Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial.
Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.


Incidence and risk factors for stroke in pregnancy and the puerperium.
To estimate the incidence, mortality, and risk factors for pregnancy-related stroke in the United States. The Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, for the years 2000-2001 was queried for International Classification of Diseases, 9th Revision, codes for stroke among all pregnancy-related discharges. A total of 2,850 pregnancy-related discharges included a diagnosis of stroke for a rate of 34.2 per 100,000 deliveries. There were 117 deaths or 1.4 per 100,000 deliveries. Twenty-two percent of survivors were discharged to another facility. The risk of stroke increased with age, particularly ages 35 years and older. African-American women were at a higher risk, odds ratio (OR) 1.5 (95% confidence interval [CI] 1.2-1.9). Medical conditions that were strongly associated with stroke included migraine headache, OR 16.9 (CI 9.7-29.5), thrombophilia, OR 16.0 (CI 9.4-27.2), systemic lupus erythematosus, OR 15.2 (CI 7.4-31.2), heart disease, OR 13.2 (CI 10.2-17.0), sickle cell disease, OR 9.1 (CI 3.7-22.2), hypertension, OR 6.1(CI 4.5-8.1) and thrombocytopenia, OR 6.0 (CI 1.5-24.1). Complications of pregnancy that were significant risk factors were postpartum hemorrhage, OR 1.8 (CI 1.2-2.8), preeclampsia and gestational hypertension, OR 4.4 (CI 3.6-5.4), transfusion OR 10.3 (CI 7.1-15.1) and postpartum infection, OR 25.0 (CI 18.3-34.0). The incidence, mortality and disability from pregnancy related-stroke are higher than previously reported. African-American women are at an increased risk, as are women aged 35 years and older. Risk factors, not previously reported, include lupus, blood transfusion, and migraine headaches. Specific strategies, not currently employed, may be required to reduce the devastation caused by stroke during pregnancy and the puerperium. II-2.


The cholera toxin-derived CTA1-DD vaccine adjuvant administered intranasally does not cause inflammation or accumulate in the nervous tissues.
Although highly effective, the use of GM1-receptor binding holotoxins as nasal mucosal adjuvants has recently been cautioned due to the risk for their accumulation in the brain and other nervous tissues. Therefore we have explored the efficacy of the CTA1-DD adjuvant for its ability to enhance nasal immune responses in mice. We found that despite the lack of a mucosal binding element, the B cell-targeted CTA1-DD molecule was an equally strong adjuvant as cholera toxin (CT). The potency of CTA1-DD was not a result of endotoxin contamination because more than a 50-fold higher dose of LPS was needed to achieve a similar enhancement. Moreover, the adjuvant effect was TLR4-independent and absent in mutant CTA1-E112K-DD, lacking enzymatic activity. The CTA1-DD adjuvant augmented germinal center formations and T cell priming in the draining lymph nodes, and contrary to CT, promoted a balanced Th1/Th2 response with little effect on IgE Ab production. CTA1-DD did not induce inflammatory changes in the nasal mucosa, and most importantly did not bind to or accumulate in the nervous tissues of the olfactory bulb, whereas CT bound avidly to the nervous tissues. We believe that the nontoxic CTA1-DD adjuvant is an attractive solution to the current dilemma between efficacy and toxicity encountered in CT-holotoxin adjuvant or Escherichia coli heat-labile toxin-holotoxin adjuvant strategies and provides a safe and promising candidate to be included in future vaccines for intranasal administration.


Point mutations in the middle of 16S ribosomal RNA of E. coli produced by deletion loop mutagenesis.
Using the plasmid pKK3535 , which contains the rrnB operon of Escherichia coli in pBR322, a deletion mutation was constructed which lacks bases 822 to 874 in the middle of the 16S ribosomal RNA. This results in an "amputation" of a very distinct stem and loop structure in the RNA. By forming a heteroduplex between the deletion plasmid and the original pKK3535 and by modifying the single-stranded deletion loops with bisulfite, we produced plasmids containing one or two base changes at positions 839, 840, 841, 867 or 876. The clustering of the mutations near the top of the stem, and the inability to get base changes at other positions, suggests that single alterations at particular positions severely affect the formation of a functional ribosome. The ability to recover mutations at these positions is not determined by the secondary structure of the DNA during bisulfite mutagenesis. Restriction enzyme analysis of 12 revertants from a slow growing mutant (altered at positions 839 and 876) shows that they did not compensate for the mutation by re-establishing the original wild type sequence.


Hypoxia-inducible factor (HIF) in human tumorigenesis.
Hypoxia is a major event that occurs in most solid tumors. Intratumoral hypoxia is sufficient to activate the key transcription factor, hypoxia-inducible factor (HIF) that mediates the activation of the "survival machinery" in cancer cells. HIF can also be induced by oxygen-independent genetic alterations that activate a variety of oncogenic signaling pathways or inactivate tumor suppressors. Increased tumor HIF occurs at early stages of carcinogenesis and is often correlated with increased angiogenesis, malignant progression, poor patient prognosis and chemoradio-resistance. HIF-alpha subunit, the oxygen-regulated subunit of HIF is overexpressed in a wide range of human solid tumors. Nuclear HIF-alpha protein immunostaining was restricted to tumor cells compared to normal tissues. Herein, we review and discuss the role of HIF in tumorigenesis and describe the overexpression of HIF-alpha proteins in human cancers and its association with overall clinical outcomes.


Social media and organ donor registration: the Facebook effect.
Despite countless media campaigns, organ donation rates in the United States have remained static while need has risen dramatically. New efforts to increase organ donation through public education are necessary to address the waiting list of over 100,000 patients. On May 1, 2012, the online social network, Facebook, altered its platform to allow members to specify "Organ Donor" as part of their profile. Upon such choice, members were offered a link to their state registry to complete an official designation, and their "friends" in the network were made aware of the new status as a donor. Educational links regarding donation were offered to those considering the new organ donor status. On the first day of the Facebook organ donor initiative, there were 13 054 new online registrations, representing a 21.1-fold increase over the baseline average of 616 registrations. This first-day effect ranged from 6.9× (Michigan) to 108.9× (Georgia). Registration rates remained elevated in the following 12 days. During the same time period, no increase was seen in registrations from the DMV. Novel applications of social media may prove effective in increasing organ donation rates and likewise might be utilized in other refractory public health problems in which communication and education are essential.


Resveratrol inhibits pulmonary fibrosis by regulating miR-21 through MAPK/AP-1 pathways.
To explore the molecular mechanism of Res in regulation of pulmonary fibrosis (PF). Rats were injected with bleomycin (BLM) to establish a PF model and treated with resveratrol (Res) and/or miR-21 agomir. After 14 days, lung tissues were collected for Hematoxylin-eosin and Masson's staining, and real-time quantitative polymerase chain reaction and Western blot were performed to detect fibrosis-related protein expression and the activation of the TGF-β1/Smad pathway. In vitro, MRC-5 cells were pretreated with TGF-β1, Res, and/or miR-21 agomir. After 48 h, total soluble collagen was detected with a Sircol Soluble Collagen Assay. Subsequently, a miR-21 mimic was transfected into MRC-5 cells, and a luciferase reporter assay was employed to verify whether miR-21 targeted Smad7. Res reversed the increased levels of miR-21 induced by BLM and alleviated serious PF symptoms, but agomiR-21 treatment effectively impaired the above manifestations. In vivo, miR-21 inhibited the decreases of TGF-β1 and p-Smad2/3 that were induced by Res. In vitro, miR-21 significantly disrupted the positive effect of Res on TGF-β-induced collagen deposition, as well as the levels of Fn, α-SMA, p-Smad2, and Smad7. In addition, Smad7 was found to be a direct target of miR-21-5p. TGF-β stimulation led to an enormous increase in p-c-Jun, c-Jun, and c-Fos, which were significantly reduced by Res. Finally, miR-21 sharply reduced the increased phosphorylation levels of ERK, JNK and p38 that were induced by Res. Res inhibits BLM-induced PF by regulating miR-21 through MAPK/AP-1 pathways.


All-fiber micromachined microcell.
This Letter presents an open-path, all-fiber microcell and a micromachining method for its production. The proposed micromachining method utilizes the selective etching of a purposely designed phosphorus-doped fiber that is spliced in between two standard lead-in fibers. Microcells with various open optical-path lengths were successfully demonstrated. The proposed microcell can be used as a transmission cell or as a miniature Fabry-Perot resonator. The transmission losses and fringe contrast were experimentally investigated over a range of prototype microcells with different lengths. For example, the insertion losses below 1 dB were demonstrated for 50 μm or shorter open path prototype microcells, when immersed in dematerialized water.


Spatial summation in the human fovea: Do normal optical aberrations and fixational eye movements have an effect?
Psychophysical inferences about the neural mechanisms supporting spatial vision can be undermined by uncertainties introduced by optical aberrations and fixational eye movements, particularly in fovea where the neuronal grain of the visual system is fine. We examined the effect of these preneural factors on photopic spatial summation in the human fovea using a custom adaptive optics scanning light ophthalmoscope that provided control over optical aberrations and retinal stimulus motion. Consistent with previous results, Ricco's area of complete summation encompassed multiple photoreceptors when measured with ordinary amounts of ocular aberrations and retinal stimulus motion. When both factors were minimized experimentally, summation areas were essentially unchanged, suggesting that foveal spatial summation is limited by postreceptoral neural pooling. We compared our behavioral data to predictions generated with a physiologically-inspired front-end model of the visual system, and were able to capture the shape of the summation curves obtained with and without pre-retinal factors using a single postreceptoral summing filter of fixed spatial extent. Given our data and modeling, neurons in the magnocellular visual pathway, such as parasol ganglion cells, provide a candidate neural correlate of Ricco's area in the central fovea.


[Contemporary diagnostic methods and treatment for occupational bronchial asthma].
Occupational bronchial asthma remains rather prevalent condition developing due to industrial allergens both of organic and inorganic origin. Diagnostic tool is a complex approach including study of occupational and allergologic anamnesis, immune and allergy status, respiratory volumes. Diagnosis leads to first therapeutic step--elimination of contact with occupational allergen. Treatment of occupational asthma includes inhalation steroids, beta 2-agonists, cholinergic antagonists, methylxanthines. Objective of this treatment is maximal control of the disease with minimal therapy facilities--these are contemporary ideas of medical management for such occupational patients.


Understanding polycarbazole-based polymer:CdSe hybrid solar cells.
We report for the first time the fabrication and characterization of organic-inorganic bulk heterojunction (BHJ) hybrid solar cells made of poly[N-9″-hepta-decanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3'-benzothiadiazole)] (PCDTBT) and pyridine-capped CdSe nanorods. By optimizing both CdSe loading and active layer film thickness, the power conversion efficiencies (PCEs) of PCDTBT:CdSe hybrid solar cells were able to reach 2%, with PCDTBT:CdSe devices displaying an open-circuit voltage (V(OC )) that is 35% higher than P3HT:CdSe devices due to the deeper HOMO level of PCDTBT polymer. The performance of PCDTBT:CdSe devices is limited by its morphology and also its lower LUMO energy offset compared to P3HT:CdSe devices. Hence, the performance of PCDTBT:CdSe solar cells could be further improved by modifying the morphology of the films and also by including an interlayer to generate a built-in voltage to encourage exciton dissociation. Our results suggest that PCDTBT could be a viable alternative to P3HT as an electron donor in hybrid BHJ solar cells for high photovoltage application.


Chest wall perforator flaps for partial breast reconstruction after conservative surgery: Prospective analysis of safety and reliability.
Breast-conserving surgery associated with adjuvant radiotherapy is the state of the art in the surgical treatment of breast cancer. Oncoplastic surgery through dermo-adipose flaps based in perforating arteries (muscle sparing flaps) for partial reconstruction is increasingly used as a good option for avoiding musculocutaneous flaps. In this study we evaluate the outcomes of the use of chest wall perforator flaps in the replacement of partial breast volume. A prospective cohort study of female patients that underwent a conservative oncoplastic surgery procedure with partial breast reconstruction using a dermo-adipose flap of perforating arteries of the chest wall was conducted between November 2020 and March 2022 at our centre. Primary outcomes were surgical morbidity, positive margins and reoperation rates. Characteristics associated with the occurrence of complications were further identified. Forty-five patients underwent the procedure of interest during the study period. The mean age was 55 years. The median larger dimension of the tumor was 23 mm. Lateral intercostal artery perforator (LICAP), lateral thoracic artery perforator (LTAP), a combined flap and Anterior Intercostal Artery Perforator/Medial Intercostal Artery Perforator (AICAP)/(MICAP) were performed in 22, 16, 2 and 5 patients, respectively. The mean operative time was 126 min. A total of 9 (20.0%) patients required a reoperation after definitive diagnosis, 4 due to positive margins and 5 due to immediate/early surgical morbidity. Local perforator flaps in oncoplastic breast-conserving surgery are a good option for immediate reconstruction after conservative surgery, showing low morbidity and favourable outcomes.


[Shock lung syndrome in myocardial infarct (electron microscopic and biochemical study)].
A comprehensive clinical sample (375 cases of myocardial infarction, with uncomplicated course in 115, pulmonary edema in 80, cardiac asthma in 37, pulmonary edema combined with cardiogenic shock in 55, and other complications in 88; 89 fatal cases altogether) was used to demonstrate that the shock lung associated with myocardial infarction was rooted in strained operation of various pulmonary functions other than gaseous exchange and inadequate inactivation of vasoactive substances (histamine, serotonin, kinins). The ultrastructural pattern of the shock lung is characterized by damaged aerohematic barrier edema, hypercoagulation, atelectases and the sludging of aggregated erythrocytes. Acute respiratory insufficiency is not always associated with cardiogenic shock and may develop spontaneously in myocardial infarction.


Secure and defensive high self-esteem.
Long-standing theories have suggested high self-esteem (SE) can assume qualitatively different forms that are related to defensiveness. The authors explored whether some high-SE individuals are particularly defensive because they harbor negative self-feelings at less conscious levels, indicated by low implicit SE. In Study 1, participants high in explicit SE but low in implicit SE showed the highest levels of narcissism--an indicator of defensiveness. In Studies 2 and 3, the correspondence between implicit and explicit SE predicted defensive behavior (in-group bias in Study 2 and dissonance reduction in Study 3), such that for high explicit-SE participants, those with relatively low implicit SE behaved more defensively. These results are consistent with the idea that high SE can be relatively secure or defensive.


Neuroblastoma with intracerebral metastases and the need for neurosurgery: a single-center experience.
Intracerebral metastases in neuroblastoma patients are rare, and information about the indication for and the outcome of neurosurgical procedures in this setting is scarce in the literature. The authors' aim in the present study was to report a single-center experience with the neurosurgical treatment of intracerebral metastases in neuroblastoma. This study is a retrospective single-center analysis of all neurosurgical strategies used in the treatment of intracerebral metastases in neuroblastoma patients. Between 2009 and 2017, 237 pediatric patients (94 girls, 143 boys) with a mean age of 39 months at diagnosis were treated for neuroblastoma. Five (2.1%) of the 237 patients had a neurosurgical procedure for intracerebral metastases. The metastases occurred a mean of 46 months after initial diagnosis. All of these patients had neuroblastoma stage 4. Indications for surgery were recurrent metastases after initial successful oncological treatment or progression of the metastasis under oncological treatment as well as deterioration of neurological function. Intraoperatively, the tumor usually had a distinguishable dissection plane but was infiltrative to adjacent nerves in some spots. Mean overall survival after the neurosurgical procedure was 22 months. Furthermore, in another 3 patients, a neurosurgical procedure was done for an intracranial but extracerebral metastasis. Neurosurgical procedures for intracerebral metastases in neuroblastoma patients are rare and were performed in 2.1% of patients in the present study. Intracerebral metastases occurred during disease progression, and the prognosis after surgery was very limited. The main indications for surgery were rapid neurological deterioration or recurrence of the metastasis after initial successful oncological treatment. Intraoperatively, the metastases usually had a distinguishable dissection plane from the normal brain tissue.


[Genetic burden of psychosomatic diseases and exogenous risk-factors of cardiovascular diseases in healthy students with different physiological and psychological adaptation abilities].
Exogenous risk factors of cardiovascular diseases and genetic burden of psychosomatic pathologies have been studied in practically healthy students with various physiological and psychological adaptation abilities for differential analysis of the risk for development of cardiological diseases. The complex of genetic burden of psychosomatic pathologies and exogenous risk factors was significantly more frequent in practically healthy students with strong profile of adaptation mechanisms, increased circadian profile, zero type and weak persistence of fixated set.


Heme oxygenase-1 induction in the brain during lipopolysaccharide-induced acute inflammation.
Delirium occurs in 23% of sepsis patients, in which pro-inflammatory cytokines and nitric oxide are suggested to be involved. However, in animal experiments, even a subseptic dose of lipopolysaccharide (LPS) injection induces both pro-inflammatory cytokines and inducible nitric oxide synthase in the brain, suggesting that the brain oxidative reaction can be induced in the subseptic condition. Then, we evaluated the changes of heme oxygenase-1 (HO-1), a sensitive oxidative marker, as well as interleukin (IL)-1beta, IL-6, and inductible nitric oxide synthase (iNOS) mRNA in the hypothalamus and hippocampus of rats using real-time PCR after peripheral injection of LPS (2.0 mg/kg). As a result, these four kinds of mRNAs were induced significantly in both areas after LPS injection. These results suggest that peripheral inflammation induces an oxidative reaction in the brain, even if the inflammation is not lethal. It is also considered that several pathways are involved in brain HO-1 induction.


Growth patterns during childhood and the relationship with acylation-stimulating protein.
Acylation-stimulating protein (ASP) is an adipose tissue-derived hormone, which stimulates glucose and free fatty acid (FFA) uptake into adipocytes. Changes in ASP metabolism are associated with alterations in lipid metabolism. As postnatal catch-up growth has been associated with dyslipidaemia in later life, we investigated the association between ASP and birth size, adult size and different growth patterns during childhood. The associations were investigated by multiple regression analyses in 285 young adults, aged 18-24. Subsequently, differences in ASP were analysed in four clinically relevant subgroups, young adults either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age with idiopathic short stature (ISS) or with normal stature (controls). Weight gain during childhood, particularly fat accumulation, was positively related to ASP levels in early adulthood, independent of birth size, age and gender. Foetal growth, reflected by birth size, was not related to ASP levels. Between the subgroups, no differences in ASP were found, but SGA-CU and ISS subjects had significantly higher levels of FFA. Exaggerated weight gain during childhood, but not foetal growth, contributes to alterations in ASP metabolism, which may be associated with impaired FFA uptake and delayed triglycerides clearance. Therefore, exaggerated weight gain during childhood should be prevented.


Periodic climate cooling enhanced natural disasters and wars in China during AD 10-1900.
Recent studies have linked climatic and social instabilities in ancient China; the underlying causal mechanisms have, however, often not been quantitatively assessed. Here, using historical records and palaeoclimatic reconstructions during AD 10-1900, we demonstrate that war frequency, price of rice, locust plague, drought frequency, flood frequency and temperature in China show two predominant periodic bands around 160 and 320 years where they interact significantly with each other. Temperature cooling shows direct positive association with the frequency of external aggression war to the Chinese dynasties mostly from the northern pastoral nomadic societies, and indirect positive association with the frequency of internal war within the Chinese dynasties through drought and locust plagues. The collapses of the agricultural dynasties of the Han, Tang, Song and Ming are more closely associated with low temperature. Our study suggests that food production during the last two millennia has been more unstable during cooler periods, resulting in more social conflicts owing to rebellions within the dynasties or/and southward aggressions from northern pastoral nomadic societies in ancient China.


Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice.
Autophagy plays an important role in the maintenance of normal heart function. However, the role of autophagy in the inulin resistant and diabetic heart is not well understood. Furthermore, the upstream signaling and the downstream targets involved in cardiac autophagy regulation during obesity and type 2 diabetes mellitus (T2DM) are not fully elucidated. The aim of this study was to measure autophagic flux and to dissect the upstream and downstream signaling involved in cardiac autophagy regulation in the hearts of obese T2DM mice. Our study demonstrated that cardiac autophagic flux is suppressed in the heart of obese diabetic (ob/ob) mice due to impaired autophagosome formation. We showed that suppression of autophagy was due to sustained activation of mTOR as we could restore cardiac autophagy by inhibiting mTOR. Moreover, the novel finding of this study is that while IGF-1 receptor-mediated Akt activation contributes to cardiac hypertrophy, it is not involved in mTOR activation and autophagy suppression in obesity and T2DM. In contrast, inhibition of ERK signaling abolished mTOR activation and restored autophagy in the heart of obese diabetic (ob/ob) mice. The study identifies mechanisms regulating cardiac autophagy in obesity and T2DM that are mediated by ERK/mTOR but are distinct from Akt. The findings are of significant importance as they demonstrate for the first time the contribution of IGF-1 receptors (IGF-1R) and Akt signaling in cardiac hypertrophy but not in cardiac autophagy regulation in obesity and T2DM.


Forensic application of DNA 'fingerprints'.
Many highly polymorphic minisatellite loci can be detected simultaneously in the human genome by hybridization to probes consisting of tandem repeats of the 'core' sequence. The resulting DNA fingerprints produced by Southern blot hybridization are comprised of multiple hypervariable DNA fragments, show somatic and germline stability and are completely specific to an individual. We now show that this technique can be used for forensic purposes; DNA of high relative molecular mass (Mr) can be isolated from 4-yr-old bloodstains and semen stains made on cotton cloth and digested to produce DNA fingerprints suitable for individual identification. Further, sperm nuclei can be separated from vaginal cellular debris, obtained from semen-contaminated vaginal swabs, enabling positive identification of the male donor/suspect. It is envisaged that DNA fingerprinting will revolutionize forensic biology particularly with regard to the identification of rape suspects.


Wheat in the Mediterranean revisited--tetraploid wheat landraces assessed with elite bread wheat Single Nucleotide Polymorphism markers.
Single Nucleotide Polymorphism (SNP) panels recently developed for the assessment of genetic diversity in wheat are primarily based on elite varieties, mostly those of bread wheat. The usefulness of such SNP panels for studying wheat evolution and domestication has not yet been fully explored and ascertainment bias issues can potentially affect their applicability when studying landraces and tetraploid ancestors of bread wheat. We here evaluate whether population structure and evolutionary history can be assessed in tetraploid landrace wheats using SNP markers previously developed for the analysis of elite cultivars of hexaploid wheat. We genotyped more than 100 tetraploid wheat landraces and wild emmer wheat accessions, some of which had previously been screened with SSR markers, for an existing SNP panel and obtained publically available genotypes for the same SNPs for hexaploid wheat varieties and landraces. Results showed that quantification of genetic diversity can be affected by ascertainment bias but that the effects of ascertainment bias can at least partly be alleviated by merging SNPs to haplotypes. Analyses of population structure and genetic differentiation show strong subdivision between the tetraploid wheat subspecies, except for durum and rivet that are not separable. A more detailed population structure of durum landraces could be obtained than with SSR markers. The results also suggest an emmer, rather than durum, ancestry of bread wheat and with gene flow from wild emmer. SNP markers developed for elite cultivars show great potential for inferring population structure and can address evolutionary questions in landrace wheat. Issues of marker genome specificity and mapping need, however, to be addressed. Ascertainment bias does not seem to interfere with the ability of a SNP marker system developed for elite bread wheat accessions to detect population structure in other types of wheat.


Psychopathic personality in children: genetic and environmental contributions.
The current study investigates whether the underlying factor structure of psychopathic personality traits found in adults is similar to that in children and what the extent of the genetic and environmental influences are on these psychopathic traits. Psychopathic personality traits were assessed in a community sample of 1219 twins and triplets (age 9-10 years) through caregiver reports of each child's behavior using the Child Psychopathy Scale (CPS). Confirmatory factor analyses revealed an optimal two-factor solution (callous/disinhibited and manipulative/deceitful) to the CPS subscales. Bivariate genetic modeling of the two computed factor scores revealed significant genetic as well as unique environmental influences on psychopathic personality traits in both boys and girls, with heritability estimates of 0.64 and 0.46, respectively, in boys and 0.49 and 0.58, respectively, in girls. No shared environmental influences on psychopathic personality traits were found. The relationship between the two factors was mediated by both genetic and unique environmental factors common to both traits.


Comparative study of protein-protein interaction observed in PolyGalacturonase-Inhibiting Proteins from Phaseolus vulgaris and Glycine max and PolyGalacturonase from Fusarium moniliforme.
The PolyGalacturonase-Inhibiting Proteins (PGIP) of plant cell wall limit the invasion of phytopathogenic organisms by interacting with the enzyme PolyGalacturonase (PG) they secrete to degrade pectin present in the cell walls. PGIPs from different or same plant differ in their inhibitory activity towards the same PG. PGIP2 from Phaseolus vulgaris (Pv) inhibits the PG from Fusarium moniliforme (Fm) although PGIP1, another member of the multigene family from the same plant sharing 99% sequence similarity, cannot. Interestingly, PGIP3 from Glycine max (Gm) which is a homologue of PGIP2 is capable of inhibiting the same PG although the extent of similarity is lower and is 88%. It therefore appears that subtle changes in the sequence of plant PGIPs give rise to different specificity for inhibiting pathogenic PGs and there exists no direct dependence of function on the extent of sequence similarity. Structural information for any PGIP-PG complex being absent, we resorted to molecular modelling to gain insight into the mechanism of recognition and discrimination of PGs by PGIPs. We have built homology models of PvPGIP1 and GmPGIP3 using the crystal structure of PvPGIP2 (1OGQ) as template. These PGIPs were then docked individually to FmPG to elucidate the characteristics of their interactions. The mode of binding for PvPGIP1 to FmPG considerably differs from the mode observed for PvPGIP2-FmPG complex, regardless of the high sequence similarity the two PGIPs share. Both PvPGIP2 and GmPGIP3 despite being relatively less similar, interact with residues of FmPG that are known from mutational studies to constitute the active site of the enzyme. PvPGIP1 tends to interact with residues not located at the active site of FmPG. Looking into the electrostatic potential surface for individual PGIPs, it was evident that a portion of the interacting surface for PvPGIP1 differs from the corresponding region of PvPGIP2 or GmPGIP3. van der Waals and electrostatic interactions play an active role in PGIPs for proper recognition and discrimination of PGs. Docking studies reveal that PvPGIP2 and GmPGIP3 interact with the residues constituting the active site of FmPG with implications that the proteins bind/block FmPG at its active site and thereby inhibit the enzyme.


Shape selection of twist-nematic-elastomer ribbons.
How microscopic chirality is reflected in macroscopic scale to form various chiral shapes, such as straight helicoids and spiral ribbons, and how the degree of macroscopic chirality can be controlled are a focus of studies on the shape formation of many biomaterials and supramolecular systems. This article investigates both experimentally and theoretically how the chiral arrangement of liquid crystal mesogens in twist-nematic-elastomer films induces the formation of helicoids and spiral ribbons because of the coupling between the liquid crystalline order and the elasticity. It is also shown that the pitch of the formed ribbons can be tuned by temperature variation. The results of this study will facilitate the understanding of physics for the shape formation of chiral materials and the designing of new structures on basis of microscopic chirality.


Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells.
Local bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions. We analysed osteoclastogenesis of wildtype (wt) and PTEN(-/-) cells in vitro and in vivo, pit resorption and qPCR of osteoclasts in vitro. Mice with a myeloid cell-specific deletion of PTEN and wt littermate mice were investigated by bone histomorphometry and clinical and histological assessment in the human tumour necrosis factor (TNF)-transgenic (hTNFtg) arthritis model. We show that myeloid-specific PTEN(-/-) mice display increased osteoclastogenesis in vitro and in vivo compared to wt mice. Loss of PTEN did not affect the generation or survival of osteoclast precursor cells. However, PTEN deficiency greatly enhanced receptor activator of nuclear factor κ-B ligand (RANKL)-induced expression of the master transcription factor of osteoclastogenesis, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), resulting in markedly increased terminal differentiation of osteoclasts in vitro. We also observed increased osteoclastogenesis under inflammatory conditions in the hTNFtg mouse model of arthritis, where hTNFtg/myeloid-specific PTEN(-/-) mice displayed enhanced local bone destruction as well as osteoclast formation in the inflamed joints. The extent of synovial inflammation, however, as well as recruitment of osteoclast precursor cells was not different between wt and myeloid-specific PTEN(-/-) mice. These data demonstrate that loss of PTEN and, therefore, sustained PI3-Kinase signalling in myeloid cells especially, elevates the osteoclastogenic potential of myeloid cells, leading to enhanced inflammatory local bone destruction. Therefore, although our study allows no direct translational conclusion since we used a conditional knockout approach, the therapeutic targeting of the PI3-Kinase pathway may be of benefit in preventing structural joint damage.


Magnesium supplement enhances spatial-context pattern separation and prevents fear overgeneralization.
Enhancement of pattern separation could be helpful in improving the quality of normal daily learning and in treating individuals with cognitive impairment and certain psychiatric disorders. Previously, we have shown that elevating brain magnesium, by a novel magnesium compound (magnesium-L-threonate; MgT), enhances extinction of fear memory without enhancing amygdala-dependent fear memory. Here, we investigated the effects of MgT treatment on contextual-fear memory and subsequent pattern separation. Sprague-Dawley male rats were treated with MgT for 4 weeks and memory was evaluated using a spatial-context fear conditioning task. The pattern separation ability of MgT-treated rats was assessed using a spatial-context-discrimination task. MgT treatment did not enhance the retention of contextual-fear memory. Interestingly, the ability to discriminate between two, more or less distinct, contexts was enhanced in MgT-treated rats. Our results suggest that elevation of brain magnesium might be helpful in enhancing spatial-context discrimination and/or pattern separation besides preventing aversive-event-induced overgeneralization of fear.


New evidence on the allocation of NIH funds across diseases.
The responsiveness of NIH (National Institutes of Health) funding to disease burden is a long-standing issue of policy interest. Previous analyses of this issue have been hindered by data constraints, have not specified channels through which the NIH funding process could be responsive to disease considerations, and have not examined differences across NIH institutes and centers. We collected data from the NIH's new RCDC (Research, Condition, and Disease Categorization) database on funding for 107 diseases in 2008 and linked these to data on deaths and hospitalizations for these diseases. We used RCDC data and information from another NIH database--RePORTER--to determine institute-specific funding for these diseases and also funding by award type. We used these data to examine the overall responsiveness of NIH funding to disease burden, within-institute responsiveness, and the responsiveness of different types of NIH awards. Overall, we found a strong and statistically significant relationship between NIH funding and deaths and hospitalizations associated with a disease. We detected some evidence that more "applied" grant mechanisms--in particular, funding for clinical trials--are more responsive than other types of funding. We also found evidence of differences across institutes in their extent of responsiveness. Overall, the data suggest that NIH funding is responsive to the two measures of disease burden. More applied grant mechanisms also may serve as "safety valves" in the allocation process, allowing Congress, disease advocacy groups, and others to apply pressure to address particular health priorities in a more fine-grained way than is possible through investigator-initiated "basic" research grants alone.


Pathobiology of platelet-activating factors.
Throughout the evolution of knowledge about inflammation, a primary goal has been to understand this important biological response in sufficient depth to prevent the unwanted tissue injury that may spontaneously occur or that may coevolve to produce disease. That is, although the host defense systems normally function in a protective manner, excessive activation or alterations of the homeostatic regulation of the inflammatory responses often results in overt tissue injury and organ dysfunction. Thus, significant attention has been focused upon precise definition of the interactions of the myriad of involved cells and mediators so that interventions may be developed to block these events to prevent and control inflammatory tissue injury. PAF, as a relative newcomer to the investigative eye of experimental pathologists, is a potent proinflammatory mediator of many aspects of the complex host defense system. No doubt, its role in the initiation and maintenance of tissue injury or disease will be conclusively documented with additional research and forthcoming advances in biomedical technology. At present, however, we must be content to accept the conclusion that, while it is tempting to speculate that this unique phospholipid is involved in many different disease processes, unequivocal details to this end are lacking. Nonetheless, the spectrum of antagonists of PAF action which are currently evolving [cf. 95-100] will undoubtedly permit assessment of the putative contributions of PAF to many biological conditions associated with disease. At that time, meaningful conclusions as to the biological role of PAF in human tissue injury and disease may be provided.


Rotational stability and clinical outcomes of a new one piece toric intraocular lens with anchor-wing haptics.
To evaluate the safety and efficacy of a new toric intraocular lens (IOL) with anchor-wing haptics. The new toric IOL with anchor-wing haptics (NS60YT, NIDEK Co., Ltd.) was implanted in eligible patients with age-related cataracts with preoperative corneal astigmatism of 1.0 D or greater at a university hospital and two private hospitals in Japan. The following IOL cylinder powers were evaluated: 1.50 D (NS60YT3), 2.25 D (NS60YT4), 3.00 D (NS60YT5) and 4.50 D (NS60YT7). All patients were assessed out to 12 months postoperatively. The primary endpoint was visual acuity (VA) with spherical addition at 6 months postoperatively, and the primary analysis calculated the proportion of eyes with VA with spherical addition of 0.1 logMAR or better. The magnitude of rotation was compared to the intended axis of IOL implantation at each postoperative examination. Adverse events were evaluated for the safety analysis. This study enrolled 64 eyes of 53 patients. At 6 months postoperatively, for all IOL powers, VA with spherical addition of 0.1 logMAR or better was achieved in 90% [95% confidence interval (CI): 80-96] of eyes. The mean IOL rotation was 5.3 ± 4.3° at 12 months postoperatively. The mean magnitude of rotation ranged from 1.9° to 2.5° between each postoperative examination from 1 day to 12 months. There were no vision-threatening intraoperative or postoperative complications for the duration of the study. The NS60YT IOL remained stable after implantation and was efficacious for treating 1.00 D or greater astigmatism in patients with senile cataracts. This study was registered at ClinicalTrials.gov ( NCT03242486 ) on August 8, 2017 - Retrospectively registered.


Extracorporeal Membrane Oxygenation as a Bridge to Initial Medical Therapy in a Patient With Decompensated Pulmonary Arterial Hypertension Presenting With Biventricular Failure.
Extracorporeal membrane oxygenation (ECMO) can be used as a bridge to medical therapy in decompensated right heart failure due to pulmonary arterial hypertension (PAH). A middle-aged man with previously undiagnosed pulmonary hypertension was successfully bridged to intravenous prostanoid therapy with venoarterial ECMO support after presenting with cardiogenic shock and hypoxemic respiratory failure. Although the patient initially had biventricular failure, PAH was suspected due to underlying mixed connective tissue disease and disproportionate right ventricular dysfunction. On occasion, patients with PAH may present with biventricular failure. A high index of suspicion for PAH and serial reassessment of left ventricular function following correction of shock may demonstrate improvement in left ventricular function, allowing for initiation of pulmonary vasodilator therapy.


Smartphone technology for fostering goal-directed ambulation and object use in people with moderate Alzheimer's disease.
Purpose: This study was aimed at assessing a smartphone-based intervention to help 11 individuals with moderate Alzheimer's disease and ambulation problems to manage goal-directed, walker-assisted ambulation and object use (i.e., to reach specific destinations and put away objects at those destinations independently).Method: The study was carried out according to a non-concurrent multiple baseline design across participants. Two measures were recorded, that is, the number of target responses performed correctly (with each target response consisting of reaching a destination and putting away an object), and the number of observation intervals with indices of enjoyment/appreciation (e.g., smiles and positive comments). During baseline, the participants were provided with a walker and three objects that were to be transported to and put away at specific destinations. During the intervention, the participants also had the smartphone-based technology that provided them with instructions about the destinations and objects, praise, and preferred stimulation.Results: During baseline, the mean frequency of correct target responses was virtually zero. The mean frequency of intervals with indices of enjoyment/appreciation ranged from zero to close to one. During the intervention, the mean frequencies for the two measures were slightly below three and just over three, respectively. The maximum frequencies possible were three and four, respectively.Conclusions: A smartphone-based intervention may be suitable to foster goal-directed, walker-assisted ambulation and object use as well as enjoyment/appreciation in participants like those involved in this study.IMPLICATIONS FOR REHABILITATIONA smartphone-based intervention may be used to promote goal-directed, walker-assisted ambulation and object use as well as indices of enjoyment/appreciation in persons with moderate Alzheimer disease.The technology for such intervention might involve (a) a smartphone with Android operating system, light sensor, Bluetooth v4.0, and MacroDroid, (b) Bluetooth headphones or earpieces, and (c) battery-powered light sources.The technology may provide the participants with instructions about the destinations to reach and the objects to put away at those destinations, and with praise and brief periods of preferred stimulation at the target destinations.The technology may be considered easy to access, friendly for the participants, and suitable for use by staff within daily contexts.


Evaluation of fine needle aspiration biopsy in oral cavity and head and neck region with different stains techniques.
The present study aimed to evaluate the Fine Needle Aspiration Biopsy in different staining techniques in nodular lesions of the oral cavity and head and neck region, as their sensitivity, specificity and accuracy, staining with Panoptic, Papanicolaou and Hematoxylin-Eosin (H&E) stains. 46 patients who sought the Clinic of the Discipline of Clinical Stomatology at FOUSP were selected consecutively, with nodular lesions in the oral cavity and head and neck region. The material obtained by FNAB was sent on 6 different slides, stained by the method of Panoptic, Papanicolaou and H&E, to the same pathologist only with the clinical diagnosis. After the final report of FNAB, the biopsy report was issued, serving as gold standard. After the calculations, the results of sensitivity, specificity and accuracy for Panoptic staining were 28.6%, 76% and 15.4%, respectively. The result of sensitivity, specificity and accuracy for Papanicolaou staining were 71.4%, 76.7% and 23.3%, respectively. The result of sensitivity, specificity and accuracy for H&E staining were 82.1%, 23.3%, 28.6%, respectively. We can conclude, according to the methodology of this study that, H&E and Papanicolaou stains showed the same sensitivity of diagnosing malignant neoplasms. H&E stain showed a better specificity for diagnosing benign neoplasms, compared with Papanicolaou and Panoptic stains. H&E stain showed better accuracy, to give definitive diagnosis, followed by Papanicolaou and Panoptic stains.


Implementation and Outcomes of a Comprehensive Tobacco Free Workplace Program in Opioid Treatment Centers.
Tobacco use is exceedingly high among individuals receiving care for opioid addiction, but not commonly addressed by clinicians in treatment settings. Taking Texas Tobacco Free (TTTF) is a comprehensive tobacco-free workplace (TFW) program that builds treatment centers' capacity to address tobacco use with evidence-based tobacco cessation policies and practices. Here, we examine the process and outcomes of TTTF's implementation within 7 opioid addiction centers. Program goals were structured according to the RE-AIM framework. Pre- and post-implementation data were collected from client facing and non-client facing employees to assess changes in education, training receipt, knowledge, and intervention behaviors, relative to program goals. Centers reported tobacco screenings conducted and nicotine replacement therapy (NRT) delivered through 6 months post-implementation. Overall, 64.56% of employees participated in TTTF-delivered tobacco education, with a 54.9% gain in tobacco control and treatment knowledge (p < 0.0001), and significant increases in exposure to education about tobacco use and harms among individuals with opioid use disorder (p = 0.0401). There were significant gains in clinicians' receipt of training in 9/9 tobacco education areas (ps ≤ 0.0118). From pre- to post-implementation, there were mean increases in the use of the 5A's (ask, advise, assess, assist, and arrange) and other evidence-based interventions for tobacco cessation, with statistically significant gains seen in NRT provision/referral (p < 0.0001). Several program goals were achieved or exceeded; however, 100% center participation in specialized clinical trainings was among notable exceptions. One program withdrew due to competing pandemic concerns; all others implemented comprehensive TFW policies. Overall, TTTF may have improved participating opioid treatment centers' capacity to address tobacco use, although study limitations, including lower post-implementation evaluation response rates, suggest that results require replication in other opioid addiction treatment settings.


Oral health decline in patients after stroke: a qualitative study.
Introduction To develop and implement effective oral care interventions for patients after stroke, there is a need to understand the causes behind the decline in their oral health. This qualitative study was, therefore, undertaken to explore experiences and views of health service providers about the causes of oral health decline in this group of patients.Methods A purposively selected sample of healthcare service providers who work in two NHS Trusts in the North of England were interviewed utilising a semi-structured interview technique. Interviews were conducted with the assistance of a topic guide and continued until data saturation (n = 30) was reached. The constant comparative approach was used to analyse the data.Results Two major factors, perceived by the participants, were thought to cause oral health decline in patients after stroke. Post-stroke neurological deficits resulting in oral-related functional disturbances was the first. The second was the barriers leading to difficulties in performing or receiving daily oral care. These barriers were related to the patients, their service providers, or the environment in which care is being delivered.Conclusions This study described the major factors affecting the oral health of patients after stroke, which can offer a starting point for developing effective oral care interventions for them.


Expanding use of archaeology in climate change response by changing its social environment.
Climate science has outlined targets for reductions of greenhouse gas emissions necessary to provide a substantial chance of avoiding the worst impacts of climate change on both natural and human systems. How to reach those targets, however, requires balancing physical realities of the natural environment with the complexity of the human social environment, including histories, cultures, and values. Archaeology is the study of interactions of natural and social environments through time and across space. As well, the field of cultural resources management, which includes archaeology, regularly engages with values such as site significance and allocation of funding that the modern social environment ascribes to its own history. Through these two approaches, archaeology has potential to provide both data for and methods of addressing challenges the global community faces through climate change. To date, however, archaeology and related areas of cultural heritage have had relatively little role in the global climate response. Here, we assess the social environment of archaeology and climate change and resulting structural barriers that have limited use of archaeology in and for climate change with a case study of the US federal government. On this basis, we provide recommendations to the fields of archaeology and climate response about how to more fully realize the multiple potential uses of archaeology for the challenges of climate change.


Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin.
Loss of p53 function in cancer cells commonly results in a condition of genomic instability. This is believed to emanate from a loss of the G1 checkpoint response to DNA damage. While the role of p53 in the induction of a G1 arrest is well-accepted, additional p53 functions are being discovered. Cell cycle checkpoints presumably function to allow additional time for DNA repair after damage is incurred, however, genetic studies in yeast suggest that components of the checkpoint pathway may also be involved in DNA lesion processing (Lydall and Weinert, 1995). Recent evidence suggests that this may also be the case for p53, as suggested by numerous reports linking p53 function to DNA repair. Thus, loss of p53 function might contribute to genomic instability independent of G1-arrest. In the present study, we explored the effect of p53 disruption and consequences of antisense GADD45 expression on the DNA repair capacity of human colon carcinoma RKO cells. DNA repair was assayed using host-cell reactivation of u.v.-damaged reporter plasmids and unscheduled DNA synthesis experiments in transiently-transfected cells. We show that a number of transfected genes that suppress p53 function reduce the ability of cells to repair u.v.-induced DNA damage. Moreover, cells in which expression of the p53-regulated gene GADD45 was blocked by antisense vectors, also showed altered levels of DNA repair. Blocking Gadd45 expression by constitutive antisense expression sensitized cells to killing by u.v.-radiation or by cis-platinum (II) diamine-dichloride (CDDP, or cisplatin), a cancer chemotherapy drug which produces DNA cross-links. These findings suggest the involvement of downstream effectors of the p53 pathway in the coordination of cell cycle arrest and DNA repair.


The high hip center.
Revision of a failed acetabular component presents many challenges to the arthroplasty surgeon. The goal in most cases should be to reconstruct the acetabulum by positioning the hip center as close as possible to the anatomic hip center. However, severe acetabular bone stock deficiency and distorted acetabular anatomy often preclude placement of the acetabular component at the true anatomic hip center. In these cases, many options exist for reconstruction of the acetabulum, including placement of the cup superiorly at a high hip center. Although biomechanical studies have shown that superolateral placement of the hip center may lead to increased moments and forces across the hip (leading to potentially higher rates of loosening), superior only displacement of the hip center does not seem to adversely affect the forces about the hip. Proximal placement of the hip center facilitates contact between intact, viable host bone and the acetabular implant, thereby reducing the need for structural bone grafts, and increasing the chances for stable bony ingrowth. With proper patient selection and meticulous surgical technique, the high hip center can be a useful technique for reconstruction of the deficient acetabulum in the patient with a loose acetabular component after total hip arthroplasty.


Solitary fibrous tumors in the central nervous system. A clinicopathologic review of 18 cases and comparison to meningeal hemangiopericytomas.
Solitary fibrous tumors (SFTs) of the central nervous system are rare neoplasms that usually present as dura-based masses and clinically resemble meningiomas. Histologically, they can be similar to fibrous meningioma or hemangiopericytoma (HPC). In particular, densely cellular regions seen in some SFTs can be indistinguishable from HPC. Little is known about the biological behavior of SFTs, although most seem amenable to total resection. To define the clinicopathologic spectrum of SFTs in the central nervous system and to outline their differences from HPC and meningioma. We present the clinicopathologic features of 18 patients with SFT and compare them with those of an age- and sex-matched cohort of HPCs. Eleven SFTs were supratentorial, 3 were infratentorial, and 4 were intraspinal. Four of the 18 tumors were intra-axial (2 in the lateral ventricles and 2 within the spinal cord). Histologically, SFTs were similar to their soft tissue counterparts. Six tumors (6/18) had densely cellular regions, and 1 tumor showed frankly anaplastic features. All but 3 patients underwent gross total resection, and there were no metastases or tumor-related mortalities during the median follow-up of 40 months. In contrast, there were 15 local recurrences (83%), 5 extracranial metastases (27%), and 4 tumor-related deaths (22%) in the HPC cohort. Our study presents the clinicopathologic features of SFT as a distinct entity from both meningioma and HPC. We also present unusual examples of anaplastic, intraventricular, and intramedullary spinal SFTs that expand the clinicopathologic spectrum of these uncommon and sometimes diagnostically difficult neoplasms.


Giant mandibular osteoma, CT findings for the primary care provider.
We report a very rare case of 35-year-old female with a giant mandibular osteoma in the angle of the mandible. We highlight the importance of CT in diagnosing as well as defining the extent of this rare case so that proper management can be undertaken. We also showcase the importance of angiography to show relationship of this mass with the surrounding vessels.


A phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies.
This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 weeks every 4-week schedule. The study also sought to determine the maximum tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. The initial starting dose of ILX-295501 was 100 mg/m(2), which was equivalent to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m(2). Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m(2); and a modified continual reassessment model was used for dose assignment to determine the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%. Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m(2). The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m(2), which was determined to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clinically relevant levels of oxidized hemoglobin (methemoglobin) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with peak plasma concentrations (C(max)) achieving 6.02 h, on average, after oral administration. The pharmacokinetic behavior of ILX-295501 was characterized by dose proportionality, a relatively small apparent volume of distribution at steady state (V(ss)/F), averaging 8.02 +/- 14.08 liters, and low apparent total body clearance (CL(t)/F) rate (mean, 0.036 +/- 0.116 liters/h). The initial drug distribution phase was rapid [harmonic mean half-life (t(1/2alpha)), 2.1 +/- 7.0 min], whereas the terminal elimination phase was slow (harmonic mean t(1/2beta,) 150.6 +/- 80.2 h). The recommended dose for Phase II studies of the oral DSU ILX-295501 administered weekly for 3 weeks every 4 weeks is 1000 mg/m(2)/day for both minimally pretreated and HP patients. The characteristics of the myelosuppressive effects of ILX-295501, the paucity of severe nonhematological toxicities, and preliminary antitumor activity warrant disease-directed evaluations of ILX-295501.


S100B Levels in Patients with Type 2 Diabetes Mellitus and Co-Occurring Depressive Symptoms.
Depression is a comorbid condition in patients with Type 2 Diabetes mellitus (T2DM). S100B, a glia derived protein, is linked to depression and has been suggested as a biomarker for depression outcomes in several populations. However, to date there is no data about S100B levels and depression in patients with T2DM. Objective. We hypothesized that S100B serum levels are increased in patients with T2DM and recently diagnosed, drug-free depressive symptoms, and could be used for the diagnosis of depression in T2DM. Methods. Overall 52 patients (62 ± 12 years, female 66, 7%) with no history of depression deriving from the Diabetes out-patient clinic of our University Hospital underwent a one-to-one interview with a psychiatrist and filled a self-assessment (Zung) questionnaire. Serum S00B levels were compared between 30 (63±12 years, female 66, 7%) diabetic patients without depressive symptoms vs 22 patients (62 ±12 years, female 68, 2%) with T2DM and depressive symptoms. Results. There was no difference in serum levels of S100B between patients with T2DM without depressive symptoms vs diabetic patients suffering from depressive symptoms (2.1 (1.9-10.9) pg/ml vs 2.4 (1.9-14.8) pg/ml, p=0. 637+). Moreover, linear regression analysis did not show any association between lnS100B levels and depressive symptoms (β = 0.084, 95% CI 0.470-0.871, and p=0.552), Zung self-assessment score (β = 0.048, 95% CI -0.024-0.033, and p=0.738), and other patients' characteristics. Conclusions. In patients with T2DM there is no correlation between S100B serum levels and newly detected mild depressive symptoms. The brain biochemistry pathways of depression in T2DM warrant further investigation in a larger scale population.


A PKA-ezrin-Cx43 signaling complex controls gap junction communication and thereby trophoblast cell fusion.
Cell fusion occurs as part of the differentiation of some cell types, including myotubes in muscle and osteoclasts in remodeling bone. In the human placenta, mononuclear cytotrophoblasts in a human chorionic gonadotropin (hCG)-driven process fuse to form multinucleated syncytia that allow the exchange of nutrients and gases between the maternal and fetal circulation. Experiments in which protein kinase A (PKA) is displaced from A-kinase anchoring proteins (AKAPs), or in which specific AKAPs are depleted by siRNA-mediated knockdown, point to ezrin as a scaffold required for hCG-, cAMP- and PKA-mediated regulation of the fusion process. By a variety of immunoprecipitation and immunolocalization experiments, we show that ezrin directs PKA to a molecular complex of connexin 43 (Cx43, also known as GJA1) and zona occludens-1 (ZO-1, also known as TJP1). A combination of knockdown experiments and reconstitution with ezrin or Cx43 with or without the ability to bind to its interaction partner or to PKA demonstrate that ezrin-mediated coordination of the localization of PKA and Cx43 is necessary for discrete control of Cx43 phosphorylation and hCG-stimulated gap junction communication that triggers cell fusion in cytotrophoblasts.


Extra-esophageal gastroesophageal reflux disease and asthma: understanding this interplay.
Gastroesophageal reflux disease (GERD) is a condition that develops when there is reflux of stomach contents, which typically manifests as heartburn and regurgitation. These esophageal symptoms are well recognized; however, there are extra-esophageal manifestations of GERD, which include asthma, chronic cough, laryngitis and sinusitis. With the rising incidence of asthma, there is increasing interest in identifying how GERD impacts asthma development and therapy. Due to the poor sensitivity of endoscopy and pH monitoring, empiric therapy with proton pump inhibitors (PPIs) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. If unresponsive, diagnostic testing with pH monitoring off therapy and/or impedance/pH monitoring on therapy, may be reasonable in order to assess for baseline presence of reflux with the former and exclude continued acid or weakly acid reflux with the latter tests. PPI-unresponsive asthmatics, without overt regurgitation, usually have either no reflux or causes other than GERD. In this group, PPI therapy should be discontinued. In those with GERD as a contributing factor acid suppressive therapy should be continued as well as optimally treating other etiologies requiring concomitant treatment. Surgical fundoplication is rarely needed but in those with a large hiatal hernia, moderate-to-severe reflux by pH monitoring surgery might be helpful in eliminating the need for high-dose acid suppressive therapy.


A randomized controlled trial of pelvic floor muscle training for stages I and II pelvic organ prolapse.
Forty-seven women participated in a pilot study for a multi-centre randomized controlled trial of the effectiveness of pelvic floor muscle training (PFMT) for women with prolapse. Women with symptomatic stage I or II prolapse [measured by Pelvic Organ Prolapse Quantification (POP-Q)] were randomized to a 16-week physiotherapy intervention (PFMT and lifestyle advice; n = 23) or a control group receiving a lifestyle advice sheet (n = 24). Symptom severity and quality of life were measured via postal questionnaires. Blinded POP-Q was performed at baseline and follow-up. Intervention women had significantly greater improvement than controls in prolapse symptoms (mean score decrease 3.5 versus 0.1, p = 0.021), were significantly more likely to have an improved prolapse stage (45% versus 0%, p = 0.038) and were significantly more likely to say their prolapse was better (63% versus 24%, p = 0.012). The data support the feasibility of a substantive trial of PFMT for prolapse. A multi-centre trial is underway.


Treatment of obstructive sleep apnoea patients in community dental care: knowledge and attitudes among general dental practitioners and specialist dentists.
Obstructive sleep apnoea (OSA) is an increasing problem worldwide. Yet, a large number of patients may remain undiagnosed. Dentists could suspect OSA, but little is known about their knowledge and attitudes towards the topic. An email questionnaire was sent to dentists working in Helsinki Health Centre, Helsinki, Finland (n = 226). It consisted of demographic data, items on dentists' overall knowledge of OSA and factors associated with it, and their possibilities and willingness to take part in the recognition and treatment of OSA patients. Altogether, 70·9% (n = 134) of dentists eligible for the study completed the questionnaire. Of them, 79·1% (n = 106) were general practitioners and 20·9% (n = 28) dentists with specialty training. Continuous positive airway pressure (CPAP) (99·3%) and weight control (99·3%) were both generally acknowledged as effective methods to treat OSA. Regarding the efficacy of other treatment modalities, significant differences were found between general practitioners' and specialists' opinions. For example, mandibular advancement devices (MAD) were less often reported by general practitioners (69·8%) than specialists (89·3%) (P < 0·05). The possible risk factors, signs and symptoms, and consequences of OSA were overall well recognised regardless the years in dental profession, but specialists saw more often that nocturnal sweating (P < 0·01) and snoring (P < 0·05) may signify OSA. Dentists could play an important role in suspecting OSA, but they may need more education to cope with that.


Comparison of databases useful for the analysis of vaginal microbiota in Japanese women using next-generation sequencing data (QIIME 2 software).
Approximately 10% of children are born prematurely, and bacterial vaginosis during pregnancy is associated with preterm delivery. Highly accurate species-level vaginal microflora analysis helps control bacteria-induced preterm birth. Therefore, we aimed to conduct a bioinformatic analysis of gene sequences using 16S databases and compare their efficacy in comprehensively identifying potentially pathogenic vaginal microbiota in Japanese women. The 16 s rRNA databases, Silva, Greengenes, and the basic local alignment search tool (BLAST) were compared to determine whether the classification quality could be improved using the V3-V4 region next-generation sequencing (NGS) sequences. It was found that NGS data were aligned using the BLAST database with the QIIME 2 platform, whose classification quality was higher than that of Silva, and the combined Silva and Greengenes databases based on the mutual complementarity of the two databases. The reference database selected during the bioinformatic processing influenced the recognized sequence percentage, taxonomic rankings, and accuracy. This study showed that the BLAST database was the best choice for NGS data analysis of Japanese women's vaginal microbiota.


OKT3 treatment of steroid-resistant renal allograft rejection.
The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methylprednisolone (MP), 5-10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7-14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2-14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.


Sound-driven dissipative self-assembly of aromatic biomolecules into functional nanoparticles.
Dissipative self-assembly processes were recently exploited to assemble synthetic materials into supramolecular structures. In most cases, chemical fuel or light driven self-assembly of synthetic molecules was reported. Herein, experimental and computational approaches were used to unveil the role of acoustic cavitation in the formation of supramolecular nanoaggregates by dissipative self-assembly. Acoustic cavitation bubbles were employed as an energy source and a transient interface to fuel and refuel the dissipative self-assembly of simple aromatic biomolecules into uniform nanoparticles. Molecular dynamics simulations were applied to predict the formation of metastable aggregates and the dynamic exchange of the interacting molecules in the nanoaggregates. The intracellular trafficking and dissipative dissolution of the nanoparticles were tracked by microscopy imaging.


; ASPECTS OF NUTRITION IN PATIENTS WITH CONGESTIVE HEART FAILURE.
Congestive heart failure (CHF) is a significant healthcare problem, and is associated with high levels of morbidity and mortality. The majority of patients have poor quality of life in spite of the modern evidence-based treatment. Malnutrition is more common in patients with HF, especially at the severe stage of HF, and is associated with the risk of complications and mortality. Consequently, evaluation of malnutrition in patients with HF, monitoring of patients in this regard, and identifying the right assessment tools are the basis for developing of an effective nutritional strategy that can have a significant impact on the treatment and management of such patients.; Our aim was to study the prevalence of different markers of malnutrition, their association with nutrient indices, and their correlation with CHF in Georgian population.; The total of 96 patients relevant to the research objective (43 female and 53 male with average age 69.85) were enrolled in the study. Nutritional screening was performed using the GNRI, which was calculated as follows: GNRI=14.89× serum albumin (g/dL) +41.7*body weight÷ideal body weight. Ideal body weight=22* square of height in meters and PNI was calculated as follows: PNI=10* serum albumin (g/dL) +0.005*total lymphocyte (count per mm3) and The Controlling Nutritional Status (CONUT) score was calculated by serum albumin score plus total cholesterol score and total lymphocyte score. Peripheral venous blood was tested for acute phase reactant (hsCRP, Interleukin-6, fibrinogen, acid glycoprotein) and for protein-energy malnutrition (prealbumin, albumin, lymphocytes, lipid profile and transferrin).; By examining the correlation between the CONUT, GNRI and PNI indices, a significant negative correlation was found between CONUT and PNI. We quantitatively compared results obtained using CONUT, GNRI and PNI scale risk groups, as the primary picture suggested it in our study group (ambulatory, quite compensated CHF). CONUT and PNI represent best option.; Prealbumin, lipid profile data, transferrin decreases with increasing risk for CONUT and PNI, with Interleukin-6 increasing on both calculators. Changes in other data are not correlated.


Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids.
The merozoite stage of the malaria parasite that infects erythrocytes and causes the symptoms of the disease is initially formed inside host hepatocytes. However, the mechanism by which hepatic merozoites reach blood vessels (sinusoids) in the liver and escape the host immune system before invading erythrocytes remains unknown. Here, we show that parasites induce the death and the detachment of their host hepatocytes, followed by the budding of parasite-filled vesicles (merosomes) into the sinusoid lumen. Parasites simultaneously inhibit the exposure of phosphatidylserine on the outer leaflet of host plasma membranes, which act as "eat me" signals to phagocytes. Thus, the hepatocyte-derived merosomes appear to ensure both the migration of parasites into the bloodstream and their protection from host immunity.


Transgenesis affects endogenous soybean allergen levels less than traditional breeding.
The regulatory body that oversees the safety assessment of genetically modified (GM) crops in the European Union, the European Food Safety Authority (EFSA), uniquely requires that endogenous allergen levels be quantified as part of the compositional characterization of GM versions of crops, such as soybean, that are considered to be major allergenic foods. The value of this requirement for assessing food safety has been challenged for multiple reasons including negligible risk of altering allergen levels compared with traditional non-GM breeding. Scatter plots comparing the mean endogenous allergen levels in non-GM soybean isoline grain with the respective levels in GM grain or concurrently grown non-GM commercial reference varieties clearly show that transgenesis causes less change compared with traditional breeding. This visual assessment is confirmed by the quantitative fit of the line of identity (y = x) to the datasets. The current science on allergy does not support the requirement for quantifying allergen levels in GM crops to support safety assessment.


Switching of bradykinin-mediated nociception following partial sciatic nerve injury in mice.
Bradykinin (BK) is well known as a potent mediator of pain and hyperalgesia. Using a highly sensitive nociception test, we found that intraplantar (i.pl.) injection of BK produced nociceptive hyper-responses in partial sciatic nerve-injured mice, compared with the control sham-operated animals. By use of selective agonists and antagonists, we revealed that BK nociception in sham-operated mice was mediated through B2 receptor, whereas that in injured mice was mediated through B1 receptor. When we examined the activation of extracellular signal-regulated protein kinase (ERK) in dorsal root ganglion (DRG) neurons upon i.pl. injection of BK, phosphorylated ERK was mainly observed in unmyelinated neurons in sham-operated mice, and in case of nerve-injured mice, ERK was mainly activated in myelinated neurons and satellite cells. The B1 receptor agonist, [Lys-des-Arg(9)]-BK also produced nociceptive response and activated ERK only in nerve-injured mice. BK or B1 agonist-induced activation of ERK in DRG neurons of nerve-injured mice was completely blocked by pretreatment with antisense oligodeoxynucleotide (AS-ODN) for B1 receptor. We found that in sham-operated mice mainly B2 receptors were expressed in unmyelinated DRG neurons with a very little presence of B1 receptor. After nerve injury, B2 receptor expression drastically decreased, whereas B1 receptors were newly expressed mainly in myelinated DRG neurons and satellite cells. Finally, BK nociception in sham-operated mice was blocked by AS-ODN for B2 receptors and that in injured mice by AS-ODN for B1 receptors. Altogether, these findings confirm a switching of receptor and fiber subtype for BK nociception after peripheral nerve injury, which might contribute to the pathobiology of neuropathic pain.


Degradation and transformation of natural organic matter accountable for disinfection byproduct formations by UV photolysis and UV/chlor(am)ine.
This research aimed to investigate the degradation of natural organic matter responsible for the formation of trihalomethane (THM), haloacetic acid (HAA) and haloacetonitrile (HAN) during ultraviolet (UV) photolysis and a co-exposure of UV with chlorine (UV/chlorine) and chloramine (UV/chloramine). Low pressure UV (LPUV) and vacuum UV (VUV) lamps were used for photolysis. VUV and LPUV irradiation changed aromatic/unsaturated structures to aliphatic ones, resulting in decreased THM and HAN formation. Following irradiation for 60 min, LPUV decreased THM and HAN by 16% ± 2% and 20% ± 6%, respectively. VUV decreased THM and HAN formation by 23% ± 3% and 20% ± 8%, respectively. HAA formation increased following photolysis. UV/chlorine treatment decreased THM, HAA and HAN. Higher chlorine doses had an inversely proportional relationship with THM and HAN formation. A chlorine dose of 4 mg·L-1 led to the greatest reductions, corresponding to 42% ± 2%, 10% ± 10% and 18% ± 6% for THM, HAA and HAN, respectively. UV/chloramine decreased the formation of THM more than UV/chlorine. With a chloramine dose of 4 mg·L-1, THM, HAA and HAN formation decreased by 74% ± 10%, 10% ± 10% and 11% ± 10%, respectively. This study showed the potential use of UV/chlor(am)ine for controlling the formation of THM, HAA and HAN.


The accuracy of transvaginal ultrasonography in the diagnosis of endometrial abnormalities.
To evaluate the diagnostic accuracy of transvaginal ultrasonography for endometrial abnormalities in women with abnormal uterine bleeding. In a prospective study, 136 consecutive patients underwent transvaginal ultrasonography, hysteroscopy, and endometrial sampling through suction curettage or directed biopsy. The ultrasonographic findings were evaluated on the basis of the final diagnosis established by hysteroscopy and histologic examination. Receiver operating characteristic curve analysis and likelihood ratios were used. Likelihood ratios algebraically combine sensitivity and specificity to describe more than the independent values themselves, specifically the change in odds favoring disease given a particular test result. In 21 of the 136 patients, hysteroscopy detected polyps or submucous myomas, which curettage failed to detect. In 67 premenopausal women, ultrasonography demonstrated a sensitivity in diagnosing endometrial abnormalities of 88% and a specificity of 68%, using a cutoff point of 5 mm of single-layer endometrial thickness. The positive likelihood ratio was 2.8 (95% confidence interval [CI] 1.66-4.55) and negative likelihood ratio 0.18 (95% CI 0.07-0.46). In 69 postmenopausal women, using a cutoff point of 3 mm, the sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 97%, 74%, 3.7 (95% CI 2.18-6.38), and 0.04 (95% CI 0.01-0.28) respectively. Transvaginal ultrasonography is an excellent first-step diagnostic method of excluding the endometrial abnormalities in women with postmenopausal bleeding but is of limited use in premenopausal women with irregular bleeding. Ultrasonography may reduce the number of invasive endometrial investigations by approximately 40%.


Temporal waves of coherent gene expression during Drosophila embryogenesis.
Animal development depends on localized patterns of gene expression. Whole-genome methods permit the global identification of differential expression patterns. However, most gene-expression-clustering methods focus on the analysis of entire expression profiles, rather than temporal segments or time windows. In the current study, local clustering of temporal time windows was applied to developing embryos of the fruitfly, Drosophila melanogaster. Large-scale developmental events, involving temporal activation of hundreds of genes, were identified as discrete gene clusters. The time-duration analysis revealed six temporal waves of coherent gene expression during Drosophila embryogenesis. The most powerful expression waves preceded major morphogenetic movements, such as germ band elongation and dorsal closure. These waves of gene expression coincide with the inhibition of maternal transcripts during early development, the specification of ectoderm, differentiation of the nervous system, differentiation of the digestive tract, deposition of the larval cuticle and the reorganization of the cytoskeleton during global morphogenetic events. We discuss the implications of these findings with respect to the gene regulatory networks governing Drosophila development. Data and software are available from the UC Berkeley web resource http://flydev.berkeley.edu/cgi-bin/GTEM/dmap_dm-ag/index_dmap.htm


Characterization of a mineral waste resulting from the melting treatment of air pollution control residues.
Air pollution control (APC) residues which are generated by municipal solid waste (MSW) incineration show a high-level of pollution potential. In order to stabilize such APC residues, the French power supply company (EDF) is developing a thermal treatment process which leads to the production of a vitrified material. A structural characterization of the vitrified product was carried out by applying complementary investigation methods: XRD, SEM, Raman spectroscopy, EPMA, and data interpretation methods such as mineralogical analysis and principal component analysis (PCA). The major phase of the material was a solid solution of melilite type composed of five end-members: gehlenite (44%), åkermanite (25%), ferri-gehlenite (5%), sodamelilite (14%) and hardystonite (11%). The minor phases identified were spinels and pyroxenes. An ANC leaching test was performed in order to observe the treatment effect on pollutant release. The natural pH was close to 10, and the major element release was less than in the case of untreated APC. This was a consequence of melilite formation. The effect of pH was fundamental for heavy metals release: lower solubilization occurs at pH 10 than at APC's natural pH (11-12).


Does smoking status affect the association between baseline white blood cell count and in-hospital mortality of patients presented with acute coronary syndrome? The Greek study of acute coronary syndromes (GREECS).
In this work, we sought to investigate whether smoking status modifies the effect of white blood cell count (WBC) on in-hospital mortality of patients presented with acute coronary syndrome (ACS). A sample of 6 hospitals located in Greek urban and rural regions was selected. We recorded almost all consecutive patients due to ACS, from October 2003 to September 2004 (2172 patients). The mean (standard deviation) WBC count was 9.14 (3.16) cells/dL. The in-hospital mortality rate was higher in patients of upper tertile compared to those of lower tertile of WBC (p<0.05). The interaction between smoking status and WBC count revealed that smoking status modifies the effect of WBC count on mortality (p for interaction=0.004). Thus, stratified analysis showed that the WBC count is an independent predictor of in-hospital mortality only among former and current smokers. We demonstrated that the association between WBC count and mortality modified by smoking status and that WBC count is a predictor of mortality only among former and current smokers.


Bone cement embolism attached to central venous catheter.
We report on a rare complication of poly(methyl methacrylate) (PMMA), injected into the spine, which then inadvertently leaked into the venous system. This resulted in an embolism of PMMA and produced a mass surrounding a triple lumen central venous catheter located in the superior vena cava. The catheter as well as the attached mass of PMMA was retrieved safely by cardiothoracic surgery. This case emphasizes the importance of prompt diagnosis and treatment and illustrates the need for close monitoring of patients undergoing any spinal surgery that includes vertebroplasty.


The effect of virtual reality on anxiety, stress, and hemodynamic parameters during cesarean section: A randomized controlled clinical trial.
To investigate the effect of virtual reality (VR) on anxiety, stress, and hemodynamic parameters during cesarean section (CS). This is a randomized controlled clinical trial conducted at the operating theatre / Maternal and Children Hospital, Najran, Saudi Arabia from February to October 2021. The study comprised a random sample of 351(176 study and 175 control) low-risk pregnant women undergoing elective CS with regional anesthesia. Data collection was carried out using 5 instruments. Basic and clinical data sheet, maternal hemodynamic parameters assessment sheet, brief measure of preoperative emotional stress, a novel visual facial anxiety scale, and maternal satisfaction scale. Virtual reality group exposed to 3D natural videos associated with calm Quran or music voices via phone using VR glasses immediately after anesthesia until completion of skin suture. The control group left for routine hospital care. The VR group showed significantly lower stress and anxiety levels immediately after skin suture and 2h postoperative (p=0.000). Maternal satisfaction 2 hours after CS showed that 58% of the VR group were completely satisfied compared to 11.3% of the control group (FET=135.359 p=0.000). Virtual reality have an impact on hemodynamic parameters at some time points while peripheral oxygen saturation did not differ significantly (p>0.05). Virtual reality significantly reduced anxiety and stress among women undergoing CS under regional anesthesia. Virtual reality may be added to the routine intraoperative techniques that help induce patient relaxation and increase satisfaction.


Crystal structure and substrate specificity of Drosophila 3,4-dihydroxyphenylalanine decarboxylase.
3,4-Dihydroxyphenylalanine decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase, catalyzes the decarboxylation of a number of aromatic L-amino acids. Physiologically, DDC is responsible for the production of dopamine and serotonin through the decarboxylation of 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively. In insects, both dopamine and serotonin serve as classical neurotransmitters, neuromodulators, or neurohormones, and dopamine is also involved in insect cuticle formation, eggshell hardening, and immune responses. In this study, we expressed a typical DDC enzyme from Drosophila melanogaster, critically analyzed its substrate specificity and biochemical properties, determined its crystal structure at 1.75 Angstrom resolution, and evaluated the roles residues T82 and H192 play in substrate binding and enzyme catalysis through site-directed mutagenesis of the enzyme. Our results establish that this DDC functions exclusively on the production of dopamine and serotonin, with no activity to tyrosine or tryptophan and catalyzes the formation of serotonin more efficiently than dopamine. The crystal structure of Drosophila DDC and the site-directed mutagenesis study of the enzyme demonstrate that T82 is involved in substrate binding and that H192 is used not only for substrate interaction, but for cofactor binding of drDDC as well. Through comparative analysis, the results also provide insight into the structure-function relationship of other insect DDC-like proteins.


Sequences and expression of pyruvate dehydrogenase genes from Pseudomonas aeruginosa.
A mutant of Pseudomonas aeruginosa, OT2100, which appeared to be defective in the production of the fluorescent yellow-green siderophore pyoverdine had been isolated previously following transposon mutagenesis (T. R. Merriman and I. L. Lamont, Gene 126:17-23, 1993). DNA from either side of the transposon insertion site was cloned, and the sequence was determined. The mutated gene had strong identity with the dihydrolipoamide acetyltransferase (E2) components of pyruvate dehydrogenase (PDH) from other bacterial species. Enzyme assays revealed that the mutant was defective in the E2 subunit of PDH, preventing assembly of a functional complex. PDH activity in OT2100 cell extracts was restored when extract from an E1 mutant was added. On the basis of this evidence, OT2100 was identified as an aceB or E2 mutant. A second gene, aceA, which is likely to encode the E1 component of PDH, was identified upstream from aceB. Transcriptional analysis revealed that aceA and aceB are expressed as a 5-kb polycistronic transcript from a promoter upstream of aceA. An intergenic region of 146 bp was located between aceA and aceB, and a 2-kb aceB transcript that originated from a promoter in the intergenic region was identified. DNA fragments upstream of aceA and aceB were shown to have promoter activities in P. aeruginosa, although only the aceA promoter was active in Escherichia coli. It is likely that the apparent pyoverdine-deficient phenotype of mutant OT2100 is a consequence of acidification of the growth medium due to accumulation of pyruvic acid in the absence of functional PDH.


Accuracy of the ETDQ-7 for Identifying Persons with Eustachian Tube Dysfunction.
Objective To compare the accuracy of the Eustachian Tube Dysfunction Questionnaire (ETDQ-7) in identifying people with eustachian tube (ET) dysfunction based on symptoms and an objective ET function test. Study Design Cross-sectional study. ObjSettingective Tertiary referral center. Subjects and Methods Fifty-five subjects with and without symptoms suggestive of ET dysfunction completed the ETDQ-7 and had their ET function evaluated by the percentage of middle ear pressure equilibrated after 5 swallows (PEq5) either during a pressure chamber test (intact tympanic membranes) or by the inflation-deflation test (nonintact tympanic membranes). ETDQ-7 score ≥14.5 and PEq5 <60% were used to define ET dysfunction, and sensitivity, specificity, and receiver operating characteristic curves were used to assess the level of association between ETDQ-7 scores and PEq5. Results Twenty-five asymptomatic subjects (group 1 = 15 females, 15 white; mean ± SD age, 32 ± 12.8 years) and 30 subjects with ET dysfunction symptoms (group 2 = 17 females, 25 white; age, 27 ± 16.3 years) were included in the analysis. ETDQ-7 sensitivity and specificity regarding correct group assignment were 70% and 100%, respectively, and with respect to predicting PEq5<60%, 54% and 78%. An area under the curve (AUC) of 0.68 (95% CI, 0.53-0.83) at the participant level and 0.64 (95% CI, 0.50-0.77) at the ear level indicated a moderate level of association that was lower, though not statistically significant, for nonintact tympanic membranes (AUC = 0.63 at the participant level and AUC = 0.49 at the ear level). Conclusion The ETDQ-7 score had a higher correlation with the ET dysfunction symptoms than with an objective measure of ET function.


Building and maintaining interprofessional collaborative practice in eyecare: Learnings from the Queensland Paediatric Optometry Alignment Program.
The Queensland Children's Hospital Paediatric Optometry Alignment Program commenced with a pilot phase to assess its feasibility, effectiveness and acceptability. This study identified the barriers that hinder effective interprofessional collaboration and the facilitators that contribute to its success, and assessed changes in optometrists' satisfaction since the pilot phase of the collaborative care programme. Qualitative deductive and inductive content analysis was applied to open-ended free-text survey responses collected in 2018 from the optometrists involved in the Program's pilot phase. The responses were coded using the Theoretical Domains Framework (TDF) to categorise barriers and facilitators into key themes. Key behavioural determinants were mapped to the COM-B (Capability, Opportunity, Motivation-Behaviour) elements of the Behaviour Change Wheel model to identify intervention strategies. Intervention recommendations were derived from behaviour change mapping and compared with programme quality improvement initiatives. A cross-sectional explanatory survey informed by the TDF was conducted within the current 2023 cohort, and a longitudinal comparative analysis was carried out using data from the 2018 survey. Among the 97 surveys distributed in 2018, 44 respondents participated; from this group, 38 individuals contributed a total of 200 free-text responses. Facilitators (240 comments) outnumbered barriers (65 comments). Key facilitators were accessible and timely care, professional development, confidence and positive outcome beliefs. Barriers included communication, information handover, credibility, relationships and skill gaps. Optometrists actively engaged in the programme in 2023 reported heightened satisfaction with their involvement, increased confidence and greater engagement in paediatric eyecare delivery. However, challenges in clinical information transfer persist. The interprofessional collaborative model of paediatric eyecare has contributed efficiencies within the health system by building paediatric care capacity in the community, fostering professional credibility and promoting interdisciplinary trust. Insights gained should prove valuable for other paediatric eyecare services exploring hospital-to-community care models.


Pedigree construction and disease confirmation: a pilot study in Wales exploring the role of nonclinical personnel.
Pedigree construction and disease confirmation are the means by which reported family histories are translated into a verified clinical tool informing risk assessment and management decisions by clinical genetics staff. In this study, we hypothesised that pedigree generation data processes do not generally require the clinical expertise of genetic counsellors and that they could be successfully transferred to nonclinical data administrators. We made a pragmatic comparison of two processes of pedigree generation by different personnel from 14 consecutive family history questionnaires containing 88 living and decease affected individuals. The pedigrees generated by the genetic counsellor and the data administrator were compared; discrepancies were quantified and their source determined. The information gathered by the data administrator mirrored that of the genetic counsellors in 89% of cases. Time was saved by permitting direct access to cancer registry and local oncology centre databases. Constructing a pedigree is not always a case of transferring clear-cut data. Decisions need to be made about which cancers to confirm. Notable differences emerged in the number of pieces of information not transferred. Ambiguous information was often interpreted differently, suggesting the need for clinical staff to review pedigrees after their initial plotting by the data administrator. This study demonstrates a good degree of concordance between pedigrees constructed by a nonclinical data administrator and those of experienced genetic counsellors. However, the redirection of all pedigree activity to nonclinical personnel up to the point of risk review is not possible at present.