Lead discovery, chemistry optimization, and biological evaluation studies of novel biamide derivatives as CB2 receptor inverse agonists and osteoclast inhibitors

N,N'-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB(2) inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A-C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB(2) inverse agonists with the highest CB(2) binding affinity (CB(2)K(i) of 22-85 nM, EC(50) of 4-28 nM) and best selectivity (CB(1)/CB(2) of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 μM. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.

Is there a correlation between venlafaxine therapy during pregnancy and a higher incidence of necrotizing enterocolitis?

BACKGROUND: Novel antidepressant drugs are increasingly used by women of child bearing age. However, potentially harmful effects on fetus and newborn remain unknown. METHODS: Case report and literature review. RESULTS: We present preterm twins whose mother was treated with venlafaxine, a nonselective serotonin reuptake inhibitor, throughout pregnancy until delivery. The twins developed neonatal necrotizing enterocolitis. CONCLUSION: The question whether there might be a correlation between maternal serotonin reuptake inhibitor therapy and neonatal necrotizing enterocolitis is discussed.

A Study and Application of the Process of Supergene Enrichment of Silver Ores.

In many deposits of silver ores the grade of the ore de­creases considerably a few hundred feet below the surface. It is believed that in many cases the better ores owe their richness in part to the process of sulphide enrichment. It is recognized, however, that many rich silver ores are hypogene deposits that have been affected very little, if any, by processes of enrichment.

Study and Correlation of Belt and Cambrian Arkoses near Limespur, Montana

In the vicinity of Limespur, Montana, a siding along the Northern Pacific Railroad near Whitehall, Montana, occurs a characteristic type of arkose where­ in many small red mineral grains are distributed throughout the rock mass. It is in this respect that this arkose differs from other arkoses in the surrounding region.

Casting materials and their application in research and teaching

From a biological point of view, casting refers to filling of anatomical and/or pathological spaces with extraneous material that reproduces a three-dimensional replica of the space. Casting may be accompanied by additional procedures such as corrosion, in which the soft tissue is digested out, leaving a clean cast, or the material may be mixed with radiopaque substances to allow x-ray photography or micro computed topography (µCT) scanning. Alternatively, clearing of the surrounding soft tissue increases transparency and allows visualization of the casted cavities. Combination of casting with tissue fixation allows anatomical dissection and didactic surgical procedures on the tissue. Casting materials fall into three categories namely, aqueous substances (India ink, Prussian blue ink), pliable materials (gelatins, latex, and silicone rubber), or hard materials (methyl methacrylates, polyurethanes, polyesters, and epoxy resins). Casting has proved invaluable in both teaching and research and many phenomenal biological processes have been discovered through casting. The choice of a particular material depends inter alia on the targeted use and the intended subsequent investigative procedures, such as dissection, microscopy, or µCT. The casting material needs to be pliable where anatomical and surgical manipulations are intended, and capillary-passable for ultrastructural investigations.

Fatal contact shot to the chest caused by the gas jet from a muzzle-loading pistol discharging only black powder and no bullet: case study and experimental simulation of the wounding effect.

In modern medico-legal literature, only a small number of publications deal with fatal injuries from black powder guns. Most of them focus on the morphological features such as intense soot soiling, blast tattooing and burn effects in close-range shots or describe the wound ballistics of spherical lead bullets. Another kind of "unusual" and potentially lethal weapons are handguns destined for firing only blank cartridges such as starter and alarm pistols. The dangerousness of these guns is restricted to very close and contact range shots and results from the gas jet produced by the deflagration of the propellant. The present paper reports on a suicide committed with a muzzle-loading percussion pistol cal. 45. An unusually large stellate entrance wound was located in the precordial region, accompanied by an imprint mark from the ramrod and a faint greenish discoloration (apparently due to the formation of sulfhemoglobin). Autopsy revealed an oversized powder cavity, multiple fractures of the anterior thoracic wall as well as ruptures of the heart, the aorta, the left hepatic lobe and the diaphragm. In total, the zone of mechanical destruction had a diameter of approx. 15 cm. As there was no exit wound and no bullet lodged in the body, the injury was caused exclusively by the inrushing combustion gases of the propellant (black powder) comparable with the gas jet of a blank cartridge gun. In contact shots to ballistic gelatine using the suicide's pistol loaded with black powder but no projectile, the formation of a nearly spherical cavity could be demonstrated by means of a high-speed camera. The extent of the temporary cavity after firing with 5 g of black powder roughly corresponded to the zone of destruction found in the suicide's body.

Loss to follow-up of HIV-infected women after delivery: The Swiss HIV Cohort Study and the Swiss Mother and Child HIV Cohort Study.

INTRODUCTION HIV-infected pregnant women are very likely to engage in HIV medical care to prevent transmission of HIV to their newborn. After delivery, however, childcare and competing commitments might lead to disengagement from HIV care. The aim of this study was to quantify loss to follow-up (LTFU) from HIV care after delivery and to identify risk factors for LTFU. METHODS We used data on 719 pregnancies within the Swiss HIV Cohort Study from 1996 to 2012 and with information on follow-up visits available. Two LTFU events were defined: no clinical visit for >180 days and no visit for >360 days in the year after delivery. Logistic regression analysis was used to identify risk factors for a LTFU event after delivery. RESULTS Median maternal age at delivery was 32 years (IQR 28-36), 357 (49%) women were black, 280 (39%) white, 56 (8%) Asian and 4% other ethnicities. One hundred and seven (15%) women reported any history of IDU. The majority (524, 73%) of women received their HIV diagnosis before pregnancy, most of those (413, 79%) had lived with diagnosed HIV longer than three years and two-thirds (342, 65%) were already on antiretroviral therapy (ART) at time of conception. Of the 181 women diagnosed during pregnancy by a screening test, 80 (44%) were diagnosed in the first trimester, 67 (37%) in the second and 34 (19%) in the third trimester. Of 357 (69%) women who had been seen in HIV medical care during three months before conception, 93% achieved an undetectable HIV viral load (VL) at delivery. Of 62 (12%) women with the last medical visit more than six months before conception, only 72% achieved an undetectable VL (p=0.001). Overall, 247 (34%) women were LTFU over 180 days in the year after delivery and 86 (12%) women were LTFU over 360 days with 43 (50%) of those women returning. Being LTFU for 180 days was significantly associated with history of intravenous drug use (aOR 1.73, 95% CI 1.09-2.77, p=0.021) and not achieving an undetectable VL at delivery (aOR 1.79, 95% CI 1.03-3.11, p=0.040) after adjusting for maternal age, ethnicity, time of HIV diagnosis and being on ART at conception. CONCLUSIONS Women with a history of IDU and women with a detectable VL at delivery were more likely to be LTFU after delivery. This is of concern regarding their own health, as well as risk for sexual partners and subsequent pregnancies. Further strategies should be developed to enhance retention in medical care beyond pregnancy.

Time-order errors and standard-position effects in duration discrimination: An experimental study and an analysis by the sensation-weighting model

Studies have shown that the discriminability of successive time intervals depends on the presentation order of the standard (St) and the comparison (Co) stimuli. Also, this order affects the point of subjective equality. The first effect is here called the standard-position effect (SPE); the latter is known as the time-order error. In the present study, we investigated how these two effects vary across interval types and standard durations, using Hellström’s sensation-weighting model to describe the results and relate them to stimulus comparison mechanisms. In Experiment 1, four modes of interval presentation were used, factorially combining interval type (filled, empty) and sensory modality (auditory, visual). For each mode, two presentation orders (St–Co, Co–St) and two standard durations (100 ms, 1,000 ms) were used; half of the participants received correctness feedback, and half of them did not. The interstimulus interval was 900 ms. The SPEs were negative (i.e., a smaller difference limen for St–Co than for Co–St), except for the filled-auditory and empty-visual 100-ms standards, for which a positive effect was obtained. In Experiment 2, duration discrimination was investigated for filled auditory intervals with four standards between 100 and 1,000 ms, an interstimulus interval of 900 ms, and no feedback. Standard duration interacted with presentation order, here yielding SPEs that were negative for standards of 100 and 1,000 ms, but positive for 215 and 464 ms. Our findings indicate that the SPE can be positive as well as negative, depending on the interval type and standard duration, reflecting the relative weighting of the stimulus information, as is described by the sensation-weighting model.

Carbonate chemistry, temperature and salinity of Lady Elliot Island Reef 2009-2010

Ocean acidification leads to changes in marine carbonate chemistry that are predicted to cause a decline in future coral reef calcification. Several laboratory and mesocosm experiments have described calcification responses of species and communities to increasing CO2. The few in situ studies on natural coral reefs that have been carried out to date have shown a direct relationship between aragonite saturation state (Omega arag) and net community calcification (Gnet). However, these studies have been performed over a limited range of Omega arag values, where extrapolation outside the observational range is required to predict future changes in coral reef calcification. We measured extreme diurnal variability in carbonate chemistry within a reef flat in the southern Great Barrier Reef, Australia. Omega arag varied between 1.1 and 6.5, thus exceeding the magnitude of change expected this century in open ocean subtropical/tropical waters. The observed variability comes about through biological activity on the reef, where changes to the carbonate chemistry are enhanced at low tide when reef flat waters are isolated from open ocean water. We define a relationship between net community calcification and Omega arag, using our in situ measurements. We find net community calcification to be linearly related to Omega arag, while temperature and nutrients had no significant effect on Gnet. Using our relationship between Gnet and Omega arag, we predict that net community calcification will decline by 55% of its preindustrial value by the end of the century. It is not known at this stage whether exposure to large variability in carbonate chemistry will make reef flat organisms more or less vulnerable to the non-calcifying physiological effects of increasing ocean CO2 and future laboratory studies will need to incorporate this natural variability to address this question.

Seawater carbonate chemistry, calcification and respiration duirng experiments with a pteropod Creseis acicula, 2010

Among marine calcifiers, shelled pteropods are expected to be particularly sensitive to ocean acidification, generated by the uptake of anthropogenic CO2 by the ocean, and the associated decrease of the seawater saturation state with respect to aragonite (omega aragonite). The few available studies have mostly focused on polar species although pteropods are also important components of temperate and tropical ecosystems. It is also unknown which parameter of the carbonate system controls calcification. Specimens of the temperate Mediterranean species Creseis acicula were maintained under seven different conditions of the carbonate chemistry, obtained by manipulating pH and total alkalinity, with the goal to disentangle the effects of pH and omega aragonite. Respiration, excretion as well as rates of net and gross calcification were not directly affected by a decrease in pH but decreased significantly with a decrease of omega aragonite. The decrease of gross calcification rates is consistent with that reported for polar species. Although the organisms were apparently able to maintain gross calcification rates under slightly undersaturated aragonite conditions, the clear net dissolution signal observed below saturation suggests that they are not able to build a shell in seawater corrosive to aragonite. The decrease in respiration and excretion, and the low O:N molar ratio, could be due to the short time that the organisms were allowed to acclimatize to their new environment.

Seawater carbonate chemistry, pigments and proteins during experiments with phytoplankton, 2010

In the high-nutrient, low-chlorophyll waters of the Gulf of Alaska, microcosm manipulation experiments were used to assess the effect of CO2 on growth and primary production under iron-limited and iron-replete conditions. As expected, iron had a strong effect on growth and photosynthesis. A modest and variable stimulation of growth and biomass production by CO2 (high CO2: 77-122 Pa; low CO2: 11-17 Pa) was observed under both iron-replete and iron-limited conditions, though near the limit of precision of our measurements in slow-growing low-iron experiments. Physiological acclimations responsible for the changes in growth were assessed. Under iron-limited conditions, growth stimulation at high CO2 appeared to result from an increase in photosynthetic efficiency, which we attribute to energy savings from down-regulation of the carbon concentrating mechanisms. In some cases, iron-rich photosynthetic proteins (PsbA, PsaC, and cytochrome b6) were down-regulated at elevated CO2in iron-limited controls. Under iron-replete conditions, there was an increase in growth rate and biomass at high CO2 in some experiments. This increase was unexpectedly supported by reductions in cellular carbon loss, most likely decreased respiration. We speculate that this effect may be due to acclimation to decreased pH rather than high CO2. The variability in responses to CO2 among experiments did not appear to be caused by differences in phytoplankton community structure and may reflect the sensitivity of the net response of phytoplankton to antagonistic effects of the several parameters that co-vary with CO2.