The immunologic self.
Immunology has been referred to as the science of self/non-self discrimination. Who or what is the "I" of which we often speak? It has been identified with body, brain, soul, and memories. There has been a diversity of ways to characterize the self, including denying its importance and existence, and to date no satisfactory conceptualization has been achieved. This article addresses the concept of self from an immunological perspective, a perspective that offers insights into the philosophic issues associated with the concept of self and personal identity. The article proposes that the immunological and the psychological are two aspects of one and the same self, offers criteria for an adequate conceptualization of the self, and discusses the philosophical and psychological implications of the immunological views of self. It concludes that we must move away from a simplistic, exclusively inward or mentalistic conception of the self.


The kinetics of anterior chamber ofloxacin penetration.
Thirty-five patients received topical ofloxacin 0.3% before routine cataract surgery. Ofloxacin was administered one drop every 2 h for five doses 1 day before surgery and one drop every 5 min for five doses immediately before surgery. Aqueous sampling was performed at variable periods 30-150 min after the last topical dose. The mean aqueous ofloxacin concentration was 793 +/- 516 ng/ml (range, 143-2,400 ng/ml). A significant correlation between time from last dose and aqueous humor concentration was found (r = 0.39, p = 0.025). The mean ofloxacin concentration was greater in those patients who received their last dose >1 h before aqueous aspiration (957 +/- 559 ng/ml versus 554 +/- 338 ng/ml, p = 0.02). From a best-fit scatter plot of concentration versus time, the maximal aqueous concentration of 1,000 ng/ml occurs at approximately 2h after topical administration.


Anatomy of the healthy worker effect: a critical review.
The healthy worker effect is the composite result from factors such as (1) selection of the work force, (2) changes in lifestyle accompanying employment, and (3) methodological characteristics of the standardized mortality ratio (SMR). While the choice of the general population as the comparison population is the underlying reason for this effect, no more feasible, widely accepted or "better" alternative is yet available. Much of the current understanding of the healthy worker effect has been limited to an examination of selection of the work force. The purpose of this report is to illustrate, using examples from a large cohort study, the importance of many factors other than selection. They include employment-associated benefits such as economic gain, medical insurance and lifestyle changes, the proportion of active workers, the calculation method, data completeness, length of follow-up and certain characteristics of SMR methodology. It is shown that some of the healthy worker effect is characteristic of SMR methodology and that the strength of the healthy worker effect depends on the proportion of active workers in the cohort. Furthermore, the disappearance of the healthy worker effect may be due to factors such as aging of the cohort and can be totally unrelated to the true increase in the mortality risk. In other words, its disappearance, in many instances, may be an artifact of SMR methodology.


Overexpression of c-met proto-oncogene but not epidermal growth factor receptor or c-erbB-2 in primary human colorectal carcinomas.
The epidermal growth factor receptor (EGFR) and the protein products of c-erbB-2 and c-met proto-oncogenes belong to a family of growth factor receptors with tyrosine kinase activity. In human colonic carcinomas, the expression of the EGFR and c-erbB-2 have been studied at the protein level only, while c-met expression has not been reported. We have examined the mRNA expression of these genes in human normal colorectal mucosa and primary carcinomas. The results demonstrate that the normal mucosa shows highly variable levels of EGFR and c-erbB-2 mRNAs, but expresses consistently low amounts of c-met mRNA. Colorectal carcinomas did not express significantly higher levels of the EGFR and c-erbB-2 mRNAs than the normal mucosa. In contrast, c-met was consistently and significantly overexpressed (mean sixfold) in carcinomas as compared with normal mucosa. Seventy percent of paired normal-tumor specimens showed a tumor to normal c-met mRNA ratio of greater than 4. The expression of c-met mRNA was also enhanced in the adenomas, suggesting that over-expression of this proto-oncogene may have mechanistic significance in the early stages of human colorectal carcinogenesis.


Ionium-Thorium Chronology of Deep-Sea Sediments of the Western North Pacific Ocean.
The rate of deposition of deep-sea deposits collected at the depths of 6215 to 8450 m in the western part of the North Pacific Ocean was estimated by means of the ionium/thorium ratio. The ratio was determined by an alpha-ray spectrometer. Results showed the rate of 0.5 to 0.8 mm/10(3) yr for the upper 10-cm layer below the sea bottom.


The diagnosis of tumours involving the parapharyngeal space by computed tomography.
Tumours arising within or adjacent to the parapharyngeal space are usually large at presentation and present difficulties in the choice of surgical approach. The findings on contrast-enhanced computed tomography (CT) of 30 patients with mass lesions in this region are presented. Contrast-enhanced CT can provide reliable information regarding the size and extent of a mass, its site of origin and likely histological type, as well as its relationship to surrounding neurovascular structures.


Tandem overexpression of five human factors renders murine hepatocytes susceptible to hepatitis C virus.
Development of mouse model of hepatitis C virus (HCV) infection has great significance in drug screening and vaccine research. The barriers of interspecies transmission of HCV are increasingly better understood. Human factors, namely low-density lipoprotein receptor (hLDLR), CD81 (hCD81), scavenger receptor class B type I (hSCARB1), occludin (hOCLN) and claudin 1 (hCLDN1) are all required for rendering mouse hepatocytes permissive to HCV. With the aim to humanize mouse hepatocytes we constructed two recombinant vectors tandemly expressing the first three and the last two HCV entry factors mentioned above, respectively. Cotransfection of mouse hepatocytes with these vectors made them permissive to HCV binding and entry. Tandem overexpression of hLDLR, hSCARB1, hCD81, hCLDN1 and hOCLN is a novel approach to tailoring mouse hepatocytes to HCV binding and entry which can be further used to establish a mouse model of HCV infection as a basis for developing antiviral drugs and vaccines.


Optimal control problems of epidemic systems with parameter uncertainties: application to a malaria two-age-classes transmission model with asymptomatic carriers.
The main scope of this paper is to study the optimal control practices of malaria, by discussing the implementation of a catalog of optimal control strategies in presence of parameter uncertainties, which is typical of infectious diseases data. In this study we focus on a deterministic mathematical model for the transmission of malaria, including in particular asymptomatic carriers and two age classes in the human population. A partial qualitative analysis of the relevant ODE system has been carried out, leading to a realistic threshold parameter. For the deterministic model under consideration, four possible control strategies have been analyzed: the use of Long-lasting treated mosquito nets, indoor residual spraying, screening and treatment of symptomatic and asymptomatic individuals. The numerical results show that using optimal control the disease can be brought to a stable disease free equilibrium when all four controls are used. The Incremental Cost-Effectiveness Ratio (ICER) for all possible combinations of the disease-control measures is determined. The numerical simulations of the optimal control in the presence of parameter uncertainty demonstrate the robustness of the optimal control: the main conclusions of the optimal control remain unchanged, even if inevitable variability remains in the control profiles. The results provide a promising framework for the designing of cost-effective strategies for disease controls with multiple interventions, even under considerable uncertainty of model parameters.


Role of vasopressin in 24-hour blood pressure regulation in diabetic patients with autonomic neuropathy.
To evaluate the role of vasopressin (AVP) on blood pressure (BP) in diabetic patients with autonomic neuropathy (AN), 10 patients were studied on a fixed sodium and potassium diet. On days 4 and 7, a 24-h BP monitoring, as well as blood and urine samples for sodium, potassium, creatinine, and osmolality determinations were obtained for every 4-h period; either placebo or an AVP-V1-antagonist (d(CH2)5Tyr(me)AVP; 0.5 mg; AVPi) were given iv at 1 PM. On placebo, systolic BP (SBP) showed a progressive elevation during the day, declining after 12 PM (8 AM to 12 AM 122+/-9; 12 AM to 4 PM 125+/-11; 4 PM to 8 PM 134+/-14; 8 PM to 12 PM 136+/-14; 12 PM to 8 AM 131+/-17 mm Hg). On AVPi this rise in SBP was blunted: 8 AM to 12 AM 125+/-122; 12 AM to 4 PM 121+/-21; 4 PM to 8 PM 126+/-16; 8 PM to 12 PM 129+/-14; 12 PM to 8 AM 124+/-12 mm Hg. Creatinine clearance and diureses were greater during the night, both with placebo and AVPi. Plasma osmolality did not change on either day, although serum sodium decreased after AVPi, reaching the lowest values at 4 PM to 8 PM period (137+/-4.7 v 131+/-3.8 mEq/L; P < .05). With placebo, fractional excretion of sodium (FENa) increased from 0.43%+/-0.32% during 12 h of orthostasis to 0.92%+/-1.05% during 12 h of recumbency (P < .02). With AVPi, the FENa on orthostasis did not differ from that with placebo, although BP values were lower and did not increase with recumbency (0.58+/-0.57 v 0.73%+/-0.49%; NS). In conclusion, our results show that in diabetic patients with AN, vasopressin participates in BP control by stimulating vascular and renal V1 receptors, which results in vasoconstriction and sodium reabsorption.


Therapeutic neovascularization by transplantation of mobilized peripheral blood mononuclear cells for limb ischemia. A comparison between CD34+ and CD34- mononuclear cells.
Autolougous transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized human peripheral blood mononuclear cells (PBMNCs) improves limb ischemia in patients with arteriosclerosis obliterans of lower extremities and with diabetic foot. However, the mechanism of action of PBMNCs remains elusive. Here, we studied comparatively the effects of the G-CSF-mobilized PBMNCs and CD34-depleted G-CSF-mobilized PBMNCs in an ischemia model of athymic nude mice. Fluorescence- labeled human PBMNCs [1 x 10(6)] were intramuscularly injected into the unilateral ischemic hindlimbs of mice. Laser Doppler imaging analysis revealed a significantly augmented blood perfusion at day 7, 14 and 28 after operation. The capillary density was also markedly increased and the rate of limb loss was significantly reduced in cell-transplanted groups when compared with those in PBS group. In comparison with G-CSF-mobilized PBMNCs, the therapeutic efficiency of G-CSF-mobilized PBMNCs deprived of CD34+ cells was impaired. Transplanted cells were found to accumulate around arterioles and scatter in capillary networks. Incorporation of transplanted cells into new capillaries was observed in the G-CSF-mobilized PBMNCs group, but was not detected in the group deprived of CD34+ cells. There was an elevated expression of VEGF in ischemic tissue. Colocalization of VEGF and transplanted mononuclear cells within adductor tissue was demonstrated. These findings indicate that G-CSF-mobilized PBMNCs promote vascular growth not only by incorporating into vessel walls but also by supplying angiogenic factors. The depletion of CD34+ cells attenuated the therapeutic efficiency of G-CSF-mobilized PBMNCs in response to ischemia-induced neovascularization.


'Acceptance of loss' and industrial rehabilitation: an empirical study.
414 disabled persons admitted into one Industrial Rehabilitation Unit over a period of 44 weeks were administered with Osuji's (1969; 1975) 'Acceptance of Loss'-Scale (ALS) during their first and fifth week at the center. The rehabilitees' performances at the center in terms of lateness, absenteeism, and employability rating by the final case conference panel were recorded. Two hypotheses were tested viz: that the ability to stick to a course of industrial rehabilitation (i.e. complete the course) and the ability to perform well at the course among those who complete the course will be a function of the level of acceptance of loss. The two hypotheses were upheld, indicating a high predictive validity of the ALS. The results are discussed in the light of the self-concept theory of Lecky, the cognitive balance and cognitive dissonance theories of Heider and Festinger respectively.


1alpha-hydroxycholecalciferol. Long-term treatment of patients with uraemic osteodystrophy.
Three adolescents with uraemic osteodystrophy were treated for 7 months with daily oral doses of 1alpha-hydroxycholecalciferol (0.25-10.0 mug). All the patients were hypocalcaemic and had high serum levels of alkaline phosphatase before the treatment. A rapid rise in serum calcium and a slow, but pronounced decline in serum alkaline phosphatase concentration were observed during the period of treatment. 1alpha-Hydroxycholecalciferol induced hypercalcaemia in two situations. In both cases the hypercalcaemia was transient, serum calcium being normalized in a few days by withdrawal of the drug. Withdrawal of the drug also in other situations resulted in a fall in serum calcium concentration in a couple of days. This suggests that 1alpha-hydroxycholecalciferol should be given daily or every other day. The response did not subside during 7 months of treatment. On the contrary, the maintenance dose necessary to keep serum calcium constant was smaller than the initial dose necessary to normalize serum calcium. Bone mineral content, estimated by photon absorptiometry, rose. The rachitic bone lesions seen radiologically were significantly ameliorated during the treatment.


Next-Generation Sequencing Revealed TP53 Mutations to Be Malignant Marker for Intraductal Papillary Mucinous Neoplasms That Could Be Detected Using Pancreatic Juice.
The aims of this study were to identify the genetic mutations associated with malignant intraductal papillary mucinous neoplasms (IPMNs) and evaluate the possibility of detecting mutations in pure pancreatic juice by next-generation sequencing. Resected tissues were collected from 50 patients with IPMN, and pure pancreatic juice samples were collected from 19 patients who had a resection. The extracted DNA was amplified by multiplex polymerase chain reaction targeting 52 cancer-related genes, including KRAS, GNAS, RNF43, and TP53; the mutations were then detected by next-generation sequencing and then analyzed for correlations with the clinicopathological characteristics. In the resected tissues, the most frequently detected mutations were in KRAS, GNAS, TP53, and RNF43, in 88%, 76%, 36%, and 30% of cases, respectively. Univariate and multivariate analyses revealed that only TP53 mutations were associated with malignant IPMNs (P = 0.023). In the pure pancreatic juice, TP53 mutations were detected in 5 of 10 resected samples with malignant IPMN and in 4 of 5 pancreatic juice samples with mutation in resected samples. From 52 cancer-related gene analysis, only TP53 mutation was associated with malignant IPMNs. TP53 mutation could also be detected in pure pancreatic juice, potentially making it a useful tool to diagnose malignant IPMNs preoperatively.


Plastic cup traps equipped with light-emitting diodes for monitoring adult Bemisia tabaci (Homoptera: Aleyrodidae).
Equipping the standard plastic cup trap, also known as the CC trap, with lime-green light-emitting diodes (LED-plastic cup trap) increased its efficacy for catching Bemisia tabaci by 100%. Few Eretmocerus eremicus Rose and Zolnerowich and Encarsia formosa Gahan were caught in LED-plastic cup traps. The LED-plastic cup traps are less expensive than yellow sticky card traps for monitoring adult whiteflies in greenhouse crop production systems and are more compatible with whitefly parasitoids releases for Bemisia nymph control.


Use of 11C-MPDX and PET to study adenosine A1 receptor occupancy by nonradioactive agonists and antagonists.
Adenosine A1 receptors (A1Rs) in human and rodent brains can be visualized with the radioligand 8-dicyclopropylmethyl-1-(11)C-methyl-3-propylxanthine ((11)C-MPDX) and PET. Here we investigated whether A1R occupancy by nonradioactive agonists and antagonists can be assessed with this technique. Small-animal PET scans with arterial blood sampling were obtained for 4 groups of isoflurane-anesthetized Wistar rats: controls (n = 7); pretreated with a centrally active A1R agonist, N(6)-cyclopentyladenosine (CPA; 0.25 mg/kg intraperitoneally; dissociation constant, 0.48 nM; n = 7); pretreated with a moderate dose of caffeine (antagonist for A1Rs and adenosine A2A receptors; 4 mg/kg intraperitoneally; dissociation constant, 11 μM; n = 6); and pretreated with a high dose of caffeine (40 mg/kg intraperitoneally; n = 6). The administration of CPA resulted in a strong reduction (>50%) in the heart rate, and caffeine administration resulted in a small increase (10%-15%). A caffeine dose of 4 mg/kg (n = 6) resulted in 65.9% A1R occupancy, and a dose of 40 mg/kg (n = 6) resulted in 98.5% occupancy (calculated from a modified Lassen plot). However, the administration of CPA resulted in an increase in (11)C-MPDX binding in the brain. Small-animal PET with (11)C-MPDX can be used to assess antagonist but not agonist binding at A1Rs. Changes in tracer uptake after the administration of CPA resembled previously reported changes induced by treatment of rats with ethanol and an adenosine kinase inhibitor (ABT702). Thus, the administration of an exogenous agonist or increasing the level of an endogenous agonist have similar effects. Agonists and antagonists may bind to different sites on the A1R protein having allosteric interactions.


Human pulp response after partial pulpotomy with two calcium hydroxide products.
Twenty human permanent teeth were used to study the pulpal response of two calcium hydroxide products, Dycal and Pulpdent Multi-Cal, after partial pulpotomy. Teeth were extracted at 4 months, fixed, and prepared for histologic examination. All 10 teeth treated with Dycal showed complete soft tissue healing and bridge formation. No stained bacteria were seen throughout the serial sections. One tooth treated with Dycal showed acceptable histologic results, dentin deposition in the root canal. Six cases dressed with Pulpdent Multi-Cal showed acceptable histologic results, whereas four teeth showed severe inflammation or necrosis associated with bacterial penetration into the pulp tissue. Clinically, one tooth treated with Pulpdent Multi-Cal showed pulpal pain and was extracted at 90 days. Our data support the thesis that human permanent pulps will promote tissue healing and dentin bridge formation as long as bacterial microleakage is excluded.


A new Pax gene, Pax-9, maps to mouse chromosome 12.
Members of the Pax gene family have recently been shown to play important roles in mouse embryogenesis. Of eight so far characterized Pax genes, three have been associated with mouse developmental mutants. Here we report the cloning of a new Pax gene, Pax-9. Most of the DNA sequence encoding the highly conserved paired domain has been determined and compared with previously known paired domains. This comparison classifies Pax-9 as a member of the same subgroup as Pax-1/undulated. By analysis of the segregation of a Pax-9 restriction fragment length polymorphism and a large number of simple sequence length polymorphisms in an interspecific C57BL/6 x Mus musculus mollosinus backcross, Pax-9 was mapped close to the D12Nds1 locus on the proximal part of Chromosome (Chr) 12.


Interactions of excitatory and inhibitory feedback topologies in facilitating pattern separation and retrieval.
Within the brain, the interplay between connectivity patterns of neurons and their spatiotemporal dynamics is believed to be intricately linked to the bases of behavior, such as the process of storing, consolidating, and retrieving memory traces. Memory is believed to be stored in the synaptic patterns of anatomical circuitry in the form of increased connectivity densities within subpopulations of neurons. At the same time, memory recall is thought to correspond to activation of discrete areas of the brain corresponding to those memories. Such regional subpopulations can selectively activate during memory recall or retrieval, signifying the process of accessing a single memory or concept. It has been shown previously that recovery of single memory activity patterns is mediated by global neuromodulation signifying transition into different cognitive states such as sleep or awake exploration. We examine how underlying topology can affect memory awake activation and sleep reactivation when such memories share increasing proportions of neurons. The results show that while single memory activation is diminished with increased overlap, pattern separation can be recovered by offsetting excitatory associations between two memories with targeted and heterogeneous inhibitory feedback. Such findings point to the importance of excitatory-to-inhibitory current balance at both the global and local levels in the context of memory retrieval and replay, and highlight the role of network topology in memory management processes.


Micellization of Mixed System of Bile Salt and Nonionic Surfactant: Sodium Deoxycholate and Decanoyl-N-methylglucamide.
Micelle formation was studied for mixed surfactant systems of a nonionic surfactant, nonanoyl-N-methylglucamine (MEGA-10) with a bile salt, sodium deoxycholate (NaDC), in water at 30 degreesC. NaDC and MEGA-10 are quite different from each other in terms not only of hydrophobic but also of hydrophilic groups. Surface tension of the aqueous solution (gamma) at different mixing ratios was measured by the drop volume method, and critical micellization concentrations (CMCs) were determined from the gamma vs CMC curves at discrete mole fractions of MEGA-10 (XMEGA) in the surfactant mixture. The CMC-XMEGA curve showed a positive deviation from ideal mixing. The apparent interaction parameter (WR) upon micelle formation was evaluated by applying the Rubingh equations derived on the basis of the regular solution theory. The different theory developed by Motomura et al. has been also applied. The analysis of CMC data indicated that the properties of mixed micelles are different between the ranges below and above XMEGA congruent with 0.2 where an azeotrope exists and that the composition of mixed micelles is very similar to that of monomeric species in bulk solution. Copyright 1998 Academic Press.


Biosynthesis of the yeast cell wall: selective assays and regulation of some mannosyl transferase activities.
Assays have been developed for some transfer reactions involved in the synthesis of Saccharomyces cerevisiae wall mannoproteins, both in a particulate preparation in the presence of EDTA or Triton X-100, and after lipid extraction with chloroform-methanol at -20 C. The mannosyl transferase activities were also studied in cells made permeable to GDP-mannose by toluene-ethanol treatment ("in situ"). In these permeabilized cells, the glycosylating reactions dependent on lipid carriers (dolichol derivatives) did not function, but those independent of them were unaffected. The lipid-independent mannosyl transferase activities were partially inhibited by nucleotide diphosphates probably in a competitive manner. Increase of the nucleotide diphosphate pool "in vivo" might slow down the speed of the transfer reactions carried out by the mannan synthetase system.


Biofeedback as a means to alter electromyographic activity in a total knee replacement patient.
This paper presents a single case controlled study of a 75-year-old male having bilateral total knee replacement. Baseline EMG recordings demonstrated differential levels of vastus medialis and vastus lateralis muscle activity in both knees during exercise, with increased vastus lateralis activity compared to vastus medialis activity. The purpose of the study was to use electromyographic (EMG) biofeedback training to train the patient to equalize vastus medialis and vastus lateralis EMG activity during exercise. After 11 and 13 training sessions for the left and right knees, respectively, differences between vastus medialis and vastus lateralis activity had markedly decreased. Following the termination of biofeedback training, EMG activity during exercise showed a return toward baseline levels. Several concomitant changes in psychological and physical function were noted. These results suggested that EMG biofeedback can be used to train vastus medialis and vastus lateralis activity in total knee replacement patients, and that biofeedback training may produce positive benefits in other functional areas.


The phenothiazine drugs inhibit hERG potassium channels.
Cardiovascular adverse effects from phenothiazine drugs are common. The most serious consequences of treatment, arrhythmias and sudden death, are probably rare and most likely to be caused primarily by blockade of cardiac potassium channels such as the human ether-a-go-go-related gene (hERG) channel, which plays a central role in arrhythmogenesis. This phenomenon has been previously reported to occur with a few phenothiazine drugs. However, phenothiazine drugs are composed of pharmacologically and structurally diverse groups. The effects of many of the phenothiazine drugs on hERG channels expressed in mammalian cell lines remain unknown. Therefore, we investigated the effects of four distinct phenothiazine drugs (thioridazine, chlorpromazine, trifluoperazine, and perphenazine) on hERG channel expressed in chinese hamster ovary (CHO) cells. HERG channels were expressed in CHO cells, and ion currents were measured using the patch-clamp technique. Thioridazine, perphenazine, trifluoperazine, and chlorpromazine blocked hERG potassium channels with the following IC(50) values: IC(50) values were 224 +/- 42 nM for thioridazine, 1003 +/- 71 nM for perphenazine, 1406 +/- 124 nM for trifluoperazine, and 1561 +/- 281 nM for chloropromazine. Inhibition of hERG channels by thioridazine was characterized by significant changes in voltage dependence, the value of V(1/2), the half-maximal activation potential, and shift into negative potential, that is, the amount of block was greater at more positive potential. No significant changes were noted in other drugs.


Protective effect of tryptophan and cysteine against carbon tetrachloride-induced liver injury.
The effects of the administration of tryptophan and/or cysteine on carbon tetrachloride (CCl4)-induced hepatic injury were investigated. Rats received CCl4 (1 ml/kg ip) followed 6 hr later by tryptophan (300 mg/kg) and/or cysteine (950 mg/kg) via stomach tube and rats were killed after 24 hr. Treatment with tryptophan, cysteine, or both reduced the degree of hepatic necrosis observed histologically. While CCl4 caused polyribosomal disaggregation and decreased [14C]leucine incorporation into liver proteins in vitro and in vivo, treatment with tryptophan, cysteine, or both caused a shift in polyribosomes toward heavier aggregation and protein synthesis was increased. Serum activities of lactic dehydrogenase (LDH), glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and gamma-glutamyl-transpeptidase were markedly increased after CCl4 alone but after subsequent treatment with cysteine or with tryptophan and cysteine appreciable decreases occurred. Glutathione concentration decreased but total amount remained constant in the livers of CCl4-treated rats while subsequent treatment with cysteine alone or together with tryptophan elevated both levels of glutathione. Using isolated hepatocytes, CCl4 caused decreases in cell viability, in release of LDH, and in [14C]leucine incorporation into protein. Treatment with CCl4 and tryptophan and/or cysteine revealed that cysteine alone or with tryptophan improved cell viability and decreased LDH release of the cells, while tryptophan alone or with cysteine improved protein synthesis. Upon cytologic evaluation, the isolated hepatocytes revealed membrane distortions after CCl4 alone but these were less marked after CCl4 plus tryptophan, cysteine, or both (most improvement). Thus, tryptophan and cysteine act in a beneficial manner against CCl4-induced hepatic injury in the rat.


[Modern treatment methods for multiple myeloma: guidelines from the Dutch Haemato-Oncology Association (HOVON)].
The treatment for multiple myeloma has undergone many changes over the past decade. Intensive therapy with autologous stem-cell support has improved the clinical outcome significantly in younger patients. Reduced intensity conditioning regimens have lowered the high treatment-related mortality of myeloablative allogeneic transplantation. New effective anti-myeloma drugs such as bortezomib and thalidomide analogues have become available. These new developments have made it necessary to formulate recommendations to facilitate decisions concerning the management of myeloma patients. The Myeloma Working Party of the Dutch Haemato-Oncology Association (Stichting Haemato-Oncologie voor Volwassenen Nederland) has developed therapy guidelines based on phase-II and phase-III studies as well as the expertise of the working party. These include upfront induction therapy followed by autologous transplantation for patients aged up to 65 years and oral melphalanprednisone treatment for patients with severe co-morbidities and patients over the age of 65 years. Patients under the age of 66 with an HLA-identical (family) donor are candidates for non-myeloablative stem-cell transplantation following autologous stem-cell transplantation. For second-line treatment, thalidomide, combined with dexamethasone is recommended. Younger patients responding to second-line treatment are candidates for a second autologous transplant. Bortezomib is indicated for those patients refractory to the previous two lines of treatment. All patients should receive long-term bisphosphonates. Erythropoietin may be considered in symptomatic anaemia as well as antibiotic prophylaxis during induction therapy which includes dexamethasone.


Differential effect of the ultra-low dose and standard estrogen plus dydrogesterone therapy on thrombin generation and fibrinolysis in postmenopausal women.
The objective of this study was to estimate the effects of different doses of oral hormone therapy (HT) on thrombin generation and fibrinolytic activity in postmenopausal women after 12 months of treatment. Thrombin generation, fibrinolysis activators and inhibitors were determined before and after 12 months of treatment. Participants (180) were assigned (1:1:1) as follows: (1) standard HT group, 17β-estradiol (1 mg/day) with dydrogesterone (5 mg/day); (2) ultra-low dose HT group, 17β-estradiol (0.5 mg/day) with dydrogesterone (2.5 mg/day); (3) control group, no treatment. The standard HT led to a higher concentration of prothrombin 1 + 2 fragment (by 5.8%) with lower antithrombin activity (by 6.1%). Compared with baseline, we observed a reduction in mean antithrombin activity in the standard HT group and increases in mean levels of prothrombin 1 + 2 fragment in two HT groups. We found decreases after treatment in both standard and ultra-low dose HT groups in plasminogen activator inhibitor-1 (PAI-1) activity (-32.4% and -19.6%, respectively) and PAI-1 antigen (-9.9% and -7.8%, respectively). Intergroup analysis revealed reduction in both mean PAI-1 activities and PAI-1 antigen levels in the two treatment groups when compared with the control. Contrary to the standard estrogen plus dydrogesterone treatment, ultra-low dose HT revealed positive effects on hemostasis by intensifying fibrinolysis through a decrease in both PAI-1 activity and antigen levels, and with no impact on thrombin generation.


Chromatin maintenance and dynamics in senescence: a spotlight on SAHF formation and the epigenome of senescent cells.
Senescence is a stable proliferation arrest characterized by profound changes in cellular morphology and metabolism as well as by extensive chromatin reorganization in the nucleus. One particular hallmark of chromatin changes during senescence is the formation of punctate DNA foci in DAPI-stained senescent cells that have been called senescence-associated heterochromatin foci (SAHF). While many advances have been made concerning our understanding of the effectors of senescence, how chromatin is reorganized and maintained in senescent cells has remained largely elusive. Because chromatin structure is inherently dynamic, senescent cells face the challenge of developing chromatin maintenance mechanisms in the absence of DNA replication in order to maintain the senescent phenotype. Here, we summarize and review recent findings shedding light on SAHF composition and formation via spatial repositioning of chromatin, with a specific focus on the role of lamin B1 for this process. In addition, we discuss the physiological implication of SAHF formation, the role of histone variants, and histone chaperones during senescence and also elaborate on the more general changes observed in the epigenome of the senescent cells.


Percutaneous screw fixation for fractures of the scaphoid.
We describe a percutaneous technique for screw fixation of all types of fractures of the scaphoid. During a 15-year period ending in 1984, 280 cases were treated by this method; 198 of them returned for evaluation in 1986 and comprise the material for this report. After a mean postoperative time of 82 months, 89% of the recent fractures had united as well as 81.8% of those with delayed or nonunion and 42.8% of those with sclerotic nonunion.


DAVID: Database for Annotation, Visualization, and Integrated Discovery.
Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.


Resolving bony abnormality evolves to diffuse large B-cell lymphoma.
Primary lymphoma of bone is a rare malignancy that can mimic infection and benign bone lesions radiographically. Malignant conversion of osseous lesions has been reported; evolution to lymphoma has not. We describe an adolescent male diagnosed with atypical osteoid osteoma who, despite near resolution of bony changes involving the anterior tibia, was diagnosed with monostotic diffuse large B-cell lymphoma four years later. Indolent lymphoma of the initial lesion is unlikely. This case highlights the importance of clinical suspicion of malignancy even with recurrence of similar clinical presentation and hints at possible osseous microenvironment abnormalities predisposing to the development of lymphoma.


Gating deficits in model networks: a path to schizophrenia?
Gating deficits and hallucinatory sensations are prominent symptoms of schizophrenia. Comparing these abnormalities with the failure modes of network models is an interesting way to explore how they arise. We present a network model that can both propagate and gate signals. The model exhibits effects reminiscent of clinically observed pathologies when the balance between excitation and inhibition that it requires is not properly maintained.


[Physiopathological aspects of the treatment of benign prostatic hypertrophy. Role of prostatic stroma and estrogens].
The hypothesis of the etiopathogenesis of Benign Prostatic Hypertrophy (BPH) on the basis of stroma-epithelium interaction is presented. The fetal prostate has its origin in the urogenital sinus depending on the dehydrotestosterone stimulating the stromal cells having androgenic receptors. This stroma hyperplasia is considered to be the initial factor in the BPH formation. The inequality in growth factors is also relevant for its formation. Stimulating factors, especially the epidermal growth factor (EGF) prevail on involution factors. The stromal cell has estrogenic receptors. The estrogens from the testosterone aromatization are the first stimulus on the prostatic stroma on the transitional and periurethral area stimulating the glandular epithelium causing BPH. The knowledge of BPH etiopathogenesis will make its rational medical treatment possible, and eventually slow or stop its growth when therapy in its early evolutive stages is prescribed.


Physical activity patterns in Greenland: a country in transition.
To examine differences in physical activity patterns among Inuit in Greenland in relation to social transition. The Inuit in Greenland are an indigenous population in the circumpolar north who are experiencing rapid social transition. Physical activity patterns were assessed by the International Physical Activity Questionnaire (long version). The population was divided into six groups according to different stages of social change, measured on the basis of education, current residence and occupation. Data were collected in a country-wide cross-sectional population survey among adult Inuit in Greenland from 2005 to 2009. Men with long vocational or academic education living in towns (latest stage of social change) spent significantly less time on occupational physical activity (p = 0.001) compared with hunters and fishermen in villages (earliest stage of social change) (trend test p = 0.01). Women in the latest stage of change spent significantly less time on domestic physical activity (p < 0.001) (trend test p = 0.06) compared with women in the earliest stage of social change. This was also found for physical activity during transportation (p = 0.02 and p = 0.01 for men and women, respectively). No significant difference was found for leisure time physical activity. Men and women in the latest stage of social change spent more time on sedentary activity (p < 0.001). Differences in physical activity patterns among Inuit in Greenland included decreasing time spent on domestic and occupational physical activity and increasing time spent on sedentary activities along with social change. Knowledge of changes in physical activity patterns in relation to social transition is important in prevention of obesity, type 2 diabetes and lifestyle diseases.


Complex neurovascular variation in one upper limb.
Variations in the arterial pattern of the upper limb are frequently encountered during dissection of the human body. However, multiple variations in one limb are infrequently encountered. Dissection of the left amputated upper limb, 15 cm above the intercondyler line, of a female cadaver revealed the following variations. 1. The superficial brachial artery descends behind the bicepital apneurosis and continues as the radial artery. 2. The deep (definitive) brachial artery continues in the forearm as the ulnar artery under the superficial flexor muscles of the forearm. 3. The median artery arises from the ulnar artery 5 cm below the intercondyler line and continues deep to the flexor retinaculum. 4. The median artery terminates in the hand as princeps pollicis and radials indicis arteries. 5. The median nerve forms a loop surrounding the median artery 4 cm below the intercondyler line and bifurcates 2 cm above the flexor retinaculum.


Vitronectin-binding surface proteins of Staphylococcus aureus.
S. aureus strain ISP 546 was selected (of 55 strains tested) to define optimal conditions for expression of vitronectin binding. High binding was expressed when the strain was grown on blood agar and in Todd-Hewitt broth. Binding was optimal in the 6.0 to 7.2 pH range and was unaffected by divalent cations and ionic strength. Binding was partially inhibited by D-mannose, heparin, types I and IV collagen, fibronectin, fibrinogen and vitronectin, but was not affected by other carbohydrates or glycoproteins tested. Cell surface binding components were extracted with the aid of 1 M LiCl (pH 5.0) from strain ISP 546 grown in Todd Hewitt broth. Vitronectin binding proteins were purified by affinity chromatography on heparin-Sepharose. Fractions inhibiting binding of 125I-labelled vitronectin to strain ISP 546 were eluted by 0.01 M NaOH, dialysed, concentrated and subjected to SDS-PAGE. Silver staining revealed one major band (70 kDa) and two minor bands (34 and 36 kDa).


Globally rising soil heterotrophic respiration over recent decades.
Global soils store at least twice as much carbon as Earth's atmosphere1,2. The global soil-to-atmosphere (or total soil respiration, RS) carbon dioxide (CO2) flux is increasing3,4, but the degree to which climate change will stimulate carbon losses from soils as a result of heterotrophic respiration (RH) remains highly uncertain5-8. Here we use an updated global soil respiration database9 to show that the observed soil surface RH:RS ratio increased significantly, from 0.54 to 0.63, between 1990 and 2014 (P = 0.009). Three additional lines of evidence provide support for this finding. By analysing two separate global gross primary production datasets10,11, we find that the ratios of both RH and RS to gross primary production have increased over time. Similarly, significant increases in RH are observed against the longest available solar-induced chlorophyll fluorescence global dataset, as well as gross primary production computed by an ensemble of global land models. We also show that the ratio of night-time net ecosystem exchange to gross primary production is rising across the FLUXNET201512 dataset. All trends are robust to sampling variability in ecosystem type, disturbance, methodology, CO2 fertilization effects and mean climate. Taken together, our findings provide observational evidence that global RH is rising, probably in response to environmental changes, consistent with meta-analyses13-16 and long-term experiments17. This suggests that climate-driven losses of soil carbon are currently occurring across many ecosystems, with a detectable and sustained trend emerging at the global scale.


Sample preparation of carbadox, furazolidone, nitrofurazone, and ethopabate in medicated feeds for high pressure liquid chromatography.
Medicated feeds (pelleted or mash) containing guarantees of carbadox, furazolidone, nitrofurazone, and ethopabate are pretreated with water, extracted with 95% dimethylformamide overnight at room temperature, cleaned up on a column of alumina, and injected into a high pressure liquid chromatograph for quantitative measurement. Carbadox, nitrofurazone, and furazolidone can be separated; chromatograms show excellent baseline resolution, and results are in good agreement with colorimetric methods. The same extraction and cleanup can be used to improve colorimetric methods for furazolidone and nitrofurazone.


AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress.
AVE 0991, the nonpeptide angiotensin-(1-7) (Ang-(1-7)) analog, is recognized as having beneficial cardiovascular effects. However, the mechanisms have not been fully elucidated. This study was designed to investigate the effects of AVE 0991 on cardiac hypertrophy and the mechanisms involved. Mice were underwent aortic banding to induce cardiac hypertrophy followed by the administration of AVE 0991 (20 mg kg·day (-1)) for 4 weeks. It was shown that AVE 0991 reduced left ventricular hypertrophy and improved heart function, characterized by decreases in left ventricular weight and left ventricular end-diastolic diameter, and increases in ejection fraction. Moreover, AVE 0991 significantly down-regulated mean myocyte diameter and attenuate the gene expression of the hypertrophic markers. Furthermore, AVE 0991 inhibited the expression of NOX 2 and NOX 4, meaning that AVE 0991 reduced oxidative stress of cardiac hypertrophy mice. Our data showed that AVE 0991 treatment could attenuate cardiac hypertrophy and improve heart function, which may be due to reduce oxidative stress.


Chaperone and anti-chaperone: two-faced synuclein as stimulator of synaptic evolution.
Previous studies have shown that beta-synuclein (beta-syn), the homologue of alpha-syn, inhibited alpha-syn aggregation and stabilized Akt cell survival signaling molecule, suggesting that beta-syn was protective against alpha-syn-related neurodegenerative disorders, such as Parkinson's disease and diffuse Lewy body disease. However, emerging evidence argues that the situation may be not so simple. Two missense mutations of beta-syn were identified in familial and sporadic diffuse Lewy body disease, and wild type beta-syn was induced to form fibril structures in vitro, while, alpha-syn was shown to be protective against neurodegeneration caused by deletion of cysteine-string protein-alpha, the presynaptic cochaperone to Hsc70 in mice. Collectively, alpha- and beta-syn are both, but in varying degrees, featured with two opposite properties, namely normal chaperone and anti-chaperone. By reviewing recent progress in syn biology with a particular focus on beta-syn, this manuscript refers to the intriguing possibility that the dual syn proteins might have acquired a driving force for synaptic evolution. Hypothetically, the anti-chaperone syn may provoke stress-induced diverse responses, whereas, the chaperone syn may provide buffering for them, allowing accumulation of nonlethal phenotypic variations in synapses. Consequently, dual syn proteins may cope with forthcoming stresses in the brain by stimulating adaptive evolution. In this context, failure to regulate this process due to various causes, such as gene mutations and environmental risk factors, may result in imperfect adaptability against stresses, leading to neurodegenerative disorders.


Cardiac Amyloidosis: Diagnosis and Treatment Strategies.
Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.


[Intestinal mechanisms of compensation and morphologic and functional adaptation after resection of bypass].
The intestine's ability to adapt following extensive resection is well known, and includes augmentation in calibre and the thickness of the wall, increased villus height, changes in motility, and qualitative and quantitative alterations in the flora. Positive identification of the mechanisms through which this morphological and functional adaptation takes place still forms the subject of research. An account is given of the latest views concerning the way in which compensation of the intestine takes place after resection and by-pass surgery.


Fluid and electrolyte management of very low birth weight infants.
Recent advances in medical knowledge and technology have markedly improved the survival rates of very low birth weight infants. Optimizing the neuro-developmental outcomes of these survivors has become an important priority in neonatal care, which includes appropriate management for achieving fluid and electrolyte balance. This review focuses on the principles of providing maintenance fluid to these infants, including careful assessment to avoid excessive fluid administration that may increase the risk of such neonatal morbidities as necrotizing enterocolitis, patent ductus arteriosus, and bronchopulmonary dysplasia (BPD). The review also describes the principles of fluid and electrolyte management of infants with BPD, which includes the strategy of providing adequate nutrition to promote normal growth.


Evidence for a novel thioredoxin-like catalytic property of gonadotropic hormones.
It has been proposed that dithiol-disulfide interchange and oxidation-reduction reactions may play a role in hormone-induced receptor activation. Inspection of the sequences of the gonadotropic hormones revealed a homologous tetrapeptide (Cys-Gly-Pro-Cys) between the beta subunit of lutropin (LH) and the active site of thioredoxin (TD). The beta subunit of follitropin (FSH) has a similar sequence (Cys-Gly-Lys-Cys). Thioredoxin is a ubiquitous protein serving as an electron donor for ribonucleotide reductase, but it also exhibits disulfide isomerase activity. The catalytic activity of TD was assayed by its ability to reactivate reduced and denatured ribonuclease. In this assay, the purified ovine FSH and bovine LH preparations tested were approximately 60 and approximately 300 times, respectively, as active as TD on a molar basis. This heretofore unsuspected catalytic property of FSH and LH may be important in understanding their mechanism of receptor activation and signal transduction.


[Perception of difficulties in family medicine in the delivery of health to economic immigrants].
To find the problems, as seen by family doctors, in care for immigrants, with description of proposed solutions. Transversal and descriptive. 262 doctors from 18 health centres in a district. Each professional received a questionnaire containing social and demographic variables, number of immigrants seen per day, their place of origin, 6 items on accessibility, 5 on barriers to care, 6 on clinic, and 7 on solutions. 159 doctors, 57.2% women, replied. Average age was 41.1; 64% saw 2-3 immigrants a day. 52.3% (95% CI, 45.0%-61.4%) recognised that care for immigrants posed professional problems. They said that immigrants attended as an emergency more often (81.1%); they more often had no clinical records (74.7%); and they had difficulties obtaining a health card (53%). 67% expressed no difficulties for getting to the hospital. Perceived barriers were the mobility of immigrants (82.9%), language (82.3%), and culture (71.3%). Solutions suggested were translators (95.6%) or cultural intermediary (82.7%). Clinically, doctors saw no differences of pathology in immigrants (56.7%), and no greater psychiatric pathology (66%). Lack of skill in contagious pathologies hampered care (60.3%). 82.8% affirmed that specific protocols were needed. 80.3% argued for a unit of imported diseases. Among care priorities were information on health circuits and making the health card easier to obtain. The difficulties sustained by a broad range of professionals are diverse, with access and linguistic-cultural questions standing out. To palliate them, sensitivity from health staff and action from management are needed.


Rapid opioid detoxification using opioid antagonists: history, theory and the state of the art.
Rapid opioid detoxification is a technique for detoxifying patients addicted to narcotics which is increasing in popularity. This technique is potentially useful in getting some patients through the withdrawal phase of substance abuse therapy so that they may engage in further treatment earlier in the course of their disease. However, this procedure, which can and should be done safely, has in the past been pushed to limits which approach boundaries outside of the provider's area of expertise. This paper attempts to present a critical review of previous publications relating to rapid opioid detoxification to address these and other issues. There appears to be a pharmacologic basis for the efficacy of this treatment on a longer-term basis which centers around upregulation of opioid receptors induced by opioid antagonists. This paper also attempts to offer evidence in support of this theory.


Mental health inpatient treatment expenditure trends in China, 2005-2012: evidence from Shandong.
Mental health is increasingly becoming a huge public health issue in China. Yet for various cultural, healthcare system, and social economic reasons, people with mental health need have long been under-served in China. In order to inform the current on-going health care reform, empirical evidences on the economic burden of mental illnesses in China are urgently needed to contribute to health policy makers' understanding of the potential benefits to society from allocating more resources to preventing and treating mental illness. However, the cost of mental illnesses and particularly its trend in China remains largely unknown. To investigate the trend of health care resource utilization among inpatients with mental illnesses in China, and to analyze what are the factors influencing the inpatient costs. Our study sample included 15,721 patients, both adults and children, who were hospitalized over an eight-year period (2005-2012) in Shandong Center for Mental Health (SCMH), the only provincial psychiatric hospital in Shandong province, China. Data were extracted from the Health Information System (HIS) at SCMH, with detailed and itemized cost data on all inpatient expenses incurred during hospitalization. The identification of the patients was based on the ICD-10 diagnoses recorded in the HIS. Descriptive analysis was done to analyze the trend of hospitalization cost and length of stay during the study period. Multivariate stepwise regression analysis was conducted to assess the factors that influence hospitalization cost. Among the inpatients in our sample, the most common mental disorders were schizophrenia, schizotypal and delusional disorders. The disease which had the highest per capita hospital expense was behavioral and emotional disorders with onset usually occurring in childhood and adolescence (RMB 8,828.4; US$ 1,419.4, as compared to the average reported household annual income of US$ 2,095.3 in China). The average annual growth rate of per capita hospitalization cost was 23.6%, with the inpatient cost reaching RMB 11,949 (US$ 1921.1) in 2012. The hospitalization cost was found to be strongly associated with hospital length of stay, level of care, age, employment status, admission diagnoses, and frequency of hospitalization. Our study found that mental health inpatient resources use, particularly hospitalization cost, has been growing at an increasing rate. In our sample, hospitalization cost nearly tripled from 2005 to 2012. Mental illnesses and the related economic burden on the population will continue to grow, making mental health a major public health issue in China. Hospital length of stay was found to be increasing in our sample, and positively correlated with hospitalization cost. Childhood and adolescence behavioral and emotional disorders were found to be significantly associated with higher inpatient cost. The policy implications generated from the results of this study are two-fold: first of all, in order to meet the growing need of mental health care in China, the government needs to significantly increase its spending in preventing and treating mental illnesses. Second, cost containment in inpatient care would become a major challenge for mental health policy makers in China. Government support, clinical practices and guideline development, as well as research are urgently needed to promote mental health prevention and improve the efficiency of mental health system in China. The current mental health system, like the overall healthcare system in China, relies heavily on hospital inpatient care. In order to build a sustainable mental health care system to meet increasing population need in China, it is crucial to integrate mental health care reform with the ongoing primary health care reform. Future mental health policy reform and research in China should put more focus on how to strengthen primary care system as well as community support, establish effective two-tier referring mechanism between hospital and primary care system, and to ensure continuity of care.


Reducing the bias of probing depth and attachment level estimates using random partial-mouth recording.
To evaluate the bias and precision of probing depth (PD) and clinical attachment level (CAL) estimates of random and fixed partial examination methods compared with full-mouth examinations. PD and CAL were calculated on six sites for up to 28 teeth (considered to be the gold standard with no bias) and three fixed-site selection methods (FSSMs) that resulted in a partial examination of sites: the Ramfjord method, and the NIDCR methods used in NHANES I, and NHANES 2000. Finally, seven random-site selection methods (RSSMs) were created by sampling the following number of sites: 84, 42, 36, 28, 20, 15, 10 and 6. To compare bias and precision of the methods we calculated percent relative bias and relative error. Estimates of means, standard deviations (SD), relative bias and relative error for RSSMs were almost identical to the full-mouth examination, but SDs increase slightly when fewer than 28 sites were sampled and relative bias and error increase for methods sampling fewer than 20 sites. The FSSMs had very low relative error, but much higher relative bias indicating underestimation. The FSSM with the smallest bias and error was the Ramfjord method, but the Random 36 method had less bias and less relative error. The NHANES 2000 method was the FSSM with the lowest bias and relative error for estimates of Extent Scores (percent of sites > or =3, 4, 5, or 5 mm PD or CAL) but random methods sampling fewer sites performed just as well. Both FSSMs and RSSMs underestimated prevalence, especially prevalence of less frequently occurring conditions, but most RSSMs were less likely to underestimate prevalence than the FSSMs. The promise of reducing bias and increasing precision of the estimates support the continued development and examination of RSSMs.


Behavioral ratings and outcome of medical treatment for encopresis.
The relationship between behavior problems and encopresis remains controversial. Recent research suggests that children with encopresis do have numerous behavior problems, but that these problems are generally not as severe as the behavior problems found in children referred for mental health services. This study explores the relationship between baseline behavior ratings of encopretic boys, ages 6-11, on a standardized rating form, the Child Behavior Checklist (CBCL), and outcome of medical treatment for their encopresis. A strong correlation between the product of the sum of the factors on the internalizing scales and the sum of the factors on the externalizing scales and their interaction on the CBCL was associated with outcome. Specifically, moderate elevations of this function predicted good outcome at 3, 6, and 12 months. Very high elevations and minimal or no elevation predicted poor outcome at 3, 6, and 12 months. Possible reasons for these somewhat surprising results are discussed.


Multiple myeloma in young men. Clinical course and electron microscopic studies of bone marrow plasma cells.
Two cases of multiple myeloma in young men are described. Electron microscopic characteristics of the bone marrow plasma cells are presented. Multiple myeloma is unusual in the young, and when onset in male patients occurs between the ages of 15 and 25 years, the clinical course is more mild and survival longer, even though response to chemotherapy is limited.


[Successful treatment of refractory peripheral T-cell lymphoma by allogeneic peripheral blood stem cell transplantation].
A 40-year-old man was admitted to our hospital suffering from abdominal pain. He revealed marked splenomegaly, lymphadenopathy and pancytopenia. Lymph node biopsy showed diffuse proliferation of medium to large atypical lymphoid cells. Immunohistochemically the cells were positive for T-cell markers. He was diagnosed as having peripheral T cell lymphoma (PTCL) with involvement of the spleen and bone marrow. Because of refractoriness to combination chemotherapies and splenic irradiation, we performed allogeneic peripheral blood stem cell transplantation from an HLA-identical sister. Conditioning was consisted of conventional doses of total body irradiation and cyclophosphamide, and GVHD prophylaxis was performed with cyclosporine and methotrexate. After the patient developed grade III graft-versus-host disease, his splenomegaly improved dramatically. Although the effectiveness of allogeneic hematopoietic cell transplantation in the treatment of malignant lymphoma is controversial, we should consider this as a second-line therapy to refractory subsets of PTCL.


In vitro activity of the benzotriazine dioxide SR 4233 against human tumour colony-forming units.
SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a novel bioreductive agent selectively toxic to hypoxic cells. It is active as a radiation sensitiser in vitro. Using a human tumour cloning system we have studied the effects of SR 4233 against freshly explanted human tumour specimens under hypoxic and non-hypoxic culture conditions. For hypoxic conditions, final concentrations of SR 4233 of 10.0-500 mumol/l were used in short-term (1 h) exposure experiments. Final concentrations in non-hypoxic experiments ranged from 10 to 1350 mumol/l. 25 tumour specimens were tested under each culture condition. Of those, 14 (56%) were evaluable. The most common tumour types recruited included ovarian, non-small cell lung, and breast cancer. A moderate concentration-dependent increase in the frequency of inhibited tumour specimens under non-hypoxic conditions was observed with zero out of 10 sensitive specimens at 10 mumol/l as compared with five out of 14 (36%) sensitive specimens at 500 mumol/l (P < 0.02). However, when hypoxic conditions were used SR 4233 had a profound antitumour activity, (two out of 14 specimens sensitive at 10 mumol/l compared with 10 out of 10 specimens sensitive at 500 mumol/l, P < 0.00005). We conclude that SR 4233 is active against tumour colony-forming units in vitro and that its antitumour activity is greatly increased against hypoxic tumour cells.


To treat or not to treat basilic vein aneurysms? A clinical dilemma.
Superficial venous aneurysms are a very uncommon disease probably associated with thrombosis and recurrent pulmonary thromboembolisms. Surgical treatment is safe and is performed in symptomatic cases. Surgical repair of superficial venous aneurysms is a recommended treatment, and no postoperative complications usually occur. The aim of this study is to report our experience treating superficial venous aneurysms, because they can cause devastating consequences. Obviously, they should be surgically treated if they are symptomatic, but there exists the possibility of complications such as thromboembolic events; however, they are unpredictable. Thus, the only solution to remove the potential risk of developing pulmonary or other embolic events is prophylactic surgery and anticoagulant therapy, also in low-risk patients.


Cerd4, third member of the d4 gene family: expression and organization of genomic locus.
Two members of the d4 family of presumptive transcription modulators, neuro-d4 (Neud4) and ubi-d4/Requiem (Req), have been characterized previously. We cloned and characterized the third member of this gene family, cer-d4 (Cerd4), from chicken and mouse cDNA libraries. The expression patterns of Cerd4 gene in both species are similar and more restricted than expression patterns of other two d4 genes. The main sites of Cerd4 expression are retina and cerebellum, where multiple transcripts could be detected. Two major types of Cerd4 proteins are a full-length isoform possessing all domains characteristic to the d4 family and truncated XZ isoform without C-terminal tandem of PHD fingers. The developmental kinetics of expression of these isoforms is different. The intron/exon structure of human Cerd4 gene is similar to that of neuro-d4 and ubi-d4/Requiem genes, but most introns of Cerd4 gene are much larger than the corresponding introns of the other two genes.


Initial experience with 150 cases of laparoscopic assisted colectomy.
Despite multiple reports of large series in the literature over the past decade, laparoscopic assisted colectomy (LAC) has not received widespread acceptance by the surgical community. Critics of LAC note concerns regarding unproved benefits and increased complexity of the procedures. The authors report their initial experience with 150 procedures. A retrospective review of 150 consecutive LACs was performed by the authors. Mean operative time for completed LAC, converted procedures, right, and sigmoid resections were 164 minutes, 203 minutes, 121 minutes, and 177 minutes, respectively. Twenty-two patients had additional concurrent laparoscopic procedures. Thirty-nine patients had undergone previous abdominal surgery. The conversion rate was 12%. Mean length of stay for all patients was 4.5 days. There were 8 major and 16 minor complications. There were no port site metastases. Major complications and conversion rate decreased from the first 50 cases to the last 50 cases. LAC can be safely performed with superior quality of life outcomes in comparison with open colectomy. The authors believe that LAC will eventually become the gold standard for colon resection. The learning curve is discussed as an ongoing process, rather than a set number of procedures.


Control of the collapse of bimodal light beams by magnetically tunable birefringences.
Using a system of coupled nonlinear Schrödinger equations (CNLSEs), we show that nonlinear light propagation in self-focusing Kerr media can be controlled via a suitable combination of linear and circular birefringences. In particular, magneto-optical effects are taken as a specific physical example, which enables the introduction of both types of birefringences simultaneously via the joint action of the Cotton-Mouton and the Faraday effect. We demonstrate the efficient management of the collapse of (2 + 1)D beams in magneto-optic dielectric media, which may result in either the acceleration or the suppression of the collapse. However, our study also shows that a complete stabilization of the bimodal beams (i.e., the propagation of two-dimensional solitary waves) is not possible under the proposed conditions. The analysis is performed by directly numerically solving the CNLSEs, as well as by using the variational approximation, both showing consistent results. The investigated method allows high-power beam propagation in Kerr media while avoiding collapse, thus offering a viable alternative to the techniques applied in non-instantaneous and/or non-local nonlinear media.


Preventing postoperative haematomas in microvascular reconstruction of the head and neck: lessons learnt from 126 consecutive cases.
Free tissue transfer has become a safe and reliable means for repairing soft tissue and bony defects of the head and neck. Although operative success has reached 98%, the incidence of significant postoperative complications is also relatively high (32%). One common and significant complication is haematoma formation, occurring at both donor and recipient sites, and yet there are minimal published studies on its incidence, aetiology or outcome. A retrospective analysis of both donor- and recipient-site wound haematoma was carried out to identify causative factors and the effect on patient outcome. A 5-year review of 132 consecutive microvascular free tissue transfers to head and neck defects at The Royal Melbourne Hospital, for the period February 2001 to February 2006, was conducted. Of 126 included cases, 27 postoperative haematomas resulted. Statistically significant associations were found for each of smoking, non-steroidal anti-inflammatory drug use and the use of corticosteroids preoperatively with the incidence of postoperative haematoma formation. Postoperative blood pressure control and the adequacy of primary tumour excision at the flap recipient site were also found to have significant associations with haematoma formation. Drain tube outputs served as accurate indicators for haematoma. There are significant reversible factors that contribute to the development of postoperative haematomas in head and neck reconstructive surgery. Preoperative modifications should, therefore, be sought. Similarly, close monitoring of patient blood pressure during the initial 24 h postoperative period by theatre and recovery staff is important, as is the adequacy of postoperative analgesia.


Cryptococcus neoformans infection in malignancy.
Cryptococcosis is an opportunistic invasive fungal infection that is well described and easily recognised when it occurs as meningitis in HIV-infected persons. Malignancy and its treatment may also confer a higher risk of infection with Cryptococcus neoformans, but this association has not been as well described. A case of cryptococcosis in a cancer patient is presented, and all cases of coincident C. neoformans infection and malignancy in adults published in the literature in English between 1970 and 2014 are reviewed. Data from these cases were aggregated in order to describe the demographics, type of malignancy, site of infection, clinical manifestations, treatment and outcomes of cryptococcosis in patients with cancer. Haematologic malignancies accounted for 82% of cases, with lymphomas over-represented compared to US population data (66% vs. 53% respectively). Cryptococcosis was reported rarely in patients with solid tumours. Haematologic malignancy patients were more likely to have central nervous system (P < 0.001) or disseminated disease (P < 0.001), receive Amphotericin B as part of initial therapy (P = 0.023), and had higher reported mortality rates than those with solid tumours (P = 0.222). Providers should have heightened awareness of the possibility of cryptococcosis in patients with haematologic malignancy presenting with infection.


Neuroradiology of the sequelae of spinal cord trauma.
More than 850 patients with acute injuries to the spinal cord were explored by means of neuroradiological procedures (1954-1981). The sequelae of cord damage were assessed in 125 of these patients and the results of neuroradiological examinations correlated with the surgical or autopsy findings. Such opportunities to demonstrate the changes that follow the acute phase of a spinal cord injury are infrequent because of a lack of centralized team care and continuity of follow-up. Chronic post-traumatic changes, induced by mechanical kinetic or non-mechanical energies, were demonstrated after a long period of time, occasionally after two to ten years. They were classified into six groups. Disturbances of arterial circulation are emphasized as a major source of aggravation of the post-traumatic state of the spinal cord.


Examining the Complex Relation Among Religion, Morality, and Death Anxiety: Religion Can Be a Source of Comfort and Concern Regarding Fears of Death.
This study examined the relationship among religiosity, morality, and fear of death. Students ( n = 328, 75% women, Mage = 18.9) completed measures of fear of death, frequency of immoral behavior, discrepancy between ideal and actual religious practices, strength of religious beliefs, views of God as punishing or forgiving, and behavior efficacy (the extent to which fate in the afterlife was perceived to be determined by behavior in this life). Frequency of immoral behavior was not related to fears of death, but both strength of religious views and behavior efficacy were negatively correlated with fears of death. In contrast, perceived failure to live up to religious standards was associated with more death anxiety, especially among those with punishing views of God. These findings support the idea that some aspects of religion can help protect people from death anxiety, whereas other aspects of religion can exacerbate fears of death.


Superior vena cava syndrome and bilateral subclavian vein thrombosis. CT and radionuclide venography correlation.
Radionuclide venography (RNV) and CT with contrast infusion were performed in a patient with superior vena cava (SVC) syndrome and upper extremity swelling due to SVC and bilateral subclavian vein thrombosis resulting from infection of a Le Veen peritoneovenous shunt. Although CT was suggestive of thrombosis and excluded extrinsic compression by a mass, obstruction of the SVC and deliniation of collateral venous channels were best demonstrated by RNV.


New material for low-dose brachytherapy seeds: Xe-doped amorphous carbon films with post-growth neutron activated 125I.
We report a novel material for use in (125)I brachytherapy that consists of amorphous carbon films grown by ion-beam-assisted deposition and doped with Xe (5 at%) by implantation. Samples of these films grown on Si substrates were irradiated with neutrons in a TRIGA-I nuclear reactor for the production (125)Xe, and latter characterized by gamma spectroscopy. The results indicate that the (124)Xe was efficiently converted into (125)Xe, the precursor of (125)I, and support the activity calculations for a model brachytherapy seed.


Quantitation of monomeric and non-monomeric forms of albumin.
The use of polyacrylamide gel electrophoresis for the quantitation of albumin dimer in commercial albumin samples typically results in an overestimation of the percentage of dimer, as a consequence of significant deviations from Beer's law. This report describes a polyacrylamide gel electrophoresis technique which employs an internal standard for quantitation of albumin dimer. A constant amount of beta-2-glycoprotein I is added to the sample prior to electrophoresis, and the amount of albumin dimer is determined by comparison to that of beta 2-glycoprotein I. A number of commercial albumin solutions were analyzed by this technique; the results were in accord with those obtained by gel permeation chromatography and demonstrated the utility of this method as a rapid screening technique.


Post-traumatic stress impacts on quality of life in children after road traffic accidents: prospective study.
There is little knowledge on health-related quality of life (HRQOL) of injured children and adolescents after road traffic accidents (RTA). Although findings in injured adults suggest that post-traumatic stress symptoms (PTSS) may be important predictors of HRQOL, this issue has never been prospectively examined in children. The aim of the present study was therefore to prospectively assess HRQOL in children after RTA and specifically examine the impact of PTSS on HRQOL. Sixty-eight children (aged 6.5-14.5 years) were interviewed 1 month and 1 year after an RTA using the Child PTSD Reaction Index and the Toegepast Natuurwetenschappelijk Onderzoek-Academisch Ziekenhuis Leiden (TNO-AZL) Questionnaire for Children's Health-Related Quality of Life. Parents and physicians were assessed with questionnaires. Eleven children (16.2%) showed moderate to severe post-traumatic stress reactions at 1 month, and 12 children (17.6%) at 1 year. At 1 month, patients reported reduced motor functioning and autonomy and impairments in some parts of emotional functioning compared to a community sample. At 1 year all dimensions of HRQOL were within or above normal ranges. Multivariate analysis indicated that PTSS at 1 month significantly predicted HRQOL at 1 year. This prospective study provides evidence for a long-term negative influence of early PTSS on HRQOL in injured children. The return of injured children to pre-injury HRQOL may therefore not only depend on optimal medical care but also on awareness and timely interventions regarding PTSS.


Parent-adolescent congruency in reports of adolescent sexual behavior and in communications about sexual behavior.
Agreement between mothers' and adolescents' reports of communication about sex, satisfaction with the parent-child relationship, maternal disapproval of adolescent sexual activity, and adolescent sexual behavior was investigated in a sample of 745 African American adolescents (ages 14-17) and their mothers. Congruence between the 2 sets of reports tended to be low. Adolescent perceptions and reports were found to be more predictive of adolescent sexual behavior than maternal reports. Mothers tended to underestimate the sexual activity of their teens and teens tended to underestimate their mother's level of disapproval of their engaging in sexual activity. Reasons for these misperceptions were explored.


Depressive symptoms in relation to periodontal health in a Jordanian sample.
This cross-sectional study examines the relationship of depression symptoms to periodontal diseases and decayed (D), missing (M) and filled teeth (FT) in a sample of the Jordanian population. Subjects escorting dental patients attending two dental hospitals in North Jordan were included. Each subject received full periodontal examination, including probing pocket depth (PPD), clinical attachment level (CAL), gingival index (GI) and plaque index (PI). The numbers of M, D and F teeth were also recorded. The Zung Self-rating Depression Scale was used to determine susceptibility to depression. The frequency of high susceptibility to depression among periodontitis-free subjects and those with periodontitis was found to be 48% and 50% respectively. There was no statistically significant association between susceptibility to depression symptoms and periodontal parameters, including PPD, CAL, PI and GI (P > 0.05). HOWEVER, SUBJECTS WITH LOW SUSCEPTIBILITY TO DEPRESSION HAD SIGNIFICANTLY MORE FT THAN SUBJECTS HIGHLY SUSCEPTIBLE TO DEPRESSION. High susceptibility to depression does not play a significant role in the aetiology and severity of periodontitis in the population studied.


Carbon nanoparticle ionic liquid hybrids and their photoluminescence properties.
A fluorescent carbon nanoparticle ionic liquid hybrids (CNPIL) with high conductivity is synthesized by a facile one-step microwave method from ionic liquid 1-butyl-3-methylimidazolium glutamine salt and Glucose. This CNPIL exhibits excellent PL properties: bright and colorful PL covering the entire visible-NIR spectral range, up conversion PL properties, pH dependent and can be controlled by the reaction condition.


Peer-assessed behavioural characteristics and sociometric rejection: differences between pupils who have moderate learning difficulties and their mainstream peers.
The outcomes of social inclusion and skills training programmes for pupils with special educational needs have been mixed. Programmes are generally based on research with mainstream samples yet it has been suggested that the social skills important for sociometric acceptance may be different for children who have special educational needs. The study aims to compare peer-assessed behavioural characteristics associated with sociometric status for included children who have moderate learning difficulties and their mainstream classmates. Mainstream classmates (N=867) of all the children ascertained as having Moderate Learning Difficulties (MLD) and included in mainstream middle schools (8-12 years) in one English county. Subgroups of rejected mainstream (n=38) and pupils with MLD (n=32) were further investigated. Discriminant function analysis was carried out with peer assessment items as predictors of sociometric status group membership in the mainstream sample and contrasted with previously reported data from pupils with MLD in the same classes. Cluster analysis was used to identify behavioural subtypes within the rejected groups drawn from each sample. For pupils with MLD subtypes were validated using teacher assessments of social behaviour. Systematic differences were identified across different analyses between the peer-assessed behavioural characteristics associated with rejected sociometric status for pupils with MLD and for mainstream pupils. The appropriateness of generic social skills training programmes for promoting the social inclusion of pupils with MLD should be questioned and consideration given to rejected pupil subtypes.


Capillary gas chromatographic method for mandelic and phenylglyoxylic acids in urine.
In support of an occupational investigation of styrene exposure, a capillary gas chromatographic method was developed for the quantitation of the styrene metabolites mandelic and phenylglyoxylic acids. The method was based on that of Guillemin and Bauer, in which phenylglyoxylic acid was converted to mandelic acid by reduction before instrumental analysis. The earlier method had to be modified for use with capillary columns; the resulting method was sensitive, selective and reproducible. The detection limit was approximately 0.001 mg/ml urine. Approximately less than 5% relative precision was achieved in the range of 0.05-2 mg/ml urine. Mandelic acid was resolved from other components of urine and from by-products of derivatization.


Lipomas of anterior neck simulating thyroid nodules: diagnosis by fine-needle aspiration.
The anterior neck is an unusual location for lipomas. Cervical lipomas can be mistaken for non-functioning thyroid nodules. We report eight cases from our files diagnosed by fine needle aspiration (FNA). Our purpose is to call attention to this simple technique in establishing an accurate diagnosis and how it can contribute to better patient management by avoiding unnecessary thyroid suppressive therapy and/or surgery. We advocate using FNA as the initial diagnostic test on palpable masses in the neck. The differential diagnosis must include thyroid lipomatosis, thyrolipoma or adenolipoma, amyloid goiter with fatty infiltration, and fat-containing thyroidal neoplasms (papillary carcinoma and follicular neoplasms).


Bogus concerns about the false prototype enhancement effect.
Two experiments addressed the mechanism responsible for the false prototype effect, the phenomenon in which a prototype gradient can be obtained in the absence of learning. Previous demonstrations of this effect have occurred solely in a single-category paradigm in which transfer patterns are assigned or not to the learning category. We tested the hypothesis that any extraneous variable potentially responsible for this effect, such as compactness varying with pattern distortion (Zaki & Nosofsky, 2004), may be functional in the single-category paradigm but not when multiple categories are available at the time of transfer. In the present study, subjects received a bogus or a real category learning phase, followed by a transfer test that required assignment into 1 or 3 prototype categories. The results showed that a minimal prototype gradient was obtained in the bogus conditions, with performance approaching chance levels when classification into 3 categories was required. In contrast, a substantial prototype gradient effect was found following learning. We conclude that the prototype gradient typically obtained following multiple-category learning is primarily driven by real learning and that the false prototype effect is itself an artifact of the single-category paradigm.


A case of parameatal urethral cyst with calculi.
Parameatal urethral cyst is very rare. Although 15 cases have been reported in Japan, no case of parameatal urethral cyst with calculi has previously been reported. We report the first case of parameatal urethral cyst with calculi in a 22-year-old female patient.


Measurement of large low-order aberrations by using a series of through-focus Ronchigrams.
A method for measuring large aberrations up to second order (defocus, 2-fold astigmatism and axial coma), which uses a through-focus series of Ronchigrams, is proposed. The method is based on the principle that line-focus conditions in Ronchigrams can be locally detected and low-order aberrations can thereby be measured. The proposed method provides auto-tuning of large low-order aberration; in particular, iterative aberration measurement and correction reduce low-order aberrations from several thousand nanometers to less than a few hundred nanometers, which can be handled by conventional fine-aberration tuning methods.


[Headache following epidural anesthesia].
A study of the side effects of epidural anesthesia for painless delivery in 100 patients showed that 90% of the post partum patients were very satisfied with the analgesia and did not consider symptoms post partum to be very debilitating and did not blame the epidural anesthesia for the symptoms. Severe pain in the occiput and the cervical spine occurred in only two cases. In one case, the cerebro-spinal fluid was punctured. Headaches following epidural anesthesia are described as a great disadvantage of this method of obstetric analgesia. However, the headaches were no more common in the group with epidural anesthesia than in the compare group. No correlation was found with puncture of the dura which is suspected in the literature. Retention of urine was not found to be correlated to the epidural anesthesia. Uniformity of the responses by the maternity patients were striking especially if one considered that the social condition and the psychic condition of the individual woman such as attitude to delivery, presence of the husband at delivery, and other factors were not evaluated.


Stillbirth due to placental hypoperfusion after salpingo-oophorectomy for an ovarian cyst.
Gravid oophorectomy past mid-pregnancy may be necessary, but the alterations of blood flow to supply the placenta may present risks to the mother and fetus. A salpingo-oophorectomy for a mucinous cystadenoma resulted in a postoperative hemorrhage of 2 L and fetal death. The placenta demonstrated a unique lesion that was consistent with global hypoperfusion of the placenta. The postoperative hemorrhage occurred despite good immediate operative hemostasis. Blood flow was shunted from the uteroplacental circulation due to the large utero-ovarian collateral circulation.


Poliomyelitis-like illness due to Japanese encephalitis virus.
Acute flaccid paralysis remains common among Vietnamese children despite a pronounced fall in the incidence of poliomyelitis. During 1995, all 22 children presenting with acute flaccid paralysis to a referral centre in Ho Chi Minh City, Vietnam, had virological cultures and antibody measurements done on serum, cerebrospinal fluid, and faeces. A year later the children were reassessed and electrophysiological studies were done. Wild poliovirus type 1 was isolated from the faeces of only one patient, and non-polio enteroviruses from three patients. 12 (55%) of the 22 children with acute flaccid paralysis had evidence of acute Japanese encephalitis virus (JEV) infection, compared with only one (1%) of 88 age-matched hospital controls (children with diphtheria; p<0.0001). Compared with JEV-negative patients, weakness in JEV-infected children was more rapid in onset, tended to be asymmetrical, but was less likely to involve the arms. All 12 children with JEV infection were febrile at the onset of weakness, seven had acute retention of urine, and ten had CSF pleiocytosis. Seven of eight JEV-negative patients met the case-definition of Guillain-Barré syndrome, compared with only one of 12 JEV-positive children. At follow-up, patients with JEV infection had greater disability and were more likely to have muscle wasting than were JEV-negative children. Nerve conduction and electromyographic studies indicated damage to the anterior horn cells. JEV causes an acute flaccid paralysis in children that has similar clinical and pathological features to poliomyelitis. In endemic areas, children with acute flaccid paralysis should be investigated for evidence of JEV infection.


Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus.
Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to generate a knock-in GFP reporter mouse at the Gdf11 locus. Phenotypic and genomic characterization of founder animals from these injections revealed a subset that contained the correct targeting event and exhibited GFP expression that, within the hematopoietic system, was restricted predominantly to lymphoid cells. Yet, in another subset of founder mice, we detected aberrant integration events at the target site that dramatically and inaccurately shifted hematopoietic GFP expression from the lymphoid to the myeloid lineage. Additionally, we recovered multiple Gdf11 deletion alleles that modified the C-terminus of the GDF11 protein. When bred to homozygosity, most of these alleles recapitulated skeletal phenotypes reported previously for Gdf11 knockout mice, suggesting that these represent null alleles. However, we also recovered one Gdf11 deletion allele that encodes a novel GDF11 variant protein ("GDF11-WE") predicted to contain two additional amino acids (tryptophan (W) and glutamic acid (E)) at the C-terminus of the mature ligand. Unlike the other Gdf11 deletion alleles recovered in this study, homozygosity for the Gdf11WE allele did not phenocopy Gdf11 knockout skeletal phenotypes. Further investigation using in vivo and in vitro approaches demonstrated that GDF11-WE retains substantial physiological function, indicating that GDF11 can tolerate at least some modifications of its C-terminus and providing unexpected insights into its biochemical activities. Altogether, our study confirms that one-step zygotic injections of CRISPR/Cas gene editing complexes provide a quick and powerful tool to generate gene-modified mouse models. Moreover, our findings underscore the critical importance of thorough characterization and validation of any modified alleles generated by CRISPR, as unintended on-target effects that fail to be detected by simple PCR screening can produce substantially altered phenotypic readouts.


Wip1-expressing feeder cells retain pluripotency of co-cultured mouse embryonic stem cells under leukemia inhibitory factor-deprivated condition.
The optimization of in vitro culture conditions for embryonic stem cells (ESCs) is a matter of critical importance; a prompt supply of a sufficient population of cells that retain their pluripotency capabilities must be secured in order to make possible future cell therapies. Despite a number of reports asserting that a variety of cytokines, signaling ligands, and small molecules can help in maintaining the pluripotency of ESCs, mammalian feeder cells continue to be broadly accepted as the method of choice for ESC cultures. This appears to be because mammalian feeder cells seem to produce some as-yet-unidentified factor that makes them very effective as feeder cells. In this study, we investigated wild-type p53 inducible phosphatase (Wip1), the knockdown of which increases Wnt inhibitory factor-1 expression, in its feeder functions toward mouse embryonic stem cells, lowering the effect of Wnt, one of key signaling in maintaining stemness of ESCs. For this purpose, Wip1 was stably expressed in mouse embryonic fibroblast cell line (STO) using retro-viral gene delivery system and then the function as a feeder cell was monitored either with or without leukemia inhibitory factor (LIF) in culture medium. We demonstrated that mouse embryonic stem cells grown with Wip1 expressing STO showed higher alkaline phosphatase activity and sustained Oct-4 expression level even under LIF deprivation condition compared to both control and Wip1 phosphatase activity dead mutant expressing STO. These results imply that Wip1 phosphatase activity in feeder cells is important to retain pluripotency of mouse embryonic stem cells under LIF deprivation conditions. These results indicate that genetically engineered feeder cells such as Wip1 expressing cell lines, are alternative strategy for the optimization of maintenance and expansion of mouse embryonic stem cells.


[Analysis of the neuronal activity of cortical-subcortical structures of a conditioned reflex].
Neuronal activity of the orbital cortex, the caudate nucleus and the amygdala were studied in chronic experiments on dogs and cats by the method of alimentary and defensive conditioned reflexes. A spatial distribution of neurones involved in the alimentary and defensive conditioned reflexes, was revealed in the caudate nucleus head. The units responding to conditioned alimentary stimuli are localized primarily in the ventral segment. Similarity of responses to surroundings and to trigger conditioned alimentary stimuli was found between the units of the ventral segment in the caudate nucleus head and of the amygdala basolateral part. The influence of stimulation of the amygdala on the orbital cortex units was established in the alimentary conditioned reflex in dogs. A conclusion has been drawn that in elaboration of an alimentary conditioned reflex the neurones of three levels become organized into a definite system, providing for an adequate reaction of the organism to the conditioned stimulus.


Spontaneous in vitro production of thyroglobulin specific helper factor in patients with autoimmune thyroid diseases.
We have investigated regulatory cell abnormalities in patients with autoimmune thyroid diseases through in vitro thyroglobulin (Tg) specific helper factor production. Helper activities were measured in the mice spleen cell assays, using hapten-carrier system. Peripheral blood leukocytes (PBL) from 5 out of 6 patients produced the Tg specific helper factor not only when they were stimulated in vitro with Tg but also when they were not stimulated. On the contrary, normal PBL did not produce the factor when they were not stimulated in vitro. However, 3 out of 5 normal PBL did produce the factor when they were stimulated in vitro with Tg. From several lines of studies, this helper factor was specific for Tg in its production and action. From these results it is concluded that (a) Tg specific helper T cells are already activated in vivo in patients with autoimmune thyroid diseases, indicating the presence of immunoregulatory abnormalities in these patients, and that (b) normal PBL have a potential to produce this helper factor when they are appropriately stimulated.


Sono-dispersion of TiO2 nanoparticles over clinoptilolite used in photocatalytic hydrogen production: Effect of ultrasound irradiation during conventional synthesis methods.
Hydrogen evolution via water splitting was investigated over the sonochemically synthesized TiO2-clinoptilolite photocomposites. To this aim, a series of photocatalysts containing 10wt% titania were prepared by impregnation and solid state dispersion (SSD) methods in the presence and absence of ultrasound irradiation. The samples were characterized by XRD, FESEM, EDX, BET, FTIR, PL and UV-vis techniques and tested for the water splitting. The characterization results indicated that ultrasound irradiation endowed the photocatalysts with uniform morphology, higher surface area and more homogenous dispersion. In addition, the analyses also exhibited less population of particle aggregates, a strong titania-support interaction and lower electron-hole pairs recombination rate. These features were more prominent when ultrasound was employed during SSD method. The TiO2/Clinoptilolite photocatalyst prepared by the ultrasound assisted SSD method (TiO2/CLT(US)), had more uniform active sites dispersion, high separation efficiency of electron-hole pairs and as a consequence, high surface density of active sites. The highest photocatalytic activity, 569.88 [Formula: see text] , was obtained for the TiO2/CLT(US) sample which was about 8 times more than that of P-25 as a reference sample. Furthermore, the TiO2/CLT(US) photocomposite as optimal photocatalyst showed sufficient reusability, making it a good choice for photocatalytic water splitting applications.


Adolescents' view and experiences of living with type 1 diabetes.
This literature review explores the perceptions and experiences of adolescents living with type 1 diabetes. The number of adolescents living with this condition is growing in Western societies. It is important to understand their views and experiences to ensure they receive optimum support. A systematic database search identified studies conducted between 2004 and 2014 undertaken in five countries. Most participants were aged 13-17 years, although some studies included participants aged 11-18 years. Key findings identified were: striving for autonomy; parental conflict; yearning for social acceptance; and concerns about diabetes education. Thematic analysis identified psychosocial, management, and knowledge of type 1 diabetes as the main themes. The review also identified that the psychosocial effects of living with type 1 diabetes were significant. Adolescents would benefit from more in-depth research on this subject and more innovative ways to help them cope better with their condition.