Mortality from Parkinson's disease and other causes in men who were prisoners of war in the Far East.
During World War II, more than 140000 Allied prisoners of war (POWs) were held captive by the Japanese in conditions of extreme privation. There have been concerns that the survivors are at increased risk of degenerative neurological disorders, especially Parkinson's disease. We assembled a cohort of British ex-POWs and analysed their mortality in a 46-year follow-up study. Using records held by the War Pensions Agency, we abstracted data on 11915 British former POWs. 11134 men were traced, and observed numbers of deaths between 1952 and 1997 were compared with those expected from national rates for the male population of England and Wales. Standardised mortality ratios (SMR) were calculated. Overall, mortality was lower than expected (7474 deaths vs 8796.2 expected; SMR 0.85 [95% CI 0.83-0.87]). Death rates from Parkinson's disease among the former POWs were slightly below the national average, though this difference was not statistically significant (35 deaths vs 43.2 expected; SMR 0.81 [0.56-1.13]). A similar pattern was seen for other degenerative neurological disorders (motorneuron disease 0.62 [0.31-1.11], multiple sclerosis 0.88 [0.42-1.61], and dementia 0.88 [0.68-1.11]). The former POWs had significantly lower than expected mortality from all major causes of death (ischaemic heart disease 0.81 [0.78-0.85], cerebrovascular disease 0.88 [0.81-0.95], all malignant neoplasms 0.92 [0.88-0.95], and respiratory disease 0.79 [0.74-0.85]). They also had below average rates of death from tuberculosis (0.44 [0.26-0.71]) and suicide (0.77 [0.57-1.02]), though the latter relation was not statistically significant. Mortality from diseases of the liver was increased (chronic liver disease and cirrhosis 1.68 [1.28-2.17], primary carcinoma of the liver 2.42 [1.75-3.26]). There is little evidence that men who were POWs in the Far East have higher rates of death than the male population generally. The only exception is diseases of the liver, which may be due to infection with hepatitis B or C virus during captivity. Death-certification data cannot provide a complete picture of physical and mental health, but the period of severe malnutrition, frequent infections, exhaustion, and intense psychological stress seems not to have increased susceptibility to neurodegenerative disease.


[Comments on Nigel Wiseman's "A Practical Sictionary of Chinese Medicine"--on Wiseman' s literal translation].
Comments were made on the word-for-word literal translation method used by Mr. Nigel Wiseman in A Practical Dictionary of Chinese Medicine. He believes that only literal translation can reflect Chinese medical concepts accurately. The so-called "word-for-word" translation is actually "English-word-for-Chinese-character" translation. First, he made a list of Single Characters with English Equivalents, and then he replaced each character of Chinese medical terms with the assigned English equivalent. Many English terms thus produced are confusing. The defect of the word-for-word literal translation stems from the erroneous idea that the single character constitutes the basic element of meaning corresponding to the notion of "word" in English, and the meaning of a disyllabic or polysyllabic Chinese word is simply the addition of the meanings of the two or more characters. Another big mistake is the negligence of the polysemy of Chinese characters. One or two English equivalents can by no means cover all the various meanings of a polysemous character as a monosyllabic word. Various examples were cited from this dictionary to illustrate the mistakes.


Association of dietary quality indices with glycemic status in korean patients with type 2 diabetes.
The present study was performed to evaluate the relationship between dietary quality indices including the Diet Quality Index-International (DQI-I), Alternate Healthy Eating Index (AHEI), and Healthy Diet Indicator (HDI) and glycemic status in Korean patients with type 2 diabetes. A total of 110 consecutive outpatients with type 2 diabetes who visited 2 university hospitals in Seoul and Seongnam from April 2004 to November 2006 were enrolled as subjects. At the time of enrollment, anthropometric parameters, dietary habits, experience of exercise, and metabolic parameters were obtained. Experienced registered dietitians collected one-day dietary intake using the 24-hour recall method. The mean scores for DQI-I, AHEI, and HDI were 68.9 ± 8.2, 39.4 ± 8.9, and 5.0 ± 1.3, respectively. After adjustment for age, body mass index, and energy intake, DQI-I and HDI were found to have a significant correlation with hemoglobin A1c (HbA1c) (r = -0.21, p < 0.05; r = -0.28, p < 0.05), fasting plasma glucose (r = -0.21, p < 0.05; r = -0.23, p < 0.05), and postprandial 2-h glucose (r = -0.30, p < 0.05; r = -0.26, p < 0.05, respectively). However, AHEI did not have a significant correlation with HbA1c. In conclusion, the DQI-I and HDI may be useful tools in assessing diet quality and adherence to dietary recommendations in Korean patients with type 2 diabetes. Future research is required to determine whether the dietary quality indices have predictive validity for dietary and glycemic changes following diet education in a clinical setting.


Quality of life measures as a preliminary clinical indicator in patients with primary brain tumors.
The health-related quality of life (HRQOL) measures serve as valuable indicators of survival in patients with newly diagnosed primary brain tumors (PBTs). HRQOL outcomes may benefit clinical decision-making by individualizing patient treatment and improving communications between the doctor, patient, and families. Exploring the individual items of the European Organization and Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QOL) measures may be predictive of prognosis. We prospectively collected the validated HRQOL and standard clinical and radiological measures from 48 patients with newly diagnosed PBT. The patients were followed every 3 months over 2 years. No proxies were allowed. Questionnaire responses were compared between two groups: Patients with recurrence and/or death (n = 26) and patients without a recurrence (n = 22). A total of 17 patients succumbed to a tumor-related death. Statistical analysis utilizing nonparametric t-tests and Wilcoxon sign tests assessed QOL responses. Significant group differences were noted in the QOL measures with more negative responses in the recurrence group. EORTC QLQ-C30 questions revealed a poor global HRQOL scale (P < 0.005) and pain interfering with daily activities (P < 0.05). EORTC QLQ-BN20 questions revealed weakness of the legs (P < 0.05), coordination difficulties (P < 0.005), and unsteady gait (P < 0.05). Hospital Anxiety and Depression Scale (HADS) questions reflected a patient who is slowed down (P < 0.01) and "frightened" (P < 0.05). Our analysis of longitudinal HRQOL measures may shed light on the prognostic significance of HRQOL measures in patients with newly diagnosed PBT. Further research is warranted to determine which selected individual measures of the EORTC QOL measures may be predictive of a patient's progression-free and overall survival and to test their validity and reliability in clinical trials.


Glass-transition-induced color-changing resins containing layered polydiacetylene.
A phase-segregated composite of polystyrene (PSt) and layered polydiacetylene (PDA) was formed through simultaneous polymerization and crystallization. As the motion of PSt chains with glass transition is transferred to that of PDA, the color change was achieved by the shortening of the conjugation length with deformation of the layered structure.


Expression of eicosanoid biosynthetic and catabolic enzymes in peritoneal endometriosis.
Increased peritoneal eicosanoid concentrations have been reported in endometriosis patients and might be important in disease-associated pain and inflammation. Here, we evaluated the expression of key biosynthetic and catabolic enzymes involved in this abnormal eicosanoid production in peritoneal macrophages and endometriotic lesions. Peritoneal macrophages, endometriotic lesions and matched eutopic endometrium were collected from endometriosis patients (n = 40). Peritoneal macrophages and eutopic endometrium samples were also collected from disease-free women (n = 25). Expression of type IIA secretory phospholipase A(2) (sPLA(2)-IIA), cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and 5-lipoxygenase (5-LO) was quantified by real-time PCR, and these five key enzymes were localized by immunohistochemistry. sPLA(2)-IIA, COX-2 and mPGES-1 mRNA was significantly increased in peritoneal macrophages of endometriosis patients compared with controls (P = 0.006, P = 0.016 and P = 0.025, respectively). In endometriosis patients, sPLA(2)-IIA, mPGES-1 and 15-PGDH mRNA was significantly enhanced in peritoneal lesions compared with matched eutopic endometrium (P < 0.001, P < 0.001 and P = 0.005, respectively). In eutopic endometrium, a significant decrease in 15-PGDH mRNA was found in the endometriosis group compared with controls (P = 0.023). Finally, sPLA(2)-IIA, COX-2, mPGES-1 and 15-PGDH immunostaining was found mainly in endometrial glands, whereas 5-LO was distributed throughout the glands and stroma. Our study highlights an imbalance between eicosanoid biosynthesis and degradation in endometriosis patients. Both peritoneal macrophages and endometriotic lesions may be involved. Research into new molecules inhibiting biosynthetic enzymes (such as sPLA(2)-IIA and mPGES-1) and/or activating catabolic enzymes (such as 15-PGDH) may prove to be a major field of investigation in the development of targeted medical therapies.


Hypothyroid-mediated changes in adult rat diaphragm muscle contractile properties and MHC isoform expression.
The purpose of the present study was to examine the effect of acute hypothyroidism on myosin heavy chain (MHC) isoform composition and contractile properties in the adult rat diaphragm muscle. Hypothyroidism was induced by the addition of propylthiouracil (0.05%) in the drinking water for a period of 3 wk. MHC isoform composition of control and hypothyroid diaphragm muscles was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In vitro isometric contractile properties of midcostal diaphragm muscle segements were measured at 26 degrees C, whereas the maximal unloaded shortening velocity was measured at 15 degrees C with the "slack test" method. Serum triiodothyronine and thyroxine values were significantly lower in the hypothyroid compared with the control group. A small but significant increase in the percentage of slow MHC isoform in the diaphragm was observed with acute hypothyroidism, whereas the percentage of the fast MHC isoforms (2A, 2X, and 2B) did not significantly differ between groups. Peak twitch force did not differ between groups. However, twitch contraction and half-relaxation times were significantly prolonged in the hypothyroid group compared with control. Maximal specific force was reduced in the hypothyroid compared with the control group, averaging 15.7 and 19.8 N/cm2, respectively (P < 0.05). The maximal unloaded shortening velocity averaged 4.3 and 8.2 muscle lengths/s in the hypothyroid and control groups, respectively (P < 0.05). We conclude that acute hypothyroidism results in alterations in adult diaphragm muscle contractile properties that cannot be attributed solely to changes in MHC isoform composition.


High glycogen levels in brains of rats with minimal environmental stimuli: implications for metabolic contributions of working astrocytes.
The concentration of glycogen, the major brain energy reserve localized mainly in astrocytes, is generally reported as about 2 or 3 micromol/g, but sometimes as high as 3.9 to 8 micromol/g, in normal rat brain. The authors found high but very different glycogen levels in two recent studies in which glycogen was determined by the routine amyloglucosidase procedure in 0.03N HCl digests either of frozen powders (4.8 to 6 micromol/g) or of ethanol-insoluble fractions (8 to 12 micromol/g). To evaluate the basis for these discrepant results, glycogen was assayed in parallel extracts of the same samples. Glycogen levels in ethanol extracts were twice those in 0.03N HCl digests, suggesting incomplete enzyme inactivation even with very careful thawing. The very high glycogen levels were biologically active and responsive to physiologic and pharmacological challenge. Glycogen levels fell after brief sensory stimulation, and metabolic labeling indicated its turnover under resting conditions. About 95% of the glycogen was degraded under in vitro ischemic conditions, and its "carbon equivalents" recovered mainly as glc, glc-P, and lactate. Resting glycogen stores were reduced by about 50% by chronic inhibition of nitric oxide synthase. Because neurotransmitters are known to stimulate glycogenolysis, stress or sensory activation due to animal handling and tissue-sampling procedures may stimulate glycogenolysis during an experiment, and glycogen lability during tissue sampling and extraction can further reduce glycogen levels. The very high glycogen levels in normal rat brain suggest an unrecognized role for astrocytic energy metabolism during brain activation.


Evaluation of Safety and Medium-Term Functional Outcomes of a Medial Fixed-Bearing Unicompartmental Knee Arthroplasty with Ultra-Highly Cross-Linked Polyethylene.
The primary objective of this study was to evaluate the in vivo safety of a unicompartmental knee arthroplasty design with sequentially annealed cross-linked polyethylene by evaluating reoperation rate, in particular those related to excessive polyethylene wear or breakage. The secondary objective was to examine functional outcomes via standardized questionnaires. This was a 5-year institutional review board-approved prospective single-surgeon case series of the first 152 consecutive patients with symptomatic medial unicompartmental osteoarthritis implanted with a partial knee replacement between May 2010 and December 2014. Study participants were asked to complete the Knee injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthrtis Index (WOMAC) questionnaires at preoperation and 2 to 5 years postoperation. Major complications and all reoperations were recorded and we produced Kaplan-Meier survivorship curves with the end point of revision to TKA. Pre- and postoperative differences for KOOS and WOMAC were evaluated by paired t-tests. The median length of follow-up was 7.2 (0-9.72) years. Seven patients required revision surgery to TKA (4.9% of patients): four with progression of arthritis in other compartments, two for infection, and one for loosening of the femoral component and subsequent progression of pain. There were no failures of polyethylene. Survival of cohort was 99.3 and 97.9% at 2 and 5 years, respectively. Patients significantly improved (p-value < 0.001) between preoperative assessment and at 2 years, with no decline at 5 years postoperation. These preliminary midterm results with this fixed-bearing design and cross-linked polyethylene were encouraging with no catastrophic failures of polyethylene. Patient reported outcomes were significantly improved and revision rates were acceptable and lower than registry reported results.


Family reconciliation as a response to adolescent crises.
Concern for adolescents who act in dangerous, life-threatening ways has heightened dramatically in recent years. Many of these adolescents appear to come from nuclear families isolated from their kinship systems. Without the mediating effects of kin, the adolescent transition can become a major crisis. Kinship systems remain cohesive when members can reconcile their beliefs about essential aspects of family functioning with the demands for adaptation during major life transitions. Reconciliation is lost when members believe that kin can no longer be trusted to insure their well-being. Kinship fragmentation ensues as family members leave the field or are excluded. Isolated nuclear families then rapidly lose the resilience to respond to life transitions without resorting to extreme, maladaptive solutions. The Systemic Crisis Intervention Program (SCIP) uses the opportunity of the crisis precipitated by the adolescent's life-threatening behavior to alter family myths that have led to network fragmentation. Crisis teams mobilize and meet with kin in four-hour gatherings to foster reconciliation and kinship system reintegration.


Microglia NLRP3 Inflammasomes Activation Involving Diabetic Neuroinflammation in Diabetic Mice and BV2 Cells.
Hyperglycemia-induced microglia activation can cause a continuous release of proinflammatory cytokines, which gradually damages neurons and contributes to central diabetic neuroinflammation. This study aimed to illustrate the possible mechanism related to NLRP3 inflammasome and the aggravation of diabetes neuroinflammation. The targeted proteins from BV2 cells and brain tissues were tested by Western blot or immunohistochemistry. Cytokines from cell supernatant and serum were detected by ELISA. Meanwhile, cytoplasm and mitochondria ROS were determined by DCFHDA and Mito sox Red, respectively. In vitro, BV2 cells were stimulated by different glucose concentrations (5.5 to 65 mM/L) above physiological values and maintained for different periods (12 to 48h). The proinflammatory cytokines IL-1β, IL18, IL6, TNFα and cytoplasm ROS were significantly increased in a dose-dependent manner, while mitochondrial ROS was unaffected. NLRP3 inflammasomes, MAPKs, and NF-κB pathways were obviously activated at the concentration of 35 mM/L for 12h. Inhibition assay using specific inhibitors indicated that the treatment of glucose (35 mM/L for 12h) could stimulate NLRP3 inflammasome activation via ROS/JNK MAPKs/NF-κB pathway. In STZ induced diabetes mice models, microglia NLRP3, ASC, and caspase-1 proteins were highly expressed, and serum cytokines IL-1β, IL6, IL18, and TNFα were remarkably increased. Microglia NLRP3 inflammasomes activation involves diabetic neuroinflammation in diabetic mice and BV2 cells via ROS/JNK MAPKs/NF-κB pathways.


The microbiological diagnosis of infective endocarditis.
Variables affecting the isolation of microorganisms causing endocarditis include the volume of blood cultured, the number of blood cultures obtained, prior antimicrobial therapy, the type of microorganism involved, and blood culture technique. Culture-negative infective endocarditis is most frequently associated with prior antimicrobial therapy and nonbacterial agents, such as fungi, chlamydiae, and rickettsiae. For the diagnosis of bacterial endocarditis, culture of two to three separately collected blood samples of at least 10 ml, and preferably 20 ml, each generally suffices; however, in cases who have recently received antibiotics it may be necessary to culture an additional two to three blood samples or to consider use of beta-lactamase, antimicrobial adsorbent resins, or lysis-concentration, the last of which is also the most effective method for recovering mycobacteria and fungi from blood.


[Drug-induced liver injury caused by an herbal medicine, bofu-tsu-sho-san].
A 37-year-old woman was admitted to a hospital with jaundice. Within a couple of weeks, her liver function improved with only symptomatic therapy. About 30 to 60 days before admission, she had taken a herbal medicine, bofu-tsu-sho-san. A diagnosis of drug-induced liver injury was made according to the diagnostic scale proposed at the Digestive Disease Week-Japan 2004. A drug-lymphocyte stimulation test for each ingredient of bofu-tsu-sho-san; the results were positive for Cnidii Rhizoma, Angelicae Radix and Menthae Herba. The liver biopsy specimen revealed features of acute hepatitis. Physicians should be aware that bofu-tsu-sho-san can cause liver injury, as this drug is commonly used as an over-the-counter medicine.


endAFS, a novel family E endoglucanase gene from Fibrobacter succinogenes AR1.
The complete nucleotide sequence of endAFS, an endoglucanase gene isolated from the ruminal anaerobe Fibrobacter succinogenes AR1, was determined. endAFS encodes two overlapping open reading frames (ORF1 and ORF2), and it was proposed that a -1 ribosomal frameshift was required to allow contiguous synthesis of a 453-amino-acid endoglucanase. A proline- and threonine-rich region at the C terminus of ORF1 and rare codons for arginine and threonine were coincident with the proposed frameshift site. ENDAFS is proposed to be a member of subgroup 1 of family E endoglucanases, of which endoglucanases from Thermomonospora fusca and Persea americana (avocado) are also members. Endoglucanases from Clostridium thermocellum and Pseudomonas fluorescens form subgroup 2.


Asymptomatic free-floating vitreous cyst masquerading as cysticercosis.
A male patient aged 37 years, referred with the diagnosis of right eye intravitreal cysticercosis, was diagnosed as asymptomatic free-floating vitreous cyst after thorough evaluation. The patient was kept under observation, since baseline visual acuity was unaffected. No change was noted over the period of 6 months.


Study of polymorphisms in 4q27, 10p15, and 22q13 regions in autoantibodies stratified type 1 diabetes patients.
Type 1 diabetes (T1D) is a multifactorial disease mainly associated with the human leukocyte antigen region. Previous studies suggested the association of interleukin-2 (IL2) gene polymorphisms and its alpha- and beta-chain receptor (IL2RA and IL2RB) variants with different autoimmune diseases such as T1D, celiac disease, multiple sclerosis, and rheumatoid arthritis. All T1D studies were conducted in diabetic patients younger than 17 years at diagnosis. The aim of our study was to replicate these associations not only in pediatric patients, but also in individuals with late onset. We performed a genetic association study of chromosomal regions 4q27, 10p15, and 22q13 containing the IL2, IL2RA, and IL2RB genes in 445 T1D subjects and 828 healthy controls. Seven single nucleotide polymorphisms (SNPs) were selected, previously described as genetic factors related to several autoimmune diseases, and were analyzed by TaqMan assays. The reported association with T1D patients of the IL2RA-rs41295061 located in the 10p15 region was replicated and our data suggest a trend of association of the polymorphisms IL2-rs17388568 and IL2-rs6822844 in 4q27. The effect of these markers was independent of the age at disease onset. Furthermore, the polymorphisms studied in 4q27 were not dependent on the presence of autoantibodies; however, the effect of the associated SNP in 10p15 (IL2RA-rs41295061) was specific of patients sera positive for diabetes antibodies. In conclusion, our results seem to indicate that late-onset and young T1D patients share most genetic factors located in the studied regions, but some markers could correlate with the presence of T1D specific autoantibodies.


Platelet-Released Growth Factors Influence Wound Healing-Associated Genes in Human Keratinocytes and Ex Vivo Skin Explants.
Platelet-released growth factors (PRGFs) or other thrombocyte concentrate products, e.g., Platelet-Rich Fibrin (PRF), have become efficient tools of regenerative medicine in many medical disciplines. In the context of wound healing, it has been demonstrated that treatment of chronic or complicated wounds with PRGF or PRF improves wound healing in the majority of treated patients. Nevertheless, the underlying cellular and molecular mechanism are still poorly understood. Therefore, we aimed to analyze if PRGF-treatment of human keratinocytes caused the induction of genes encoding paracrine factors associated with successful wound healing. The investigated genes were Semaphorin 7A (SEMA7A), Angiopoietin-like 4 (ANGPLT4), Fibroblast Growth Factor-2 (FGF-2), Interleukin-32 (IL-32), the CC-chemokine-ligand 20 (CCL20), the matrix-metalloproteinase-2 (MMP-2), the chemokine C-X-C motif chemokine ligand 10 (CXCL10) and the subunit B of the Platelet-Derived Growth Factor (PDGFB). We observed a significant gene induction of SEMA7A, ANGPLT4, FGF-2, IL-32, MMP-2 and PDGFB in human keratinocytes after PRGF treatment. The CCL20- and CXCL10 gene expressions were significantly inhibited by PRGF therapy. Signal transduction analyses revealed that the PRGF-mediated gene induction of SEMA7A, ANGPLT4, IL-32 and MMP-2 in human keratinocytes was transduced via the IL-6 receptor pathway. In contrast, EGF receptor signaling was not involved in the PRGF-mediated gene expression of analyzed genes in human keratinocytes. Additionally, treatment of ex vivo skin explants with PRGF confirmed a significant gene induction of SEMA7A, ANGPLT4, MMP-2 and PDGFB. Taken together, these results describe a new mechanism that could be responsible for the beneficial wound healing properties of PRGF or related thrombocytes concentrate products such as PRF.


[Management of hepatolenticular degeneration during pregnancy].
Hepatolenticular degeneration (Wilson's disease, WD) is a kind of autosomal recessive genetic disease characterized by disorders of copper metabolism. It is caused by mutations in the ATP7B gene, resulting in impaired excretion of copper into the bile, and then pathological deposition in the liver, brain, and other organs. Early diagnosis and treatment can significantly improve the prognosis of patients with WD. However, there is still no clear consensus on the treatment and management of WD during pregnancy. Herein, the clinical management of WD during pregnancy is summarized for clinicians' reference.


Migration of human melanoma cells on hyaluronate is related to CD44 expression.
Phenotypic and functional aspects of melanoma-hyaluronate interactions were investigated by studying the expression of CD44, cell migration, and transmembrane penetration of human melanoma cell lines on hyaluronate-coated substrates. Expression of CD44 was tested by flow cytometry on seven human melanoma cell lines. Strong reactivity with anti-CD44 monoclonal antibody was observed in four of seven of the cell lines. Migration studies of CD44(+) cell lines on hyaluronic acid- and chondroitin-6-sulfate-coated substrates, using time-lapse video-microscopy, showed a dramatic dose-dependent increase in migration rate on hyaluronate but not on chondroitin-6-sulfate. Moreover, CD44(-) cell lines showed no modification in migration rate on either substrate. Addition of soluble hyaluronate produced a dose-dependent inhibition of acceleration of CD44(+)cells on hyaluronate-coated substrates, whereas addition of chondroitin-6-sulfate had no effect. Migration inhibition experiments with soluble CD44 (CD44 receptor globulin) also showed specific blocking of the migration of CD44(+) cells on hyaluronate. Haptotactic invasion was increased in CD44(+) cell lines through hyaluronate-coated polycarbonate membranes, whereas no change was detected on chondroitin-6-sulfate-coated membranes. CD44(-) cell lines showed no response to either type of coating. In the melanoma cell lines tested, the expression of CD44 correlated with in vitro migration and invasiveness on hyaluronate substrates. Taken together, our data are consistent with the suggestion that CD44 may play a role in stimulating in vivo aggressiveness of tumors through hyaluronate-rich stroma.


Preterm infants' responses to taste/smell and tactile stimulation during an apneic episode.
A nonprobability sample of 14 nonventilated preterm infants, with a mean postconceptional age of 33.9 weeks, was examined to determine their responses to two interventions during apnea. The interventions included a traditional tactile stimulation of moderate shaking applied to the infant's leg and an experimental oral intervention consisting of taste, smell, and oral tactile stimulation. Infants served as their own control. Each infant received four randomly assigned trials (two of each intervention) when they experienced an apneic episode. The time interval for reinitiation of respiratory effort was significantly shorter after infants received the experimental stimulation (p = 0.0101). Behavioral state changed to alertness when the infants received the traditional tactile intervention yet remained unchanged when the experimental stimulation was administered during apnea (p = 0.0202).


Acetabular fractures: Epidemiology and mortality based on 2,132 fractures from the Swedish Fracture Register.
To describe the epidemiology of acetabular fractures including patient characteristics, injury mechanisms, fracture patterns, treatment, and mortality. We retrieved information from the Swedish Fracture Register (SFR) on all patients with acetabular fractures, of the native hip joint in the adult skeleton, sustained between 2014 and 2020. Study variables included patient age, sex, injury date, injury mechanism, fracture classification, treatment, and mortality. In total, 2,132 patients with acetabular fractures from the SFR were included in the study. The majority of the patients were male (62%) and aged over 70 years old (62%). For patients aged > 70 years, the 30-day mortality was 8% and one-year mortality 24%. For patients aged ≤ 70 years, the 30-day mortality was 0.2% and one-year mortality 2%. Low-energy injuries (63%) and anterior wall fractures (20%) were most common. Treatment was most often non-surgical (75%). The majority of patients who sustain an acetabular fracture are elderly (> 70 years), of male sex, and the fracture most commonly occurs after a simple, low-energy fall. Non-surgical treatment is chosen in the majority of acetabular fracture patients. The one-year mortality for elderly patients with acetabular fracture is similar to the mortality after hip fracture, and a similar multidisciplinary approach to care for these patients should be considered.


Distilling nonlocality.
Two parts of an entangled quantum state can have a correlation, in their joint behavior under measurements, that is unexplainable by shared classical information. Such correlations are called nonlocal and have proven to be an interesting resource for information processing. Since nonlocal correlations are more useful if they are stronger, it is natural to ask whether weak nonlocality can be amplified. We give an affirmative answer by presenting the first protocol for distilling nonlocality in the framework of generalized nonsignaling theories. Our protocol works for both quantum and nonquantum correlations. This shows that in many contexts, the extent to which a single instance of a correlation can violate a Clauser-Horne-Shimony-Holt inequality is not a good measure for the usefulness of nonlocality. A more meaningful measure follows from our results.


Polymer Acceptors for High-Performance All-Polymer Solar Cells.
All-polymer solar cells (all-PSCs) have attracted considerable attention owing to their pronounced advantages of excellent mechanical flexibility/stretchability and greatly enhanced device stability as compared to other types of organic solar cells (OSCs). Thanks to the extensive research efforts dedicated to the development of polymer acceptors, all-PSCs have achieved remarkable improvement of photovoltaic performance, recently. This review summarizes the recent progress of polymer acceptors based on the key electron-deficient building blocks, which include bithiophene imide (BTI) derivatives, boron-nitrogen coordination bond (B←N)-incorporated (hetero)arenes, cyano-functionalized (hetero)arenes, and fused-ring electron acceptors (FREAs). In addition, single-component-based all-PSCs are also briefly discussed. The structure-property correlations of polymer acceptors are elaborated in detail. Finally, we offer our insights into the development of new electron-deficient building blocks with further optimized properties and the polymers built from them for efficient all-PSCs.


Metal-dependent inhibition of HIV-1 integrase.
Human immunodeficiency virus type 1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Therefore, IN inhibitors are being sought for chemotherapy against AIDS. We had previously identified a series of salicylhydrazides as potent inhibitors of IN in vitro (Neamati, N.; et al. J. Med. Chem. 1998, 41, 3202-3209.). Herein, we report the design, synthesis, and antiviral activity of three novel mercaptosalicylhydrazide (MSH) derivatives. MSHs were effective against the IN catalytic core domain and inhibited IN binding to HIV LTR DNA. They also inhibited catalytic activities of IN in IN-DNA preassembled complexes. Site-directed mutagenesis and molecular modeling studies suggest that MSHs bind to cysteine 65 and chelate Mg(2+) at the active site of HIV-1 IN. Contrary to salicylhydrazides, the MSHs are 300-fold less cytotoxic and exhibit antiviral activity. They are also active in Mg(2+)-based assays, while IN inhibition by salicylhydrazides is strictly Mn(2+)-dependent. Additionally, in target and cell-based assays, the MSHs have no detectable effect on other retroviral targets, including reverse transcriptase, protease, and virus attachment, and exhibit no detectable activity against human topoisomerases I and II at concentrations that effectively inhibit IN. These data suggest that MSHs are selective inhibitors of HIV-1 IN and may serve as leads for antiviral therapeutics.


Successful pregnancy following single blastocyst transfer in a renal transplant recipient.
Numerous spontaneous pregnancies have been reported in renal transplant recipients; however, only a few pregnancies after the use of assisted reproductive techniques. The authors report a case of renal transplant recipient with secondary infertility who delivered a healthy baby without any complications. The report highlights the importance of minimal stimulation protocol during ovarian stimulation, single embryo transfer, and the need for multispecialty care for these patients. To the best of the authors' knowledge, the present report is the first such case from India and also the second in the world to report a blastocyst transfer among renal transplant recipients.


Virus-associated Trichodysplasia spinulosa.
This review discusses the evolution of an emerging dermatologic entity, virus-associated trichodysplasia spinulosa (TS), and its association with the novel human TS polyomavirus. We will describe how this distinct dermatologic diagnosis has arisen from the convergence of strikingly similar histopathologic findings observed across several case reports. The case of virus-associated TS exemplifies how a combination of astute clinicopathologic observation and a well-designed molecular genetic approach can provide insights into the pathogenesis of cutaneous disease.


The influence of dispositional optimism on post-visit anxiety and risk perception accuracy among breast cancer genetic counselees.
Much is unknown about the influence of dispositional optimism and affective communication on genetic counselling outcomes. This study investigated the influence of counselees' optimism on the counselees' risk perception accuracy and anxiety, while taking into account the affective communication during the first consultation for breast cancer genetic counselling. Counselees completed questionnaires measuring optimism, anxiety and the perceived risk that hereditary breast cancer runs in the family before, and anxiety and perceived risk after the first consultation. Consultations were videotaped. The duration of eye contact was measured, and verbal communication was rated using the Roter Interaction Analysis System. Less-optimistic counselees were more anxious post-visit (β = -.29; p = .00). Counsellors uttered fewer reassuring statements if counselees were more anxious (β = -.84; p = .00) but uttered more reassurance if counselees were less optimistic (β = -.76; p = .01). Counsellors expressed less empathy if counselees perceived their risk as high (β = -1.51; p = .04). An increase in the expression of reassurance was related to less post-visit anxiety (β = -.35; p = .03). More empathy was related to a greater overestimation of risk (β = .92; p = .01). Identification of a lack of optimism as a risk factor for high anxiety levels enables the adaptation of affective communication to improve genetic counselling outcomes. Because reassurance was related to less anxiety, beneficial adaptation is attainable by increasing counsellors' reassurance, if possible. Because of a lack of optimally adapted communication in this study, further research is needed to clarify how to increase counsellors' ability to adapt to counselees.


Transfer of copper from a chelated 67Cu-antibody conjugate to ceruloplasmin in lymphoma patients.
The Lym-1 monoclonal antibody was conjugated with the bifunctional chelating agent 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N ',N'',N'''-tetraacetic acid (BAT), using 2IT as a linker, and radiolabeled with 67Cu to make the radiopharmaceutical, 67Cu-2IT-BAT-Lym-1. Ten patients received a total of 18 doses of 67Cu-2IT-BAT-Lym-1 as targeted, systemic radiotherapy. The beta phase of blood clearance, when corrected for 67Cu decay, was positive or flat, a phenomenon not observed in similar patients treated with 131I-Lym-1. The flat beta phase of blood clearance suggested recycling of 67Cu from 67Cu-2IT-BAT-Lym-1 to another plasma protein. Therefore, the amount of 67Cu transferred from the radiopharmaceutical to CP, Alb, and TF was measured using affinity-purified polyclonal antibodies. The fraction of plasma 67Cu precipitated by anti-human CP increased daily; most blood radioactivity was 67Cu-CP after a median of 4 days (range 2-7 days). The transfer of 67Cu to CP was observed in all patients and was consistent from dose to dose within the same patient. An average of 2.8 +/- 1.5% (range 0.8-7.8%) of the 67Cu dose (%ID) was transferred to CP. The release rate of 67Cu-CP from the liver into the blood was 0.9 +/- 0.4 %ID/day for the first 3 days. The 67Cu-CP effective clearance half-life was 3.7 +/- 0.7 days. Subtraction of the 67Cu-CP activity from the total blood radioactivity yielded a biphasic blood clearance similar to that obtained for patients given 131I-Lym-1. Cu-67-CP increased the AUC for whole blood by 24 +/- 10%. The %ID of 67Cu recycled correlated with GGT, ALT, and alkaline phosphatase levels; r = 0.958 (p < 0.001), 0.857 (p < 0.01), and 0.822 (p < 0.01), respectively. Albumin levels correlated negatively with recycled copper (r = -0.745, p < 0.05). The data suggest that the liver metabolizes 67Cu-2IT-BAT-Lym-1 and recycles a small fraction of the 67Cu, transferring it to CP.


Midsagittal Brain Variation among Non-Human Primates: Insights into Evolutionary Expansion of the Human Precuneus.
The precuneus is a major element of the superior parietal lobule, positioned on the medial side of the hemisphere and reaching the dorsal surface of the brain. It is a crucial functional region for visuospatial integration, visual imagery, and body coordination. Previously, we argued that the precuneus expanded in recent human evolution, based on a combination of paleontological, comparative, and intraspecific evidence from fossil and modern human endocasts as well as from human and chimpanzee brains. The longitudinal proportions of this region are a major source of anatomical variation among adult humans and, being much larger in Homo sapiens, is the main characteristic differentiating human midsagittal brain morphology from that of our closest living primate relative, the chimpanzee. In the current shape analysis, we examine precuneus variation in non-human primates through landmark-based models, to evaluate the general pattern of variability in non-human primates, and to test whether precuneus proportions are influenced by allometric effects of brain size. Results show that precuneus proportions do not covary with brain size, and that the main difference between monkeys and apes involves a vertical expansion of the frontal and occipital regions in apes. Such differences might reflect differences in brain proportions or differences in cranial architecture. In this sample, precuneus variation is apparently not influenced by phylogenetic or allometric factors, but does vary consistently within species, at least in chimpanzees and macaques. This result further supports the hypothesis that precuneus expansion in modern humans is not merely a consequence of increasing brain size or of allometric scaling, but rather represents a species-specific morphological change in our lineage.


Levels of glutathione reductase and glutathione peroxidase of human platelets in unstable angina and myocardial infarction.
Levels of glutathione peroxidase and glutathione reductase were measured in the platelets of 30 patients, 10 of them affected by unstable angina, 10 of them reperfused after myocardial infarction and 10 matched healthy controls. The specific activities of both the enzymes were lowered in both group of patients. Glutathione reductase activity resulted markedly lowered.


In vivo gene targeting of IL-3 into immature hematopoietic cells through CD117 receptor mediated antibody gene delivery.
Targeted gene transfection remains a crucial issue to permit the real development of genetic therapy. As such, in vivo targeted transfection of specific subsets of hematopoietic stem cells might help to sustain hematopoietic recovery from bone marrow aplasia by providing local production of growth factors. Balb/C mice were injected intravenously, with an anti-mouse c-kit (CD117) monoclonal antibody chemically coupled to a human IL-3 gene-containing plasmid DNA. Mice were sacrificed for tissue analyses at various days after injection of the conjugates. By ELISA, the production of human IL-3 was evidenced in the sera of animals 5 days after treatment. Cytofluorometric analysis after in vivo transfection of a reporter gene eGFP demonstrated transfection of CD117+/Sca1+ hematopoietic immature cells. By PCR analysis of genomic DNA and RNA using primer specific pIL3 sequences, presence and expression of the human IL-3-transgene were detected in the bone marrow up to 10 days in transfected mice but not in control animals. These data clearly indicate that antibody-mediated endocytosis gene transfer allows the expression of the IL-3 transgene into hematopoietic immature cells, in vivo. While availability of marketed recombinant growth factors is restricted, this targeting strategy should permit delivery of therapeutic genes to tissues of interest through systemic delivery. In particular, the ability to specifically target growth factor expression into repopulating hematopoietic stem cells may create new opportunities for the treatment of primary or radiation-induced marrow failures.


Genome-wide association study for morphological, phenological, quality, and yield traits in einkorn (Triticum monococcum L. subsp. monococcum).
Einkorn (Triticum monococcum L. subsp. monococcum, 2n = 2× = 14, AmAm) is a diploid wheat whose cultivation was widespread in the Mediterranean and European area till the Bronze Age, before it was replaced by the more productive durum and bread wheats. Although scarcely cultivated nowadays, it has gained renewed interest due to its relevant nutritional properties and as source of genetic diversity for crop breeding. However, the molecular basis of many traits of interest in einkorn remain still unknown. A panel of 160 einkorn landraces, from different parts of the distribution area, was characterized for several phenotypic traits related to morphology, phenology, quality, and yield for 4 years in two locations. An approach based on co-linearity with the A genome of bread wheat, supported also by that with Triticum urartu genome, was exploited to perform association mapping, even without an einkorn anchored genome. The association mapping approach uncovered numerous marker-trait associations; for 37 of these, a physical position was inferred by homology with the bread wheat genome. Moreover, numerous associated regions were also assigned to the available T. monococcum contigs. Among the intervals detected in this work, three overlapped with regions previously described as involved in the same trait, while four other regions were localized in proximity of loci previously described and presumably refer to the same gene/QTL. The remaining associated regions identified in this work could represent a novel and useful starting point for breeding approaches to improve the investigated traits in this neglected species.


A Comparison of the Effect of Salt on Polypeptides and Translatable mRNAs in Roots of a Salt-Tolerant and a Salt-Sensitive Cultivar of Barley.
The effect of salt stress on polypeptide and mRNA levels in roots of two barley (Hordeum vulgare L.) cultivars differing in salt tolerance (cv CM 72, tolerant; cv Prato, sensitive) was analyzed using two-dimensional polyacrylamide gel electrophoresis. Preliminary experiments indicated that germination of Prato was inhibited significantly in the presence of NaCl, but growth of the surviving Prato seedlings was not substantially different from that of CM 72. Fluorographs of two-dimensional gels containing in vivo labeled polypeptides or in vitro translation products were computer analyzed to identify and quantitate changes that resulted when plants were grown in the presence of 200 millimolar NaCl for 6 days. The patterns of in vivo labeled polypeptides and in vitro products of CM 72 and Prato were qualitatively the same. Salt caused quantitative changes in numerous polypeptides and translatable mRNAs, but, overall, the changes were relatively small. Salt did not induce the synthesis of unique polypeptides or translatable mRNAs and did not cause any to disappear. Because of the similarities of the two cultivars with respect to growth and polypeptide patterns and the slight changes in polypeptide and translation product levels caused by salt, specific polypeptides or translatable mRNAs that are related to salt tolerance in barley could not be identified.


Implementation of an optical crossbar network based on directional switches.
We have implemented an all-optical digital switching network based on ferroelectric liquid crystal arrays used as directional switches. It connects eight input to eight output channels simultaneously and randomly. The reconfiguration rate of the system can reach 100 kHz by using a parallel-driven 6 x 6 ferroelectric liquid crystal array. The modulation bandwidth in each channel depends only on the transmitters and receivers, not on the system itself.


Sexual assault and psychosis in two large general population samples: Is childhood and adolescence a developmental window of sensitivity?
Research has shown a strong relationship between psychosis and sexual assault. Theories on developmental trauma as a causal factor for psychosis suggest that exposure to sexual trauma in childhood would have a stronger association with psychosis than sexual trauma in adulthood. We hypothesized that exposure to sexual trauma earlier in childhood and adolescence would be more strongly associated with hallucinations, delusional beliefs and psychotic disorder than sexual trauma that occurred later in life. Using the 2007 and 2014 Adult Psychiatric Morbidity Surveys (N = 14,949) we calculated the prevalence of sexual assault, hallucinations, delusional beliefs, and psychotic disorder. We used logistic regression to examine the relationship between age of exposure to sexual assault (first exposure <16 vs first exposure ≥16) and odds of hallucinations, delusions, and psychotic disorder. Sexual assault at any age was associated with an increased odds of hallucinations (aOR = 2.00, 95%CI = 1.63-2.46), delusional beliefs (aOR = 2.55, 95%CI = 2.24-2.89) and psychotic disorder (aOR = 5.28, 95%CI = 3.59-7.76). There was no significant difference, however, in the prevalence of hallucinations, delusional beliefs or psychotic disorders in individuals first exposed to sexual assault <16 and individuals first exposed ≥16. Contrary to our hypothesis, we did not find evidence that exposure to sexual assault in childhood and adolescence was more strongly associated with hallucinations, delusional beliefs or psychotic disorder than exposure to sexual assault age >16. Our findings do not support the idea that childhood and adolescence are uniquely sensitive periods for the emergence of psychotic experiences or psychotic disorder in relation to sexual trauma.


Validation of the revised MDRD formula and the original Cockcroft and Gault formula for estimation of the glomerular filtration rate using Australian data.
The estimation of glomerular filtration rate (eGFR) using the MDRD (Modification of Diet in Renal Disease) formula is a recommended practice in Australia, New Zealand and other countries. Since the original development of this formula, an international process to align assays for serum creatinine has been undertaken and a revised version of the MDRD formula has been produced for these assays. Additionally, the Cockcroft and Gault (C&G) formula remains recommended for drug dosing decisions, although there are different versions of the formula using either actual weight or calculated ideal body weight. We aimed to assess these formulae using Australian data. We assessed the revised MDRD and the C&G formulae by comparison with radio-isotope GFR measurements using patients routinely referred for this test. The MDRD was compared to GFR corrected for body surface area and the C&G to the uncorrected GFR. The MDRD was shown to have the expected scatter of over +/-30% but with median values not significantly different from isotopic GFR measurements and without a systematic deviation due to age, gender, height, weight or body mass index (BMI). The original C&G formula generally provided a good estimate of GFR, however the use of ideal body weight rather than actual body weight produced an under-estimated GFR in this population which was more prominent with increasing age and BMI. The MDRD and original C&G formulae were found to be valid in an Australian setting. The C&G formula, when calculated using weight estimated from patient height, was found to underestimate GFR in some patients.


Induction chemotherapy in non small cell lung cancer stage IIIa-b and IV and second-line treatment.
This study investigates the treatment management and survival of inoperable advanced non-small cell lung cancer (NSCLC) patients. The objective was to treat all patients with induction chemotherapy and then to stratify them for surgery, radiotherapy, second-line chemotherapy or supportive treatment. Of the 359 patients enrolled in the study, 336 fulfilled the study criteria and were classified as follows: 90 stage IIIa, 135 stage IIIb and 111 stage IV. Histological types included 131 squamous cell, 123 adenocarcinomas, 53 undifferentiated non-small, 15 large cell, 3 adenosquamous, 3 bronchoalveolar and 8 unclassified. For all patients induction therapy involved Cisplatin (CDDP) combined chemotherapy and 84% of the patients were also treated with Vindesine and Epirubicin. The mean number of courses was 4 (minimum 2, maximum 11). The result of induction therapy was 49% complete and partial for at least 8 weeks; with minor response included, the total response rate was 67.6%. Fourteen patients (4.16%) achieved analytically complete response, 151 (45%) partial response and 62 (18.5%) minor response. The second-line treatment implemented was as follows: surgical excision, 22 patients (Group A); radiotherapy, 106 patients (Group B); chemotherapy, 91 patients (Group C) and supportive treatment, 117 patients (Group D). Median survival in months was 72 (range 5-120+), 12 (range 2-118), 15 (range 3-48) and 7 (range 3-120) for Groups A-D respectively. There was a statistically significant difference in survival in Group A patients (p < 0.001) but no difference was observed between Groups B and C. Group D patients had significantly lower survival than the other three groups. In conclusion, induction chemotherapy renders a reasonably high response rate in operable NSCLC patients and second-line radiotherapy treatment is not superior to second-line chemotherapy.


The mechanics of minor groove width variation in DNA, and its implications for the accommodation of ligands.
In duplex DNA, groove width and depth are salient structural features that may influence the binding of drugs and proteins. These features are affected by movement of the bases, which for example may enforce groove compression or expansion through a rolling action of the adjacent base-pairs. Moreover, the sugar-phosphate backbone can also undergo limited movement, independently of the bases, which will affect the groove shape. We have examined how the movement of the sugar-phosphate backbone may affect the minor groove width for a fixed base geometry. In agreement with earlier studies, the sugar-phosphate backbone is found to have a certain degree of conformational flexibility in A and B-like helices, and we note a comparable freedom even in the highly curved TATA element of the TATA-binding protein/DNA complex. Phosphate mobility is highly anisotropic in all cases with favoured directions that can significantly change the groove width, independent of any changes in base geometry. We describe how the movement of the sugar-phosphate backbone may affect the accommodation of drugs and proteins in the minor groove, and we present a co-ordinate scheme which emphasises the groove adjustments associated with ligand binding. The observations have implications for the related problem of how cognate molecules are accommodated in the major groove.


Iatrogenic subcutaneous emphysema after dental treatment.
Subcutaneous emphysema as a complication of a dental procedure is uncommon. When it does occur, it can result in significant and sometimes alarming cervicofacial swelling. Management in most cases involves close observation while awaiting spontaneous resolution. However, in some cases the swelling can progress to cause serious complications and even death. Even though such complications are more commonly seen by our dental and oromaxillofacial surgery colleagues, otolaryngologists should be aware of this condition since we are often asked to consult in these cases. We describe the case of a 13-year-old girl who presented to the emergency department of our institution with an unusually dramatic acute-onset cervicofacial swelling after she had undergone a dental procedure earlier in the day. Computed tomography revealed subcutaneous emphysema. The patient was admitted to the hospital for close observation, and within 24 hours her condition had improved significantly. Shortly after discharge, she experienced a complete recovery. We review the clinical presentation, physical examination findings, diagnostic workup, and management of this complication.


Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions.
Drug-induced skin rashes are poorly understood idiosyncratic reactions, and current methods cannot predict their occurrence. Most idiosyncratic drug reactions are thought to be caused by chemically reactive metabolites, and the skin is a frequent site of idiosyncratic reactions; however, the skin has a very limited capacity to metabolize drugs. To balance this, the skin represents a protective barrier with a very active immune response against pathogens and other types of skin injury. Therefore its response to reactive metabolites is quite different from that of the liver. The purpose of this review is to integrate emerging findings into proposed mechanisms of drug and carcinogen metabolism in the skin that are likely responsible for rashes and other immune responses of the skin. Current evidence suggests the skin possesses significant sulfotransferase and flavin monooxygenases activities, but very low cytochromes P450 activity. However, there are skin-specific P450s that are not present in the liver. The manner in which the skin responds to neoantigens through local antigen presentation and innate immune sensing is reviewed with a focus on insights gained from the contact hypersensitivity (CHS) field. The roles of keratinocytes and Langerhans cells, and the emerging function of NOD-like receptors, are highlighted.


Minimal compression of ultrathin sections with use of an oscillating diamond knife.
With the aim to minimize compression artefacts in ultrathin sections, coincident with the stroke direction, we have invented an oscillating diamond knife. Results and theoretical considerations explaining its function are discussed. During conventional ultrathin sectioning the resultant compression is in the order of 20-35% of section height. This holds true for sections of samples embedded into Lowicryl HM20 and of the polymer polystyrene, cut with a 45 degrees diamond knife and floated on water. The oscillating knife reduces this compression almost completely. It consists of a diamond knife on which a low voltage piezoelectric translator (piezo) is mounted, which oscillates when the piezo is driven by an alternating voltage source. No additional cutting artefacts were observed in the micrographs when they were compared with sections produced without oscillating the knife.


Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens.
A randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of drospirenone (1, 2 or 3 mg) combined with estradiol (1 mg) in the treatment of climacteric symptoms in healthy postmenopausal women. The frequency of hot flushes was significantly decreased in all treatment groups (range 86-90%) in comparison to placebo (45%, p < or = 0.001) and remained suppressed at 16 weeks. Treatment with drospirenone and estradiol also decreased the intensity and severity of sweating, sleep problems, depression, nervousness, and urogenital symptoms. Most adverse events were mild or moderate, with similar rates observed in all groups. No serious adverse events or clinically significant laboratory abnormalities attributed to treatment occurred. These results demonstrate that the combinations of 1, 2, and 3 mg drospirenone with 1 mg estradiol are safe and effective for the treatment of climacteric symptoms.


Intraventricular administration of morphine for control of intractable cancer pain in 90 patients.
To quantitate the relief of intractable cancer pain by the use of intraventricular morphine administration. Intraventricular morphine administration was performed through an Ommaya reservoir. An initial dose of 0.25 mg of morphine sulfate per 24 hours was administered to all of the patients. This dose was progressively increased in 0.25-mg increments until optimal analgesia was attained. Sixty men and 30 women with a median age of 58 years (range, 23-80 yr) entered the study. The median duration of pain was 6 months (range, 0.5-120 mo). A daily morphine dose of up to 1 mg was adequate to achieve an analgesic effect in 77% of the patients. Only nine patients (10%) achieved < 50% pain relief. Using a multiple regression analysis, only the morphine dosage was found to be an independent prognostic factor. The most frequent side effect (22%) was nausea/vomiting. Also, there were two patients with opioid intolerance and two with intracerebral hematomas. Three reservoirs failed. Intraventricular morphine administration is a useful method for palliation of intractable cancer pain.


Glycosaminoglycan levels and proteoglycan expression are altered in the hippocampus of patients with mesial temporal lobe epilepsy.
Extracellular matrix proteoglycans (PGs) and glycosaminoglycans (GAGs) play a crucial role in cell differentiation and synaptogenesis by modulating neurite outgrowth. The chondroitin sulfate (CS)-rich PG, the receptor protein tyrosine phosphatase zeta/beta (RPTP zeta/beta), has been related to neural morphogenesis and axon guidance. Hippocampal sclerosis is the most frequent pathologic finding in patients with intractable mesial temporal lobe epilepsy (MTLE), which is associated with neuron loss, reactive gliosis, and mossy fiber sprouting. In the present study, we investigated the concentration of CS, heparan sulfate (HS) and hyaluronic acid (HA) in the hippocampus and temporal neocortex as well as RPTP zeta/beta expression in the hippocampus of patients with MTLE. Compared to autopsy control tissue, epileptic hippocampi showed a significantly increased concentration of CS (224%; p=0.0109) and HA (146%; p=0.039). HS was instead similar to control values. No differences were found in the concentration of CS, HS, or HA in the temporal neocortex of epileptic patients when compared to control values. In contrast, RPTP zeta/beta immunoreactivity was induced in astrocytes of the inner molecular layer of the dentate gyrus of the sclerotic hippocampus. Because matrix compounds have been associated with tissue injury and repair, the present findings suggest that changes in PGs and GAGs might be related to damage-induced gliosis and neuronal reorganization in the hippocampus of MTLE patients.


Host-guest complexations of local anaesthetics by cucurbit[7]uril in aqueous solution.
The cucurbit[7]uril (CB[7]) host molecule forms very stable host-guest complexes with the local anaesthetics procaine (K(CB[7]) = (3.5 +/- 0.7) x 10(4) dm(3) mol(-1)), tetracaine (K(CB[7]) = (1.5 +/- 0.4) x 10(4) dm(3) mol(-1)), procainamide (K(CB[7]) = (7.8 +/- 1.6) x 10(4) dm(3) mol(-1)), dibucaine (K(CB[7]) = (1.8 +/- 0.4) x 10(5) dm(3) mol(-1)) and prilocaine (K(CB[7]) = (2.6 +/- 0.6) x 10(4) dm(3) mol(-1)) in aqueous solution (pD = 4.75). The stability constants are 2-3 orders of magnitude greater than the values reported for binding by the comparably sized beta-cyclodextrin host molecule. The inclusion by CB[7] raises the first pK(a) values of the anaesthetics by 0.5-1.9 pK units, as the protonated forms are bound more strongly in acidic solution. The complexation-induced chemical shift changes in the guest proton resonances provide an indication of the site(s) of binding and the effects of protonation on the location of the binding sites.


Analysis of whole blood tacrolimus concentrations in liver transplant patients exhibiting impaired liver function.
In transplant patients with impaired liver function, HPLC methodologies have been suggested for monitoring whole blood tacrolimus concentrations because of the reported inaccuracy of immunoassay for whole blood tacrolimus concentrations. One hundred fifty whole blood samples from 50 subjects enrolled in a multicenter liver transplant trial were chosen for HPLC/MS/MS analysis without consideration of the clinical status of the patient at the time of sampling. These samples were chosen to represent the sampling intervals during the 12-week posttransplantation period. Retrospectively, the authors identified a subset of 39 samples from 27 subjects exhibiting impaired liver function as demonstrated by bilirubin concentrations > 3.0 mg/dL (mean +/-SD = 7.5 +/- 5.6 mg/dL). The authors compared the agreement of concentrations obtained from the PRO-Trac II ELISA and HPLC/MS/MS by least squares linear regression analysis and Bland/Altman analysis, in this subset against the agreement of concentrations for 76 samples with normal bilirubin. In the samples obtained from patients with impaired liver function the resulting regression equation was: ELISA = 1.19(HPLC) + 0.7; r = 0.9. The mean difference (HPLC/MS/MS - ELISA) was -2.5 ng/mL +/- 2.9 ng/mL (mean +/- SD). While 71% of samples agreed within 3 ng/mL, 3% (n = 1) exhibited a difference >10 ng/ml. The corresponding evaluation of the samples with normal bilirubin concentrations resulted in the regression equation ELISA = 0.96(HPLC) + 0.9; r = 0.9, and a mean difference of -0.6 ng/mL +/- 2.3 ng/mL. The authors conclude that while a small subset of patients with cholestasis may require closer evaluation with a more specific methodology, the majority of the patients may be satisfactorily monitored with the PRO-Trac II ELISA.


[A case of anhidrotic ectodermal dysplasia diagnosed during investigation of asthmatic attack].
A 24-year old man was hospitalized because of a severe asthmatic attack in August 2003. The asthma attack was well controlled by mechanical ventilation, intravenous hydrocortisone and inhaled beta2-agonist. Physical examination revealed sparse hair, reduced sweating and hypodontia. We also confirmed the absence of sweat glands in a biopsied skin specimen. The diagnosis based on these findings was anhidrotic ectodermal dysplasia A mutation in the EDA (ectodysplasin-A) gene which led to an X-linked anhidrotic ectodermal dysplasia was found, and the same genetic mutation was detected in the patient's mother.


Current controversies in the radiotherapeutic management of adult low-grade glioma.
Over the last decade, the results of four prospective clinical trials of supratentorial low-grade glioma (LGG) in adults have been published. The data from the nearly 1,000 patients treated on these studies are summarized in this presentation, addressing the following three current controversies in the radiotherapeutic management of these patients: (1) optimum timing of radiation therapy (RT); (2) optimum RT dose; and (3) addition of chemotherapy to RT. The 5-year overall survival (OS) and progression-free survival (PFS) rates in these four studies ranged from 58% to 72% and from 37% to 55%, respectively. Significant prognostic factors included extent of surgical resection, histology, tumor size, and age. The European Organization for Research and Treatment of Cancer (EORTC) study 22845 randomized 311 adults to postoperative observation or RT. There was no difference in the 5-year OS rate between the two arms, but the irradiated patients had a significantly improved 5-year PFS rate. EORTC study 22844 randomized 379 adults to low- versus high-dose RT. Similarly, an intergroup study conducted by the North Central Cancer Treatment Group (NCCTG), Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Group (ECOG) randomized 211 adults to low- versus high-dose RT. There was no difference in the 5-year OS or PFS rates between the two dose groups in either study. A Southwest Oncology Group (SWOG) study randomized 60 adults with incompletely resected LGG to RT alone or RT plus lomustine (CCNU) chemotherapy. There was no difference in outcome between the two treatment arms. Further prospective clinical trials are needed to define the optimal management strategy for adults with supratentorial LGG. The schemata from recently completed and ongoing LGG studies will be presented.


Early life exposure to residential green space impacts cognitive functioning in children aged 4 to 6 years.
During early childhood, neuronal networks are highly susceptible to environmental factors. Previous research suggests that green space exposure is beneficial for cognitive functioning. Here, we investigate the associations between residential green space exposure and behavioral problems and cognitive development in children aged four to six years. We included children participating in the ENVIRONAGE birth cohort. Residential green spaces were calculated based on high-resolution land cover data within several buffers (50-1,000 m) around the residence. The children's behavior was assessed with the Strengths and Difficulties Questionnaire (SDQ) among 411 children. In addition, to evaluate cognitive function, 456 children completed four tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We used multivariate logistic and linear regression models while accounting for potential confounders and covariables. An interquartile (IQR) increase of residential green space within 50 m was associated with a 38% (95% CI: 56;14) lower odds of a child having hyperactivity problems. Additionally, we found a beneficial influence of residential green space in close proximity (50-100 m) on the attention and psychomotor speed, represented by the Motor Screening Task. For example, we found a decrease of 0.45 (95% CI: -0.82;-0.09) pixel units from target center with an IQR increase of residential green space in a 50 m buffer. In addition, we observed an improved visual recognition/working memory, represented by the Delayed Matching to Sample Task within all included buffers (50-1000 m). For example, we observed a decrease of 4.91% (95 %CI: -7.46;-2.36) probability of an error occurring if the previous trial was correct and a 2.02% (95 %CI: 0.08; 3.97) increase of correct trials with an IQR increase of green space within a 100 m buffer. This study provides additional indications for a beneficial influence of green space exposure on the development of behavioral problems and cognitive function as young as four years of age.


Enzymatic processing of platinated RNAs.
The broadly prescribed antitumor drug cisplatin coordinates to DNA, altering the activity of cellular proteins whose functions rely upon sensing DNA structure. Cisplatin is also known to coordinate to RNA, but the effects of RNA-Pt adducts on the large number of proteins that process the transcriptome are currently unknown. In an effort to address how platination of an RNA alters the function of RNA processing enzymes, we have determined the influence of [Pt(NH(3))(2)](2+)-RNA adducts on the activities of 3'-->5' and 5'-->3' phosphodiesterases, a purine-specific endoribonuclease, and a reverse transcriptase. Single Pt(II) adducts on RNA oligonucleotides of the form (5'-U(6)-XY-U(5)-3': XY = GG, GA, AG, GU) are found to block exonucleolytic digestion. Similar disruption of endonucleolytic cleavage is observed, except for the platinated XY = GA RNA where RNase U2 uniquely tolerates platinum modification. Platinum adducts formed with a more complex RNA prevent reverse transcription, providing evidence that platination is capable of interfering with RNA's role in relaying sequence information. The observed disruptions in enzymatic activity point to the possibility that cellular RNA processing may be similarly affected, which could contribute to the cell-wide effects of platinum antitumor drugs. Additionally, we show that thiourea reverses cisplatin-RNA adducts, providing a chemical tool for use in future studies regarding cisplatin targeting of cellular RNAs.


[Successful treatment of a venous ulcer in an unusual manner].
Wound treatment is increasingly becoming the domain of specially trained medical personal. The flood of diverse wound treatments and bandaging techniques grows continuously. Studies which compare the effectiveness deliver such a variety of results that medical personal are starting to doubt trusted methods. The presented case study shows how a non-medical measure, in this case a change in the person administering the treatment, or in other words the interpersonal relationship aspect, can significantly contribute to wound healing.


Association of Digoxin With Preserved Echocardiographic Indices in the Interstage Period: A Possible Mechanism to Explain Improved Survival?
Background For patients with hypoplastic left heart syndrome, digoxin has been associated with reduced interstage mortality after the Norwood operation, but the mechanism of this benefit remains unclear. Preservation of right ventricular (RV) echocardiographic indices has been associated with better outcomes in hypoplastic left heart syndrome. Therefore, we sought to determine whether digoxin use is associated with preservation of the RV indices in the interstage period. Methods and Results We conducted a retrospective cohort study of prospectively collected data using the public use data set from the Pediatric Heart Network Single Ventricle Reconstruction trial, conducted in 15 North American centers between 2005 and 2008. We included all patients who survived the interstage period and had echocardiographic data post-Norwood and pre-Glenn operations. We used multivariable linear regression to compare changes in RV parameters, adjusting for relevant covariates. Of 289 patients, 94 received digoxin at discharge post-Norwood. There were no significant differences in baseline clinical characteristics or post-Norwood echocardiographic RV indices (RV end-diastolic volume indexed, RV end-systolic volume indexed, ejection fraction) in the digoxin versus no-digoxin groups. At the end of the interstage period and after adjustment for relevant covariates, patients on digoxin had better preserved RV indices compared with those not on digoxin for the ΔRV end-diastolic volume (11 versus 15 mL, P=0.026) and the ΔRV end-systolic volume (6 versus 9 mL, P=0.009) with the indexed ΔRV end-systolic volume (11 versus 20 mL/BSA1.3, P=0.034). The change in the RV ejection fraction during the interstage period between the 2 groups did not meet statistical significance (-2 versus -5, P=0.056); however, the trend continued to be favorable for the digoxin group. Conclusions Digoxin use during the interstage period is associated with better preservation of the RV volume and tricuspid valve measurements leading to less adverse remodeling of the single ventricle. These findings suggest a possible mechanism of action explaining digoxin's survival benefit during the interstage period.


The interaction of leukocytes with platelets in blood coagulation.
The concept that leukocytes play an active role in hemostasis and thrombosis has only recently been accepted. Leukocytes may influence coagulation directly, by the production of procoagulant and anticoagulant molecules, or indirectly, by actions on vascular cells including platelets, endothelial cells, and other leukocytes. This review examines the role of leukocytes in coagulation with an emphasis on regulation of leukocyte function by interactions, with platelets. Activated platelets may serve both to localize leukocytes in areas of thrombosis and to modulate their function. Over the past year, several in vitro studies further defined molecular mechanisms by which leukocytes may regulate coagulation. Further, in vivo studies have provided support for the relevance of these mechanisms in pathophysiologic coagulation.


Vitamin D in Nature: A Product of Synthesis and/or Degradation of Cell Membrane Components.
The review discusses the data on vitamin D accumulation in animals, plants, and other organisms. 7-Dehydrocholesterol (7-DHC) and ergosterol are considered to be the only true precursors of vitamin D, although even vitamin D2 (ergocalciferol) is not fully comparable to vitamin D3 (cholecalciferol) in regard to their functions. These precursors are converted by UV radiation into the corresponding D vitamins. There are a few published reports that this reaction can also occur in the dark or under blue light, which is unexpected and requires explanation. Another unexpected result is conversion of pro-vitamins D (7-DHC and ergosterol) into vitamin D3 and D2 via pre-vitamin D at low temperatures (<16°C) in the lichen Cladonia rangiferina. An extensive survey of literature data leads to the conclusion that vitamin D is synthesized from (1) 7-DHC via lanosterol (D3) in land animals; (2) 7-DHC via cycloartenol (D3) in plants; (3) ergosterol via lanosterol (D2) in fungi; and (4) 7-DHC or ergosterol (D3 or D2) in algae. Vitamin D primarily accumulates in organisms, in which it acts as a pro-hormone, e.g., land animals. It can also be found as a degradation product in many other species, in which spontaneous conversion of some membrane sterols upon UV irradiation leads to the formation of vitamins D3 or D2, even if they are not necessarily needed by the organism. Such products accumulate due to the absence of metabolizing enzymes, e.g., in algae, fungi, or lichens. Other organisms (e.g., zooplankton and fish) receive vitamins D with food; in this case, vitamins D do not seem to carry out biological functions; they are not metabolized but stored in cells. A few exceptions were found: the rainbow trout and at least four plant species that accumulate active hormone calcitriol (but not vitamin D) in relatively high amounts. As a result, these plants are very toxic for grazing animals (cause enzootic calcinosis). In connection with the proposal of some scientists to produce large quantities of vitamin D with the help of plants, the accumulation of calcitriol in some plants is discussed.


Endothelial cell migration and morphogenesis on silk fibroin scaffolds containing hydroxyapatite electret.
The purpose of this study was to evaluate the effects of composite wound dressing films made of silk fibroin (SF) containing hydroxyapatite (HA) or polarized HA (pHA) powders on endothelial cell (EC) behaviors that have important roles in the wound-healing process. XRD revealed the SF films to be semicrystalline, with a broad peak centered at about 20.7° which is characteristic of β-sheets embedded within an amorphous matrix. The SF composite films with 0.6 (w/v)% in concentration of HA powder (HA/SF) or pHA powder (pHA/SF) contained HA crystals of amorphous and silk II crystalline structures. SEM observation showed that there were differences in SF morphology between HA/SF and pHA/SF. The pHA/SF exhibited a furry texture around the pHA crystals, most likely due to the stored charged and zeta potentials. The HA/SF and pHA/SF films enhanced EC migration compared with that on the SF film. The number of migrated cells on the HA/SF and pHA/SF was ~1.5 times larger than that on the SF. The quantitative analysis of the endothelial morphogenesis indicated that the pHA/SF film enhanced the formation of capillary-like structures compared with SF and HA/SF. Thus, pHA/SF may potentially stimulate and contribute to the enhancement of angiogenesis in the wound-healing process.


PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia.
Purpose: Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism.Experimental Design: Human primary CML CD34+ cells and retrovirally BCR-ABL-driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by GSK126- or EZH2-specific shRNA in vitro and in vivo Recruitment of EZH2 and H3K27me3 on the promoter of tumor-suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation assay.Results: Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown.Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. Clin Cancer Res; 24(1); 145-57. ©2017 AACR.


Pedicular fixation in the osteoporotic spine: a pilot in vivo study on long-term ovariectomized sheep.
Spinal instrumentation success is greatly affected by the presence of osteoporosis. To date, however, no data exist on in vivo investigations on biomaterial and surgical techniques in the osteoporotic spine. In the present study 24 uncoated and 24 HA-coated screws were implanted in the L3, L4 and L5 pedicles of eight sheep (four ovariectomized, OVX Group; four sham-operated, Control Group). At four months, uncoated screws showed a significant decrease of about -22% in the extraction torque of the OVX Group as compared to the Control Group (p < 0.005). The extraction torque of HA-coated screws significantly (p < 0.0005) improved in both groups when compared to that of uncoated screws and showed increases ranging from 133% to 157%. Pedicle trabecular bone of OVX sheep showed a significant decrease in BV/TV (-30%; p < 0.05) and Tb.Th (-33%; p < 0.01). The affinity index (AI) results revealed significant (p < 0.0005) differences between uncoated and HA-coated screws for both groups: values were lower for uncoated than HA-coated screws by about -35%. A significant difference was also found for the AI data of uncoated screws between the OVX and Control Groups (-13%, p < 0.005). The current findings have demonstrated that long-term ovariectomized sheep can be used to study in vivo osteointegration in the osteoporotic spine. The HA coating has proven to improve bone purchase and bone-screw interface strength in healthy and osteopenic animals.


Molecular Characterization of a Novel Cathepsin L in Macrobrachium nipponense and Its Function in Ovary Maturation.
Cathepsin L genes, which belonged to cysteine proteases, were a series of multifunctional protease and played important roles in a lot of pathological and physiological processes. In this study, we analyzed the characteristics a cathepsin L (named Mn-CL2) in the female oriental river prawn, Macrobrachium nipponense which was involved in ovary maturation. The Mn-CL2 was1,582 bp in length, including a 978 bp open reading frame that encoded 326 amino acids. The Mn-CL2 was classified into the cathepsin L group by phylogenetic analysis. Real-time PCR (qPCR) analysis indicated that Mn-CL2 was highly expressed in the hepatopancreas and ovaries of female prawns. During the different ovarian stages, Mn-CL2 expression in the hepatopancreas and ovaries peaked before ovarian maturation. In situ hybridization studies revealed that Mn-CL2 was localized in the oocyte of the ovary. Injection of Mn-CL2 dsRNA significantly reduced the expression of vitellogenin. Changes in the gonad somatic index also confirmed the inhibitory effects of Mn-CL2 dsRNA on ovary maturation. These results suggest that Mn-CL2 has a key role in promoting ovary maturation.


The mechanisms of pharmacokinetic food-drug interactions - A perspective from the UNGAP group.
The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives.


Fruits are vehicles of drug-resistant pathogenic Candida tropicalis.
Of 123 identified isolates from the fruit surface, C. tropicalis was the most frequently found species, followed by Meyerozyma caribbica and Candida krusei. All three fluconazole-resistant C. tropicalis were non-susceptible to voriconazole and belonged to the same predominant genotype of azole-resistant C. tropicalis causing candidemia in patients in Taiwan. Our findings provide evidence that fruit should be washed before eaten not only to remove chemicals but also potential drug-resistant pathogenic microbes, especially for immunocompromised individuals. To keep precious treatment options in patients, we not only continuously implement antimicrobial stewardship in hospitals but also reducing/stopping the use of agricultural fungicide classes used in human medicine.


[Mandibular fractures in cattle - a review of 108 cases].
Mandibular fractures are among the most common fractures in cattle. The medical records of 108 cattle with a mandibular fracture, that were referred to the University of Zurich Veterinary Hospital from 2005 to 2019, were analysed to document the types of treatment, complications and long-term outcomes. Cattle, still alive at the time of retrospective analysis, underwent clinical and radiographic examinations. A fall was the single most common cause of a mandibular fracture (48,1 %), and a third of all cattle had a concomitant disease at the time of referral. Seventy-five cattle (69,4 %) had a single fracture, 26 (24,1 %) had two fractures and seven (6,5 %) had three fractures of the mandible. The molar part of the mandibular body was most commonly (40,7 %) fractured followed by the diastema (23,6 %), the pars incisiva (13,4 %), the ramus (12,1 %) and the symphysis (10,2 %) of the mandible. The majority of cattle (84/108, 77,8 %) had open fractures. Treatment was instituted in 63/108 animals (58,3 %) with 77/148 fractures. Of these fractures, 28 were treated with plate osteosynthesis, 25 with an external fixator, 8 with cerclage wire, 7 using mixed techniques, 4 with fragment excision, 4 underwent conservative treatment and one a mucosal suture. In total, 45/108 animals (41,7 %) were culled because of multiple fractures, concomitant diseases and because of economic reasons. Complications occurred in 34 (54,0 %) treated cattle; 22 had abnormal wound healing of which 18 developed osteomyelitis complicated by a sequestrum (14). Of the treated 63 cattle, 56 (88,9 %) were discharged. The mean postoperative productive life was 46 ± 29,2 months for animals that were deceased at the time of the study. Thirteen of the cattle with a sequestrum remained in the herd for 15 to 92 months (mean, 47 months) and one for 2 months. The life expectancy after treatment did not differ significantly from that of the Brown Swiss and Swiss Holstein dairy cattle populations, where the cattle of this study mainly came from. Eleven cattle were available for long-term follow-up; all had a good general health status but nine had dental abnormalities including missing teeth, steps or enamel points, which did not noticeably affect the body condition of the animals. Surgical treatment of selected mandibular fractures had a favourable prognosis (52/63 healed, 82,5 %) in cattle.


When pharmacology meets the microbiome: new targets for therapeutics?
This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc.


Machine Learning-Enabled Clinical Information Systems Using Fast Healthcare Interoperability Resources Data Standards: Scoping Review.
Machine learning-enabled clinical information systems (ML-CISs) have the potential to drive health care delivery and research. The Fast Healthcare Interoperability Resources (FHIR) data standard has been increasingly applied in developing these systems. However, methods for applying FHIR to ML-CISs are variable. This study evaluates and compares the functionalities, strengths, and weaknesses of existing systems and proposes guidelines for optimizing future work with ML-CISs. Embase, PubMed, and Web of Science were searched for articles describing machine learning systems that were used for clinical data analytics or decision support in compliance with FHIR standards. Information regarding each system's functionality, data sources, formats, security, performance, resource requirements, scalability, strengths, and limitations was compared across systems. A total of 39 articles describing FHIR-based ML-CISs were divided into the following three categories according to their primary focus: clinical decision support systems (n=18), data management and analytic platforms (n=10), or auxiliary modules and application programming interfaces (n=11). Model strengths included novel use of cloud systems, Bayesian networks, visualization strategies, and techniques for translating unstructured or free-text data to FHIR frameworks. Many intelligent systems lacked electronic health record interoperability and externally validated evidence of clinical efficacy. Shortcomings in current ML-CISs can be addressed by incorporating modular and interoperable data management, analytic platforms, secure interinstitutional data exchange, and application programming interfaces with adequate scalability to support both real-time and prospective clinical applications that use electronic health record platforms with diverse implementations.


Engineered T lymphocytes eliminate lung metastases in models of pancreatic cancer.
Pancreatic cancer is known as one of the most lethal cancers in the world. A majority of advanced stage pancreatic cancer patients are diagnosed with distant metastasis and given poor prognoses, calling for a better therapeutic option. Mesothelin, which is overexpressed in pancreatic cancer and other solid tumors, is a potential target for pancreatic cancer immunotherapy. Adoptive transfer of T cells engineered with chimeric antigen receptors (CART cells) was effective for treating CD19-positive leukemia, but it is more difficult for CART cells to eliminate solid tumors. Because distal metastasis is an important malignant behavior of solid tumors, we investigated whether meso-CART cells exert anti-tumor effects against distant metastases. After expressing meso-CAR in human primary T lymphocytes, the resultant meso-CART cells released cytokines in response to and exhibited cytolytic effects on mesothelin-positive tumor cells in vitro. Injection of meso-CART cells into tumor-bearing mice moderately delayed subcutaneous tumor growth and eliminated lung metastases. This is the first study to show that meso-CART cells are effective against lung metastases induced by intravenous injection of pancreatic tumor cells. Our results suggest that meso-CART cells may be an effective clinical treatment for mesothelin-positive primary and metastatic tumors in pancreatic cancer patients.


Cognitive mechanisms of methylphenidate in ADHD: Do improvements in sustained attention mediate behavioral improvements in the natural environment?
The relation between sustained attention in the laboratory and behaviors exhibited in naturalistic settings among children with Attention Deficit/Hyperactivity Disorder (ADHD) remains unclear. Additionally, research on stimulant medication effects in these areas and their association with one another remains scarce. Twenty-one children with ADHD and 21 children without ADHD completed a novel continuous performance test (CPT) involving high cognitive demands (e.g., visual search). Participants with ADHD also attended a Summer Treatment Program and received three doses of stimulant medication (placebo, low, and high). Their behavior in classroom and peer settings was observed and recorded, and they completed the CPT in each medication condition. The CPT measures of bias and sensitivity were used in analyses. Results indicated that children with ADHD had impaired overall performance and worse bias during the second half of the task compared to controls. Methylphenidate improved both naturalistic behavior and overall CPT performance but did not specifically improve the sustained attention deficit. Despite improvements in overall CPT performance, medication-related improvement in CPT performance did not mediate medication-related improvement in observed behavior in classroom or recreational settings. As such, our findings suggest that although children with ADHD do demonstrate a sustained attention deficit, salutary psychostimulant effects on CPT performance are not indicative of, or causally linked to, psychostimulant effects on presenting problems in naturalistic settings.


Augmented reality visualization for aiding biopsy procedure according to computed tomography based virtual plan.
The purpose of this study was to develop and verify an intraoperative module for supporting navigated biopsy procedures using optical see-through head-mounted display (HMD). Biopsy procedure including entry and endpoints of needle insertion was planned preoperatively having regard to the resection region segmentation and safety margin definition. Biopsy procedures were performed by two users using an intraoperative optical navigation module on a specially prepared brain phantom. Two visualization techniques were compared: an accurate augmented reality one, where a virtual plan is superimposed onto surgical field by using optical see-through HMD together with personalized calibration method and visualization on the external display. Averaged errors from 24 trials using external display were 2.04 ± 0.83 mm for the first user and 2.69 ± 1.11 mm for the second one, while applying HMD 2.50 ± 0.93 mm (the first user) and 2.17 ± 0.82 mm (the second user), respectively. Proper usage of HMD visualization preceded by the personalized calibration allows the user to perform navigated biopsy procedure with comparable accuracy to its equivalent with the external display. Additionally, augmented reality visualization improves ergonomics and enables focusing on the surgical field without losing a direct line of sight with the field of view as it happens for external displays. However, ensuring high accuracy of augmented reality visualization still requires proper calibration and some user experience, which is challenging.


Small cell carcinoma of the esophagus. Analysis of 14 cases and literature review.
The aims of this study are to retrospectively analyze data on the epidemiology, clinical characteristics, and treatment outcomes of 14 cases of small cell carcinoma of the esophagus. Patient records were reviewed for data on demographics, presenting symptoms, diagnosis, disease stage, type of treatment and outcome. Between January 1990 and December 2001, 14 patients with small cell carcinoma of the esophagus were treated at the National Cancer Center Hospital, representing 0.8% of all esophageal carcinomas diagnosed during this period. Eleven patients presented with extensive disease at the time of diagnosis, while three patients were noted to have limited disease. Nine patients received combination chemotherapy with or without radiotherapy. Three of these patients achieved a complete response to first-line treatment and two of them have survived more than two years. Five patients underwent esophagectomy as an initial treatment with curative intent. All of these patients developed early relapse after esophagectomy, and only one patient has survived more than two years. The overall median survival was 7.7 months (range: 0.6-89.1 months) for all 14 patients. Although curative esophagectomy may be effective as a primary treatment in some patients, systemic chemotherapy with or without concurrent radiotherapy should be considered as an important treatment option for small cell carcinoma of the esophagus.


[Influences of Hydrological Scenarios on the Bioavailability, Fate, and Balance of Chromophoric Dissolved Organic Matter in Lake Poyang].
Lake Poyang has significant differences in hydrological characteristics between the flood and dry seasons. Unraveling the optical composition, bioavailability, fate, and balance of chromophoric dissolved organic matter (CDOM) and organic carbon fluxes in Lake Poyang under different hydrological conditions can help provide advanced schemes on carbon cycling, the transfer and transformation of organic matter, and water resource management of the lake. Three fluorescent components, including a humic-like (C1), a tryptophan-like (C2), and a tyrosine-like (C3) component, were obtained using three-dimensional fluorescence spectroscopy coupled with parallel factor analysis. Prior to and after 28 days of laboratory biodegradation, the means of a254 and the terrestrial humic-like (C1) component in the flood season were both significantly higher than that in the dry season (t-test, P<0.01), indicating that the terrestrial humic-like (C1) component contributed importantly to the CDOM pool. The contribution percentages of protein-like components in the dry season were 81.7% of the summed fluorescent components of CDOM, indicating that there might be discharge of domestic wastewater from areas surrounding the lake in the dry season. The bioavailabilities of the humic-like (C1) component and DOC were 14.0% and 43.2%, respectively, in the dry season. This can be explained by a declined-dilution effect in the lake during the dry rather than in the flood season. We observed no significant difference in the bioavailability of protein-like components under different hydrological conditions. The bioavailability of C1 (i.e.,%ΔC1) showed a decreasing trend from the southern inflowing river mouths to the downstream northern outlet at Hukou in both the flood and dry seasons, indicating that the bioavailability of the C1 decreased following the migration of CDOM in the lake. In the dry season and flood season, Lake Poyang was the source of DOC with fluxes of 14.0×103 t·mon-1 and 1.4×103 t·mon-1, respectively, whereas CDOM fluxes in corresponding periods were the source and weak sink with corresponding fluxes of 9.3×1010 m3·(m·mon)-1 and 1.1×1010 m3·(m·mon)-1, respectively. Therefore, the lake released substantial organic matter to the downstream receiving waters during the dry season, whereas in the flood season, the higher water level in the Yangtze River resulted in a prolonged water residence time of the lake, and a fraction of CDOM was bio-degraded into inorganic nutrients, favoring the metabolisms and the eutrophication process of the lake ecosystem.