Perception of dental visit pictures in children with autism spectrum disorder and their caretakers: A qualitative study.
One of the most common ways to communicate to children with autism spectrum disorder (ASD) is by using pictures. This study was conducted to identify the easiest perception of dental visit by children with ASD when using pictures as printed photographs. Purposive sampling was used to recruit participants from a school for children with special needs in south Jakarta. Semi-structured interviews were conducted with 10 autistic children aged 13-17 years, 2 parents, and 2 teachers. Open-ended questions were asked to participants regarding pictures of dental clinic personnel and activity. Conversations were noted, tape recorded, and then categorized to extract a theme. The data were analyzed using Dedoose mixed methods software. Most respondents showed a positive perception of the dental visit pictures. Many of the pictures were easily recognized by children with ASD, but some failed to be understood. Caretakers not only gave their perception but also recommendations for improvement of the pictures. Dental visit pictures could be used as useful communication tools for children with ASD. Based on the results, the pictures related to dental visit were generally easy to understand, however, some needed correction to be comprehensible.


The human immunodeficiency virus type 1 capsid p2 domain confers sensitivity to the cyclophilin-binding drug SDZ NIM 811.
Human immunodeficiency virus type 1 (HIV-1) specifically incorporates the host cell peptidyl-prolyl isomerase cyclophilin A into virions via contacts with the capsid (CA) domain of the Gag polyprotein Pr55gag. The immunosuppressant drug cyclosporin A and the nonimmunosuppressive cyclosporin A analog SDZ NIM 811 bind to cyclophilin A and inhibit its incorporation into HIV-1 virions. Both drugs inhibit the virion association of cyclophilin A and the replication of HIV-1 with a similar dose dependence. In contrast, these compounds are inactive against other primate lentiviruses which do not incorporate cyclophilin A, such as simian immunodeficiency virus (SIV). To locate determinants which confer sensitivity to SDZ NIM 811, we generated chimeric proviruses between HIV-1 and SIVmac. A hybrid SIVmac which has the CA-p2 domain of the Gag polyprotein replaced by the corresponding domain from HIV-1 replicated in an established CD4+ cell line and in human but not macaque peripheral blood mononuclear cells. The transfer of the HIV-1 CA-p2 domain to SIVmac led to the efficient incorporation of cyclophilin A, and SDZ NIM 811 effectively inhibited both the virion association of cyclophilin A and the spread of the hybrid virus in infected cultures. We conclude that the HIV-1 CA-p2 domain contains determinants which confer the necessity to interact with cyclophilin A for efficient virus replication. Furthermore, our data show that the CA-p2 domain can play a crucial role in species tropism.


Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival.
Recent evidence suggests chronic myeloid leukemia (CML) stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, after retransplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off were able to persist in vivo and reinitiate leukemia in secondary recipients on Bcr-Abl reexpression. Bcr-Abl knockdown in human CD34(+) CML cells cultured for 12 days in physiologic growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%; however, the surviving fraction was enriched for primitive leukemic cells capable of growth in a long-term culture-initiating cell assay and expansion on removal of dasatinib and addition of growth factors. Together, these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance.


Role of Social Support in Improving Infant Feeding Practices in Western Kenya: A Quasi-Experimental Study.
We designed and tested an intervention that used dialogue-based groups to engage infants' fathers and grandmothers to support optimal infant feeding practices. The study's aim was to test the effectiveness of increased social support by key household influencers on improving mothers' complementary feeding practices. Using a quasi-experimental design, we enrolled mothers, fathers, and grandmothers from households with infants 6-9 months old in 3 rural communities (1 intervention arm with fathers, 1 intervention arm with grandmothers, and 1 comparison arm) in western Kenya. We engaged 79 grandmothers and 85 fathers in separate dialogue groups for 6 months from January to July 2012. They received information on health and nutrition and were encouraged to provide social support to mothers (defined as specific physical actions in the past 2 weeks or material support actions in the past month). We conducted a baseline household survey in December 2011 in the 3 communities and returned to the same households in July 2012 for an endline survey. We used a difference-in-difference (DiD) approach and logistic regression to evaluate the intervention. We surveyed 554 people at baseline (258 mothers, 165 grandmothers, and 131 fathers) and 509 participants at endline. The percentage of mothers who reported receiving 5 or more social support actions (of a possible 12) ranged from 58% to 66% at baseline in the 3 groups. By endline, the percentage had increased by 25.8 percentage points (P=.002) and 32.7 percentage points (P=.001) more in the father and the grandmother intervention group, respectively, than in the comparison group. As the number of social support actions increased in the 3 groups, the likelihood of a mother reporting that she had fed her infant the minimum number of meals in the past 24 hours also increased between baseline and endline (odds ratio [OR], 1.14; confidence interval [CI], 1.00 to 1.30; P=.047). When taking into account the interaction effects of intervention area and increasing social support over time, we found a significant association in the grandmother intervention area on dietary diversity (OR, 1.19; CI, 1.01 to 1.40; P=.04). No significant effects were found on minimum acceptable diet. Engaging fathers and grandmothers of infants to improve their knowledge of optimal infant feeding practices and to encourage provision of social support to mothers could help improve some feeding practices. Future studies should engage all key household influencers in a family-centered approach to practice and support infant feeding recommendations.


Improving the feasibility of economical proton-boron-11 fusion via alpha channeling with a hybrid fast and thermal proton scheme.
The proton-boron-11 (p-B11) fusion reaction is much harder to harness for commercial power than the easiest fusion reaction, namely, the deuterium and tritium (DT) reaction. The p-B11 reaction requires much higher temperatures, and, even at those higher temperatures, the cross section is much smaller. However, as opposed to tritium, the reactants are both abundant and nonradioactive. It is also an aneutronic reaction, thus avoiding radioactivity-inducing neutrons. Economical fusion can only result, however, if the plasma is nearly ignited; in other words if the fusion power is at least nearly equal to the power lost due to radiation and thermal conduction. Because the required temperatures are so high, ignition is thought barely possible for p-B11, with fusion power exceeding the bremsstrahlung power by only around 3%. We show that there is a high upside to changing the natural flow of power in the reactor, putting more power into protons, and less into the electrons. This redirection can be done using waves, which tap the alpha particle power and redirect it into protons through alpha channeling. Using a simple power balance model, we show that such channeling could reduce the required energy confinement time for ignition by a factor of 2.6 when energy is channeled into thermal protons, and a factor of 6.9 when channeled into fast protons near the peak of the reactivity. Thus, alpha channeling could dramatically improve the feasibility of economical p-B11 fusion energy.


Rethinking Social Cognition in Light of Psychosis: Reciprocal Implications for Cognition and Psychopathology.
The positive symptoms of psychosis largely involve the experience of illusory social actors and yet our current measures of social cognition, at best, only weakly predict their presence. We review evidence to suggest that the range of current approaches in social cognition is not sufficient to explain the fundamentally social nature of these experiences. We argue that social agent representation is an important organising principle for understanding social cognition and that alterations in social agent representation may be a factor in the formation of delusions and hallucination in psychosis. We evaluate the feasibility of this approach in light of clinical and non-clinical studies, developmental research, cognitive anthropology and comparative psychology. We conclude with recommendations for empirical testing of specific hypotheses and how studies of social cognition could more fully capture the extent of social reasoning and experience in both psychosis and more prosaic mental states.


Effects of a protease inhibitor, ulinastatin, on coagulation and fibrinolysis in abdominal surgery.
Ulinastatin is well known to inhibit the activity of polymorphonuclear leukocyte elastase (PMNE). The PMNE concentration correlates with the activities of coagulation and fibrinolysis. The purpose of the present study was to investigate the effects of ulinastatin, a protease inhibitor, on coagulation and fibrinolysis in abdominal surgery. Thirty patients, aged 40 to 70 years, with American Society of Anesthesiologists (ASA) physical status I or II, scheduled for major abdominal surgery, were enrolled. Anesthesia was induced with midazolam and thiopental, and was maintained with sevoflurane, nitrous oxide in oxygen, and an epidural block. An infusion of ulinastatin, 6000 units x kg(-1) in 30 min, was started 1 h after the start of surgery in the ulinastatin group (15 patients). In the control group (15 patients), no protease inhibitors were infused. White blood cell count; platelet count; prothrombin time; activated partial thromboplastin time; and plasma concentrations of PMNE, antithrombin (AT), fibrin/fibrinogen degradation product (FDP), fibrinogen, plasminogen, plasmin-(alpha2) plasmin inhibitor complex (PIC), and thrombin-antithrombin complex (TAT) were measured before, at the end of, and 12 h after surgery. TAT, PIC, and FDP after surgery were significantly lower in the ulinastatin group than in the control group. AT was decreased in the control group but not in the ulinastatin group, with significant differences between the two groups. Ulinastatin could inhibit coagulation and fibrinolysis in abdominal surgery.


Inhibition of beta-lactamase of Bacillus licheniformis 749/C by compound PS-5, a new beta-lactam antibiotic.
By use of a new computer-assisted u.v.-spectrophotometric assay method, the kinetic parameters of the reaction catalysed by Bacillus licheniformis 749/C beta-lactamase were re-examined and the mode of inhibition of the enzyme by compound PS-5, a novel beta-lactam antibiotic, was studied with benzylpenicillin as substrate. (1) The fundamental assay conditions for the determination of Km and V were examined in detail with benzylpenicillin as substrate. In 0.1 M-sodium/potassium phosphate buffer, pH 6.8, at 30 degrees C, initial substrate concentrations of benzylpenicillin above 0.7 mM were very likely to lead to substrate inhibition. The Km value of the enzyme for benzylpenicillin at initial concentrations from 1.96 to 0.07 mM was calculated to be 97-108 microM. (2) The Km values of the enzyme for 6-aminopenicillanic acid, ampicillin and cephaloridine were found to be 25, 154-161 and 144-161 microM respectively. (3) Compound PS-5 was virtually unattacked by Bacillus licheniformis 749/C beta-lactamase. (4) The activity of the enzyme was diminished by compound PS-5, to extents depending on the duration of incubation and the concentration of the inhibitor. The rate of inactivation of the enzyme by compound PS-5 followed first-order kinetics. (5) In an Appendix, a new computer-assisted u.v.-spectrophotometric enzyme assay method, in which a single reaction progress curve of time-absorbance was analysed by the integrated Michaelis-Menten equation, was devised for the accurate and precise determination of the kinetic constants of beta-lactamase. For conversion of absorbance readings into molar substrate concentrations, the initial or final absorbance reading that was independent of the reaction time was used as the basis of calculation. In calculation of Km and V three systematic methods of data combination were employed for finer analysis of the reaction progress curve. A list of the computer program named YF6TAIM is obtainable from the author on request or as Supplementary Publication SUP 50100 (12 pages) from the British Library Lending Division, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., on the terms indicated in Biochem. J. (1978) 169, 5.


Polarization-independent nematic liquid crystal phase modulator based on optical compensation with sub-millisecond response.
In this paper, we propose a design utilizing two identically parallel-aligned nematic liquid crystal (LC) plates for fast-response and polarization-independent phase modulator. Driven by synchronized voltage signals, such a polarizer-free variable phase modulator shows a wide tunable range from zero to more than 3π, back and forth at 532nm. Due to the optical compensation of the two plates, the rise and fall time of the phase retardation corresponds to the switching-on time of the two plates. Several advantages are illustrated based on the optical compensation of two identical parallel-aligned plates. First, zero phase retardation is obtained, which overcomes the residual phase due to surfaced anchored liquid crystal molecules. The second advantage is sub-millisecond response of rise and fall of retardation since simultaneous relaxation of the two plates remains optically hidden during the synchronized voltages fall. This fast-response and polarization-independent phase modulator has great potential for practical use, including optical communications and light field imaging systems.


Follow-up of ankle stiffness and electromechanical delay in immobilized children: three cases studies.
Clinical manual tests refer to increased ankle stiffness in children immobilized due to hip osteochondritis. The aim of the present study was to investigate musculo-articular stiffness via different techniques in immobilized children to confirm or not and quantify these observations. Ankle stiffness was quantified monthly during the long immobilization period in three diseased children and compared to healthy age-matched children. Sinusoidal perturbations were used to evaluate musculo-articular (MA) stiffness of the ankle plantar-flexors. The stiffness index (SI(MA-EMG)) was the slope of the linear relationship between angular stiffness and plantar-flexion torque normalized with electromyographic activity of the triceps surae (TS). The stiffness of the ankle plantar-flexors was also indirectly evaluated using the TS electromechanical delay (EMD). SI(MA-EMG) was greater for diseased children, and this higher stiffness was confirmed by the higher EMD values found in these immobilized children. Furthermore, both parameters indicated that ankle stiffness continues to increase through immobilization period. This study gives a quantitative evaluation of ankle stiffness changes through the immobilization period imposed to children treated for hip osteochondritis. The use of EMD measurement to indirectly evaluate these stiffness changes is also validated. This study shed for the first time some light into the patterns of muscle modifications following immobilization in children.


Minimum 2-Year Outcomes of Arthroscopic Management of Symptomatic Hip Labrum Tears in Patients With Global Acetabular Overcoverage.
To report minimum 2-year patient-reported outcomes (PROs) after hip arthroscopy (HA) for symptomatic labral tears in patients with global acetabular overcoverage. This study was a retrospective case series of patients who underwent HA from April 2008 to April 2013. The inclusion criteria were patients with global acetabular overcoverage, defined as a lateral center-edge angle greater than 40°, and with coxa profunda, defined radiologically by the ilioischial line lateral to the acetabular floor. Only patients with minimum 2-year follow-up and no history of hip conditions or surgery were included. We recorded demographic, examination, radiologic, and intraoperative findings; intraoperative procedures performed; and the following PROs: modified Harris Hip Score (mHHS), Non-Arthritic Hip Score, Hip Outcome Score-Activities of Daily Living (HOS-ADL), Hip Outcome Score-Sports-Specific Subscale (HOS-SSS), visual analog scale, and patient satisfaction. The inclusion criteria were met by 39 patients, of whom 35 (89.7%) had 2-year follow-up. There was no distinct pattern of examination findings. The study population had a mean acetabular inclination of -1.19° and an anterior center-edge angle of 35°. There was no association with measures of acetabular retroversion. Intrasubstance tearing of the labrum occurred in 75% of patients (mean tear size, 2.68 hours on acetabular clock face; mean location, 11.5 to 3 on acetabular clock face). There were significant improvements in the mean scores for all PROs: mHHS, 13.5 ± 17.7 points (P < .01); Non-Arthritic Hip Score, 14.3 ± 21.3 (P < .001); HOS-ADL, 11.6 ± 19.7 (P < .001); HOS-SSS, 17.1 ± 35.1 (P < .001); and visual analog scale, -2.77 ± 2.58 (P < .001). The mean patient satisfaction rating was 6.61. The improvements in mHHS, HOS-ADL, and HOS-SSS did not reach the minimal clinically important difference. The incidence of secondary procedures was 17% (4 patients underwent conversion to total hip arthroplasty and 2 required revision HA). HA in patients with global acetabular overcoverage was associated with improvements in PROs and pain at minimum 2-year follow-up. However, these improvements did not reach the minimal clinically important difference for the mHHS, HOS-ADL, and HOS-SSS. The incidence of secondary procedures was 17%. The pattern of labral injury is predominantly intrasubstance labral damage with a narrow rim of adjacent chondral injury. Level IV, therapeutic case series.


Foreign bodies in tracheobronchial tree in children: a review of cases over a twenty-year period.
Foreign body inhalation into the tracheobronchial tree of children is rather rare but serious problem. It may be hazardous and even cause fatal sequelae in the children if misdiagnosed and not managed promptly. We retrospectively reviewed the records of 81 patients with foreign bodies inhaled into the larynx, trachea and bronchi. The children were all treated during the 20-year period from July 1976 through June 1996 at Chang Gung Memorial Hospital. Of these patients, 82% were 36 months of age or younger. The male to female ratio was 3:1. All of the patients initially received flexible fiberoptic bronchoscopy to identify the foreign objects. The foreign bodies were removed by jet ventilation bronchoscopy with apneic techniques under general anesthesia. Peanuts were found to be the most common causative foreign body agent which occurred in 53 instances (65%). The most common manifestation was coughing, with subsequent dyspnea and audible wheezing. The foreign bodies were lodged in the left bronchus more than in the right. The most obvious radiologic evidence observed in aspirated children were emphysematous changes at same side of the foreign bodies caused by "expansile check-valve" phenomenon. Four patients showed radio-opaque objects on chest roentgenograms. Six patients required second extraction procedures due to the retained foreign bodies. Neither serious complications nor deaths occurred in these patients due to the foreign body inhalation. Early diagnosis and management is essential in children with foreign bodies in the airways to prevent morbidity or death. Small materials or food bits should be kept far away from young child.


Unintended consequences: ventures and misadventures in the education of professional psychologists.
Increasing professionalization of psychology, accelerated by expansion of professional schools, has evoked concern among critics, who claim that many practitioners ignore scientific research and engage in practices that are demonstrably useless or harmful. Recent data on admissions to professional schools and performance of professional school graduates show cause for concerns of the critics. If psychology is to maintain its stature as a profession, exclusionary controls as well as hortatory requirements for the practice of psychology and the education of practitioners must be established and enforced. Before more stringent standards can be imposed, convincing means for evaluating competence in professional work and quality in professional education must be developed. Local and institutional actions to advance those aims are proposed.


R&D and market size: Who benefits from orphan drug legislation?
Since the early 80s, incentives have been introduced to stimulate R&D for rare diseases. We develop a theoretical model to study the impact of push and pull incentives on the intensive and extensive margin of optimal R&D investments. The model describes the mechanisms by which the type of incentives provided may favor R&D for orphan diseases with comparatively high prevalence. In our empirical analysis, we merge data on orphan drug designations by the Food and Drug Administration with Orphanet data on disease characteristics. In line with the theoretical results, we find evidence supporting the idea that the incentives adopted may have contributed substantially to widening the gap between more and less rare diseases classified as orphan. Our theoretical and empirical findings together suggest that, if providing some therapeutic option to patients with very rare diseases is a priority, a revision of the current system of incentives should be considered.


Autogenous dorsal reconstruction: maximizing the utility of diced cartilage and fascia.
The problem of reconstructing the dorsum of the nose is complex and a source of frustration for both patients and surgeons. Dorsal deficiencies due to various etiologies and the need for dorsal contouring cause the plastic surgeon to look to time-honored techniques such as osseocartilaginous rib grafts while also searching for other options that may be less technically challenging and have the benefit of temporal success. Diced cartilage wrapped with deep temporal fascia is just such a method to achieve reliable dorsal reconstructions. The various ways to use diced cartilage and deep temporal fascia are discussed.


Fast image classification using a sequence of visual fixations.
Based on human retinal sampling distributions and eye movements, a sequential resolution image preprocessor is developed. Combined with a nearest neighbor classifier, this preprocessor provides an efficient image classification method, the sequential resolution nearest neighbor (SRNN) classifier. The human eye has a typical fixation sequence that exploits the nonuniform sampling distribution of its retina. If the retinal resolution is not sufficient to identify an object, the eye moves in such a way that the projection of the object falls onto a retinal region with a higher sampling density. Similarly, the SRNN classifier uses a sequence of increasing resolutions until a final class decision is made. Experimental results on texture segmentation show that the preprocessor used in the SRNN classifier is considerably faster than traditional multiresolution algorithms which use all the available resolution levels to analyze the input data.


Arterial spin labelling: predictive role in surgical bleeding of paediatric optic pathway gliomas.
To analyse the performance of arterial spin labelling (ASL) in predicting surgical bleeding in a paediatric cohort of optic pathway glioma (OPG). Preoperative ASL data were obtained for 51 OPG in 40 patients, aged from 9 months to 16 years. The relative cerebral blood flow (rCBF) in the tumour areas with the highest CBF (maximum rCBF) was measured and then correlated with qualitative local bleeding (graded no, moderate, and major by the neurosurgeon) and quantitative global surgical bleeding (assessed in millilitres using haematocrit data). Intratumoural maximum rCBF was significantly higher when qualitative local bleeding was high (median value in the no, moderate, and major bleeding groups equal to 0.81, 1.39 and 4.22, respectively, p=0.004), but there was no difference in global quantitative bleeding (p=0.7 for the total blood loss). The maximum tumour rCBF cut-off value of 1.1 yielded a sensitivity of 73%, a specificity of 78%, and an accuracy of 76% (39/51 tumours) in detecting haemorrhagic OPG. Choosing a maximum tumour rCBF cut-off value > 1.7 improved the specificity in diagnosing tumours with high bleeding risk with a specificity of 94%, a sensitivity of 53%, and an accuracy of 82% (42/51 tumours). ASL tumoural rCBF is a useful and simple diagnostic tool to help predict high intraoperative tumoural bleeding risk in paediatric OPG.


Functional modulation of Crohn's disease myofibroblasts by anti-tumor necrosis factor antibodies.
Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-alpha (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-alpha, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn's disease (CD) myofibroblasts. Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor-human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti-TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.


Habitual intake of iron, copper, and zinc and the risk of type 2 diabetes in a prospective cohort: The CAVAS (Cardiovascular Disease Association Study).
Unlike iron, evidence of the association between dietary copper and zinc intake and type 2 diabetes (T2D) risk is limited. This study aimed to examine the prospective associations of dietary intake of iron (total, plant-based, and animal-based), copper, and zinc with T2D risk among adults aged ≥40 years. For 16,666 participants, dietary intakes (baseline, cumulative average, and most recent) of iron, copper, and zinc were calculated from repeated food frequency questionnaires; a modified Poisson regression model with a robust error estimator was conducted. In men, positive associations between T2D and baseline dietary intake of Cu and Zn, cumulative average dietary intake of Fe (total and animal-based), Cu and Zn, and most recent dietary intake of Fe (total, plant-based, and animal-based), Cu, and Zn [most recent diet: for total Fe, IRR(95%CI) = 1.93 (1.41-2.64); for plant-based Fe, 1.56 (1.15-2.11); for animal-based Fe, 1.44 (1.09-1.90); for Cu, 3.17 (2.33-4.30); for Zn, 2.18 (1.64-2.89)] were observed, where as in women, there were positive associations of only cumulative average dietary Zn intake and most recent dietary intake of plant-based Fe, Cu, and Zn [most recent diet: for plant-based Fe, 1.30 (1.01-1.68); for Cu, 1.62 (1.27-2.08); for Zn, 2.07 (1.61-2.66)]. Dietary intakes of iron (total, plant-based, and animal-based), copper, and zinc may be positively associated with T2D risk. These positive associations are predominantly observed in most recent diet and appear to be stronger compared to baseline and cumulative average diet.


Distribution and persistence of pyrethroids in runoff sediments.
Pyrethroids are commonly used insecticides in both agricultural and urban environments. Recent studies showed that surface runoff facilitated transport of pyrethroids to surface streams, probably by sediment movement. Sediment contamination by pyrethroids is of concern due to their wide-spectrum aquatic toxicity. In this study, we characterized the spatial distribution and persistence of bifenthrin [BF; (2-methyl(1,1'-biphenyl)-3-yl)methyl 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate] and permethrin [PM; 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (3-phenoxyphenyl)methyl ester] in the sediment along a 260-m runoff path. Residues of BF and PM were significantly enriched in the eroded sediment, and the magnitude of enrichment was proportional to the downstream distance. At 145 m from the sedimentation pond, BF was enriched by >25 times, while PM isomers were enriched by >3.5 times. Pesticide enrichment along the runoff path coincided with enrichment of organic carbon and clay fractions in the sediment, as well as increases in adsorption coefficient K(d), suggesting that the runoff flow caused selective transport of organic matter and chemical-rich fine particles. Long persistence was observed for BF under both aerobic and anaerobic conditions, and the half-life ranged from 8 to 17 mo at 20 degrees C. The long persistence was probably caused by the strong pesticide adsorption to the solid phase. The significant enrichment, along with the prolonged persistence, suggests that movement of pyrethroids to the surface water may be caused predominantly by the chemically rich fine particles. It is therefore important to understand the fate of sediment-borne pyrethroids and devise mitigation strategies to reduce offsite movement of fine sediment.


Infant formula as a cause of aluminium toxicity in neonatal uraemia.
Aluminium toxicity occurred in two infants with congenital uraemia who had never received phosphate binders or other aluminium-containing agents or intravenous fluids. One patient was treated by peritoneal dialysis from the age of two weeks and died at three months after the sudden onset of neurological symptoms; the other died after one month of conservative management without dialysis. Brain aluminium concentration was high in both infants (6.4 and 47 micrograms/g, respectively) whereas bone aluminium content was normal and there were no histological changes or stainable aluminium on bone biopsy specimens. Both infants were fed with 'Similac PM 60/40'. To investigate possible sources of aluminium, powdered milk formula, sterilised water used for preparation of the feed, and dialysate concentrate (first patient) were analysed. Aluminium concentration was high (232 +/- 60 ng/ml) in powdered milk but negligible in sterilised water and dialysate concentrate (4 ng/ml and 3.4 +/- 2.4 ng/ml, respectively). These findings indicate that proprietary infant milk formula is another source of aluminium. Aluminium-free milk should contribute to the prevention of aluminium toxicity in infants with renal failure.


Investigating the use of quick response codes in the gross anatomy laboratory.
The use of quick response (QR) codes within undergraduate university courses is on the rise, yet literature concerning their use in medical education is scant. This study examined student perceptions on the usefulness of QR codes as learning aids in a medical gross anatomy course, statistically analyzed whether this learning aid impacted student performance, and evaluated whether performance could be explained by the frequency of QR code usage. Question prompts and QR codes tagged on cadaveric specimens and models were available for four weeks as learning aids to medical (n = 155) and doctor of physical therapy (n = 39) students. Each QR code provided answers to posed questions in the form of embedded text or hyperlinked web pages. Students' perceptions were gathered using a formative questionnaire and practical examination scores were used to assess potential gains in student achievement. Overall, students responded positively to the use of QR codes in the gross anatomy laboratory as 89% (57/64) agreed the codes augmented their learning of anatomy. The users' most noticeable objection to using QR codes was the reluctance to bring their smartphones into the gross anatomy laboratory. A comparison between the performance of QR code users and non-users was found to be nonsignificant (P = 0.113), and no significant gains in performance (P = 0.302) were observed after the intervention. Learners welcomed the implementation of QR code technology in the gross anatomy laboratory, yet this intervention had no apparent effect on practical examination performance.


Quality of life with atrial fibrillation: do the spouses suffer as much as the patients?
Atrial fibrillation (AF) can have a significant effect on quality of life (QoL). Other chronic diseases are known to not only affect the patient but to also impact the QoL of persons living with them. Scant data exist on the QoL effect of AF in spouses/significant others (SOs). An anonymous survey regarding the perceived effect of AF on QoL was designed and distributed to both patients and spouses/SOs during an educational symposium about living with AF. Both were asked to fill out the survey independently according to how their life was affected by either their AF or their partner's AF. Questions included demographics, perceived impairment of overall QoL on a 5-point scale, as well as effect on subcategories of QoL, namely daily activity, work life, sex life, physical activity, psychological well-being, and social activity. Five hundred and sixty-eight subjects completed the survey of which 411 were AF patients and 129 were spouses/SOs. The perceived effect of AF on overall QoL (N = 527) was similar in patients and spouses (AF patients: mild 42.0%, moderate 26.0%, severe 32.0% vs. spouses: 44.1%, 25.2%, 31.7%; P = 0.917). This result did not change when adjusted for age and gender. There was also no significant difference between patients and spouses in the subcategories of QoL with the exception of the perceived effect on work life, which was greater in patients than spouses (P = 0.041). AF has a similar perceived impact on the QoL of spouses and patients. QoL improvement strategies for patients with AF should take spouses into account.


Do working memory capacity and test anxiety modulate the beneficial effects of testing on new learning?
Although testing has repeatedly been shown to be one of the most effective strategies for consolidating retention of studied information (the backward testing effect) and facilitating mastery of new information (the forward testing effect), few studies have explored individual differences in the beneficial effects of testing. The current study recruited a large sample (1,032 participants) to explore the potential roles of working memory capacity and test anxiety in the enhancing effects of testing on new learning, and the converse influence of testing on test anxiety. The results demonstrated that administering interim tests during learning appears to be an effective technique to potentiate new learning, regardless of working memory capacity and test anxiety. At a final test on all studied materials, individuals with low working memory capacity benefited more from interim testing than those with high working memory capacity. These testing effects are minimally modulated by levels of trait/state test anxiety, and low-stake interim testing neither reduced nor increased test anxiety. Overall, the results imply that low-stake interim tests can be administered to boost new learning irrespective of learners' level of WMC, test anxiety, and of possible reactive effects of testing on test anxiety. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Pyrroloquinoline quinone drives ATP synthesis in vitro and in vivo and provides retinal ganglion cell neuroprotection.
Retinal ganglion cells are highly metabolically active requiring strictly regulated metabolism and functional mitochondria to keep ATP levels in physiological range. Imbalances in metabolism and mitochondrial mechanisms can be sufficient to induce a depletion of ATP, thus altering retinal ganglion cell viability and increasing cell susceptibility to death under stress. Altered metabolism and mitochondrial abnormalities have been demonstrated early in many optic neuropathies, including glaucoma, autosomal dominant optic atrophy, and Leber hereditary optic neuropathy. Pyrroloquinoline quinone (PQQ) is a quinone cofactor and is reported to have numerous effects on cellular and mitochondrial metabolism. However, the reported effects are highly context-dependent, indicating the need to study the mechanism of PQQ in specific systems. We investigated whether PQQ had a neuroprotective effect under different retinal ganglion cell stresses and assessed the effect of PQQ on metabolic and mitochondrial processes in cortical neuron and retinal ganglion cell specific contexts. We demonstrated that PQQ is neuroprotective in two models of retinal ganglion cell degeneration. We identified an increased ATP content in healthy retinal ganglion cell-related contexts both in in vitro and in vivo models. Although PQQ administration resulted in a moderate effect on mitochondrial biogenesis and content, a metabolic variation in non-diseased retinal ganglion cell-related tissues was identified after PQQ treatment. These results suggest the potential of PQQ as a novel neuroprotectant against retinal ganglion cell death.


Internet of Things Implementation of Nitrate and Ammonium Sensors for Online Water Monitoring.
In this work, we proposed a new wireless sensor to contribute to research aimed at continuous monitoring of nitrate and ammonium in water, which as leading agents of water pollution have become the source of a serious problem today. In this research, a well-implemented application of an electroanalytical sensor was achieved by combining it with the internet of things (IoT) concept, which is the most modern technique for wireless data collection. We developed a portable IoT system and ion-selective nitrate and ammonium electrodes and monitored the nitrate and ammonium levels of the water online. The system was produced in a low-cost manner (under $25) and it enabled data acquisition without energy-related problems, thanks to the support of solar energy and mobile power bank. The recovery rates of the sensors were tested with the standard addition method and response was obtained between 101.74 and 147.01%.


Frequent Genetic Mismatch between Vaccine Strains and Circulating Seasonal Influenza Viruses, Hong Kong, China, 1996-2012.
The World Health Organization selects influenza vaccine compositions biannually to cater to peaks in temperate regions. In tropical and subtropical regions, where influenza seasonality varies and epidemics can occur year-round, the choice of vaccine remains uncertain. Our 17-year molecular epidemiologic survey showed that most influenza A(H3N2) (9/11) and B (6/7) vaccine strains had circulated in East Asia >1 year before inclusion into vaccines. Northern Hemisphere vaccine strains and circulating strains in East Asia were closely matched in 7 (20.6%) of 34 seasons for H3N2 and 5 (14.7%) of 34 seasons for B. Southern Hemisphere vaccines also had a low probability of matching (H3N2, 14.7%; B, 11.1%). Strain drift among seasons was common (H3N2, 41.2%; B, 35.3%), and biannual vaccination strategy (Northern Hemisphere vaccines in November followed by Southern Hemisphere vaccines in May) did not improve matching. East Asia is an important contributor to influenza surveillance but often has mismatch between vaccine and contemporarily circulating strains.


Ubiquitin signaling and the proteasome drive human DNA-protein crosslink repair.
DNA-protein crosslinks (DPCs) are large cytotoxic DNA lesions that form following exposure to chemotherapeutic drugs and environmental chemicals. Nucleotide excision repair (NER) and homologous recombination (HR) promote survival following exposure to DPC-inducing agents. However, it is not known how cells recognize DPC lesions, or what mechanisms selectively target DPC lesions to these respective repair pathways. To address these questions, we examined DPC recognition and repair by transfecting a synthetic DPC lesion comprised of the human oxoguanine glycosylase (OGG1) protein crosslinked to double-stranded M13MP18 into human cells. In wild-type cells, this lesion is efficiently repaired, whereas cells deficient in NER can only repair this lesion if an un-damaged homologous donor is co-transfected. Transfected DPC is subject to rapid K63 polyubiquitination. In NER proficient cells, the DPC is subject to K48 polyubiquitination, and is removed via a proteasome-dependent mechanism. In NER-deficient cells, the DNA-conjugated protein is not subject to K48 polyubiquitination. Instead, the K63 tag remains attached, and is only lost when a homologous donor molecule is present. Taken together, these results support a model in which selective addition of polyubiquitin chains to DNA-crosslinked protein leads to selective recruitment of the proteasome and the cellular NER and recombinational DNA repair machinery.


Development of a multispectral tissue characterization system for optimization of an implantable perfusion status monitor for transplanted liver.
Optimizing wavelength selection for monitoring perfusion during liver transplant requires an in-depth characterization of liver optical properties. With these, the impact of liver absorption and scattering properties can be investigated to select optimal wavelengths for perfusion monitoring. To accomplish this, we are developing a single integrating-sphere-based technique using a unique spatially resolved diffuse reflectance system for multispectral optical properties determination for thick samples. We report early results using a monochromatic source to measure the optical properties of well characterized tissue phantoms made from polystyrene spheres and Trypan blue. The presented results demonstrate the feasibility of using this unique system to measure optical properties of tissue phantoms. We are currently in the process of implementing an automated Levenberg-Marquardt diffuse-reflectance-profile fitting algorithm to enable near realtime robust computation of sample optical properties. Future work will focus on the incorporation of multispectral capability to provide needed data to facilitate development of more realistic liver tissue phantoms.


Patterns of tuberculosis in the Americas: how can modern biomedicine inform the ancient past?
Tuberculosis (TB) is an infectious disease that continues to take its toll on human lives. Paleopathological research indicates that it has been a significant cause of death among humans for at least five thousand years. Because of the devastating consequences to human health, social systems, and endangered primate species, TB has been the subject of many and varied research efforts throughout the world, efforts that are amassing an enormous amount of data concerning the causative agent Mycobacterium tuberculosis. Despite sequencing of the M. tuberculosis genome and numerous molecular epidemiological studies, many questions remain regarding the origin, evolution, and future co-evolutionary trajectory of M. tuberculosis and humans. Indeed, the origin of pre-Columbian New World TB has been and remains hotly debated, and resolution of this controversy will likely only come with integration of data and theory from multiple disciplines. In this paper, we discuss the pre-Columbian TB controversy, and then use research from biological and biomedical sciences to help inform paleopathological and archaeological studies of this ubiquitous disease that plagued our ancient forbears.


How many acute beds do we really need?
At the end of 1972 two new "best-buy" district general hospitals should open at Bury St. Edmunds and Frimley, eventually serving their catchment areas at a ratio of two acute beds per 1,000 population. This study shows that one of these areas is already operating below this projected target as a result of a considerable decline in the bed ratio over the past decade. Drastic shortening of the average length of stay has permitted an increase in admission rates from 60 to 79 per 1,000 population over the decade, while costs per case measured at constant prices have fallen. These changes have taken place more rapidly than in the U.K. generally. The evidence points to the pattern of clinical management as the main reason for this and suggests that similar gains could be achieved on a national scale, even without waiting for new buildings and expanded community services.


Relationship Between Sleep Quality, Depression Symptoms, and Blood Glucose in Pregnant Women.
Sleep quality during pregnancy affects maternal/child health. We aimed to assess changes in sleep quality during pregnancy and determine its relationship to maternal mood, blood glucose, and work schedule among primiparous women. We conducted a prospective/longitudinal/observational study. Ninety-two pregnant women were recruited from Midwestern hospital. Mood and sleep quality data were collected using Edinburgh Postnatal Depression Scale/Pittsburgh Sleep Quality Index at Gestational Weeks 22 and 32. Forty-three women completed the study. Twenty-six women (63%) were African American and the mean age was 23.64 (SD = 3.82) years. Rate of poor sleep quality increased during pregnancy with 25% of women had scores indicative of depression symptoms. Poor sleep quality score was related to mood scores (p < .05) and work schedule. Blood glucose was not significantly related to sleep duration. In conclusion, poor sleep quality during pregnancy was associated with poor mood and work schedule, suggesting that interventions targeting mental health and lifestyles are needed.


First Lower Two-Thirds Osteomyocutaneous Facial Allograft Perfused by a Unilateral Facial Artery: Outcomes and Vascularization at 1 Year after Transplantation.
Facial allotransplantation provides a unique opportunity to restore facial form and function in severely disfigured patients. Using a single unilateral facial artery for vascularization can significantly reduce surgical duration and thus facilitate the practice of face transplantation. A 33-year-old man with a history of high-energy ballistic trauma received a facial allograft comprising the lower two-thirds of the face, including maxilla and mandible. Vascular anastomoses involved one unilateral facial artery and two veins. Vascularization patterns, airway volume, and facial functions were assessed before and 1 year after transplantation. In addition, immunosuppressive therapy and rejection episodes were recorded. One year after transplantation, the facial allograft is well perfused and gradually improving in function. Unilateral facial artery anastomosis remains patent and collateralization with the contralateral side is taking place through collaterals of the submental arteries. Bony perfusion of the maxilla and mandible is provided periosteally. Bilateral venous outflow is evident. Airway volume is significantly increased compared with before transplantation, and gastrostomy and tracheostomy tubes have been securely removed. The recipient has gained the abilities to smell, speak, feel, and grimace 1 year after transplantation. Steroids were successfully weaned after 9 months, leaving the patient on dual immunosuppressive therapy with tacrolimus and mycophenolate mofetil. Two rejection episodes occurred, of which one was treated by steroid pulse and the other by adjusting the maintenance therapy. In this patient, a facial allograft comprising the lower two-thirds of the face including the maxilla and mandible is sufficiently perfused by one unilateral facial artery. Bilateral venous outflow, however, seems to be necessary. Facial allotransplantation can significantly and securely improve facial form and function. Therapeutic, V.


The Medial Pillar Island Flap for Oncoplastic Breast Reconstruction of Upper Pole Defects.
Breast deformity is common following lumpectomy. Use of ptotic lower pole tissue for restoration of volume in the upper pole is quite appealing since it allows for a concomitant lift. This study presents the medial pillar island flap technique of oncoplastic breast reconstruction of upper pole defects. Vascular anatomy of the lower pole of the breast was investigated with cadaver study. The medial pillar island flap was designed utilizing the territory of the inferior pole of the breast as an island flap pedicled medially by the internal mammary artery perforators surrounded by the soft tissue of the medial pillar. It was transposed to the upper pole lumpectomy defect as an independent flap from superomedial pedicle which was utilized for nipple transposition. The dominant internal mammary artery perforator supplying the medial pillar island flap was consistently found in the fourth interspace at a mean distance of 8.5 cm (range, 8 to 10) from the sternal midline. Thirty patients underwent the procedure, with a mean age of 61 years and mean body mass index of 28.9. The average size of the defect was 170 cm(3) (range, 48 to 295 cm(3)). The majority of the patients (n = 28) underwent opposite breast symmetry surgery as well. The average follow up was 12 months. Complication rate was 23.3%. Reoperation rate was 16.7%. There was no evidence of flap compromise or nipple areola complex necrosis. Patient satisfaction was high, with a mean score of 4.1 (range, 2 to 5) out of 5. The medial pillar island flap has reliable vascularity based on the internal mammary artery system. The flap carries lower pole breast tissue as confined by the medial and lateral pillars of a vertical mastopexy design, offering unrestricted arc of rotation for effective reconstruction of upper pole lumpectomy defects as it is completely dissected from the chest wall and the inframammary fold. The two flap design, along with superomedial pedicle, accomplishes versatility for flap inset. The technique was proven to result in safe outcomes without major complications.


[Basic principles of surgical policy in complicated chronic pancreatitis].
The paper presents some experience with surgical treatment of 183 patients with complicated forms of chronic pancreatitis. The type of a surgical intervention depended on the pattern of pancreatic morphological changes. Operations of internal drainage of the pancreas in 103 patients with ductal hypertension provide the largest percentage (92.4%) of good and satisfactory results. Resectional methods of surgical treatment for chronic pancreatitis (n = 36) without signs of intraductal hypertension and with the prevalence of predominant lesions in some portions of the gland yield 80% good and satisfactory results. The incidence of postoperative complications following pancreatic resections is higher than those after drainages (16.2 versus 11.6%). The paper gives a concept of combined operations on the pancreas and bile ducts in chronic pancreatitis complicated by stricture of the distal common bile duct, revealed in 24.4% of cases.


Management of hyperuricemia in gout: focus on febuxostat.
Gout is the most common inflammatory arthritis in an elderly population, and can be diagnosed with absolute certainty by polarization microscopy. However, diagnosis may be challenging because atypical presentations are more common in the elderly. Management of hyperuricemia in the elderly with gout requires special consideration because of co-medication, contra-indications, and risk of adverse reactions. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used sensibly in the elderly, especially when renal function impairment is present. However, if used at the lowest dose that maintains the serum urate level below 5.0 to 6.0 mg/dL (0.30 to 0.36 mmol/L), the excess urate in the body will eventually be eliminated, acute flares will no longer occur, and tophi will resolve. Febuxostat, a new xanthine oxidase inhibitor, is welcomed, as few alternatives for allopurinol are available. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment. Its antihyperuricemic efficacy at 80 to 120 mg/day is better than "standard dosage" allopurinol (300 mg/day). Long-term safety data and efficacy data on tophus diminishment and reduction of gout flares have recently become available. Febuxostat may provide an important option in patients unable to use allopurinol, or refractory to allopurinol.


Therapist effects in yearlong psychodynamic therapy: An exploratory study.
A large body of research indicates that therapists can have a strong impact on treatment outcome, but little is known about the relationship between therapist effects and treatment phase. Our objective was to examine the interactive effect of therapist effectiveness and treatment phase on the outcome of 1 year of dynamic therapy. Therapists' effectiveness scores were defined as the extent of change for each therapist on the OQ-45 scores across their clients at five time points. The sample included 24 therapists who conducted psychodynamic therapy with 65 clients in a naturalistic setting. A three-level hierarchical linear model was applied. In accordance with the hypotheses, a significant main effect was found for effectiveness (estimate = 1.69, p < .05), for the two-way interactions between effectiveness and time (estimate = 1.36, p < .01), and for effectiveness and initial severity of symptoms (estimate = -0.02, p < .05). Simple slope analysis was conducted showing that among the less effective therapists, no significant change in outcome was found as time progressed; among the more effective therapists, outcome improved as time progressed. In addition, therapists were more influential in the treatments of clients with low initial severity. Our findings lend some support to the notion that therapist effects become increasingly influential as therapy progresses. The findings highlight the need for further research into changes in the magnitude of therapists' effect in various phases of therapy. Furthermore, the severity level of the initial symptoms of the client should be taken into account.


Macular pigment: a review of current knowledge.
The existence of the macula lutea of the human retina has been known for more than 200 years. It is established that the xanthophylls lutein and zeaxanthin are responsible for the yellow color. The effect of macular photopigments on blue-light filtration and color perception is well established. It has been postulated that the pigment might serve to reduce chromatic aberration and to improve visual acuity. The antioxidant capabilities of these xanthophylls combined with their ability to trap short-wavelength light may serve to protect the outer retina, retinal pigment epithelium, and choriocapillaris from oxidative damage. Current ideas on the pathophysiology of age-related macular degeneration may be compatible with the proposed function of lutein and zeaxanthin. This review will summarize our knowledge about macular pigment regarding current efforts in research and the epidemiology of age-related eye disease.


Development and Evaluation of C10 and SNAC Erodible Tablets for Gastric Delivery of a GIP/GLP1 Peptide in Monkeys.
The permeation enhancers (PEs) sodium caprate (C10) and sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) have been utilized for the intestinal and gastric delivery of macromolecules, respectively. However, the potential of C10 for the gastric delivery of a peptide and the ability of SNAC to deliver other peptides to the stomach beyond semaglutide have not been investigated. In this study, we have developed and evaluated C10 and SNAC-containing erodible tablets for the gastric delivery of a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP/GLP1) dual agonist peptide (LY) in cynomolgus monkeys. We also evaluated the impact of release rates on the in vivo performance of C10 and SNAC. Furthermore, we compared the oral exposure of the LY peptide and semaglutide with different proteolytic stabilities using a SNAC erodible tablet. Additionally, we investigated the mechanism of action of SNAC for improving gastric absorption of the LY peptide via tissue distribution in monkey. C10 and SNAC tablets released the peptide and PE by erosion from the tablet surface with 100% release within 60 min at pH 6.8. Following a single oral administration to monkeys, C10 and SNAC erodible tablets at 300 mg exhibited similar LY mean absolute oral bioavailability of 5.7% and 4.2%, respectively. The C10 immediate release capsule (500 mg) with faster dissolution profile (10 min) showed a decrease in the LY oral bioavailability; however, a faster dissolution profile (15 min) with erodible SNAC tablet resulted in a relatively higher LY oral bioavailability compared to the slow-release erodible tablets (60 min). Using SNAC as the PE, the combination of slow-release tablet design and LY peptide with higher pepsin stability resulted in about 4-fold higher mean oral bioavailability in the monkeys than semaglutide (4.2% vs 1.2%, respectively). In the monkey gastric tissue, SNAC was found to reduce tight junction protein levels and increase the peptide uptake into the gastric epithelium suggesting its permeation enhancing mechanism via both paracellular and transcellular pathways. Taking these data altogether, the enhanced proteolytic stability of the LY peptide combined with the optimal erodible tablets enabled the gastric delivery of the LY peptide with a higher oral bioavailability than semaglutide.


Regulating transcription: a chemical perspective.
Many human diseases are characterized by altered gene expression patterns caused by malfunctioning transcriptional regulators. This has spurred new efforts in the development of artificial transcription factors that regulate the expression of specific genes either positively or negatively. Despite impressive advances in the last decade, artificial transcription factors that reconstitute all of the functions of natural regulators are not yet a reality. Such factors will be powerful chemical tools for unraveling the mechanisms by which gene expression is regulated and in the long term offer considerable therapeutic potential.


Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia.
T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy characterized by the recurrent inv(14)(q11q32)/t(14;14)(q11;q32) or t(X;14)(q28;q11) leading to activation of either the TCL1 or MTCP1 gene, respectively. However, these primary genetic events are insufficient to drive leukemogenesis. Recently, activating mutations in JAK3 have been identified in other T-cell malignancies. Since JAK3 is essential for T-cell maturation, we analyzed a cohort of 32 T-PLL patients for mutational hot spots in the JAK3 gene using a step-wise screening approach. We identified 14 mutations in 11 of 32 patients (34%). The most frequently detected mutation in our cohort was M511I (seen in 57% of cases) previously described as an activating change in other T-cell malignancies. Three patients carried two mutations in JAK3. In two patients M511I and R657Q were simultaneously detected and in another patient V674F and V678L. In the latter case we could demonstrate that the mutations were on the same allele in cis. Protein modeling and homology analyses of mutations present in other members of the JAK family suggested that these mutations likely activate JAK3, possibly by disrupting the activation loop and the interface between N and C lobes, increasing the accessibility of the catalytic loop. In addition, four of the 21 patients lacking a JAK3 point mutation presented an aberrant karyotype involving the chromosomal band 19p13 harboring the JAK3 locus. The finding of recurrent activating JAK3 mutations in patients with T-PLL could enable the use of JAK3 inhibitors to treat patients with this unfavorable malignancy who otherwise have a very poor prognosis.


Clock accuracy and precision evolve as a consequence of selection for adult emergence in a narrow window of time in fruit flies Drosophila melanogaster.
Although circadian clocks are believed to have evolved under the action of periodic selection pressures (selection on phasing) present in the geophysical environment, there is very little rigorous and systematic empirical evidence to support this. In the present study, we examined the effect of selection for adult emergence in a narrow window of time on the circadian rhythms of fruit flies Drosophila melanogaster. Selection was imposed in every generation by choosing flies that emerged during a 1 h window of time close to the emergence peak of baseline/control flies under 12 h:12 h light:dark cycles. To study the effect of selection on circadian clocks we estimated several quantifiable features that reflect inter- and intra-individual variance in adult emergence and locomotor activity rhythms. The results showed that with increasing generations, incidence of adult emergence and activity of adult flies during the 1 h selection window increased gradually in the selected populations. Flies from the selected populations were more homogenous in their clock period, were more coherent in their phase of entrainment, and displayed enhanced accuracy and precision in their emergence and activity rhythms compared with controls. These results thus suggest that circadian clocks in D. melanogaster evolve enhanced accuracy and precision when subjected to selection for emergence in a narrow window of time.


Radiological and pathological characteristics of synovial hemangioma of the knee.
Synovial hemangioma, a rare benign tumor that occurs most frequently in the knee in children and young adults, has four histological subtypes: Venous, arteriovenous, cavernous and capillary hemangiomas. Since the clinical presentation and radiological findings of synovial hemangioma are non-specific, there is frequently a long period between the onset and the diagnosis. The cases of nine patients, pathologically diagnosed with synovial hemangioma and surgically treated, were retrospectively analyzed. All nine patients had persistent knee pain. In addition, three patients also had a swollen knee with intra-articular hemorrhage. Plain radiography revealed intra-articular phleboliths in two patients. In seven patients, T1-weighted magnetic resonance imaging showed low signal intensity with small signal voids. On T2-weighted imaging, all patients showed high signal intensity containing small signal voids. All patients underwent surgical excision; there was no postoperative recurrence after the final operation, and the knee pain had disappeared at the final follow-up. From the pathological findings, the diagnoses were venous hemangioma, cavernous hemangioma and capillary hemangioma (three patients each).


Prevalence of serological markers for celiac disease (IgA and IgG class antigliadin antibodies and IgA class antiendomysium antibodies) in patients with autoimmune rheumatologic diseases in Belo Horizonte, MG, Brazil.
Patients with autoimmune rheumatologic conditions and celiac disease tend to have a variety of autoantibodies, many of which have no clear pathogenic role. The literature contains frequent reports of celiac disease being more prevalent in patients with rheumatologic diseases, although this remains controversial. To investigate the prevalence of positive serum tests for celiac disease, particularly IgA and IgG antigliadin (AGA) antibodies and IgA antiendomysium antibodies (EmA) in patients with autoimmune rheumatologic diseases. A second aim was to correlate positive serum tests with prednisone and immunosuppressant medication. A total of 190 adults and pediatric patients with a variety of autoimmune rheumatologic diseases (systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis and spondyloarthrophathies) were evaluated and tested for IgA and IgG antigliadin-antibodies and IgA antiendomysium antibodies. Patients with positive serum tests underwent endoscopic duodenal biopsies for pathology studies. There were four positive sera (2.1%) for AGA IgA, all of which tested negative for AGA IgG and EmA. Three sera (1.6%) tested positive for AGA IgG; all were negative for AGA IgA and EmA. The EmA test at a 1:2.5 serum dilution tested positive in 94 patients (49.5%); at a 1:5 serum dilution it was positive in 41 patients (21.6%). Eleven subjects tested positive for EmA at 1:40 dilution; and all of these tested negative for IgA tissue antitransglutaminase (tTG) antibodies. Nine of the 11 EmA-positive patients and all 7 patients with positive antigliadin antibodies tests underwent duodenal endoscopic biopsies, and no significant changes were demonstrated in their duodenal mucosa. A positive EmA was associated with elevated optical density AGA IgA readings; however, there was no relationship between positive EmA and AGA IgG optical density readings. Prednisone and immunosuppressant use were unrelated to AGA IgA optical density readings or AGA IgG readings. These drugs were associated with fewer positive EmA tests. Positive AGAA, AGAG or EmA results are probably nonspecific for the presence of celiac disease among autoimmune rheumatologic disease patients. The intake of prednisone and immunosuprressant drugs seems to reduce the prevalence of IgA EmA, but it does not interfere with antigliadin antibodies tests.Further studies are required to estimate more accurately the prevalence of this disease in rheumatologic patients.


A tool for prediction of risk of rehospitalisation and mortality in the hospitalised elderly: secondary analysis of clinical trial data.
To construct and internally validate a risk score, the '80+ score', for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI). Two acute internal medicine wards at Uppsala University hospital. Patient data were used from a randomised controlled trial investigating the effects of a comprehensive clinical pharmacist intervention. Data from 368 patients, aged 80 years and older, admitted to one of the study wards. Time to rehospitalisation or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk estimation was constructed. The 80+ score was internally validated, and the discriminatory ability of the score and of STOPP, START and MAI was assessed using C-statistics. Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI). We developed and internally validated a score for prediction of risk of rehospitalisation and mortality in hospitalised older people. The score discriminated risk better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions.


Heart Failure and Thermoregulatory Control: Can Patients With Heart Failure Handle the Heat?
Upon heat exposure, the thermoregulatory system evokes reflex increases in sweating and skin blood flow responses to facilitate heat dissipation and maintain heat balance to prevent the continuing rise in core temperature. These heat dissipating responses are mediated primarily by autonomic and cardiovascular adjustments; which, if attenuated, may compromise thermoregulatory control. In patients with heart failure (HF), the neurohumoral and cardiovascular dysfunction that underpins this condition may potentially impair thermoregulatory responses and, consequently, place these patients at a greater risk of heat-related illness. The aim of this review is to describe thermoregulatory mechanisms and the factors that may increase the risk of heat-related illness in patients with HF. An understanding of the mechanisms responsible for impaired thermoregulatory control in HF patients is of particular importance, given the current and projected increase in frequency and intensity of heat waves, as well as the promotion of regular exercise as a therapeutic modality. Furthermore, novel therapeutic strategies that may improve thermoregulatory control in HF, and the clinical relevance of this work in this population will be discussed.


Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport.
Activated protein C (PC) is a serine protease that regulates blood coagulation by inactivating coagulation factors Va and VIIIa. PC deficiency is an autosomally inherited disorder associated with a high risk of recurrent venous thrombosis. The aim of the study was to explore the mechanisms responsible for severe PC deficiency in a patient with the protein C A267T mutation by in-vitro expression studies. Huh7 and CHO-K1 cells were transiently transfected with expression vectors containing wild-type (WT PC) and mutated PC (A267T PC) cDNAs. PC mRNA levels were assessed by qRT-PCR and the PC protein levels were measured by ELISA. The mRNA levels of WT PC and A267T PC were similar, while the intracellular protein level of A267T PC was moderately decreased compared to WT PC. The secretion of A267T PC into the medium was severely impaired. No differences in molecular weights were observed between WT and A267T PC before and after treatment with endo-β-N-acetylglucosaminidase. Proteasomal and lysosomal degradations were examined using lactacystin and bafilomycin, respectively, and revealed that A267T PC was slightly more susceptible for proteasomal degradation than WT PC. Intracellular co-localization analysis indicated that A267T PC was mainly located in the endoplasmic reticulum (ER), whereas WT PC was observed in both ER and Golgi. In contrast to what has been reported for other PC mutants, intracellular degradation of A267T PC was not the main/dominant mechanism underlying the reduced intracellular and secretion levels of PC. Our results indicate that the A267T mutation most likely caused misfolding of PC, which might lead to increased retention of the mutated PC in ER.


ErCas12a CRISPR-MAD7 for Model Generation in Human Cells, Mice, and Rats.
MAD7 is an engineered class 2 type V-A CRISPR-Cas (Cas12a/Cpf1) system isolated from Eubacterium rectale. Analogous to Cas9, it is an RNA-guided nuclease with demonstrated gene editing activity in Escherichia coli and yeast cells. Here, we report that MAD7 is capable of generating indels and fluorescent gene tagging of endogenous genes in human HCT116 and U2OS cancer cell lines, respectively. In addition, MAD7 is highly proficient in generating indels, small DNA insertions (23 bases), and larger integrations ranging from 1 to 14 kb in size in mouse and rat embryos, resulting in live-born transgenic animals. Due to the different protospacer adjacent motif requirement, small-guide RNA, and highly efficient targeted gene disruption and insertions, MAD7 can expand the CRISPR toolbox for genome enginnering across different systems and model organisms.


Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
Activation of a naive T cell is a highly energetic event, which requires a substantial increase in nutrient metabolism. Upon stimulation, T cells increase in size, rapidly proliferate, and differentiate, all of which lead to a high demand for energetic and biosynthetic precursors. Although amino acids are the basic building blocks of protein biosynthesis and contribute to many other metabolic processes, the role of amino acid metabolism in T cell activation has not been well characterized. We have found that glutamine in particular is required for T cell function. Depletion of glutamine blocks proliferation and cytokine production, and this cannot be rescued by supplying biosynthetic precursors of glutamine. Correlating with the absolute requirement for glutamine, T cell activation induces a large increase in glutamine import, but not glutamate import, and this increase is CD28-dependent. Activation coordinately enhances expression of glutamine transporters and activities of enzymes required to allow the use of glutamine as a Krebs cycle substrate in T cells. The induction of glutamine uptake and metabolism requires ERK function, providing a link to TCR signaling. Together, these data indicate that regulation of glutamine use is an important component of T cell activation. Thus, a better understanding of glutamine sensing and use in T cells may reveal novel targets for immunomodulation.


Light Acclimation of the Colonial Green Alga Botryococcus braunii Strain Showa.
In contrast to single cellular species, detailed information is lacking on the processes of photosynthetic acclimation for colonial algae, although these algae are important for biofuel production, ecosystem biodiversity, and wastewater treatment. To investigate differences between single cellular and colonial species, we studied the regulation of photosynthesis and photoprotection during photoacclimation for the colonial green alga Botryococcus braunii and made a comparison with the properties of the single cellular species Chlamydomonas reinhardtii We show that B. braunii shares some high-light (HL) photoacclimation strategies with C. reinhardtii and other frequently studied green algae: decreased chlorophyll content, increased free carotenoid content, and increased nonphotochemical quenching (NPQ). Additionally, B. braunii has unique HL photoacclimation strategies, related to its colonial form: strong internal shading by an increase of the colony size and the accumulation of extracellular echinenone (a ketocarotenoid). HL colonies are larger and more spatially heterogenous than low-light colonies. Compared with surface cells, cells deeper inside the colony have increased pigmentation and larger photosystem II antenna size. The core of the largest of the HL colonies does not contain living cells. In contrast with C. reinhardtii, but similar to other biofilm-forming algae, NPQ capacity is substantial in low light. In HL, NPQ amplitude increases, but kinetics are unchanged. We discuss possible causes of the different acclimation responses of C. reinhardtii and B. braunii Knowledge of the specific photoacclimation processes for this colonial green alga further extends the view of the diversity of photoacclimation strategies in photosynthetic organisms.


Diurnal Dynamics of Gaseous and Dissolved Metabolites and Microbiota Composition in the Bovine Rumen.
Diurnal patterns of ruminal fermentation metabolites and microbial communities are not commonly assessed when investigating variation in ruminal CH4 production. The aims of this study were to monitor diurnal patterns of: (i) gaseous and dissolved metabolite concentrations in the bovine rumen, (ii) H2 and CH4 emitted, and (iii) the rumen microbiota. Furthermore, the effect of dietary inclusion of linseed oil on these patterns was assessed. Four rumen cannulated multiparous cows were used in a cross-over design with two 17 days periods and two dietary treatments: a control diet and a linseed oil supplemented diet [40% maize silage, 30% grass silage, 30% concentrate on dry matter (DM) basis for both diets; fat contents of 33 vs. 56 g/kg of DM]. On day 11, rumen contents were sampled for 10 h after morning feeding to profile gaseous and dissolved metabolite concentrations and microbiota composition. H2 and CH4 emission (mass per unit of time) was measured in respiration chambers from day 13 to 17. A 100-fold increase in ruminal H2 partial pressure (contribution to the total pressure of rumen headspace gases) was observed at 0.5 h after feeding. This peak was followed by a decline to basal level. Qualitatively similar patterns after feeding were also observed for H2 and CH4 emission, ethanol and lactate concentrations, and propionate molar proportion, although the opposite pattern was seen for acetate molar proportion. Associated with these patterns, a temporal biphasic change in the microbial composition was observed as based on 16S ribosomal RNA with certain taxa specifically associated with each phase. Bacterial concentrations (log10 16S ribosomal RNA gene copies based) were affected by time, and were increased by linseed oil supplementation. Archaeal concentrations (log10 16S ribosomal RNA gene copies based) tended to be affected by time and were not affected by diet, despite linseed oil supplementation decreasing CH4 emission, tending to decrease the partial pressure of CH4, and tending to increase propionate molar proportion. Linseed oil supplementation affected microbiota composition, and was most associated with an uncultivated Bacteroidales taxon. In summary, our findings support the importance of diurnal dynamics for the understanding of VFA, H2, and CH4 production.


D- and L-lactate dehydrogenases during invertebrate evolution.
The L-lactate and D-lactate dehydrogenases, which are involved in the reduction of pyruvate to L(-)-lactate and D(+)-lactate, belong to evolutionarily unrelated enzyme families. The genes encoding L-LDH have been used as a model for gene duplication due to the multiple paralogs found in eubacteria, archaebacteria, and eukaryotes. Phylogenetic studies have suggested that several gene duplication events led to the main isozymes of this gene family in chordates, but little is known about the evolution of L-Ldh in invertebrates. While most invertebrates preferentially oxidize L-lactic acid, several species of mollusks, a few arthropods and polychaetes were found to have exclusively D-LDH enzymatic activity. Therefore, it has been suggested that L-LDH and D-LDH are mutually exclusive. However, recent characterization of putative mammalian D-LDH with significant similarity to yeast proteins showing D-LDH activity suggests that at least mammals have the two naturally occurring forms of LDH specific to L- and D-lactate. This study describes the phylogenetic relationships of invertebrate L-LDH and D-LDH with special emphasis on crustaceans, and discusses gene duplication events during the evolution of L-Ldh. Our phylogenetic analyses of L-LDH in vertebrates are consistent with the general view that the main isozymes (LDH-A, LDH-B and LDH-C) evolved through a series of gene duplications after the vertebrates diverged from tunicates. We report several gene duplication events in the crustacean, Daphnia pulex, and the leech, Helobdella robusta. Several amino acid sequences with strong similarity to putative mammalian D-LDH and to yeast DLD1 with D-LDH activity were found in both vertebrates and invertebrates. The presence of both L-Ldh and D-Ldh genes in several chordates and invertebrates suggests that the two enzymatic forms are not necessarily mutually exclusive. Although, the evolution of L-Ldh has been punctuated by multiple events of gene duplication in both vertebrates and invertebrates, a shared evolutionary history of this gene in the two groups is apparent. Moreover, the high degree of sequence similarity among D-LDH amino acid sequences suggests that they share a common evolutionary history.


[Lessons learnt from COVID-19: technology for organizing a forced self-isolation regime].
The lessons of COVID-19 have confirmed the effectiveness of measures aimed at strict self-isolation and quarantine. In the People's Republic of China, where any violation of the regime requirements was qualified as a criminal offense, the virus was neutralized when the pandemic was only gaining momentum in Europe and America. However, without proper organization of a restrictive regime, self-isolation can lead to negative consequences in terms of deterioration of health and standard of living. The pandemic has undoubtedly significantly complicated our lives, has taken millions of lives, caused disability, deterioration of material status, rupture of marital ties. One of the reasons for this development of events was the unsatisfactory organization of leisure during self-isolation. The inability to calmly wait out, endure COVID-associated adversities in most countries caused mass popular unrest, gave rise to panic moods. Only those who managed to curb the negative consequences and direct them in the right direction managed to come out of the pandemic with dignity. The authors have developed an organizational technology of the forced self-isolation regime based on the complex of measures and proposed this technology for introduction to daily life of the population during the period of restrictive regimes. The authors are sure that it is especially important to organize leisure and create the most comfortable conditions of the isolated living for the elderly, who are the most sensitive to changes in life stereotypes. The authors propose a set of measures to efficiently organize leisure during self-isolation with physical therapy, cognitive training, as well as measures to fit the body and develop psychological relief, making it possible to reverse the threat of the pandemic in higher health potential and better family relations.


Effects of nitric oxide synthase inhibitors 1-(2-trifluoromethylphenyl)--imidazole (TRIM) and 7-nitroindazole (7-NI) on learning and memory in mice.
Nitric oxide (NO) plays an important role in hippocampal long-term potentiation (LTP), which is involved in memory processes. This led to the hypothesis that nitric oxide synthase (NOS) inhibitors will have disturbing effects on learning and memory. The aim of our study was to investigate the effects of the new selective neuronal and inducible NOS inhibitor 1- (2-trifluoromethylphenyl) imidazole (TRIM) (10-50 mg/kg) on learning and memory and compare it to the nonselective NOS inhibitor 7-NI (15-45 mg/kg) using different behavioral tests in Swiss mice, thus clarifying the role of neuronal NOS (nNOS) and endothelial NOS (eNOS) in cognitive processes. TRIM had no specific effect on either learning or memory parameters, while 7-NI (30 mg/kg) disturbed spatial memory in the probe trial of the Morris water maze test, which was performed on the last day of the test. No differences between TRIM and the control groups were observed, while 7-NI (30 and 45 mg/kg) significantly disturbed memory in the novel object recognition test. In the social transmission of food preference test, both TRIM (50 mg/kg) and 7-NI (45 mg/kg) impaired hippocampal olfactory memory, but the total food consumption was also significantly decreased at these doses. In the passive avoidance test, TRIM did not disturb the performance, while memory impairment was observed, even with lower doses of 7-NI. All of these results suggest that TRIM has no clear effect on cognitive impairment compared to 7-NI and that inhibition of both nNOS and eNOS are necessary for the deterioration of memory processes.


Polydrug fatality involving metaxalone.
A 29-year old female with a history of depression was found dead in a hotel room. The death scene investigation found empty pill bottles and an empty liter bottle of wine. Metaxalone, a centrally acting muscle relaxant, along with citalopram, ethanol, and chlorpheniramine were identified in the postmortem samples and quantitated by gas chromatography-mass spectrometry. The concentration of metaxalone in femoral vein blood was 39 mg/L. The heart blood concentration was 54 mg/L. Femoral vein blood concentrations of citalopram and chlorpheniramine were 0.77 mg/L and 0.04 mg/L, respectively. Ethanol levels were 0.13 g/dL in vitreous and 0.08 g/dL in heart blood. Other tissue samples were also analyzed. The authors consider the metaxalone concentrations toxic and potentially fatal. The citalopram concentrations were lower than those reported in fatal cases for this drug alone. Death was ascribed to polydrug abuse/overdose with metaxalone a major contributor. This represents the first reported case to our knowledge in which a metaxalone overdose significantly contributed to death.


Loss of the fragile X mental retardation protein decouples metabotropic glutamate receptor dependent priming of long-term potentiation from protein synthesis.
Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). FMRP is a negative regulator of local mRNA translation downstream of group 1 metabotropic glutamate receptor (Gp1 mGluR) activation. In the absence of FMRP there is excessive mGluR-dependent protein synthesis, resulting in exaggerated mGluR-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus. Understanding disease pathophysiology is critical for development of therapies for FXS and the question arises of whether it is more appropriate to target excessive LTD or excessive mGluR-dependent protein synthesis. Priming of long-term potentiation (LTP) is a qualitatively different functional consequence of Gp1 mGluR-stimulated protein synthesis at the same population of CA1 synapses where LTD can be induced. Therefore we determined if LTP priming, like LTD, is also disrupted in the Fmr1 knockout (KO) mouse. We found that mGluR-dependent priming of LTP is of comparable magnitude in wild-type (WT) and Fmr1 KO mice. However, whereas LTP priming requires acute stimulation of protein synthesis in WT mice, it is no longer protein synthesis dependent in the Fmr1 KO. These experiments show that the dysregulation of mGluR-mediated protein synthesis seen in Fmr1 KO mice has multiple consequences on synaptic plasticity, even within the same population of synapses. Furthermore, it suggests that there is a bifurcation in the Gp1 mGluR signaling pathway, with one arm triggering synaptic modifications such as LTP priming and LTD and the other stimulating protein synthesis that is permissive for these modifications.


Early clinical experience with a metaphyseal loading implant: Why have a stem?
This is a prospective cohort study of patients undergoing total hip replacement using an uncemented, proximally coated stem with a short tapered distal stem. Patients with a minimum of 24 months of clinical and radiological follow-up were included in this study. There were 18 males and 34 females. Average age at surgery was 40 years. The diagnoses included developmental dysplasia of the hip in 20 patients, osteoarthritis in 15, avascular necrosis of the femoral head in nine, and inflammatory arthritis in three. Average follow-up was 46 months (range 25-78). There was no evidence of subsidence of any stem at the final follow-up. Interface buttressing was observed in 52 patients on the AP view and in 32 on the lateral view. This was seen in Gruen zones 1, 7, 8 and 14. Heterotopic ossification was seen in 15 patients. Distal cortical hypertrophy was seen in three patients. Three patients had one episode of dislocation and two patients had superficial wound infection. None of the hips has been revised and there was no radiological evidence of aseptic loosening. The high percentage of patients exhibiting condensation of the bone and interface buttressing at the lower reaches of the metaphysis suggest the objective of proximal loading is being achieved. We believe that early stability and durable biological fixation can be achieved by this cementless implant, in which the stem is designed to avoid any contact with the diaphyseal cortex.


Cancers after renal transplantation: multicenter experience.
Renal transplant recipients are at higher risk of certain tumors such as lymphomas and skin cancers and than the general and dialysis populations. We retrospectively studied the prevalence of tumors in adult renal transplant recipients in four Tunisian centers of transplantation in Tunis, Monsatir and Sfax from January 1986 to January 2005. The study included 36 patients; 19 men and 17 women with a mean age of 34.6 years (range from 18-54 years). The mean time since dialysis to transplantation was 43 months (6-131months). Maintenance therapy was based on calcineurin inhibitors (CNI) in 86 % of cases, on antimetabolites and corticosteroids in 100 % of cases. Anti-thymoglobulin was administered in a mean course of 12.4 days in 78 % of the patients. Acute rejection occurred in 25 cases and was treated with polyclonal or monoclonal antibodies on 40 % of cases. Incidence of cancer among our population was 7 % and occurred after a mean period of 54 months of transplantation (range from 4-160 months). Eighty three percent of the tumors were solid, and the rest were in the skin. Kaposi sarcoma formed 41.6 % and non-Hodgkin or Hodgkin lymphoma 27.7 % of the solid tumors, while spinocellular carcinoma formed 83% and basocellular carcinoma 17% of the skin tumors. Switching CNI to sirolimus in 8.3% cases was associated with a favorable outcome. Mortality was the outcome in 33.3% of the patients with cancer, while partial or complete regression of cancers was observed in 55.5% cases after decreasing the doses of the immunosuppressive medications. We conclude that post renal transplant cancer is mainly characterized by the predominance of Kaposi sarcoma favored by solar exposure and rigorously induced and maintained immunosuppression. Careful follow-up may results in early intervention and decrease mortality.


Adverse drug reactions to a cephalosporins in hospitalized patients with a history of penicillin allergy.
Estimates on the cross-reactivity between cephalosporin and penicillin range from 1 to 16%. Patients with a history of penicillin allergy usually receive less optimal and more costly alternatives even if cephalosporins are a more viable alternative. One hundred eighty-six patients admitted to Winthrop University Hospital in a 7.5-month period, who reported penicillin allergy and received cephalosporin, were sent surveys. Eighty-three patients completed the survey and their charts were reviewed. Seven of 83 patients (8.4%) from a larger group of 186 penicillin-allergic patients developed a reaction to a cephalosporin. The exact 95% confidence interval is 3.5-16.6%. Six of seven (85.7%) penicillin-allergic patients who reacted to cephalosporin reported a definite history of an immediate reaction to penicillin, including hives. Only 1 of 62 (1.6%) patients who reported that their penicillin reaction was delayed, probable, or unknown had a cephalosporin reaction (p < 0.001). Thirty percent (3 of 10 patients) of penicillin-allergic patients, who received a second-generation cephalosporin, had a reaction, whereas 5.5% (4 of 73 patients) of those patients given only a first-, third-, and fourth-generation cephalosporin reacted (p < 0.04). None of those patients who received a fourth-generation cephalosporin reacted. Four of 15 (26.7%) patients who received a cephalosporin with an amino benzyl ring developed a reaction, as compared with 3 of 68 (4.4%) patients who received a cephalosporin without the ring (p < 0.02). Four patients with severe cephalosporin reactions had a rash, shortness of breath, difficulty swallowing, lightheadedness, and anaphylaxis. Patients who recall a definite history of an immediate type of penicillin allergy are more likely to develop a cephalosporin reaction compared with patients who reported a delayed, a probable, or an unknown penicillin reaction. Penicillin-allergic patients who receive second-generation cephalosporins, especially those with an amino benzyl side chain, are more likely to develop a reaction to cephalosporin. Although the incidence of reactions to cephalosporin in penicillin-allergic patients is low, those patients who reacted had more severe manifestations including anaphylaxis. Thus, continued caution regarding administration of cephalosporin, especially those with amino benzyl side chains, to patients who have a definite history of an immediate reaction to penicillin is advised.


Nefazodone treatment of adolescent depression: an open-label study of response and biochemistry.
The purpose of this study was to find whether nefazodone, effective in adult depression, might be similarly improve symptoms of adolescent depression. Secondary purpose was to relate platelet serotonin content to response, and to find if nefazodone's effect on platelet content was similar to that of the SSRIs. 10 adolescents meeting DSMIV criteria for major depression received up to 400 mg of nefazodone for an eight week period. Response was assessed at baseline, 1, 2, 4, and 8 weeks by BDI and HDRS; platelet serotonin (5HT) content was obtained at baseline and final visit (for two dropouts, this was done at last visit, i.e., week 4). In LOCF analysis, significant improvement was found in both HDRS (20.9 to 8.9, p = .01) and BDI (24.6 to 10.2, p = .01). Eight of nine patients with available data showed increases in platelet 5HT content (.02). In seven patients of eight completers with available data, there was a nonsignificant trend for patients with platelet 5HT baseline greater than 30 ng/10(8) platelets to show a greater change in HDRS than those with a baseline of less than 30 ng/10(8) platelets (p = .07). Further double-blind study of nefazodone in adolescent depression is indicated; nefazodone appears to increase platelet 5HT content.


[Yellow nail syndrome].
We describe a 77 year old man with a prior history of recurrent airway infections, who presented with a history of cough, dyspnea and increased mucous production that had lasted several months. On chest X-ray a pleural effusion was observed. Subsequent thoracocentesis demonstrated an exudate with predominant eosinophils. An infectious cause was ruled out. The pleural effusion subsequently recurred and he was admitted for pleural biopsy, which revealed chronic pleuritis. On physical examination yellow nails on fingers and toes were noted. Subsequently, after exclusion of other diseases, a diagnosis of yellow nails syndrome was established. He was treated with corticosteroids, which were tapered over 6 months. One year later the eosinophilia had subsided, however the pleural effusion remained, although on a much smaller scale.


Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature.
Clostridium difficile is most commonly associated with colonic infection. It may, however, also cause disease in a variety of other organ systems. Small bowel involvement is often associated with previous surgical procedures on the small intestine and is associated with a significant mortality rate (4 of 7 patients). When associated with bacteremia, the infection is, as expected, frequently polymicrobial in association with usual colonic flora. The mortality rate among patients with C. difficile bacteremia is 2 of 10 reported patients. Visceral abscess formation involves mainly the spleen, with 1 reported case of pancreatic abscess formation. Frequently these abscesses are only recognized weeks to months after the onset of diarrhea or other colonic symptoms. C. difficile-related reactive arthritis is frequently polyarticular in nature and is not related to the patient's underlying HLA-B27 status. Fever is not universally present. The most commonly involved joints are the knee and wrist (involved in 18 of 36 cases). Reactive arthritis begins an average of 11.3 days after the onset of diarrhea and is a prolonged illness, taking an average of 68 days to resolve. Other entities, such as cellulitis, necrotizing fasciitis, osteomyelitis, and prosthetic device infections, can also occur. Localized skin and bone infections frequently follow traumatic injury, implying the implantation of either environmental or the patient's own C. difficile spores with the subsequent development of clinical infection. It is noteworthy that except for cases involving the small intestine and reactive arthritis, most of the cases of extracolonic C. difficile disease do not appear to be strongly related to previous antibiotic exposure. The reason for this is unclear. We hope that clinicians will become more aware of these extracolonic manifestations of infection, so that they may be recognized and treated promptly and appropriately. Such early diagnosis may also serve to prevent extensive and perhaps unnecessary patient evaluations, thus improving resource utilization and shortening length of hospital stay.