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Purine metabolism plays a pivotal role in bacterial life cycle, however, regulation of the de novo and purine salvage pathways have not been extensively detailed in mycobacteria. By gene knockout, biochemical and structural analyses, we identified Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb) guaB1 gene product as a novel type of guanosine 5’-monophosphate reductase (GMPR), which recycles guanosine monophosphate to inosine monophosphate within the purine salvage pathway and contains cystathione β-synthase (CBS) domains with atypical orientation in the octamer. CBS domains share a much larger interacting area with a conserved catalytic domain in comparison with the only known CBS containing protozoan GMPR and closely related inosine monophosphate dehydrogenase structures. Our results revealed essential effect of pH on allosteric regulation of Msm GMPR activity and oligomerization with adenine and guanosine nucleotides binding to CBS domains.Bioinformatic analysis indicated the presence of GMPRs containing CBS domains across the entire Actinobacteria phylum.

We present models suitable for simulating tuned plasma discharges under an argon atmosphere. The proposed model and its numerical analysis facilitated the designing of a plasma discharge nozzle; relevant experiments were then compared and evaluated. The plasma chamber is suitable for surface treatment at a nanometric distance from the material-air interface; such an operation can create interesting layers of inorganic/organic materials designed as resonant structures. The paper demonstrates the ability of a plasma discharge to function as a parametric tool that modifies the electromagnetic and mechanical properties on the surface of the applied material.

A search for narrow, low-mass, scalar, and pseudoscalar resonances decaying to bottom quark-antiquark pairs is presented. The search is based on events recorded in root s = 13 TeV proton-proton collisions with the CMS detector at the LHC, collected in 2016, and corresponding to an integrated luminosity of 35.9 fb(-1). The search selects events in which the resonance would be produced with high transverse momentum because of the presence of initial- or final-state radiation. In such events, the decay products of the resonance would be reconstructed as a single large-radius jet with high mass and two-prong substructure. A potential signal would be identified as a narrow excess in the jet invariant mass spectrum. No evidence for such a resonance is observed within the mass range from 50 to 350 GeV, and upper limits at 95% confidence level are set on the product of the cross section and branching fraction to a bottom quark-antiquark pair. These constitute the first constraints from the LHC on exotic bottom quark-antiquark resonances with masses below 325 GeV.

The article discusses modeling procedures to capture the physical and chemical processes present in operational measurement with a high-precision inductive flowmeter. In this context, a theoretical model and a numerical solution are proposed. Exploiting the combined finite element method (FEM) and the finite volume method (FVM), we prepared numerical models of multiple variants of the flowmeter and computed the output voltage on the device's electrodes. The model joins together the magnetic, electric, and current fields; a flow field; and a physical-chemical nonlinear ion model. The results were obtained by means of the FEM/FVM in ANSYS software and verified via experimental testing.

Drugs deposited in human teeth are well preserved; the spectrum of toxicological investigations may therefore be supplemented by an analysis method for drugs in teeth. A liquid chromatography–electrospray ionization tandem mass spectrometry assay for the detection and quantification of basic drugs of abuse in bovine dentin samples was developed and validated. The drugs and metabolites amphetamine, methamphetamine, methylenedioxymethylamphetamine, methylenedioxyethylamphetamine, codeine, morphine, cocaine and benzoylecgonine were extracted from 50 mg ground dentin powder by ultrasonication for 60 min in methanol 3 times. The extracts were analyzed on a triple-quadrupole mass-spectrometer in multiple reaction monitoring mode. The method was validated and proved to be accurate, precise, selective, specific and stable with good linearity within the calibration range and a lower limit of quantification of 10 to 20 pg/mg. To artificially load bovine dentin samples with drugs, the natural process of de- and remineralization in the oral cavity was mimicked by a pH-cycling experiment. The artificially drug-loaded dentin samples showed drug concentrations of 20 to 80 pg/mg. The method can be applied in further in vitro experiments as well as in post-mortem cases, especially where limited sample tissue is available. Copyright © 2014 John Wiley & Sons, Ltd.

In this article, I describe how my personal experience of death prompted the writing of a novel and how the practice of writing about death led me to develop a critical inquiry into Continental philosophy and other theories of death. I discuss philosophical approaches to living authentically in the face of death and the human tendency to search for meaning. I undertake a close reading of Helen Garner’s The Spare Room (2008) in light of these issues and the changing attitudes to death since modernism, particularly the need for open communication about death and the importance for the dying in feeling that their life has significance for other people.

The aim of this study is using protoplast electrofusion for somatic hybridization, especially for increasing of genetic variability in selected important vegetable species of Brassica, Cucumis and Solanum genus and possibility of including this method into breeding approaches to obtain new breeding materials. Mesophyll protoplasts were isolated from in vitro cultured plants of Brassica olearacea (B. oleracea var. capitata, B. oleracea var. botrytis), Cucumis spp. (C. metuliferus, C. melo) and Solanum tuberosum dihaploid plants and wild Solanum species (S. pinnatisectum, S. bulbocastanum). Hypocotyl protoplasts were isolated from etiolated seedlings of Brassica oleracea (cabbage, cauliflower) and callus protoplasts of Cucumis melo. Enzymatic mixture of 1% or 2% Cellulase Onozuka R-10 and 0.25% or 1% Macerozyme R-10 in rinsing solution Pgly/W5 (2,1) was used for isolation of mesophyll and hypocotyl protoplasts or callus protoplasts. Leaves, hypocotyls and/or calli were segmented and put into a thermostat at 25°C for 16-18 hours. Protoplasts were isolated using a conventional method (filtration, centrifugation and purification with 20% sucrose gradient). Purified protoplasts were rinsed with pre-fusion solution (0.4 M manitol and 1 mM CaCl 2 ) and fusion solution (0.4 M manitol), after centrifugation their required density was obtained by dilution with fusion solution. Viability of isolated protoplasts used for electrofusions was more than 80% (determined using FDA). Fusing partner components were mixed in the ratio of 1:1. There were fused protoplasts of Brassica genus: mesophyll and hypocotyl, Cucumis genus: mesophyll and callus, Solanum genus: mesophyll and mesophyll. Protoplast fusion was performed using apparatus ECM 2001 and in electroporation chamber for 20-30 μl with the 0.5 mm electrode distance. Following parameters were used fbr fusions: for protoplast alignment - 5V AC and 1 MHz frequency with individual duration of action, for fusion - 1 pulse 10V DC of length 80 μs (3). Following electrofusions protoplasts were viable and undamaged. Homofusion and heterofusion products and also unfused protoplasts could be observed. Subsequent culturing was done in medium LCM1 (2) or SW11 (1) in a thermostat at 25°C for 2 weeks in the dark. Regeneration of cell walls was recorded and first division was found in 6-8 days of culture, in Solanum genus microcolonies were found in 15 days. The experiments have not been finished yet.

This paper presents the impact of salt & pepper noise with four motion estimation algorithms. The performance of full search (FS) algorithm, three-step search (TSS) algorithm, new three-step search (NTSS) algorithm, and four-step search (4S5) algorithm under influence of salt & pepper noise has been described for three of famous video sequences. The experimental results show that, the maximum noise density for good estimation depends on the kind of video sequence, block size and the estimated algorithm used. It is observed that, the worst performance is usually in a case of using FS algorithm and the best performance is usually in a case of using NTSS algorithm.

Drugs deposited in human teeth are well preserved; the spectrum of toxicological investigations may therefore be supplemented by an analysis method for drugs in teeth. A liquid chromatography-electrospray ionization tandem mass spectrometry assay for the detection and quantification of basic drugs of abuse in bovine dentin samples was developed and validated. The drugs and metabolites amphetamine, methamphetamine, methylenedioxymethylamphetamine, methylenedioxyethylamphetamine, codeine, morphine, cocaine and benzoylecgonine were extracted from 50 mg ground dentin powder by ultrasonication for 60 min in methanol 3 times. The extracts were analyzed on a triple-quadrupole mass-spectrometer in multiple reaction monitoring mode. The method was validated and proved to be accurate, precise, selective, specific and stable with good linearity within the calibration range and a lower limit of quantification of 10 to 20 pg/mg. To artificially load bovine dentin samples with drugs, the natural process of de- and remineralization in the oral cavity was mimicked by a pH-cycling experiment. The artificially drug-loaded dentin samples showed drug concentrations of 20 to 80 pg/mg. The method can be applied in further in vitro experiments as well as in post-mortem cases, especially where limited sample tissue is available.

Summary In 2009, a federally funded clinical and research consortium (PID–NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

We report on the further development and tests of an low–cost optical all‐sky monitor recently tested at the Karlovy Vary Observatory. The recent instrumentation is simple based on a Sigma 8 mm f3.5 EX DG fish–eye lens and CANON 1000D digital CMOS camera. It is a low‐cost device suitable for easy replication and still able to detect brighter optical transients simultaneously to GRB triggers. Such OTs have been observed for some of the GRBs such as GRB990123, GRB060117, or recently GRB0803 indicating that some fraction of GRBs can generate optical transient emission accessible by simple small aperture instrumentation as described here. These efforts are accompanied by development of dedicated programmes to access and to evaluate all‐sky images, these efforts will be also briefly described.

The EUCARPIA multi-site rust evaluation was repeated in 2010 for the fourth time. The trials were sown at 24 sites in 11 countries in Europe. The 20 Italian/Hybrid (Lolium multiflorum and L. boucheanum, respectively) and 34 perennial ryegrass (L. perenne) cultivars were sown in separate trials. The cultivars were grown as rows in a completely randomized block design with four replicates. Rust incidence was scored in the year of seeding by each of the participants. The method used to test cultivars for rust resistance was based on an estimation of the percentage of leaf area affected. Crown rust (Puccinia coronata f. sp. lolii) was again the most frequently observed rust on both ryegrass species. Stem rust (P. graminis f.sp. graminicola) was reported at only one site for Italian and at four sites for perennial ryegrass. Variation in resistance to crown rust among cultivars was significant at 17 sites for Italian and at 16 sites for perennial ryegrass. The cultivars ‘Tarandus’, ‘Gosia’, ‘Caballo’ and ‘Domino’ showed the highest level of resistance of all the Italian ryegrass cultivars tested. ‘Gwendal’ and ‘Bocage’ were the most crown rust resistant perennial ryegrass cultivars. The ranking of the mean crown rust susceptibility of the cultivars was highly correlated with the corresponding ranking of cultivars in the 2001, 2004 and 2007 trials, respectively. This was true for both perennial and Italian ryegrass. Coefficients of rank order correlations of average cultivar disease scores between the years were greater than rs = 0.97 (p < 0.05) for Italian and rs = 0.86 (p < 0.05) for perennial ryegrass, respectively. Therefore, there is no evidence that crown rust resistance of an individual cultivar was overcome by the rust pathogen over the 9 years of experimentation.

A 75-year-old man with generalized subcutaneous fat necrosis was found to have an islet cell carcinoma of the pancreas. The histologic diagnosis of islet cell carcinoma was confirmed by electron microscopy, which showed characteristic intracytoplasmic granules. This is the second report of the association of islet cell carcinoma of the pancreas with generalized subcutaneous fat necrosis.

Examines some proposed configurations of pyroelectric sensor arrays scanned either by a CCD (charge-coupled device) structure or by the matrix approach. The pyroelectric array sensor is based on a single-crystal pyroelectric plate (LiTaO/sub 3/) covered by an array of electrodes created by photolithography. The proposed approach has been experimentally verified by a mathematical model and by a scanning structure element. >

Comparative embryology has been neglected in the past decades. In our opinion the decreased interest has been caused by the fact that the time factor has not sufficiently been respected. Therefore we used the Staging and Ageing Method (Stĕrba 1999) to determine the ontogenetic age of embryos and to state the time tables and time relations of various ontogenetic events. We examined 167 embryos and fetuses of four dolphin species (collection Dr. Senckenbergische Anatomie, Frankfurt am Main). The study of intrauterine development and growth while consistently respecting the time factor enabled us to determine the time course of organogenesis of all organ systems. The resulting comparison with other mammals detected the time lag in ossification, retardation of odontogeny, the time of the origin and development of the fluke, dorsal fin and flipper, etc. We believe the Staging and Ageing Method serves for a much more efficient evaluation of existing embryological collections which very often contain embryos of unknown age.

The adaptation of cetaceans to aquatic life habits is reflected, in their nasal region, in three marked changes from the original relations found in land mammals. These changes include (1) the loss of the sense of smell, (2) translocation of the nostrils from the tip of the rostrum to the vertex of the head, and (3) elongation of the anterior head to form a rostrum protruding far towards anterior. The morphogenetic processes taking place during embryogenesis of the nasal skull play a decisive part in the development of all these changes. The lateral parts of the embryonic nasal capsule, encompassing the nasal passages, change their position from horizontal to vertical. At the same time, the structures of the original nasal floor (the solum nasi) are shifted in front of the nasal passages towards the rostrum. The structures of the original nasal roof (the tectum nasi) and of the nasal side wall (the paries nasi) are translocated behind the nasal passages towards the neurocranium. The medial nasal septum (the septum nasi) mostly loses its connection to the nasal passages and is produced into a point protruding far towards anterior. The transformed embryonic nasal skull of the Cetacea can be divided into three sections: 1. The median structures. These include the cartilaginous structures, viz., the rostrum nasi, the septum interorbitale and the spina mesethmoidalis, which are accompanied by the dermal bones, the vomer and the praemaxillare. In adult cetaceans the rostrum nasi is mostly preserved as a robust cartilage of the skull, which may possibly serve as a sound transmitting structure of the sonar system, or it may be responsible for the sensing of water streams and vibrations. 2. The posterior side wall structures. These include the following cartilaginous structures that are mostly heavily reduced or mutually fused: the cupula nasi anterior, the tectum nasi, the lamina cribrosa, the paries nasi, the commissura orbitonasalis, the cupula nasi posterior, the processus paraseptalis posterior, the crista semicircularis, the frontoturbinale, the ethmoturbinale I and the maxilloturbinale. The cartilaginous structures are largely accompanied by the dermal bone, the maxillare. Of these embryonic elements, very little is preserved in adult cetaceans. The cartilages of the cupula nasi anterior form the variable skeleton around the nostrils. In Physeter the tectum nasi forms a very long cartilaginous bar that passes through the whole giant anterior head of the sperm whale as a structure accompanying the left nasal passage. 3. The anterior side wall structures. These include the cartilaginous structures, viz., the cartilago ductus nasopalatini, the cartilago paraseptalis, the processus lateralis ventralis and the lamina transversalis anterior, accompanied by the dermal bones, the praemaxillare and the vomer. These structures participate in the formation of the robust rostrum of the cetacean skull, and they are partly preserved even in adults in the form of the isolated ossa pararostralia (the Meckelian ossicles). The comparison of morphogeny of the nasal skull has also made it possible to draw certain conclusions on the phylogeny and systematics of Cetacea. Already the earliest embryonic stages permit us to discern weighty transformations of the original nasal skull of land mammals. These transformations are common to all embryos examined. This fact indicates a common origin of all Cetacea, which thus form a single monophyletic order. However, later embryonic stages show some different modifications of the nasal capsule according to which at least three major groups can be distinguished within the order Cetacea, probably ranking as superfamilies: Balaenopteroidea, Physeteroidea and Delphinoidea. Our observations, being in full accordance with other morphological, and embryological, as well as molecular biological results, suggest that the division of the order Cetacea into two suborders, Mysticeti and Odontoceti, is no longer tenable.

In adult cetaceans (Fig. 50, 51) only some of the embryonic cartilaginous structures of the nasal skull are preserved as cartilage. The cartilaginous tissue either ossifies to form independent skull bones, or it becomes integrated into the bony tissue of the dermal bones, or it is dissolved and resorbed. These processes are readily understood if one realizes that most of the cartilaginous anlagen play only a transitory part during embryonic development. Capable of being built up quickly and simply, the cartilaginous tissue introduces the morphogenetic processes and paves the way for the bone tissue which is slower to build up and more complicated. The particular cartilaginous nasal elements are subject to the following modifications.

The exact knowledge of the continuous course of morphogenesis, described in the preceding chapters, is of extraordinary importance for the true interpretation of the individual structures of the heavily transformed cetacean nasal skull. Examinations made at individual stages, however exact, for the most part do not permit the recognition of natural connections and often lead to pure speculation. Thus, it is no surprise that even the earliest known attempt at such interpretation was accompanied by a grave error. In the place of the lamina transversalis anterior and the cartilago paraseptalis, Mayer (1835) thought he had found a rudimentary maxilloturbinale. His interpretation was later adopted by Kukenthal (1893) and Boenninghaus (1903) without any appreciable change, and it has been used even in recent times (Cave 1987, 1988; Praderi and Cave 1994) in attempts at clarifying the origin of the questionable Meckelian ossicles (see Sect. 7.5). Similarly, several contradictory and untenable interpretations have been presented especially for the anterior, less so for the posterior side wall structures (Kukenthal 1893; Abel 1902; Gruhl 1911; De Burlet 1913a,b, 1914a,b, 1916; Honigmann 1915, 1917; Schreiber 1916; Eales 1950). At the same time, the basic tendency of the transformation processes had already been correctly established, as indicated, above all, by the papers of De Burlet (1916) and Honigmann (1917). An attempt at a new evaluation of the hitherto known findings and at a unification of the different interpretations was made by De Beer (1937) in his monograph of the development of the mammalian skull. Not until much later was it possible to study the transformation processes and translocations of the nasal structures in a continuous course, first in Phocoena (Klima and Van Bree 1985) and then also in Physeter (Klima 1987a).

The most extensive material available for this study was that of Stenella attenuata, comprising an almost continuous developmental series of a total of 14 embryos ranging between 21 and 225 mm in size. Four of the embryos, 39, 43, 57 and 85 mm in size, have been partly studied in an earlier paper (Klima 1987a), the rest are presented here for the first time. The results obtained here from Stenella serve as a comparative basis for observations obtained from all other species. For this reason, they are discussed here in considerable depth.

The way in which the nostrils have been translocated during the evolution of cetaceans can be traced in fossil skull material as well as in the course of the embryonic development of their skull.

The almost continuous developmental series of embryonic Stenella, Delphinus, Phocoena and Physeter served to follow the course of early morphogeny of the nasal skull as a continuous process (Fig. 27-30). Only in this way are the transformations and displacements of the individual structures of the nasal skeleton of cetaceans understandable, and their homologization with the corresponding structures in terrestrial mammals can be demonstrated.

The phylogenetic origin of Cetacea is derived from Mesonychidae, a group of Condylarthra from the Palaeocene, from which the first ancient cetaceans (Archaeoceti) arose as a side line of hoofed mammals about 50 million years ago (Van Valen 1968; Szalay 1969; Thenius 1969, 1987; Gaskin 1976, 1982; Barnes and Mitchell 1978; Fordyce 1980, 1988; Barnes et al. 1985). The close relationship of cetaceans to ungulates, especially to artiodactyls, had already been suspected by Flower (1883) and was later confirmed by serological (Boyden and Gemeroy 1950) and molecular biological (Milinkovitch 1992a,b) findings.

OBJECTIVE--To measure age and sex specific mortality in adults (15-59 years) in one urban and two rural areas of Tanzania. DESIGN--Reporting of all deaths occurring between 1 June 1992 and 31 May 1995. SETTING--Eight branches in Dar es Salaam (Tanzania's largest city), 59 villages in Morogoro rural district (a poor rural area), and 47 villages in Hai district (a more prosperous rural area). SUBJECTS--40,304 adults in Dar es Salaam, 69,964 in Hai, 50,465 in Morogoro rural. MAIN OUTCOME MEASURES--Mortality and probability of death between 15 and 59 years of age (45Q15). RESULTS--During the three year observation period a total of 4929 deaths were recorded in adults aged 15-59 years in all areas. Crude mortalities ranged from 6.1/1000/year for women in Hai to 15.9/1000/year for men in Morogoro rural. Age specific mortalities were up to 43 times higher than rates in England and Wales. Rates were higher in men at all ages in the two rural areas except in the age group 25 to 29 years in Hai and 20 to 34 years in Morogoro rural. In Dar es Salaam rates in men were higher only in the 40 to 59 year age group. The probability of death before age 60 of a 15 year old man (45Q15) was 47% in Dar es Salaam, 37% in Hai, and 58% in Morogoro; for women these figures were 45%, 26%, and 48%, respectively. (The average 45Q15s for men and women in established market economies are 15% and 7%, respectively.) CONCLUSION--Survivors of childhood in Tanzania continue to show high rates of mortality throughout adult life. As the health of adults is essential for the wellbeing of young and old there is an urgent need to develop policies that deal with the causes of adult mortality.

Calcium antagonists are commonly used drugs in the treatment of hypertension in elderly patients. One of the drugs of this group is verapamil. Especially its slow release formula is convenient for use in elderly patients (drug is given once daily). The aim of our study was to evaluate the antihypertensive efficacy of 240 mg slow release verapamil given once daily in elderly hypertensives using ambulatory blood pressure monitoring (ABPM). We also evaluated the safety of this slow release formula using trough to peak ratio.Twenty hypertensives of mean age 67.5 +/- 5.3 were enrolled into the study. Our study was performed using double-blind, placebo-controlled cross-over study design. After a 2-week wash-out period 24-hour ABPM was performed for the first time and then twice: after 2 weeks of placebo or 240 verapamil slow-release and after 2 weeks of verapamil or placebo treatment. The readings prior to and after the treatment were taken using the same procedure. Blood pressure measurements were recorded every 15 minutes between 7.00 and 23.00 and every 30 minutes between 23.00 and 7.00.Verapamil treatment statistically significantly reduced (p0.05) mean 24 hour systolic blood pressure from 148.88 +/- 7.56 mmHg to 132.24 +/- 6.13 mmHg and diastolic respectively from 96.68 +/- 6.05 to 83.04 +/- 5.40 mmHg. Heart rate decreased from 77.16 +/- 3.84 BPM to 68.88 +/- 4.41 BPM. Placebo-corrected trough to peak ratio was 70% for systolic blood pressure.

Pressure sores may be associated with underlying osteomyelitis that is difficult to differentiate clinically from infection or colonization of adjacent soft tissue. Cultures of bone specimens are frequently contaminated with organisms residing in adjacent soft tissue. The three objectives of this cohort study were to (1) determine the accuracy of clinical evaluation for osteomyelitis; (2) evaluate the potential role of quantitative cultures of bone in differentiating osteomyelitis from soft-tissue infection or colonization; and (3) assess the impact of treating osteomyelitis on the outcome of pressure sores.Thirty-six patients with pressure sores related to spinal cord injury or cerebrovascular accident underwent clinical evaluation for osteomyelitis, followed by percutaneous needle biopsy of bone. Routine semiquantitative and quantitative, aerobic and anaerobic cultures of bone specimens were performed. Pathologic examination of bone tissue was used as the standard criterion for diagnosing osteomyelitis.Six (17%) of 36 patients were diagnosed by pathologic examination as having osteomyelitis. The sensitivity and specificity of clinical evaluation were 33% and 60%, respectively. When positive, quantitative bone cultures yielded a similar number of bacterial isolates and a comparable range of bacterial concentration in patients with osteomyelitis vs those without osteomyelitis. Pressure sores healed in all six patients with osteomyelitis after appropriate therapy.Clinical evaluation for osteomyelitis is often inaccurate. Pathologic examination of bone tissue is required for definitive diagnosis of osteomyelitis. Quantitative bone cultures do not help differentiate osteomyelitis from infection or colonization of adjacent soft tissue. It is possible that treatment of osteomyelitis may improve the outcome of associated pressure sores.

7526 Background: PEM and ERL have been approved as second-line monotherapy for locally advanced or metastatic NSCLC. The combination of PEM + ERL showed synergistic activity in preclinical studies. This multicenter, randomized, open-label study assessed the efficacy and safety of PEM + ERL vs PEM. Methods: Patients (pts) with NSQ NSCLC who have failed one prior platinum-based chemotherapy regimen for advanced or metastatic disease, ≥1 measurable lesion by RECIST, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 were eligible. Pts received PEM 500 mg/m2 (with vitamin B12 and folic acid supplementation) q3w alone or combined with ERL 150 mg daily until progression. The primary endpoint of progression-free survival (PFS) was analyzed using the log-rank test with one-sided alpha of 0.20. Results: Of 165 pts with NSQ NSCLC who were randomized (PEM: 86; PEM + ERL: 79), 159 were treated (PEM: 83 and PEM + ERL: 76). The baseline characteristics for PEM/PEM + ERL were: median age of 61/64 yrs...

Several compounds, such as 4-MAPC (4-methyl-3-oxo-4-aza-5 alpha-pregnane-20- carboxylate), that inhibit conversion of testosterone (T) to dihydrotestosterone (DHT) by 5 alpha-reductase have been demonstrated to reduce prostate size in rats and dogs. The current studies were undertaken to determine if this effect is due to a reduction in cell number, in epithelial cell synthetic activity, or both. Eight-week-old intact rats were treated daily for 14 days with sesame seed oil, 4-MAPC (10 mg/kg), 4-MAPC + testosterone propionate (TP, 1 mg/kg), or 4-MAPC + TP (3 mg/kg). Rats were killed 24 hours after the last injection. In the animals treated only with 4-MAPC, ventral prostate weight was reduced 37%, but the 14% reduction in total DNA was not significant. The mean intraprostatic concentration of prostatein, a major secretory protein, was reduced 45% (P less than 0.05). The 3 mg/kg dose of TP increased ventral prostate weight, prostatein concentrations, and acid phosphatase activity, even though DNA/ventral prostate was similar to that in control animals. These observations indicate that the reduction in ventral prostate weight in adult rats is due in part to a reduction in cell number, but the primary effect was due to a reduction in synthetic activity, and possibly atrophy of the epithelial cells. Furthermore, TP in pharmacologic doses increased ventral prostate weight and synthetic activity without increasing DNA.

To determine the extent of myocardial involvement in acquired immunodeficiency syndrome, we reviewed specimens of cardiac tissue obtained during autopsies of 54 patients with this disease. Forty-nine of the specimens showed subtle microscopic changes, the most common being lymphocytic infiltration (49 cases), unevenness of myocardial fibers (34 cases), interstitial fibrosis (28 cases), and myocardial atrophy (22 cases). Twenty-one of the specimens showed a morphologic abnormality that may be classified as a mild cardiomyopathy. Four had microscopic evidence of lymphocytic myocarditis; clinically, however, such myocarditis was diagnosed in only 1 patient, who died of cardiac failure. In a retrospective review, 7 additional hearts (among the 54) showed mild, nonspecific cardiac changes. The causative mechanism and significance of AIDS-related cardiac involvement remain uncertain; nevertheless, physicians should be aware of such involvement, to avoid overburdening the heart with medications that would further impair the myocardium. (Texas Heart Institute Journal 1991;18:116-21)