Brief communication: the use of alternative dental measurements on deciduous teeth.
The present study investigates the utility of cervical measurements in deciduous teeth and how they correlate with traditional measurements of the crown. First, this study establishes definitions by which these measurements could reliably be taken. Next, deciduous cervical and traditional crown diameters were taken on three distinct skeletal samples: a Neolithic assemblage from Central Anatolia (Çatalhöyük, n = 85), a precontact sample from Northern California (CA-ALA-329, n = 34), and a group of intrusive burials interred at Çatalhöyük that date between AD 60 and 1650 (n = 38). Across the dentition there are positive correlations between crown and cervical measurements, which tend to be higher in anterior teeth than in posterior teeth. Both measurements show low correlations with age; however, cervical measurements show fewer negative correlations with age. An intraobserver error study found low levels of error for both types of measurements. On a subset of the Çatalhöyük sample (n = 9), a principal components and biological distance analysis were conducted comparing the two types of measurements. Also, all three samples were subject to a canonical discriminant function analysis and the results from cervical and crown measurements were compared. All analyses produced slightly different results for each type of data suggesting that crown and cervical measurements capture different aspects of tooth shape. While cervical and crown measurements provide different statistical results, cervical measurements can provide information relevant to anthropological studies and may allow for larger datasets to be used by allowing the inclusion of teeth with modified crowns.


Transcriptomic analyses of sexual dimorphism of the zebrafish liver and the effect of sex hormones.
The liver is one of the most sex-dimorphic organs in both oviparous and viviparous animals. In order to understand the molecular basis of the difference between male and female livers, high-throughput RNA-SAGE (serial analysis of gene expression) sequencing was performed for zebrafish livers of both sexes and their transcriptomes were compared. Both sexes had abundantly expressed genes involved in translation, coagulation and lipid metabolism, consistent with the general function of the liver. For sex-biased transcripts, from in addition to the high enrichment of vitellogenin transcripts in spawning female livers, which constituted nearly 80% of total mRNA, it is apparent that the female-biased genes were mostly involved in ribosome/translation, estrogen pathway, lipid transport, etc, while the male-biased genes were enriched for oxidation reduction, carbohydrate metabolism, coagulation, protein transport and localization, etc. Sexual dimorphism on xenobiotic metabolism and anti-oxidation was also noted and it is likely that retinol x receptor (RXR) and liver x receptor (LXR) play central roles in regulating the sexual differences of lipid and cholesterol metabolisms. Consistent with high ribosomal/translational activities in the female liver, female-biased genes were significantly regulated by two important transcription factors, Myc and Mycn. In contrast, Male livers showed activation of transcription factors Ppargc1b, Hnf4a, and Stat4, which regulate lipid and glucose metabolisms and various cellular activities. The transcriptomic responses to sex hormones, 17β-estradiol (E2) or 11-keto testosterone (KT11), were also investigated in both male and female livers and we found that female livers were relatively insensitive to sex hormone disturbance, while the male livers were readily affected. E2 feminized male liver by up-regulating female-biased transcripts and down-regulating male-biased transcripts. The information obtained in this study provides comprehensive insights into the sexual dimorphism of zebrafish liver transcriptome and will facilitate further development of the zebrafish as a human liver disease model.


Biicosahedral metallaboranes: aromaticity in metal derivatives of three-dimensional analogues of naphthalene.
Consideration of the well-known very stable icosahedral B12H12(2-) as a three-dimensional analogue of benzene was extended by the recent synthesis of the biicosahedral B21H18(-) as a three-dimensional analogue of naphthalene. The preferred structures of metallaboranes derived from B21H18(-) have now been examined by density functional theory. The isoelectronic species CpNiB20H17 and CpCoCB19H17 have the 46 skeletal electrons expected by the Wade-Mingos and Jemmis rules for a structure consisting of two face-sharing fused icosahedra. The CpM units in these structures energetically prefer to be located at a meta vertex of the biicosahedron. The analogous ferraboranes CpFeB20H17 with only 44 skeletal electrons also have related biicosahedral structures. The presence of an agostic hydrogen atom bridging an Fe-B edge compensates for the two-electron deficiency in CpFeB20H17 relative to CpNiB20H17. The nucleus-independent chemical shift (NICS) values of these systems indicate them to be strongly aromatic.


De novo cutaneous neoplasm: biologic behavior in an immunosuppressed patient.
The treatment of cutaneous squamous cell carcinoma in patients who are immunosuppressed should include early and adequate excision and extremely close follow-up. If the patients' tumor is aggressive, treatment should be aggressive even with discontinuation of the immunosuppression, which may lead to the death of the allograft. Sacrifice of the allograft in such an instance will lead to survival of the patient. In our patient, the continuous survival of the allograft with good renal function, in spite of the discontinuation of the immunosuppressive agents, can be interpreted only on the basis of graft adaptation.


JAK1/2 and Pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease.
The myeloproliferative neoplasm myelofibrosis is characterized by frequent deregulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, and JAK inhibitors were shown to reduce splenomegaly and ameliorate disease-related symptoms. However, the mutant clone and bone marrow fibrosis persist in the majority of patients. Using preclinical models, we explored whether JAK and pan-deacetylase inhibitor combination yielded additional benefits. The combination of the JAK1/2 inhibitor ruxolitinib and panobinostat was investigated using two different mouse models of JAK2(V617F)-driven disease. A Ba/F3 JAK2(V617F) cell-driven leukemic disease model was used to identify tolerated and efficacious doses. The drugs were then evaluated alone and in combination in a mouse model of myeloproliferative neoplasm-like disease based on transplantation of bone marrow transduced with a retrovirus expressing JAK2(V617F). Exposures were determined in blood and tissues, and phosphorylated STAT5 and acetylated histone H3 pharmacodynamic readouts were assessed in spleen and bone marrow. Histologic analysis was conducted on spleen and bone marrow, including staining of reticulin fibers in the latter organ. The combination of ruxolitinib and panobinostat was found to have a more profound effect on splenomegaly, as well as on bone marrow and spleen histology, compared with either agent alone, and the analysis of pharmacodynamic readouts showed that ruxolitinib and panobinostat have nonoverlapping and complementary effects. Combining JAK1/2 and pan-deacetylase inhibitors was fairly well tolerated and resulted in improved efficacy in mouse models of JAK2(V617F)-driven disease compared with the single agents. Thus, the combination of ruxolitinib and panobinostat may represent a promising novel therapeutic modality for myeloproliferative neoplasms.


Expression of genes coding for antioxidant enzymes and heat shock proteins is altered in primary cultures of rat hepatocytes.
The expression of genes for heat shock proteins in the HSP70 family and genes for antioxidant enzymes was studied in rat hepatocytes cultured in either L-15 or Williams E media on a collagen matrix for up to 48 hours. The mRNA transcripts for the heat shock proteins hsp70, hsc70, and grp78 were induced dramatically when hepatocytes were cultured in L-15, and to a lesser extent when cultured in Williams E. The increase in hsp70 and hsc70 mRNA levels in the cultured hepatocytes was correlated with an increase in the nuclear transcription of these two genes and the binding activity of the heat shock transcription factor to the heat shock element. Culturing rat hepatocytes in either L-15 or Williams E resulted in a decrease in the levels of the mRNA transcripts for catalase and glutathione peroxidase and the activities of these two enzymes. However, the expression of Cu/Zn-superoxide dismutase, i.e., the level of the mRNA transcript or the enzymatic activity, did not change appreciably when hepatocytes were cultured for up to 48 hours. The decline in catalase and glutathione peroxidase expression in the cultured hepatocytes was correlated with a decrease in the GSH/GSSG ratio and an increase in lipid peroxidation. These data show that the expression of several genes involved in cellular protection change when hepatocytes are placed in primary cultures. Therefore, one must be careful in extrapolating from primary cultures to the liver in vivo, especially when studying processes that might be affected by heat shock proteins or antioxidant enzymes.


Social and cultural aspects of infertility in Mozambique.
Findings of an anthropological study of socio-cultural aspects of infertility among members of the matrilineal ethnic group Macua in the north of Mozambique are presented. Infertile women apply various strategies to have a child. Traditional healers are visited much more often than the modern hospital, and the explanations the infertile women themselves give for their infertility more often originated from the traditional healers than from the hospital staff. Almost all of the interviewed women commit adultery in the hope to conceive. Some of them apply fostering as a partial solution for childlessness. The Macua infertile women experience various consequences due to their infertility, of which exclusion from certain social activities and traditional ceremonies is perceived as a very problematic one. The matrilineal kinship system means that the husband and his family do not mistreat and repudiate her. Infertility must be considered as a serious reproductive health problem in Mozambique. For the long term preventive measures may be more influential than curative one. The findings of this study can be used to elaborate culturally sensitive health education programmes.


Multiply-charged ions and interstellar chemistry.
Gaseous molecules and ions, and even dust grains, can accumulate charge in the interstellar medium (ISM) by harvesting the energy of UV photons, cosmic rays, helium ions and metastable atoms. This Perspective views the various modes of gas-phase formation of multiply-charged cations and the possible impact of their reactions on the chemical and ionization structure of the ISM, in the light of what is still very limited knowledge. Emphasis is given to gas-phase reactions of multiply-charged cations with atoms, molecules and electrons that lead to charge reduction, charge separation and chemical bond formation and these are examined for multiply-charged atoms, small molecules, hydrocarbons, polycyclic aromatic hydrocarbons and fullerenes, primarily as dications but also as a function of charge state. The increased electrostatic interaction due to multiple charge is seen to promote bonding to individual charge sites on large molecules (e.g. fullerenes) and allow ensuing "surface" chemistry under the influence of Coulomb repulsion. The unique ability of multiply charged cations to undergo charge separation reactions, either unimolecular or bimolecular, can feature in the production in the ISM of internally cold, but translationally hot, cations of lower charge state or hot atoms that may provide the driving force for subsequent chemical reactions in what is otherwise an ultracold environment. Available chemical kinetic models that account for the role of multiply-charged ions in the ISM are few and of limited scope and the observation of these ions in the ISM has remained elusive.


The effects of varied rest periods between sets to failure using the bench press in recreationally trained men.
The purpose of this study was to determine the rate of recovery for recreational weight trainers between 2 sets of bench press to volitional exhaustion. Twenty-eight men performed 2 sets of the bench press at 75% of their previously determined 1 repetition maximum (1RM) to volitional exhaustion. Rest periods of 1, 3, or 5 minutes between sets were utilized on the 3 separate testing days. There was a significant decrease in the number of repetitions performed between the second sets at all rest periods. There were no significant differences in work performed (repetitions x weight) during the second set with the 3- and 5-minute rest periods, but the total work with a 1-minute rest period (1,389.1 +/- 529.9) was significantly less than both the 3- (1,494.9 +/- 451.0) and 5-minute (1,711.4 +/- 478.0) rest period. The data indicated that subjects were unable to fully recover between the first and second sets of maximal resistance exercise, regardless of the rest period. However, subjects were able to maintain a performance level of 8-12 repetitions and sustain the total work performed per set with as little as 3 minutes rest between sets.


Blockade of delta opioid receptors in the ventrolateral periaqueductal gray region inhibits the fall in arterial pressure evoked by hemorrhage.
Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. The central mechanism that initially triggers the fall in arterial pressure evoked by hemorrhage is not well understood, although opioid neurons are thought to play a role. This study tested the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the ventrolateral periaqueductal gray (vlPAG), a region importantly involved in opioid analgesia. Depressor sites were first identified by microinjecting DL-homocysteic acid (20 nmol/0.1 microl) or beta-endorphin (0.5 nmol/0.1 microl) into the vlPAG of halothane-anesthetized rats. Consistent with earlier reports, DL-homocysteic acid injection into the caudal vlPAG lowered arterial pressure and heart rate; beta-endorphin evoked a comparable depressor response, but did not affect heart rate. Naloxone or selective opioid receptor antagonists were subsequently injected into the vlPAG 5 min before hemorrhage (1.9 or 2.5 ml/100 g of body weight over 20 min) was initiated using the same stereotaxic coordinates. Naloxone injection into the caudal vlPAG completely prevented the fall in arterial pressure evoked by hemorrhage. The response was dose-dependent and evident with both fixed volume and fixed pressure hemorrhage. The delta opioid receptor antagonist naltrindole inhibited hemorrhagic hypotension significantly in both conscious and anesthetized rats but mu and kappa receptor antagonists were ineffective. beta-Endorphin(1--27), an endogenous opioid receptor antagonist, was also significantly inhibitory. Naltrindole was ineffective when injected into the dorsolateral periaqueductal gray and did not influence cardiovascular function in nonhemorrhaged animals. These data support the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the vlPAG.


Short- and Long-Term Implications of Human Milk Microbiota on Maternal and Child Health.
Human milk (HM) is considered the most complete food for infants as its nutritional composition is specifically designed to meet infant nutritional requirements during early life. HM also provides numerous biologically active components, such as polyunsaturated fatty acids, milk fat globules, IgA, gangliosides or polyamines, among others; in addition, HM has a "bifidogenic effect", a prebiotic effect, as a result of the low concentration of proteins and phosphates, as well as the presence of lactoferrin, lactose, nucleotides and oligosaccharides. Recently, has been a growing interest in HM as a potential source of probiotics and commensal bacteria to the infant gut, which might, in turn, influence both the gut colonization and maturation of infant immune system. Our review aims to address practical approaches to the detection of microbial communities in human breast milk samples, delving into their origin, composition and functions. Furthermore, we will summarize the current knowledge of how HM microbiota dysbiosis acts as a short- and long-term predictor of maternal and infant health. Finally, we also provide a critical view of the role of breast milk-related bacteria as a novel probiotic strategy in the prevention and treatment of maternal and offspring diseases.


Fetus in fetu in a harbor seal (Phoca vitulina richardi): histopathologic, genetic, and toxicologic analysis.
A young harbor seal (Phoca vitulina richardi), stranded on the coast of California, was found to have a 20-cm-diameter cranial cervical mass. Surgical excision revealed the subcutaneous mass to be covered in haired skin with multiple glabrous areas and structures resembling a jaw with tooth buds, eyelids, and a tail. The mass deformed the host pup's skull. Histologic examination revealed a complete vertebra in the tail, teeth in the jaw, and areas resembling tongue and larynx. Class 1 MHC sequences amplified by polymerase chain reaction from the mass and the host twin were identical. The mass was diagnosed as a fetus in fetu, a rare congenital anomaly in which 1 conjoined twin is completely enclosed in the body of the other twin. The host pup died, and no additional defects were found; however, blubber levels of persistent organic pollutants were high. The cause of the congenital anomaly in this pup is uncertain.


Mapping of neural networks onto the memory-processor integrated architecture.
In this paper, an effective memory-processor integrated architecture, called memory-based processor array for artificial neural networks (MPAA), is proposed. The MPAA can be easily integrated into any host system via memory interface. Specifically, the MPA system provides an efficient mechanism for its local memory accesses allowed by row and column bases, using hybrid row and column decoding, which is suitable for computation models of ANNs such as the accessing and alignment patterns given for matrix-by-vector operations. Mapping algorithms to implement the multilayer perceptron with backpropagation learning on the MPAA system are also provided. The proposed algorithms support both neuron and layer level parallelisms which allow the MPAA system to operate the learning phase as well as the recall phase in the pipelined fashion. Performance evaluation is provided by detailed comparison in terms of two metrics such as the cost and number of computation steps. The results show that the performance of the proposed architecture and algorithms is superior to those of the previous approaches, such as one-dimensional single-instruction multiple data (SIMD) arrays, two-dimensional SIMD arrays, systolic ring structures, and hypercube machines.


Influence of oestradiol on protein expression and methionine utilization during morphogenesis of Paracoccidioides brasiliensis.
The temporal sequence of cytosolic protein expression during phase transition of Paracoccidioides brasiliensis was examined. Electrophoretic analysis of cytosol proteins by one-dimensional SDS-PAGE revealed numerous differences between the mycelial and yeast forms as well as alterations induced by 17 beta-oestradiol. Using either protein staining or fluorography of [35S]methionine-labelled proteins 30 phase-specific bands were detected, 12 mycelial-associated bands (range 30 to 140 kDa) and 18 yeast-associated bands (range 22 to 127 kDa). In cells undergoing mycelial to yeast transition after a shift from 25 degrees C to 37 degrees C, the protein patterns showed a temporal progression toward the yeast profile with the accumulation of yeast bands prior to observable morphogenesis. Five novel protein bands (range 23 to 50 kDa) were detected by silver staining during transition. Treatment of temperature-shifted mycelial cultures with 2.6 x 10(-7) M-oestradiol altered observed profiles; 4 of 12 mycelial-associated bands were maintained whereas the appearance of the 5 novel transition bands and 9 of 18 yeast-associated bands was blocked or delayed. Analysis of [35S]methionine-labelled proteins revealed that oestradiol induced label uptake by mycelial cells, blocked the synthesis of a 92 kDa yeast-specific band 72 h into transition, and diminished label incorporation 120 h into transition. In conjunction with these steroid-induced alterations of protein expression, little or no morphological transformation occurred. These results support our hypothesis that, analogous to mammalian steroid receptor action, the functional responses of P. brasiliensis to oestradiol are related to regulation of protein expression, presumably mediated via a specific binding protein-ligand complex.


Surface characterization and platelet adhesion studies of self-assembled monolayer with phosphonate ester and phosphonic acid functionalities.
Because of its well-defined surface configuration and creative chemical structure, an alkanethiol self-assembled monolayer (SAM) on gold is a model surface for a blood compatibility investigation. In this study two laboratory-synthesized long-chain alkanethiols, HS(CH(2))(10)PO(3)-(C(2)H(5))(2) and HS(CH(2))(10)PO(3)H(2), were employed for the direct preparation of SAMs with nonionic and ionic functional groups. Various instrumental analyses confirmed the high purity of the phosphonate ester and phosphonic acid terminated alkanethiols. The surface characterization results showed the -PO(3)H(2) terminated SAM was more hydrophilic than the -PO(3)(C(2)H(5))(2) one. Higher hysteresis values for the -PO(3)(C(2)H(5))(2) and -PO(3)H(2) terminated SAMs were noted, which were possibly due to the steric hindrance of the bulky terminal groups. In addition, the O(2) plasma + EtOH-rinse pretreated Au sample was hydrophilic because of the residual gold oxide on the surface. This finding was supported by electron spectroscopy for chemical analysis (ESCA) as well. The ESCA analysis also indicated bulky and polar terminal groups [-PO(3)(C(2)H(5))(2) and -PO(3)H(2)] were situated in the outermost layer of its monolayer. The platelet reactivity on the SAM with the nonionic group -PO(3)(C(2)H(5))(2) was less than those of the ionic terminated SAMs -COOH and -PO(3)H(2). The O(2) plasma + EtOH-rinse pretreated gold substrate exhibited the least platelet-activating surface among the different pretreated Au substrates studied.


Strain-Induced Isomerization in One-Dimensional Metal-Organic Chains.
The ability to use mechanical strain to steer chemical reactions creates completely new opportunities for solution- and solid-phase synthesis of functional molecules and materials. However, this strategy is not readily applied in the bottom-up on-surface synthesis of well-defined nanostructures. We report an internal strain-induced skeletal rearrangement of one-dimensional (1D) metal-organic chains (MOCs) via a concurrent atom shift and bond cleavage on Cu(111) at room temperature. The process involves Cu-catalyzed debromination of organic monomers to generate 1,5-dimethylnaphthalene diradicals that coordinate to Cu adatoms, forming MOCs with both homochiral and heterochiral naphthalene backbone arrangements. Bond-resolved non-contact atomic force microscopy imaging combined with density functional theory calculations showed that the relief of substrate-induced internal strain drives the skeletal rearrangement of MOCs via 1,3-H shifts and shift of Cu adatoms that enable migration of the monomer backbone toward an energetically favorable registry with the Cu(111) substrate. Our findings on this strain-induced structural rearrangement in 1D systems will enrich the toolbox for on-surface synthesis of novel functional materials and quantum nanostructures.


Interferon-alpha mediates suppression of C-reactive protein: explanation for muted C-reactive protein response in lupus flares?
C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFNalpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. The interference of all 12 IFNalpha subtypes with CRP promoter activity induced by IL-6 and IL-1beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. CRP promoter activity was inhibited by all single IFNalpha subtypes, as well as by 2 different mixtures of biologically relevant IFNalpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFNalpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFNalpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFNalpha. The current study demonstrates that IFNalpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFNalpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFNalpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.


Semiclassical optimization of entrainment stability and phase coherence in weakly forced quantum limit-cycle oscillators.
Optimal entrainment of a quantum nonlinear oscillator to a periodically modulated weak harmonic drive is studied in the semiclassical regime. By using the semiclassical phase-reduction theory recently developed for quantum nonlinear oscillators [Y. Kato, N. Yamamoto, and H. Nakao, Phys. Rev. Res. 1, 033012 (2019)10.1103/PhysRevResearch.1.033012], two types of optimization problems, one for the stability and the other for the phase coherence of the entrained state, are considered. The optimal waveforms of the periodic amplitude modulation can be derived by applying the classical optimization methods to the semiclassical phase equation that approximately describes the quantum limit-cycle dynamics. Using a quantum van der Pol oscillator with squeezing and Kerr effects as an example, the performance of optimization is numerically analyzed. It is shown that the optimized waveform for the entrainment stability yields faster entrainment to the driving signal than the case with a simple sinusoidal waveform, while that for the phase coherence yields little improvement from the sinusoidal case. These results are explained from the properties of the phase sensitivity function.


Aerobic radiosensitization by SR 4233 in rodent and human cells: mechanistic and therapeutic implications.
Mammalian cells surviving exposure to the bioreductive, cytotoxic agent SR 4233 under hypoxic conditions are sensitized to X-irradiation under aerobic conditions (and in the absence of drug). Fits of both the single-hit, multi-target and linear-quadratic expressions to survival data, as well as direct measurement of surviving fractions after a dose of 2 Gy, indicate that the aerobic radiosensitization produced by SR 4233 can increase both the initial and final 'slopes' of the X-ray survival curve. The amount of radiosensitization produced, and whether the modification is principally in the slope or shoulder region of the survival curve, varies from cell line to cell line. Rodent cells are radiosensitized equally whether the drug treatment is given immediately before or after, the irradiation, but human cells are only sensitized for SR 4233 exposure administered before irradiation. Using rodent CHO cells, time-course experiments for SR 4233 and X-rays given in sequence, in which an interval of up to 2 h was interposed between the treatments, reveal different kinetics for the loss of radiosensitization depending on whether the hypoxic drug exposure was given before or after the aerobic irradiation. When SR 4233 treatment is given pre-irradiation, the radiosensitization effect persists for at least 2 h, but it does not when drug is given after irradiation. Taken together, the finding of a difference between rodent and human cells with respect to post-irradiation sensitization by SR 4233, and the differing time-course kinetics for this effect as a function of how the drug and radiation are sequenced, suggest that while SR 4233 behaves in a radiomimetic manner in most respects, there may be subtle differences in the nature of the lesions produced by the drug, the important cellular targets for this damage, and/or the cell's management of the damage.


Polypeptide-GalNAc-T6 expression predicts better overall survival in patients with colon cancer.
Colorectal carcinoma (CRC) is the second leading cause of cancer mortality worldwide. O-glycosylated mucins at the cell surface of colonic mucosa exhibit alterations in cancer and are involved in fundamental biological processes, including invasion and metastasis. Certain members of the GalNAc-transferase family may be responsible for these changes and are being investigated as novel biomarkers of cancer. In the present study the prognostic significance of GalNAc-T6 was investigated in patients with CRC patients. GalNAc-T6 expression was observed in all three colon cancer cell lines analyzed by reverse transcription-polymerase chain reaction, immunofluorescence and flow cytometry. A cohort of 81 colon cancer specimens was analyzed by immunohistochemical staining using MAb T6.3. It was demonstrated that GalNAc-T6 was expressed in 35/81 (43%) cases of colon cancer but not in the normal colonic mucosa. No association was observed with the clinical-pathologic parameters. However, patients expressing GalNAc-T6 had a significantly increased overall survival (median, 58 months; P<0.001) compared with GalNAc-T6 negative patients, especially those with advanced disease. These results suggest that GalNAc-T6 expression predicts an improved outcome in patients with CRC. The molecular mechanism underlying the less aggressive behavior of colon cancer cells expressing GalNAc-T6 remains to be elucidated.


More accurate neuronavigation data provided by biomechanical modeling instead of rigid registration.
It is possible to improve neuronavigation during image-guided surgery by warping the high-quality preoperative brain images so that they correspond with the current intraoperative configuration of the brain. In this paper, the accuracy of registration results obtained using comprehensive biomechanical models is compared with the accuracy of rigid registration, the technology currently available to patients. This comparison allows investigation into whether biomechanical modeling provides good-quality image data for neuronavigation for a larger proportion of patients than rigid registration. Preoperative images for 33 neurosurgery cases were warped onto their respective intraoperative configurations using both the biomechanics-based method and rigid registration. The Hausdorff distance-based evaluation process, which measures the difference between images, was used to quantify the performance of both registration methods. A statistical test for difference in proportions was conducted to evaluate the null hypothesis that the proportion of patients for whom improved neuronavigation can be achieved is the same for rigid and biomechanics-based registration. The null hypothesis was confidently rejected (p < 10(-4)). Even the modified hypothesis that fewer than 25% of patients would benefit from the use of biomechanics-based registration was rejected at a significance level of 5% (p = 0.02). The biomechanics-based method proved particularly effective in cases demonstrating large craniotomy-induced brain deformations. The outcome of this analysis suggests that nonlinear biomechanics-based methods are beneficial to a large proportion of patients and can be considered for use in the operating theater as a possible means of improving neuronavigation and surgical outcomes.


Tramadol exposures reported to statewide poison control system.
Tramadol is a unique analgesic that has been associated with seizures on overdose. To determine the toxic effects associated with tramadol exposure. A retrospective chart review of tramadol exposures reported to a multisite, state-wide poison control system over a 2.5-year period was performed. A total of 602 cases were retrieved; 190 had sufficient data for study evaluation. Cases with coingestants or unknown outcomes were eliminated. Of the 190 remaining cases, 55% were females. Acute ingestions represented 90.0%, chronic ingestions 7.9%, and acute on chronic 2.1% of the overdoses. Ages of the patients ranged from 9 months to 80 years. Suicide attempts represented the largest group of exposures. Main symptoms included central nervous system (CNS) depression (27.4%), nausea and vomiting (21.1%), tachycardia (17.4%), and seizures (13.7%). Dosage ranged from a taste amount to 5000 mg. The smallest amount of tramadol associated with seizure was 200 mg, and 84.6% of seizures occurred within 6 hours of time of ingestion. Logistic regression analysis showed an association between seizures and tramadol use in males, chronic use, suicide attempts, intentional abuse or misuse, and tachycardia (HR >100 beats/min). No effect was seen in 36.3% of patients, minor effects in 43.7%, moderate effects in 19.5%, and major effects in 0.5%. Symptoms resolved within 24 hours in 96.7% of the 121 patients who had symptoms. Naloxone improved CNS depression in 7 of 8 patients in whom a response was documented. Tramadol overdoses frequently cause CNS depression, nausea/vomiting, tachycardia, and seizures. Symptoms generally resolve within 24 hours. Accidental ingestions in children were well tolerated, primarily causing sedation.


A multifunctional nanoplatform for imaging, radiotherapy, and the prediction of therapeutic response.
Gold nanoparticles have garnered interest as both radiosensitzers and computed tomography (CT) contrast agents. However, the extremely high concentrations of gold required to generate CT contrast is far beyond that needed for meaningful radiosensitization, which limits their use as combined therapeutic-diagnostic (theranostic) agents. To establish a theranostic nanoplatform with well-aligned radiotherapeutic and diagnostic properties for better integration into standard radiation therapy practice, a gold- and superparamagnetic iron oxide nanoparticle (SPION)-loaded micelle (GSM) is developed. Intravenous injection of GSMs into tumor-bearing mice led to selective tumoral accumulation, enabling magnetic resonance (MR) imaging of tumor margins. Subsequent irradiation leads to a 90-day survival of 71% in GSM-treated mice, compared with 25% for irradiation-only mice. Furthermore, measurements of the GSM-enhanced MR contrast are highly predictive of tumor response. Therefore, GSMs may not only guide and enhance the efficacy of radiation therapy, but may allow patients to be managed more effectively.


Tuberculosis Mastitis: Fever of Unknown Origin in a Kidney Transplant Recipient.
Tuberculous mastitis is a rare presentation of tuberculosis, which is a major health problem in kidney transplant recipients due to its high incidence and prevalence, and difficulty in diagnosis as well as high risk of morbidity and mortality. In daily practice, physicians may frequently be led to a misdiagnosis such as breast carcinoma or abscess. We believe it is crucial for clinicians to recognize this important presentation of the disease. Therefore, we present a case of tuberculous mastitis in a kidney transplant recipient who was admitted with fever of unknown origin and successfully treated using standard anti-tuberculosis therapy without any complications.


Cardiovascular health effects of internet-based encouragements to do daily workplace stair-walks: randomized controlled trial.
Although the hazardous health effects of a sedentary lifestyle are well known, many adults struggle with regular physical activity. Simple and efficient encouragements for increased physical activity are needed. To determine the effect on cardiovascular health of email-based encouragements to do daily stair-walks at work together with colleagues among adults in sedentary occupations. A single-blind randomized controlled trial was performed at a large administrative company in Copenhagen, Denmark. Participants were 160 office workers (125 women, 35 men; mean age 42 years, SD 10; sitting 89.5% of work time). At baseline, aerobic fitness was 37 mL/min/kg (SD 9), mean blood pressure was 118/79 mmHg (SD 14/9), and mean body mass index (BMI) was 23 kg/m(2) (SD 4). Participants were randomly assigned (2:1 ratio) to an email group receiving weekly email-based encouragements to walk the stairs for 10 minutes a day or to a control group receiving weekly reminders to continue their usual physical activities. The primary outcome was the change from baseline to 10-week follow-up in aerobic fitness determined from a maximal cycle test. The examiner was blinded to group allocation. Adherence to the email encouragements was fairly high with 82.7% of the participants performing at least 3 sessions of 10-minute stair-walks per week (mean 3.3, SD 1.3). Mean heart rate reached 167 beats/min (SD 10) during stair-walks. In the intention-to-treat analysis, aerobic fitness increased 1.45 mL/min/kg (95% CI 0.64-2.27) at 10-week follow-up in the email group compared with the control group. In participants with low aerobic fitness at baseline (n=56), aerobic fitness increased 1.89 mL/min/kg (95% CI 0.53-3.24), and systolic and diastolic blood pressure decreased 4.81 mmHg (95% CI 0.47-9.16) and 2.67 mmHg (95% CI 0.01-5.32), respectively, in the email group compared with the control group. Body weight decreased in the email group of those with low aerobic fitness compared with the control group, but this was not statistically significant. Simple and inexpensive email-based encouragements to do daily stair-walks together with colleagues at work improves cardiovascular health among adults in sedentary occupations. There exists an enormous potential to prevent the hazardous health effects of a sedentary lifestyle through the use of email-based encouragements to do short bouts of physical activity at the workplace. Clinicaltrials.gov NCT01293253; http://clinicaltrials.gov/ct2/show/NCT01293253 (Archived by WebCite at http://www.webcitation.org/6HWG2jw68).


Perturbation measurements of papillary muscle elasticity.
Small step-length perturbations (less than 0.5% Lmax) have been applied to rabbit papillary muscle for the purpose of measuring muscle stiffness at rest and during isometric twitch-force development. These stiffness-force measurements were fitted to four mechanical analogs to evaluate whether any of the models adequately predict the mechanical properties of papillary muscle. Stiffness-force relations have been measured at varied initial muscle lengths so that a broad range of applicability of an analog could be evaluated. This study shows that none of the four experimentally definable analogs predicts the stiffness-force responses of the muscle over a physiological range of initial muscle lengths. A two-segment nonhomogeneous analog has the same stiffness-force characteristics as a six-parameter lumped model but cannot be differentiated from the lumped model without a measurement of segmental variations. It is concluded that the passive elastic elements of papillary muscle cannot be controlled only by the manipulation of total muscle length so as to deduce cross-bridge mechanical properties from whole-muscle measurements.


Meta-analysis of cryoablation versus microwave ablation for small renal masses: is there a difference in outcome?
We aimed to compare local and metastatic recurrence of small renal masses primarily treated by cryoablation or microwave ablation. The MEDLINE, CINAHL, and PUBMED databases were searched to review the treatment of small renal masses with cryoablation or microwave ablation. Fifty-one studies met the inclusion criteria. Fifty-one studies representing 3950 kidney lesions were analyzed. No differences were detected in the mean patient age (P = 0.150) or duration of follow-up (P = 0.070). The mean tumor size was significantly larger in the microwave ablation group compared with the cryoablation group (P = 0.030). There was no difference between microwave ablation and cryoablation groups in terms of primary effectiveness (93.75% vs. 91.27%, respectively; P = 0.400), cancer-specific survival (98.27% vs. 96.8%, respectively; P = 0.470), local tumor progression (4.07% vs. 2.53%, respectively; P = 0.460), or progression to metastatic disease (0.8% vs. 0%, respectively; P = 0.120). Patient age was predictive of overall complications in the multivariate analysis (P = 0.020). Local tumor progression with cryoablation was predicted by the mean follow-up duration using univariate (P = 0.009) and multivariate regression (P = 0.003). Clear cell and angiomyolipoma were more frequent in the microwave ablation group (P < 0.0001 and P = 0.03328, respectively), and papillary, chromophobe, and oncocytoma were more frequent in the cryoablation group (P < 0.0001, P < 0.0001, and P = 0.0004, respectively). Open access was used more often in the microwave ablation group than in the cryoablation group (12.20% vs. 1.04%, respectively; P < 0.0001), and percutaneous access was used more frequently in the cryoablation group than in the microwave ablation group (88.64% vs. 37.20%, respectively; P = 0.0021). There is no difference in local or metastatic recurrence between cryoablation- and microwave ablation-treated small renal masses.


Spatial pattern characteristics of water footprint for maize production in Northeast China.
Water footprint (WF) methodology is essential for quantifying total water consumption of crop production and making efficient water management policies. This study calculated the green, blue, grey and total WFs of maize production in Northeast China from 1998 to 2012 and compared the values of the provinces. This study also analyzed the spatial variation and structure characteristics of the WFs at the prefecture level. The annual average WF of maize production was 1029 m(3) per ton, which was 51% green, 21% blue and 28% grey. The WF of maize production was highest in Liaoning Province, moderate in Heilongjiang Province and lowest in Jilin Province. The spatial differences of the WFs calculated for the 36 major maize production prefectures were significant in Northeast China. There was a moderate positive spatial autocorrelation among prefectures that had similar WFs. Local indicator of spatial autocorrelation index (LISA) analysis identified prefectures with higher WFs in the southeast region of Liaoning Province and the southwest region of Heilongjiang Province and prefectures with lower WFs in the middle of Jilin Province. Spatial differences in the WF of maize production were caused mainly by variations in climate conditions, soil quality, irrigation facilities and maize yield. The spatial distribution of WFs can help provide a scientific basis for optimizing maize production distribution and then formulate strategies to reduce the WF of maize production.


Mice with adenine phosphoribosyltransferase deficiency develop fatal 2,8-dihydroxyadenine lithiasis.
Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.


Issues in evaluating fish consumption rates for Native American tribes.
The environmental health goals of many Native American tribes are to restore natural resources and ensure that they are safe to harvest and consume in traditional subsistence quantities. Therefore, it is important to tribes to accurately estimate risks incurred through the consumption of subsistence foods. This article explores problems in conventional fish consumption survey methods used in widely cited tribal fish consumption reports. The problems arise because of the following: (1) widely cited reports do not clearly state what they intend to do with the data supporting these reports, (2) data collection methods are incongruent with community norms and protocols, (3) data analysis methods omit or obscure the highest consumer subset of the population, (4) lack of understanding or recognition of tribal health co-risk factors, and (5) restrictive policies that do not allow inclusion of tribal values within state or federal actions. In particular, the data collection and analysis methods in current tribal fish consumption surveys result in the misunderstanding that tribal members are satisfied with eating lower contemporary amounts of fish and shellfish, rather than the subsistence amounts that their cultural heritage and aboriginal rights indicate. A community-based interview method developed in collaboration with and used by the Swinomish Tribe is suggested as a way to gather more accurate information on contemporary consumption rates. For traditional subsistence rates, a multidisciplinary reconstruction method is recommended.


A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African-American infants.
There are natural mutations in the coding and noncoding regions of the human immunodeficiency virus type 1 (HIV-1) CC-chemokine coreceptor 5 (CCR5) and in the related CCR2 protein (the CCR2-64I mutation). Individuals homozygous for the CCR5-Delta32 allele, which prevents CCR5 expression, strongly resist HIV-1 infection. Several genetic polymorphisms have been identified within the CCR5 5' regulatory region, some of which influence the rate of disease progression in adult AIDS study cohorts. We genotyped 1,442 infants (1,235 uninfected and 207 HIV-1 infected) for five CCR5 and CCR2 polymorphisms: CCR5-59353-T/C, CCR5-59356-C/T CCR5-59402-A/G, CCR5-Delta32, and CCR2-64I. The clinical significance of each genotype was assessed by measuring whether it influenced the rate of perinatal HIV-1 transmission among 667 AZT-untreated mother-infant pairs (554 uninfected and 113 HIV-1 infected). We found that the mutant CCR5-59356-T allele is relatively common in African-Americans (20.6% allele frequency among 552 infants) and rare in Caucasians and Hispanics (3.4 and 5.6% of 174 and 458 infants, respectively; P < 0.001). There were 38 infants homozygous for CCR5-59356-T, of whom 35 were African-Americans. Among the African-American infants in the AZT-untreated group, there was a highly significant increase in HIV-1 transmission to infants with two mutant CCR5-59356-T alleles (47.6% of 21), compared to those with no or one mutant allele (13.4 to 14.1% of 187 and 71, respectively; P < 0.001). The increased relative risk was 5.9 (95% confidence interval, 2.3 to 15.3; P < 0.001). The frequency of the CCR5-59356-T mutation varies between population groups in the United States, a low frequency occurring in Caucasians and a higher frequency occurring in African-Americans. Homozygosity for CCR5-59356-T is strongly associated with an increased rate of perinatal HIV-1 transmission.


Unraveling the link between hypertension and depression in older adults: a meta-analysis.
To perform a meta-analyses to understand the current status of and risk factors for depression in older adults with hypertension. Eight electronic databases and two clinical trial registries were searched to identify studies examining the incidence of and risk factors for depression among older adults with hypertension. The databases were searched from inception to June 2023. The included studies were evaluated using the Newcastle-Ottawa scale and the evaluation tool recommended by the Agency for Health care Research and Quality. A total of 18 studies with 29,694 patients were included. Meta-analysis results showed that the prevalence of depression in older adults with hypertension was 29%. The risk factors for depression among this population included sex [OR value 95% confidence interval 2.24 (1.32, 3.82)], education level [OR 95% CI 1.79 (1.02, 3.14)], residence [OR 95% CI 1.37 (1.24, 1.52)], comorbidities [OR 95% CI 1.79 (1.69, 1.90)], hypertension classification [OR 95% CI 2.81 (1.79, 4.42)], marital status [OR 95% CI 1.50 (1.33, 1.69)], sleep status [OR 95% CI 2.86 (2.21, 3.69)], activity limitation [OR 95% CI 3.42 (2.84, 4.13)], drinking [OR 95% CI 2.25 (1.58, 3.19)], social support [OR 95% CI 3.26 (2.42, 4.41)], living alone [OR 95% CI 1.79 (1.57, 2.04)], stressful events [OR 95% CI 1.62 (1.39, 1.90)], and course of diseases [OR 95% CI 3.23 (2.10, 4.97)]. The incidence of depression in older adults with hypertension is high, and there are many risk factors. Clinical health care professionals should intervene early to target the above risk factors to reduce the incidence of depression in older adults with hypertension worldwide. PROSPERO (york.ac.uk), identifier [CRD42023417106].


[The burnout syndrome in communicative professional workers].
To study the specific features of the burnout syndrome (BOS) in communicative professional workers, the authors examined 138 communicative workers (94 females and 44 males); of them there were 51 physical education masters, 43 elementary school teachers, 20 consulting shop assistants, and 24 legal officers. BOS was detected in more than two thirds of elementary school teachers and more than a third of physical education masters, consulting shop assistants, legal officers, and practitioners. The completely developed BOS was most frequently encountered in elementary school teachers (in every four individuals), slightly less frequently in practitioners, consulting shop assistants, and legal officers (in every ten persons). The highest BOS levels were observed in elementary school teachers having a service length of less than 5 years and in legal officers and practitioners having a service length of more than 10 years. The paper provides evidence for the expediency of complex preventive measures for the representatives of these professions and for psychological support of their professional activities.


Total pancreatectomy and islet cell autotransplantation: outcomes, controversies and new techniques.
Chronic pancreatitis is a challenging disease; the constellation of chronic abdominal pain and metabolic derangements present unique difficulties to the treating physician. Initial treatment revolves around lifestyle modification, pain control, and management of exocrine insufficiency. In refractory cases, total pancreatectomy with islet cell auto transplantation (TP-IAT) is an option for patients with diffuse disease not amenable to subtotal pancreatectomy or a decompressive (drainage) operation. This procedure aspires to alleviate pain and avoid surgically induced brittle diabetes, a morbid complication of total pancreatectomy alone. Herein, we review the indications, optimal timing, surgical outcomes and controversies for TP-IAT, focusing on recently published reports.


The internet of things for personalized health.
Advances in information and communications technologies (ICT) enable new personalized health care concepts which are often characterized by four "P" terms, i.e. personalized, predictive, preventive and participatory. However, real world implementations of the complete 4P spectrum hardly exist today. The Internet of Things (IoT) has been defined as an extension to the current Internet that enables pervasive communication between the physical and the virtual world. Smart devices and enabling elements like Near Field Communication (NFC) and Radio Frequency Identification (RFID) technology already exist and increasingly will be a mainstream element of our lives. This future vision paper attempts to assess if and how the Internet of Things for personalized health (IoT4pH) can help to facilitate the 4P healthcare paradigm and discusses related challenges and opportunities.


Effect of a quality-controlled fermented nutraceutical on skin aging markers: An antioxidant-control, double-blind study.
The aim of the present study was to determine whether oral supplementation with a fermented papaya preparation (FPP-treated group) or an antioxidant cocktail (antioxidant-control group, composed of 10 mg trans-resveratrol, 60 µg selenium, 10 mg vitamin E and 50 mg vitamin C) was able to improve the skin antioxidant capacity and the expression of key skin genes, while promoting skin antiaging effects. The study enrolled 60 healthy non-smoker males and females aged 40-65 years, all of whom showed clinical signs of skin aging. The subjects were randomly divided into two matched groups, and were administered FPP or antioxidant treatment of a 4.5 g/day sachet sublingually twice a day for 90 days in a double-blind fashion. The parameters investigated were: Skin surface, brown spots, skin evenness, skin moisturization, elasticity (face), redox balance, nitric oxide (NO) concentration, and the expression levels of key genes (outer forearm sample). As compared with the baseline (day 0) and antioxidant-control values, FPP-treated subjects showed a significant improvement in skin evenness, moisturization and elasticity. The two treatments improved the MDA and SOD skin concentrations, but only the FPP-treated group showed a higher SOD level and a significant NO increase, along with significant upregulation of acquaporin-3 and downregulation of the potentially pro-aging/carcinogenetic cyclophilin-A and CD147 genes (P<0.05). Progerin was unaffected in both treatment groups. In conclusion, these findings suggest that orally-administered FPP showed a consistent biological and gene-regulatory improvement in the skin, as was also demonstrated in previous experimental and clinical trials testing other tissues, while common oral antioxidants had only a minor effect.


Blood Bank Specimen Mislabeling: A College of American Pathologists Q-Probes Study of 41 333 Blood Bank Specimens in 30 Institutions.
-Incorrectly labeled patient blood specimens create opportunities for laboratory testing personnel to mistake one patient's specimen for a specimen from a different patient. Transfusion of blood that is typed on specimens that are mislabeled can result in acute hemolytic transfusion reactions. -To assess the rates of blood bank ABO typing specimens that are mislabeled and/or contain blood belonging to another patient (so-called wrong blood in tube [WBIT]), and to compare these rates with those determined in a similar study performed in 2007. -Participants enrolled in this College of American Pathologists Q-Probes study for the first quarter of 2015 tallied the number of mislabeled and WBIT ABO blood typing specimens. Outcome measurements were the number of mislabeled and WBIT instances per 1000 specimens. We also evaluated the effects of various practice characteristics, in particular the use of bar coding, on the outcome measurements. -A total of 30 institutions submitting data on 41 333 ABO blood typing specimens recorded aggregate rates of 7.4 instances of mislabeling (306 specimens) and 0.43 instances of WBIT (10 of 23 234) per 1000 specimens submitted. Mislabeling rates were lower in institutions requiring that specimens be labeled with patients' birth dates than those that did not. The rates of specimen mislabeling and WBIT were otherwise unassociated with any of the other practice variables evaluated. -The rates of ABO blood typing specimen mislabeling and WBIT are not statistically different from those determined in a similar study performed in 2007 (P = .94 and P = .10). The use of bar coding was not associated with lower mislabeling (P = .80) or WBIT rates (P = .79).


Corticothalamic axons contact blood vessels as well as nerve cells in the thalamus.
Corticothalamic axons in cats and rats were studied after labelling by intracortical injections of axonally transported markers. Individual axons were traced to their terminal branches. Many preterminal segments had a tightly spiral or winding course which was often closely adjacent to a thalamic blood vessel. Electron micrographs of such axons showed them lying immediately adjacent to the vascular basement membrane, without the astrocytic cytoplasm that generally separates neural processes from the basement membrane of vessels. The functional nature of this neurovascular relationship remains to be explored.


[Effect of papaverine on blood circulation in experiments on anesthetized and waking animals].
Experiments on rats have shown that papaverine (1 mg/kg) produces hypotension, tachycardia, and increases myocardial contractility in animals under general anesthesia. In freely moving animals, it enhances cardiac contractile function to a considerably greater extent than in anesthetized animals, exerting no marked effect on arterial pressure or heart rate. It is suggested that different papaverine effect on animals under general anesthesia and on freely moving ones, is due to the influences exerted by narcotic substances on both central component of cardiovascular tone regulation and directly on the myocardium.


Transfection of interleukin-12 cDNAs into tumor cells induces cytotoxic immune responses against native tumor: implications for tumor vaccination.
Interleukin-12 (IL-12) is a heterodimeric cytokine that is central to the development of T helper 1-dependent cellular immunity. Although this cytokine has potential therapeutic application as an antineoplastic agent, the systemic infusion of IL-12 has led to toxic fatalities; hence, restriction of expression of IL-12 to the microenvironment of target tumor cells has obvious appeal. In this study, we examined whether tumor cells that were liposome-transfected with IL-12 could enhance the induction of cytolytic lymphocyte immunity to the native tumor. The plasmid expression vector that we used has several useful features including replication to high copy number as an episome and a polycistronic message enabling the production of both the p35 and p40 subunits of IL-12 without alternative splicing; up to 3 ng/mL/10(6)/48 hours of IL-12 was produced following transfection. Tumor cells transfected with IL-12 were superior to untransfected cells in the induction of lymphocyte-mediated cytolysis. IL-12 transfectants induced a heterogeneous population of natural killer, lymphokine activated killer, and cytolytic T lymphocytes, the latter of which exhibited tumor-specific activity. Our studies suggest that liposome-mediated transfection of tumor cells with an episomal, high copy number plasmid vector expressing both IL-12 subunits is a promising approach to cancer vaccination, a strategy that could be implemented ex vivo in treating malignancies such as metastatic ovarian cancer.


Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency.
To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.


Low temperature magnetic instabilities in triply charged fulleride polymers
The electronic properties of the C3-60 polymer in Na2Rb0.3Cs0.7C60 were studied by X-band and high field (109.056 GHz) ESR. They are characteristic of a strongly correlated quasi-one-dimensional metal down to 45 K. On further cooling, a pseudogap of magnetic origin opens at the Fermi level below 45 K with three-dimensional magnetic ordering occurring below T(N) approximately 15 K, as confirmed by the observation of an antiferromagnetic resonance mode. The Na2Rb1-xCsxC60 family of polymers offers a unique way to chemically control the electronic properties, as the opening of the gap in this system of predominantly itinerant electrons is an extremely sensitive function of the interchain separation.


Avatar- and self-related processes and problematic gaming: A systematic review.
The concept of self has become increasingly relevant to understanding the psychological mechanisms of problematic online gaming. Many gaming activities feature in-game avatars that enable the adoption of, and experimentation with, different roles and identities. Avatars enable players to compensate for perceived deficiencies in their real-world self (e.g., lack of physical strength, beauty, or social status). Currently, how avatar- and self-related processes may develop and maintain problematic gaming, including gaming disorder (GD), is unclear. This systematic review examined 18 quantitative studies of avatar- and self-related concepts and problematic gaming, including 13 survey-based and 5 neuroimaging studies. Despite variability in the conceptualization and measurement of avatar/self-related concepts, survey-based studies have consistently reported that negative self-concept, avatar identification, and large self-avatar discrepancies are significantly associated with problematic gaming. Poor self-concept appears to be a risk factor for GD, particularly for games that facilitate role-playing and identity formation. Further research and clinical evidence are needed to explain how avatar- and self-related processes may relate to the addictive mechanisms of GD (e.g., cognitive distortions, reward-seeking, inhibitory control, self-regulation systems), amid calls for problem gaming-related assessment and interventions to incorporate a focus on avatar identification.


Reisolation of Staphylococcus aureus from bovine milk following experimental inoculation is influenced by fat percentage and specific immunoglobulin G1 titer in milk.
The associations of management parameters, herd characteristics, and individual cow factors with bovine mastitis have been subject of many studies. The present study aimed to evaluate the association between milk composition parameters, including fat, protein, lactose, urea, and specific immunoglobulin levels, at the time of experimental bacterial inoculation of the mammary gland and subsequent shedding dynamics of Staphylococcus aureus. Sixty-eight cows were experimentally infected with S. aureus and closely monitored for 3 wk. Mixed model analyses were used to determine the influence of management and herd characteristics (farm and experimental group), individual cow factors (days in milk, milk yield, and quarter position), and a challenge-related parameter (inoculation dose) in combination with either the milk components fat, protein, lactose and urea, or the S. aureus-specific antibody isotype titers at the time of bacterial inoculation, on the number of S. aureus reisolated from milk after inoculation. A positive association was observed between the milk fat percentage and the number of S. aureus reisolated from quarter milk, and a negative relationship between the S. aureus-specific IgG1 titer in milk and the number of S. aureus. These findings should be considered in the development of a vaccine against S. aureus-induced bovine mastitis.


Optimal use of external demands in hospitals - a Delphi study from the Netherlands.
Regulatory authorities focus on promoting compliance of hospitals with a variety of external demands. Due to the amount of these external demands, hospitals might prioritise to cope with the external demands. In this study, we explore to what extent a risk-based prioritisation system developed by one Dutch hospital, is applicable in other hospitals as well. The specific research question was: can a risk-based prioritisation system help hospitals cope with the pressures of external demands? We conducted a Delphi study, containing three rounds with seven quality and safety managers. All participants were experienced in coping with external demands in Dutch hospitals in general and their own hospital specifically. These experts were granted access to a sample selection of a database containing about 1500 external demands (January 2014). Prior to the Delphi study, a baseline measurement was carried out, where all participants answered open-ended questions aimed at identifying existing practices, possible challenges concerning external demands and to prepare the survey for the group Delphi study. We identified a high level of consensus during our Delphi research. The experts agreed that at present, Dutch hospitals do not cope with external demands systematically. The participants agreed that the database and the risk-based prioritisation system are useful tools to cope with the amount of external demands and indicated that they would also like to use these tools themselves in the future. In this study, the participants agreed that the database and the risk-based prioritisation system are both applicable and useful tools to cope with the amount of external demands. Further research addressing the use of the risk-based-priority system for specific subsets of external demand is also needed.


Long-term increase in subfoveal choroidal thickness after surgery for senile cataracts.
To evaluate the impact of cataract surgery on subfoveal choroidal thickness and central retinal thickness in the elderly. Prospective observational case series. This cohort study included 29 eyes of 29 patients with senile cataract, but no previous ocular surgery or other ocular abnormality. All 29 eyes received standard surgery by phacoemulsification and intraocular lens implantation. Subfoveal choroidal thickness and central retinal thickness were measured at baseline and 1, 3, and 6 months postoperatively by spectral-domain optical coherence tomography. Multiple regression analysis was conducted to identify predictors of larger changes in subfoveal choroidal thickness, including sex, age, baseline choroidal thickness, axial length, refractive status before surgery, and duration of surgery. The 29 patients with senile cataract received cataract surgery without complication. Mean subfoveal choroidal thickness was 193.8, 208.9, 210.2, and 209.3 μm at baseline and at postoperative 1, 3, and 6 months, respectively, with a statistically significant increase after surgery (repeated-measures ANOVA; P < .0001). In 20 eyes (69.0%), subfoveal choroidal thickness remained high even 6 months after surgery. Multiple regression analysis revealed that male sex (P = .014) and thicker baseline choroid (P = .0048) predicted larger increases in subfoveal choroidal thickness. In contrast, the tendency of transient increase in central retinal thickness was not statistically significant. Most elderly patients with senile cataracts are expected to maintain increased subfoveal choroidal thickness for at least 6 months after cataract surgery.


Altered behavior in mice with deletion of the alpha2-antiplasmin gene.
The α2-antiplasmin (α2AP) protein is known to be a principal physiological inhibitor of plasmin, and is expressed in various part of the brain, including the hippocampus, cortex, hypothalamus and cerebellum, thus suggesting a potential role for α2AP in brain functions. However, the involvement of α2AP in brain functions is currently unclear. The goal of this study was to investigate the effects of the deletion of the α2AP gene on the behavior of mice. The motor function was examined by the wire hang test and rotarod test. To evaluate the cognitive function, a repeated rotarod test, Y-maze test, Morris water maze test, passive or shuttle avoidance test and fear conditioning test were performed. An open field test, dark/light transition test or tail suspension test was performed to determine the involvement of α2AP in anxiety or depression-like behavior. The α2AP knockout (α2AP-/-) mice exhibited impaired motor function compared with α2AP+/+ mice. The α2AP-/- mice also exhibited impairments in motor learning, working memory, spatial memory and fear conditioning memory. Furthermore, the deletion of α2AP induced anxiety-like behavior, and caused an anti-depression-like effect in tail suspension. Therefore, our findings suggest that α2AP is a crucial mediator of motor function, cognitive function, anxiety-like behavior and depression-like behavior, providing new insights into the role of α2AP in the brain functions.


Electronic and magnetic properties of SrTiO(3)/LaAlO(3) interfaces from first principles.
A number of intriguing properties emerge upon the formation of the epitaxial interface between the insulating oxides LaAlO(3) and SrTiO(3). These properties, which include a quasi two-dimensional conducting electron gas, low temperature superconductivity, and magnetism, are not present in the bulk materials, generating a great deal of interest in the fundamental physics of their origins. While it is generally accepted that the novel behavior arises as a result of a combination of electronic and atomic reconstructions and growth-induced defects, the complex interplay between these effects remains unclear. In this report, we review the progress that has been made towards unraveling the complete picture of the SrTiO(3)/LaAlO(3) interface, focusing primarily on present ab initio theoretical work and its relation to the experimental data. In the process, we highlight some key unresolved issues and discuss how they might be addressed by future experimental and theoretical studies.


Churg-Strauss syndrome associated with elevated levels of serum interleukin-5 and T cell receptor-Cβ gene rearrangement.
A 58-year-old woman was diagnosed with Churg-Strauss syndrome (CSS) based on the symptoms of bronchial asthma, eosinophilia, mononeuritis multiplex and histological examination of the right sural nerve. Prior to treatment, the serum interleukin (IL)-5 level was high, and rearrangement of the T cell receptor (TCR) gene was identified. This is the first report of TCR gene rearrangement in a patient with CSS. The expanded T cell clone may be responsible for the overproduction of IL-5. Further studies are warranted to disclose a prevalence of TCR gene rearrangement in CSS patients and its pathophysiological roles in the development of this disease.


Nuclear mutations in the petite-negative yeast Schizosaccharomyces pombe allow growth of cells lacking mitochondrial DNA.
The fission yeast Schizosaccharomyces pombe has never been found to give rise to viable cells totally lacking mitochondrial DNA (rho(o)). This paper describes the isolation of rho(o) strains of S. pombe by very long term incubation of cells in liquid medium containing glucose, potassium acetate and ethidium bromide. Once isolated, the rho(o) strains did not require potassium acetate or any other novel growth factors. These nonrespiring strains contained no mitochondrial DNA (mtDNA) detectable either by gel-blot hybridization using as probe a clone containing the entire S. pombe mtDNA, or by 1',6-diamidino-2-phenylindole staining of whole cells. Induction of rho(o) derivatives of standard laboratory strains was not reproducible from culture to culture. The cause of this irreproducibility appears to be that growth of the rho(o) strains of S. pombe depended on nuclear mutations that occurred in some, but not all, of the initial cultures. Two independent rho(o) isolates contained mutations in unlinked genes, termed ptp1-1 and ptp2-1. These mutations allowed reproducible ethidium bromide induction of viable rho(o) strains. No other phenotypes were associated with ptp mutations in rho+ strains.


Gamma-linolenic acid levels correlate with clinical efficacy of evening primrose oil in patients with atopic dermatitis.
Atopic dermatitis (AD) has been related to a deficiency of delta-6-desaturase, an enzyme responsible for the conversion of linoleic acid to gamma-linolenic acid (GLA). Evening primrose oil (EPO) contains high amounts of GLA. Therefore, this study investigated whether EPO supplementation results in an increase in plasma GLA and its metabolite dihomo-gamma-linolenic acid (DGLA) correlating with clinical improvement of AD, assessed by the SCORing Atopic Dermatitis (SCORAD) index. The open study included 21 patients with AD. EPO (4-6 g) was administered daily for 12 weeks. Before treatment, and 4 and 12 weeks after initiation of EPO supplementation, objective SCORAD was assessed and plasma concentrations of GLA and DGLA were determined by gas chromatography. A significant increase in plasma GLA and DGLA levels and a decrease in the objective SCORAD were observed 4 and 12 weeks after initiation of EPO treatment. In the per-protocol population (n = 14), a significant inverse correlation between the changes in plasma GLA levels and SCORAD was found (P = 0.008). The clinical disease activity under EPO treatment correlates with the individual increase in plasma GLA levels. Thus, the results of this pilot study indicate that an increase in plasma GLA might be used as predictive parameter for responsiveness of AD to EPO therapy.


Nanoprocess and nanoscale surface functionalization on cathode materials for advanced lithium-ion batteries.
Nanotechnology-driven development of cathode materials is an essential part to revolutionize the evolution of the next generation lithium ion batteries. With the progress of nanoprocess and nanoscale surface modification investigations on cathode materials in recent years, the advanced battery technology future seems very promising - Thanks to nanotechnology. In this review, an overview of promising nanoscale surface deposition methods and their significance in surface functionalization on cathodes is extensively summarized. Surface modified cathodes are provided with a protective layer to overcome the electrochemical performance limitations related to side reactions with electrolytes, reduce self-discharge reactions, improve thermal and structural stability, and further enhance the overall battery performance. The review addresses the importance of nanoscale surface modification on battery cathodes and concludes with a comparison of the different nanoprocess techniques discussed to provide a direction in the race to build advanced lithium-ion batteries.


Interaction of a peptide derived from C-terminus of human TRPA1 channel with model membranes mimicking the inner leaflet of the plasma membrane.
The transient receptor potential ankyrin 1 channel (TRPA1) belongs to the TRP cation channel superfamily that responds to a panoply of stimuli such as changes in temperature, calcium levels, reactive oxygen and nitrogen species and lipid mediators among others. The TRP superfamily has been implicated in diverse pathological states including neurodegenerative disorders, kidney diseases, inflammation, pain and cancer. The intracellular C-terminus is an important regulator of TRP channel activity. Studies with this and other TRP superfamily members have shown that the C-terminus association with lipid bilayer alters channel sensitivity and activation, especially interactions occurring through basic residues. Nevertheless, it is not yet clear how this process takes place and which regions in the C-terminus would be responsible for such membrane recognition. With that in mind, herein the first putative membrane interacting region of the C-terminus of human TRPA1, (corresponding to a 29 residue peptide, IAEVQKHASLKRIAMQVELHTSLEKKLPL) named H1 due to its potential helical character was chosen for studies of membrane interaction. The affinity of H1 to lipid membranes, H1 structural changes occurring upon this interaction as well as effects of this interaction in lipid organization and integrity were investigated using a biophysical approach. Lipid models systems composed of zwitterionic and anionic lipids, namely those present in the lipid membrane inner leaflet, where H1 is prone to interact, where used. The study reveals a strong interaction and affinity of H1 as well as peptide structuration especially with membranes containing anionic lipids. Moreover, the interactions and peptide structure adoption are headgroup specific.


Appreciating the Persona paradox: lessons from participatory design sessions with HIV+ gay men.
Eliciting user requirements from HIV-positive gay men who smoke can be challenging. This is because of the complex relationship between social stigma and gender identities (e.g., gay, masculine, HIV+, and smoking status). Inspired to engage HIV-positive gay men in the development of a web-assisted tobacco intervention, we used personas as a main communication tool in our participatory design sessions. Personas are characters created by users that embody part of their own behaviours, thoughts, and motivations. In an apparent paradox, this article is a description of how the use of personas to ensure less realistic self-representation provided an impetus for more self-disclosure. Findings and feedbacks from this study reveal that personas are an effective design tool to engage users in sensitive topics. Implications for future work are also discussed.


The Milk Microbiota of the Spanish Churra Sheep Breed: New Insights into the Complexity of the Milk Microbiome of Dairy Species.
Milk from healthy animals has classically been considered a sterile fluid. With the development of massively parallel sequencing and its application to the study of the microbiome of different body fluids, milk microbiota has been documented in several animal species. In this study, the main objective of this work was to access bacterial profiles of healthy milk samples using the next-generation sequencing of amplicons from the 16S rRNA gene to characterise the milk microbiome of the Churra breed. A total of 212 samples were collected from two Churra dairy farms with a different management system. The core milk microbiota in Churra ewes includes lesser genera (only two taxa: Staphylococcus and Escherichia/Shigella) than studies reported in other dairy species or even in a previous study in Assaf sheep milk. We found that diversity values in the two flocks of Churra breed were lower than the diversity of the milk microbiota in Assaf. The non-metric multidimensional scaling (NMDS) ordination using Bray-Curtis distance separates samples based on their microbiota composition. The information reported here might be used to understand the complex issue of milk microbiota composition.


An Application of HFE-D for Evaluating Sea Water Intrusion in Coastal Aquifers of Southern Vietnam.
The coastal aquifers and inland waters of the Long Xuyen Quadrangle and Ca Mau Peninsula of southern Vietnam have been significantly impacted by sea water intrusion (SI) as a result of recent anthropogenic activities. This study identified the evolution and spatial distribution of hydrochemical conditions in coastal aquifers at this region using Hydrochemical Facies Evolution Diagram (HFE-D) and Geographical Information System mapping. Hydraulic heads and water chemistry were measured at 31 observation wells in four layered aquifers during dry and rainy seasons in early (2005), and more recent (2016), stages of agricultural development. Hydrochemical facies associated with intrusion or freshening stages were mapped in each aquifer after assigning mixing index values to each facies. The position of groundwater freshening and SI phases differed in Holocene, Upper Pleistocene, Middle Pleistocene, and Lower Pleistocene aquifers. The geographic position of freshening and intrusion fronts differ in dry and rainy seasons, and shifted after 11 years of groundwater abstraction in all four aquifers. The spatial and temporal differences in hydrochemical facies distributions according to HFE-D reflect the relative impact of SI in the four aquifers. The study results provide a better understanding of the evolution of groundwater quality associated with SI in a peninsular coastal aquifer system, and highlight the need for improving groundwater quality and management in similar coastal regions.


One-sided difference schemes and transonic flow.
Two one-sided conservation form difference approximations to a scalar one-dimensional convex conservation law are introduced. These are respectively of first- and second-order accuracy and each has the minimum possible band-width. They are nonlinearly stable, they converge only to solutions satisfying the entropy condition, and they have sharp monotone profiles. No such stable approximation of order higher than two is possible. Dimensional splitting algorithms are constructed and used to approximate the small-disturbance equation of transonic flow. These approximations are also nonlinearly stable and without nonphysical limit solutions.


Complement C3aR depletion reverses HIF-1α-induced metabolic impairment and enhances microglial response to Aβ pathology.
Microglia are the major cell type expressing complement C3a receptor (C3aR) in the brain. Using a knockin mouse line in which a Td-tomato reporter is incorporated into the endogenous C3ar1 locus, we identified 2 major subpopulations of microglia with differential C3aR expression. Expressing the Td-tomato reporter on the APPNL-G-F-knockin (APP-KI) background revealed a significant shift of microglia to a high-C3aR-expressing subpopulation and they were enriched around amyloid β (Aβ) plaques. Transcriptomic analysis of C3aR-positive microglia documented dysfunctional metabolic signatures, including upregulation of hypoxia-inducible factor 1 (HIF-1) signaling and abnormal lipid metabolism in APP-KI mice compared with wild-type controls. Using primary microglial cultures, we found that C3ar1-null microglia had lower HIF-1α expression and were resistant to hypoxia mimetic-induced metabolic changes and lipid droplet accumulation. These were associated with improved receptor recycling and Aβ phagocytosis. Crossing C3ar1-knockout mice with the APP-KI mice showed that C3aR ablation rescued the dysregulated lipid profiles and improved microglial phagocytic and clustering abilities. These were associated with ameliorated Aβ pathology and restored synaptic and cognitive function. Our studies identify a heightened C3aR/HIF-1α signaling axis that influences microglial metabolic and lipid homeostasis in Alzheimer disease, suggesting that targeting this pathway may offer therapeutic benefit.


Socioeconomic status, family negative emotional climate, and anti-inflammatory gene expression among youth with asthma.
The glucocorticoid receptor gene NR3C1 is an important down-regulator of inflammation and is typically under-expressed in individuals with low socioeconomic status (SES). Negative emotionality has been suggested as a potential mediator of SES disparities in health outcomes. In this study, we expand this literature by naturalistically assessing negative emotionality in a key emotional environment: the family. In a sample of 104 youth with asthma (10-17 years) and their primary caregiver, we assessed SES via caregiver report, emotional expression by youth and parents in the home over four days using the electronically activated recorder (EAR), and NR3C1 expression via blood collected from youth. Although there was not a direct effect of SES on NR3C1 expression, bootstrapping mediation analyses showed a significant indirect path such that lower SES was associated with a more negative family emotional climate, which in turn predicted reduced NR3C1 expression. No mediation effects were found for family positive emotional climate. This research demonstrates the importance of examining the effects of SES on emotion expression in the family context and suggests a critical biopsychosocial pathway underlying SES-based health disparities that may extend beyond youth.


Tooth wear among five-year-old children in Jakarta, Indonesia.
This study aimed to evaluate the prevalence of tooth wear among preschool children in Jakarta, Indonesia, and examine the risk factors associated with its occurrence. An epidemiological survey was conducted with a cross-sectional study design. The participants were recruited via cluster sampling. Tooth wear was clinically assessed by one examiner using the Basic Erosive Wear Examination (BEWE) criteria. The children's caries experience was also recorded. The parents of the participating children completed a self-administered questionnaire to answer demographic questions about the children and gather information about the children's diet and oral health behaviors as well as the parents' dental health-related knowledge. The data were analyzed using the Chi-square test and binary logistic regression. A total of 752 five-year-old children were invited to participate, with 691 (92%) enrolling in the study. Tooth wear occurred in 23% (161/691, BEWE > 0) of the participants, in which 78% (125/161) had at least one moderate tooth wear status (BEWE = 2). The consumption of citrus drinks, fruit juice, and vitamin C supplement drinks, together with the child's caries experience, the father's education level, and the family's socioeconomic status, were significantly associated with tooth wear. The five-year-old preschool children in Jakarta had a relatively low prevalence of tooth wear. Those consuming more acidic drinks, those with a higher socioeconomic status, and those with an absence of caries experience had a higher risk of tooth wear.


Range Expansion of Tick Disease Vectors in North America: Implications for Spread of Tick-Borne Disease.
Ticks are the major vectors of most disease-causing agents to humans, companion animals and wildlife. Moreover, ticks transmit a greater variety of pathogenic agents than any other blood-feeding arthropod. Ticks have been expanding their geographic ranges in recent decades largely due to climate change. Furthermore, tick populations in many areas of their past and even newly established localities have increased in abundance. These dynamic changes present new and increasing severe public health threats to humans, livestock and companion animals in areas where they were previously unknown or were considered to be of minor importance. Here in this review, the geographic status of four representative tick species are discussed in relation to these public health concerns, namely, the American dog tick, Dermacentor variabilis, the lone star tick, Amblyomma americanum, the Gulf Coast Tick, Amblyomma maculatum and the black-legged tick, Ixodes scapularis. Both biotic and abiotic factors that may influence future range expansion and successful colony formation in new habitats are discussed.


Pharmacy-based laboratory services: past or future and risk or opportunity?
Laboratory diagnostics has undergone relevant changes in organization and complexity, providing new opportunities and risks. Many laboratory tests are now available on compact, easy to operate and reliable instruments, making it possible for facilities other than the traditional clinical laboratories (e.g., pharmacies) to conduct on-site or mobile testing. Ideally, although there is nothing wrong with a rational decentralization, on-site laboratory testing must still be considered a knowledge service, and a core set of competency-quality-consultancy prerequisites should be fulfilled to ensure that results of tests performed outside the clinical laboratories can reach the highest degree of efficiency and clinical efficacy. Pharmacies were historically involved in clinical chemistry. At the European level, the existing pharmacy syllabus gives to students and postgraduates the physiopathological knowledge a good basis for such an evolution.


Two cases of trisomy 16 mosaicism ascertained postnatally.
Postnatally ascertained trisomy 16 mosaicism is a rare diagnosis, with only three reported cases to date with no defined clinical phenotype. Trisomy 16 mosaicism diagnosed prenatally is common and associated with variable pregnancy outcomes ranging from stillbirth with multiple congenital abnormalities to an apparently normal newborn, making the genetic counseling very challenging. It is not clear whether uniparental disomy (UPD) 16 contributes to the phenotype, although it has been suggested that maternal UPD 16 affects the rate of intra-uterine growth retardation (IUGR) and congenital anomalies. We report on two further cases of trisomy 16 mosaicism confined to fibroblasts diagnosed postnatally. Patient 1 presented at birth with severe hypospadias, unilateral postaxial polydactyly, and different hair color with midline demarcation. His growth and development were normal at 11 months of age. Patient 2 was born with IUGR, significant craniofacial and body asymmetry, asymmetric skin hyperpigmentation, unilateral hearing loss, scoliosis, VSD, unexplained dilated cardiomyopathy, feeding difficulties, failure to thrive, and recurrent respiratory tract infections. She died at 7 months of age from respiratory failure. These two further cases of postnatally diagnosed trisomy 16 mosaicism highlight the variability of clinical features and outcome in this diagnosis. While Patient 2 presented with typical features of chromosomal mosaicism, Patient 1 had mild and transient features with essentially normal outcome, suggesting that trisomy 16 mosaicism may be under-diagnosed.


[Techniques of mechanical suture formation in Swenson's operation in children].
The authors describe briefly the design and method of working with a special suturing instrument in formation of an extraperitoneal anastomosis by a modification of Swenson's operation in children suffering from developmental anomalies of the large intestine. The instrument ensures one-stage stitching of the intestine along its entire circumference before its resection. The anastomosis is formed four times more rapidly and the manipulation is more aseptic. Eight children were operated on with the use of the instrument and no complications occurred.


LC-MS-Based Profiling Provides New Insights into Apocarotenoid Biosynthesis and Modifications in Citrus Fruits.
Apocarotenoids contribute to fruit color and aroma, which are critical quality and marketability attributes. Previously, we reported that the red peels of citrus fruits, which are characterized by higher expression levels of a carotenoid cleavage dioxygenase 4b (CitCCD4b) gene, accumulate higher levels of β-citraurin and β-citraurinene than yellow peels. Here, we identified and quantified 12 apocarotenoids, either volatile or nonvolatile, in citrus peel using liquid chromatography-mass spectrometry (LC-MS). Our results show that red peels contain also dramatically higher amounts of β-apo-8'-carotenal, crocetin dialdehyde known from saffron, β-citraurol, β-cyclocitral, and 3-OH-β-cyclocitral and up to about 17-fold higher levels of 3-OH-β-cyclocitral glucoside (picrocrocin isomer). The content of these apocarotenoids was also significantly increased in different CitCCD4b-overexpressing transgenic callus lines, compared with corresponding controls. Transient expression of CitCCD4b in Nicotiana benthamiana leaves resulted in a striking increase in the 3-OH-β-cyclocitral level and the accumulation of picrocrocin. Thus, our work reinforces the specific function of CitCCD4b in producing C10 apocarotenoid volatiles and C30 pigments in citrus peel and uncovers its involvement in the biosynthesis of picrocrocin, C20 dialdehyde, and C30 alcohol apocarotenoids, suggesting the potential of this enzyme in metabolic engineering of apocarotenoids and their derivatives.


Solubilization of Escherichia coli recombinant proteins from inclusion bodies.
The high levels of expression produced by molecular cloning techniques make bacteria particularly useful for producing recombinant proteins. However, these proteins often are difficult to purify, owing to their tendency to aggregate and precipitate within the bacteria as insoluble inclusion bodies. Formation of inclusion bodies is especially common for nonbacterial proteins. Although no single method can be applied to every protein, a number of strategies are available to solubilize inclusion body proteins. This protocol describes one such method.


Initiating research with doubly vulnerable populations.
Some research questions can only be answered by members of a vulnerable group. Frequently members of these groups are doubly vulnerable as they experience more than one factor that diminishes their autonomy. Initiating research with doubly vulnerable persons presents unique and often difficult challenges. Because of these challenges, many researchers purposefully exclude doubly vulnerable groups from research endeavours. Thus, the health care needs and concerns of individuals considered doubly vulnerable are often not addressed in the scientific literature. This article presents two challenges frequently encountered when initiating research with doubly vulnerable populations: resolving pre-investigation issues and gaining access to vulnerable populations. Ethically sound strategies for confronting these challenges are discussed. Researchers' experiences with doubly vulnerable populations are also incorporated. Only when doubly vulnerable groups receive the appropriate research attention are the standards of their care and their quality of life enhanced.


Intrapulmonary chemoreceptor control of ventilatory movements in the self-ventilating chicken.
The importance of intrapulmonary chemoreceptors (IPC), sensitive to PCO2 in the lung, in the control of ventilatory movements is yet to be demonstrated in the self-ventilating bird. We distinguished between the effects of PCO2 on IPC and on extrapulmonary CO2-sensitive receptors (EPC) in anaesthetized cockerels by denervating IPC in the right lung, ligating the left pulmonary artery and changing PICO2. Left IPC were thus exposed to a combination of PCO2 from inspired gas and dead space, while EPC were exposed to greatly increased arterial PCO2 resulting from the ventilation-perfusion inequality. At 0 Torr PICO2, steady state ventilatory depth and frequency did not change (P greater than 0.5) after the ligation, although PaCO2 rose by 12.2 +/- 1.7 Torr. After the ligation, ventilatory movements were more sensitive to increasing PICO2. Tracheostomy, which results in a greater decrease in PCO2 in the innervated lung after ligation, produced greater effects. We conclude that these responses were due to the strong controlling influence of IPC on ventilatory movements in the self-ventilating cockerel.


Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis.
The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis). Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families. Six sites in the United States. European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample. Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment. In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R2 0.13-0.20%). Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education).