Antisperm contraceptive vaccines: where we are and where we are going?
This is a review of current status and future perspectives on the development of antisperm contraceptive vaccines (CV) and immunocontraceptives. The development of antisperm CV is an exciting proposition. There is a strong rationale and recent data indicating that this proposition can translate into reality. The search for novel sperm-specific antigens/genes, that can be used for CV, continues using various recent developing technologies. Various approaches of proteomics, genomics, reproductive biology, mucosal immunity and vaccinology and several novel technologies such as gene knockout technology, phage display technology, antibody engineering, differential display technique, subtractive hybridization, and hybridoma technology are being used to delineate sperm-specific antigens and construct CV. Various sperm antigens/genes have been delineated, cloned, and sequenced from various laboratories. Vaccination with these sperm antigens (recombinant/synthetic peptide/DNA) causes a reversible contraceptive effect in females and males of various animal species, by inducing a systemic and local antisperm antibody response. The efficacy is enhanced by combination vaccination, including peptides based on various sperm antigens. Several human novel scFv antibodies with unique complementarity-determining regions (CDRs), that react with specific well-defined fertility-related sperm antigens, have been synthesized. These human infertility-related antibodies may find application in the development of novel immunocontraceptives. Besides finding the novel sperm antigens, the present and future focus is on enhancing the immunogenicity, bioefficacy, and on obliterating the inter-individual variability of the immune response, and proceeding for primate and human clinical trials. Multi-epitope vaccines combining sperm proteins involved in various steps of fertilization cascade have been found to enhance the immunogenicity and bioefficacy of the contraceptive effect. The in vitro synthesis of infertility-related human scFv antibodies may provide unique once-a-month immunocontraceptives, the first of its kind, for human use. The multi-epitope CV and preformed engineered human antibodies of defined specificity may obliterate the concern related to inter-individual variability of the immune response.


Testing the limits of 454 pyrotag sequencing: reproducibility, quantitative assessment and comparison to T-RFLP fingerprinting of aquifer microbes.
The characterization of microbial community structure via 16S rRNA gene profiling has been greatly advanced in recent years by the introduction of amplicon pyrosequencing. The possibility of barcoding gives the opportunity to massively screen multiple samples from environmental or clinical sources for community details. However, an on-going debate questions the reproducibility and semi-quantitative rigour of pyrotag sequencing, similar to the early days of community fingerprinting. In this study we demonstrate the reproducibility of bacterial 454 pyrotag sequencing over biological and technical replicates of aquifer sediment bacterial communities. Moreover, we explore the potential of recovering specific template ratios via quantitatively defined template spiking to environmental DNA. We sequenced pyrotag libraries of triplicate sediment samples taken in annual sampling campaigns at a tar oil contaminated aquifer in Düsseldorf, Germany. The abundance of dominating lineages was highly reproducible with a maximal standard deviation of ~4% read abundance across biological, and ~2% across technical replicates. Our workflow also allows for the linking of read abundances within defined assembled pyrotag contigs to that of specific 'in vivo' fingerprinting signatures. Thus we demonstrate that both terminal restriction fragment length polymorphism (T-RFLP) analysis and pyrotag sequencing are capable of recovering highly comparable community structure. Overall diversity was roughly double in amplicon sequencing. Pyrotag libraries were also capable of linearly recovering increasing ratios (up to 20%) of 16S rRNA gene amendments from a pure culture of Aliivibrio fisheri spiked to sediment DNA. Our study demonstrates that 454 pyrotag sequencing is a robust and reproducible method, capable of reliably recovering template abundances and overall community structure within natural microbial communities.


Nuclear export signal of IkappaBalpha interferes with the Rev-dependent posttranscriptional regulation of human immunodeficiency virus type I.
De novo synthesized IkappaBalpha accumulates transiently in the nucleus where it inhibits NF-kappaB-dependent transcription and reduces nuclear NF-kappaB content. A sequence present in the C-terminal domain of IkappaBalpha and homologous to the HIV-1 Rev nuclear export signal (NES) has been recently defined as a functional NES conferring on IkappaBalpha the ability to export IkappaBalpha/NF-kappaB complexes. Rev utilises its RNA-binding activity and NES sequence to promote specifically the transport of unspliced and monospliced viral RNAs to the cytoplasm. The object of this work was to determine if nuclear IkappaBalpha could interfere with Rev-dependent transport of viral RNA from the nucleus to the cytoplasm. We report that accumulation of IkappaBalpha in the cell nucleus blocks viral replication. This effect could be dissociated from the capacity of IkappaBalpha to inhibit NF-kappaB-DNA-binding activity and required a functional IkappaBalpha NES motif. Indeed, mutation of the NES abrogated the capacity of IkappaBalpha to inhibit Rev-dependent mechanisms involved in the replication of either wild-type or NF-kappaB-mutated HIV-1 molecular clones. Nuclear accumulation of a reporter protein tagged with a nuclear localization signal (NLS) and fused to the IkappaBalpha NES motif (NLS-PK-NES) was sufficient to inhibit HIV-1 replication at a post-transcriptional level by specifically blocking the expression of a Rev-dependent gene. Furthermore, in cells pulsed with TNF, a treatment which favors nuclear accumulation of newly synthesized IkappaBalpha, NLS-PK-NES expression promoted sustained accumulation of nuclear NF-kappaB lacking DNA-binding activity. This NES-mediated accumulation of inactive nuclear NF-kappaB is likely the consequence of interference in the IkappaBalpha-mediated export of NF-kappaB. These findings indicate that IkappaBalpha and Rev compete for the same nuclear export pathway and suggest that nuclear accumulation of IkappaBalpha, which would occur during normal physiological cell activation process, may interfere with the Rev-NES-mediated export pathway of viral RNAs, thus inhibiting HIV-1 replication.


[The pharmacokinetics of propranolol and its conjugated metabolites in patients with chronic ischemic heart disease and arterial hypertension with a one-time and course intake of the drug].
Pharmacokinetics of propranolol (P), 4-hydroxy-propranolol sulfate (4HOP-Sulf), and glucoronides of pharmacologically active S-enantiomer P (S-PG) and ballast R-enantiomer of P (R-PG) in the blood serum of 21 patients with chronic ischemic heart disease and/or arterial hypertension has been studied at a single and course oral P administration. The values od AUC and T1/2 for potentially active 4HOP-Sulf were significantly higher than those for unchanged P at a single and course administration. The values od AUC and T1/2 for for S-PG were approximately three times higher than those for P-PG after both a single and course administration. Thus the results presented show that potentially active 4HOP-Sulf and S-PG (which undergoes a partial deconjugation in an organism at oral administration) may contribute essentially to the value and duration of the P pharmacological effect.


Observation of CO Detection Using Aluminum-Doped ZnO Nanorods on Microcantilever.
An oscillating piezoresistive microcantilever (MC) coated with an aluminum (Al)-doped zinc oxide (ZnO) nanorods was used to detect carbon monoxide (CO) in air at room temperature. Al-doped ZnO nanorods were grown on the MC surface using the hydrothermal method, and a response to CO gas was observed by measuring a resonant frequency shift of vibrated MC. CO gas response showed a significant increase in resonant frequency, where sensitivity in the order of picogram amounts was obtained. An increase in resonant frequency was also observed with increasing gas flow rate, which was simultaneously followed by a decrease in relative humidity, indicating that the molecular interface between ZnO and H2O plays a key role in CO absorption. The detection of other gases of carbon compounds such as CO2 and CH4 was also performed; the sensitivity of CO was found to be higher than those gases. The results demonstrate the reversibility and reproducibility of the proposed technique, opening up future developments of highly sensitive CO-gas detectors with a fast response and room temperature operation.


Electrical memory characteristics of a nondoped pi-conjugated polymer bearing carbazole moieties.
Poly[bis(9H-carbazole-9-ethyl)dipropargylmalonate] (PCzDPM) is a novel pi-conjugated polymer bearing carbazole moieties that has been synthesized by polymerization of bis(9H-carbazole-9-ethyl)dipropargylmalonate with the aid of molybdenum chloride solution as the catalyst. This polymer is thermally stable up to 255 degrees C under a nitrogen atmosphere and 230 degrees C in air ambient; its glass-transition temperature is 147 or 128 degrees C, depending on the polymer chain conformation (helical or planar structure). The charge-transport characteristics of PCzDPM in nanometer-scaled thin films were studied as a function of temperature and film thickness. PCzDPM films with a thickness of 15-30 nm were found to exhibit very stable dynamic random access memory (DRAM) characteristics without polarity. Furthermore, the polymer films retain DRAM characteristics up to 180 degrees C. The ON-state current is dominated by Ohmic conduction, and the OFF-state current appears to undergo a transition from Ohmic to space-charge-limited conduction with a shallow-trap distribution. The ON/OFF switching of the devices is mainly governed by filament formation. The filament formation mechanism for the switching process is supported by the metallic properties of the PCzDPM film, which result in the temperature dependence of the ON-state current. In addition, the structure of this pi-conjugated polymer was found to vary with its thermal history; this change in structure can affect filament formation in the polymer film.


Dopamine and extinction: a convergence of theory with fear and reward circuitry.
Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes.


Developmental pathways from child maltreatment to adolescent pregnancy: A multiple mediational model.
Adolescent pregnancy (AP) is a significant public health issue. Child maltreatment (CM) represents an established risk factor, yet little is known about the explanatory mechanisms linking the phenomena. Informed by developmental theory, this study prospectively tested seven multi-level, indirect pathways that could plausibly explain the relationship between CM and AP: (1) substance use (polysubstance use and frequency); (2) sexual risk behavior; (3) depressive symptoms; (4) posttraumatic stress disorder symptoms; (5) cognitive dysregulation; (6) pregnancy desire and difficulty expectancies; and (7) age at menarche. Data came from a prospective, longitudinal cohort study of 469 ethnically diverse, nulliparous adolescent females, designed to examine the impact of substantiated CM on reproductive outcomes such as pregnancy and childbirth (265 maltreated and 204 demographically matched comparison adolescents). A multiple-mediator structural equation model was conducted to simultaneously test multiple indirect effects while accounting for confounding variables. Maltreatment had an indirect effect on pregnancy via substance use and higher pregnancy desire/lower perceived difficulty. Findings represent a step towards elucidating pathways linking CM with AP. Recommendations are offered to prevent pregnancy by addressing the pregnancy-specific mechanisms that are part of the maltreatment sequelae.


Effect of 8-hydroxy-2-(N,N-di-n-propylamino)tetralin and MDMA on the discriminative stimulus effects of the classical hallucinogen DOM in rats.
Co-administration of the 5-HT1A serotonin receptor agonist (+/-)8-hydroxy-2-(N,N-di-n-propylamino)tetralin [(+/-)8-OH DPAT] enhances the discriminative stimulus effects of the classical hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats. In the present investigation, using Sprague-Dawley rats trained to discriminate DOM (1.0 mg/kg) from saline vehicle under a VI-15 s schedule of reinforcement, it was shown that the stimulus-enhancing actions of 8-OH DPAT are related more to its R(+)-isomer than to its S(-)-enantiomer, and that the (+/-)- and R(+)8-OH DPAT-induced effects are antagonized by the 5-HT1A receptor antagonist NAN-190. (+/-)8-OH DPAT and its isomers substitute in rats trained to discriminate the designer drug N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; methylenedioxymethamphetamine) from vehicle indicating some similarity of effect. On this basis, it was hypothesized that MDMA might be capable of enhancing the DOM stimulus. Co-administration of MDMA with low (i.e., 0.1 and 0.3 mg/kg) doses of DOM resulted in greater DOM-appropriate responding than engendered by administration of DOM alone. As such, the present findings are the first to demonstrate an MDMA-induced enhancing effect on the discriminative stimulus actions of a classical hallucinogen. The results also suggest that a 5-HT1A serotonin receptor mechanism might contribute to this phenomenon.


[Clinical aspects and surgical treatment of carotid body tumors].
The authors report their experience of three cases of carotid corpuscle tumors: two are bilateral and pertaining to the same family, one of them is associated with a bilateral tympano-jugular glomus. First they review the epidemiology and definitions of such tumors and then they develop the various clinical aspects and differential diagnosis of these tumors. They insist on the necessity of a CT scan examination and of an angiography. They give their experience of the preoperative embolization of the tumour vessels. They expose various aspects of the surgical technique, pointing out the interest of a large access, the need of a regular surgery and the necessary collaboration between head and neck surgeons and vascular surgeons. Finally they discuss the opportuneness to operate bilateral glomic tumors.


An analysis of the long-term therapeutic effect of the integrated therapy of traditional Chinese medicine and radiotherapy on abdominal malignant tumor.
To observe the long-term therapeutic effect of the integrated therapy of radiotherapy and Chinese herbal drugs for treatment of abdominal malignant tumor and explore the applied value of differential treatment during radiotherapy. Sixty cases of abdominal malignant tumor with hyperactivity of fire due to yin deficiency or deficiency of both qi and blood were randomly divided into an integrated treatment group of 30 cases and a control group of 30 cases. The integrated treatment group was treated by combination of radiotherapy and Chinese herbal drugs and the control group by simple radiotherapy. The results shows that in the integrated treatment group, the score of physical state was 23.17 +/- 7.18, score of psychological quality 21.23 +/- 4.53 and total score of living quality 44.40 +/- 11.22, and survival rate for three years was 67.55%, which were significantly superior to those of the control group (P < 0.01). It is then concluded that differential treatment of TCM could play a valuable role in treating abdominal malignant tumor during radiotherapy, which can improve the long-term living quality and prolong the survival time of the patients.


Phase Ia Study of Anti-NaPi2b Antibody-Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer.
This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.


The occupation of fishing as a risk factor in cancer of the lip.
To study the role of commercial fishing and related factors in the development of lip cancer, a project that included a case-control study and a cohort analysis was undertaken in Newfoundland. Household survey data were linked with cancer-registry and census data. In comparison with other males, fishermen had a probability of development of lip cancer that was 1.5 times higher (by the case-control method, P less than 0.05) or 4.4 times higher (by cohort analysis, P less than 0.001). Despite the effect of pipe smoking, "outdoorness" and age on the development of lip cancer in general, the occupation of fishing was an additional, independent contribution to the risk. Unexpectedly, using the mouth as a third hand to handle tar-coated nets seemed to protect fishermen from the disease. It was not possible to attribute the higher risk to a particular work activity, nor was a specific responsible carcinogen identified.


Uniform high frequency expression of autoantibody-associated crossreactive idiotypes in the primary B cell follicles of human fetal spleen.
At 23 wk of gestation, the fetal spleen contains follicles of lymphocytes that coexpress B cell differentiation antigens, surface Ig, and the 67-kD pan-T lymphocyte antigen, CD5 (Leu-1). Such cells are thought to represent the normal equivalent cells of B chronic lymphocytic leukemia (CLL). This B cell leukemia is distinctive in that high proportions of patients have leukemic cells that express sIg bearing one or more crossreactive idiotypes (CRIs) that commonly are found on IgM autoantibodies. We performed immunohistochemical studies on fetal spleen at 23 wk of gestation using a panel of mAbs specific for autoantibody-associated CRIs. We find that high proportions (5-17%) of the lymphocytes within each follicle react with any one of the anti-CRI mAbs. Furthermore, there is little variation between primary follicles in the proportions of cells that express a particular CRI. Using a cocktail of four anti-CRI mAbs, we detect autoantibody-associated CRIs on approximately one-third of the lymphocytes within each of the primary B cell follicles. These data indicate that the many of the Igs produced during early B cell development may be structurally related to IgM autoantibodies and to Ig expressed in CLL and related CD5 B cell malignancies. Furthermore, these studies suggest that the repertoire of Ig V genes expressed in each primary B cell follicle may be representative of the total restricted Ig V gene repertoire expressed during early B cell ontogeny.


Fading on the S+, the S-, both, or neither.
Mentally retarded adults were presented with size and number discriminations using four stimulus conditions. In Condition 1, the S+ circles faded from large (Size 10) to smaller (Size 6) while the S- circles remained at Size 5 and number of circles varied randomly. In Condition 2, the S- squares faded in number from 1 to 5 while the S+ squares remained at Number 6, and size varied randomly. In Condition 3, simultaneous fading of the S+ and S- triangles occurred on size for 6 subjects and on number for the other 6. In Condition 4, fading did not occur on the S+ or S- hexagons. Each of the fading procedures (Conditions 1, 2, and 3) produced fewer errors on all 80 trials than did the no-fading control condition but did not differ significantly among themselves. These same results generally occurred for fading and test trials. Although fading has been used successfully to teach a variety of skills, systematic analyses of fading procedures clearly delineating component stimulus operations have been neglected.


Total knee arthroplasty in hemophilia.
Twenty-four total knee arthroplasties were performed in fourteen disabled patients with hemophilia. The average age of the patients at operation was thirty-five years. Twenty-one of the implants that were used were total condylar prostheses. Using The Hospital for Special Surgery knee-rating system after two to nine years of follow-up, the result in fifteen knees was rated as excellent; in six, as good; and in one, as fair. Two patients had a poor result that was attributable to late infection. Pain and function were markedly improved, and the average gain in range of motion was 23 degrees. Postoperative complications, in addition to the infections, included one subcutaneous hematoma, one hemolytic anemia, and one instance of inhibition to Factor VIII. The technical problems in treatment were formidable. Total knee arthroplasty in a hemophiliac can be successful, but it should be performed only with strict hematological supervision. The surgeon should be prepared to treat many potential postoperative complications.


Jekyll and Hyde in the microbial world.
Fungi are nonmotile organisms that obtain carbon from compounds in their immediate surroundings. Confronted with nutrient limitation, the yeast Saccharomyces cerevisiae undergoes a dimorphic transition, switching from spherical cells to filaments of adherent, elongated cells that can invade the substratum. A complex web of sensing mechanisms and cooperation among signaling networks (including a mitogen-activated protein kinase cascade, cyclic adenosine monophosphate-dependent protein kinase, and 5'-adenosine monophosphate-activated protein kinase) elicits the appropriate changes in physiology, cell cycle progression, cell polarity, and gene expression to achieve this differentiation. Highly related signaling processes control filamentation and virulence of many human fungal pathogens.


Acucise endopyelotomy in a porcine model: procedure standardization and analysis of safety and immediate efficacy.
The study here presented was done to test the technical reliability and immediate efficacy of the Acucise device using a standardized technique. 56 Acucise procedures were performed in pigs by a single surgeon who used a standardized technique: insert 5F angiographic catheter bilaterally up to the midureter, perform retrograde pyelogram, Amplatz super-stiff guidewire is advanced up to the level of the renal pelvis, angiographic catheters are removed, Acucise catheter balloon is advanced to the ureteropelvic junction (UPJ) level, the super-stiff guide-wire is removed and the contrast medium in the renal pelvis is aspirated and replaced with distilled water, activate Acucise at 75 watts of pure cutting current, keep the balloon fully inflated for 10 minutes, perform retrograde ureteropyelogram to document extravasation, remove Acucise catheter and pass an ureteral stent and remove guide-wire. In no case did the Acucise device present malfunction. The electrocautery activation time was 2.2 seconds (ranging from 2 to 4 seconds). The extravasation of contrast medium, visible by fluoroscopy, occurred in 53 of the 56 cases (94.6%). In no case there was any evidence of intraoperative hemorrhage. This study revealed that performing Acucise endopyelotomy routinely in a standardized manner could largely preclude intraoperative device malfunction and eliminate complications while achieving a successful incision in the UPJ. With the guidelines that were used in this study, we believe that Acucise endopyelotomy can be completed successfully and safely in the majority of selected patients with UPJ obstruction.


Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury.
The complement system has been suggested to affect injury or disease of the central nervous system (CNS) by regulating numerous physiological events and pathways. The activation of complement following traumatic CNS injury can also result in the formation and deposition of C5b-9 membrane attack complex (C5b-9/MAC), causing cell lysis or sublytic effects on vital CNS cells. Although complement proteins derived from serum/blood-brain barrier breakdown can contribute to injury or disease, infiltrating immune cells may represent an important local source of complement after injury. As the first immune cells to infiltrate the CNS within hours post-injury, polymorphonuclear leukocytes (PMNs) may affect injury through mechanisms associated with complement-mediated events. However, the expression/association of both early and terminal complement proteins by PMNs has not been fully characterized in vitro, and has not observed previously in vivo after traumatic spinal cord injury (SCI). We investigated the expression of complement mRNAs using rt-PCR and the presence of complement proteins associated with PMNs using immunofluroescence and quantitative flow cytometry. Stimulated or unstimulated PMNs expressed mRNAs encoding for C1q, C3, and C4, but not C5, C6, C7 or C9 in culture. Complement protein C1q or C3 was also detected in less than 30% of cultured PMNs. In contrast, over 70% of PMNs that infiltrated the injured spinal cord were associated with C1q, C3, C7 and C5b-9/MAC 3 days post-SCI. The localization/association of C7 or C5b-9/MAC with infiltrating PMNs in the injured spinal cord suggests the incorporation or internalization of C7 or C5b-9/MAC bound cellular debris by infiltrating PMNs because C7 and C5b-9/MAC were mostly localized to granular vesicles within PMNs at the spinal cord epicenter region. Furthermore, PMN presence in the injured spinal cord was observed for many weeks post-SCI, suggesting that this infiltrating cell population could chronically affect complement-mediated events and SCI pathogenesis after trauma. Data presented here provide the first characterization of early and terminal complement proteins associated with PMNs in vitro and in vivo after SCI. Data also suggest a role for PMNs in the local internalization or deliverance of complement and complement activation in the post-SCI environment.


Model-based assessment of neutrophil-mediated phagocytosis and digestion of bacteria across in vitro and in vivo studies.
Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5 × 106 cells/mL, renders patients increasingly vulnerable to infections. Published in vitro (n = 7) and in vivo (n = 5) studies with time-course information on bacterial and neutrophil counts were digitized to characterize the kinetics of neutrophil-mediated bacterial killing and inform on the immune systems' contribution to the clearance of bacterial infections. A mathematical model for the in vitro dynamics of bacteria and the kinetics of neutrophil-mediated phagocytosis and digestion was developed, which was extended to in vivo studies in immune-competent and immune-compromised mice. Neutrophil-mediated bacterial killing was described by two first-order processes-phagocytosis and digestion-scaled by neutrophil concentration, where 50% of the maximum was achieved at neutrophil counts of 1.19 × 106 cells/mL (phagocytosis) and 6.55 × 106 cells/mL (digestion). The process efficiencies diminished as the phagocytosed bacteria to total neutrophils ratio increased (with 50% reduction at a ratio of 3.41). Neutrophil in vivo dynamics were captured through the characterization of myelosuppressive drug effects and postinoculation neutrophil influx into lungs and by system differences (27% bacterial growth and 9.3% maximum capacity, compared with in vitro estimates). Predictions showed how the therapeutically induced reduction of neutrophil counts enabled bacterial growth, especially when falling below 0.5 × 106 cells/mL, whereas control individuals could deal with all tested bacterial burdens (up to 109 colony forming units/g lung). The model-based characterization of neutrophil-mediated bacterial killing simultaneously predicted data across in vitro and in vivo studies and may be used to inform the capacity of host-response at the individual level.


Key factor governing the physicochemical properties and extent of proton transfer in protic ionic liquids: ΔpKa or chemical structure?
In order to identify the key factor governing the transport properties and extent of proton transfer in protic ionic liquids (PILs), a series of PILs were prepared by simple neutralisation of a super-strong acid, bis(trifluoromethanesulfonyl)amide acid (H[NTf2]), with a range of amines comprising diverse structures, including secondary and tertiary amines. The bulk physicochemical properties of the resulting PILs with a wide variation in the ΔpKa values of the constituent acid and protonated bases were compared to those of previously reported PILs derived from a super-strong base, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and different acids (M. S. Miran, H. Kinoshita, T. Yasuda, M. A. B. H. Susan and M. Watanabe, Phys. Chem. Chem. Phys., 2012, 14, 5178-5186) with emphasis on the thermal stability, vibrational spectroscopy, density, viscosity, conductivity, and ionicity characteristics. The thermal stability of all PILs, as analysed by thermogravimetric analysis (TGA), was found to linearly increase with the ΔpKa values. However, isothermal TGA measurements for an extended duration indicated that [NTf2]-based PILs exhibit higher thermal stability than [DBU]-based PILs at low ΔpKa values (<15). PILs with secondary amines showed higher viscosity and lower ionic conductivity than those with tertiary amines because of the formation of multiple hydrogen bonds. The evaluated ionicity suggested that all [NTf2]-based PILs are "good PILs", irrespective of the basicity of the amines, and have higher ionicity than [DBU]-based PILs particularly at low ΔpKa values (<15).


Correction for acceleration-induced displacement artifacts in phase contrast imaging.
The acceleration-induced displacement artifact impairs the accuracy of MR velocity measurements. This study proposes a post processing method for correction of this artifact. Velocity measurements were performed in a flow phantom containing a constriction. Velocity curves were obtained from streamlines parallel to the frequency, phase, and slice directions, respectively. The acceleration-induced displacement artifact was most prominent when the frequency encoding direction was aligned with the flow direction. After correction, velocity assignment improved and a more accurate description of the flow was obtained. In vivo measurements were performed in the aorta in a patient with a repaired aortic coarctation. The correction method was applied to velocity data along a streamline parallel to the frequency encoding direction. The result after correction was a new location of the peak velocity and improved estimates of the velocity gradients.


Predicting the in vivo mechanism of action for drug leads using NMR metabolomics.
New strategies are needed to circumvent increasing outbreaks of resistant strains of pathogens and to expand the dwindling supply of effective antimicrobials. A common impediment to drug development is the lack of an easy approach to determine the in vivo mechanism of action and efficacy of novel drug leads. Toward this end, we describe an unbiased approach to predict in vivo mechanisms of action from NMR metabolomics data. Mycobacterium smegmatis, a non-pathogenic model organism for Mycobacterium tuberculosis, was treated with 12 known drugs and 3 chemical leads identified from a cell-based assay. NMR analysis of drug-induced changes to the M. smegmatis metabolome resulted in distinct clustering patterns correlating with in vivo drug activity. The clustering of novel chemical leads relative to known drugs provides a mean to identify a protein target or predict in vivo activity.


CD25+CD4+ regulatory T cells suppress CD4+ T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice.
The CD4(+) T cell-mediated inflammatory response to Pneumocystis carinii (PC) critically contributes to the clinical severity of PC pneumonia. It has been suggested that lymphopenic conditions predispose individuals to this immunopathology, although the mechanisms remain poorly understood. Another set of evidence indicates that a subpopulation of CD4(+) T cells constitutively expressing the CD25 molecule prevent lymphopenia-induced autoimmunity and inflammatory bowel disease. We tested the ability of this CD25(+)CD4(+) population to regulate CD4(+) T cell-mediated inflammatory response to PC. Adoptive transfer of CD25(-)CD4(+) cells into PC-infected recombination-activating gene-2-deficient mice led to lethal pneumonia within 13 days post-transfer. PC infection appeared to trigger CD25(-)CD4(+) cells, since recipients with reduced PC load survived up to 5 weeks after transfer. In contrast, transfer of CD25(+)CD4(+) cells did not induce lethal pneumonia and prevented the development of the disease induced by CD25(-)CD4(+) cells. Furthermore, CD25(-)CD4(+) cells reduced the PC load in the lung, while CD25(+)CD4(+) cells suppressed this immune response. Our results indicate an essential role for CD25(+)CD4(+) T cells in the control of PC-driven immunopathology, and suggest that in immunocompromised hosts PC pneumonia may result from a deficiency in regulatory T cells.


Development of target-specific treatments in multiple myeloma.
In the last decade, the novel agents lenalidomide, bortezomib, and thalidomide have dramatically improved outcomes for patients with multiple myeloma (MM). A number of new therapies with precise targets involved in MM cell growth and replication are now in development and have the potential for further improvements. Second-generation proteasome inhibitors and thalidomide derivatives may offer increased efficacy and safety. Investigational therapies with rationally selected targets in MM include inhibitors of histone deacetylase, heat shock protein 90, mammalian target of rapamycin, BCL2, Akt, mitogen-activated protein kinase, and telomerase. In addition, monoclonal antibodies directed against several targets have been developed and many are showing promise in initial clinical trials in MM. Interest in the ancient remedy of arsenic trioxide has been revived because of its proapoptotic effects on mitochondria, despite its established toxicities. In general, combination regimens are proving the most efficacious, which is to be expected given the multiple overlapping pathways responsible for MM growth and progression.


Peripelvic abscesses: a diagnostic dilemma.
Acute hematogenous peripelvic infections are common in tropical climates. However, in more temperate regions, this is a rare and often overlooked diagnosis. Because of the subtle and subacute nature of the symptoms, the diagnosis is often delayed. We report our experience with nine children treated for a hematogenous peripelvic infection. The hospital and clinic charts were reviewed of nine consecutive patients with the diagnosis of a peripelvic abscess. Patients ranged in age from 2 to 13 years. Symptoms were present from 5 to 20 days. The most consistent symptom was a hip-flexion pseudocontracture (eight patients). The initial diagnosis was correct in only three patients. Computed tomography (CT) scan was diagnostic in all nine patients, providing diagnosis and localization. Seven of the nine patients underwent irrigation and debridement followed by a variable course of intravenous (i.v.) and oral antibiotics. All seven had rapid resolution of their symptoms. Two patients were treated with i.v. antibiotics alone, one of whom had a recurrence of symptoms. All nine patients had microbiologic confirmation of the infecting organisms [seven at surgery, one from blood cultures, one from sacroiliac (SI) joint aspiration]. Eight of the nine were infected by Staphylococcus aureus and one by group A Streptococcus. All had complete resolution of their symptoms at follow-up. Although acute retrofascial abscesses are rare in temperate climates, they should be considered in the differential diagnosis in the child with lower abdominal or hip pain. CT scan was the most helpful diagnostic test in these patients. Surgical drainage resulted in the most consistent results in this small series of patients.


Medical homelessness and candidacy: women transiting between prison and community health care.
Women in contact with the prison system have high health needs. Short periods in prison and serial incarcerations are common. Examination of their experiences of health care both in prison and in the community may assist in better supporting their wellbeing and, ultimately, decrease their risk of returning to prison. We interviewed women in prisons in Sydney, Australia, using pre-release and post-release interviews. We undertook thematic analysis of the combined interviews, considering them as continuing narratives of their healthcare experiences. We further reviewed the findings using the theoretical lens of candidacy to generate additional insights on healthcare access. Sixty-nine interviews were conducted with 40 women pre-release and 29 of these post-release. Most had histories of substance misuse. Women saw prison as an opportunity to address neglected health problems, but long waiting lists impeded healthcare delivery. Both in prison and in the community, the dual stigmas of substance misuse and being a prisoner could lead to provider judgements that their claims to care were not legitimate. They feared they would be blocked from care even if seriously ill. Family support, self-efficacy, assertiveness, overcoming substance misuse, compliance with health system rules and transitional care programs increased their personal capacity to access health care. For women in transition between prison and community, healthcare access could be experienced as 'medical homelessness' in which women felt caught in a perpetual state of waiting and exclusion during cycles of prison- and community-based care. Their healthcare experiences were characterized by ineffectual attempts to access care, transient relationships with healthcare providers, disrupted medical management and a fear that stigma would prevent candidacy to health care even in the event of serious illness. Consideration of the vulnerabilities and likely points of exclusion for women in contact with the criminal justice system will assist in increasing healthcare access for this marginalised population.


Porcine soluble CD83 alleviates LPS-induced abortion in mice by promoting Th2 cytokine production, Treg cell generation and trophoblast invasion.
CD83, either in its membrance-bound form (mCD83) or soluble form (sCD83), is an important immunomodulatory molecule in humans and mice. While mCD83 is immunostimulatory, sCD83 exhibits striking immunosuppressive activities, suggesting that sCD83 may be used to combat inflammatory diseases, such as rheumatoid arthritis, graft-versus-host disease and habitual abortion. Although many studies had shed lights on the role of CD83 in humans and mice, little is known about CD83 in other animals. Recently, we showed that porcine CD83 had similar biochemical characteristics and immunoregulatory functions as its human counterpart. However, whether porcine sCD83 (psCD83) is involved in maintaining the immunological tolerance at the maternal-fetal interface and thereby prevents embryo loss and abortion during pregnancy is unclear. In this study, we used LPS-induced animal model to analyze the effect of porcine sCD83 on the mouse abortion. Results showed that psCD83 could significantly alleviate LPS-induced abortion in mice, indicating that the psCD83 had the function of fetal protection. Mechanically, psCD83-mediated fetal protection was related to the promotion on Th2 cytokine production, Treg cell differentiation and trophoblast invasion. This study provides a molecular basis for the fetal protection of psCD83, as well as a potential target for the regulation of maternal-fetal interfacial immune tolerance.


Glucose induces the translocation and the aggregation of glycogen synthase in rat hepatocytes.
Incubation of rat hepatocytes with glucose results in a decrease in the amount of glycogen synthase activity found in supernatants obtained after centrifugation of cell homogenates at 9200 g. The enzymic activity was quantitatively recovered in the sediments. This effect of translocation was dose- and time-dependent and correlated with the amount of immunoreactive enzyme determined by immunoblotting in both fractions. Hydrolysis by alpha-amylase of glycogen accumulated upon incubation with the sugar did not affect the translocation pattern. Translocation was also observed when cells were incubated with 2-deoxyglucose, which did not result in accumulation of glycogen. Immunocytochemical evidence indicates that glucose induces the aggregation of glycogen synthase molecules into clusters which are recovered in the sediments. These results indicate that glucose, in addition to activating glycogen synthase, may trigger changes in the localization of the enzyme in the cell.


[The main trends in a diphtheria epidemic process and the potentials for its elimination in a large city].
In recent years the tendency towards the activation of the epidemic process of diphtheria, i.e. the appearance of cases of diphtheria simultaneously with the increased levels of circulation of toxigenic and nontoxigenic Corynebacterium diphtheriae and with antitoxic immunity characteristics in children and adults constantly remaining low, has been registered. For the effective control of diphtheria, the profound study of such problems as bacterial carriership, antibacterial immunity and the development of supplementary means of specific prophylaxis is necessary.


Adolescent language brokering in diverse contexts: associations with parenting and parent-youth relationships in a new immigrant destination area.
In the US, children in immigrant families have a longstanding history of language brokering for their parents. Scholars have surmised that youth's role in language brokering may influence the nature of parenting practices and parent-child relationships that are important to the positive adjustment of adolescent youth. Research findings in this regard, however, have been mixed. Drawing from the family stress model and the concept of adolescent helpfulness, the present study examined how language brokering across different contexts-school, community, and home-was associated with indicators of parental support and parental behavioral control. The sample included 118 (53% female) primarily Mexican- and Central American-origin 7th, 9th, and 11th grade children in Latino immigrant families living in suburban Atlanta, an important new immigrant destination. The results from structural equation models indicated that language brokering at home-translations for items such as bills, credit card statements, and insurance forms-was associated with less parental decision-making authority, lower levels of parental knowledge, and less parent-child closeness. Language brokering pertinent to school and community contexts, on the other hand, was not associated with variations in parenting. The adverse consequences for parenting conferred by youth translating insurance forms and family financial bills may stem from the excessive cognitive demands placed on youth in these situations, as well as the elevated power that youth gain in relationship to their immigrant parents. For the country's rapidly growing population of youth being raised by immigrant Latino parents, it is important to consider that youth's role as language broker at home may affect closeness in the parent-child relationship as well as the degree to which parents are able to maintain authority over youth's behaviors.


Recent advances in oral delivery systems of resveratrol: foreseeing their use in functional foods.
Herein, we review the current state-of-the-art on the use of micro- and nano-delivery systems, a possible solution to some of the drawbacks associated with the incorporation of resveratrol in foods. Specifically, we present an overview of a wide range of micro-nanostructures, namely, lipidic and polymeric, used for the delivery of resveratrol. Also, the gastrointestinal fate of resveratrol-loaded micro-nanostructures, as a critical parameter for their use as functional food, is explored in terms of stability, bioaccessibility, and bioavailability. Different micro-nanostructures are of interest for the development of functional foods given that they can provide different advantages and properties to these foods and even be tailor-made to address specific issues (e.g., controlled or targeted release). Therefore, we discuss a wide range of micro-nanostructures, namely, lipidic and polymeric, used to deliver resveratrol and aimed at the development of functional foods. It has been reported that the use of some production methodologies can be of greater interest than others, for example, emulsification, solvent displacement and electrohydrodynamic processing (EHDP) enable a greater increase in bioaccessibility. Additionally, the use of coatings facilitates further improvements in bioaccessibility, which is likely due to the increased gastric stability of the coated micro-nanostructures. Other properties, such as mucoadhesion, can also help improve bioaccessibility due to the increase in gut retention time. Additionally, cytotoxicity (e.g., biocompatibility, antioxidant, and anti-inflammatory) and possible sensorial impact of resveratrol-loaded micro- and nano-systems in foods are highlighted.


Axonal supercharged interpositional jump-graft with a hybrid artificial nerve conduit containing adipose-derived stem cells in facial nerve paresis rat model.
Interpositional jump-graft (IPJG) technique with the hypoglossal nerve for supercharging can be applied in a facial nerve paresis case. In IPJG, an autologous nerve is required, and the donor site morbidity is unavoidable. Biodegradable nerve conduits are made from polyglycolic acid (PGA) and used recently without donor site complications after providing autologous grafts. Hybrid artificial nerve conduits with adipose-derived stem cells (ASCs) also attract attention as a nerve-regeneration enhancing agent. This study examined the effect of hybrid artificial nerve conduit on IPJG. A total of 34 Lewis rats were used and divided into 4 groups by the bridge materials: autograft (n = 8), PGA nerve conduit (n = 8), hybrid PGA nerve conduit with ASCs (n = 8), and the nontreated control groups (n = 8). ASCs were collected from 2 rats and cultured. The animals were assessed physiologically and histopathologically at 13 weeks after surgery. In compound muscle action potential, the amplitude of hybrid PGA group (3,222 ± 1,779 μV) was significantly higher than that of PGA group (1,961 ± 445 μV, P < .05), and no significant difference between hybrid PGA and autograft group. All treated groups showed a myelinated nerve regeneration with double innervation in hypoglossal and facial nerve nuclei for vibrissal muscle. This study showed the effectiveness of IPJG with a hybrid PGA conduit especially in physiological examination.


Evoked-potential audiogram of an Indo-Pacific humpback dolphin (Sousa chinensis).
An evoked-potential audiogram was measured for an Indo-Pacific humpback dolphin (Sousa chinensis) living in the dolphinarium of Nanning Zoo, China. Rhythmic 20 ms pip trains composed of cosine-enveloped 0.25 ms tone pips at a pip rate of 1 kHz were presented as sound stimuli. The dolphin was trained to remain still at the water surface and to wear soft latex suction-cup EEG electrodes used to measure the animal's envelope-following evoked potentials to the sound stimuli. Responses to 1000 rhythmic 20 ms pip trains for each amplitude/frequency combination were averaged and analysed using a fast Fourier transform to obtain an evoked auditory response. The hearing threshold was defined as the zero crossing point of the response input-output function using linear regression. Fourteen frequencies ranging from 5.6 to 152 kHz were studied. The results showed that most of the thresholds were lower than 90 dB re. 1 μPa (r.m.s.), covering a frequency range from 11.2 to 128 kHz, and the lowest threshold of 47 dB was measured at 45 kHz. The audiogram, which is a function of hearing threshold versus stimulus carrier frequency, presented a U-shape with a region of high hearing sensitivity (within 20 dB of the lowest threshold) between approximately 20 and 120 kHz. At frequencies lower than this high-sensitivity region, thresholds increased at a rate of approximately 11 dB octave(-1) up to 93 dB at 5.6 kHz. The thresholds at high frequencies above 108 kHz increased steeply at a rate of 130 dB octave(-1) up to 127 dB at 152 kHz.


High-pressure synthesis of acentric sodium pyrocarbonate, Na2[C2O5].
The inorganic pyrocarbonate salt Na2[C2O5] crystallizes in the acentric, monoclinic space group P21 with Z = 2. It contains monovalent alkali metal cations together with isolated pyrocarbonate anions. The [C2O5]2--groups consist of two planar [CO3]2--groups which are slightly tilted with respect to each other around the bridging oxygen atom. Na2[C2O5] was synthesized in a laser-heated diamond anvil cell at 20(2) GPa by heating a mixture of Na2[CO3] + CO2 to ≈800(200) K. Its crystal structure was obtained by single crystal synchrotron X-ray diffraction and confirmed by density functional theory-based calculations in combination with Raman spectroscopy. Second harmonic generation measurements verified the acentric space group symmetry. The crystal structure is characterized by alternating layers of Na+-cations and [C2O5]2--complex anions.


A Study on Clinical Characteristics and Magnetic Resonance Imaging Manifestations on Systemic Rosai-Dorfman Disease.
Rosai-Dorfman disease (RDD) is typically characterized by painless bilateral and symmetrical cervical lymphadenopathy, with associated fever and leukocytosis. The aim of the current study was to summarize the clinical features and imaging characteristics of RDD, in an effort to improve its diagnostic accuracy. The study was analyzed from 32 patients between January 2011 and December 2017; of these, 16 patients had pathologically diagnosed RDD, eight had pathologically diagnosed meningioma, and eight pathologically diagnosed lymphoma. All patients underwent computed tomography and magnetic resonance imaging (MRI). Clinical features and imaging characteristics of RDD were analyzed retrospectively. The mean apparent diffusion coefficient (ADC) values of lesions at different sites were measured, and one-way analysis of variance and the least significant difference t-test were used to compare the differences between groups and draw receiver operating characteristic curves. The tumors were excised for biopsy and analyzed using immunohistochemistry. The mean ADCs were (0.81 ± 0.10) × 10-3 mm2/s for intercranial RDD, (0.73 ± 0.05) × 10-3 mm2/s for nasopharyngeal RDD, (0.74 ± 0.11) × 10-3 mm2/s for bone RDD, and (0.71 ± 0.04) × 10-3 mm2/s for soft-tissue RDD. The optimum ADC to distinguish intracranial RDD from lymphoma was 0.79 × 10-3 mm2/s (62.5% sensitivity and 100% specificity) and to distinguish meningioma from intracranial RDD was 0.92 × 10-3 mm2/s (62.5% sensitivity and 100% specificity). Levels of C-reactive protein, erythrocyte sediment rate and D-dimer were significantly elevated (81%, 87%, and 75%, respectively). On immunohistochemistry, RDD was positive for both S-100 and CD68 proteins but negative for CD1a. Conventional MRI, combined with diffusion-weighted imaging and ADC mapping, is an important diagnostic tool in evaluating RDD patients. An accurate diagnosis of RDD should consider the clinical features, imaging characteristics, and the pathological findings.


A method to transform a variable thermal regime to a physiologically equivalent effective temperature.
We present a method to characterize variable thermal regimes in terms of an equivalent or effective temperature. Our method is based on a first order exponential transformation of a time series of temperatures to yield an exponentially-weighted mean temperature characteristic of the regime and independent of any particular species or end point. The resulting effective temperature or exponential mean, Te¯, offers an improved method for summarizing mean temperature where biological response scales exponentially to temperature. The exponential mean allows growth under varying thermal regimes to be predicted using constant temperature models and offers a compact descriptor communicating the growth capacity of variable thermal regimes. The method combines mathematical simplicity with translatability to different Q10 values without recourse to the underlining time series data. It also provides a quantitative baseline that improves on mean temperature by incorporating the effect of Jensen's inequality and it remains applicable at near zero temperatures where thermal sums lack accuracy.


Status of healthcare studies submitted to UK research ethics committees for approval in 2004-5.
In view of the increasing complexity of research ethics committee (REC) applications and thus the time and expense involved in completing the forms, continual monitoring of outcome of clinical research studies for which ethics applications have been submitted is essential in determining whether resources are being effectively used, or alternatively whether significant numbers of research proposals are abandoned because of lack of funding or manpower. Previously published surveys for which data are available examined outcome of studies receiving REC approval 10 or more years ago. A prospective questionnaire-based survey sent out in July 2006 to all 506 principal investigators who submitted research ethics applications to nine Greater Manchester RECs between April 2004 and March 2005. Data on the outcome of REC applications, and the status of the research study were collected and analysed. 288 of the 506 (57%) questionnaires were returned. 97% of REC applications were approved, and 87% of studies were in progress or had been completed 1-2 years after approval had been granted. Researchers employed by universities (51%), healthcare (43%) and the pharmaceutical industry (6%) had similar rates of success in initiating research studies. This survey suggests that most research studies submitted to RECs in Manchester, UK are approved and initiated.


A Bayesian Approach to Correcting the Attenuation Bias of Regression Using Polygenic Risk Score.
Polygenic risk score (PRS) has become increasingly popular for predicting the value of complex traits. In many settings, PRS is used as a covariate in regression analysis to study the association between different phenotypes. However, measurement error in PRS causes attenuation bias in the estimation of regression coefficients. In this paper, we employ a Bayesian approach to accounting for the measurement error of PRS and correcting the attenuation bias in linear and logistic regression. Through simulation, we show that our approach is able to obtain approximately unbiased estimation of coefficients and credible intervals with correct coverage probability. We also empirically compare our Bayesian measurement error model to the conventional regression model by analyzing real traits in the UK Biobank. The results demonstrate the effectiveness of our approach as it significantly reduces the error in coefficient estimates.


Retinol esterification in cultured rat liver cells.
Retinol esterification was examined in cultured hepatocytes and stellate cells from the rat. Esterification of [3H]retinol was linear for 2 h in both cell types. By increasing the concentration of retinol in the medium, there was a marked increase in retinol esterification in both cell types. The capacity for esterification of retinol was in the same order of magnitude in the two cell types at 3.5 microM-retinol in the medium. This represents a rate of retinol esterification which far exceeds that required to esterify the amount of retinol absorbed in the intestine. It was demonstrated in particulate homogenates from cultured hepatocytes that the esterification of retinol was dependent on acyl-CoA. Addition of 25-hydroxycholesterol or mevalonolactone promoted an increase in cholesterol esterification, whereas retinol esterification was unaffected, suggesting that cholesterol and retinol are esterified by two different enzymes. Some 80% of vitamin A in cultured hepatocytes is retinyl esters, mostly retinyl palmitate. By adding 87 microM-retinol in the medium the cells accumulated 100-fold free retinol and 2.5-3.0-fold retinyl esters within 1 h. When retinol-loaded cells were incubated without retinol, there was a marked decrease especially in free but also in esterified retinol. In the presence of 1 mM-oleic acid in the medium the amount of retinyl oleate was twice that in control cells.


Drought impacts on children's respiratory health in the Brazilian Amazon.
Drought conditions in Amazonia are associated with increased fire incidence, enhancing aerosol emissions with degradation in air quality. Quantifying the synergic influence of climate and human-driven environmental changes on human health is, therefore, critical for identifying climate change adaptation pathways for this vulnerable region. Here we show a significant increase (1.2%-267%) in hospitalisations for respiratory diseases in children under-five in municipalities highly exposed to drought. Aerosol was the primary driver of hospitalisations in drought affected municipalities during 2005, while human development conditions mitigated the impacts in 2010. Our results demonstrated that drought events deteriorated children's respiratory health particularly during 2005 when the drought was more geographically concentrated. This indicates that if governments act on curbing fire usage and effectively plan public health provision, as a climate change adaptation procedure, health quality would improve and public expenditure for treatment would decrease in the region during future drought events.


Patient-reported outcomes after oesophagectomy in the multicentre LASER study.
Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. A long-term symptom burden is common after oesophageal cancer surgery.


[Mechanism regulating healing of perforating wounds of the cornea by natural cytokine complex].
Effects of a natural complex of cytokines secreted by peripheral blood leukocytes on the healing of perforating wounds of the cornea were studied in 28 rabbits (14 animals in control and 14 in experimental groups). The process of healing of similar cut wounds of the cornea during local application of cytostatics was assessed by morphological and morphometric methods on days 1, 3, 7, 14, and 30 after the injury. Two periods, early and late, were distinguished in the morphogenesis of healing of a cut wound of the cornea under the effect of natural cytokines. The cytokines enhanced neutrophil migration to the wound canal in the early period of morphogenesis, this accelerating fibrin resorption, which was followed by filling of the wound canal with keratoblastic proliferate. In the late period of morphogenesis of wound healing (days 14-30) the functional activity of fibroblasts was increased, this being conducive to activation of collagenization of cicatricial tissue and resorption of the cicatrix as a result of a possible increase of collagenase release under the effect of cytokines. The possible mechanism of regulating effect of cytokines on corneal repair is discussed.


Osteosarcopenia: where bone, muscle, and fat collide.
As the world's population ages, the prevalence of chronic diseases increases. Sarcopenia and osteoporosis are two conditions that are associated with aging, with similar risk factors that include genetics, endocrine function, and mechanical factors. Additionally, bone and muscle closely interact with each other not only anatomically, but also chemically and metabolically. Fat infiltration, a phenomenon observed in age-related bone and muscle loss, is highly prevalent and more severe in sarcopenic and osteoporotic subjects. Clinically, when individuals suffer a combination of both disorders, negative outcomes such as falls, fractures, loss of function, frailty, and mortality increase, thus generating significant personal and socio-economic costs. Therefore, it is suggested that when bone mineral density loss is synchronic with decreased muscle mass, strength, and function, it should be interpreted as a single diagnosis of osteosarcopenia, which may be preventable and treatable. Simple interventions such as resistance training, adequate protein and calcium dietary intake, associated with maintenance of appropriate levels of vitamin D, have a dual positive effect on bone and muscle, reducing falls, fractures, and, consequently, disability. It is essential that fracture prevention approaches-including postfracture management-involve assessment and treatment of both osteoporosis and sarcopenia. This is of particular importance as in older persons the combination of osteopenia/osteoporosis and sarcopenia has been proposed as a subset of frailer individuals at higher risk of institutionalization, falls, and fractures. This review summarizes osteosarcopenia epidemiology, pathophysiology, diagnosis, outcomes, and management strategies.


Sleep-disordered breathing in patients with myelomeningocele: the missed diagnosis.
Moderate to severe sleep-disordered breathing (SDB) was identified in 20% (17 of 83) of children with spina bifida/myelomeningocele (SB/MM) at the Montreal Children's Hospital. The prevalence of SDB in patients with SB/MM elsewhere has not been determined. To establish current practices for identifying SDB in patients with SB/MM, questionnaires were sent to the coordinators of the 212 spina-bifida clinics in Canada and in the United States. Eighty-six (41%) questionnaires were returned, representing data on 13 349 patients. Although 67% of the responding centers reported availability of cardiorespiratory sleep studies, only 996 (7.5%) patients with SB/MM had been tested and only 418 (3.1%) patients had been diagnosed with SDB. Across clinics, the prevalence of SDB was directly related to the frequency of testing. Of 380 deaths over the past 10 years, SDB and sudden unexplained death during sleep were identified as the cause of death in 49 (12.8%) and 34 (8.9%) patients, respectively. Moderate to severe SDB may not have been identified in a significant number of patients with SB/MM because they have not been tested.


Metal-insulator transitions in the half-filled ionic Hubbard model.
We study electronic phase transitions in the half-filled ionic Hubbard model with an on-site Coulomb repulsion U and an ionic energy Δ by using the coherent potential approximation. For a fixed and finite Δ two transitions from the band insulator via a metallic state to a Mott insulator are found with increasing U. The values of the critical correlation-driven metal-insulator transitions U(c1)(Δ) and U(c2)(Δ) are estimated. Our results are in reasonable agreement with the ones obtained by single-site dynamical mean-field theory and determinant quantum Monte Carlo simulation.


Schistosomiasis in Lake Malaŵi villages.
Historically, open shorelines of Lake Malaŵi were free from schistosome, Schistosoma haematobium, transmission, but this changed in the mid-1980s, possibly as a result of over-fishing reducing density of molluscivore fishes. Very little information is available on schistosome infections among people in lake-shore communities and therefore we decided to summarise data collected from 1998 to 2007. Detailed knowledge of the transmission patterns is essential to design a holistic approach to schistosomiasis control involving the public health, fisheries and tourism sectors. On Nankumba Peninsula, in the southern part of the lake, inhabitants of villages located along the shores of Lake Malaŵi have higher prevalence of S. haematobium infection than those living in inland villages. Overall prevalence (all age classes combined) of urinary schistosomiasis in 1998/1999 ranged from 10.2% to 26.4% in inland villages and from 21.0% to 72.7% in lakeshore villages; for school children prevalence of infection ranged from 15.3% to 57.1% in inland schools and from 56.2% to 94.0% in lakeshore schools. Inhabitants on the islands, Chizumulu and Likoma, also have lower prevalence of infection than those living in lakeshore villages on Nankumba Peninsula. This increased prevalence in lakeshore villages is not necessarily linked to transmission taking place in the lake itself, but could also be due to the presence of more numerous typical inland transmission sites (e.g., streams, ponds) being close to the lake. Temporal data witness of intense transmission in some lakeshore villages with 30-40% of children cleared from infection becoming reinfected 12 months later (also lakeshore village). The level of S. mansoni infection is low in the lakeshore communities. Findings are discussed in relation to fishing in the lake.


Tendon-derived stem/progenitor cell aging: defective self-renewal and altered fate.
Aging is a major risk factor for tendon injury and impaired tendon healing, but the basis for these relationships remains poorly understood. Here we show that rat tendon- derived stem ⁄ progenitor cells (TSPCs) differ in both self-renewal and differentiation capability with age. The frequency of TSPCs in tendon tissues of aged animals is markedly reduced based on colony formation assays. Proliferation rate is decreased, cell cycle progression is delayed and cell fate patterns are also altered in aged TSPCs. In particular, expression of tendon lineage marker genes is reduced while adipocytic differentiation increased. Cited2, a multi-stimuli responsive transactivator involved in cell growth and senescence, is also downregulated in aged TSPCs while CD44, a matrix assembling and organizing protein implicated in tendon healing, is upregulated, suggesting that these genes participate in the control of TSPC function.


Cortical interneurons that specialize in disinhibitory control.
In the mammalian cerebral cortex the diversity of interneuronal subtypes underlies a division of labour subserving distinct modes of inhibitory control. A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation. Although several interneuron populations are known to target other interneurons to varying degrees, little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single-cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively. During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.


Impact of Right Ventricular Performance in Patients Undergoing Extracorporeal Membrane Oxygenation Following Cardiac Surgery.
Extracorporeal membrane oxygenation following cardiac surgery safeguards end-organ oxygenation but unfavorably alters cardiac hemodynamics. Along with the detrimental effects of cardiac surgery to the right heart, this might impact outcome, particularly in patients with preexisting right ventricular (RV) dysfunction. We sought to determine the prognostic impact of RV function and to improve established risk-prediction models in this vulnerable patient cohort. Of 240 patients undergoing extracorporeal membrane oxygenation support following cardiac surgery, 111 had echocardiographic examinations at our institution before implantation of extracorporeal membrane oxygenation and were thus included. Median age was 67 years (interquartile range 60-74), and 74 patients were male. During a median follow-up of 27 months (interquartile range 16-63), 75 patients died. Fifty-one patients died within 30 days, 75 during long-term follow-up (median follow-up 27 months, minimum 5 months, maximum 125 months). Metrics of RV function were the strongest predictors of outcome, even stronger than left ventricular function (P<0.001 for receiver operating characteristics comparisons). Specifically, RV free-wall strain was a powerful predictor univariately and after adjustment for clinical variables, Simplified Acute Physiology Score-3, tricuspid regurgitation, surgery type and duration with adjusted hazard ratios of 0.41 (95%CI 0.24-0.68; P=0.001) for 30-day mortality and 0.48 (95%CI 0.33-0.71; P<0.001) for long-term mortality for a 1-SD (SD=-6%) change in RV free-wall strain. Combined assessment of the additive EuroSCORE and RV free-wall strain improved risk classification by a net reclassification improvement of 57% for 30-day mortality (P=0.01) and 56% for long-term mortality (P=0.02) compared with the additive EuroSCORE alone. RV function is strongly linked to mortality, even after adjustment for baseline variables and clinical risk scores. RV performance improves established risk prediction models for short- and long-term mortality.


Behavioural mechanisms underlying parasite-mediated competition for refuges in a coral reef fish.
Parasites have been increasingly recognized as participants in indirect ecological interactions, including those mediated by parasite-induced changes to host behaviour (trait-mediated indirect interactions or TMIIs). In most documented examples, host behaviours altered by parasites increase susceptibility to predation because the predator is also a host (host-manipulation). Here, we test for a TMII in which a parasitic copepod modifies the predator-prey interaction between a small goby host and several larger predatory fish. Gobies compete for crevices in the reef to avoid predation and goby mortality increases more rapidly with increasing refuge shortage for parasitized gobies than for those free of parasites. We found interactive effects of refuge shortage and parasitism on two behaviours we predicted might be associated with parasite-mediated competition for refuges. First, as refuge-shortage increases, the rate of aggression among gobies increases and parasitism intensifies this interaction. Second, goby proximity to refuges increases as refuges become scarce, but parasitism nullifies this increase. In combination, these parasite-induced changes in behaviour may explain why parasitized gobies are poor competitors for refuges. Because the parasite is not trophically transmitted via host manipulation, these altered behaviours in parasitized gobies are likely coincidental to infection.


Mutations near the cleavage site of enterocin NKR-5-3B prepeptide reveal new insights into its biosynthesis.
Enterocin NKR-5-3B (Ent53B) is a 64-residue novel circular bacteriocin synthesized from an 87-residue prepeptide. Albeit through a still unknown mechanism, the EnkB1234 biosynthetic enzyme complex processes the prepeptide to yield its mature active, circular form. To gain insights into the key region/residue that plays a role in Ent53 maturation, several mutations near the cleavage site on the precursor peptide were generated. The interaction of the precursor peptide and EnkB1234 appeared to be hydrophobic in nature. At the Leu1 position, only mutations with helix structure-promoting hydrophobic residues (Ala, Ile, Val or Phe) were able to yield the mature Ent53B derivative. In this study, we also highlight the possible conformation-stabilizing role of the Ent53B leader peptide on the precursor peptide for its interaction with its biosynthetic enzyme complex. Any truncations of the leader peptide moiety interfered in the processing of the prepeptide. However, when propeptides of other circular bacteriocins (circularin A, leucocyclicin Q or lactocyclicin Q) were cloned at the C-terminus of the leader peptide, EnkB1234 could not process them to yield a mature bacteriocin. Taken together, these findings offer new perspectives in our understanding of the possible molecular mechanism of the biosynthesis of this circular bacteriocin. These new perspectives will help advance our current understanding to eventually elucidate circular bacteriocin biosynthesis. Understanding the biosynthetic mechanism of circular bacteriocins will materialize their application potential.


Enhanced anticancer effects of a mixture of low-dose mushrooms and Panax ginseng root extracts in human colorectal cancer cells.
Worldwide, colorectal cancer is the third most common cancer in men and the second most common in women. As conventional colorectal cancer therapies result in various side effects, there is a need for adjuvant therapy that can enhance the conventional therapies without complications. In this study, we investigated the anticancer effects of combined mixture of the several medicinal mushrooms and Panax ginseng root extracts (also called Amex7) as an adjuvant compound in the treatment of human colorectal cancer. We observed the in vivo inhibitory effect of Amex7 (1.25, 6.25, and 12.5 ml/kg, oral administration, twice daily) on tumor growth in a mouse model xenografted with HT-29 human colorectal cancer cells. In vitro, at 6, 12, and 24 h after 4% Amex7 treatment, we analyzed cell cycle by flow cytometry and the expression levels of cell cycle progression, apoptosis, and DNA damage repair-related proteins using immunoblotting and immunofluorescence staining in HT-29 cell line. As a result, Amex7 significantly suppressed tumor growth in HT-29 human colorectal cancer cells and xenografts. In vitro, Amex7 induced G2/M arrest through the regulation of cell cycle proteins and cell death by apoptosis and autophagy. Additionally, Amex7 consistently induced DNA damage and delayed the repair of Amex7-induced DNA damage by reducing the level of HR repair proteins. In conclusion, Amex7 enhanced anticancer effects through the induction of G2/M arrest and cell death, including apoptosis and autophagy. Furthermore, Amex7 impaired DNA damage repair. The present study provides a scientific rationale for the clinical use of a combined mixture of medicinal mushrooms and P. ginseng root extracts as an adjuvant treatment in human colorectal cancer.


Probing Norwalk-like virus presence in shellfish, using artificial neural networks.
A database was examined using artificial neural network (ANN) models to investigate the efficacy of predicting PCR-identified Norwalk-like virus presence and absence in shellfish. The relative importance of variables in the model and the predictive power obtained by application of ANN modelling methods were compared with previously developed logistic regression models. In addition, two country-specific datasets were analysed separately with ANN models to determine if the relative importance of the input variables was similar for geographically diverse regions. The results of this analysis found that ANN models predicted Norwalk-like virus presence and absence in shellfish with equivalent, and better, precision than logistic regression models. For overall classification performance, ANN modelling had a rate of 93%, vs 75% for the logistic regression. ANN models were able to illuminate the site-specific relationships between indicators and pathogens.


Synthesis, antimicrobial activity and modeling studies of thiazoles bearing pyridyl and triazolyl scaffolds.
In this study, novel 4-(5-((2/3/4-substituted benzyl)thio)-4-(4-substituted phenyl)-4H-1,2,4-triazol-3-yl)-2-(pyridin-3/4-yl)thiazoles were synthesized following a multi-step synthetic procedure. All the compounds were screened with a panel of gram positive/negative bacteria, yeasts, and molds for antimicrobial activity using the disc diffusion method. Then, the minimum inhibitor concentration (MIC) and the minimum bactericidal concentration (MBC) values of active compounds were determined against Micrococcus luteus, Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus using the broth microdilution technique. These compounds were also screened for their inhibitory activities against S. aureus DNA gyrase by supercoiling assay. Furthermore, the crystal structure of S. aureus DNA gyrase B ATPase was subjected to a docking experiment to identify the possible interactions between the most active ligand and the active site. Lastly, the in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules.


Primary bronchomalacia and patent ductus arteriosus: simultaneous surgical correction in an infant.
We report the clinical course of a 6-month-old girl with recurrent infection of the left lung, persistent wheezing, and a suspected congenital heart anomaly (patent ductus arteriosus. Chest radiography revealed hyperinflation and slight inflammation of the left lung. Tracheobronchoscopy and left-sided bronchography showed a collapsed segment of the left main bronchus, 3 cm long. Computed tomography confirmed hyperinflation of the left lung and atelectasis of the superior lobe. There were no signs of extramural compression. Color-flow Doppler echocardiography confirmed the suspicion of patent ductus arteriosus. To the best of our knowledge, there is no other report in the literature of a patient with this combination of anomalies. After receiving 2 weeks of antibiotic treatment, the patient underwent surgical repair The patent ductus arteriosus was closed by means of a triple-ligature procedure, and during the same operation a bronchopexy was performed, securing the left main bronchus to the closed ductus tissue by means of sutures. There have been no complications in the postoperative period. Clinical follow-up, as well as echocardiography and bronchoscopy, have yielded normal results 14 months after surgery.


Performance of broiler chickens fed diets containing DAS-68416-4 soybean meal.
Broiler chickens are a fast growing monogastric animal commonly used to evaluate the equivalence between transgenic and non-transgenic grains as part of the human safety assessment process. While commonly viewed like other livestock feeding trials, such studies are performed with transgenic crops with input traits (that are not designed to improve nutrition) to aid regulatory authorities in evaluating safety. Studies of this type are actually more similar to toxicology studies in purpose, with sensitive endpoints like growth used to detect metabolic perturbations. DAS-68416-4 soybean expresses the aryloxyalkanoate dioxygenase-12 (AAD-12) enzyme which inactivates 2,4-diclorophenoxyacetic acid (2,4-D) and provides DAS-68416-4 soybeans tolerance to this herbicide. DAS-68416-4 also expresses the phosphinothricin acetyltransferase (PAT) enzyme from Streptomyces viridochromogenes which confers tolerance to glufosinate-ammonium herbicides. A 6-week broiler study was conducted with diets containing toasted DAS-68416-4 soybean meal (40, 36, and 32% in starter, grower and finisher diets, respectively) to evaluate nutritional wholesomeness and safety compared with conventional comparators. Toasting soybean meal is required to inactivate endogenous antinutrients making soybean suitable for consumption by monogastric animals like broiler chickens. Toasting was found to denature both the AAD-12 and PAT proteins rendering them non-detectable by enzyme linked immunosorbent assays. Broiler growth and performance parameters were measured over a 6-week period of exposure to diets containing different sources of toasted soybean meal, and results indicate that DAS-68416-4 soybean is nutritionally equivalent to non-transgenic soybean.


Long- and Short-Term Trends in Outpatient Attendance by Speciality in Japan: A Joinpoint Regression Analysis in the Context of the COVID-19 Pandemic.
The COVID-19 pandemic resulted in a decline in outpatient attendance. Therefore, this study aimed to clarify long- and short-term clinic attendance trends by speciality in Japan between 2009 and 2021. A retrospective observational study of Japan's claims between 2009 and 2021 was conducted using the Estimated Medical Expenses Database. The number of monthly outpatient claims in clinics was used as a proxy indicator for monthly outpatient attendance, and specialities were categorised into internal medicine, paediatrics, surgery, orthopaedics, dermatology, obstetrics and gynaecology, ophthalmology, otolaryngology, and dentistry. The annually summarised age-standardised proportions and the percentage of change were calculated. Joinpoint regression analysis was used to evaluate long-term secular trends. The data set included 4,975,464,894 outpatient claims. A long-term statistically significant decrease was observed in outpatient attendance in internal medicine, paediatrics, surgery, ophthalmology, and otolaryngology during the pandemic. From March 2020 to December 2021, which includes the COVID-19 pandemic period, outpatient attendance in paediatrics, surgery, and otolaryngology decreased in all months compared with that of the corresponding months in 2019. For some specialities, the impact of the pandemic was substantial, even in the context of long-term trends. Speciality-specific preparedness is required to ensure essential outpatient services in future public health emergencies.


Acute cardiovascular responses to interval exercise: A systematic review and meta-analysis.
Interval exercise training is increasingly recommended to improve health and fitness; however, it is not known if cardiovascular risk is different from continuous exercise protocols. This systematic review with meta-analyses assessed the effect of a single bout of interval exercise on cardiovascular responses that indicate risk of cardiac fibrillation and infarction compared to continuous exercise. Electronic databases Medline, CINAHL, Embase, Scopus and Cochrane were searched. Key inclusion criteria were: (1) intervals of the same intensity and duration followed by a recovery period and (2) reporting at least one of blood pressure, heart rate variability, arterial stiffness or function. Cochrane Risk of Bias tool and GRADE approach were used. Meta-analyses found that systolic blood pressure responses to interval exercise did not differ from responses to continuous exercise immediately (MD 8 mmHg [95% CI -32, 47], p = 0.71) or at 60 min following exercise (MD 0 mmHg [95% CI -2, 1], p = 0.79). However, reductions in diastolic blood pressure and flow-mediated dilation with interval exercise were observed 10-15 min post-exercise. The available evidence indicates that interval exercise does not convey higher cardiovascular risk than continuous exercise. Further investigation is required to establish the safety of interval exercise for clinical populations.


Morphology of synapses formed by cholecystokinin-immunoreactive axon terminals in regio superior of rat hippocampus.
Immunocytochemical and electron microscopic methods were used to examine neurons in regio superior of rat hippocampus displaying cholecystokinin octapeptide-like immunoreactivity. Cholecystokinin-immunoreactive synaptic terminals and somata are found in all layers of regio superior but are most numerous in stratum pyramidale. The vast majority of terminals form symmetric synaptic contacts onto the somata and proximal dendrites of hippocampal pyramidal cells and onto smaller dendrites which may also arise from pyramidal cells. A very small number of cholecystokinin-immunoreactive terminals form synapses that appear asymmetric and contact dendritic shafts or spines. The somata of some pyramidal cells receive symmetric synapses from cholecystokinin-immunoreactive terminals that are joined by cytoplasmic bridges to form parts of pericellular baskets. These and adjacent pyramidal cell somata are also contacted by terminals that are not immunoreactive for cholecystokinin. No cholecystokinin-positive terminals contacted the initial segments of pyramidal cell axons. Cholecystokinin-immunoreactive cells are found in all layers of regio superior. Their somata receive a few symmetric synapses, most of which are formed by terminals not immunoreactive for cholecystokinin. Their dendrites receive a greater number of both symmetric and asymmetric contacts, some of which are immunoreactive for cholecystokinin. We conclude the following: The localization of cholecystokinin immunoreactivity in synaptic terminals contacting the somata and dendrites of hippocampal pyramidal cells is consistent with the suggestion that cholecystokinin acts as a neurotransmitter at these sites and at sites in other parts of the cerebral cortex. Results from the present and previous studies suggest that cholecystokinin-like immunoreactivity may co-exist with gamma-aminobutyrate in some non-pyramidal neurons of regio superior. Cholecystokinin-immunoreactive terminals arise mainly from non-pyramidal cells intrinsic to the hippocampus, one class of which appears to be a type of basket cell.


Oxygen desaturation during sleep in hepatopulmonary syndrome.
Sleep alters respiratory mechanics and gas exchange, which can adversely affect arterial oxygenation. Whether sleep affects oxygenation in hepatopulmonary syndrome is unknown. The aim of this study was to assess oxygen desaturation during sleep in hepatopulmonary syndrome. Twenty adults with cirrhosis including 10 controls and 10 patients with hepatopulmonary syndrome underwent home pulse-oximetry during sleep. Subjects at high risk for obstructive sleep apnea were excluded through the Berlin questionnaire. Subjects who spent more than 10% of total sleep time with arterial oxygen saturation < 90% were classified as sleep-time oxygen desaturators. Sleep-time desaturation was correlated with clinical variables. The results showed that 7 of 10 hepatopulmonary syndrome subjects and none of the 10 controls had sleep-time oxygen desaturation. The median percentage of total sleep time with arterial oxygen saturation < 90% was significantly higher in hepatopulmonary syndrome subjects than in controls (medians 25% versus 0%, P = 0.005). Hepatopulmonary syndrome subjects had significantly lower wake-time arterial oxygen saturation level (median, 97% versus 95%; P = 0.003) and mean sleep-time arterial oxygen saturation level (median, 96% versus 91%; P = 0.0008) than did the controls. Sleep-time desaturation directly correlated with alveolar-arterial oxygen gradient (P = 0.0007) and inversely correlated with wake-time arterial oxygen tension (P = 0.0007) and oxygen saturation (P < 0.0001). Oxygen desaturation occurred during sleep in 70% of hepatopulmonary syndrome subjects, the degree of which correlated with the severity of hepatopulmonary syndrome. Marked hypoxemia during sleep may occur in hepatopulmonary syndrome patients who, according to wake-time oxygen values, have only mild to moderate hypoxemia.


DAF-16/Forkhead box O transcription factor: many paths to a single Fork(head) in the road.
The Caenorhabditis elegans Forkhead box O transcription factor (FOXO) homolog DAF-16 functions as a central mediator of multiple biological processes such as longevity, development, fat storage, stress resistance, and reproduction. In C. elegans, similar to other systems, DAF-16 functions as the downstream target of a conserved, well-characterized insulin/insulin-like growth factor (IGF)-1 signaling pathway. This cascade is comprised of an insulin/IGF-1 receptor, which signals through a conserved PI 3-kinase/AKT pathway that ultimately downregulates DAF-16/FOXO activity. Importantly, studies have shown that multiple pathways intersect with the insulin/IGF-1 signaling pathway and impinge on DAF-16 for their regulation. Therefore, in C. elegans, the single FOXO family member, DAF-16, integrates signals from several pathways and then regulates its many downstream target genes.


Oral Health Status and Oral Health-Related Quality of Life in Italian Deinstitutionalized Psychiatric Patients.
The aim of this study is to investigate the oral health status and Oral Health-Related Quality of Life (OHRQoL, measured with OHIP- 14) in psychiatric patients assisted by the unique Italian mental health care system, in accordance to regulatory Law 180/78. Demographic and medical variables were retrieved from institutional medical records. General health and oral health variables, oral health-related behavior and last dental contact were recorded. Clinical evaluation was performed on each patient. For oral health data collection, a standardized medical form was used. The study involved an overall number of 67 patients. Primary diagnosis of mental illness was at mean age of 29 years. The average number of teeth per patient was 25.45 ±6,55. The overall mean value of caries experience was 9.1 decayed, missing and/or filled teeth (DMFT Index). Among affected patients (60%, n=33) the mean value of DMFT for all age groups was 11.3 (range 2-27). The present study highlighted a direct linear relationship between caries experience and OHRQoL. As the caries level increased, pain, functional and psychological discomfort scores increased. The overall caries experience value of 9.1 DMFT was lower than that reported in existing literature, which is usually related to traditionally institutionalized psychiatric patients, and most important of all, data on access to dental care is fairly good. These results, although derived from a pilot study on a limited sample, suggest that, where a psychosocial rehabilitative program is set out for psychiatric patients, as in the case of the Italian experience, the program can also determine an improvement in oral health status. It is important that programs for oral health promotion are developed in collaboration with mental health services and social measures are patient-centered as an integral part of the individual's rehabilitation program.


Response analysis of TLD-300 dosimeters in heavy-particle beams.
In vivo dosimetry is recommended as part of the quality control procedure for treatment verification in radiation therapy. Using thermoluminescence, such controls are planned in the p(65) + Be neutron and 85 MeV proton beams produced at the cyclotron at Louvain-La-Neuve and dedicated to therapy applications. A preliminary study of the peak 3 (150 degrees C) and peak 5 (250 degrees C) response of CaF2:Tm (TLD-300) to neutron and proton beams aimed to analyse the effect of different radiation qualities on the dosimetric behaviour of the detector irradiated in phantom. To broaden the range of investigation, the study was extended to an experimental 12C heavy ion beam (95 MeV/nucleon). The peak 3 and 5 sensitivities in the neutron beam, compared to 60Co, varied little with depth. A major change of peak 5 sensitivity was observed for samples positioned under five leaves of the multi-leaf collimator. While peak 3 sensitivity was constant with depth in the unmodulated proton beam, peak 5 sensitivity increased by 15%. Near the Bragg peak, peak 3 showed the highest decrease of sensitivity. In the modulated proton beam, the sensitivity values were not significantly smaller than those measured in the unmodulated beam far from the Bragg peak region. The ratio of the heights of peak 3 and peak 5 decreased by 70% from the 60Co reference radiation to the 12C heavy-ion beam. This parameter was strongly correlated with the change of radiation quality.


Lentiginosis profusa. III: Aesthetic and sanguineous aspects.
Lentiginosis profusa syndrome and progressive cardiomyopathic lentiginosis are preferable terms to "leopard syndrome". Considerable cosmetic improvement followed facial dermabrasion and light electrodesiccation of lentigines on the exposed surfaces. Hematologic evaluation did not reveal hematopoietic defect in the patient studied.


[Lateral cysts and fistulae: two different cervical lesions (author's transl)].
Branchial cysts and fistulae in the lateral part of the neck are believed to arise from the same remnant of the branchial arches. The two lesions, however, are distinct and separate. Clinical findings of the fistulae could be related to the branchial apparatus. In contradistinction the age of manifestation, the localisation, the history, th symptoms and the histological features of the lateral cervical cysts disagree in regard to the branchial origin. That is why various congenital hypotheses are discussed and rejected, partly because the existence of stratified squamous cells in cervical lymph nodes present recent suggestions. The lateral lesions and dental cysts, especially radicular cysts, are compared. Both kinds of cystic structures are often associated with an initial infection.


Early release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation.
This article presents a treatment strategy for early release of interalveolar synechiae, aiming to facilitate early oral feeding and prevent temporomandibular joint ankylosis.The treatment results of 2 patients with van der Woude syndrome were retrospectively studied. Both patients underwent early surgical release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation. The 2 patients were treated at the ages of 6 and 14 days, respectively. The interincisival distances increased from 5 and 6 mm preoperatively to 11 and 10 mm immediately after surgery. This was increased further to 25 and 20 mm at long-term follow-up (6 and 24 months).In conclusion, synechiae between the upper and lower jaws can be safely treated at a very early age under general anesthesia with fiberscopic nasotracheal intubation. The purpose of early intervention in these cases is to facilitate oral feeding and prevent temporomandibular joint ankylosis.