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A polymer electrolyte membrane (PEM) fuel cell stack requires gaskets in each cell to keep the reactant gases within their respective regions. Both sealing and electrochemical performance of the fuel cell depend on the long-term stability of the gasket materials. In this paper, the change in properties and structure of a silicone rubber gasket brought about by use in a fuel cell was studied and compared to the changes in the same silicone rubber gasket material brought about by accelerated aging. The accelerated aging conditions were chosen to relate to the PEM fuel cell environment, but with more extreme conditions of elevated temperature (140°C) and greater acidity. The dilute sulfuric acid accelerated aging solutions used had pH values of 1, 2, and 4. In an additional test, Nafion® membrane suspended in water was used for accelerated aging, to more closely correspond to a PEM fuel cell environment. The analysis showed that acid hydrolysis was the most likely mechanism of degradation and that similar degradation occurred under both real fuel cell and accelerated aging conditions. It was concluded that the accelerated aging test is a good one for rapidly screening materials for resistance to the acidic environment of the fuel cell. ©2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

Rationale, aims and objectives Inpatient rehabilitation of patients following stroke can be resource intensive, with optimal models of service delivery unclear. This study investigates the dose-response curves between physiotherapy service delivery variables and balance and function clinical outcomes. Method This was a multi-centre (15 sites), prospective, cohort study involving patients (n = 288) admitted for rehabilitation following stroke conducted across two states in Australia. Physiotherapy department resource provision variables were collected and examined for association with change in patient function and balance outcomes (Functional Independence Measure, step test, functional reach test) measured at admission and discharge from inpatient care. Results A greater amount of log-transformed physiotherapy department resource provision was associated with greater improvement in the functional independence measure [Regression coefficient (95% CI): 4.05 (1.15, 6.95)] and functional reach test [46.43 (17.03, 75.84)], while physiotherapist time provided to patients was associated with greater improvement for the step test [0.15 (0.03, 0.28)], and functional reach [0.35 (0.19, 0.52)]. Conclusion Receiving a higher rate of physiotherapist input is an important factor in attaining a greater amount of recovery in function and balance outcomes; however, the improvement by patients who received the greatest amount of input was highly variable.

Background and purpose The impact of staffing model providing weekend physiotherapy rehabilitation has not been evaluated. This study aims to determine the impact of staffing a weekend rehabilitation service with physiotherapists currently working in rehabilitation compared to acute hospital physiotherapists, on length of stay (LOS), functional independence and gait and balance, and to determine the impact on neurological, orthopaedic, and reconditioning diagnostic groups. Methods A prospective cohort study with historical control was completed in a private, metropolitan Australian rehabilitation unit. All participants admitted to the rehabilitation unit over two, 20-week periods in 2011 and 2012 were included. Weekend physiotherapy was provided by physiotherapists working in rehabilitation in 2012 (intervention) and physiotherapists working in the acute wards in 2011 (control). Outcomes included LOS, Functional Independence Measure (FIM), and gait and balance measures. Results Overall, there were 504 participants; 234 in 2012 and 270 in 2011. No difference was found in LOS between staffing models (mean difference-1.5 days, 95%CI -4.4 to 1.3). Greater FIM change (mean difference 3.5, 95%CI 0.3 to 6.7) and efficiency (FIM change/LOS: mean difference 0.3, 95%CI 0.1 to 0.5) were found with rehabilitation compared to acute staffing. There was no between-group difference in gait or balance performance. When diagnostic groups were compared, no difference in LOS was found between staffing models. Participants with an orthopaedic diagnosis had a significantly greater FIM change (mean difference 3.8, 95%CI 0.4 to 7.1), whereas FIM efficiency was improved in neurological (mean difference 0.4, 95%CI 0.1 to 0.7) and orthopaedic populations (mean difference 0.3, 95%CI 0.03 to 0.5) with rehabilitation staffing. Discussion Staffing a weekend rehabilitation service with physiotherapists currently working in rehabilitation influences functional independence. Different diagnostic groups appear to respond differently.

There is increasing interest in the investigation of so-called mechanical proteins. These are common in specialized tissues involved in contraction, cell adhesion, and detection of mechanical stimuli, such as skeletal and cardiac striated muscle, connective tissue, and various kinds of epithelia. The development of methods for manipulating single molecules, particularly atomic force microscopy (AFM), allowed the study of the mechanical properties of such proteins.1, 2 From the response of a protein molecule to an applied external force, it is now possible to determine characteristics such as stiffness and resilience, and, by means of protein engineering methods, it is becoming increasingly clear how these properties depend on the polypeptide architecture, and therefore, ultimately, on the protein sequence.3, 4 The understanding of protein energetics and folding kinetics is advancing due to an effective combination of experimental and computer-aided theoretical studies, but the rational engineering of protein thermodynamic stability and/or folding mechanisms is still a hard goal to achieve. Moreover, designing novel proteins or even specific properties remains indisputably difficult, despite a few remarkable successes,5, 6 essentially because a comprehensive and predictive theory of how a given sequence produces a unique structure is still lacking. In the case of mechanical proteins, the understanding of the relationship between sequence, structure, and mechanical properties is incomplete. To our knowledge there are only two examples of proteins which have been specifically and successfully engineered to improve their resistance to forced unfolding.7, 8 A recent effort used a recombination method, essentially swapping β strands, in an attempt to re-engineer the mechanical properties of two immunoglobulin (Ig) domains from human titin: I27, the paradigm for all protein forced unfolding studies, and a stronger homologue, I32.9 Although the engineered proteins had different mechanical strengths to the parent proteins, this methodology had two shortcomings: first, the resultant mechanical stability of the new proteins could not be predicted, and second, none of the engineered changes produced an I27 domain which was more resistant to forced unfolding than the parent protein. Herein we describe a different strategy to achieve this specific aim, namely, to produce a stronger form of I27.

Accessible summary • Eight parents of adults with learning disabilities were interviewed about their experience of managing their son or daughter’s pain. • Parents developed trial and error methods of identifying pain and managing this. • Parents reported having mixed experiences of the services their sons/daughters had received. • Parental carers play a crucial role in the pain management of adults with learning disabilities. • This research matters to people with learning disabilities because it informs professionals of the importance of listening to parental carers’ views and experiences in the successful management of ill health and pain in situations where the sufferer has limited verbal communication. Good practice statement The results of this study have already been presented to health professionals who work with people with learning disabilities, within the first author’s organization, as well as at a conference about pain in people with learning disabilities. Further work is intended to publicize the findings to people with learning disabilities and their carers. Summary There are few measures of pain for people with limited ability to communicate. Eight parents of adults with a known learning disability and associated physical health complaint were interviewed to explore their experience of identifying and managing the pain felt by their children. The parents did not often perceive their son or daughter to be in pain or discomfort, which was an unexpected finding given the sampling strategy. They described, however, specific ways of recognizing pain and would use a trial and error process to determine the cause. Parents had strategies for dealing with pain and reported mixed experiences of service interactions. The emerging themes can be related back to the pain literature and psychological theory. They emphasize the importance of involving parents in pain assessment and represent the first stage of research into a previously unexplored area.

Accessible summary • We are people with and without learning disabilities doing research together. • In this paper we talk about the good bits and the bad bits of doing research together. Summary In our paper we talk about what it is like to be a group of people with and without learning disabilities researching together. We describe the process of starting and maintaining the research group and reflect on the obstacles that we have come across, and the rewards such research has brought us. Lastly we put forward some ideas about the role of professionals in such a group that we hope people might find useful.

Additive manufacturing, sometimes referred to as 3D printing is a new, rapidly developing technology which has the potential to revolutionize fabrication of certain high value, complex products. Until now conventional elastomers have not been widely used in the additive manufacturing process. The goal of our work was to determine the feasibility of additive manufacturing using ink jet printing of elastomeric latex materials. Particle size, viscosity, and surface tension were measured for five different latex materials—poly(2-chloro-1,3-butadiene), carboxylated styrene-butadiene rubber, carboxylated butadiene-acrylonitrile copolymer, natural rubber, and prevulcanized natural rubber. The XSBR latex was predicted as the one most likely to be printable. Printing trials carried out with the XSBR as the ink proved it to be printable, although technical problems of agglomeration and print head clogging need to be addressed and both the material and process need to be optimized for consistent printing to be achieved. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 42931.

We exploit the availability of recent experimental data on a variety of proteins to develop a Web-based prediction algorithm (BPPred) to calculate several biophysical parameters commonly used to describe the folding process. These parameters include the equilibrium m-values, the length of proteins, and the changes upon unfolding in the solvent-accessible surface area, in the heat capacity, and in the radius of gyration. We also show that the knowledge of any one of these quantities allows an estimate of the others to be obtained, and describe the confidence limits with which these estimations can be made. Furthermore, we discuss how the kinetic m-values, or the Beta Tanford values, may provide an estimate of the solvent-accessible surface area and the radius of gyration of the transition state for protein folding. Taken together, these results suggest that BPPred should represent a valuable tool for interpreting experimental measurements, as well as the results of molecular dynamics simulations.

The Mouse Lymphoma Assay (MLA) Workgroup of the International Workshop on Genotoxicity Testing (IWGT), comprised of experts from Japan, Europe, and the United States, met on August 29, 2003, in Aberdeen, Scotland, United Kingdom. This meeting of the MLA Workgroup was devoted to reaching a consensus on the appropriate approach to data evaluation and on acceptance criteria for both the positive and negative/vehicle controls. The Workgroup reached consensus on the acceptance criteria for both the agar and microwell versions of the MLA. Recommendations include acceptable ranges for mutant frequency, cloning efficiency, and suspension growth of the negative/vehicle controls and on criteria to define an acceptable positive control response. The recommendation for the determination of a positive/negative test chemical response includes both the requirement that the response exceeds a defined value [the global evaluation factor (GEF)] and that there also be a positive dose-response (evaluated by an appropriate statistical method).

BACKGROUND: Robotic surgery is the latest innovation in the field of minimally invasive surgery. In the case of robotic surgery, instead of directly moving the instruments the surgeon uses a robotic system to control the instruments for surgical procedures. Robotic surgical systems have been used in various gynaecological surgeries for benign disease, such as hysterectomy (removal of the uterus), myomectomy (removal of uterine leiomyomas) and tubal reanastomosis (the reuniting of a divided tube). The mounting evidence demonstrates the feasibility and safety of robotic surgery in benign gynaecological disease. Robotic surgery is advertised as having promising advantages including more precise vision and procedures, improved ergonomics and shorter length of hospital stay. However, the main disadvantages of the robotic surgical system should not be overlooked, including the high cost of disposable instruments and retraining for both surgeons and nurses. OBJECTIVES: To assess the effectiveness and safety of robot‐assisted surgery in the treatment of benign gynaecological disease. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2011), MEDLINE and EMBASE up to November 2011 and citation lists of relevant publications. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing robotic surgery for benign gynaecological disease to laparoscopic or open surgical procedures. RCTs comparing different types of robotic assistants were also included. We contacted study authors for unpublished information, but failed in obtaining a response. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion. The domains assessed for risk of bias were allocation concealment, blinding, incomplete outcome data and selective outcome reporting. Odds ratios (OR) were used for reporting dichotomous data with 95% confidence intervals (CI), whilst mean differences (MD) were determined for continuous data. Statistical heterogeneity was assessed using the I(2) statistic. We contacted the primary authors for missing data but failed in obtaining a response. MAIN RESULTS: Two trials involving 158 participants were included. Since one included trial was published in conference proceedings, limited usable data were available for further analysis. The only analysis in this trial showed comparable rates of conversions to open surgery between the robotic group and the laparoscopic group (OR 1.41, 95% CI 0.22 to 9.01; P = 0.72). One RCT showed longer operation time (MD 66.00, 95% CI 40.93 to 91.07; P < 0.00001), higher cost (MD 1936.00, 95% CI 445.69 to 3426.31; P = 0.01) in the robotic group compared with the laparoscopic group. Also, both studies reported that robotic and laparoscopic surgery seemed comparable regarding intraoperative outcome, complications, length of hospital stay and quality of life. AUTHORS' CONCLUSIONS: Currently, the limited evidence showed that robotic surgery did not benefit women with benign gynaecological disease in effectiveness or in safety. Further well‐designed RCTs with complete reported data are required to confirm or refute this conclusion.

Blends of a highly epoxidized natural rubber (ENR50) with unmodified natural rubber (NR) and ethylene propylene elastomers (EPDM) were produced to evaluate the mixing and curing characteristics. Dodecyl succinic anhydride was used to cross-link the ENR50 component and the reactivity was assessed by monitoring the evolution of the torque in an oscillatory co-axial cylinder rheometer, as well as by DSC thermal analysis. A physical model was used to obtain a single parameter for the reactivity of the system, which corresponds to the rate constant for first order curing reactions. Although the blends were thermodynamically immiscible, displaying no significant change in Tg, the components were well dispersed at microscopic level. Better mechanical properties were obtained for blends with EPDM.

The effects of engineered disulfide bonds on protein stability are poorly understood because they can influence the structure, dynamics, and energetics of both the native and denatured states. To explore the effects of two engineered disulfide bonds on the stability of barnase, we have conducted a combined molecular dynamics and NMR study of the denatured state of the two mutants. As expected, the disulfide bonds constrain the denatured state. However, specific extended beta-sheet structure can also be detected in one of the mutant proteins. This mutant is also more stable than would be predicted. Our study suggests a possible cause of the very high stability conferred by this disulfide bond: the wild-type denatured ensemble is stabilized by a nonnative hydrophobic cluster, which is constrained from occurring in the mutant due to the formation of secondary structure.

A bell-mouthed die geometry was designed to cause convergent flow at a constant, uniform, elongational strain rate. An equation was derived, which showed that steady-state elongational viscosity could be calculated from a plot of pressure drop due to elongation against a simple function of die length. To obtain values of pressure drop due to elongation, it was necessary to correct the total pressure drop measured across the bell-mouthed dies for the contribution from shear occurring near the die wall. For this purpose, a simplified shape for the bell-mouthed dies was assumed, comprising several parallel sided segments. Applying a formula to pressure drop data measured across straight dies corresponding to these segments gave an estimate of the pressure drop due to shear across the bell-mouthed dies. Pressure drops due to elongation were determined by subtracting the pressure drop due to shear from the total pressure drop measured across the bell-mouthed dies. Measurements were also carried out with lubrication to validate the shear correction method. The results indicate that for the compound used in this study, a combination of bell-mouthed and straightsided dies can be used in a conventional capillary rheometer to determine steady-state elongational viscosity. An elongational viscosity of 190 kPa s at 90°C and at a strain rate of 10 s−1 was determined for a simple styrene-butadiene rubber compound. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 66: 1139–1150, 1997

BACKGROUND: Endometriosis is a chronic inflammatory condition that occurs during the reproductive years. It is characterised by endometrium‐like tissue developing outside the uterine cavity. This endometriotic tissue development is dependent on oestrogen produced primarily by the ovaries and partially by the endometriotic tissue itself, therefore traditional management has focused on ovarian suppression. In this review we considered the role of modulation of the immune system as an alternative approach. This is an update of a Cochrane Review previously published in 2012. OBJECTIVES: To determine the effectiveness and safety of pentoxifylline in the management of endometriosis. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED on 16 December 2020, together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing pentoxifylline with placebo or no treatment, other medical treatment, or surgery in women with endometriosis. The primary outcomes were live birth rate and overall pain (as measured by a visual analogue scale (VAS) of pain, other validated scales, or dichotomous outcomes) per woman randomised. Secondary outcomes included clinical pregnancy rate, miscarriage rate, rate of recurrence, and adverse events resulting from the pentoxifylline intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies against the inclusion criteria, extracted data, and assessed risk of bias, consulting a third review author where required. We contacted study authors as needed. We analysed dichotomous outcomes using Mantel‐Haenszel risk ratios (RRs), 95% confidence intervals (CIs), and a fixed‐effect model. For small numbers of events, we used a Peto odds ratio (OR) with 95% CI instead. We analysed continuous outcomes using the mean difference (MD) between groups presented with 95% CIs. We used the I(2) statistic to evaluate heterogeneity amongst studies. We employed the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We included five parallel‐design RCTs involving a total of 415 women. We included one additional RCT in this update. Three studies did not specify details relating to allocation concealment, and two studies were not blinded. There were also considerable loss to follow‐up, with four studies not conducting intention‐to‐treat analysis. We judged the quality of the evidence as very low. Pentoxifylline versus placebo No trials reported on our primary outcomes of live birth rate and overall pain. We are uncertain as to whether pentoxifylline treatment affects clinical pregnancy rate when compared to placebo (RR 1.38, 95% CI 0.91 to 2.10; 3 RCTs, n = 285; I(2) = 0%; very low‐quality evidence). The evidence suggests that if the clinical pregnancy rate with placebo is estimated to be 20%, then the rate with pentoxifylline is estimated as between 18% and 43%. We are also uncertain as to whether pentoxifylline affects the recurrence rate of endometriosis (RR 0.84, 95% CI 0.30 to 2.36; 1 RCT, n = 121; very low‐quality evidence) or miscarriage rate (Peto OR 1.99, 95% CI 0.20 to 19.37; 2 RCTs, n = 164; I(2) = 0%; very low‐quality evidence). No trials reported on the effect of pentoxifylline on improvement of endometriosis‐related symptoms other than pain or adverse events. Pentoxifylline versus no treatment No trials reported on live birth rate. We are uncertain as to whether pentoxifylline treatment affects overall pain when compared to no treatment at one month (MD −0.36, 95% CI −2.12 to 1.40; 1 RCT, n = 34; very low‐quality evidence), two months (MD −1.25, 95% CI −2.67 to 0.17; 1 RCT, n = 34; very low‐quality evidence), or three months (MD −1.60, 95% CI −3.32 to 0.12; 1 RCT, n = 34; very low‐quality evidence). No trials reported on adverse events caused by pentoxifylline or any of our other secondary outcomes. Pentoxifylline versus other medical therapies One study (n = 83) compared pentoxifylline to the combined oral contraceptive pill after laparoscopic surgery to treat endometriosis, but could not be included in the meta‐analysis as it was unclear if the data were presented as +/‐ standard deviation and what the duration of treatment was. No trials reported on adverse events caused by pentoxifylline or any of our other secondary outcomes. Pentoxifylline versus conservative surgical treatment No study reported on this comparison. AUTHORS' CONCLUSIONS: No studies reported on our primary outcome of live birth rate. Due to the very limited evidence, we are uncertain of the effects of pentoxifylline on clinical pregnancy rate, miscarriage rate, or overall pain. There is currently insufficient evidence to support the use of pentoxifylline in the management of women with endometriosis with respect to subfertility and pain relief outcomes.

A model was established whereby CS7BL/6 (B6) blood injected i.v. into C3H mice 7 days prior to i.v. injection of syngeneic UV-2237 tumour cells significantly increased the number of pulmonary metastases counted 21 days later as compared with levels observed in mice treated with saline, C3H or NZW blood or SRBC. This regimen of B6 allogeneic blood transfusion of C3H mice also significantly depressed splenic and pulmonary NK activity as assayed by lysis of 51Cr YAC-1 in vitro and by clearance of 111In YAC-1 in vivo respectively. Anti-asialo GMI treatment, which depletes NK activity in vivo, and Poly I:C treatment, which enhances NK activity in vivo, were associated with significantly increased and decreased pulmonary metastasis of UV-2237, respectively, in C3H mice. Depletion of CD4+ and CD8+ T cells had no effect. Cyclophosphamide pretreatment which, among other effects, depletes NK cells, significantly increased pulmonary metastasis of UV-2237 in C3H mice. This was corrected by adoptive transfer of normal C3H spleen cells but not spleen cells from anti-asialo GM 1 -treated C3H mice or B6-blood-transfused C3H mice. Furthermore, a 1:1 mixture of normal C3H spleen cells with spleen cells from B6-blood-transfused C3H mice also failed to reconstitute the cyclophosphamide-pre-treated C3H mice. We conclude that allogeneic blood transfusion augments pulmonary metastasis of the UV-2237 sarcoma in C3H mice and that the mechanism involves suppression of NK activity.

Background Uterine fibroids (UFs) are benign growths within the uterine muscle and are present in 30% of women during their reproductive years. With the exception of hysterectomy, there are no effective medical and surgical treatments for women with uterine fibroids . Acupuncture is an ancient Chinese method which has been used for both the prevention and treatment of diseases for over three thousand years. There are many types of acupuncture used to manage UFs, with body acupuncture being the most commonly used. The literature reporting the benefits or harms of acupuncture for the management of UFs has not yet been systematically reviewed. Objectives To assess the benefits and harms of acupuncture in women with uterine fibroids Search methods The following electronic databases were searched 21st May 2009: the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; AMED; the Menstrual Disorders and Subfertility Group's Specialised Register of Trials; Chinese Biomedical Literature Database (CBM); Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS); Chinese Medical Current Contents (CMCC) and China National Knowledge Infrastructure(CNKI). Citation lists, experts in the field and grey literature were also referred to. No restrictions such as language were applied. Selection criteria All randomised controlled trials (RCTs) comparing acupuncture management with placebo acupuncture, no management, Chinese medication, Western medication or other managements of uterine fibroids were considered for inclusion. Acupuncture management included either traditional acupuncture or contemporary acupuncture, regardless of the source of stimulation (for example, body, electro, scalp, elongated, fire, hand, fine needle, moxibustion). Acupuncture management without needling was excluded. Data collection and analysis Two review authors assessed trial risk of bias according to our a priori criteria. No trials were included in this version of the review, therefore no data was collected. Main results No randomized double-blind controlled trials met the inclusion criteria . Authors' conclusions The effectiveness of acupuncture for the management of uterine fibroids remains uncertain. More evidence is required to establish the efficacy and safety of acupuncture for uterine fibroids.There is a continued need for well designed RCTs with long term follow up.

Evidence exists to suggest a detrimental effect of blood transfusion on survival after resection for malignant disease. Immune suppression due to transfusion has been implicated, though this remains unproven. We have conducted a retrospective study of 69 patients (38 transfused, 31 not transfused) with squamous carcinoma of the larynx to assess the effect of blood transfusion on survival after laryngectomy. Patients were compared for age, sex, smoking habit, tumour site and stage, grade of operating surgeon, preoperative haemoglobin, tumour nucleolar organizer region status, and operation time. The minimum follow-up was 5 years. In the transfused group 21/38 died as a result of their malignant disease and only 4/31 in the untransfused group. This difference was highly significant (P less than 0.001, chi-squared test) and using a multivariate analysis the only variable associated with a decreased survival time was whether a blood transfusion had been received. We conclude that peri-operative blood transfusion is associated with decreased survival after laryngectomy. However, whether this association is causal remains unproven.

2 Various4-diamino-6-(benzyl and pyridyhnethyl)-5,6,7,8-tetrahydropyrido(4,3-d]pyrimidines (IX) have been synthesized for antimalarial and antibacterial evaluation. Alkylation of 4-amino-3-cyano-1,2,5,6-tetrahydropyridine (VI) with the requisite α-chlorotoluene or picolyl chloride in 2-butanone afforded the corresponding 4-amino-3-eyano-1-(benzyl and pyridvlmethyl)-1,2,5,6-tetraliydropyridines (VIII) (16–73%), which were cyclized to the pyrido[4,3-d]pyrimidines (IX) utilizing guanidine carbonate in dimethylformamide. Alternatively, VI was condensed with guanidine carbonate in ethyl cellosolve to give 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine (VII) (52%), which upon treatment with the appropriate α-ehlorotoluene in dimethyllormamide gave other 2,4-diamino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines (IX) (26–27%). Kight compounds were active orally against Plasmodium berghei in mice at doses ranging from 3.9 to 125 mg./kg./day for 6 days (0.6 to 19 times as potent as quinine hydrochloride), while three compounds displayed activity when administered in a single subcutaneous dose of 640 mg./kg. Four substances exhibited in vitro activity against Streptococcus faecalis (MGH-2), normal (UC-76) and drug-resistant (S18713) Staphylococcus aureus, and Streptococcus pyogenes ((1203), with MIC's ranging from > 0.25 to 10 μg./ml. Data on the inhibitory effects of various pyrido[4,3-d]pyrimidines against Streptococcus faecalis R (S. faecium var. durans, ATCC 8043), S. faecalis A (aminopterin, metholrexate-resistant), and Lactobacillus plantarum (ATCC 8014) is summarized.

2 Various4-diamino-6-(phenoxy, naphthyloxy, and phenalkoxy)quinazolines (VIII, XIV) were synthesized for antimalarial and antibacterial evaluation. Treatment of the anion of the requisite phenol or naphthol with 5-chloro-2-nitrobenzonitrile (V) gave the corresponding 2-nitro-5-(phenoxy and naphthyloxy)benzonitriles (VI) (33–78%). Alternatively, alkylation of 5-hydroxy-2-nitrobenzaldehyde (IX) with the appropriate phenalkyl halide afforded the 2-nitro-5-(phenalkoxy)benzaldehydes (X) (27–62%), which were converted to the 2-nitro-5-(phenalkoxy)benzonitriles (XII) via the intermediate oximes XI (62–87% overall). Reduction of the 2-nitrobenzonitriles (VI, XII) with stannous chloride-hydrochloric acid provided the corresponding 2-amino-5-(phenoxy, naphthyloxy, and phenalkoxy)benzonitriles (VII, XIII) (30–83%), which upon cyclization with chloroformamidine hydrochloride gave the 2,4-diaminoquinazolines VIII and XIV (12–85%). Against Plasmodium berghei in mice, eleven compounds were active orally at doses ranging from 6.3 to 174 mg./kg./day for 6 days, while seven substances displayed activity subcutaneously following single doses of 40–640 mg./kg. Fifteen compounds exhibited in vitro antibacterial activity against Streptococcus faecalis (MGH-2), normal (UC-76) and drug-resistant (S18713) Staphylococcus aureus, Escherichia coli (Vogel), and Shigella sonnei (C-10) with MIC's ranging from < 0.25 to 20 μg./ml. (gradient plate). Data on the inhibitory effects of representative compounds against Streptococcus faecalis R (S. faecium var. durans), S. faecalis A (amino-pterin, methotrexate-resistant), and Lactobacillus plantarum are presented, and overall structure-activity relationships are discussed.