Comparison of Maize Genotypes Using Drought-Tolerance Indices and Graphical Analysis under Normal and Humidity Stress Conditions.
This study aimed to identify drought-tolerant genotypes and to evaluate and compare the response of genotypes under normal conditions and humidity stress. The experiment was conducted in a Randomized Complete Block Design (RCBD) on 12 commercial single cross hybrids of maize (Zea mays L.) with three replications in two separate experiments under normal and stress conditions. GT biplot was used to compare genotypes under normal conditions and humidity stress. Based on the polygon diagrams' graphical analysis, KSC206, KSC704, KSC705 and KSC706 genotypes were identified as desirable hybrids. The ranking diagram of genotypes based on ideal genotype also showed that the KSC704 genotype had high desirability in all evaluated traits in normal and stress conditions. TOL, MP, HARM, GMP, SSI and STI indices were used to identify drought-tolerant genotypes, and the genotypes were ranked based on this index. Based on this, KSC260, SC302 and KSC400 hybrids were selected as resistant hybrids. Based on the correlation analysis between drought-tolerance indices, a positive correlation was observed between MP, GMP, HARM and STI indices. Based on the analysis of the PCA on the indices, the first and second principal components were given the titles of grain yield tolerance component under humidity stress conditions and grain yield stability component under normal humidity conditions, respectively. KSC704 was superior to other hybrids in terms of grain yield under normal conditions and stress, and the KSC260 hybrid was identified as a tolerant hybrid in terms of all studied traits under drought stress.


Early faecal excretion of inhaled plutonium.
Special individual monitoring has been performed for suspected cases of inhalation of plutonium at the Tokai Works of the Japan Nuclear Cycle Development Institute (JNC). Some experimental data obtained from this special individual monitoring during the past 20 years are presented and discussed in this paper. Our experience suggests the following conclusions. The daily plutonium excretion rate, normalised to the total excretion for the first 5 days after inhalation, was approximately in agreement with the latest ICRP 78 dosimetric model. Maximum faccal excretion is observed on the second day after inhalation of plutonium compounds. On the other hand, the activity ratio for total alpha activity observed in early faeces to that detected in nasal swabs showed a wide distribution range, and it was proven that variations in this ratio followed a log-normal distribution. The logarithmic mean probability is about 2.1 for PuO2 and about 15.7 for Pu(NO3)4. In practice, a conservative dose assessment from nasal swabs can be performed on the basis of these experimental ratios.


[Clinical and histopathological improvement of psoriasis in patients with osteoarthritis treated with chondroitin sulfate: report of 3 cases].
After prescribing chrondroitin sulfate for the symptomatic treatment of osteoarthritis, it has been observed that some patients with concomitant psoriasis experience a marked improvement of skin lesions. We describe the clinical and histopathological results of the erythematous and desquamative plaques of three patients with osteoarthritis and psoriasis treated with chondroitin sulfate. Three adult patients with bilateral knee osteoarthritis and long-standing psoriasis characterized by extensive erythematous, desquamative, and hyperkeratotic plaques, which were resistant to different treatment modalities, received 800 mg/day of chondroitin sulfate during two months. Skin biopsies were obtained before and after treatment. All three patients presented a marked clinical improvement in both pathologies. In addition to a decrease in the thickness of the epidermis (total epidermal thickness, maximal thickness from the basal layer to the beginning of the corneal layer, and maximal thickness of the corneal layer), a decrease in the number of keratinocytes in the proliferative phase, a decrease in the degree of psoriatic activity, and a substitution of parakeratotic keratinization by orthokeratotic keratinization were observed. The administration of chrondroitin sulfate resulted in a significant clinical and histological improvement of the psoriatic lesions. The confirmation of these preliminary results in future clinical trials could represent an important advance in the therapeutic armamentarium of patients with psoriasis given the excellent safety profile of this drug.


Global Outbreak of Human Monkeypox in 2022: Update of Epidemiology.
Human monkeypox was a neglected zoonotic disease considered endemic to rainforests of rural parts of Central and Western Africa, until a global outbreak in May 2022. This review describes the epidemiological characteristics of human monkeypox. Since the first confirmed case in the United Kingdom on 13 May 2022, and up until 19 September, more than 62,000 cases of human monkeypox were reported in 104 countries in the world (among them 97 countries where the monkeypox virus was not endemic). Up to today, 20 persons have died in this global outbreak. This outbreak predominantly affects men self-identifying as gay or bisexual or other men who have sex with men, and for now, there is no sign of continuous transmission of the disease in other populations. Today, the monkeypox outbreak is increasing alarmingly in many countries and presents a new challenge and a large issue for public health worldwide. The World Health Organization declared the global monkeypox outbreak a public health emergency of international concern on 24 July 2022. Before this outbreak, health professionals in many countries had a knowledge gap and a lack of experience in the management of monkeypox. Advances in the comprehension of the epidemiology of human monkeypox are necessary for effective prevention and outbreak response.


Current standards for response evaluation by imaging techniques.
Response evaluation by means of response rates using radiological imaging techniques is well established and plays a pivotal role in the development of new anti-cancer agents. It is typically employed in phase II clinical trials and acts as a surrogate for patient benefit, thereby allowing potentially active agents to be fast tracked; at the same time, inactive agents can be discarded earlier, with fewer patients being exposed to them. Response evaluation has evolved over the past 25 years, and various imaging stipulations have been introduced to try and add some uniformity to the process and enable a comparison to be made between different studies. However, imaging still requires a well-defined anatomical lesion or lesions to be viewed and relies on the measurement of a reduction in tumour size during treatment as the basis for presumed clinical benefit. This implies a cytocidal mode of action of the agent under review, but over the past 5 years increasing numbers of new cytostatic agents have been developed, such as anti-angiogenesis agents and specific enzyme receptor antagonists, where the overall effect is to prevent new tumour cells from growing or developing rather than directly killing pre-existing tumour cells. Anatomical imaging alone is therefore inappropriate as the tumour would not necessarily be expected to reduce in size. Other surrogates of tumour growth and metabolism have to be utilised. Functional studies are therefore necessary; anatomical imaging modalities such as computed tomography (CT) and magnetic resonance imaging can be modified so that dynamic studies can be undertaken, and newer techniques such as positron emission tomography scanning can be employed. The latter has poor spatial resolution but when combined with CT it has the ability to measure function while the anatomical site is accurately determined. The aim now is to devise new response evaluation techniques and criteria incorporating functional imaging to enable accurate assessment of active new anti-cancer agents.


American Cancer Society's QuitLink: randomized trial of Internet assistance.
Eligible smokers (N = 6,451) visiting the American Cancer Society's Internet site offering cessation assistance were, with informed consent, randomized to receive access either to a static Internet site with quitting advice or to one of five interactive sites provided by cooperating research partners. Three-month follow-up surveys were conducted via online survey with E-mail prompts, or telephone calls, to assess quitting success; 54% of participants provided follow-up data. Results showed no significant overall difference in cessation rates among participants assigned to the interactive or static sites. We found large differences in the utilization of the five interactive sites. When sites were grouped by level of use, a significantly higher reported 3-month cessation rate was observed among participants assigned to the more highly utilized sites than among those assigned to the less utilized sites (12.2% vs. 10.2% of all randomized participants, 26.0% vs. 22.1% of followed participants). These findings show that interactive Internet sites yielding high levels of utilization can increase quitting success among smokers seeking assistance via the Internet.


A systematic review of quality measures used in primary care dentistry.
'Quality' in primary care dentistry is poorly defined. There are significant international efforts focussed on developing quality measures within dentistry. The aim of this research was to identify measures used to assess quality in primary care dentistry and categorise them according to which dimensions of quality they attempt to measure. Quality measures were identified from the peer-reviewed and grey literature. Peer-reviewed papers describing the development and validation of measures were identified using a structured literature search. Measures from the grey literature were identified using structured searches and direct contact with dental providers and institutions. Quality measures were categorised according to domains of structure, process and outcome and by disaggregated dimensions of quality. From 22 studies, 11 validated measure sets (comprising nine patient satisfaction surveys and two practice assessment instruments) were identified from the peer-reviewed literature. From the grey literature, 24 measure sets, comprising 357 individual measures, were identified. Of these, 96 addressed structure, 174 addressed process and 87 addressed outcome. Only three of these 24 measure sets demonstrated evidence of validity testing. The identified measures failed to address dimensions of quality, such as efficiency and equity. There has been a proliferation in the development of dental quality measures in recent years. However, this development has not been guided by a clear understanding of the meaning of quality. Few existing measures have undergone rigorous validity or reliability testing. A consensus is needed to establish a definition of quality in dentistry. Identification of the important dimension of quality in dentistry will allow for the production of a core quality measurement set.


Automation and Standardization-A Coupled Approach towards Reproducible Sample Preparation Protocols for Nanomaterial Analysis.
Whereas the characterization of nanomaterials using different analytical techniques is often highly automated and standardized, the sample preparation that precedes it causes a bottleneck in nanomaterial analysis as it is performed manually. Usually, this pretreatment depends on the skills and experience of the analysts. Furthermore, adequate reporting of the sample preparation is often missing. In this overview, some solutions for techniques widely used in nano-analytics to overcome this problem are discussed. Two examples of sample preparation optimization by automation are presented, which demonstrate that this approach is leading to increased analytical confidence. Our first example is motivated by the need to exclude human bias and focuses on the development of automation in sample introduction. To this end, a robotic system has been developed, which can prepare stable and homogeneous nanomaterial suspensions amenable to a variety of well-established analytical methods, such as dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), field-flow fractionation (FFF) or single-particle inductively coupled mass spectrometry (sp-ICP-MS). Our second example addresses biological samples, such as cells exposed to nanomaterials, which are still challenging for reliable analysis. An air-liquid interface has been developed for the exposure of biological samples to nanomaterial-containing aerosols. The system exposes transmission electron microscopy (TEM) grids under reproducible conditions, whilst also allowing characterization of aerosol composition with mass spectrometry. Such an approach enables correlative measurements combining biological with physicochemical analysis. These case studies demonstrate that standardization and automation of sample preparation setups, combined with appropriate measurement processes and data reduction are crucial steps towards more reliable and reproducible data.


Optical cryoimaging of mitochondrial redox state in bronchopulmonary-dysplasia injury models in mice lungs.
Bronchopulmonary dysplasia (BPD) is a major cause of morbidity and mortality in premature infants exposed to high levels of oxygen. This is mainly attributed to increased oxidative stress and angiogenesis defects impacting lung alveolarization. Here we use optical imaging to investigate the role of Bcl-2 in modulation of oxidative stress and angiogenesis and pathogenesis of BPD. Cryoimaging of the mitochondrial redox state of mouse lungs was applied to determine the metabolic state of the lungs from Bcl-2 +/+ (control), Bcl-2-deleted in the endothelium (Bcl-2 VE-cad) and Bcl-2-deficient (Bcl-2 -/-; global null) using mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide), and FADH2 (Flavin Adenine Dinucleotide) as the primary electron carriers in oxidative phosphorylation. We observed a 47% and 26% decrease in the NADH redox in Bcl-2 deficient lungs, Bcl-2 -/- and Bcl-2 VE-cad, respectively. Thus, Bcl-2 deficiency is associated with a significant increase in oxidative stress contributing to reduced angiogenesis and enhanced pathogenesis of BPD.


Polymorphic G-protein-coupled receptors and associated diseases.
Polymorphisms are quite common in the human population. Most likely every gene could be polymorphic. Most of these variations are common and have no functional consequence. However, as we learn more about the function of G-protein-coupled receptors (GPCRs) and how amino acid differences can modulate the function enough to measure, especially in a compromised physical state, the importance of characterizing these variations becomes substantial. This review will focus on polymorphisms in receptors that bind biogenic amines, calcium, opioids, endothelin, and those that also regulate taste, skin pigmentation, and oogenesis that have been suggested to cause variations of physiology.


Changes in Commitment and Sexual Satisfaction: Trajectories in Couple Therapy.
The purpose of this study was to examine the covarying relationship between commitment and sexual satisfaction in committed relationships throughout the course of couple therapy. A sample of 366 heterosexual couples completed questionnaires regarding sexual satisfaction and commitment at each of the first five sessions of couple therapy. Cross-lagged panel analyses revealed that, between the first and second therapy sessions, there was a bidirectional relationship between commitment and sexual satisfaction, with each variable at the first session predicting the other at the second session. In addition, sexual satisfaction at the second session predicted commitment at the third session.


Freud's private mini-monograph on his own dreams. A contribution to the celebration of the centenary of The interpretation of dreams.
A virtually unknown brief commentary by Freud on the characteristics of his own dreams is described and discussed. Freud's mini-monograph, discovered after some 80 years, has autobiographical, theoretical and organisational significance in the enigmatic context of the early development of psychoanalysis. Found among papers of Alfred Adler, this extraordinary document adds to our knowledge of psychoanalytic history, including the significance of dreams in the evolution of psychoanalytic thought. Freud's commentary permitted the identification of a particular dream as his own. This dream had been presented in anonymity to the fledgling Vienna Psychoanalytic Society for interpretation. The dream was later inserted, again anonymously, into The Interpretation of Dreams with Freud's own remarkable pre-oedipal interpretation. Freud's conflicted relationships with Adler and Jung are considered in historical context.


Comparative analysis of histologically classified oligodendrogliomas reveals characteristic molecular differences between subgroups.
Molecular data of histologically classified oligodendrogliomas are available offering the possibility to stratify these human brain tumors into clinically relevant molecular subtypes. Gene copy number, mutation, and expression data of 193 histologically classified oligodendrogliomas from The Cancer Genome Atlas (TCGA) were analyzed by well-established computational approaches (unsupervised clustering, statistical testing, network inference). We applied hierarchical clustering to tumor gene copy number profiles and revealed three molecular subgroups within histologically classified oligodendrogliomas. We further screened these subgroups for molecular glioma markers (1p/19q co-deletion, IDH mutation, gain of chromosome 7 and loss of chromosome 10) and found that our subgroups largely resemble known molecular glioma subtypes. We excluded glioblastoma-like tumors (7a10d subgroup) and derived a gene expression signature distinguishing histologically classified oligodendrogliomas with concurrent 1p/19q co-deletion and IDH mutation (1p/19q subgroup) from those with predominant IDH mutation alone (IDHme subgroup). Interestingly, many signature genes were part of signaling pathways involved in the regulation of cell proliferation, differentiation, migration, and cell-cell contacts. We further learned a gene regulatory network associated with the gene expression signature revealing novel putative major regulators with functions in cytoskeleton remodeling (e.g. APBB1IP, VAV1, ARPC1B), apoptosis (CCNL2, CREB3L1), and neural development (e.g. MYTIL, SCRT1, MEF2C) potentially contributing to the manifestation of differences between both subgroups. Moreover, we revealed characteristic expression differences of several HOX and SOX transcription factors suggesting the activity of different glioma stemness programs in both subgroups. We show that gene copy number profiles alone are sufficient to derive molecular subgroups of histologically classified oligodendrogliomas that are well-embedded into general glioma classification schemes. Moreover, our revealed novel putative major regulators and characteristic stemness signatures indicate that different developmental programs might be active in these subgroups, providing a basis for future studies.


Stinging Nettles as Potential Food Additive: Effect of Drying Processes on Quality Characteristics of Leaf Powders.
Stinging nettle (Urtica dioica L.) is a ubiquitous, multi-utility, and under-utilized crop with potential health benefits owing to its nutritional and bioactive components. The objective of the work is to produce powders by drying wild stinging nettle leaves as a storable, low-cost functional additive to be used in bakery and ready-to-cook products. Convective drying (CD) and freeze-drying (FD) were applied on unblanched (U) or blanched (B) leaves, which were then milled to nettle powders (NPs). The obtained NPs were evaluated for selected physicochemical (moisture, color), techno-functional (flow indices, hygroscopicity), and phytochemical (pigments, phenols) characteristics as well as mineral contents. Blanching improved mass transfer and reduced the oxidative degradation of pigments during drying, but it caused a loss of total phenols content, antioxidant activity, and potassium content. As for the drying method, CD resulted in better flow properties (i.e., Carr Index and Hausner Ratio), while FD retained better the color, pigments, magnesium content, phenolic, and antioxidant parameters. Overall, the evaluated processing methods resulted in different technological properties that can allow for better evaluation of NPs as a food additive or ingredient. Among the NPs, blanched and freeze-dried powders despite showing inferior technological properties can be recommended as more suitable ingredients targeted f or food enrichment owing to better retention of bio-active components.


Survey of actual conditions of reasons for nurse calls: comparing a surgical ward and a medical ward.
We believe that nurse calls can play a role not merely as a means to convey patients' needs, but also as a medium to analyze and predict patients' needs using historical data of nurse calls. Therefore, we conducted a survey of actual conditions of nurse calls using "call history management system" developed for welfare institutions. The survey was intended to show patients' needs accurately by individually associating historical data, which can be collected through an information system, with reasons for calling, which usually cannot be collected automatically. Total quantities of nurse calls were 5,397 (174.1 per day, 4.59 per day per person) in the Surgery Ward and 3,404 (109.8 per day, 2.85 per day per person) in the Internal Medicine Ward; the incoming calls to the Surgical Ward were more numerous than those to the Medical Ward. The most common reason for calling was "assistance related to toileting". During the day shift and evening shift, that reason was followed by "fluid management" such as finishing of fluid administration and fluid exchange.


Sarcolipin and phospholamban inhibit the calcium pump by populating a similar metal ion-free intermediate state.
We have performed microsecond molecular dynamics (MD) simulations and protein pKa calculations of the muscle calcium pump (sarcoplasmic reticulum Ca(2+)-ATPase, SERCA) in complex with sarcolipin (SLN) to determine the mechanism by which SLN inhibits SERCA. SLN and its close analog phospholamban (PLN) are membrane proteins that regulate SERCA by inhibiting Ca(2+) transport in skeletal and cardiac muscle. Although SLN and PLB binding to SERCA have different functional outcomes on the coupling efficiency of SERCA, both proteins decrease the apparent Ca(2+) affinity of the pump, suggesting that SLN and PLB inhibit SERCA by using a similar mechanism. Recently, MD simulations showed that PLB inhibits SERCA by populating a metal ion-free, partially-protonated E1 state of the pump, E1· [Formula: see text] . X-ray crystallography studies at 40-80 mM Mg(2+) have proposed that SLN-bound SERCA populates E1·Mg(2+), an intermediate with Mg(2+) bound near transport site I. To test this proposed mode of SLN regulation, we performed a 0.5-μs MD simulation of E1·Mg(2+)-SLN in a solution containing 100 mM K(+) and 3 mM Mg(2+), with calculation of domain dynamics in the cytosolic headpiece and side-chain ionization and occupancy in the transport sites. We found that SLN increases the distance between residues E771 and D800, thereby rendering E1·Mg(2+) incapable of producing a competent Ca(2+) transport site I. Following removal of Mg(2+,) a 2-μs MD simulation of Mg(2+)-free SERCA-SLN showed that Mg(2+) does not re-bind to the transport sites, indicating that SERCA-SLN does not populate E1·Mg(2+) at physiological conditions. Instead, protein pKa calculations indicate that SLN stabilizes a metal ion-free SERCA state (E1· [Formula: see text] ) protonated at residue E771, but ionized at E309 and D800. We conclude that both SLN and PLB inhibit SERCA by populating a similar metal ion-free intermediate state. We propose that (i) this partially-protonated intermediate serves as the consensus mechanism for SERCA inhibition by other members of the SERCA regulatory subunit family including myoregulin and sarcolamban, and (ii) this consensus mechanism is utilized to regulate Ca(2+) transport in skeletal and cardiac muscle, with important implications for therapeutic approaches to muscle dystrophy and heart failure.


Association of Residents' Medical School Reputation and Urology Residency Program Ranking.
The Urology Residency Match process is a highly competitive application process that evaluates coursework performance, standardized examination scores, research productivity, quality of letter of recommendations, and participation in away rotations. With recent changes to medical school grading metrics, lack of in-person interviews, and examination scorings, less objective metrics are available to stratify applicants. We characterized the association of urology residents' medical school and urology residency program rankings. Using publicly available resources, all urology residents from 2016 to 2022 were identified. Their medical school and urology residency rankings were determined from 2022 US News and World Reports and Doximity urology residency reputation. Ordinal logistic regression modeling was used to determine the association between medical school and residency rankings. A total of 2,306 successfully matched residents were identified from 2016 to 2022. There was positive association between urology program and medical school ranking (P < .001). Within each urology program tier over the last 7 years, there was no significant change over time in the proportions of urology residents by medical school rankings (P >0.05). A consistent proportion of matched residents from higher ranked medical schools matched into top ranked urology programs, while a consistent proportion of applicants from lower ranked medical schools matched into lower ranked urology programs across each application cycle from 2016 to 2022 (P < .05). We observed that over the last 7 years trainees from higher ranked medical schools were more commonly represented in top urology programs while lower ranked urology programs were overrepresented by residents from lower ranked medical schools.


Hypofractionated adjuvant whole breast radiotherapy: progress and prospects.
Published results of randomised trials involving >7000 women confirm the safety and efficacy of hypofractionated schedules of adjuvant radiotherapy for women with early breast cancer using fraction sizes between 2 and 3 Gy assuming appropriate downward adjustments to total dose. Unnecessary concerns relating to heart tolerance, suboptimal dose distribution and duration of follow up need not discourage the routine adoption of 15- or 16-fraction schedules in women treated by breast conservation surgery for early breast cancer. Regardless of fractionation regimen, dose escalation to the index quadrant in high risk subgroups will result in a greater relative increase in late adverse effects than tumour control, a therapeutic disadvantage that can only be overcome by exploiting a marked dose-volume effect. A 15-fraction schedule of whole breast radiotherapy is unlikely to represent the lower limits of hypofractionation, and the preliminary results of a 5-fraction regimen are encouraging.


Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders.
Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders.


Incidence and characteristics of bacteremia among children in rural Ghana.
The objective of the study was to describe systemic bacterial infections occurring in acutely ill and hospitalized children in a rural region in Ghana, regarding frequency, incidence, antimicrobial susceptibility patterns and associations with anthropometrical data.Blood cultures were performed in all children below the age of five years, who were admitted to Agogo Presbyterian Hospital (APH), Asante Region, Ghana, between September 2007 and July 2009. Medical history and anthropometrical data were assessed using a standardized questionnaire at admission. Incidences were calculated after considering the coverage population adjusted for village-dependent health-seeking behavior.Among 1,196 hospitalized children, 19.9% (n = 238) were blood culture positive. The four most frequent isolated pathogens were nontyphoidal salmonellae (NTS) (53.3%; n = 129), Staphylococcus aureus (13.2%; n = 32), Streptococcus pneumoniae (9.1%; n = 22) and Salmonella ser. Typhi (7.0%; n = 17). Yearly cumulative incidence of bacteremia was 46.6 cases/1,000 (CI 40.9-52.2). Yearly cumulative incidences per 1,000 of the four most frequent isolates were 25.2 (CI 21.1-29.4) for NTS, 6.3 (CI 4.1-8.4) for S. aureus, 4.3 (CI 2.5-6.1) for S. pneumoniae and 3.3 (CI 1.8-4.9) for Salmonella ser. Typhi. Wasting was positively associated with bacteremia and systemic NTS bloodstream infection. Children older than three months had more often NTS bacteremia than younger children. Ninety-eight percent of NTS and 100% of Salmonella ser. Typhi isolates were susceptible to ciprofloxacin, whereas both tested 100% susceptible to ceftriaxone. Seventy-seven percent of NTS and 65% of Salmonella ser. Typhi isolates were multi-drug resistant (MDR). Systemic bacterial infections in nearly 20% of hospitalized children underline the need for microbiological diagnostics, to guide targeted antimicrobial treatment and prevention of bacteremia. If microbiological diagnostics are lacking, calculated antimicrobial treatment of severely ill children in malaria-endemic areas should be considered.


CPR-Total (TAFI and activated TAFI) levels in plasma/serum of hemophiliacs.
Arginine carboxypeptidase (CPR) is a single-chain plasma protein generated during coagulation from a precursor (proCPR). proCPR is the same molecule as thrombin activable fibrinolysis inhibitor (TAFI), which retards fibrin clot lysis in vitro and most likely modulates fibrinolysis in vivo. In this study, the amount of CPR-total, which includes proCPR (TAFI) and CPR (activated TAFI), in hemophiliac patients was evaluated using a newly developed enzyme linked immunosorbent assay (ELISA). The amount of CPR-total in plasma or serum of most of the hemophiliac patients was in the range of healthy individuals. There was no significant difference in hemophiliac patients with or without HIV-1 infection. However, two out of the 74 hemophiliac patients showed a significantly high level. The upregulation of CPR-total might contribute to compensate for inefficient coagulation in some hemophiliac individuals.


The N-terminal domain of VirG of Agrobacterium tumefaciens: modelling and analysis of mutant phenotypes.
Fourteen mutants in the N-terminal domain of virulence factor G (VirG) were obtained by random mutagenesis. Two mutants showed an altered phenotype, all others were non-functional. All mutants can still be phosphorylated and bind to DNA. A 3-D model was built based on the coordinates of chemotaxis protein Y (CheY). Many of the observed phenotypic changes of VirG are explained qualitatively. Combination of model building and biochemical information leads to the conclusion that the active sites of VirG and CheY must partly use different residues to perform the same phosphorylation and dephosphorylation reactions.


Sequency encoding single pixel spectroscopy based on Hadamard transform.
Single pixel spectroscopy based on Hadamard transform (SPS-HT) has been applied widely because of its capability of wavelength multiplexing and associated advantage in signal-to-noise ratio. In this paper, we propose a sequency encoding single pixel spectroscopy (SESPS) based on two-dimensional (2D) masks for concurrent coding of all Hadamard coefficients instead of one-dimensional (1D) Hadamard masks (only coding one coefficient at a time) widely used in the traditional SPS-HT. Moreover, each Hadamard coefficient is coded along the time dimension with a different sequency value such that the alternating current (AC) measurements of the time-domain signal can be used to reconstruct all Hadamard coefficients simultaneously, which reduces the influence of noise and dramatically speeds up data acquisition. We demonstrate that the SESPS with 32 spectral channels can accelerate spectral measurements from white light sources and fluorescence particles by around 14 times and 70 times, respectively, compared to measurements using a commercial spectrometer when the relative root mean square error (RMSE) is around 3% or smaller. The acceleration factors can be boosted by an extra 4 times when only eight spectral channels are used to achieve a compression ratio of 4:1, in which the relative RMSEs change only marginally. Compared to our previous SPS-HT, this new scheme can increase the speed by three orders of magnitude. This technique is expected to be useful in applications requiring high-speed spectral measurements such as the spectral flow cytometry and on-site medical diagnosis using fluorescence or Raman spectroscopy.


Histomorphometric analysis of rat alveolar wound healing with hydroxyapatite alone or associated to BMPs.
Several materials and techniques have been proposed to improve alveolar wound healing and decrease loss of bone height and thickness that normally follow dental extraction. The objective of this research was the histologic analysis of bone morphogenetic proteins implanted into dental alveoli of rats after extraction. A total of 45 adult male Wistar rats were divided into three groups of 15 animals each: control (no treatment), implanted with pure hydroxyapatite (HA, 3 mg) and implanted with hydroxyapatite plus bone morphogenetic proteins (HA/BMPs, 3 mg). Five animals from each group were sacrificed at 7, 21 and 42 days after extraction for the histometric analyses of the osteoconductive potential of hydroxyapatite associated or not with BMPs. After dissection, fixation, decalcification and serial microtomy of 6-micron thick sections, the samples were stained with hematoxylin-eosin for histologic and histometric analyses. Both HA and HA/BMPs caused a delay in wound healing compared to control animals, evaluated by the percentage of bone tissue in the alveoli. The treatment with HA/BMPs had the greatest delay at 21 days, even though it produced values similar to the control group at 42 days. The materials did not improve alveolar repair in the normal period of wound healing and the association of HA/BMPs did not have osteoconductive properties with granulated hydroxyapatite as the vehicle.


Childhood and adolescent lymphoid and myeloid leukemia.
Remarkable progress has been made in the past decade in the treatment and in the understanding of the biology of childhood lymphoid and myeloid leukemias. With contemporary improved risk assessment, chemotherapy, hematopoietic stem cell transplantation and supportive care, approximately 80% of children with newly diagnosed acute lymphoblastic leukemia and 50% of those with myeloid neoplasm can be cured to date. Current emphasis is placed not only on increased cure rate but also on improved quality of life. In Section I, Dr. Ching-Hon Pui describes certain clinical and biologic features that still have prognostic and therapeutic relevance in the context of contemporary treatment programs. He emphasizes that treatment failure in some patients is not due to intrinsic drug resistance of leukemic cells but is rather caused by suboptimal drug dosing due to host compliance, pharmacodynamics, and pharmacogenetics. Hence, measurement of minimal residual disease, which accounts for both the genetic (primary and secondary) features of leukemic lymphoblasts and pharmacogenomic variables of the host, is the most reliable prognostic indicator. Finally, he contends that with optimal risk-directed systemic and intrathecal therapy, cranial irradiation may be omitted in all patients, regardless of the presenting features. In Section II, Dr. Martin Schrappe performs detailed analyses of the prognostic impact of presenting age, leukocyte count, sex, immunophenotype, genetic abnormality, early treatment response, and in vitro drug sensitivity/resistance in childhood acute lymphoblastic leukemia, based on the large database of the Berlin-Frankfurt-Münster consortium. He also succinctly summarizes the important treatment components resulting in the improved outcome of children and young adolescents with this disease. He describes the treatment approach that led to the improved outcome of adolescent patients, a finding that may be applied to young adults in the second and third decade of life. Finally, he believes that treatment reduction under well-controlled clinical trials is feasible in a subgroup of patients with excellent early treatment response as evidenced by minimal residual disease measurement during induction and consolidation therapy. In Section III, Dr. Raul Ribeiro describes distinct morphologic and genetic subtypes of acute myeloid leukemia. The finding of essentially identical gene expression profiling by DNA microarray in certain specific genetic subtypes of childhood and adult acute myeloid leukemia suggests a shared leukemogenesis. He then describes the principles of treatment as well as the efficacy and toxicity of various forms of postremission therapy, emphasizing the need of tailoring therapy to both the disease and the age of the patient. Early results suggest that minimal residual disease measurement can also improve the risk assessment in acute myeloid leukemia, and that cranial irradiation can be omitted even in those with central-nervous-system leukemia at diagnosis. In Section IV, Dr. Charlotte Niemeyer describes a new classification of myelodysplastic and myeloproliferative diseases in childhood, which has greatly facilitated the diagnosis of myelodysplastic syndromes and juvenile myelomonocytic leukemia. The recent discovery of somatic mutations in PTPN11 has improved the understanding of the pathobiology and the diagnosis of juvenile myelomonocytic leukemia. Together with the findings of mutations in RAS and NF1 in the other patients, she suggests that pathological activation of RAS-dependent pathways plays a central role in the leukemogenesis of this disease. She then describes the various treatment approaches for both juvenile myelomonocytic leukemia and myelodysplastic syndromes in the US and Europe, emphasizing the differences between childhood and adult cases for the latter group of diseases. She also raises some controversial issues regarding treatment that will require well-controlled international clinical trials to address.


Elevated expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in cerebellar unipolar brush cells of a Down syndrome mouse model.
1. Down syndrome (DS) arises from the presence of three copies of chromosome (Chr.) 21. Fine motor learning deficits found in DS from childhood to adulthood result from expression of extra genes on Chr. 21, however, it remains unclear which if any of these genes are the specific causes of the cognitive and motor dysfunction. DS cerebellum displays morphological abnormalities that likely contribute to the DS motor phenotype. 2. The G-protein-activated inwardly rectifying potassium channel subunit 2 (GIRK2) is expressed in cerebellum and can shunt dendritic conductance and attenuate postsynaptic potentials. We have used an interbreeding approach to cross a genetic mouse model of DS (Ts65Dn) with Girk2 knockout mice and examined its relative expression level by quantitative real-time RT-PCR, Western blotting and immunohistochemistry. 3. We report here for the first time that GIRK2 is expressed in unipolar brush cells, which are excitatory interneurons of the vestibulocerebellum and dorsal cochlear nucleus. Analysis of disomic-Ts65Dn/Girk2((+/+/-)) and heterozygous-Diploid/Girk2((+/-)) mice shows that GIRK2 expression in Ts65Dn lobule X follows gene dosage. The lobule X of Ts65Dn mice contain greater numbers of unipolar brush cells co-expressing GIRK2 and calretinin than the control mouse groups. 4. These results demonstrate that gene triplication can impact specific cell types in the cerebellum. We hypothesize that GIRK2 overexpression will adversely affect cerebellar circuitry in Ts65Dn vestibulocerebellum and dorsal cochlear nucleus due to GIRK2 shunting properties and its effects on resting membrane potential.


Brocaenols A-C: novel polyketides from a marine derived Penicillium brocae.
Chemical investigation of a Penicillium brocae, obtained from a tissue sample of a Fijian Zyzyya sp. sponge, yielded two known diketopiperazines and three novel cytotoxic polyketides, brocaenols A-C. The brocaenols contain an unusual enolized oxepine lactone ring system that to the best of our knowledge is unprecedented in the literature. The structures were elucidated by using 2D-NMR methods including an INADEQUATE experiment. The absolute stereochemistry of brocaenol A was established by using a modified Mosher method. The taxonomy of the producing fungus was elucidated by using both morphological and rDNA sequence analysis.


Comparison of amlodipine or nifedipine treatment with developing congestive heart failure: effects on myocyte contractility.
Past studies have suggested that amlodipine, a dihydropyridine L-type Ca(2+) channel antagonist, may exert useful effects in congestive heart failure (CHF). The present study examined the effects of amlodipine or nifedipine treatment in a model of developing CHF on left ventricular (LV) pump function and myocyte contractility. Pigs (25 kg) were randomly assigned to 1 of 4 groups: 1) pacing-induced CHF (rapid atrial pacing at 240 bpm) for 3 weeks (n = 9), 2) concomitant Ca(2+) channel blockade with amlodipine (1.5 mg/kg/day) and rapid pacing (n = 7), 3) concomitant Ca(2+) channel blockade with nifedipine (0.7 mg/kg twice daily) and rapid pacing (n = 7), and 4) sham controls (n = 7). LV fractional shortening fell with pacing CHF from baseline values (17% +/- 1% v 42% +/- 1%, P <.05). With rapid pacing and concomitant amlodipine treatment, LV fractional shortening increased from pacing CHF values (24% +/- 1%, P <.05) but was unchanged with concomitant nifedipine treatment (20% +/- 2%, P =.2). LV myocyte velocity of shortening, as measured by high speed videomicroscopy, was reduced with pacing CHF compared with controls (42 +/- 2 microm/s v 87 +/- 9 microm/s, P <.05), and increased from pacing CHF values with amlodipine or nifedipine treatment (62 +/- 8 microm/s, 64 +/- 4 microm/s, respectively; P <.05). Inotropic response to extracellular Ca(2+) (8 mmol/L) was reduced with pacing CHF (94 +/- 5 microm/s v 160 +/- 15 microm/s, P <.05) and increased from CHF values with amlodipine or nifedipine treatment (132 +/- 14 microm/s and 133 +/- 7 microm/s, respectively, P <.05) CONCLUSIONS: These results suggest that the primary mechanism for the effects of amlodipine on myocyte contractility in developing CHF is because of direct Ca(2+) channel blockade.


Theoretical analyses on enantiospecificity of L-2-haloacid dehalogenase (DehL) from Rhizobium sp. RC1 towards 2-chloropropionic acid.
Dehalogenases continue to garner interest of the scientific community due to their potential applications in bioremediation of halogen-contaminated environment and in synthesis of various industrially relevant products. Example of such enzymes is DehL, an L-2-haloacid dehalogenase (EC 184.108.40.206) from Rhizobium sp. RC1 that catalyses the specific cleavage of halide ion from L-2-halocarboxylic acids to produce the corresponding D-2-hydroxycarboxylic acids. Recently, the catalytic residues of DehL have been identified and its catalytic mechanism has been fully elucidated. However, the enantiospecificity determinants of the enzyme remain unclear. This information alongside a well-defined catalytic mechanism are required for rational engineering of DehL for substrate enantiospecificity. Therefore, using quantum mechanics/molecular mechanics and molecular mechanics Poisson-Boltzmann surface area calculations, the current study theoretically investigated the molecular basis of DehL enantiospecificity. The study found that R51L mutation cancelled out the dehalogenation activity of DehL towards it natural substrate, L-2-chloropropionate. The M48R mutation, however introduced a new activity towards D-2-chloropropionate, conveying the possibility of inverting the enantiospecificity of DehL from L-to d-enantiomer with a minimum of two simultaneous mutations. The findings presented here will play important role in the rational design of DehL dehalogenase for improving substrate utility.


Posterior reversible encephalopathy syndrome as the initial manifestation of Guillain-Barré syndrome: case report and review of the literature.
We report a 63-year-old female patient with Guillain-Barré syndrome revealed after posterior reversible encephalopathy syndrome. The onset was characterized by hypertension, headache, and cortical blindness, followed a few days later by progressive limb and facial paresis, dysautonomia, and respiratory failure. Treatment with plasmapheresis led to a rapid improvement of the clinical picture and the disappearance of magnetic resonance abnormalities. This report reviews the literature on this unusual association and discusses possible pathophysiological mechanisms.


Aggressive surgical treatment in late-diagnosed esophageal perforation: a report of 11 cases.
Introduction. Esophageal perforation is a relatively uncommon and lethal disease usually resulting from endoscopic procedures. Delay in the diagnosis and treatment occurs in more than 50% of cases, leading to a mortality rate of 40% to 60%, but this rate decreases is 10%-25% if treatment is carried out within 24 hours of perforation. Case Presentation. To analyze the characteristics, etiology, site of perforation, presentation, time interval till diagnosis, treatment and outcome of patients with esophageal perforation. Over a five-year period, from October 2004 through March 2009, 11 patients with esophageal perforation were referred to the division of thoracic surgery of a tertiary referral hospital. In eight patients, perforations were thoracic with delayed diagnosis for at least 48 hours. Two patients had cervical esophageal perforation, and one patient had early-diagnosed Boerhaave's syndrome. Eight patients are alive after followup for a period ranging from eight months to five years. In the remaining three patients, cancer was the underlying disease and the reason of death. Conclusion. No patient with esophageal perforation should be deprived from surgical repair due to delayed diagnosis. All, except preterminal patients, should undergo exploration after resuscitation, and appropriate treatment should be carried out depending on the findings during operation. Aggressive treatment is necessary in the case of established mediastinitis.


The parasitic trematode Fasciola hepatica exhibits mammalian-type glycolipids as well as Gal(beta1-6)Gal-terminating glycolipids that account for cestode serological cross-reactivity.
Neutral glycosphingolipids from sheep-derived Fasciola hepatica liver flukes were isolated and characterized both structurally and serologically. After HPLC fractionation, glycolipids were analyzed by linkage analysis, enzymatic cleavage, and MALDI-TOF as well as electrospray ionization mass spectrometry. Obtained results revealed the presence of two types of neutral glycolipids. The first group represented mammalian-type species comprising globo- and isoglobotriaosylceramides (Gal(alpha1-4)Gal(beta1-4)Glc(1-1)ceramide and Gal(alpha1-3)Gal(beta1-4)Glc(1-1)ceramide, respectively) as well as Forssman antigen (GalNAc(alpha1-3)GalNAc(beta1-3/4)Gal(alpha1-4/3)Gal(beta1-4)Glc(1-1)ceramide). Applying Helix pomatia agglutinin, recognizing terminal alpha-linked GalNAc, to cryosections of adult flukes, the latter glycolipid could be localized to the F. hepatica gut. As Forssman antigen from the parasite and sheep host led to identical MALDI-TOF MS profiles, this glycolipid might be acquired from the definitive host. As a second group, highly antigenic glycolipids were structurally characterized as Gal(beta1-6)Gal(beta1-4)Glc(1-1)ceramide, Gal(beta1-6)Gal(alpha1-3/4)Gal(beta1-4)Glc(1-1)ceramide and Gal(beta1-6)Gal(beta1-6)Gal(alpha1-3/4)Gal(beta1-4)Glc(1-1)ceramide, the latter two structures of which exhibited both isoglobo- or globo-series core structures. Terminal Gal(beta1-6)Gal1-motifs have previously been shown to represent antigenic epitopes of neogala-series glycosphingolipids from tape worms. Using human Echinococcus granulosus infection sera, Gal(beta1-6)Gal-terminating glycolipids could be allocated to the gut in adult liver fluke cryosections. Corresponding neogala-reactive antibodies in F. hepatica infection serum were detected by their binding to E. granulosus and Taenia crassiceps neogala-glycosphingolipids. These antibodies might contribute to the known serological cross-reactivity between F. hepatica and parasitic cestode infections.


Diastereoselective synthesis of (+/-)-1',4'-dimethyluridine.
The de novo synthesis of racemic 1',4'-dimethyluridine was accomplished in 12 steps starting from 2,5-dimethylfuran and vinylene carbonate. Key steps of the sequence include the stereoconvergent preparation of a meso diacid, and a stereoselective glycosylation without neighboring group participation. Such 1',4'-disubstituted ribonucleoside analogues are undisclosed compounds, which may present interesting biological activities.


Bone tissue incorporates in vitro gallium with a local structure similar to gallium-doped brushite.
During mineral growth in rat bone-marrow stromal cell cultures, gallium follows calcium pathways. The dominant phase of the cell culture mineral constitutes the poorly crystalline hydroxyapatite (HAP). This model system mimics bone mineralization in vivo. The structural characterization of the Ga environment was performed by X-ray absorption spectroscopy at the Ga K-edge. These data were compared with Ga-doped synthetic compounds (poorly crystalline hydroxyapatite, amorphous calcium phosphate and brushite) and with strontium-treated bone tissue, obtained from the same culture model. It was found that Sr(2+) substitutes for Ca(2+) in the HAP crystal lattice. In contrast, the replacement by Ga(3+) yielded a much more disordered local environment of the probe atom in all investigated cell culture samples. The coordination of Ga ions in the cell culture minerals was similar to that of Ga(3+), substituted for Ca(2+), in the Ga-doped synthetic brushite (Ga-DCPD). The Ga atoms in the Ga-DCPD were coordinated by four oxygen atoms (1.90 A) of the four phosphate groups and two oxygen atoms at 2.02 A. Interestingly, the local environment of Ga in the cell culture minerals was not dependent on the onset of Ga treatment, the Ga concentration in the medium or the age of the mineral. Thus, it was concluded that Ga ions were incorporated into the precursor phase to the HAP mineral. Substitution for Ca(2+ )with Ga(3+) distorted locally this brushite-like environment, which prevented the transformation of the initially deposited phase into the poorly crystalline HAP.


Development of an indirect ELISA for detection of antibody to wobbly possum disease virus in archival sera of Australian brushtail possums (Trichosurus vulpecula) in New Zealand.
To develop an indirect ELISA based on recombinant nucleocapsid (rN) protein of wobbly possum disease (WPD) virus for investigation of the presence of WPD virus in Australian brushtail possums (Trichosurus vulpecula) in New Zealand. Pre- and post-infection sera (n=15 and 16, respectively) obtained from a previous experimental challenge study were used for ELISA development. Sera were characterised as positive or negative for antibody to WPD virus based on western-blot using WPD virus rN protein as antigen. An additional 215 archival serum samples, collected between 2000-2016 from five different regions of New Zealand, were also tested using the ELISA. Bayesian modelling of corrected optical density at 450 nm (OD450) results from the ELISA was used to obtain estimates of receiver operating characteristic (ROC) curves to establish cut-off values for the ELISA, and to estimate the prevalence of antibody to WPD virus. Western blot analysis showed 5/14 (36%) pre-infection sera and 11/11 (100%) post-infection sera from experimentally infected possums were positive for antibodies to WPD virus. Bayesian estimates of the ROC curves established cut-off values of OD450≥0.41 for samples positive, and OD450<0.28 for samples negative for antibody to WPD virus, for sera diluted 1:100 for the ELISA. Based on the model, the estimated proportion of samples with antibodies to WPD virus was 0.30 (95% probability interval=0.196-0.418). Of the 230 archival serum samples tested using the ELISA, 48 (20.9%) were positive for antibody to WPD virus, 155 (67.4%) were negative and 27 (11.7%) equivocal, using the established cut-off values. The proportion of samples positive for WPD virus antibody differed between geographical regions (p<0.001). The results suggested that WPD virus or a related virus has circulated among possums in New Zealand with differences in the proportion of antibody-positive samples from different geographical regions. Antibodies to WPD virus did not seem to protect possums from disease following experimental infection, as one third of possums from the previous challenge study showed evidence of pre-existing antibody at the time of challenge. These results provide further support for existence of different pathotypes of WPD virus, but the exact determinants of protection against WPD and epidemiology of infection in various regions of New Zealand remain to be established. Availability of the indirect ELISA for detection of WPD virus antibody will facilitate prospective epidemiological investigation of WPD virus circulation in wild possum populations in New Zealand.


In vitro evaluation of 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-trifluoromethylquinoline hydrochloride (NLTQ-1), a new bioreductive agent as a hypoxia marker by 19F-magnetic resonance spectroscopy (19F-MRS).
19F-labeled bioreductive drugs bound to hypoxic cells in tumors could be detected by nuclear magnetic resonance, provided that they do not lose 19F during their metabolism. NLTQ-1, a 2-nitroimidazole-linked 7-trifluoromethylquinoline, has been synthesized to furnish this aim. NLTQ-1 demonstrated hypoxic selectivities of 7-10 in various cell-lines, in vitro. Uptake studies in V79 cells showed a 5 to 6 fold greater intracellular than extracellular concentration at a range of 100-300 microM input concentrations. A strong sharp peak, which was identified as the parent compound, was observed in the 19F-NMR spectrum of 90% MeCN extracts of V79 cells aerobically exposed to NLTQ-1, indicating that NLTQ-1 was not metabolized under aerobic conditions. Similarly, 19F NMR efflux studies in intact cells showed that the NLTQ-1 was bound to the cells predominantly under hypoxic conditions. 19F-NMR spectra of intact cells, exposed under hypoxic conditions to NLTQ-1, and of their lysates, after precipitation of various cellular components, indicated that possible covalent binding of NLTQ-1 had occurred with macromolecules such as proteins and nucleic acids. Therefore, NLTQ-1 might be suitable as a 19F-MRS/MRI hypoxia probe, although further in vivo work is necessary to verify this matter.


The Contemporary Use of Intracoronary Brachytherapy for In-Stent Restenosis: A Review.
In-stent restenosis (ISR) has been a major limitation in interventional cardiology and constitutes nearly 10 % of all percutaneous coronary interventions in the United States. Drug-eluting stent (DES) restenosis proves particularly difficult to manage and poses a high risk of recurrence and repeat intervention. Intra-coronary brachytherapy (IBT) has been traditionally viewed as a potential treatment modality for ISR. However, its use was hindered by procedural complexity, cost, and the advent of newer-generation DES. Recent data suggests promising results regarding IBT for the treatment of resistant DES-ISR. This review addresses the mechanism of action of IBT, procedural details, and associated risks and complications of its use. It will also highlight the available clinical evidence supporting the use of IBT and the future directions of its utilization in the treatment of ISR.


Synthesis, Structure, and Cytotoxicity of Oxaliplatin-Based Platinum(IV) Anticancer Prodrugs Bearing One Axial Fluoride.
Fluorine plays more and more important roles in drug design and development. In recent years, fluorine-containing organic drugs have already been applied in a broad range of therapeutic areas. Herein, we report our attempt to introduce an axial fluorine ligand to Pt(IV) complexes by oxidizing oxaliplatin with electrophilic fluorinating reagents in different protic solvents. The crystal structure of one representative complex is presented. The fluorinated Pt(IV) complexes are further expanded by functionalization with different anhydrides, and their analogues bearing one different axial ligand (OAc or OH group) are also synthesized. Further investigations show that the axial fluorine atom has dramatic effects on the chemical properties of these prodrugs. These new fluorinated Pt(IV) complexes are proved to be stable in physiological conditions. For most of the fluorinated Pt(IV) complexes, a higher reduction potential indicates its greater tendency to be reduced by ascorbate. Introducing an axial fluorine ligand in Pt(IV) complexes does not lead to the increase of their lipophilicity. Moreover, these new fluorinated Pt(IV) complexes show better cytotoxicity than nonfluorinated analogues which may derive from their higher cellular accumulation in cancer cells. Therefore, the good stability and high cytotoxicity of these fluorinated Pt(IV) prodrugs indicate their great potential as a building block for further functionalization.


[Gastrocolic tumor progression--a possibility or mere supposition?].
The authors examined the five-years postoperative survival rate of fifty patients who suffered from colorectal cancer along with the fact that the large bowel one of the neighbouring organs were resected. The subjects were divided into four groups: the colorectal resection was associated with (1) stomach resection (13 patients); (2) liver metastasectomy (14 patients); (3) small bowel resection (10 patients); (4) the resection of other organs (13 patients). In the first two years of the study they were examined once in every three months, in the next two years once in every six months and then yearly. The following tests were carried out: chest X ray, abdominal sonography, irrigography or colonoscopy and CEA. On condition that the colonoscope reached the caecum and the result was negative, the test was repeated only a year later. The patients were operated on between 1985 and 1997. The statistical analysis was made with the help of the Kaplan-Meier method. During this period fifty-six complex resections were performed. Out of fifty-six patients fifty were followed. Compliance 89%. In group 1, where the average age of patients was sixty-two years, one patient died in the forty-first and the other in the fifty-second month after the surgery. Survival rate: 11/13 (83%). The survival rates for the other groups were as follows: group 2 (average age 64) twelve patients died within five years. Survival rate 2/14 (14%). The difference between the survival rates in the first two groups in significant (P = 0.0001). Group 3 (average age 67) seven died and only three survived. Survival rate: 3/10 (30%). The difference between group 1 and group 3 is significant (P = 0.0022). Group 4 (average age 64) seven patients died. Survival rate 6/13 (46%). Comparing this rate to that of the group 1, the difference is not significant (P > 0.01). Having analysed the results of the four groups it can be concluded that the patients of group 1 lived the longest (stomach resection) and those of group 2 (liver metastasectomy) died the earliest after the operation. It is surprising that the patients of group 3 lived significantly shorter than the ones of group 1 in spite of the fact that they belong by far the greatest number to stage Dukes B (group 1: 12/13 = 92%; group 3: 7/10 = 70%). The authors assume that the partial or the total absence of the stomach keeps back the growth of the tumour (gastro-colic tumour growing dependency). They think that in case of colon cancer which infiltrates the stomach surgeons experienced in gastric and colorectal surgery should be encouraged to take the risk of the double resection providing the fact that the operation is accomplishable.


Chorioretinal Hypoxia Detection Using Lipid-Polymer Hybrid Organic Room-Temperature Phosphorescent Nanoparticles.
Ischemia-induced hypoxia is a common complication associated with numerous diseases and is the most important prognostic factor in retinal vein occlusions (RVOs). Early detection and long-term visualization of retinal tissue hypoxia is essential to understand the pathophysiology and treatment of ischemic retinopathies. However, no effective solution exists to evaluate extravascular retinal tissue oxygen tension. Here, we demonstrate a lipid-polymer hybrid organic room-temperature phosphorescence (RTP) nanoparticle (NP) platform that optically detects tissue hypoxia in real-time with high signal-to-noise ratio. The fabricated NPs exhibit long-lived bright RTP, high sensitivity toward oxygen quenching, and desirable colloidal and optical stability. When tested as a hypoxia imaging probe in vivo using rabbit RVO and choroidal vascular occlusion (CVO) models via intravitreal and intravenous (IV) injections, respectively, its RTP signal is exclusively turned on where tissue hypoxia is present with a signal-to-noise ratio of 12.5. The RTP NP platform is compatible with multimodal imaging. No ocular or systemic complications are observed with either administration route. The developed organic RTP NPs present a novel platform approach that allows for biocompatible, nondestructive detection of tissue hypoxia and holds promise as a sensitive imaging tool to monitor longitudinal tissue oxygen levels and evaluate various hypoxia-driven vascular diseases.


The aetiology and outcome of 170 ulnar nerve lesions confirmed with electrophysiological testing.
The authors have studied 148 consecutive patients with 170 electrophysiologically confirmed ulnar nerve lesions, who were followed up for one to six years (median 3.8 years) to determine clinical progress and outcome. Injury and intra-operative pressure accounted for 12.9% and 7.1% of lesions respectively; 58.2% were idiopathic with no identified clinical aetiological factor. Eighty-three percent received non-operative treatment initially; 21% of these required operative intervention following further clinical/electrophysiological assessment. Partial or complete recovery occurred in 92% of intra-operative, 64% of idiopathic and 50% of injury cases respectively. Ulnar nerve lesions predominate in males and can be treated non-operatively providing clinical and electrophysiological monitoring is possible. Bilaterality is common and should be excluded. Lesions due to injury have a worse prognosis than those caused by direct continuous or repeated pressure, inflammation or where no aetiological factor exists.


Prognostic factors in adenocarcinoma of the uterine cervix.
A group of 136 female patients with adenocarcinoma of the uterine cervix, treated at Memorial Sloan-Kettering Cancer Center between 1949 and 1981, with slides available for review, formed the basis for this study. They ranged in age from 10 to 91 years. Most (73%) had abnormal bleeding, either alone or in combination with other symptoms; 15% were asymptomatic. Eighty percent had a visible abnormality, most commonly an exophytic mass. Clinical stages were: 0 (3%), IB (61%), IIA (14%), IIB (10%), III (4%). There were four major histologic subtypes: mucinous (47%), endometrioid (24%), adenosquamous (15%), and clear cell (9%) carcinoma. Of the many clinicopathologic variables evaluated for prognosis, the most significant was stage of disease (P less than 0.0001). Those with Stage IB disease had a survival probability of 76% at 5 years compared with 49% for those with Stage IIA and 34% with Stage IIB. The endometrioid pattern was associated with a more favorable prognosis than any other histologic subtype (P = 0.02). The presence of lymphatic tumor emboli and/or metastatic carcinoma in any lymph node group was associated with a less favorable prognosis for patients with Stage IB and IIA disease (P less than 0.0001).


Erythroderma: a study of incidence and aetiopathogenesis.
Thirty cases of exfoliative dermatitis (22 male and 8 female) were selected at random for study. In addition to routine history and clinical examination, investigations like histopathology of skin and lymph nodes, peripheral blood smear for abnormal cells and bone marrow examinations were done. Aetiologically, the cases could be classified into 4 categories namely exfoliation in per existing dermatoses, drug-induced exfoliation, idiopathic exfoliation and exfoliation secondary to internal malignancy. Two cases showed abnormal monocytoid cells (sezary cells) in peripheral blood smear.


Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity.
It has widely been accepted that major histocompatibility complex class I molecules (MHC-I) are limited to binding small peptides of 8-10 residues in length. However, this consensus has recently been challenged with the identification of longer peptides (≥11 residues) that can also elicit cytotoxic CD8+ T cell responses. Indeed, a growing number of studies demonstrate that these non-canonical epitopes are important targets for the immune system. As long epitopes represent up to 10% of the peptide repertoire bound to MHC-I molecules, here we review their impact on antigen presentation by MHC-I, TCR recognition, and T cell immunity.


Effects of posture on regional pulmonary blood flow in rats as measured by PET.
Using small animal PET with (68)Ga-radiolabeled human albumin microspheres (Ga-68-microspheres), we investigated the effect of posture on regional pulmonary blood flow (PBF) in normal rats. This in vivo method is noninvasive and quantitative, and it allows for repeated longitudinal measurements. The purpose of the experiment was to quantify spatial differences in PBF in small animals in different postures. Two studies were performed in anesthetized, spontaneously breathing Wistar rats. Study 1 was designed to determine PBF in the prone and supine positions. Ga-68-microspheres were given to five prone and eight supine animals. We found that PBF increased in dorsal regions of supine animals (0.75) more than in prone animals (0.70; P = 0.037), according to a steeper vertical gradient of flow in supine than in prone animals. No differences in spatial heterogeneity were detected. Study 2 was designed to determine the effects of tissue distribution on PBF measurements. Because microspheres remained fixed in the lung, PET was performed on animals in the position in which they received Ga-68-microsphere injections and thereafter in the opposite posture. The distribution of PBF showed a preference for dorsal regions in both positions, but the distribution was dependent on the position during administration of the microspheres. We conclude that PET using Ga-68-microspheres can detect and quantify regional PBF in animals as small as the rat. PBF distributions differed between the prone and supine postures and were influenced by the distribution of lung tissue within the thorax.


The Association between Vitamin D Hypovitaminosis and Cardiovascular Disease Risk in Saudi Diabetic Patients Type II.
We evaluated the prevalence and association of Vitamin D deficiency with glycemic control and CVD risk in T2DM patients. Serum 25 (OH)D3, lipid profile, glucose panel, HbA1c, serum insulin, and HOMA-IR were assessed in 93 T2DM patients and 69 controls. 10 years and lifetime ASCVD risk scores were calculated. The levels of 25(OH)D3 were significantly low in T2DM patients compared to the control. T2DM patients with hypovitaminosis D displayed significantly increased FBG, insulin, and HOMA-IR compared to normovitaminosis. Their lifetime and 10-year ASCVD risk scores were significantly higher regardless of vitamin D deficiency levels (P=0.006; P=0.023) in comparison to patients with sufficient levels of vitamin D. Among patients, the lifetime and 10 years of ASCVD risk showed a significant negative correlation with serum 25(OH)D3 and HDLc (P=0.037; 0.018) (P=0.0001), respectively, and significant positive correlation with T2DM duration, serum insulin, and HOMA-IR (P=0.018; 0.0001) (P=0.002; 0.001) (P=0.005; 0.001), respectively. The 10-year ASCVD risk exhibited a significant positive correlation with FBG (P=0.003) and HbA1c (P=0.009). T2DM duration was a predictor of vitamin D deficiency among T2DM patients (β = 0.22; CI = 0.002-0.04). There is a considerable association between lifetime and 10 years of ASCVD risk with hypovitaminosis D in T2DM, regardless of the deficiency levels which could be predicted by the diabetes duration.


Cerebrospinal fluid analysis for the diagnosis of human immunodeficiency virus-related neurologic diseases.
Although early attempts demonstrated increased amounts of p24 antigen in the cerebrospinal fluid (CSF) of AIDS patients with dementia (HADC), gene amplification based assays have recently shown a correlation between the HI virus load in CSF and dementia. Although these correlations are valid for a large population, current evidence does not favor the use of CSF HI virus load measurement for the diagnosis of HADC. By polymerase chain reaction, opportunistic infections of the central (CNS) and peripheral nervous system due to cytomegalovirus, JC virus, and herpes simplex virus types 1 and 2 and primary lymphoma caused by Epstein-Barr virus can be diagnosed with an overall sensitivity ranging from 76% to 98% and a specificity between 98% and 99.5%. In contrast, bacterial, protozal, and fungal infections of the CNS are still better diagnosed by conventional assays such as culture, antigen detection, and empirical therapy. Brain biopsy still remains the ultimate means of obtaining a specific diagnosis in selected cases.


Open-Ended Transmission Coaxial Probes for Sarcopenia Assessment.
We developed a handheld, side-by-side transmission-based probe for interrogating tissue to diagnose sarcopenia-a condition largely characterized by muscle loss and replacement by fat. While commercial microwave reflection-based probes exist, they can only be used in a lab for a variety of applications. The penetration depth of these probes is only in the order of 0.3 mm, which does not even traverse the skin layer, and minor motion of the coaxial feedlines can completely dismantle the calibration. Our device builds primarily on the transmission-based concept that allows for substantially greater signal penetration depth operating over a very broad bandwidth. Additional features were integrated to further improve the penetration, optimize the geometry for a more focused planar excitation, and juxtapose the coaxial apertures for more controlled interrogation. The larger coaxial apertures further increased the penetration depth while retaining the broadband performance. Three-dimensional printing technology made it possible for the apertures to be compressed into ellipses for interrogation in a near-planar geometry. Finally, fixed side-by-side positioning provided repeatable and reliable performance. The probes were also not susceptible to multipath signal corruption due to the close proximity of the transmitting and receiving apertures. The new concept worked from 100 MHz to over 8 GHz and could sense property changes as deep as 2-3 cm. While the signal changes due to deeper feature aberrations were more subtle than for signals emanating from the skin and subcutaneous fat layers, the large property contrast between muscle and fat is a sarcopenic indication that helps to distinguish even the deepest objects. This device has the potential to provide needed specificity information about the relevant underlying tissue.


Does annual temperature influence the prevalence of otolaryngologic respiratory diseases?
Determine if increasing annual temperature is associated with an increase in the prevalence of otolaryngologic respiratory diseases. Cross-sectional study. Patients and disease variables were extracted from the National Health Interview Survey for the calendar years 1998 to 2006 adult sample. Corresponding average annual temperature statistics were obtained from the National Climatic Data Center. The disease prevalences of hay fever, sinusitis, chronic bronchitis, and jaw/face pain (control group) were determined and tabulated according to mean annual temperature and compared graphically. Regression analysis for disease prevalence according to mean annual temperature was conducted. A total of 851,584 adults were sampled with a mean age of 35.7 years and a male:female ratio of 0.93:1. The overall disease prevalences for the disease conditions across all years of the study were (+/-95% confidence interval): hay fever (9.2% +/- 0.1%), sinusitis (15.0% +/- 0.2%), chronic bronchitis (4.5% +/- 0.1%) and pain in jaw/front of ear (4.5% +/- 0.1%). Regression analysis did not find a significant relationship between average annual temperature and the prevalence of disease for hay fever, jaw pain, or chronic bronchitis. A statistically significant but small regression coefficient (0.004) was noted for an increasing prevalence of sinusitis with increasing annual temperature (P = .031). Changes in mean annual temperature did not influence the prevalence of hay fever but did influence the prevalence of sinusitis over a 9-year period. Given the strong prevalence of hay fever and sinusitis, the effect of global warming on the otolaryngologic disease deserves continued epidemiologic surveillance.


Approximate perturbative solutions of quasispecies model with recombination.
Despite the major roles played by genetic recombination in ecoevolutionary processes, limited progress has been made in analyzing realistic recombination models to date, due largely to the complexity of the associated mechanisms and the strongly nonlinear nature of the dynamical differential systems. In this paper, we consider a many-loci genomic model with fitness dependent on the Hamming distance from a reference genome, and adopt a Hamilton-Jacobi formulation to derive perturbative solutions for general linear fitness landscapes. The horizontal gene transfer model is used to describe recombination processes. Cases of weak selection and weak recombination with simultaneous mutation and selection are examined, yielding semianalytical solutions for the distribution surplus of O(1/N) accuracy, where N is the number of nucleotides in the genome.


Proximal Tibia Skeletal Traction: Technique and Indications.
Skeletal traction is a fundamental tool for the orthopaedic surgeon caring for patients with traumatic pelvic and lower-extremity orthopaedic injuries. Skeletal traction has proven to be an effective initial means of stabilization in patients with these injuries. Traction may be used for both temporary and definitive treatment in a variety of orthopaedic injuries. With the appropriate knowledge of regional anatomy, skeletal traction pins can be placed safely and with a low rate of complications. Several methods for placing skeletal traction have been described, and it is critical for orthopaedic surgeons to be proficient not only in their application but also understanding of the appropriate indications for use. Here we present a case example of a patient with a right femur fracture and discuss the technique and indications for placement of proximal tibia skeletal traction.


Laparoscopic versus open appendectomy: a comparison of primary outcome measures.
The aim of the study was to compare laparoscopic and open appendectomy (OA) in terms of primary outcome measures. A randomized controlled trial. Place and duration of the study: Khyber Teaching Hospital, Peshawar, Pakistan, February 2008 to December 2009. A total of 160 patients were divided into two groups, A and B. Group A patients were subjected to laparoscopic appendectomy (LA), whereas Group B patients were subjected to OA. Data regarding age, gender, and primary outcome measures, such as hospital stay, operative duration, and postoperative complication, were recorded and analyzed. Percentages were calculated for categorical data, whereas numerical data were represented as mean ± SD. Chi-square test and t test were used to compare categorical and numerical variables, respectively. Probability ≤ 0.05 (P ≤ 0.05) was considered significant. After randomization, 72 patients in group A and 75 patients in group B were analyzed. The mean age of patients in groups A and B was 23.09 ± 8.51 and 23.12 ± 10.42 years, respectively, (P = 0.981). The mean hospital stay was 1.52 ± 0.76 days in group A and 1.70 ± 1.06 days in group B (P = 0.294). The mean operative duration in group A and B were 47.54 ± 12.82 min and 31.36 ± 11.43 min, respectively (P < 0.001). Pain (overall level) was significantly less in group A compared with group B (P = 0.004). The two groups were comparable in terms of other postoperative complications, such as hematoma (P = 0.87), paralytic ileus (P = 0.086), urinary retention (P = 0.504), and wound infection (P = 0.134). LA is an equivalent procedure and not superior to OA in terms of primary outcome measures.


Can Musical or Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with Mild Alzheimer's Disease? Evidence from a Randomized Controlled Trial.
Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer's disease (AD) and patients presenting chronic pain. However, their efficacy is still under debate. Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients. In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n = 31) or painting group (PG; n = 28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a 'per protocol' approach. Both singing and painting interventions led to significant pain reduction (Time effect: F = 4.71; p = 0.01), reduced anxiety (Time effect: F = 10.74; p < 0.0001), improved Quality of Life (Time effect: F = 6.79; p = 0.002), improved digit span (F = 12.93; p = 0.001), and inhibitory processes (Time effect: F = 4.93; p = 0.03). Depression was reduced over time in PG only (Time x Group effect: F = 4.53; p = 0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F = 9.29; p = 0.004). Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance.


Dumbbell-shaped cervical spinal neurilemmoma presenting as neck mass.
Cervical neurilemmoma may originate from any nerve sheath tissue in the neck including the vagus nerve, glossopharyngeal nerve, brachial plexus, sympathetic trunk and cervical spine. We report an unusual case of a dumbbell-shaped neurilemmoma arising from the cervical spinal roots in a patient who complained of having had a neck mass for several months. Computed tomographic scan and magnetic resonance imaging revealed a dumbbell-shaped tumour extending from the C4 spinal level through the intervertebral foramen into the right parapharyngeal space. Decompression surgery was performed first via the cervical approach. Five months later, the patient received laminectomy and a complete tumour excision. The symptoms and signs were significantly relieved without neurological sequelae. No evidence of recurrence was noted after one-year follow up. This two-staged operation could offer an alternative surgical approach yielding ideal therapeutic results in such a rare disease.


Universal-diverse orientation in Asian international students: confirmatory factor analysis of the Miville-Guzman universality-diversity scale, short form.
Despite apparent relevance to Asian international students, universal-diverse orientation (UDO) has not been psychometrically validated with this population. The current study investigated the most researched UDO measure, the Miville-Guzman Universality-Diversity Scale, Short Form (M-GUDS-S; Fuertes, Miville, Mohr, Sedlacek, & Gretchen, 2000), with 333 Asian international college students. The M-GUDS-S evidenced good reliability and convergent validity, and analyses confirmed a three-factor structure, supporting expanded use of the scale.


p53-independent effects of Mdm2.
Mdm2 is best known as the primary negative regulator of p53, but a growing body of evidence suggests that Mdm2 also has a number of functions independent of its role in regulating p53. Although these functions are not yet well-characterized, they have been implicated in regulating of a number of cellular processes, including cell-cycle control, apoptosis, differentiation, genome stability, and transcription, among others. It appears that Mdm2 exerts these functions through a surprisingly wide variety of mechanisms. For example, it has been shown that Mdm2 can ubiquitinate alternative targets, can stimulate the activity of transcription factors, and can directly bind to mRNA to regulate its stability. Dysregulation of p53-independent functions could be responsible for the oncogenic properties of Mdm2 seen even in the absence of p53, and may explain why approximately 10 % of human tumors overexpress Mdm2 instead of inactivating p53 through other mechanisms. As the p53-independent functions of Mdm2 present novel targets for potential therapeutic interventions, fully characterizing these cellular and pathogenic roles of Mdm2 will be important in the study of tumor biology and the treatment of cancer.


[Eukaryotic error prone DNA polymerases: suggested roles in replication, repair and mutagenesis].
A number of error-prone DNA polymerases is found among eukaryotes from yeasts up to mammalia including humans. According to the partial homology of a primary structure, they are united in families B, X, Y and display high infidelity on uninjured DNA-template, whereas they are rather accurate on DNA injuries. These DNA polymerases are characterized by the probability of base substitutions or frame shifts of 10(-3) to 7.5 x 10(-1) on DNA injuries, whereas the probability of spontaneous mutagenesis per replicated nucleotide accounts 10(-10) - 10(-12). Inaccurate DNA polymerases are terminal deoxynucleotidyl transferase (TdT), DNA polymerases beta, zeta, kappa, eta, iota, lamda, mu, and Rev1. Their principal properties are described in this review. All of the polymerases under study are deprived of the corrective 3'-->5' exonucleolytic activity. The specialization of these polymerases is contained in the capability to synthesize opposite DNA lesions (not eliminated by multiple repair systems) that is explained by the flexibility of their active sites or by the limited capability to exhibit the TdT activity. Classic DNA polymerases alpha, delta, epsilon, and gamma cannot elongate the primers with mismatched nucleotides on their 3'-ends (that leads to the replication block), whereas some of the specialized polymerases can do it. It is accompanied by the overcoming of a replication block, often with the expense of an elevated mutagenesis. How can a cell live under the conditions of such a huge infidelity of many DNA polymerases? Error-prone DNA polymerases are not found in all tissues though some of them are essential for an organism survival. Furthermore, cells must not allow for these polymerases to work effectively on uninjured DNA. After bypass of a lesion on DNA-template, it is necessary, as soon as possible, to switch catalysis of the DNA synthesis from the specialized polymerases on the relatively accurate DNA polymerases delta and epsilon (fidelity of 10(-5) - 10(-6)). It is made by the formation of the complexes of polymerases delta or epsilon with PCNA and replicative factors RP-A and RF-C. Such highly processive complexes manifest the bigger affinity to the correct primers than the specialized DNA polymerases do. The switching is stimulated by distributivity or weak processivity of the specialized DNA polymerases. The accuracy of these polymerases are augmented by the action of the corrective 3'-exonucleolytic function of DNA polymerases delta and epsilon as well as by the autonomous 3'-->5' exonucleases which are widespread among the representatives of the whole phylogenetic tree. Exonucleolytic correction slows down the replication in the presence of lesions in DNA-template but makes the replication more accurate that decreases the probability of mutagenesis and carcinogenesis.


Interaction between radiation and drug damage in mammalian cells. IV. Radiation response of adriamycin-resistant V79 cells.
Adriamycin-resistant variants derived from V79 Chinese hamster cells were examined for their radiation response properties. A stable resistant cell line (77A) demonstrated a significant reduction in the extrapolation number of the single-dose radiation survival curve. Second-step mutants from 77A cells exhibited a spectrum of radiation response states including decreased D0 values and large extrapolation numbers. A highly Adriamycin-resistant line (LZ) was found to be radiation sensitive with increased capacity for the accumulation of sublethal radiation injury. LZ cells are known to contain double-minute chromosomes and an amplified gene for the multidrug phenotype and to exhibit multidrug resistant properties. These cells require the presence of Adriamycin in their growth medium to maintain their pleiotropic characteristics. LZ cells became more resistant to radiation following reversion to an intermediate Adriamycin response as the consequence of growth in Adriamycin-free medium. Reverted cells also lost their large capacity for sublethal damage. It is suggested that detailed study of these mutants may provide insight into the identification of radiation-sensitive sites and their relationship to the genetic changes characterizing Adriamycin-resistant cell lines.


A bivariate zero-inflated negative binomial model and its applications to biomedical settings.
The zero-inflated negative binomial distribution has been widely used for count data analyses in various biomedical settings due to its capacity of modeling excess zeros and overdispersion. When there are correlated count variables, a bivariate model is essential for understanding their full distributional features. Examples include measuring correlation of two genes in sparse single-cell RNA sequencing data and modeling dental caries count indices on two different tooth surface types. For these purposes, we develop a richly parametrized bivariate zero-inflated negative binomial model that has a simple latent variable framework and eight free parameters with intuitive interpretations. In the scRNA-seq data example, the correlation is estimated after adjusting for the effects of dropout events represented by excess zeros. In the dental caries data, we analyze how the treatment with Xylitol lozenges affects the marginal mean and other patterns of response manifested in the two dental caries traits. An R package "bzinb" is available on Comprehensive R Archive Network.


[Bacteria and resistance to antibiotics in acute otitis media in paediatrics, depending on the geographical origin].
EPIDEMIOLOGY OF THE BACTERIA RESPONSIBLE: Acute otitis media (AOM) is the most common bacterial infection in childhood below the age of 5 years. Bacteria may be isolated from middle ear fluid in about two-thirds of patients. The prevalence of bacteria varies from one country to the next. The most common pathogens recovered are Streptococcus pneumoniae, Haemophilus influenzae (20-50%) and less frequently Moraxella catarrhalis (10%). However, several recent reports suggest an increasing rate of isolation of M. catarrhalis approaching 20%. Concomitant isolation of two or more organisms occurs in up to 10% of cases. The role of Group A Streptococci and Staphylococcus aureus in AOM has decreased since the use of antibiotics. EPIDEMIOLOGY OF ANTIMICROBIAL RESISTANCE: The recent spread of penicillin resistant S. pneumoniae and amoxycillin resistant H. influenzae varies considerably from one country to an other and appears related to the use of antibiotics and socio-economic conditions. A follow up of bacterial epidemiology and antibiotic resistance is necessary in each region of the world to define accurate strategies of acute otitis antibiotherapy.


Evaluation of countercurrent immunoelectrophoresis as a diagnostic tool in bacterial otitis media.
The diagnostic efficiency of countercurrent immunoelectrophoresis (CIE) and correlation of clinical and bacteriological data were studied in 184 middle ear effusions (MEE) from 125 patients diagnosed as acute primary, acute recurrent otitis media, and chronic MEE. Significant differences between stage of otitis media (OM), patient age and type of MEE were found. Streptococcus pneumoniae was isolated in 22% of the overall MEE, 26% in the acute primary and 26% in acute recurrent OM. Among the S. pneumoniae isolates, 82.5% were detected by CIE and culture, 15% only by culture and 2.5% only by CIE. Most S. pneumoniae isolates identified by culture and CIE were in a purulent MEE (64%) while those identified by culture only were in a mucoid MEE (67%). Haemophilus influenzae overall incidence was 29%; 13% of them produced beta-lactamase and only 4% were serotype b. The H. influenzae serotype b strains were detected by culture as well as CIE, so the overall effectiveness of CIE for S. pneumoniae and H. influenzae serotype b was 19.5% and 22 to 23% for acute primary and recurrent OM. Sterile cultures were obtained in 37.5% of the overall MEE. The CIE seems to be a useful screening test, culture remaining the method for definitive bacterial identification in MEE.


Pretransplant lymphopenia is a novel prognostic factor in cytomegalovirus and noncytomegalovirus invasive infections after liver transplantation.
Infection after liver transplantation (LT) remains a leading cause of morbidity and mortality. The risk of infection after LT is highest in those who are most immunosuppressed, but to date, no standard blood marker of one's degree of immunosuppression or risk index has been established. The purpose of this study was to determine whether pretransplant lymphopenia (absolute lymphocyte count < 500 cells/mm3 within 24 hours before LT) is a candidate marker of immunosuppression and could be useful in predicting the risk of cytomegalovirus (CMV) disease and non-CMV invasive infections after LT. Data were extracted from medical records for all primary, solitary LT procedures performed at Tufts Medical Center from 1999 to 2009. Two hundred seventy-six patients had sufficient data to be included in the analysis. Among these patients, 52% developed CMV or non-CMV invasive infections within 5 years of LT. Within 2 years, 23 (8%) had CMV disease, and 103 (37%) at least 1 non-CMV invasive infection. More lymphopenic patients than nonlymphopenic patients developed CMV (21% versus 4%, P < 0.001) and non-CMV invasive infections (50% versus 33%, P = 0.02). In a multivariate survival analysis, pretransplant lymphopenia was the strongest independent predictor of CMV disease [hazard ratio (HR) = 5.52, 95% confidence interval (CI) = 2.31-13.1, P = 0.001] after adjustments for known risk factors, including CMV serostatus (HR = 4.72, 95% CI = 2.01-11.1, P < 0.001). Both pretransplant lymphopenia (HR = 1.64, 95% CI = 1.14-2.53, P = 0.03) and CMV (HR = 2.93, 95% CI = 1.23-6.92, P = 0.02) independently predicted non-CMV infections. Our results suggest that pretransplant lymphopenia is a novel independent predictor of both CMV disease and non-CMV invasive infections after LT and is a candidate marker of immunosuppression in LT recipients.


Rapid changes in the phosphoproteome show diverse cellular responses following stimulation of human lung fibroblasts with endothelin-1.
The rapid phosphorylation and dephosphorylation of a variety of proteins downstream of the endothelin receptors A and B was investigated following stimulation of human lung fibroblasts with endothelin-1. Changes in the phosphorylation of proteins involved in the cell cycle, cytoskeleton, membrane channels, transcription, angiogenesis, and metabolism were observed. From observed changes in protein phosphatase 2A, CDC25 A, and caspase-2 precursor, a model for the promotion of cell cycle progression by ET-1 stimulation is proposed. This may offer insights into the mechanisms by which ET-1 exerts its mitogenic effects. The identities of the other proteins phosphorylated within 2 min of stimulation indicate that endothelin-1 also rapidly engages a diverse variety of other cellular responses.


Standardization of broth microdilution and disk diffusion susceptibility tests for Actinobacillus pleuropneumoniae and Haemophilus somnus: quality control standards for ceftiofur, enrofloxacin, florfenicol, gentamicin, penicillin, tetracycline, tilmicosin, and trimethoprim-sulfamethoxazole.
Quality control (QC) standards for the in vitro antimicrobial susceptibility testing of two fastidious veterinary pathogens, Actinobacillus pleuropneumoniae and Haemophilus somnus, were developed in a multilaboratory study according to procedures established by the National Committee for Clinical Laboratory Standards for broth microdilution and disk diffusion testing. The medium recommended for the broth microdilution testing is cation-adjusted Mueller-Hinton broth supplemented with 2% lysed horse blood, 2% yeast extract, and 2% supplement C. This medium has been designated veterinary fastidious medium. The medium recommended for the disk diffusion testing is chocolate Mueller-Hinton agar. The recommended QC organisms are A. pleuropneumoniae ATCC 27090 and H. somnus ATCC 700025. The QC MICs of ceftiofur, enrofloxacin, florfenicol, gentamicin, penicillin, tetracycline, tilmicosin, and trimethoprim-sulfamethoxazole were determined for each isolate, as were the zone size ranges. Of the results from the participating laboratories, 94.0% of the zone diameter results and 97.0% of the MIC results fell within the suggested QC ranges for all compounds. These QC guidelines should allow greater accuracy in interpreting results when testing these antimicrobial agents against fastidious pathogens.


The mechanisms for nitration and nitrotyrosine formation in vitro and in vivo: impact of diet.
The detection of 3-nitro-L-tyrosine residues associated with many disease states, including gastric cancer, has implicated a role for peroxynitrite in vivo, and thus endogenously produced nitric oxide and superoxide. Additionally, dietary nitrate has been suggested to be involved in the pathogenesis of gastric cancer through a mechanism involving reduction to nitrite and subsequent formation of potentially mutagenic nitroso-compounds. Studies have now demonstrated that a multitude of reactive nitrogen species other than peroxynitrite are capable of producing nitrotyrosine. Thus, we have reviewed the evidence that dietary nitrate, amongst other reactive nitrogen species, may contribute to the body burden of nitrotyrosine.


The Interaction of Perceived Susceptibility with Predictors of mHealth Technology Usage.
Objectives: Based on the significance of mobile healthcare (mHealth) technologies in the dynamic and competitive environment, the current study examined the interactive effect of individuals' perceived susceptibility of being ill with the performance expectancy, social influence, and facilitating conditions on their intentions and actual usage of mHealth technologies during medical emergencies/disastrous situations. Methods: Surveying 417 mHealth users in Indonesia, the current study applied structural equational modeling in SmartPLS ver.4 software to analyze the collected data. Results: Results revealed the importance of individuals' expectations regarding the performance of mHealth technologies along with the views of their social networks and facilitating conditions provided by the healthcare organizations to influence mHealth technologies' use during medical emergencies. However, results showed the strongest influence of facilitating conditions on the usage of mHealth technologies reflecting the significance of ease of use. Additionally, findings showed the significant contingent role of the perceived susceptibility of users to augment their intentions to adopt the mHealth technologies. Conclusion: The current study is expected to bring valuable insights to health service providers, health professionals, medical institutions, and practitioners by highlighting factors that facilitate individuals to use mHealth technologies during emergencies.