Insights into the Structure-Activity Relationship in Aerobic Alcohol Oxidation over a Metal-Organic-Framework-Supported Molybdenum(VI) Catalyst.
The understanding of structure-activity relationships at the atomic level has played a profound role in heterogeneous catalysis, providing valuable insights into designing suitable heterogeneous catalysts. However, uncovering the detailed roles of how such active species' structures affect their catalytic performance remains a challenge owing to the lack of direct structural information on a specific active species. Herein, we deposited molybdenum(VI), an active species in oxidation reactions, on the Zr6 node of a mesoporous zirconium-based metal-organic framework (MOF) NU-1200, using solvothermal deposition in MOFs (SIM). Due to the high crystallinity of the NU-1200 support, the precise structure of the resulting molybdenum catalyst, Mo-NU-1200, was characterized through single-crystal X-ray diffraction (SCXRD). Two distinct anchoring modes of the molybdenum species were observed: one mode (Mo1), displaying an octahedral geometry, coordinated to the node through one terminal oxygen atom and the other mode (Mo2) coordinated to two adjacent Zr6 node oxygen atoms in a tetrahedral geometry. To investigate the role of base in the catalytic activity of these Mo centers, we assessed the activity of Mo-NU-1200 for the aerobic oxidation of 4-methoxybenzyl alcohol as a model reaction. The results revealed that Mo-NU-1200 exhibited remarkably higher catalytic reactivity under base-free conditions, while the presence of base inhibited the catalytic reactivity of this species. SCXRD studies revealed that the molybdenum binding motifs (structures of the supported metal on the Zr6 node in the MOF) changed over the course of the reactions. Following the oxidation without base, both pristine coordination modes (Mo1 and Mo2) evolved into a new coordination mode (Mo3), in which the molybdenum atom coordinated to two adjacent oxygen atoms from the Zr6 node in an octahedral geometry, while in the presence of base, the pristine Mo1 coordination mode evolved entirely into the pristine Mo2. This study demonstrates the direct observation of an active species' structural evolution from metal installation to subsequent catalytic reaction. As a result, these subtle structural changes in catalyst binding motifs led to distinct differences in catalytic activities, providing a compelling strategy for elucidating structure-activity relationships.


A comparative examination of odontogenic gene expression in both toothed and toothless amniotes.
A well-known tenet of murine tooth development is that BMP4 and FGF8 antagonistically initiate odontogenesis, but whether this tenet is conserved across amniotes is largely unexplored. Moreover, changes in BMP4-signaling have previously been implicated in evolutionary tooth loss in Aves. Here we demonstrate that Bmp4, Msx1, and Msx2 expression is limited proximally in the red-eared slider turtle (Trachemys scripta) mandible at stages equivalent to those at which odontogenesis is initiated in mice, a similar finding to previously reported results in chicks. To address whether the limited domains in the turtle and the chicken indicate an evolutionary molecular parallelism, or whether the domains simply constitute an ancestral phenotype, we assessed gene expression in a toothed reptile (the American alligator, Alligator mississippiensis) and a toothed non-placental mammal (the gray short-tailed opossum, Monodelphis domestica). We demonstrate that the Bmp4 domain is limited proximally in M. domestica and that the Fgf8 domain is limited distally in A. mississippiensis just preceding odontogenesis. Additionally, we show that Msx1 and Msx2 expression patterns in these species differ from those found in mice. Our data suggest that a limited Bmp4 domain does not necessarily correlate with edentulism, and reveal that the initiation of odontogenesis in non-murine amniotes is more complex than previously imagined. Our data also suggest a partially conserved odontogenic program in T. scripta, as indicated by conserved Pitx2, Pax9, and Barx1 expression patterns and by the presence of a Shh-expressing palatal epithelium, which we hypothesize may represent potential dental rudiments based on the Testudinata fossil record.


Amplitude modulation of femtosecond laser pulses in the megahertz range for frequency-multiplexed two-photon imaging.
We present a frequency-multiplexed multi-site two-photon imaging method utilizing amplitude modulation of femtosecond laser pulses in the MHz range to tag each excitation beam and the corresponding fluorescence signals with specific frequencies. The frequency tags are generated with an interferometric scheme employing acousto-optic deflectors (AODs) to achieve precise spatial overlap of femtosecond laser pulses with periodically varying phase shift. Creating matching excitation beam patterns in each interferometer arm using multiple AOD driving frequencies, and subsequently overlapping these matching patterns, results in multiple encoded excitation beams with unique beat frequencies available for scanning. As a proof-of-concept, we demonstrate multiplexed two-photon image acquisition using test samples, and compare the performance of this approach to conventional two-photon laser scanning microscopy.


CRISPR/Cas 9-Mediated Mutations as a New Tool for Studying Taste in Honeybees.
Honeybees rely on nectar as their main source of carbohydrates. Sucrose, glucose, and fructose are the main components of plant nectars. Intriguingly, honeybees express only 3 putative sugar receptors (AmGr1, AmGr2, and AmGr3), which is in stark contrast to many other insects and vertebrates. The sugar receptors are only partially characterized. AmGr1 detects different sugars including sucrose and glucose. AmGr2 is assumed to act as a co-receptor only, while AmGr3 is assumedly a fructose receptor. We show that honeybee gustatory receptor AmGr3 is highly specialized for fructose perception when expressed in Xenopus oocytes. When we introduced nonsense mutations to the respective AmGr3 gene using CRISPR/Cas9 in eggs of female workers, the resulting mutants displayed almost a complete loss of responsiveness to fructose. In contrast, responses to sucrose were normal. Nonsense mutations introduced by CRISPR/Cas9 in honeybees can thus induce a measurable behavioral change and serve to characterize the function of taste receptors in vivo. CRISPR/Cas9 is an excellent novel tool for characterizing honeybee taste receptors in vivo. Biophysical receptor characterization in Xenopus oocytes and nonsense mutation of AmGr3 in honeybees unequivocally demonstrate that this receptor is highly specific for fructose.


Functional and safety outcomes after benign prostatic enlargement surgeries in men with detrusor underactivity compared with normal detrusor contractility: Systematic review and meta-analysis.
Men with detrusor underactivity (DUA) and concomitant bladder outlet obstruction (BOO) due to benign prostatic enlargement (BPE) may present poorer functional outcomes after surgical desobstruction. This study aimed to evaluate the safety and efficacy of BPE surgery in men with DUA compared with those with normal detrusor contractility (NC). This review was performed according to the 2020 PRISMA framework. A comprehensive literature search was performed until May 7, 2023, using MEDLINE, EMBASE, and Cochrane Database. No date limits were imposed. Only comparative studies were accepted. The primary endpoint was to assess if there was any difference in short- and long-term functional outcomes after BPE surgery in men with DUA and NC. The secondary endpoint was to evaluate the differences in perioperative outcomes and postoperative complications between the two groups. Meta-analysis was performed using Review Manager (RevMan) software. There were 5 prospective nonrandomized studies and 12 retrospective studies, including 1701 DUA and 1993 NC patients. Regarding surgical procedures, there were eight TURP (transurethral resection of the prostate) studies, four GreenLight PVP (photoselective vaporization of the prostate) studies, two HoLEP (Holmium laser enucleation of the prostate) studies, one GreenLight PVP/HoLEP study, one Holmium laser incision of the prostate study, and one study did not report the type of surgery. We did not find a statistically significant difference between the two groups in terms of perioperative outcomes, including postoperative catheterization time, hospitalization time, urinary retention, need to recatheterization, transfusion rate, or urinary tract infections. Also, we found no significant differences in long-term complications, such as bladder neck stenosis or urethral stenosis. Posttreatment bladder recatheterization and retreatment rate for BPE regrowth could not be evaluated properly, because only one study reported these findings. When we analyzed functional outcomes at 3 months, those with NC had lower International Prostatic Symptom Score (IPSS), lower quality-of-life (QoL) score, better maximum flow rate (Qmax), and lower post-voiding residual (PVR) of urine. These results were maintained at 6 months postoperatively, with exception of PVR that showed no difference. However, at 12 and more than 12 months the functional outcomes became similar regarding IPSS and QoL. There were few data about Qmax and PVR at longer follow-up. In this meta-analysis, data suggest that BOO surgical treatment in patients with concomitant BPE and DUA appears to be safe. Despite patients with DUA may present worse functional outcomes in the short postoperative term compared with the NC population, IPSS and QoL scores become comparable again after a longer follow-up period after surgery.


Physicochemical Significance of Topological Indices: Importance in Drug Discovery Research.
Quantitative Structure-Activity Relationship (QSAR) studies describing the correlations between biological activity as dependent parameters and physicochemical and structural descriptors, including topological indices (TIs) as independent parameters, play an important role in drug discovery research. The emergence of graph theory in exploring the structural attributes of the chemical space has led to the evolution of various TIs, which have made their way into drug discovery. The TIs are easy to compute compared to the empirical parameters, but they lack physiochemical interpretation, which is essential in understanding the mechanism of action. Hence, efforts have been made to review the work on the advances in topological indices, their physicochemical significance, and their role in developing QSAR models. A literature search has been carried out, and the research article providing evidence of the physicochemical significance of the topological parameters as well as some recent studies utilizing these parameters in the development of QSAR models, have been evaluated. In this review, the physicochemical significance of TIs have been described through their correlations between empirical parameters in terms of explainable physicochemical properties, along with their application in the development of predictive QSAR models. Most of these findings suggest a common trend of TIs correlation with MR rather than logP or other parameters; nevertheless, the developed models may be useful in both drug and vaccine development.


Identification of PIKfyve kinase as a target in multiple myeloma.
The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased in vitro chemical library screen. The activity of APY0201 was confirmed in all 25 cell lines tested and in 40% of 100 ex vivo patient-derived primary samples, with increased activity in primary samples harboring trisomies and lacking t(11;14). The broad anti-multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point half maximal effective concentration (EC50) at nanomolar concentrations in, respectively, 65%, 40%, and 5% of the tested cell lines. Upregulation of genes in the lysosomal pathway and increased cellular vacuolization were observed in vitro following APY0201 treatment, although these cellular effects did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings indicate promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and suggest a strategy to enrich for likely responders.


[Ultrastructural features of cardiac muscle fibers of albino rats during the pregnancy and puerperal cycle].
In the present study we evaluated the morphology of left ventricular cardiomyocytes of albino rats during pregnancy and puerperium by means of transmission electron microscopy. Once pregnancy was confirmed, 77 rats were randomly divided in two groups, respectively, gestation (G) and puerperium (P). The animals of the gestation group were divided into four subgroups, according to gestational age: 1st (G-A), 7th (G-B), 14th (G-C) and 21st (G-D) days of pregnancy. The group defined as puerperium was divided into three subgroups: 7th (P-A), 14th (P-B) and 21st (P-C) days of puerperium. In the end of each established period, the animals were sacrificed and fragments of the medium third of the left ventricle were resected and routinely prepared for electron microscopy analysis. The results obtained with transmission electron microscopy analysis revealed a gradative increase of the cardiomyocytes during pregnancy (increase of myofibrils, which are permeated by numerous mitochondria at the end of gestation). The blood capillary wall showed progressive thinning, with an increase of pynocytotic vesicles in endothelial cells, and intense sarcolemal folding at T-tubule level (capillary tunnels). In the puerperium group, there is a progressive regression in these alterations returning to pre-gestational level at the end of the puerperium cycle. These findings indicate the occurrence of hypertrophy of cardiomyocytes during pregnancy. The findings indicate the occurrence of hypertrophy of cardiomyocytes during pregnancy.


Trends in Clinical Breast Density Assessment From the Breast Cancer Surveillance Consortium.
Changes to mammography practice, including revised Breast Imaging Reporting and Data System (BI-RADS) density classification guidelines and implementation of digital breast tomosynthesis (DBT), may impact clinical breast density assessment. We investigated temporal trends in clinical breast density assessment among 2 990 291 digital mammography (DM) screens and 221 063 DBT screens interpreted by 722 radiologists from 144 facilities in the Breast Cancer Surveillance Consortium. After age-standardization, 46.3% (95% CI = 44.1% to 48.6%) of DM screens were assessed as dense (heterogeneously/extremely dense) during the BI-RADS 4th edition era (2005-2013), compared to 46.5% (95% CI = 43.8% to 49.1%) during the 5th edition era (2014-2016) (P = .93 from two-sided generalized score test). Among DBT screens in the BI-RADS 5th edition era, 45.8% (95% CI = 42.0% to 49.7%) were assessed as dense (P = .77 from two-sided generalized score test) compared to 46.5% (95% CI = 43.8% to 49.1%) dense on DM in BI-RADS 5th edition era. Results were similar when examining all four density categories and age subgroups. Clinicians, researchers, and policymakers may reasonably expect stable density distributions across screened populations despite changes to the BI-RADS guidelines and implementation of DBT.


UDP-Glucuronosyltransferases 1A6 and 1A9 are the Major Isozymes Responsible for the 7-O-Glucuronidation of Esculetin and 4-Methylesculetin in Human Liver Microsomes.
Esculetin (6,7-dihydroxycoumarin, ET) and 4-methylesculetin (6,7-dihydroxy-4-methylcoumarin, 4-ME) are typical coumarin derivatives that are attracting considerable attention because of their wide spectrum of biologic activities, but their metabolism remains unknown. This study aimed to elucidate the in vitro UDP-glucuronosyltransferase (UGT) metabolism characteristics of ET and 4-ME. 7-O-monoglucuronide esculetin (ET-G) and 7-O-monoglucuronide 4-methylesculetin (4-ME-G) were identified by liquid chromatography-mass spectrometry (LC-MS) and (1)H-nuclear magnetic resonance ((1)HNMR) when ET or 4-ME was incubated with human liver (HLM) in the presence of UDP-glucuronic acid. Screening assays with 12 human expressed UGTs demonstrated that the formations of ET-G and 4-ME-G were almost exclusively catalyzed by UGT1A6 and UGT1A9. Phenylbutazone and carvacrol (UGT1A6 and UGT1A9 chemical inhibitors, respectively) at different concentrations (50, 100, and 200 μM) significantly inhibited the formation of glucuronidates of ET and 4-ME in HLM, UGT1A6, and UGT1A9 when the concentrations of ET and 4-ME ranged from 10 to 300 μM (P < 0.05). Clearance rates of ET in HLM, HIM, UGT1A6, and UGT1A9 were 0.54, 0.16, 0.69, and 0.14 ml/min/mg, respectively. Corresponding clearance rates values of 4-ME were 0.59, 0.03, 0.14, and 0.04 ml/min/mg, respectively. In conclusion, 7-O-monoglucuronidation by UGT1A6 and UGT1A9 was the predominant UGT metabolic pathway for both ET and 4-ME in vitro. The liver is probably the major contributor to the glucuronidation metabolism of ET and 4-ME. ET showed more rapid metabolism than 4-ME in glucuronidation.


Molecular mechanism of base pairing infidelity during DNA duplication upon one-electron oxidation.
The guanine radical cation (G(•+)) is formed by one-electron oxidation from its parent guanine (G). G(•+) is rapidly deprotonated in the aqueous phase resulting in the formation of the neutral guanine radical [G(-H)(•)]. The loss of proton occurs at the N1 nitrogen, which is involved in the classical Watson-Crick base pairing with cytosine (C). Employing the density functional theory (DFT), it has been observed that a new shifted base pairing configuration is formed between G(-H)(•) and C constituting only two hydrogen bonds after deprotonation occurs. Using the DFT method, G(-H)(•) was paired with thymine (T), adenine (A) and G revealing substantial binding energies comparable to those of classical G-C and A-T base pairs. Hence, G(-H)(•) does not display any particular specificity for C compared to the other bases. Taking into account the long lifetime of the G(-H)(•) radical in the DNA helix (5 s) and the rapid duplication rate of DNA during mitosis/meiosis (5-500 bases per s), G(-H)(•) can pair promiscuously leading to errors in the duplication process. This scenario constitutes a new mechanism which explains how one-electron oxidation of the DNA double helix can lead to mutations.


Dissecting the functional specificities of two Hox proteins.
Hox proteins frequently select and regulate their specific target genes with the help of cofactors like Extradenticle (Exd) and Homothorax (Hth). For the Drosophila Hox protein Sex combs reduced (Scr), Exd has been shown to position a normally unstructured portion of Scr so that two basic amino acid side chains can insert into the minor groove of an Scr-specific DNA-binding site. Here we provide evidence that another Drosophila Hox protein, Deformed (Dfd), uses a very similar mechanism to achieve specificity in vivo, thus generalizing this mechanism. Furthermore, we show that subtle differences in the way Dfd and Scr recognize their specific binding sites, in conjunction with non-DNA-binding domains, influence whether the target gene is transcriptionally activated or repressed. These results suggest that the interaction between these DNA-binding proteins and the DNA-binding site determines the architecture of the Hox-cofactor-DNA ternary complex, which in turn determines whether the complex recruits coactivators or corepressors.


Ambush of Clostridium difficile spores by ramoplanin: activity in an in vitro model.
Clostridium difficile infection (CDI) is a gastrointestinal disease caused by C. difficile, a spore-forming bacterium that in its spore form is tolerant to standard antimicrobials. Ramoplanin is a glycolipodepsipeptide antibiotic that is active against C. difficile with MICs ranging from 0.25 to 0.50 μg/ml. The activity of ramoplanin against the spores of C. difficile has not been well characterized; such activity, however, may hold promise, since posttreatment residual intraluminal spores are likely elements of disease relapse, which can impact more than 20% of patients who are successfully treated. C. difficile spores were found to be stable in deionized water for 6 days. In vitro spore counts were consistently below the level of detection for 28 days after even brief (30-min) exposure to ramoplanin at concentrations found in feces (300 μg/ml). In contrast, suppression of spore counts was not observed for metronidazole or vancomycin at human fecal concentrations during treatment (10 μg/ml and 500 μg/ml, respectively). Removal of the C. difficile exosporium resulted in an increase in spore counts after exposure to 300 μg/ml of ramoplanin. Therefore, we propose that rather than being directly sporicidal, ramoplanin adheres to the exosporium for a prolonged period, during which time it is available to attack germinating cells. This action, in conjunction with its already established bactericidal activity against vegetative C. difficile forms, supports further evaluation of ramoplanin for the prevention of relapse after C. difficile infection in patients.


[Physiopathology of polycystic ovary syndrome].
The Polycystic Ovary Syndrome (PCOS) includes three phenotypic compartments, not always fully associated, consisting in hyperandrogenism, anovulation and metabolic syndrome, secondary to insulin resistance. The pathophysiological grounds lie upon two main components, i.e.: the theca-interstitial cell (TIC) and the granulosa cell (GC) dysregulations, the former accounting for hyperandrogenism and the latter for anovulation, and both of them being under the influence of hyperinsulinism. The former mainly results from an enzymatic overactivity, yielding an exaggerated output of androgens by the TIC, but the type(s) of enzymes as well as the genetic or adaptative nature of its (their) dysregulation are still controversial. The main consequence of the CG dysregulation is the follicular arrest just before the time of dominance. This might result from an intrinsic abnormality in CG, involving the IGFs and/or the Inhibin/Activin/Follistatin systems. Alternatively, the CTI might have deleterious effects on GC, mainly via the intra-ovarian hyperandrogenism. The latter should not be regarded any more as an atretogenic phenomenon. It is closely related to the two main morphological features of PCOS, i.e.: the stromal hyperplasia and the excessive follicular number.


Na(+)-Ca2+ exchange and Ca2+ depletion in rat proximal tubules.
The removal of external Ca2+ ([Ca2+]o) reduces cytosolic Ca2+ ([Ca2+]i) in rat proximal tubules. In this report the role of external Na+ ([Na+]o) on the changes of [Ca2+]i and Ca2+ efflux caused by withdrawal of [Ca2+]o is described in rat renal proximal tubules. In aequorin-loaded tubules [Ca2+]i decreased from 235 +/- 25 to 48 +/- 16 (n = 4, P = 0.017), and 45Ca2+ fractional efflux ratio (45Ca2+ FER) increased from 0.94 +/- 0.03 to 1.64 +/- 0.19 (n = 6, P = 0.021) when Ca2+ was withdrawn from the bathing media of Krebs buffer (KB). The fall of [Ca2+]i, as well as the activation of 45Ca2+ FER, was reversed when [Na+]o in Ca(2+)-free KB was lowered isosmotically from 150 to 15 mM. However, when tubules were superfused with only 5 mM [Na+]o before [Ca2+]o was removed, [Ca2+]i also declined, but 45Ca2+ FER did not increase. The Na(+)-Ca2+ exchange inhibitor dichlorobenzamil (DCB) added after [Ca2+]o was removed evoked responses similar to [Na+]o removal, although DCB also inhibited internal Ca2+ release. These results are congruous with stimulation of Na+ influx in exchange for [Ca2+]i in Ca(2+)-free KB. However, even though total tubular Na+ was higher in Ca(2+)-free KB after 10 min, the initial rate of 22Na+ influx was not different without or with [Ca2+]o.(ABSTRACT TRUNCATED AT 250 WORDS)


Protection of COVID-19 vaccination and previous infection against Omicron BA.1, BA.2 and Delta SARS-CoV-2 infections.
Given the emergence of the SARS-CoV-2 Omicron BA.1 and BA.2 variants and the roll-out of booster COVID-19 vaccination, evidence is needed on protection conferred by primary vaccination, booster vaccination and previous SARS-CoV-2 infection by variant. We employed a test-negative design on S-gene target failure data from community PCR testing in the Netherlands from 22 November 2021 to 31 March 2022 (n = 671,763). Previous infection, primary vaccination or both protected well against Delta infection. Protection against Omicron BA.1 infection was much lower compared to Delta. Protection was similar against Omicron BA.1 compared to BA.2 infection after previous infection, primary and booster vaccination. Higher protection was observed against all variants in individuals with both vaccination and previous infection compared with either one. Protection against all variants decreased over time since last vaccination or infection. We found that primary vaccination with current COVID-19 vaccines and previous SARS-CoV-2 infections offered low protection against Omicron BA.1 and BA.2 infection. Booster vaccination considerably increased protection against Omicron infection, but decreased rapidly after vaccination.


Primary tuberculous enteritis.
Because of the large influx of immigrants from the Third World into this country, primary enteric tuberculosis, although rare, can still be found in all sections of the United States. The fact that it may mimic the more common neoplastic and granulomatous diseases, coupled with the relative paucity of instances, increases the likelihood of a misdiagnosis. Diagnosis may be further complicated by a false-negative Mantoux test (purified protein derivative skin test) and lack of evidence of tuberculosis elsewhere in the patient. Adequate treatment consists of appropriate chemotherapeutic agents and the judicious use of surgical resection. Given appropriate treatment, the outcome in most patients should be favorable.


Proliferation of Tau 304-380 Fragment Aggregates through Autocatalytic Secondary Nucleation.
The self-assembly of the protein tau into neurofibrillary tangles is one of the hallmarks of Alzheimer's disease and related tauopathies. Still, the molecular mechanism of tau aggregation is largely unknown. This problem may be addressed by systematically obtaining reproducible in vitro kinetics measurements under quiescent conditions in the absence of triggering substances. Here, we implement this strategy by developing protocols for obtaining an ultrapure tau fragment (residues 304-380 of tau441) and for performing spontaneous aggregation assays with reproducible kinetics under quiescent conditions. We are thus able to identify the mechanism of fibril formation of the tau 304-380 fragment at physiological pH using fluorescence spectroscopy and mass spectrometry. We find that primary nucleation is slow, and that secondary processes dominate the aggregation process once the initial aggregates are formed. Moreover, our results further show that secondary nucleation of monomers on fibril surfaces dominates over fragmentation of fibrils. Using separate isotopes in monomers and fibrils, through mass spectroscopy measurements, we verify the isotope composition of the intermediate oligomeric species, which reveals that these small aggregates are generated from monomer through secondary nucleation. Our results provide a framework for understanding the processes leading to tau aggregation in disease and for selecting possible tau forms as targets in the development of therapeutic interventions in Alzheimer's disease.


The effects of ultrasonic energy on peripheral nerves: implications for ultrasound-assisted liposuction.
The integration of ultrasound-assisted liposuction with traditional suction-assisted lipoplasty has extended the role of liposuction in body contouring. Although there are ample data regarding the effects of ultrasound on peripheral nerves from studies with the Cavitron ultrasound surgical aspirator, there is little information concerning the effects of modern ultrasound body contouring equipment on neural tissue. This study was designed to evaluate the functional and histologic effects of ultrasound energy on rat peripheral nerves (sciatic nerves) using a commonly-used ultrasound-assisted liposuction generator. After the application of ultrasound to exposed rat sciatic nerves, operative magnification was used to assess any visible injury. The sciatic function index was serially measured to quantify immediate and long-term functional effects on the nerves. Our results showed immediate visible injury using low amplitude settings (level 6), but no functional evidence of injury until much higher settings were used (level 9). All animals in the groups with initial functional impairment had returned to normal or near-normal function at completion of the study (51 days). Histologic examination revealed no evidence of damage in the low amplitude groups. Histologic analysis of the high amplitude groups displayed diffuse infiltration of the nerve, with foamy histiocytes and an increased number of mast cells, consistent with remote neural injury followed by myelin breakdown and repair.


Membrane-associated signal transduction modulates contractile responses to Ca2+ in saponin-skinned coronary smooth muscle.
Experiments on saponin-permeabilized bovine and porcine coronary arteries were performed to examine whether fluoride-induced contractile mechanisms are retained after permeabilization and whether they modulate muscle tension without a change in cytoplasmic Ca2+. Fluoride induced reversible contractions in skinned coronary smooth muscle and shifted the apparent Ca2(+)-sensitivity of the contractile system to lower Ca2+ values. Force development to fluoride required exogenous ATP and a minimum Ca2+ concentration (pCa less than 8) of the bathing medium. Force development occurred when the concentration of free Ca2+ available to the contractile apparatus seemed to be sufficiently controlled by a Ca2(+)-EGTA buffering system. The effects of fluoride were enhanced by Al3+ and imitated by both guanylyl-imidodiphosphate and 4 beta-phorbol-12,13-dibutyrate which suggests the involvement of both GTP-binding protein(s) and of the C-kinase pathway. Under conditions of sufficiently controlled Ca2+ buffering, saponin-skinned arteries responded to histamine or carbachol with an increase in muscle tension which was inhibited by specific receptor blocking agents (diphenhydramine, atropine), and which required the presence of both exogenous ATP and a low concentration of Ca2+ (pCa 7) which per se did not result in a contractile response. It is concluded that agents acting on different steps of membrane-associated signal transduction pathways are able to induce contractile responses of saponin-skinned vascular smooth muscle without a change in cytosolic Ca2+ concentration.


Evaluation of the Effect of an Aqueous Extract of Azadirachta indica (Neem) Leaves and Twigs on Glycemic Control, Endothelial Dysfunction and Systemic Inflammation in Subjects with Type 2 Diabetes Mellitus - A Randomized, Double-Blind, Placebo-Controlled Clinical Study.
Neem tree (Azadirachta indica) offers different bioactives ranging from pesticides to therapeutic molecules, depending on which part of the plant is used and the extraction methodology and the solvent used. This study was aimed at evaluating the safety and efficacy of a standardized aqueous extract of Azadirachta indica leaves and twigs (NEEM) on glycemic control, endothelial dysfunction, and systemic inflammation in patients with type 2 diabetes mellitus (T2DM). In this randomized, double-blind, placebo-controlled clinical study (RCT), 80 T2DM subjects, who have already been on standard metformin therapy, received either 125 mg, 250 mg, 500 mg of NEEM or placebo twice daily for 12 weeks. Postprandial blood sugar level (PPBS), fasting blood sugar level (FBS), glycosylated hemoglobin (HbA1c), insulin resistance (IR), endothelial function, oxidative stress, systemic inflammation, IL-6 and TNF-α, platelet aggregation and lipid profile were assessed. Adverse drug reactions, if any, were noted. GraphPad Prism 8 was used to perform statistical analysis. NEEM at the doses of 125, 250, and 500 mg BID significantly reduced PPBS (from 194.4±14 to 173.1±12.8mg/dL, 192.3±17.1 to 161.8±9.7mg/dL, and 205.9±7.2 to 159.3±7.1mg/dL, respectively), FBS (from 119.2±5.0 to 109.2±5.7mg/dL, 115.5±4.4 to 103.7±4.2mg/dL, and 120.7±4.2 to 97.3±3.7mg/dL, respectively), HbA1c (from 6.87 ± 0.4% to 6.64 ± 0.4%, 7.52 ± 0.4% to 6.86 ± 0.3%, and 7.78 ± 0.2% to 6.26 ± 0.4%, respectively), and IR (from 4.5 ± 1.2 to 3.4 ± 0.9, 3.8 ± 1.1 to 2.5 ± 0.6, and 4.6 ± 1.3 to 2.0 ± 0.6, respectively) compared to placebo. Also, NEEM significantly improved endothelial function, decreased oxidative stress and systemic inflammation compared to placebo. The efficacy was significant with all the doses, but no effect on platelet aggregation or lipid profile was observed. NEEM may significantly ameliorate hyperglycemia, endothelial dysfunction, and systemic inflammation, on top of what metformin could do, in subjects with T2DM.


Pancreatic phlegmon. Clinical features and course.
The clinical course of 19 patients with pancreatic phlegmon, as diagnosed by computed tomography (CT) and clinical criteria, was assessed retrospectively and compared to that of eight patients with pancreatic abscess diagnosed either at surgery or with percutaneous aspiration. Controls consisted of 55 patients with uncomplicated acute pancreatitis without CT scans and 11 patients with acute pancreatitis in whom CT scans were negative or only consistent with acute pancreatitis (no phlegmon). The age, sex, and presumed etiology of the pancreatitis were not significantly different in the four groups. Patients with phlegmon had a higher incidence of severe pancreatitis as defined by Ranson's criteria, presence of an abdominal mass, as well as a longer duration of fever, abdominal pain and leukocytosis than controls without CT scans. With the exception of a palpable abdominal mass and fever lasting over five days, the results were similar when comparing the phlegmon group and controls with CT scans, although the severity of the disease and prolonged abdominal pain tended to be increased in the former patients. There was no statistically significant difference in clinical or laboratory criteria between the phlegmon and abscess groups, although the latter group had longer hospital stays and periods with no oral intake (npo). Management of patients with phlegmon tended to include TPN, longer npo periods, antibiotics, and longer hospital stay than in controls without CT scans. Controls with CT scans were managed similarly to the phlegmon group because of prolonged amylase elevation and abdominal pain. Percutaneous aspiration was successful in differentiating abscess from phlegmon in five of six cases. Major complications were rare in the phlegmon group and spontaneous resolution was the rule. Pancreatic phlegmon is a distinct clinical/radiologic entity which may be very difficult to differentiate clinically from pancreatic abscess. Early percutaneous thin-needle aspiration of the inflammatory mass (under CT guidance) seems to be the diagnostic procedure of choice. Management is nonsurgical unless complications arise. The role of TPN and antibiotics is unknown, and controlled studies of these therapeutic approaches in pancreatic phlegmon are needed.


Spatial organization of AMPAR subtypes in ON RGCs.
Retinal ganglion cells (RGCs) receive glutamatergic input from bipolar cells through NMDA- and AMPA-type glutamate receptors. Both GluA2-containing, Ca(2+)-impermeable AMPA receptors (CI-AMPARs) and GluA2-lacking, Ca(2+)-permeable AMPA receptors (CP-AMPARs) contribute to light-evoked responses in ON RGCs; however, specific roles for each subtype are not well understood. Here, we present evidence that light intensity determines the subtype of AMPAR that is activated during the synaptic response in ON RGCs. Using current voltage analysis of the EPSC we show that light intensities near RGC threshold, intensities that travel through the well described primary rod pathway, evoke synaptic currents that are preferentially mediated by CP-AMPARs. Synaptic responses evoked by spontaneous release of transmitter from bipolar cell terminals also preferentially activate CP-AMPARs. Conversely, higher light intensities, most likely carried by secondary rod pathways, activate CI-AMPARs. The same pattern of CP-AMPAR and CI-AMPAR activation was observed in mice containing only functional rods, suggesting that the recruitment of CI-AMPARs at higher light intensity does not require cone stimulation. When glutamate spillover was induced by blocking transporters with TBOA, both the near threshold and spontaneous EPSCs contained a significant CI-AMPAR component. We propose that CI-AMPARs are activated by "spillover" of synaptic glutamate only during bright illumination, or when glutamate uptake is blocked. Glutamate may spill over to more distant sites at the same synapse, or perhaps as far as neighboring synapses. Together, our data suggest that the spatial organization of AMPARs at ON RGCs synapses allows for selective, intensity-dependent activation of AMPARs with distinct subunit composition.


Development of a high-dynamic range, GFP-based FRET probe sensitive to oxidative microenvironments.
We report the optimization of a novel redox-sensitive probe with enhanced dynamic range and an exceptionally well-positioned oxidative midpoint redox potential. The present work characterizes factors that contribute to the improved Förster resonance energy transfer (FRET) performance of this green fluorescent protein (GFP)-based redox sensor. The α-helical linker, which separates the FRET donor and acceptor, has been extended in the new probe and leads to a decreased FRET efficiency in the linker's reduced, 'FRET-off' state. Unexpectedly, the FRET efficiency is increased in the new linker's oxidized, 'FRET-on' state compared with the parent probe, in spite of the longer linker sequence. The combination of a lowered baseline 'FRET-off' and an increased 'FRET-on' signal significantly improves the dynamic range of the probe for a more robust discrimination of its reduced and oxidized linker states. Mutagenesis of the cysteine residues within the α-helix linker reveals the importance of the fourth, C-terminal cysteine and the relative insignificance of the second cysteine in forming the disulfide bridge to clamp the linker into the high-FRET, oxidized state. To further optimize the performance of the redox probe, various cyan fluorescent protein (CFP)/yellow fluorescent protein (YFP) FRET pairs, placed at opposite ends of the improved redox linker (RL7), were quantitatively compared and exchanged. We found that the CyPet/YPet and ECFP/YPet FRET pairs when attached to RL7 do not function well as sensitive redox probes due to a strong tendency to form heterodimers, which disrupt the α-helix. However, monomeric versions of CyPet and YPet (mCyPet and mYPet) eliminate dimerization and restore redox sensitivity of the probe. The best performing probe, ECFP-RL7-EYFP, exhibits an approximately six-fold increase in FRET efficiency in vitro when passing from the oxidized to the reduced state. We determined the midpoint redox potential of the probe to be -143 ± 6 mV, which is ideal for measuring glutathione (GSH/GSSG) redox potentials in oxidative compartments of mammalian cells (e.g. the endoplasmic reticulum).


[Differential diagnosis of late endogenous affective psychoses].
On the basis of examining 102 patients with late endogenous affective psychoses, it has been shown that among them (like among younger patients) there exists a group of cases the nosological differentiation of which based on conventional criteria presents certain difficulties. However, in the older patients these "intermediate" cases are more frequent (about 30% of all cases) than in the younger ones. It has been also shown that at the older age the nosologically more typical paroxysmal and/or phasic endogenous psychoses are void of a number of clinico-nosological properties characteristic of analogous diseases of the younger age.


Nutrient intake and adherence to dietary recommendations among US workers.
To assess nutrient intake according to dietary guidelines among US worker groups. Participants of 1999 to 2004 National Health and Nutrition Examination Survey completed two 24-hour recall dietary interviews to assess daily intake of protein, carbohydrate, fat, cholesterol, calcium, sodium, and fiber. Employed participants (n = 8987) were classified as (1) white collar, (2) service worker, (3) farmer, and (4) blue collar. Nutrient intake varied by occupational group, particularly for fiber, sodium, calories, and percentage of calories from protein, saturated fat, and carbohydrate. Adherence to recommendations was noted for saturated fat and cholesterol, but workers were poorly adherent to recommendations for all other nutrients, particularly fiber. Workers display differences in nutrient intake across occupational groups with poor eating behaviors evident across all groups. Fiber is particularly poorly consumed, with less than 5% of all US workers meeting the recommendations.


Characterizing the dissemination of misinformation on social media in health emergencies: An empirical study based on COVID-19.
The dissemination of misinformation in health emergencies poses serious threats to public health and increases health anxiety. To understand the underlying mechanism of the dissemination of misinformation regarding health emergencies, this study creatively draws on social support theory and text mining. It also explores the roles of different types of misinformation, including health advice and caution misinformation and health help-seeking misinformation, and emotional support in affecting individuals' misinformation dissemination behavior on social media and whether such relationships are contingent on misinformation ambiguity and richness. The theoretical model is tested using 12,101 textual data about COVID-19 collected from Sina Weibo, a leading social media platform in China. The empirical results show that health caution and advice, help seeking misinformation, and emotional support significantly increase the dissemination of misinformation. Furthermore, when the level of ambiguity and richness regarding misinformation is high, the effect of health caution and advice misinformation is strengthened, whereas the effect of health help-seeking misinformation and emotional support is weakened, indicating both dark and bright misinformation ambiguity and richness. This study contributes to the literature on misinformation dissemination behavior on social media during health emergencies and social support theory and provides implications for practice.


Functional and Anatomical Testing in Intermediate Risk Chest Pain Patients with a High Coronary Calcium Score: Rationale and Design of the FACC Study.
Current guidelines do not recommend coronary computed tomography angiography (CCTA) in patients with high levels of coronary calcium, as severe calcification leads to difficulties in estimating stenosis severity due to blooming artifacts obscuring the vessel lumen. Whether the CCTA-derived fractional flow reserve (FFRCT) improves the diagnostic performance of CCTA in patients with high levels of coronary calcification has not been sufficiently evaluated. We hypothesize that a noninvasive diagnostic strategy using FFRCT will perform comparably to an invasive diagnostic strategy in the detection of hemodynamically significant coronary artery disease (CAD) in clinical stable chest pain patients with high levels of coronary calcium. In this prospective, blinded, multicenter study, patients with suspected stable CAD referred for CCTA and demonstrating an Agatston score >399 will be included. Patients accepting inclusion will, in addition to CCTA, undergo invasive coronary angiography (ICA) and invasive FFR measurement. FFRCT analyses are performed by an external core laboratory blinded to any patient data, and the FFRCT results are blinded to all participating study sites. The primary objective is to evaluate whether FFRCT can identify patients with and without hemodynamically significant CAD, when ICA with FFR is the reference standard. A negative study result would question the clinical usefulness of FFRCT in patients with high levels of coronary calcium. A positive study result, however, would imply a reduction in the number of patients referred for coronary catheterization and, at the same time, increase the proportion of patients with hemodynamically significant CAD at the subsequent invasive examination.


[Quantitative determination of 7 proteins in csf of patients with Guillain Barre syndrome].
Quantitative determinations were done for seven protein components namely albumin, IgG, transferrin, alpha-2 macroglobulin, IgA, IgM and ceruloplasmin in the CSF and sera from patients with Guillain Barré syndrome. The results showed that each of the protein significantly increased. All of these correlated remarkably with the increased values of total proteins in CSF. It seemed that the concentrations of the protein in CSF were influenced by those of the proteins in serum and the size of the corresponding protein molecule.


A differential diagnosis of the inspirational spells of Muhammad the Prophet of Islam.
This paper reviews the spells of Muhammad, the Prophet of Islam. During these spells, Muhammad sensed the approach of a figure whom he thought to be the Angel Gabriel. The inspirational message transmitted to Muhammad during these spells helped form the religion of Islam. This is a review of the historical details of these spells and an attempt to reach a medical diagnosis. Although an unequivocal decision is not possible from existing knowledge, psychomotor or complex partial seizures of temporal lobe epilepsy would be the most tenable diagnosis. An examination of Western civilization's views of Muhammad's spells reveals historical and modern misconceptions about epilepsy.


Organotypic Brain Slices of ADULT Transgenic Mice: A Tool to Study Alzheimer's Disease.
Transgenic mice have been extensively used to study the Alzheimer pathology. In order to reduce, refine and replace (3Rs) the number of animals, ex vivo cultures are used and optimized. Organotypic brain slices are the most potent ex vivo slice culture models, keeping the 3-dimensional structure of the brain and being closest to the in vivo situation. Organotypic brain slice cultures have been used for many decades but were mainly prepared from postnatal (day 8-10) old rats or mice. More recent work (including our lab) now aims to culture organotypic brain slices from adult mice including transgenic mice. Especially in Alzheimer´s disease research, brain slices from adult transgenic mice will be useful to study beta-amyloid plaques, tau pathology and glial activation. This review will summarize the studies using organotypic brain slice cultures from adult mice to mimic Alzheimer's disease and will highlight advantages and also pitfalls using this technique.


Illicit drug use as a challenge to the delivery of end-of-life care services to homeless persons: perceptions of health and social services professionals.
Homeless persons tend to die younger than the housed population and have complex, often unmet, end-of-life care needs. High levels of illicit drug use among this population are a particular challenge for health and social services professionals involved in end-of-life care services delivery. This article explores the challenges of end-of-life care services to homeless illicit drug users based on data collected during a national study on end-of-life care services delivery to homeless persons in Canada. The authors conducted qualitative interviews with 50 health and social services professionals involved in health services delivery to homeless persons in five cities. Interviews were transcribed verbatim and analysed thematically. Themes were organised into two domains. First, barriers preventing homeless illicit drug users from accessing end-of-life care services, such as competing priorities (e.g. withdrawal management), lack of trust in healthcare providers and discrimination. Second, challenges to end-of-life care services delivery to this population in health and social care settings, including non-disclosure of illicit drug use, pain and symptom management, interruptions in care, and lack of experience with addictions. The authors identify a need for increased research on the role of harm reduction in end-of-life care settings to address these challenges.


Diversity in fall characteristics hampers effective prevention: the precipitants, the environment, the fall and the injury.
Falls among the elderly are common and characteristics may differ between injurious and non-injurious falls. Among 887 older Australian women followed for 1.6 years, 32% fell annually. Only 8.5% resulted in fracture and/or hospital admission. The characteristics of those falls are indistinguishable from those not coming to medical attention. The precipitants and environment of all falls occurring among a large cohort of older Caucasian women were categorised by injury status to determine if the characteristics differed between injurious and non-injurious falls. Among 887 Australian women (70+ years), falls were ascertained using monthly postcard calendars and a questionnaire was administered for each fall. Hospital admissions and fractures were independently confirmed. All falls were reported for a mean observation time of 577 (IQR 546-607) days per participant, equating to a total 1400 person-years. Thirty-two percent fell at least once per year. The most common features of a fall were that the faller was walking (61%) at home (61%) during the day (88%) and lost balance (32%). Only 12% of all falls occurred at night. Despite no difference in the type of injury between day and night, the likelihood of being hospitalised from a fall at night was 4.5 times greater than that of a daytime fall with adjustment for injury type and participant age (OR 4.5, 95% CI 2.1, 9.5; p < 0.001). Of all falls, approximately one third were associated with no injury to the faller (31%), one third reported a single injury (37%) and one third reported more than one injury (32%). In 95% of falls, the faller was not admitted to hospital. Only 5% of falls resulted in fracture(s). Our findings demonstrate the significant diversity of precipitants and environment where falls commonly occur among older community-dwelling women. Falls resulting in fracture and/or hospital admission collectively represent 8.5% of all falls and their characteristics are indistinguishable from falls not coming to medical attention and incurring no apparent cost to the health system.


Ghana 3D Telemedicine International MDT: A proof-of-concept study.
A real-time 3D Telemedicine system - leveraging Microsoft's Holoportation™ communication technology - enabled an international multidisciplinary team meeting (MDT) to consult with complex reconstructive patients before, during, and after an overseas surgical collaboration. A proof-of-concept international 3D MDT clinic took place in November 2022, between the Canniesburn Plastic Surgery Unit, UK, and the National Reconstructive Plastic Surgery and Burns Centre, Korle Bu Teaching Hospital, Ghana. The 3D system was utilised 1) previsit to assess patients and enable logistical planning, 2) on-site in Ghana to further allow patients to see themselves and proposed operations in 3D, and 3) post visit to debrief the team and patients. Four Ghana patients were followed through their patient journey (mandibular ameloblastoma, sarcoma thigh, maxillary tumour, sarcoma back). Thirteen participants (four patients, four Ghana clinicians, and five UK clinicians) completed feedback on the 3D MDT. Outcome measures were rated highly with satisfaction 84.31/100, perceived benefit 4.54/5, overall quality 127.3/147 (Telehealth Usability Questionnaire), and usability 83.2/100 (System Usability Scale). These data show close alignment with that previously published on high-income countries. This novel technology has the potential to enhance the delivery of overseas surgical visits to low-to-middle-income countries, by improving planning, informed discussion with patients, expert consensus on complex cases, and fostering engagement with professionals who may be thousands of miles away. This is the first demonstration that real-time 3D Telemedicine can both work, and enhance care within an international MDT clinic, and may thus enable change in the approach to overseas surgical collaborations.


Genome re-sequencing of semi-wild soybean reveals a complex Soja population structure and deep introgression.
Semi-wild soybean is a unique type of soybean that retains both wild and domesticated characteristics, which provides an important intermediate type for understanding the evolution of the subgenus Soja population in the Glycine genus. In this study, a semi-wild soybean line (Maliaodou) and a wild line (Lanxi 1) collected from the lower Yangtze regions were deeply sequenced while nine other semi-wild lines were sequenced to a 3-fold genome coverage. Sequence analysis revealed that (1) no independent phylogenetic branch covering all 10 semi-wild lines was observed in the Soja phylogenetic tree; (2) besides two distinct subpopulations of wild and cultivated soybean in the Soja population structure, all semi-wild lines were mixed with some wild lines into a subpopulation rather than an independent one or an intermediate transition type of soybean domestication; (3) high heterozygous rates (0.19-0.49) were observed in several semi-wild lines; and (4) over 100 putative selective regions were identified by selective sweep analysis, including those related to the development of seed size. Our results suggested a hybridization origin for the semi-wild soybean, which makes a complex Soja population structure.


Long-term remission following withdrawal of dopamine agonist therapy in subjects with microprolactinomas.
Reports suggest that up to 70% of patients with microprolactinomas treated with dopamine agonist therapy may achieve long-term normoprolactinaemic remission following drug withdrawal. Yet, there is no consensus on the duration of therapy nor is therapeutic interruption universally practised. We have assessed remission rates in a large cohort of treatment-naive subjects with microprolactinomas. Subjects received dopamine agonist (DA) therapy with either cabergoline or bromocriptine for a period of 2 to 3 years in the majority of cases, followed by a trial of treatment withdrawal. Retrospective analysis of clinic records of 89 patients (mean age 32.7 +/- 8.4 years, 84 women and 5 men) who had received either cabergoline (n = 67) (0.5-3 mg weekly) or bromocriptine (n = 22) (2.5-10 mg daily) for a mean duration of 3.1 years. Following withdrawal of therapy, 57 subjects developed recurrence (64%) and the mean time to recurrence was 9.6 months (range 1-44 months), while 32 subjects (36%) remained in remission beyond 1 year (mean 3.6 years, range 1-7 years). There was no difference in remission rates between subjects treated with cabergoline (n = 21) and bromocriptine (n = 11), but a direct relationship between pretreatment prolactin concentration and risk of recurrent symptomatic hyperprolactinaemia was observed. No subjects developed clinical features to suggest tumour expansion following therapeutic discontinuation. This study confirms that abrupt withdrawal of chronic dopamine agonist therapy, following 2 to 3 years of treatment is safe and associated with long-term remission in 30-40% of subjects with microprolactinomas. This therapeutic strategy is convenient and applicable in clinical practice.


Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX, and Fas-mediated cell death does not involve DAXX, RIP, or RAIDD.
Jun kinase signaling can be elicited by death receptor activation, but the mechanism and significance of this event are still unclear. It has been reported that cross-linking Abs to Fas trigger c-Jun N-terminal kinase (JNK) signaling via caspase-mediated activation of MEKK1 (JNK kinase kinase), elevation of ceramide levels or by recruitment of death domain associated protein (DAXX) to Fas. The effect of physiological ligand for Fas on JNK signaling was never investigated, although evidence is accumulating that Fas ligand is able to induce cellular responses distinct from those evoked by Ab-mediated cross-linking of Fas. Therefore, we investigated the effect of Fas ligand on JNK signaling. Like its ability to induce cell death, Fas ligand reliably activated JNK only upon extensive aggregation of the receptor. Although this was partially dependent on caspase activation, DAXX was not required. DAXX and other death receptor-associated proteins, which have been reported to bind directly or indirectly to Fas, such as receptor interacting protein (RIP) and RIP-associated ICH-1/CED-3-homologous protein with a death domain (RAIDD), were shown to be dispensable for Fas ligand-induced apoptosis.


Persistence of herpes simplex virus DNA in cerebrospinal fluid of neonates with herpes simplex virus encephalitis.
The significance of detecting herpes simplex virus (HSV) DNA in the cerebrospinal fluid (CSF) of infants with HSV encephalitis after receipt of prolonged therapy with high-dose (60 mg kg(-1) day(-1)) acyclovir is unknown. We report the clinical and laboratory characteristics, neuroimaging studies and outcomes of four neonates with HSV encephalitis who had persistence of CSF HSV DNA, by polymerase chain reaction (PCR) after 15 to 21 days of high-dose acyclovir therapy. Retrospective chart review. All four infants had abnormal neuroimaging studies and subsequently experienced severe developmental delay or death. A persistently positive CSF HSV PCR in neonates may be another risk factor for worse neurodevelopmental outcome. Prospective studies are needed to document how often HSV DNA persists in CSF, elucidate whether it represents an initially high CSF viral load, ongoing viral replication or viral resistance, and determine its possible association with neurodevelopmental impairment.


African iron overload.
African iron overload has been recognised in sub-Saharan Africa for seventy years. The condition is distinct from the well-characterised HLA-linked haemochromatosis described in Caucasians. Increased dietary iron intake predisposes to the condition. Recent evidence suggest that African iron overload may be caused by an interaction between increased dietary iron and a genetic defect not associated with the HLA-locus. Iron deposition is prominent both in macrophages and in hepatic parenchymal cells. Iron overload is distinct from alcoholic liver disease, although the excess dietary iron is derived from a traditional beverage that contains alcohol. African iron overload has clinical consequences. It is a cause of hepatic fibrosis and cirrhosis, and associations with diabetes mellitus, peritonitis, scurvy and osteoporosis have been described. African iron overload may be a cause of hepatocellular carcinoma. The disorder is associated with a poor outcome in tuberculosis, an infection that is highly prevalent in sub-Saharan Africa.


Novel aspects of striatal plasticity associated with long-term levo-dopa administration.
"Striatal plasticity" is a term describing a variety of morphological and functional changes occurring both at pre- and post-synaptic level within the basal ganglia. In most cases striatal plasticity occurs when a loss of dopamine (DA) fibers in the striatum, in the course of Parkinsonism takes place. Plastic events include early pre-synaptic and long-term post-synaptic changes. In the context of long-term changes associated with striatal plasticity the role of intrinsic striatal catecholamine cells is emerging. This neuronal population expresses both tyrosine hydroxylase (TH) and DA transporter (DAT). These TH-positive cells are normally resident within the human caudate putamen but they dramatically increase during parkinsonism reaching an amount roughly corresponding to 50% of nigrostriatal neurons counted in control brains. This evidence led to hypothesize fascinating mechanisms bridging these neurons either with compensatory changes or the onset of aberrant behavioral activity. Very recently the occurrence of these neurons was described during DA replacement therapy in parkinsonism, thus suggesting that these cells may represent the anatomical basis for plastic phenomena. Thus, the present article, in the attempt to describe novel mechanisms generating striatal plasticity, details these cells in development and adult life and their potential role in maturation phenomena occurring in parkinsonism.


Let the Chart Spark: Embedding Semantic Context into Chart with Text-to-Image Generative Model.
Pictorial visualization seamlessly integrates data and semantic context into visual representation, conveying complex information in an engaging and informative manner. Extensive studies have been devoted to developing authoring tools to simplify the creation of pictorial visualizations. However, mainstream works follow a retrieving-and-editing pipeline that heavily relies on retrieved visual elements from a dedicated corpus, which often compromise data integrity. Text-guided generation methods are emerging, but may have limited applicability due to their predefined entities. In this work, we propose ChartSpark, a novel system that embeds semantic context into chart based on text-to-image generative models. ChartSpark generates pictorial visualizations conditioned on both semantic context conveyed in textual inputs and data information embedded in plain charts. The method is generic for both foreground and background pictorial generation, satisfying the design practices identified from empirical research into existing pictorial visualizations. We further develop an interactive visual interface that integrates a text analyzer, editing module, and evaluation module to enable users to generate, modify, and assess pictorial visualizations. We experimentally demonstrate the usability of our tool, and conclude with a discussion of the potential of using text-to-image generative models combined with an interactive interface for visualization design.


Utility of multispectral imaging in automated quantitative scoring of immunohistochemistry.
Automated scanning devices and image analysis software provide a means to overcome the limitations of manual semiquantitative scoring of immunohistochemistry. Common drawbacks to automated imaging systems include an inability to classify tissue type and an inability to segregate cytoplasmic and nuclear staining. Immunohistochemistry for the membranous marker α-catenin, the cytoplasmic marker stathmin and the nuclear marker Ki-67 was performed on tissue microarrays (TMA) of archival formalin-fixed paraffin-embedded tissue comprising 471 (α-catenin and stathmin) and 511 (Ki-67) cases of prostate adenocarcinoma. These TMA were quantitatively analysed using two commercially available automated image analysers, the Ariol SL-50 system and the Nuance system from CRi. Both systems use brightfield microscopy for automated, unbiased and standardised quantification of immunohistochemistry, while the Nuance system has spectral deconvolution capabilities. Overall concordance between scores from both systems was excellent (r=0.90; 0.83-0.95). The software associated with the multispectral imager allowed accurate automated classification of tissue type into epithelial glandular structures and stroma, and a single-step segmentation of staining into cytoplasmic or nuclear compartments allowing independent evaluation of these areas. The Nuance system, however, was not able to distinguish reliably between tumour and non-tumour tissue. In addition, variance in the labour and time required for analysis between the two systems was also noted. Despite limitations, this study suggests some beneficial role for the use of a multispectral imaging system in automated analysis of immunohistochemistry.


Occurrence of Toxoplasma gondii in water from wells located on farms.
Among various species of parasitic protozoans which may contaminate drinking water, Toxoplasma gondii is of a special importance due to the high incidence of infections with this parasite noted in animals and humans. The objective of this study was to determine the frequency of occurrence of T. gondii in drinking water on farms in the area of the Lublin province (eastern Poland) with respect to health risk among the inhabitants, and to assess the role of water in the transmission of Toxoplasma infections in the rural environment. Studies were conducted on 87 farms located in the Lublin province, 14 of which were classified as possessing a good hygienic state, and 73 as possessing a poor hygienic state. A total number of 114 drinking water samples were taken, 80 samples from shallow household wells with a windlass, 16 from deep wells with a pump, and 18 from the water supply system. In microscopic and PCR examinations of 114 water samples, T. gondii was found in 15 (13.2%) and 31 (27.2%) of samples, respectively. The presence of T. gondii DNA detected by PCR test was found significantly more frequently in water samples from the shallow windlass-operated wells than in those from deep wells (p < 0.05) and water supply system (p < 0.01). Water samples collected from shallow wells located on farms of poor hygienic state contained significantly more frequently DNA of T. gondii than samples from shallow wells located on farms of good hygienic state (43.1% vs. 13.3%, p < 0.05). In 26.3% of water samples, oocysts of other protozoans were found belonging to Isospora, Eimeria, and Cryptosporidium. Serologic examinations for the presence of anti-Toxoplasma antibodies conducted among 99 inhabitants of the farms where household wells were used showed 64.6% of seropositive results in IgG class antibodies and 1.0% in IgM class antibodies. Clinical cases of toxoplasmosis were also noted. In the total population examined, a positive correlation was observed between the consumption of unboiled well water and the presence of antibodies against T. gondii (p < 0.05), this correlation being especially strong on farms of poor hygienic state enclosing shallow wells (p < 0.001). In conclusion, the recorded presence of T. gondii in well water provides an evidence of the potential risk of waterborne infection for humans and animals. Therefore, it seems necessary to implement prophylactic actions on the endangered farms.


Electrospun fibers of chitosan-grafted polycaprolactone/poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) blends.
Chitosan-grafted polycaprolactone (CS-g-PCL)/poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) fiber blends were prepared via wet electrospinning, and their morphology, hydrophilicity, water absorption, biodegradation, cytotoxicity, and thermal, mechanical and antibacterial properties were analyzed. IR spectra revealed strong H-bonding interactions between CS-g-PCL and PHBHHx. SEM and DSC analysis confirmed the immiscibility of the blends at all compositions studied. As the proportion of CS-g-PCL increased, the overall crystallinity of the blends increased, the melting temperature of PCL decreased, and each component promoted the crystallization of the others. The hydrophilicity, water absorption and weight loss in buffered solution decreased as the PHBHHx content increased. DMA and tensile tests indicated a synergistic effect on the mechanical properties at a blend composition of 70/30, leading to an optimal combination of stiffness, strength, ductility and toughness. The fibers retained adequate rigidity and strength under physiological conditions. The 70/30 blend exhibited the highest biocide action against Gram-positive and Gram-negative bacteria. The fibers did not induce toxicity over human dermal fibroblasts. These biodegradable, biocompatible electrospun fibers could be used as scaffolds for tissue engineering.


The effects of lifestyle change on indicators of cardiometabolic health in semi-nomadic pastoralists.
Non-communicable disease risk and the epidemic of cardiometabolic diseases continue to grow across the expanding industrialized world. Probing the relationships between evolved human physiology and modern socioecological conditions is central to understanding this health crisis. Therefore, we investigated the relationships between increased market access, shifting subsistence patterns and cardiometabolic health indicators within Daasanach semi-nomadic pastoralists who vary in their engagement in traditional lifestyle and emerging market behaviors. We conducted cross-sectional socioecological, demographic and lifestyle stressor surveys along with health, biomarker and nutrition examinations among 225 (51.6% female) Daasanach adults in 2019-2020. We used linear mixed-effects models to test how differing levels of engagement in market integration and traditional subsistence activities related to blood pressure (BP), body composition and blood chemistry. We found that systolic and diastolic BP, as well as the probability of having high BP (hypertension), were negatively associated with distance to market, a proxy for market integration. Additionally, body composition varied significantly by socioeconomic status (SES), with significant positive associations between BMI and body fat and higher SES among adults. While evidence for evolutionary mismatch and health variation have been found across a number of populations affected by an urban/rural divide, these results demonstrate the effects of market integration and sedentarization on cardiometabolic health associated with the early stages of lifestyle changes. Our findings provide evidence for the changes in health when small-scale populations begin the processes of sedentarization and market integration that result from myriad market pressures.


A quantum chemical and statistical study of flavonoid compounds (flavones) with anti-HIV activity.
The molecular orbital semi-empirical method AM1 was employed to calculate a set of molecular properties (variables) of 22 flavonoid compounds (flavones) with anti-HIV-1 activity and nine new compounds were proposed for anti-HIV-1 activity prediction. Pattern recognition techniques, principal component analysis (PCA), hierarchical cluster analysis (HCA), stepwise discriminant analysis (SDA) and K-nearest neighbor (KNN), were employed in order to reduce dimensionality and investigate which subset of variables could be more effective for classifying the flavones according to their degree of anti-HIV-1 activity. The PCA, HCA, SDA and KNN studies showed that the variables log P (partition coefficient), molecular volume (VOL) and electron affinity (EA) are responsible for the separation between anti-HIV-1 active and inactive compounds. The prediction study was done with a new set of nine analog compounds by using the PCA, HCA, SDA and KNN methods and only one of them was predicted as active against HIV-1.


Tumor suppressor p53 status does not determine the differentiation-associated G₁ cell cycle arrest induced in leukemia cells by 1,25-dihydroxyvitamin D₃ and antioxidants.
Vitamin D derivatives can induce differentiation of human acute myeloid leukemia (AML) cells. Here, we investigated if the G₁ cell cycle block associated with monocytic differentiation is modulated by the p53 status of the cells treated with 1,25D, alone or with plant antioxidants carnosic acid (C) or silibinin (S), and a p38 MAPK inhibitor SB202190 (SB), a combination (D-C/S-SB) previously shown to enhance differentiation of AML p53null cells. D-C/S-SB enhanced differentiation of OCI-AML3 (p53wt) and as expected HL60 (p53 null) cells, but not of MOLM-13 (p53wt) cells. Conversely, MOLM-13 (p53wt) cells treated with 1,25D and/or D-C/S-SB, resembled HL60 (p53 null) cells in rapid G₁ block, while OCI-AML3 (p53wt) cells showed a delayed G₁ block when treated in a similar way, indicating that there is no relationship between the p53 status and G₁ block. Western blot analysis revealed that 1,25D and D-C/S-SB increased the inhibitory phosphorylation levels MEK-1 (P-Thr286), but decreased the levels of activated ERK1/2 (Thr202/Tyr204;Thr185/Tyr187), again without any apparent relationship to the p53 status. Interestingly, the increased levels of p21(Waf1/Cip1) were insufficient to promote a G₁ block in this system, as only cell lines with increased levels of p27(Kip1) and p35Nck5a, an activator of Cdk5, showed a rapid G₁ block. Overall, our data show that the p53-p21 axis is unlikely to have a role in differentiation-associated G₁ block in AML cells with wt p53, and that this block is achieved by several, possibly co-operating but redundant pathways, that include inhibition of MEK-1 by p35Nck5a-activated Cdk5.


Current status of hypertension control around the world.
It is well established that hypertension is an important risk factor for cardiovascular disease. Data from epidemiological and observational studies have demonstrated increasing risk of stroke, myocardial infarction, cardiovascular death and all cause mortality associated with high blood pressure. Despite the significance of the problem with respect to overall health, control of high blood pressure is far from being optimal. Data from the National Health and Nutrition Survey have shown that those achieving target blood pressure values less than 140/90 mmHg are only 34% of the hypertensive population. The situation is no better in the rest of the world and even worse in the developing countries. Epidemiological transition taking place in developing countries with a decline in communicable diseases and an increase in noncommunicable have resulted in an improvement in life expectancy, thus causing predictable shifts in causes of death. Aging of the populations, urbanization and socioeconomic changes in the developing world have led to an increase in the prevalence of hypertension, with low control rates due to scarce health resources and insufficient health infrastructure. Thus prevention, detection, treatment and control of hypertension play a crucial role in protection of cardiovascular disease, not only in the developed countries but also in the developing world and implementation of hypertension guidelines should be reinforced around the world.


Metabolic and functional consequences of introducing inositol 1,4,5-trisphosphate into saponin-permeabilized human platelets.
In an earlier study we reported the effect of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in releasing Ca2+ from highly purified human platelet intracellular membrane vesicles. [Authi & Crawford (1985) Biochem. J. 230, 247-253]. We have now investigated the metabolic and functional consequences of introducing Ins(1,4,5)P3 into saponin-permeabilized platelets. Washed human platelets when resuspended in a suitable medium were permeabilized with saponin (10-14 micrograms/ml) to allow entry of low-Mr water-soluble molecules without significant release of the cytoplasmic marker enzyme protein lactate dehydrogenase. Saponin-permeabilized platelets show identical platelet responses (shape change, aggregation and release of 5-hydroxy[14C]tryptamine) to both collagen (5 micrograms/ml) and thrombin (0.1 unit/ml) as obtained with intact cells, indicating that there is minimal disturbance to the surface membrane receptor topography for these two agonists. Ins(1,4,5)P3 (1-10 microM) added to saponin-treated platelets (but not to intact platelets) induced dose-related shape change, aggregation and release of 5-hydroxy[14C]tryptamine which at maximal doses was comparable with responses obtained with thrombin or collagen. The cyclo-oxygenase inhibitors indomethacin and aspirin, if added prior to saponization and Ins(1,4,5)P3 addition, completely inhibited both aggregation and release of 5-hydroxy[14C]tryptamine (EC50 for indomethacin, 50 nM; for aspirin, 30 microM). We believe that Ins(1,4,5)P3 induces the release of Ca2+ from intracellular storages sites which stimulates the Ca2+-dependent phospholipase A2 releasing arachidonic acid from membrane phospholipids. Arachidonic acid is then converted to the aggregatory prostanoids (prostaglandin H2 and thromboxane A2) resulting in the observed responses. This concept is supported by the use of the thromboxane receptor antagonists EPO 45 and EPO 92, both of which also completely inhibit Ins(1,4,5)P3-induced responses in saponin-permeabilized platelets. Electron microscopy of the platelet preparations revealed that thrombin- and collagen-induced platelet aggregates of intact and saponized cells were identical, showing extensive pseudopod formation and dense granule release. The Ins(1,4,5)P3-induced aggregates also showed similar dense granule release but an almost total absence of pseudopod formation. These results are discussed in the light of the second messenger role of Ins(1,4,5)P3 in stimulus-response coupling in platelets.


Low-complexity transcoding of JPEG images with near-optimal quality using a predictive quality factor and scaling parameters.
A common transcoding operation consists of reducing the file size of a JPEG image to meet bandwidth or device constraints. This can be achieved by reducing its quality factor (QF) or reducing its resolution, or both. In this paper, using the Structural SIMilarity (SSIM) index as the quality metric, we present a system capable of estimating the QF and scaling parameters to achieve optimal quality while meeting a device's constraints. We then propose a novel low-complexity JPEG transcoding system which delivers near-optimal quality. The system is capable of predicting the best combination of QF and scaling parameters for a wide range of device constraints and viewing conditions. Although its computational complexity is an order of magnitude smaller than the system providing optimal quality, the proposed system yields quality results very similar to those of the optimal system.


Development of a Multisensory Wearable System for Monitoring Cigarette Smoking Behavior in Free-Living Conditions.
This paper presents the development and validation of a novel multi-sensory wearable system (Personal Automatic Cigarette Tracker v2 or PACT2.0) for monitoring of cigarette smoking in free-living conditions. The contributions of the PACT2.0 system are: (1) the implementation of a complete sensor suite for monitoring of all major behavioral manifestations of cigarette smoking (lighting events, hand-to-mouth gestures, and smoke inhalations); (2) a miniaturization of the sensor hardware to enable its applicability in naturalistic settings; and (3) an introduction of new sensor modalities that may provide additional insight into smoking behavior e.g., Global Positioning System (GPS), pedometer and Electrocardiogram(ECG) or provide an easy-to-use alternative (e.g., bio-impedance respiration sensor) to traditional sensors. PACT2.0 consists of three custom-built devices: an instrumented lighter, a hand module, and a chest module. The instrumented lighter is capable of recording the time and duration of all lighting events. The hand module integrates Inertial Measurement Unit (IMU) and a Radio Frequency (RF) transmitter to track the hand-to-mouth gestures. The module also operates as a pedometer. The chest module monitors the breathing (smoke inhalation) patterns (inductive and bio-impedance respiratory sensors), cardiac activity (ECG sensor), chest movement (three-axis accelerometer), hand-to-mouth proximity (RF receiver), and captures the geo-position of the subject (GPS receiver). The accuracy of PACT2.0 sensors was evaluated in bench tests and laboratory experiments. Use of PACT2.0 for data collection in the community was validated in a 24 h study on 40 smokers. Of 943 h of recorded data, 98.6% of the data was found usable for computer analysis. The recorded information included 549 lighting events, 522/504 consumed cigarettes (from lighter data/self-registered data, respectively), 20,158/22,207 hand-to-mouth gestures (from hand IMU/proximity sensor, respectively) and 114,217/112,175 breaths (from the respiratory inductive plethysmograph (RIP)/bio-impedance sensor, respectively). The proposed system scored 8.3 ± 0.31 out of 10 on a post-study acceptability survey. The results suggest that PACT2.0 presents a reliable platform for studying of smoking behavior at the community level.


The Relationship between Health Information Technology Laboratory Tracking Systems and Hospital Financial Performance and Quality.
The objective of this study is to explore the relationship between hospitals Health Information Technology (HIT), and financial and quality performance. The study merged the 2017 Centers for Medicare & Medicaid Services (CMS) Healthcare Cost Report Information System, American Hospital Association Annual Survey, and two CMS Hospital Compare datasets. A total of 3002 hospitals were analyzed using multivariate analysis. We found that hospitals with laboratory tracking systems reported better financial performance on five financial performance measures. Policymakers should consider developing policies that facilitate exploration and adoption of various hospital HIT capabilities that measurably improves hospital quality of care.


[One of the variants of lucid catatonia with long-term remissions].
The presentation concerns 10 observations of lucid catatonia and protracted remission. Among the group of schizophrenia these cases constitute only 0.8% of all cases. They are characterized by a prevalence of negative signs and catatonic disorders which can be alloted to the anergic pole and are seen during the entire development of the disease. The most striking feature of such cases is their "outpatient" development of the process. The protracted remissions (15-37 years) are characterized by an expressed defect without positive symptoms.


Lung cancer among workers in chromium chemical production.
An elevated risk of lung cancer among workers in chromate production facilities has previously been reported. This excess risk is believed to be the result of exposure to hexavalent chromium. There have been mixed reports about whether trivalent chromium exposure is also associated with an excess lung cancer risk. Previous studies of measured hexavalent chromium exposure and lung cancer risk have not examined cigarette smoking as a risk factor. A cohort of 2,357 workers first employed between 1950 and 1974 at a chromate production plant was identified. Vital status of the workers was followed until December 31, 1992. Work histories of cohort members were compiled from the beginning of employment through 1985, the year the plant closed. Annual average exposure estimates, based on historical exposure measurements, were made for each job title in the plant for the years 1950-1985. These exposure estimates were used to calculate the cumulative hexavalent chromium exposure of each member of the study population. Following closure of the plant, settled dust samples were collected and analyzed for hexavalent and trivalent chromium. The trivalent/hexavalent concentration ratios in each plant area were combined with historic air-sampling data to estimate cumulative trivalent chromium exposure for each individual in the study cohort. Smoking status (yes/no) as of the beginning of employment and clinical signs of potential chromium irritation were identified from company records. Cumulative hexavalent chromium exposure showed a strong dose-response relationship for lung cancer. Clinical signs of irritation, cumulative trivalent chromium exposure, and duration of work were not found to be associated with a risk of lung cancer when included in a proportional hazards model with cumulative hexavalent chromium exposure and smoking. Age-specific data on cumulative hexavalent chromium exposure, observed and expected numbers of lung cancer cases, and person-years of observation are provided. Cumulative hexavalent chromium exposure was associated with an increased lung cancer risk; cumulative trivalent chromium exposure was not. The excess risk of lung cancer associated with cumulative hexavalent chromium exposure was not confounded by smoking status. The current study offers the best quantitative evidence to date of the relationship between hexavalent chromium exposure and lung cancer. Am. J. Ind. Med. 38:115-126, 2000. Published 2000 Wiley-Liss, Inc.


Psychological distress after stroke and aphasia: the first six months.
We explored the factors that predicted psychological distress in the first six months post stroke in a sample including people with aphasia. Prospective longitudinal observational study. Participants with a first stroke from two acute stroke units were assessed while still in hospital (baseline) and at three and six months post stroke. Distress was assessed with the General Health Questionnaire-12. Other measures included: NIH Stroke Scale, Barthel Index, Frenchay Aphasia Screening Test, Frenchay Activities Index, MOS Social Support Scale and social network indicators. Logistic regression was used to identify predictors of distress at each stage post stroke; and to determine what baseline factors predicted distress at six months. Eighty-seven participants were able to self-report on measures used, of whom 32 (37%) had aphasia. 71 (82%) were seen at six months, including 11 (16%) with aphasia. Predictors of distress were: stroke severity at baseline; low social support at three months; and loneliness and low satisfaction with social network at six months. The baseline factors that predicted distress at six months were psychological distress, loneliness and low satisfaction with social network (Nagelkerke R(2) = 0.49). Aphasia was not a predictor of distress at any time point. Yet, at three months post stroke 93% of those with aphasia experienced high distress, as opposed to 50% of those without aphasia (chi(2) (1) = 8.61, P<0.01). Factors contributing to distress after stroke vary across time. Loneliness and low satisfaction with one's social network are particularly important and contribute to long-term psychological distress.


Autophagy in unicellular eukaryotes.
Cells need a constant supply of precursors to enable the production of macromolecules to sustain growth and survival. Unlike metazoans, unicellular eukaryotes depend exclusively on the extracellular medium for this supply. When environmental nutrients become depleted, existing cytoplasmic components will be catabolized by (macro)autophagy in order to re-use building blocks and to support ATP production. In many cases, autophagy takes care of cellular housekeeping to sustain cellular viability. Autophagy encompasses a multitude of related and often highly specific processes that are implicated in both biogenetic and catabolic processes. Recent data indicate that in some unicellular eukaryotes that undergo profound differentiation during their life cycle (e.g. kinetoplastid parasites and amoebes), autophagy is essential for the developmental change that allows the cell to adapt to a new host or form spores. This review summarizes the knowledge on the molecular mechanisms of autophagy as well as the cytoplasm-to-vacuole-targeting pathway, pexophagy, mitophagy, ER-phagy, ribophagy and piecemeal microautophagy of the nucleus, all highly selective forms of autophagy that have first been uncovered in yeast species. Additionally, a detailed analysis will be presented on the state of knowledge on autophagy in non-yeast unicellular eukaryotes with emphasis on the role of this process in differentiation.


Dentistry at the crossroads.
The dental practice pattern is shifting from small dental office to large corporate dental groups. This article analyzes the powers behind this change, and discusses the choices dental practitioners are facing and the reasons why many may choose to work in a corporate practice setting. Dental associations and specialty groups need to reaffirm their mission to provide quality oral health care. Dental treatment should not be viewed as a commodity used to measure corporate profitability.


Effects of captopril on contractility after myocardial infarction: experimental observations.
After large myocardial infarction, compromised left ventricular (LV) function and changes in the peripheral circulation result in the syndrome of chronic congestive heart failure. Although treatment with angiotensin-converting enzyme inhibitors improve cardiovascular function, it is difficult to determine whether this benefit is due to changes in organ versus muscle function. The rat model of heart failure, created by ligating the left coronary artery, results in pathophysiology that is similar to that seen in patients, i.e., increased LV end-diastolic pressure and volume, hypertrophy of the noninfarcted myocardium, prolongation of the time constant of LV relaxation, decreased venous compliance, and increased total blood volume. In noninfarcted papillary muscles, isolated from rats with heart failure, maximal developed tension and peak rate of tension rise (+dT/dt) are decreased, time to peak tension is prolonged, and myocardial stiffness is increased. Morphologic changes include an increase in papillary muscle myocyte cross-sectional area and an increase in myocardial hydroxyproline content. Captopril (2 g/liter drinking water) alters LV loading by decreasing arterial pressure, increasing venous compliance, and decreasing blood volume. This results in a decrease in LV end-diastolic pressure and volume. In the noninfarcted myocardium, time to peak tension is shortened, whereas developed tension, +dT/dt, and muscle stiffness remain abnormal. Captopril decreases myocyte cross-sectional area, but collagen content remains elevated. Thus, in the rat infarct model of heart failure, treatment with captopril alters LV remodeling and hypertrophy but produces only modest improvement in muscle function.(ABSTRACT TRUNCATED AT 250 WORDS)


Toward a rational management of concomitant carotid and coronary artery disease.
Patients with angina undergoing carotid endarterectomy have a high perioperative mortality. Our aim was to assess the outcome of carotid endarterectomy in patients with concomitant coronary artery disease, in particular, to examine the timing of carotid endarterectomy and CABG. A retrospective study was performed at a tertiary and secondary referral centre for cardiovascular disease. Over a five-year period 71 carotid endarterectomies and 6,590 coronary artery bypasses were performed. Significant (>70%) internal carotid stenoses were found in 35 (0.5%) patients due for CABG. Of these, 23 patients underwent Combined procedures (Carotid and CABG), 9 Reverse staged (CABG then Carotid), and 3 Prior staged carotid endarterectomies (Carotid then CABG). 36 other carotid endarterectomies were in patients evaluated cardiologically, but did not require CABG (Isolated group). Risk factors, 30 day perioperative outcome including hospital inpatient stay and early follow-up are reported. The Combined group 30-day perioperative mortality rate was 4.3% and permanent stroke rate 8.6%. There were no major complications in Reverse or Prior staged cases. Isolated group mortality was 2.7% with no strokes. Risk factors were more prevalent in the combined group; 56% previous myocardial infarction, 39% hypertension, 35% a history of raised cholesterol and 46% intermittent claudication. All cases were followed up for a mean of 18.4 months, with no carotid stroke related events. Overall hospital stay for staged patients was a mean 19.3 days (SE=2.4) days compared to mean 9.8 days for combined patients (SE=0.97, p<0.001). Patients with combined cardiac and carotid disease benefit from assessment of both systems in order to stage CABG and carotid endarterectomy. Risk factors were more prevalent in the combined group; a combined procedure offered a median difference of 8 days less hospital inpatient stay compared to the staged cases. Our experience suggests that carefully planned management of concomitant coronary and carotid disease can achieve better results.


Patterns of density dependence in measles dynamics.
An important question in metapopulation dynamics is the influence of external perturbations on the population's long-term dynamic behaviour. In this paper we address the question of how spatiotemporal variations in demographic parameters affect the dynamics of measles populations in England and Wales. Specifically, we use nonparametric statistical methods to analyse how birth rate and population size modulate the negative density dependence between successive epidemics as well as their periodicity. For the observed spatiotemporal data from 60 cities, and for simulated model data, the demographic variables act as bifurcation parameters on the joint density of the trade-off between successive epidemics. For increasing population size, a transition occurs from an irregular unpredictable pattern in small communities towards a regular, predictable endemic pattern in large places. Variations in the birth rate parameter lead to a bifurcation from annual towards biennial cyclicity in both observed data and model data.


Finite-temperature many-body perturbation theory for anharmonic vibrations: Recursions, algebraic reduction, second-quantized reduction, diagrammatic rules, linked-diagram theorem, finite-temperature self-consistent field, and general-order algorithm.
A unified theory is presented for finite-temperature many-body perturbation expansions of the anharmonic vibrational contributions to thermodynamic functions, i.e., the free energy, internal energy, and entropy. The theory is diagrammatically size-consistent at any order, as ensured by the linked-diagram theorem proved in this study, and, thus, applicable to molecular gases and solids on an equal footing. It is also a basis-set-free formalism, just like its underlying Bose-Einstein theory, capable of summing anharmonic effects over an infinite number of states analytically. It is formulated by the Rayleigh-Schrödinger-style recursions, generating sum-over-states formulas for the perturbation series, which unambiguously converges at the finite-temperature vibrational full-configuration-interaction limits. Two strategies are introduced to reduce these sum-over-states formulas into compact sum-over-modes analytical formulas. One is a purely algebraic method that factorizes each many-mode thermal average into a product of one-mode thermal averages, which are then evaluated by the thermal Born-Huang rules. Canonical forms of these rules are proposed, dramatically expediting the reduction process. The other is finite-temperature normal-ordered second quantization, which is fully developed in this study, including a proof of thermal Wick's theorem and the derivation of a normal-ordered vibrational Hamiltonian at finite temperature. The latter naturally defines a finite-temperature extension of size-extensive vibrational self-consistent field theory. These reduced formulas can be represented graphically as Feynman diagrams with resolvent lines, which include anomalous and renormalization diagrams. Two order-by-order and one general-order algorithms of computing these perturbation corrections are implemented and applied up to the eighth order. The results show no signs of Kohn-Luttinger-type nonconvergence.


Predictors of survival in periampullary cancers following pancreaticoduodenectomy.
Cancers of the ampulla of Vater, distal common bile duct, and pancreas are known to have dismal prognosis. It is often reported that ampullary cancers are less aggressive relative to the other periampullary carcinomas. We sought to evaluate predictors of survival for periampullary cancers following pancreaticoduodenectomy to identify biologic behavior. We reviewed the records of all patients who underwent pancreaticoduodenectomy for periampullary carcinoma between 1992 and 2007 at the Ohio State University Medical Center. Demographics, treatment, and outcome/survival data were analyzed. Kaplan-Meier survival curves were created and compared by log-rank analysis. Multivariate analysis was undertaken using Cox proportional-hazards method. 346 consecutive periampullary malignancies (249 pancreatic cancers, 79 ampullary carcinomas, 18 extrahepatic cholangiocarcinomas) treated by pancreaticoduodenectomy were identified. Pancreatic cancer histology correlated with the shortest median survival (17.1 months), followed by cholangiocarcinoma (17.9 months) and ampullary carcinoma (44.3 months) (P < 0.001). Potential predictors of decreased survival on univariate analysis included site of origin, preoperative jaundice, microscopic positive margin, nodal metastasis, lymphovascular invasion, neural invasion, and poor differentiation. Only nodal metastasis (median 16.2 versus 29.9 months, P < 0.001) and neural invasion (median 17.7 versus 47.9 months, P < 0.00001) significantly predicted outcome on multivariate analysis. Although ampullary cancers have the best prognosis overall, when controlled for tumor stage, only presence of neural invasion and nodal metastasis predict poor survival following pancreaticoduodenectomy. Biological behavior remains the most important prognostic indicator in periampullary cancers amenable to resection, regardless of site of origin.


Virulence and attenuation of murine cytomegalovirus.
Murine cytomegalovirus (MCMV) was rapidly and regularly attenuated by passage through mouse embryo cell culture. This attenuation was manifested by alteration of lethality for suckling mice and by a striking loss of capacity to multiply in liver and spleen of weanling mice. The attenuation was selective in that the passaged virus multiplied vigorously in other organs and established high titer infections in submaxillary glands and pancreas comparable to those seen with wild virus. Furthermore, attenuated virus no longer induced transient suppression of antibody and interferon responsiveness which was a regular feature of wild MCMV infection. Wild and attenuated MCMV shared the property of being poor immunogens. They induced anti-CMV complement-fixing or neutralizing antibody very slowly with barely detectable levels present at the end of the first 2 weeks of infection. The close antigenic relationship between wild and attenuated agents was demonstrated by nearly identical neutralization by a rabbit antiserum induced with wild MCMV. Furthermore, survivors of neonatal infection with attenuated virus were fully protected against subsequent challenge with potentially lethal doses of wild MCMV. Virulence could be rapidly restored by back passage in mice.