly and the palliation of both disease- and treatment-related symptoms is of importance in the practice of cancer medicine in all patients. Many older patients are treated within community hospitals, in which anticancer therapies are less likely to be given and in which the palliation of symptoms should be of primary importance. Many oncologists struggle with the palliation of symptoms in patients who are near the end of life. This is despite the considerable energies that are spent in palliating symptoms in patients who are receiving anticancer therapies at all disease stages. The management of pain has advanced considerably recently with improvements in pain assessment and pharmacologic interventions. However, elderly patients are less likely than younger patients to receive proper pain management. Elderly patients also are less likely to take opioids for pain because of their attitudes and beliefs. Fatigue, dyspnea, and psychologic issues also are of importance in the management of elderly cancer patients both during anticancer therapy and near the time of death. Some elderly cancer patients die in the care of a hospice, although many are not referred to this service. There are many barriers to the provision of palliative medicine and these may be related to health practitioners, to the patients themselves, or to the health care system of which they are part. The increased educational efforts of health professionals are needed to ensure that all patients, including the elderly, have adequate palliation of their cancer-related symptoms.

Funding for patient-oriented research. Critical strain on a fundamental linchpin.

CONTEXT: Interest in clinical investigative careers has declined over the past 2 decades. While several factors are likely involved in this decline, one is the perceived difficulty in obtaining support for investigator-initiated clinical research projects. OBJECTIVE: To analyze the priority scores and funding rates of patient-oriented research (POR) compared with laboratory-oriented research (LOR) when grant applications to the National Institutes of Health (NIH) are reviewed by study sections of the NIH Division of Research Grants. DESIGN: Research grant applications submitted to NIH were classified by the applicant as involving human subjects or not (LOR). Those classified as involving human subjects were divided into clinical (POR) and nonclinical research. The association of priority score and POR or LOR status was evaluated using chi2 statistical techniques. SETTING AND PARTICIPANTS: Twelve thousand investigator-initiated grant applications (RO1s) in 2 of the 1994 NIH review cycles. MAIN OUTCOME MEASURES: Grant application priority scores and funding rates. RESULTS: On the basis of the following 3 criteria, POR applications fare less well than LOR applications: (1) POR status and ranking in the total application pool; (2) percentage of POR vs LOR applications in the top 20th percentile; and (3) funding rates of POR applications. Furthermore, the fate of a POR application depended on which study section reviewed the application. Those applications that were reviewed in study sections that primarily reviewed POR applications fared equivalently to LOR applications; in contrast, POR applications reviewed in study sections that primarily reviewed LOR applications encountered a less favorable fate. CONCLUSIONS: These objective data provide strong support to the clinical research community's concern that investigator-initiated POR applications are not reviewed equitably at the NIH. By restructuring the review process, fairness is likely to be restored. Without restructuring, the POR component of the medical research community may be critically damaged.