[A Case of Long-Term Survival with Tumor Resection and DOX plus DTIC Therapy for Desmoid Tumor after FAP Surgery].
The patient is a 22-year-old, female. She had a family history of familial adenomatous polyposis(FAP)and a prophylactic total colorectal resection was performed for FAP at age of 18. She presented with fever and abdominal distention and palpated a mass with tenderness in the right lower abdomen. Contrast-enhanced CT scan of the abdomen showed a heterogeneous contrast effect around the tumor margins. With the diagnosis of intra-abdominal desmoid tumor, a partial duodenal resection, small bowel mass resection, and right fallopian tube resection were performed along with the tumor, and an artificial anus was created with the jejunum. Contrast-enhanced CT scan of the abdomen 16 months after resection of desmoid tumor showed a 6.5 cm long desmoid tumor recurrence in the mesentery. She received 5 courses of doxorubicin (DOX)plus dacarbazine(DTIC)therapy followed by continued NSAIDs. Seven years after the operation, she has been able to maintain the shrinkage of the recurrent tumor and is still on medication. Long-term surveillance is necessary because of the possibility of the appearance of other associated lesions in the future.


Utilizing Linear Polymers to Optimize Remanent Polarization and Construct Multilayer Interfaces to Obtain High-Efficient Poly(vinylidene fluoride)-Based Energy-Storage Composites.
Polyvinylidene fluoride (PVDF) has been widely studied as a ferroelectric polymer for energy dielectric applications. However, high-polarization PVDF has a low-efficiency issue, owing to high residual polarization. This study introduces highly insulating, low-loss linear polycarbonate (PC) into PVDF-based dielectrics. The PC layer optimizes the remanent polarization (Dr) of PVDF and maintains it within a small range, thus achieving a high charge-discharge efficiency. The multilayer structural design of PVDF-based dielectrics adjusts the interlayer electric field distribution. We have thoroughly studied the influence of the number and proportion of PC layers on the polarization and breakdown of the multilayer films as well as achieved collaborative regulation of dual parameters. Our results indicate that three layers of PC-PVDF-PC (CPC) films containing a large proportion of PC can polarize under high electric fields and maintain excellent charge-discharge efficiency, achieving an energy density and efficiency of 11.48 J/cm3 and 92.4%, respectively, under 610 kV/mm. The PVDF-based dielectrics prepared in this work are all organic films, and their flexibility and foldability are conducive to the preparation of flexible devices.


Advancing cryo-electron microscopy data analysis through accelerated simulation-based flexible fitting approaches.
Flexible fitting based on molecular dynamics simulation is a technique for structure modeling from cryo-EM data. It has been utilized for nearly two decades, and while cryo-EM resolution has improved significantly, it remains a powerful approach that can provide structural and dynamical insights that are not directly accessible from experimental data alone. Molecular dynamics simulations provide a means to extract atomistic details of conformational changes that are encoded in cryo-EM data and can also assist in improving the quality of structural models. Additionally, molecular dynamics simulations enable the characterization of conformational heterogeneity in cryo-EM data. We will summarize the advancements made in these techniques and highlight recent developments in this field.


Fe/Fe3C Encapsulated in N-Doped Carbon Tubes: A Recyclable Catalyst for Hydrogenation with High Selectivity.
Herein, a series of Fe-based catalysts have been designed and prepared by grinding a mixture of MIL-88d and melamine, and then the mixture was followed by pyrolysis. An unusual Fe/Fe3C-activated site is uniformly encapsulated in the N-doped carbon tubes obtained by pyrolysis of the film-like nanocrystals of MIL-88d. Experimental characterizations and theoretical calculations demonstrate that the surface N sites can effectively trap the nitrobenzene and aniline by their phenyl groups with the formation of three C-N bonds that made the catalyst exhibit excellent catalytic activity (turnover frequencies of ≤11268 h-1 calculated on the basis of nitrobenzene) and chemoselectivity for the reduction of nitro derivatives under facile conditions.


Effect of 90° domain walls on the low-field permittivity of PbZr(0.2)Ti(0.8)O3 thin films.
We report on the contribution of 90° ferroelastic domain walls in strain-engineered PbZr(0.2)Ti(0.8)O(3) thin films to the room-temperature permittivity. Using a combination of phenomenological Ginzburg-Landau-Devonshire polydomain thin-film models and epitaxial thin-film growth and characterization, the extrinsic or domain wall contribution to the low-field, reversible dielectric response is evaluated as a function of increasing domain wall density. Using epitaxial thin-film strain we have engineered a set of samples that possess a known quantity of 90° domain walls that act as a model system with which to probe the contribution from these ferroelastic domain walls. We observe a strong enhancement of the permittivity with increasing domain wall density that matches the predictions of the phenomenological models. Additionally, we report experimentally measured bounds to domain wall stiffness in such PbZr(0.2)Ti(0.8)O(3) thin films as a function of domain wall density and frequency.


The measurement of cough response to bronchoconstriction induced by methacholine inhalation in healthy subjects: An examination using the Astograph method.
We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch. Healthy never-smokers (21 men, 20 women; mean 22.3 ± 3.7 years) participated. None had a >3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects' ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects' tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV1) decreased to <90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined. The number of coughs was 11.1 ± 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity. Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects.


Managements of locally advanced unresectable thymic epithelial tumors.
Surgery is the treatment of choice for thymic epithelial tumors (TET), but the resectability is about 60-70%. For those with locally advanced unresectable TETs (LAU-TETs), some controversies about the prognostic factors and treatment modalities existed. The aims of this study are to elucidate the roles of various therapeutic options and to determine the survival and prognostic factors of LAU-TETs. Twenty-seven patients diagnosed with LAU-TETs underwent treatment in Taipei Veterans General Hospital between 1979 and 1997. Multiple treatment modalities, including surgical intervention, irradiation and chemotherapy, were advocated for these patients. The clinicopathological factors and the effects of the treatment modalities were evaluated retrospectively. Twenty seven cases of LAU-TETs, included 18 thymomas (12 at stage III and 6 at stage IVa) and 9 thymic carcinomas (4 at stage III and 5 at stage IVa), were enrolled for study. The overall 5-year and 10-year survival rates were 54.6% and 35.1%, respectively. Patients receiving debulking surgery and those with irradiation dosage higher than 4400 cGy had significantly better survivals (P = 0.021 and P = 0.016, respectively). Aggressive debulking surgery and sufficient irradiation dosage provide better survivals for patients with LAU-TETs, especially for those with thymoma.


Development of dendritic form and function.
The nervous system is populated by numerous types of neurons, each bearing a dendritic arbor with a characteristic morphology. These type-specific features influence many aspects of a neuron's function, including the number and identity of presynaptic inputs and how inputs are integrated to determine firing properties. Here, we review the mechanisms that regulate the construction of cell type-specific dendrite patterns during development. We focus on four aspects of dendrite patterning that are particularly important in determining the function of the mature neuron: (a) dendrite shape, including branching pattern and geometry of the arbor; (b) dendritic arbor size;


Investigation of killer cell immunoglobulin-like receptor gene diversity III. KIR2DL3.
The allelic variation of one of the chromosome 19 KIR genes, KIR2DL3, has been investigated using a polymerase chain reaction sequence-specific oligonucleotide probe-based methodology. The procedure has been applied to a healthy Northern Irish control group in order to establish phenotype and genotype frequencies in this Caucasian population. In addition, cell line DNA and Centre d'Etude du Humaine (CEPH) families, both from the 13th International Histocompatibility Workshop have been investigated, establishing control data for this gene.


Smoking and tuberculosis in Hong Kong.
To study the relationship between smoking and tuberculosis in Hong Kong. Indirect sex and age adjustment was used to compare the prevalence of ever smokers between a sample of 851 patients from the 1996 tuberculosis notification registry and the general population. The clinical characteristics of smokers and non-smokers were compared by stratified univariate analysis and multiple logistic regression. Tuberculosis patients were more likely to have smoked than population controls. The respective odds ratios for ever smoking between tuberculosis patients and population controls were 2.44 and 2.08 for males and females aged 16-64 (Mantel-Haenszel weighted OR = 2.40, P < 0.001), and 2.09 and 2.83 for males and females aged > or = 65 (Mantel-Haenszel weighted odds ratio = 2.19, P < 0.001). Male sex, age > or = 65, working at onset of illness, regular alcohol use, drug abuse and absence of contact history were associated with ever smokers (all P < 0.05). Ever smokers were more likely to have cough (OR 1.69), dyspnoea (OR 1.84), upper zone involvement (OR 1.67), cavity (OR 1.76), miliary lung involvement (OR 2.77), positive sputum culture (OR 1.43), but less isolated extrathoracic involvement (OR 0.31), even after controlling for the confounding background variables (all P < 0.05). There was a consistent association between smoking and tuberculosis. More aggressive lung involvement was also found among ever smokers.


Informing Environmental Water Management Decisions: Using Conditional Probability Networks to Address the Information Needs of Planning and Implementation Cycles.
One important aspect of adaptive management is the clear and transparent documentation of hypotheses, together with the use of predictive models (complete with any assumptions) to test those hypotheses. Documentation of such models can improve the ability to learn from management decisions and supports dialog between stakeholders. A key challenge is how best to represent the existing scientific knowledge to support decision-making. Such challenges are currently emerging in the field of environmental water management in Australia, where managers are required to prioritize the delivery of environmental water on an annual basis, using a transparent and evidence-based decision framework. We argue that the development of models of ecological responses to environmental water use needs to support both the planning and implementation cycles of adaptive management. Here we demonstrate an approach based on the use of Conditional Probability Networks to translate existing ecological knowledge into quantitative models that include temporal dynamics to support adaptive environmental flow management. It equally extends to other applications where knowledge is incomplete, but decisions must still be made.


Tubing extrusion made easier, part I.
To produce tubing with consistent properties, it is important to know the material, understand the process, control the basics, and keep the goal, that is, the product in focus. Tips on controlling the process and producing the required results are provided in this two-part article. Part I focusses on the melt and material sensitivities.


Molecular characterization of transposable-element-associated mutations that lead to constitutive L-ornithine aminotransferase expression in Saccharomyces cerevisiae.
The cargB or CAR2 gene, coding for ornithine aminotransferase, was isolated by functional complementation of a cargB- mutation in Saccharomyces cerevisiae. It was used as a hybridization probe to analyse RNA and chromosomal DNA from four strains bearing cis-dominant regulatory mutations leading to constitutive, mating-type-dependent, ornithine aminotransferase synthesis. The four mutations appear to be insertions. Their size and restriction pattern suggested that they were transposable elements, Ty1. All were inserted in the same orientation with respect to the cargB gene. We cloned the cargB gene with its associated insertion from two constitutive mutants (cargB+ Oh-1 and cargB+ Oh-2). We determined the sequence of the cargB 5' region from the wild-type gene and from the two mutated genes. The DNA sequences of the extremities of the two insertions were very homologous but not identical and were similar to previously reported Ty1 element direct repeats (delta). The same five-base-pair sequence, ATATA, was found at both ends of both Ty1 elements, indicating that both Ty1 were transposed to the same site. This site is located 115 base pairs upstream from the putative cargB coding region. The 5' end of cargB transcript as determined by S1 mapping was the same in the wild-type strain and in the four mutants. The cargB transcript was not detected in the wild-type strain grown under non-induced conditions, while under the same conditions it was present in all four mutants.


Characteristics of Recombinant Phytase (rSt-Phy) of the Thermophilic mold Sporotrichum thermophile and its applicability in dephytinizing foods.
Sporotrichum thermophile produces very low titres of phytase (St-Phy) extracellularly, which is acidstable, thermostable, and protease insensitive with broad substrate specificity, and therefore, the gene encoding phytase (St-Phy) has been cloned and expressed in E. coli. The purified recombinant phytase (rSt-Phy) has the molecular mass of 55 kDa with Km and Vmax (calcium phytate), kcat and kcat/Km of 0.143 mM, 185.05 nmoles mg(-1) s(-1), 5.1 × 10(3) s(-1), and 3.5 × 10(7) M(-1) s(-1), respectively. Mg(2+) and Ba(2+) display slight stimulatory effect on the enzyme, while it is inhibited by other ions to a varied extent. The enzyme is also inhibited by chaotropic agents (guanidinium hydrochloride, potassium iodide, and urea), Woodward's reagent K, and 2,3-butanedione but resistant to both pepsin and trypsin. The rSt-Phy is useful in dephytinization of tandoori and naan (unleavened flat Indian breads), and bread, liberating soluble inorganic phosphate that mitigates anti-nutrient effects of phytic acid.


Modification of the core lipids of low density lipoproteins produces selective alterations in the expression of apoB-100 epitopes.
The conformation of the apolipoprotein B-100 associated with low density lipoproteins (LDL) is not fixed. Rather, the conformations of several regions are subject to alteration by a variety of metabolic and therapeutic perturbations that change either the lipid compositions and/or sizes of LDL particles. However, because these perturbations simultaneously alter several structural-compositional features of the particles it has been difficult to relate structural-compositional features of LDL to apoB-100 conformations. Furthermore, in in vivo studies several days pass between samplings, thus different sets of particles are studied before and after experimental perturbation. In the present experiments more discrete perturbations of LDL were obtained in vitro by incubating LDL with very low density lipoproteins (VLDL) in the presence of partially purified human plasma lipid transfer proteins. The conformations of apoB on the LDL particles then were examined a) by probing epitope expression and b) by examining interactions between LDL and LDL-receptors in cultured human fibroblasts. During incubations with VLDL and lipid transfer proteins, the diameters of LDL particles decreased; the percentage composition of LDL triglycerides increased three-to fivefold; concomitantly, cholesteryl esters decreased. Lipid transfer protein was required for the transfer to occur and the magnitude of the increase in LDL-triglycerides depended upon the duration of incubation, the ratio of VLDL/LDL, and unknown properties specific to the various LDL preparations. The fact that the triglyceride contents of all LDL preparations were not identically affected suggests that initial packaging of the core region may affect capacity for lipid exchange.(ABSTRACT TRUNCATED AT 250 WORDS)


A determination of the sub-units of arachin by osmometry. Arachins A, B, and A1.
1. Osmotic pressure determinations of dissociated arachins are a particularly suitable method for determination of the number of sub-units in the protein, because they yield a number-average molecular weight. 2. Arachin, in 8m-urea-0.1m-sulphite, produces 12 sub-units from the form of molecular weight 345000. 3. When the urea concentration is varied the molecules became fully dissociated at 6m-urea-0.1m-sulphite. Although sulphite is necessary to break disulphide bridges, concentrations greater than 0.1m cause a re-aggregation of the sub-units. Similar results were obtained in guanidine solutions. 4. A new form of arachin has been discovered, A1, migrating more rapidly than arachin A. 5. The N-terminal residues of arachin have been re-investigated on more highly purified samples: they are glycine, valine and (iso)leucine in the proportions 4:1:1. 6. The three forms of arachin have the structure (B) beta(4)gammadelta, (A) alpha(2)beta(2)gammadelta and (A1) alpha(4)gammadelta, for the forms of molecular weight 170000. 7. Dissociation in 8m-urea produces some fragments, detected by gel electrophoresis, which appear to be dimers of the type alpha-S-S-beta, beta-S-S-beta, held together by disulphide bonds.


Combined Aerobic Training and Mediterranean Diet Is Not Associated with a Lower Prevalence of Sarcopenia in Italian Older Adults.
Previous studies found a lower prevalence of sarcopenia in older adults engaged in regular aerobic training (AT) or with greater adherence to a Mediterranean (MED) diet. However, the effect of their combination on sarcopenia indices is unknown. The present study tested the association between AT plus a MED diet and the presence of sarcopenia and its defining elements in a sample of Italian older adults enrolled in the Longevity Check-up 7+ (Lookup 7+) project. Analyses were conducted in participants 65+ years, with a body mass index of at least 18.5 kg/m2, engaged in regular AT, and without missing information for the variables of interest. MED diet adherence was evaluated via a modified version of the MEDI-LITE score and categorized as low, moderate, or high. The presence of sarcopenia was established by handgrip strength and appendicular skeletal muscle mass (ASM) values below sex-specific cut-points recommended by the European Working Group on Sarcopenia in Older People 2. Data from 491 older adults were analyzed for the present study. The mean age was 72.7 ± 5.7 years, and 185 (37.7%) were women. MED diet adherence was low in 59 (12.0%) participants, moderate in 283 (57.6%), and high in 149 (30.3%). Sarcopenia was identified in 26 participants (5.3%), with no differences across MED diet adherence groups. The results of binary logistic regression showed no significant associations between AT plus adherence to a MED diet and dynapenia, low ASM, or sarcopenia. The findings of the present study indicate that the combination of AT with a MED diet is not associated with a lower probability of sarcopenia or its defining elements in Italian older adults enrolled in Lookup 7+. Further research is warranted to establish whether exercise frequency, volume, intensity, and length of engagement in AT impact the association between MED diet and sarcopenia.


Exposure of UK industrial plumbers to asbestos, Part II: Awareness and responses of plumbers to working with asbestos during a survey in parallel with personal sampling.
Throughout the European Union, millions tonnes of asbestos were used in the manufacture of products for building and for industrial installations. Today, in the UK, it is estimated that over half a million non-domestic premises alone have asbestos-containing materials in them and it is recognized that those working in building maintenance trades continue to be at significant risk. In part II, the awareness of UK plumbers to when they are working with asbestos was investigated and compared with the monitored levels reported in part I. The plumbers were issued by post with passive samplers, activity logs to monitor a working week and a questionnaire. The activity logs were used to assess whether maintenance workers were knowingly or unknowingly exposed to airborne asbestos fibres during a course of a working week. The questionnaire was designed to gather information on their: age, employment status, current and past perception of the frequency which they work with asbestos and knowledge of the precautions that should be taken to limit exposure and risk. Approximately 20% of workers reported on the sample log that they had worked with asbestos. There was a high correlation (93%) between the sampling log replies that they were knowingly working with asbestos and measured asbestos on the passive sampler. However, some 60% of the samples had >5 microm long asbestos structures found by transmission electron microscopy (TEM) analysis suggesting that the plumbers were aware of about only one-third of their contacts with asbestos materials throughout the week. This increased to just over one half of the plumbers being aware of their contact based on the results for phase contrast microscopy (PCM) countable asbestos fibres. The results from the questionnaire found that over half of the plumbers replying thought that they disturb asbestos only once a year and 90% of them thought they would work with asbestos for<10 h year-1. Their expectations and awareness of work with asbestos were therefore far lower than found during the period of monitoring. The response to an open question on the precautions to be taken, found that 61% of plumbers would avoid disturbance and 59% would use respiratory protection if they did disturb asbestos. However, their awareness of the methods and the need to reduce their risk by control of emissions at source was very low and suggests that further awareness raising and training is needed. The survey was carried out prior to the introduction of the duty to manage and gives a useful baseline to assess the impact of regulatory initiatives.


Stress Mediates the Association Between Pain and Alcohol Use in College Students.
Alcohol use in young adults is highly prevalent and associated with numerous consequences, including academic difficulties and motor vehicle accidents. Pain is one factor that has been increasingly shown to be associated with higher rates of alcohol consumption and riskier patterns of drinking among undergraduate students. Although pain has traditionally been viewed as a lesser concern for young adults, current research demonstrates that pain may be more prevalent in younger populations than originally thought. However, little is known about how common psychosocial factors, such as stress and subjective social status (SSS), influence the association between pain and alcohol consumption in college students. The study's goal was to examine the effect of stress and SSS on the relationship between pain and alcohol consumption. Participants (N = 445, 39.3% women, Mage = 22.98) were 18- to 25-year-old college students who completed an online questionnaire. Pain was significantly associated with total weekly alcohol consumption (r(445) = .22, p < 0.001); this association was significantly mediated by stress (b = 0.15, SE = 0.04, 95% CI = [.07,0.23]). SSS was significantly positively associated with alcohol consumption (r(445) = .22, p < 0.001) but was not found to significantly moderate the relationship between stress and alcohol use. Results suggest that efforts to reduce college student alcohol use should include assessment of pain and stress given their association with alcohol consumption. Further, findings suggest that future studies are warranted to prospectively examine pain as an antecedent for alcohol use and to examine the utility of incorporating stress management techniques in pain-focused interventions to indirectly target alcohol use.


Growth differentiation factor 15 is not associated with glycemic control in patients with type 2 diabetes mellitus treated with metformin: a post-hoc analysis of AIM study.
Growth differentiation factor 15 (GDF15) was newly discovered to be a promising target of metformin. The study was aimed to investigate the relationship between GDF15 and glycemic control after metformin treatment in patients with type 2 diabetes mellitus. The study was a post-hoc analysis of AIM (the effect of Acarbose on glycemic variability in patients with type 2 diabetes mellitus using premixed Insulin compared to Metformin) study. The participants were randomly assigned to 12 weeks of metformin (MET) or acarbose (ACA) treatment combined with insulin. Serum GDF15 levels of 51 subjects from MET group and 53 subjects from ACA group were measured at baseline and after a 12-week treatment. Fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2-h PG) and glycated hemoglobin A1c (HbA1c) were measured at baseline and endpoint. After a 12-week treatment, serum GDF15 levels significantly increased in MET group [baseline vs. endpoint, 936.70 (741.00, 1205.40) pg/mL vs. 1265.20 (1027.90, 1634.00) pg/mL, P < 0.001], but not in ACA group [baseline vs. endpoint, 920.60 (701.45, 1332.55) pg/mL vs. 893.80 (663.25, 1284.05) pg/mL, P = 0.944]. However, there were no significant differences of glycemic control parameters (ΔFPG, Δ2-h PG and ΔHbA1c) between subgroups of MET group divided by median of ΔGDF15 (all P > 0.05). Spearman correlation coefficient and analysis of covariance after adjustment for baseline HbA1c levels showed that ΔGDF15 was not correlated with ΔFPG, Δ2-h PG and ΔHbA1c (all P > 0.05). Serum GDF15 levels were significantly elevated after metformin treatment in patients with type 2 diabetes mellitus. However, the increase was not an indicator of the glucose-lowering effect of metformin. Clinicaltrials.gov, NCT02438397 . Registered 8 May 2015.


Hormonal therapy in prostate cancer: historical approaches.
Hormonal therapy has been the standard of care for advanced prostate cancer for over 6 decades. Treatments to suppress testosterone have expanded beyond surgical castration and estrogens to include steroidal and nonsteroidal antiandrogens, luteinizing hormone-releasing hormone agonists, and, most recently, gonadotropin-releasing hormone antagonists. Yet, despite this extensive therapeutic armamentarium, long-term survival of patients with advanced prostate cancer remains poor. Many issues regarding hormonal treatment of prostate cancer continue to be controversial, including the benefits of combined androgen blockade versus monotherapy, the optimal timing of treatment, and the value of new therapeutic approaches and strategies, such as intermittent androgen deprivation and adjuvant chemotherapy.


Inherited deficiency of the fourth component of human complement.
The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes, C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes, and is also remarkable by the high frequency of the null alleles, C4A*Q0 and C4B*Q0. Despite considerable structural homology, the gene products of the two loci differ in hemolytic activities, antigenic reactivities and covalent binding affinities to antigens and antibodies. Complete C4 deficiency is exceptional because this condition appears only in homozygotes for the very rare double-null haplotype C4AQ0,BQ0. In contrast, partial C4 deficiency is a common immune protein defect in all human populations as a consequence of the high frequency of the C4 half-null haplotypes. Complete C4 deficiency in most cases gives rise to SLE and an increased susceptibility to infections, and partial C4 deficiencies predispose to different auto-immune diseases related to extended HLA haplotypes bearing the C4 half-null haplotypes. Studies at the DNA level have shown that about half of the null alleles are due to deletions involving C4A and 21-OHA, C4B and 21-OHA or C4B and 21-OHB. Larger deletions including both C4A and C4B genes have never been observed. Partial C4 deficiency may be observed in combination with other complement deficiencies or immune defects, and allo- or auto-anti-C4 immunization is also a possible consequence of this genetic abnormality. Although the pathogenesis of the diseases related to complete and partial C4 deficiencies is not yet clearly understood, it is evident that C4 null alleles represent interesting markers and additive risk factors for autoimmune phenomena.


Maternal serum alpha-fetoprotein levels in pregnancies among black and white women with fetal open spina bifida: a United States collaborative study.
In the present study second-trimester maternal serum alpha-fetoprotein levels were analyzed from 146 pregnancies associated with fetal open spina bifida to identify whether affected pregnancies from the black population were associated with higher maternal serum alpha-fetoprotein levels than their white counterparts. Pregnancies in black women not affected by open spina bifida are already known to have higher maternal serum alpha-fetoprotein levels. All of the cases were analyzed with gestational ages assigned by last menstrual period, and all maternal serum alpha-fetoprotein values were expressed as multiples of the median, to correct for differences in gestational age and assay among the 15 centers reporting data. The levels from affected pregnancies in white and black women fit log Gaussian distributions, with medians of 3.10 and 4.37 multiples of the median, respectively, on the basis of singleton, unaffected, white pregnancy medians. These results support adjustment of maternal serum alpha-fetoprotein values for race in black women; in addition, if a screening program's policy is to screen at a comparable risk in the two races, a higher maternal serum alpha-fetoprotein multiple of the median cutoff would be justified for black women.


Consensus statement for the treatment of infantile haemangiomas with propranolol.
Although most infantile haemangiomas do not require treatment due to a natural history of spontaneous involution, some require early intervention. The Australasian Vascular Anomalies Network and the Australasian Paediatric Dermatology Network have developed a consensus statement for the treatment of infantile haemangiomas with oral propranolol. Infants with haemangiomas that are life threatening, at risk of ulceration, or at risk of causing a significant functional impairment, psychological impact or physical deformity should be treated early with oral propranolol. Oral propranolol is safe and effective and in most healthy infants oral propranolol can be started in an outpatient setting.


An A alpha Ser-434 to N-glycosylated Asn substitution in a dysfibrinogen, fibrinogen Caracas II, characterized by impaired fibrin gel formation.
We have identified a unique N-glycosylated Asn substitution for a Ser at position 434 of the A alpha chain of an abnormal fibrinogen designated fibrinogen Caracas II. This dysfibrinogen was characterized by impaired fibrin monomer aggregation. Since there were 4 Thr residues immediately following the mutation, a new Asn-X-Thr/Ser-type consensus sequence, Asn-Thr-Thr arose for N-glycosylation of the Asn. The extra oligosaccharide was found to consist mainly of a disialylated biantennary structure comprising 81.9%, while a neutral and a monosialylated biantennary oligosaccharide represented only 3.6% and 14.5%, respectively. The mutation resides in the carboxyl-terminal region of the A alpha chain, which could fold back to form an extra small globular region located near the central region of the molecule (Erickson, H.P., and Fowler, W.E. (1983) Ann. N. Y. Acad. Sci. 408, 146-163; Weisel, H.P., Stauffacher, C.V., Bullitt, E., and Cohen, C. (1985) Science 230, 3124-3133). Therefore, the participation of this region, referred to as an additional central domain or an alpha domain, in fibrin gel formation is strongly implicated.


Serum erythropoietin levels in septic shock.
Erythropoietin is a glycoprotein hormone mainly released by the kidney, which stimulates red blood cell production. However, in sepsis, the mechanisms responsible for the final increase in circulating erythropoietin remain unclear Seventeen critically ill patients with Simplified Acute Physiologic Score average 66 (range 43 to 103) were included in this study. Ten patients survived and seven died within 28 days. Blood samples obtained at different times were assayed for erythropoietin, cytokine levels and lactate measurements. PCO2 gap was assessed to detect the presence of gastric mucosal acidosis. Erythropoietin decreased in the patients who survived while it remained high or increased in non-survivors (37+/-6.5 vs 147+/-6. 7 UI/l respectively, P<0.05). Erythropoietin plasma levels were correlated with IL-6 levels (r=0.84, P<0.05) and TNFalpha levels (r=0.84, P<0.05). We observed a significant positive relationship between erythropoietin plasma levels and lactate concentrations (r= 0.89, P< 0. 05) and with PCO2 gap (r=0.9, P < 0.05). No correlation was found between erythropoietin concentration and the other parameters. High serum erythropoietin levels in non-survivors were observed with septic shock despite an increase in the levels of proinflammatory cytokines. We found a relationship between erythropoietin concentration and biological markers of tissue hypoperfusion i.e. lactate levels or PCO2 gap. This relationship could suggest tissue hypoperfusion as the stimulating factor for erythropoietin production in septic shock.


Organotitanium Nucleophiles in Asymmetric Cross-Coupling Reaction: Stereoconvergent Synthesis of Chiral α-CF3 Thioethers.
Asymmetric Ni-catalyzed cross-coupling reactions have become a very attractive tool for the stereoselective construction of valuable organic chiral materials. While various nucleophiles are used in such transformation, organotitanium(IV) has not been used before. Herein we demonstrate, for the first time, that organotitanium species can serve as efficient coupling partners in asymmetric cross-couplings, which have proven to be beneficial, compared to the commonly used organomagnesium and organozinc counterparts. This principle is exemplified by the first asymmetric catalytic synthesis of CF3-substituted thioethers via a Ni-catalyzed stereoconvergent cross-coupling reaction. Thioether moieties and their derivatives are common motifs in many biologically active compounds, and their enantioenriched fluorinated analogs should be of great interest in the search for novel drugs and agrichemicals.


Immunohistochemical study of 3 beta-hydroxysteroid dehydrogenase in sex cord-stromal tumors of the ovary.
3 beta-Hydroxysteroid dehydrogenase (3 beta-HSD), which converts pregnenolone to progesterone, was localized immunohistochemically in 18 thecomas, 23 fibromas, 5 granulosa-cell tumors, 5 sclerosing stromal tumors, and 2 steroid-cell tumors. Immunohistochemical study of estrogen, progesterone, and testosterone was also performed in serial sections of thecomas and fibromas. In thecomas, immunoreactivity of 3 beta-HSD was observed only in luteinized theca cells and thecomatous tumor cells with abundant pale to vacuolated cytoplasm but not in spindled tumor cells and thecomatous tumor cells with small to moderate amounts of pale to vacuolated cytoplasm. Immunoreactivity of steroids was not observed in thecomas except for testosterone immunoreactivity in one case. No immunoreactivity of steroids or the enzyme was present in fibromas. No tumor cells were positive for 3 beta-HSD in any of the cases of granulosa-cell tumor examined. Immunoreactivity of 3 beta-HSD was present in cells in steroid-cell tumors and polygonal tumor cells with prominent cytoplasmic vacuoles in two cases of sclerosing stromal tumor. Thus, 3 beta-HSD can be a good immunohistochemical marker of steroidogenesis in functioning ovarian neoplasms.


Metabolism in myocutaneous flaps studied by in situ microdialysis.
The aim of this investigation was to follow the metabolism of myocutaneous flaps using microdialysis. After subcutaneous implantation of a microdialysis catheter into the flap tissue, serial samples were collected and changes in composition of the extracellular fluid assessed. Ten women underwent reconstructions with transverse rectus abdominis myocutaneous (TRAM) or latissimus dorsi flaps. Glucose, glycerol, and lactate concentrations were measured in the flaps and compared with those in adipose control tissue located over the hip. A transient rise in glucose was observed initially in the flaps. The glycerol concentration also increased significantly, and remained increased for approximately 12 hours after the operation. The lactate concentration changed in the same direction, but stayed elevated in the flap tissue during the entire investigation (24 hours). Neither of these parameters changed to the same extent in the control tissue. In one of the patients a haematoma developed postoperatively in the flap. This incident was accompanied by a sharp decline in glucose, and marked additional increases in glycerol and lactate concentrations. It may well be that this "metabolic pattern" in flap tissue signals threatening flap ischaemia. If so, this new microdialysis technique may be useful as a postoperative surveillance tool in myocutaneous flap surgery.


[Discussion on the Application of Supercritical Carbon Dioxide Technology for Sterilization of Medical Devices].
Traditional medical device sterilization processes are mature, but there are constraints when using on medical devices by new materials. With increasing environmental concerns, using of ethylene oxide sterilization has been limited by global environmental protection administrations. Exploring new sterilization methods for medical devices is urgently needed. This paper reviews the supercritical carbon dioxide sterilization technology by arranging the exploratory work of industry researchers. In the paper, we introduce the theory of supercritical carbon dioxide sterilization technology, microbial inactivation ability, material influence research and sterilization equipment. Then we discuss the concerns and possibilities of the technology applied to the medical device industry basing on the good manufacturing practices.


Medical Students' (Dis)comfort with Assessing Religious and Spiritual Needs in a Standardized Patient Encounter.
Most patients want to discuss their religious and spiritual concerns, yet few physicians discuss it. First-year medical students (n = 92) interviewed a standardized patient experiencing spiritual distress. There was a significant difference among the students' reasoning for their (dis)comfort and (mis)matching religion with their patient (X2 = 21.0831, p < .05). Most students whose religion matched their patient felt comfortable because of having this in common with their patient. Most students whose religion did not match that of their patient ascribed their comfort to their religious belief to be open and accepting. Discomfort may stem from more individual factors than a (mis)match in religion, as most of the students reported feeling comfortable.


Multi-slice computed tomography: A tool for non-invasive temperature measurement?
To investigate the potential of multi-slice computed tomography (MSCT) as a tool for non-invasive temperature measurement. Samples of water, 0.9% saline, sunflower oil and dilutions of (1:32, 1:64, 1:128) contrast agent (Iopromid 370, BayerSchering Pharma, Berlin) were heated in a plexiglass phantom. In a first set-up, samples of 0.9% saline solution were scanned at defined temperatures (25 degrees -75 degrees C; 5 degrees C intervals) using a clinical CT scanner. Scan parameters (tube current-time product, tube voltage, collimation, slice thickness) were systematically varied. In a second set-up samples of the different fluids (water, sunflower oil, contrast agent dilutions) were scanned using the following scan protocol: 250 mAs, 140 kV, 1.2 mm collimation, 9.6 mm slice thickness. CT numbers were measured in reconstructed axial images at the different temperatures. A regression analysis was performed to investigate the relationship between temperature and CT number. Standard deviation of measured CT numbers decreased with increasing tube current-time product, increasing tube voltage, thicker collimation and higher slice thickness. Regression analysis showed an inverse relationship between temperature and CT number for all fluids with regression coefficients of -0.471 (0.9% saline), 0.447 (water), -0.679 (sunflower oil), -0.420 (contrast agent 1:32), -0.414 (contrast agent 1:64) and -0.441 (contrast agent 1:128), respectively. Multi-slice computed tomography can depict thermal density expansion of different fluids. Based on these results the implementation of a temperature discrimination of several degrees C at a high spatial resolution is achievable.


Oral candidiasis in Sjögren's syndrome: prevalence, clinical correlations, and treatment.
Red, nonulcerated, uncomfortable oral mucosal lesions that are often thought to be caused by chronic xerostomia develop in some patients with Sjögren's syndrome (SS). However, we find that these lesions (1) clinically resemble chronic atrophic candidiasis (CAC), (2) usually yield Candida species from their surface, and (3) can be eliminated by topical antifungal drugs in spite of continuing xerostomia. In 246 patients who had primary or secondary SS, we correlated the presence or absence of atrophic oral mucosal lesions with the patient's salivary function and other clinical features. The 91 patients (37%) who had these lesions were older, had a greater frequency of primary SS and of oral symptoms, had had oral symptoms for a longer period, had more salivary gland inflammation, and had lower stimulated parotid flow rates than the 155 patients without CAC (p less than 0.05). However, unstimulated whole salivary flow rates and denture status were not significantly different. Topical antifungal treatment, begun on 47 patients, eliminated lesions in some. The methods of treating CAC are discussed. Candida-associated oral mucosal lesions do not develop in all patients with SS, but in susceptible patients, SS leads to a reversible form of CAC that is not associated with dentures.


Depletion of T lymphocytes with immunotoxin retards the progress of experimental allergic encephalomyelitis in rhesus monkeys.
FN18-CRM9 is an anti-rhesus anti-CD3 immunotoxin that can transiently deplete T cells to 1% of initial values in both the blood and lymph node compartments and can induce long-term tolerance to mismatched renal allografts. We have investigated the ability of this immunotoxin to interdict the course of an experimental rhesus T-cell-driven autoimmune disease, experimental allergic encephalomyelitis (EAE) induced by myelin basic protein. Monkeys showing CSF pleocytosis were then treated with FN18-CRM9 alone or in combination with cranial irradiation (325 or 650 cGy). EAE in nontreated control monkeys progressed rapidly. Paralysis occurred 4-6 days after CSF pleocytosis. Paralysis was either delayed or never occurred in treated monkeys, and histopathology revealed few inflammatory plaques that were notable for their low or absent T cell content. While T cells repopulate in the periphery posttreatment, they do not return to the CNS in large numbers, suggesting that the newly repopulated T cells have lost their previously acquired CNS homing capability. Anti-CD3 immunotoxin may be useful in treating clinical T-cell-driven autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.


Provider and patient perception of psychiatry patient health literacy.
Inadequate health literacy in adults is a nationwide issue that is associated with worse health outcomes. There is a paucity of literacy regarding rates of inadequate health literacy in psychiatric populations. The aim of the study was to identify an existing tool that would easily identify patients who had inadequate health literacy, so that a targeted intervention could be performed. Secondarily we attempted to compare rates of inadequate health literacy with providers' perception of patients' health literacy. We assessed health literacy in a psychiatric population by administering the Brief Health Literacy Survey (BHLS). Additionally, all psychiatry residents, psychiatrists, nurse practitioners, pharmacists, and social workers were surveyed to assess their perception of patient health literacy. Differences between patient health literacy and provider expectations of patient health literacy were compared. Inadequate health literacy was identified in 31 out of 61 patients (50.8%) using 2 questions from the BHLS. Only 9 (29%) of patients who were identified as having inadequate health literacy were identified by both BHLS questions. In contrast, almost 100% of providers identified their patients, in general, as having inadequate health literacy. These results identify a higher rate of health literacy in a psychiatric inpatient population than in the general population. However, providers at this institution likely over-identify health literacy. This highlights the need for a health literacy tool that can easily target patients with inadequate health literacy for an intervention.


Biotransformation, a new approach to aminoglycoside biosynthesis: II. Gentamicin.
Utilizing a paromamine-producing mutant of Micromonospora purpurea blocked in the production of gentamicin, bioconversion of various minor gentamicin components into the gentamicin C complex was demonstrated. The compounds tested were structurally related to the gentamicin C's and are found as minor components in the gentamicin fermentation. Based upon the bioconversions detected, a branched pathway for the biosynthesis of the gentamicin C components is proposed.


Characterization of antigenic determinants on human myeloid colony forming cells with monoclonal antibodies.
Immunologic characterization of myeloid progenitor cells (CFUGM) provides a new dimension for identification and separation of this hemopoietic cell population from other cells within marrow and peripheral blood. Monoclonal antibodies against human anti Ia-like (HLA-DR) determinants and against T lymphocytes were utilized to more precisely define the cell surface antigenic structure of human CFUGM. Complement-mediated cytotoxicity testing demonstrated the presence of HLA-DR antigens and absence of a T lymphocyte antigen on the clonogenic CFUGM. Similar degrees of cytotoxicity were noted for B lymphocytes and CFUGM using anti HLA-DR monoclonal antibodies. Our studies with the anti T lymphocyte antibody suggest that T lymphocytes may be selectively removed from marrow cells without depletion of myeloid precursor cells.


Modifying the criteria of the American Joint Commission on Cancer staging system in melanoma.
The currently used staging system in melanoma has not been significantly modified since 1988. While this four-stage system effectively stratifies patients into prognostic groups, additional discriminating criteria have been reported that is not presently incorporated in the staging system. The following additions and modifications are suggested based on a review of the recent literature: 1) for stage I and II patients, Clark's level of invasion is only predictive in patients with melanomas less than 1 mm, the best statistical fit for tumor thickness cutoffs are less than 1 mm, 1 to 2 mm, 2 to 4 mm, and greater than 4 mm, and ulceration should be included as part of the staging system; 2) in stage III patients, the presently used criteria of 3 cm in size needs to abandoned and replaced by the number of lymph nodes involved and the number of lymph node basins involved; and 3) local recurrence presenting as local metastases and satellite disease represent a biologic continuum of regional lymphatic dissemination and should both be classified in the stage III prognostic groups. These modifications, if accepted, should provide the ability to better stratify patients for future adjuvant therapy trials.


A hairpin-like structure within an AU-rich mRNA-destabilizing element regulates trans-factor binding selectivity and mRNA decay kinetics.
In mammals, rapid mRNA turnover directed by AU-rich elements (AREs) is mediated by selective association of cellular ARE-binding proteins. These trans-acting factors display overlapping RNA substrate specificities and may act to either stabilize or destabilize targeted transcripts; however, the mechanistic features of AREs that promote preferential binding of one trans-factor over another are not well understood. Here, we describe a hairpin-like structure adopted by the ARE from tumor necrosis factor alpha (TNFalpha) mRNA that modulates its affinity for selected ARE-binding proteins. In particular, association of the mRNA-destabilizing factor p37(AUF1) was strongly inhibited by adoption of the higher order ARE structure, whereas binding of the inducible heat shock protein Hsp70 was less severely compromised. By contrast, association of the mRNA-stabilizing protein HuR was only minimally affected by changes in ARE folding. Consistent with the inverse relationship between p37(AUF1) binding affinity and the stability of ARE folding, mutations that stabilized the ARE hairpin also inhibited its ability to direct rapid mRNA turnover in transfected cells. Finally, phylogenetic analyses and structural modeling indicate that TNFalpha mRNA sequences flanking the ARE are highly conserved and may stabilize the hairpin fold in vivo. Taken together, these data suggest that local higher order structures involving AREs may function as potent regulators of mRNA turnover in mammalian cells by modulating trans-factor binding selectivity.


Acute renal failure following trauma.
Acute renal failure is often fatal, but usually this complication following trauma is avoidable. Of fifteen patients with acute tubular necrosis associated with severe trauma, thirteen survived. This is a marked improvement in survival rate compared with the rates previously published. We credit the improvement to aggressive medical and surgical treatment by a team of orthopaedic surgeons, nephrologists, and surgeons.


Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase mRNA levels are specifically altered in torn rotator cuff tendons.
Rotator cuff tears are a cause of pain and disability in the shoulder. The molecular changes associated with rotator cuff tearing are unclear. A subset of matrix metalloproteinases and tissue inhibitors of metalloproteinase, which are involved in extracellular matrix remodeling and degradation, were evaluated. There would be an increase in the mRNA level of specific matrix metalloproteinase and a decrease in the mRNA level of specific tissue inhibitors of metalloproteinase in rotator cuff tendon tissue obtained from patients with rotator cuff tears. Controlled laboratory study. Tissue was obtained from 10 patients undergoing rotator cuff repair for full-thickness rotator cuff tears. Also, tissue was obtained from cadaveric specimens with no gross evidence of rotator cuff tearing. Reverse transcription polymerase chain reaction was performed for the collagenases (MMP-1, MMP-8, MMP-13), the stromelysins (MMP-3, MMP-10, MMP-11), and the tissue inhibitors of metalloproteinase (TIMP-1, TIMP-2, TIMP-3, TIMP-4). Western blotting was performed to confirm the mRNA changes demonstrated in collagenase-3 (MMP-13). There was a significant increase in collagenase-3 (MMP-13) mRNA levels, a decrease in stromelysin-1 (MMP-3) mRNA levels, and a decrease in tissue inhibitor of metalloproteinase-2, -3, and -4 mRNA levels. Western blotting demonstrated an increase in the active form of collagenase-3 (MMP-13) in rotator cuff tendon tears. The mRNA levels of specific matrix metalloproteinases and tissue inhibitors of metalloproteinase are altered in torn rotator cuff tendons. With the known action of the matrix metalloproteinases and tissue inhibitors of metalloproteinase in extra-cellular matrix remodeling, these findings suggest that their roles in remodeling of rotator cuff tears should be further investigated.


Acute myocardial infarctions and stroke triggered by laboratory-confirmed respiratory infections in Denmark, 2010 to 2016.
BackgroundSeveral studies have investigated a possible association between respiratory infection and acute myocardial infarction (MI). As both influenza and pneumococcal infections are vaccine preventable, understanding the populations affected by virus-induced cardiovascular complications is important to guide public health and clinical practice.AimThis observational study aimed to quantify the association between laboratory-confirmed respiratory bacteria or virus infections and risk of first MI or stroke, by using self-controlled case series (SCCS) analysis of anonymised linked electronic Danish health records.MethodsThe SCCS method was used to determine the relative incidence of the first event of MI and stroke occurring within 28 days after laboratory-confirmed respiratory infections compared with the baseline time period.ResultsIn the age and season adjusted analyses for first acute MI, the incidence ratios (IR) of a MI event occurring during the risk period were significantly elevated following a Streptococcus pneumoniae infection with values of 20.1, 11.0 and 4.9 during 1-3, 4-7 and 8-14 days, respectively and following respiratory virus infection with values of 15.2, 4.5 and 4.4 during 1-3, 8-14 and 15-28 days, respectively. The significantly elevated IRs for stroke following an S. pneumoniae infection were 25.5 and 6.3 during 1-3 and 8-14 days, respectively and following respiratory virus infection 8.3, 7.8 and 6.2 during 1-3, 4-7 and 8-14 days, respectively.ConclusionThis study suggested a significant cardiovascular event triggering effect following infection with S. pneumoniae and respiratory viruses (mainly influenza), indicating the importance of protection against vaccine-preventable respiratory infections.


Quantitative ultrasound of the calcaneus reflects the mechanical properties of calcaneal trabecular bone.
To provide new information about the potential role of quantitative ultrasound (QUS) in fracture risk prediction, we assessed whether QUS and densitometric variables derived from measurements of intact cadaveric feet were associated with the mechanical properties of calcaneal trabecular bone. We obtained 31 intact cadaveric feet from the local anatomic gifts program, including 13 men and 18 women, with a mean age of 77 years (range 50-91 years). Broadband ultrasound attenuation (BUA) and ultrasound transit velocity (SOS) were assessed in the intact cadaveric feet using a water-based ultrasound system. In addition, we measured the bone mineral density (BMD) of the posterior calcaneus using dual-energy X-ray absorptiometry. Cubes of trabecular bone were then removed from the calcaneus at approximately the same location as the QUS measurements were obtained, and the elastic modulus and ultimate strength of the trabecular bone specimens were measured by compressing them in the mediolateral direction. We found that QUS variables were moderately to strongly correlated with the mechanical properties of calcaneal trabecular bone (r2 = 0.48-0.63, p < 0.001 for all). However, the strongest associations with the mechanical properties trabecular bone were provided by calcaneus BMD and trabecular bone apparent density (r2 = 0.66-0.88). BUA and densitometric measurements were independently associated with elastic modulus, but not with ultimate strength. Our results indicate that QUS measurements of the intact heel are associated with the mechanical properties of calcaneal trabecular bone and, in some cases, provide information in addition to that provided by BMD or density measurements.


First-Line Genomic Profiling in Previously Untreated Advanced Solid Tumors for Identification of Targeted Therapy Opportunities.
Precision oncology using comprehensive genomic profiling (CGP) by next-generation sequencing is aimed at companion diagnosis and genomic profiling. The clinical utility of CGP before the standard of care (SOC) is still not resolved, and more evidence is needed. To investigate the clinical utility of next-generation CGP (FoundationOne CDx [F1CDx]) in patients with previously untreated metastatic or recurrent solid tumors. This multicenter, prospective, observational cohort study enrolled patients with previously untreated advanced solid tumors between May 18, 2021, and February 16, 2022, with follow-up through August 16, 2022. The study was conducted at 6 hospitals in Japan. Eligible patients were aged 20 years or older and had Eastern Cooperative Oncology Group performance status of 0 to 1 with previously untreated metastatic or recurrent cancers in the gastrointestinal or biliary tract; pancreas, lung, breast, uterus, or ovary; and malignant melanoma. Comprehensive genomic profiling testing before SOC for advanced solid tumors. Proportion of patients with actionable or druggable genomic alterations and molecular-based recommended therapy (MBRT). A total of 183 patients met the inclusion criteria and 180 patients (92 men [51.1%]) with a median age of 64 years (range, 23-88 years) subsequently underwent CGP (lung [n = 28], colon/small intestine [n = 27], pancreas [n = 27], breast [n = 25], biliary tract [n = 20], gastric [n = 19], uterus [n = 12], esophagus [n = 10], ovary [n = 6], and skin melanoma [n = 6]). Data from 172 patients were available for end point analyses. Actionable alterations were found in 172 patients (100.0%; 95% CI, 97.9%-100.0%) and druggable alternations were identified in 109 patients (63.4%; 95% CI, 55.7%-70.6%). The molecular tumor board identified MBRT for 105 patients (61.0%; 95% CI, 53.3%-68.4%). Genomic alterations included in the companion diagnostics list of the CGP test were found in 49 patients (28.5%; 95% CI, 21.9%-35.9%) in a tumor-agnostic setting. After a median follow-up of 7.9 months (range, 0.5-13.2 months), 34 patients (19.8%; 95% CI, 14.1%-26.5%) received MBRT. The findings of this study suggest that CGP testing before SOC for patients with advanced solid tumors may be clinically beneficial to guide the subsequent anticancer therapies, including molecularly matched treatments.


INTRAMUSCULAR EPINEPHRINE RESULTS IN REDUCED ANESTHETIC RECOVERY TIME IN AMERICAN ALLIGATORS (ALLIGATOR MISSISSIPPIENSIS) UNDERGOING ISOFLURANE ANESTHESIA.
Inhalants are commonly used to anesthetize reptiles, but volatile anesthetics have been associated with prolonged recovery times. The objective of this study was to determine the effects of intramuscular (IM) epinephrine on anesthetic recovery times following isoflurane anesthesia in a population of subadult American alligators ( Alligator mississippiensis ). In this prospective randomized crossover study, five clinically healthy alligators were anesthetized for 90 min with the use of isoflurane. Alligators were randomly assigned into one of two treatment groups: Group E received IM epinephrine (0.1 mg/kg), and Group S received an equal volume of 0.9% saline administered after isoflurane was discontinued. Time from the end of inhalant administration to return of spontaneous ventilation, return of the palpebral reflex, movement in response to a standardized toe pinch, and spontaneous movement was recorded. The time of extubation was noted and occurred following the return of spontaneous ventilation and movement. Pulse rate, surface body temperature, and airway gases including expiratory and inspiratory isoflurane concentrations and end-tidal carbon dioxide were measured every 5 min throughout the study. The time from the end of anesthesia to extubation was significantly faster in Group E (51.2 ± 16.7 min) compared to Group S (107.4 ± 43.7 min). Pulse rate was significantly higher within the first 15 min following epinephrine injection compared to the saline group at these time points. Therefore, IM epinephrine administered at the end of general anesthesia can significantly hasten anesthetic recovery from isoflurane in alligators.


Divergent and Orthogonal Approach to Carbazoles and Pyridoindoles from Oxindoles via Indole Intermediates.
The previously unexplored Grignard addition to oxindoles provides a regiospecific approach to 2- and 2,3-disubstituted indole derivatives in high yields via a one-pot aromatization driven dehydration pathway. This method allows a convenient preparation of diallyl indoles that are used as ring-closing metathesis (RCM) precursors for the orthogonal synthesis of pyrido[1,2- a]indoles and carbazoles. The synthetic utility of this method is illustrated by the synthesis of a microtubulin inhibitor and naturally occurring carbazole alkaloids.


Penile squamous cell carcinoma: anatomic, pathologic and viral studies in Paraguay (1993-2007).
In developed countries, penile squamous cell carcinoma (SCC) account for < 1% of all malignancies in men. It is more frequent in rural populations of Africa, Asia and Latin America, where it may constitute nearly 10% of all carcinomas. In Paraguay, approximately 30-40 new cases are diagnosed per year. Different subtypes of penile carcinomas have been described. Most SCCs are of the usual type (60%). Less frequent variants include basaloid (10%), warty (10%), papillary (15%), verrucous (3%), sarcomatoid (4%) and adenosquamous (1%). Mixed forms also exist. Because there is a correlation between histologic subtype and biologic behavior, accurate subtyping is important. The prevalence of human papillomavirus (HPV) in invasive SCC is approximately 42%, with a strong association of HPV and basaloid and warty variants. Among the most important prognostic factors are histologic grade and depth of invasion. It is important for surgical pathologists to know the anatomy of the penis and possible routes of tumor spread because negative resection margins are crucial to avoid local recurrences. The most frequently involved margins are the urethra and periurethral tissues, including Buck's fascia. Probable precursor lesions of penile carcinoma include squamous hyperplasia, low and high grade squamous intraepithelial neoplasia and lichen sclerosus.


Plant-based production of an orally active cyclotide for the treatment of multiple sclerosis.
Multiple sclerosis (MS) is a debilitating disease that requires prolonged treatment with often severe side effects. One experimental MS therapeutic currently under development is a single amino acid mutant of a plant peptide termed kalata B1, of the cyclotide family. Like all cyclotides, the therapeutic candidate [T20K]kB1 is highly stable as it contains a cyclic backbone that is cross-linked by three disulfide bonds in a knot-like structure. This stability is much sought after for peptide drugs, which despite exquisite selectivity for their targets, are prone to rapid degradation in human serum. In preliminary investigations, it was found that [T20K]kB1 retains oral activity in experimental autoimmune encephalomyelitis, a model of MS in mice, thus opening up opportunities for oral dosing of the peptide. Although [T20K]kB1 can be synthetically produced, a recombinant production system provides advantages, specifically for reduced scale-up costs and reductions in chemical waste. In this study, we demonstrate the capacity of the Australian native Nicotiana benthamiana plant to produce a structurally identical [T20K]kB1 to that of the synthetic peptide. By optimizing the co-expressed cyclizing enzyme, precursor peptide arrangements, and transgene regulatory regions, we demonstrate a [T20K]kB1 yield in crude peptide extracts of ~ 0.3 mg/g dry mass) in whole plants and close to 1.0 mg/g dry mass in isolated infiltrated leaves. With large-scale plant production facilities coming on-line across the world, the sustainable and cost-effective production of cyclotide-based therapeutics is now within reach.


Evolution of Fish Let-7 MicroRNAs and Their Expression Correlated to Growth Development in Blunt Snout Bream.
The lethal-7 (let-7) miRNA, known as one of the first founding miRNAs, is present in multiple copies in a genome and has diverse functions in animals. In this study, comparative genomic analysis of let-7 miRNAs members in fish species indicated that let-7 miRNA is a sequence conserved family in fish, while different species have the variable gene copy numbers. Among the ten members including let-7a/b/c/d/e/f/g/h/i/j, the let-7a precursor sequence was more similar to ancestral sequences, whereas other let-7 miRNA members were separate from the late differentiation of let-7a. The mostly predicted target genes of let-7 miRNAs are involved in biological process, especially developmental process and growth through Gene Ontology (GO) enrichment analysis. In order to identify the possible different functions of these ten miRNAs in fish growth development, their expression levels were quantified in adult males and females of Megalobrama amblycephala, as well as in 3-, 6-, and 12-months-old individuals with relatively slow- and fast-growth rates. These ten miRNAs had similar tissue expression patterns between males and females, with higher expression levels in the brain and pituitary than that in other tissues (p < 0.05). Among these miRNAs, the relative expression level of let-7a was the highest among almost all the tested tissues, followed by let-7b, let-7d and let-7c/e/f/g/h/i/j. As to the groups with different growth rates, the expression levels of let-7 miRNAs in pituitary and brain from the slow-growth group were always significantly higher than that in the fast-growth group (p < 0.05). These results suggest that let-7 miRNA members could play an important role in the regulation of growth development in M. amblycephala through negatively regulating expression of their target genes.


Differential staining of the cell cycle of plant cells using safranin and indigo-picrocarmine.
A trichrome staining technique using safranin-indigo-picrocarmine (SIPC) can be used to distinguish the various stages of the cell cycle in onion root tip. When the tissue was fixed first in formalin followed by picric acid and stained in SIPC, a clear differentiation of interphase nuclei into four color classes, viz., green, orange, red and brown can be recorded. Replacing crystal violet for safranin produces a similar pattern of differentiation of interphase nuclei into green, light blue, blue and deep blue. Autoradiographic study using 3H-thymidine as a DNA precursor demonstrates the reliability of the SIPC staining technique. All the orange and red nuclei are found to be labelled and therefore are in S phase of the cell cycle. Almost all the green nuclei are unlabelled and may be assigned to G1. The larger brown nuclei which are mostly unlabelled can be considered in G2 phase.


Cardiac taurine and principal amino acids in right and left ventricles of patients with either aortic valve stenosis or coronary artery disease: the importance of diabetes and gender.
Free intracellular taurine and principal α-amino acids (glutamate, glutamine, aspartate, asparagine and alanine) are abundant in human heart. They are cellular regulators and their concentration can change in response to disease and cardiac insults and have been shown to differ between hypertrophic left ventricle (LV) and the relatively "normal" right ventricle (RV) in patients with aortic valve stenosis (AVS). This difference has not been shown for coronary artery disease (CAD) and there are no studies that have simultaneously compared amino acid content in LV and RV from different pathologies. In this study we investigated the effect of disease on taurine and principal amino acids in both LV and RV, measured in myocardial biopsies collected from patients with either AVS (n = 22) or CAD (n = 36). Amino acids were extracted and measured using HPLC. Intra- and inter-group analysis was performed as well as subgroup analysis focusing on gender in AVS and type 2 diabetes in CAD. LV of both groups has significantly higher levels of taurine compared to RV. This difference disappears in both diabetic CAD patients and in male AVS patients. Alanine was the only α-amino acid to be altered by diabetes. LV of female AVS patients had significantly more glutamate, aspartate and asparagine than corresponding RV, whilst no difference was seen between LV and RV in males. LV of females has higher glutamate and glutamine and less metabolic stress than LV of males. This work shows that in contrast to LV, RV responds differently to disease which can be modulated by gender and diabetes.


[Expression of neurotrophic and inflammatory mediators in rectosigmoid endometriosis].
To evaluate the expression of neurotrophic (NGF, NPY and VIP) and pro-inflammatory (TNF-α) mediators in the rectum and sigmoid fragments compromised by endometriosis. Twenty-four patients were selected to undergo surgical treatment of endometriosis of the rectum and sigmoid colon with a segmental resection technique, followed by end-to-end anastomosis with a circular stapler from January 2005 to December 2007. The study included premenopausal women who underwent surgical treatment for deep endometriosis infiltrating the rectum with involvement of the rectum and sigmoid, reaching the level of the muscle layer, submucosa or mucosa. Twenty-four rectum and sigmoid fragments with histologically confirmed endometriosis, one from each of the 24 selected patients, were used for the study group. For the control group, we used a fragment of the distal resection margin called anastomosis ring from each of the 24 patients enrolled in the study. Samples were grouped into Tissue Micro Array (TMA) blocks and subjected to immunohistochemistry to evaluate the expression of tumor necrosis factor alpha (TNF-α), nerve growth factor (NGF), neuropeptide Y (NPY) and P vasoactive intestinal peptide (VIP), followed by semiquantitative analysis of immunostaining by reading the relative optical density (OD). There was higher optical density relative to TNF-α immunostaining and NGF in the study group (samples with intestinal endometriosis), DO=0.01, for the two proteins, respectively (p<0.05), compared to controls without endometriosis. There was no statistically significant difference in the optical density of immunostaining of NPY and VIP. We identified increased immunostaining of TNF-α antibodies and fragments of NGF in the rectum and sigmoid compromised by endometriosis compared to disease-free controls. We did not identify any statistical difference in immunostaining of NPY and VIP proteins.


[WHO classification and cytogenetic analysis of 435 cases with myelodysplastic syndrome].
To investigate the WHO classification and cytogenetic characteristics of primary myelodysplastic syndrome (MDS) in adults of Shanghai area and then compare them with those of western countries. The consecutive samples of 435 patients with MDS in Sino-US Shanghai Leukemia Cooperative Group were collected prospectively and diagnosed with WHO classification. Cytogenetic analysis was performed using chromosome G-banding and fluorescence in situ hybridization (FISH) techniques. The median onset age in the patients was 58 (18-90) years. The proportion of cases with refractory cytopenia with multilineage dysplasia (RCMD) was highest ,accounting for 69.6% (303/435). Other subtypes were refractory anemia with excess blasts (RAEB) 24.1% (105/435), refractory anemia (RA) 2.3% (10/435), myelodysplastic syndrome, unclassifiable (MDS-U) 2.3% (10/435), refractory anemia with ringed sideroblasts (RAS) 1.2% (5/435) and 5q-syndrome 0.5% (2/435) in turn. The proportions of RA, RAS and 5q-syndrome were higher in western countries and RCMD subtype was lower. Eleven cases had failure of chromosome analysis. In the remaining 424 cases with success the frequency of chromosome abnormality was 38.7%, with the highest in RAEB- I (62.5%), and then RAEB-II (48.4%) and RCMD (34.5%) in turn. The sequence of common chromosome abnormalities was + 8 (12.7% ), complex karyotype (9.0%), chromosome translocation (7.8%), - 20q (6.6%), -7/-7q (5.2%), -5/-5q (4.2%) and- Y(2.4%), while the sequential order in western countries -5/-5q, -7/-7q, +8, 11q and 12p/12q. Chromosome prognosis was grouped according to International Prognosis Scoring System (IPSS), 289 cases were in the group with good chromosome prognosis (68.2%), 81 cases in group with medium prognosis (19.1%) and 54 cases in group with poor prognosis (12.7%). Seventeen patients had normal chromosome examination because of lower percentage of abnormal cells. However, the detection sensitivity of abnormality with FISH may sometimes be high. The WHO subtype and chromosome abnormality distributions of MDS in Shanghai were different from those in western countries. The combination of FISH and conventional chromosome examination could improve the detection sensitivity.


Mesenchymal Stem Cells Within Gelatin/CaSO4 Scaffolds Treated Ex Vivo with Low Doses of BMP-2 and Wnt3a Increase Bone Regeneration.
The delivery of osteogenic factors is a proven therapeutic strategy to promote bone regeneration. Bone morphogenetic proteins (BMPs) constitute a family of cytokines with well-known osteogenic and bone regenerative abilities. However, clinical uses of BMPs require high doses that have been associated with complications such as osteolysis, ectopic bone formation, or hematoma formation. In the present work, we sought to improve bone tissue engineering through an approach that combines the use of bone marrow-derived mesenchymal stem cells (BMMSCs), composite scaffolds, and osteoinductive agents. We employed a composite gelatin/CaSO4 scaffold that allows for an early expansion of seeded BMMSCs, which is followed by an increased level of osteogenic differentiation after 10 days in culture. Furthermore, this scaffold enhanced bone formation by BMMSCs in a mouse model of critical-sized calvarial defect. More importantly, our results demonstrate that ex vivo pretreatment of BMMSCs with low amounts of BMP-2 (2 nM) and Wnt3a (50 ng/mL) for 24 h cooperatively increases the expression of osteogenic markers in vitro and bone regeneration in the critical-sized calvarial defect mouse model. These data provide a strong rationale for the development of an ex vivo cooperative use of BMP-2 and Wnt3a. Osteogenic factor cooperation might be applied to reduce the required amount of growth factors while obtaining higher therapeutic effects.


Association of obesity and physical activity in adult males of Dharan, Nepal.
Obesity is one of the most apparent-yet most neglected public health problems. Physical activity is a crucial element in the development of obesity but still its importance in the occurrence of obesity varies in different populations. This paper aims to study the burden of obesity and its association with physical activity was carried out in a rapidly urbanizing town. A cross-sectional study to investigate the prevalence of obesity and its association with physical activity was carried out in one thousand adult males of Dharan municipality. Tools of data collection included interview and physical measurements such as blood pressure, height and weight measurements, and waist and hip circumferences. Odds ratios (ORs) and their 95% confidence intervals for obesity were computed across various demographic and other variables without adjusting and then adjusting for physical activity. The prevalence of overweight and obesity in the population was 32.9% and 7.2% respectively. The study showed that physical inactivity is more importantly associated with obesity in the older population. The trend of young being more obese is reversed after adjusting for physical activity so that those in the older age were more obese than the younger ones. Similarly, those in to the business, vocational and clerical works, those who were more literate and those in the higher socio-economic status were significantly associated with obesity even after correcting for physical activity. The prevalence of overweight and obesity is high in the males of Dharan. The value and effect of physical activity seem to vary across different age-groups and socio-economic status and occupations. The young, the technical persons or businessmen and the more prosperous ones probably need to bring down their calorie intake along with emphasis on physical activity in order to bring down their weight and cardiovascular risk.


γ-Fe₂O₃ nanoparticle surface controls PtFe nanoparticle growth and catalytic properties.
We report a novel method for synthesis of alloy PtFe nanoparticles (NPs) of different compositions using γ-Fe2O3 NPs as an iron source. We show here other growth mechanisms than conventional nucleation on a NP surface leading to core-shell NP or seeded NP growth. Depending on reaction conditions, different compositions of PtFe NPs can be obtained. PtFe NPs may coexist with γ-Fe2O3 NPs in the reaction product. This mixture obtained in situ allows much higher catalytic activity in hydrogenation of methyl-3-buten-2-ol than that of only PtFe nanoparticles or merely mixed PtFe and γ-Fe2O3 NPs. The presence of both PtFe and γ-Fe2O3 NPs allows formation of dense and stable NP arrays which hold promise for catalytic applications in microreactors or other reactor designs where a catalytic film is favoured.


Transcriptional and translational dynamics of light neurofilament subunit RNAs during Xenopus laevis optic nerve regeneration.
Neurofilaments (NFs), which comprise one of three cytoskeletal polymers of vertebrate axons, are heteropolymers of multiple NF subunit proteins. During Xenopus laevis optic nerve regeneration, NF subunit composition undergoes progressive changes that correlate with regenerative success. Understanding the relative contributions of transcriptional and post-transcriptional gene regulatory mechanisms to these changes should therefore provide insights into the control of the axonal growth program. Previously, we examined this issue with respect to the medium neurofilament protein (NF-M). Because the integrity of NF heteropolymers depends upon maintaining properly balanced expression among multiple subunits, we have now extended this analysis to include the four light NF subunits - peripherin, the light NF triplet protein (NF-L), and two additional alpha-internexin-like proteins. Within 3 days after an optic nerve crush injury to one eye, primary transcript levels of NF subunits increased in both eyes. Levels of mRNA, however, increased in only the operated eye and did so later than did increases in primary transcript, indicating that mRNA levels are under significant post-transcriptional regulation. As measured by polysome profiling, the translational efficiencies of individual NF subunit mRNAs also shifted throughout regeneration, with operated eye mRNAs being generally more translationally active than those of unoperated eyes. Also, in operated eyes, the precise mix of efficiently and poorly translated messages throughout regeneration varied independently for each subunit, indicating that their translations are fine-tuned separately. These results suggest a model whereby traumatic disruption of visual circuitry leads to increased expression of NF primary transcripts in both eyes. These increases are subsequently modulated post-transcriptionally to accommodate shifting demands at each phase of regeneration for NF heteropolymers of differing composition in regrowing axons.


[Diagnosis and treatment of aquired aplastic anemia].
To analyse the results of diagnosis and treatment of patients with aquired aplastic anemia (AA) in one center. All AA patients, diagnosed and treated in one clinic in 1998-2005, were included in the trial. In severe and very severe AA (SAA/VSAA) the patients (n = 19) received combined immunosuppressive therapy (IST) with antithymocytic globulin (ATG) and cyclosporin A (CsA), in non-severe AA (NSAA) the patients (n = 9) were given monotherapy with CsA. Allogenic transplantation of bone marrow (alloTBM) was made in 4 young patients with SAA/VSAA. The diagnosis of AA was established in 33 patients (19 males and 14 females): NSAA in 9, SAA in 19, VSAA in 5, idiopathic--in 26, posthepatic--in 5, associated with pregnancy--in 2 patients. Age median was 20 years (13-53). The clone of paroxysmal nocturnal hemoglobinuria (PNH) was identified in 7 of 33 patients (21%), antigen HLA-DRB1 *15 in 6 of 11 patients (55%). In median of 26-month follow-up 31 patients (94%) were alive. In IST, complete or partial remissions were obtained in 88% patients. Median of the interval to achievement of transfusion independence made up 2.5 months. All the patients after alloTBM are in complete remission, chronic extensive transplant against host reaction was observed in one case. Introduction of updated protocols provides long-term survival of more than 80% AA patients. To optimize treatment outcomes, it is necessary to include newly diagnosed AA patients into ongoing multicenter studies.


Effect of conditioned medium of mesenchymal stem cells on the in vitro maturation and subsequent development of mouse oocyte.
Mesenchymal stem cells (MSCs) secrete a variety of cytokines and growth factors in addition to self-renewal and multiple forms of differentiation. Some of these secreted bioactive factors could improve meiotic maturation in vitro and subsequent embryo developmental potential. The aim of the present study was to determine whether in vitro maturation (IVM) of mouse oocyte with or without cumulus cells could be improved by contact with conditioned medium (CM) of MSCs as well as the efficiency of CM to support follicular growth and oocyte maturation in the ovarian organ of mice cultured on soft agar. The developmental potential of matured oocyte was assessed by blastocyst formation after in vitro fertilization (IVF). Germinal vesicle stage oocytes with or without cumulus cells were subjected to IVM in either CM, Dulbecco's modified Eagle's medium (DMEM), alpha-minimum essential medium (alpha-MEM) or human tubal fluid (HTF). Approximately 120 oocytes were studied for each medium. CM produced a higher maturation rate (91.2%) than DMEM (54.7%), alpha-MEM (63.5%) and HTF (27.1%). Moreover, CM improved embryo development to blastocyst stage significantly more than DMEM and HTF (85 vs 7% and 41.7%, respectively) but there was no significant difference compared with alpha-MEM (85 vs 80.3%). The behavior of cortical granules of IVM oocytes cultured in CM revealed cytoplasmic maturation. Moreover, CM also supported preantral follicles growth well in organotypic culture on soft agar resulting in the maturation of 60% of them to developmentally competent oocytes. The production of estrogen progressively increased approximately 1-fold every other day during organ culture, while a dramatic 10-fold increase in progesterone was observed 17 h after human chorionic gonadotropin stimulus at the end of culture. Thus, CM is an effective medium for preantral follicle growth, oocyte maturation, and sequential embryo development.


Degradation of Polymethylmethacrylate (PMMA) Bioreactors Used for Algal Cultivation.
This paper depicts characteristics of degradation of walls of bioreactors made of polymethylmethacrylate (PMMA) which was used to culture algae. The degradation processes take place stimulated by lighting of external surface and interaction with cultured species on internal surface. Results presented are representative for degradation of a bioreactor tube after the 4-year cultivation of Chlorella sp. Microscopic observations, roughness and transmission tests showed that changes have occurred on the inner surface. The result of use is a decrease in transmission and an increase in roughness. Microscopic observations showed that particles remained after culture, especially in cracks.


Differences in lectin binding patterns of normal endometrium and endometrial adenocarcinoma, with special reference to staining with Ulex europeus agglutinin 1 and peanut agglutinin.
Differences in glycoconjugate composition between proliferative endometrium and endometrial adenocarcinoma were investigated by histochemical techniques using seven different lectins as probes. For light microscopy, the avidin-biotin-peroxidase complex (ABC) method was used. Concanavalin A (Con A), wheat germ agglutinin (WGA), and Ricinus communis agglutinin (RCA) stained almost all glandular cells in both proliferative (normal) and malignant endometria. Ulex europeus agglutinin 1 (UEA-1) strongly stained cancer cells, especially well-differentiated adenocarcinoma, but it scarcely stained normal endometrium. Peanut agglutinin (PNA) binding sites were observed only along the apical surface of normal endometrial glands, while the cytoplasm of endometrial adenocarcinoma cells was often positive for PNA. Soybean agglutinin (SBA) faintly reacted with proliferative endometrium and occasionally with malignant cells. Dolichos biflorus agglutinin (DBA) slightly stained proliferative and malignant endometria. By electron microscopic examinations using horseradish peroxidase (HRP)-labeled lectins, we observed that UEA-1, PNA, and Con A stained the Golgi membranes and plasma membrane of carcinoma cells. In addition, the Con A reaction was positive in the endoplasmic reticulum and nuclear envelope. These results revealed the differences in oligosaccharide chains between normal and malignant endometria, suggesting that UEA-1 and PNA, in particular, may be useful indicators of malignancy of the endometrium.


Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis.
All-trans retinoic acid (ATRA) is a biologically active isomer of retinoic acid (RA). Topical ATRA (retin-a, retin-a micro, atralin, renova, and avita) is the active pharmaceutical ingredient for FDA-approved treatments for acne and skin wrinkles. Oral formulations (Vesanoid) treat acute promyelocytic leukemia, but oral dosing can induce severe side effects. Despite benefits in various rodent models of inflammatory bowel disease (IBD), toxicity and controversial clinical observations have diminished enthusiasm for ATRA IBD clinical trials. To circumvent these issues and to use ATRA's key role in maintaining gut tolerance, we developed a poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) encapsulated ATRA formulation aimed at directing ATRA delivery to immune structures of the gut, limiting systemic exposure. Initially, ATRA MS was developed as a component of a combinatorial product (TreXTAM) that also contained encapsulated transforming growth factor (TGF)-β and ATRA in a 1:2 w/w ratio. Although the combination was optimal, benefit was also observed when ATRA MS was given alone in the CD4+ CD25-T-cell adoptive transfer (ACT) colitis model. We used the ACT and DSS-induced murine models of colitis to expand on the dose-dependent effects of oral ATRA MS when given alone. The DSS model was also used to compare the efficacy of ATRA MS and soluble ATRA, while healthy animals were used to compare the pharmacokinetics of the two drugs. In both the ACT and DSS-induced murine models of colitis, ATRA MS was observed to be effective in ameliorating disease. ATRA MS was also observed to be more effective than soluble ATRA in these models and displayed more favorable pharmacokinetics. We suggest ATRA MS, as a standalone product, may attenuate IBD and perhaps limit fibrosis, while limiting systemic side effects.


Short-term endurance training after coronary artery bypass grafting improves insulin resistance parameters in patients with hypertension.
It has been shown that short-term exercise training improves insulin resistance parameters in patients with ischaemic heart disease. The effects of such a rehabilitation programme in patients with hypertension have not been well established. To assess whether short-term endurance training after coronary artery bypass grafting (CABG) may improve metabolic parameters and reduce blood pressure in patients with hypertension. The study group consisted of 30 male patients (15 with hypertension and 15 normotensive) aged 55+/-2.1 years who underwent CABG 1 to 6 months before the initiation of a 3-week endurance training. Glucose, insulin and C-peptide blood levels as well as binding and degradation of 125I-insulin by erythrocyte receptors were assessed before and after the training programme. The effects of training on blood pressure values were also evaluated. A significant improvement (p<0.01) in the insulin resistance parameters, i.e. binding and degradation of labelled insulin was noted only in patients with hypertension. This was accompanied by a significant (p<0.05) increase in the HDL-cholesterol level. In the subgroup with hypertension, both the exercise systolic and diastolic pressures decreased significantly (p<0.05 and p<0.01, respectively), and similar changes were noted in the resting systolic and diastolic blood pressures values (p<0.05). Rehabilitation after CABG based on the endurance training was especially effective in patients with hypertension in whom beneficial changes in some metabolic risk factors of ischaemic heart disease as well as the reduction in the blood pressure values were observed.


Clinicopathologic Characteristics and Outcome Descriptors of Metaplastic Breast Carcinoma.
Metaplastic breast carcinoma is an aggressive form of breast cancer that accounts for 0.5% to 3% of all breast cancers. To study the clinicopathologic characteristics and outcomes of this rare disease. Retrospective study of patients with a diagnosis of metaplastic breast carcinoma between 2000 and 2019. Hematoxylin-eosin-stained slides were reviewed and additional clinical data were obtained from electronic medical records. Univariable and multivariable Cox proportional hazard regression analyses were used to determine associations between overall survival and several clinicopathologic variables. Of the 125 patients with metaplastic breast carcinoma identified, only patients with high-grade disease (N = 115) were included in the data analysis. A total of 38 participants (33%) were white, 66 (57%) were African American, and 11 (10%) belonged to other ethnicities. The median age at diagnosis was 57 years. The median tumor size was 3 cm. Heterologous histology was seen in 30% of cases. Multivariable analyses showed that patients with a larger tumor size had worse overall survival (hazard ratio [HR], 1.25; 95% CI, 1.10-1.44; P < .001). Distant metastatic disease was also associated with worse overall survival on multivariable analysis (HR, 10.27; 95% CI, 2.03-55.54; P = .005). In addition to treatment with either partial or complete mastectomies, 84 patients (73%) received chemotherapy. Multivariable analyses showed that chemotherapy had no effect on overall survival (HR, 0.53; 95% CI, 0.09-6.05; P = .55). A larger tumor size and distant metastatic disease are associated with worse overall survival in patients with metaplastic breast carcinoma. Additional studies are needed to further characterize our findings.


[The Cu/Zn index in cutaneous tumors with X-ray microanalysis].
Cu and Zn are two important elements, in straight relation with some malignancies. We have studied a group of patients with several types of cutaneous tumours and we have determined the values of both elements in serum and tumour tissues. The Cu/Zn ratio is in relation to the bigger or lesser malignity of process.


Relation between preclinical atherosclerosis and venous thromboembolism in patients with thrombophilias - longitudinal study.
Preclinical atherosclerosis may represent a risk factor for venous thromboembolism (VTE). In longitudinal study we followed longitudinally 96 patients (32 men) with thrombophilias with (n=51) and without (n=45) history of VTE. In both groups we studied the changes of preclinical atherosclerosis at peripherally located arteries detected by ultrasound. In addition, we assessed changes in selected risk factors of atherosclerosis. During the mean follow-up of 56.0+/-7.62 months we did not find significant change in preclinical atherosclerosis defined as Belcaro score in either group (-3 % in the VTE group vs 0 % in non VTE group). Significant increase in body mass index (1.03+/-1.98 kg*m(-2), resp. 1.21+/-1.67 kg*m(-2), p<0.01) and non-significant increase in systolic blood pressure were detected in both groups. Waist circumference increased significantly only in patients without VTE (4.11+/-7.84 cm, p<0.05). No differences in changes of risk factors under study between both groups were detected. In summary, patients with thrombophilia and history of VTE showed no evidence of greater progression of atherosclerosis or increase in traditional risk factors of atherosclerosis than patients with thrombophilia without history of VTE. Unfavorable changes of body mass index, waist circumference and systolic blood pressure were detected in both groups during study period.


Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases.
MicroRNAs are fine tuners of diverse biological responses and are expressed in various cell types of the liver. Here we hypothesized that circulating microRNAs (miRNAs) may serve as biomarkers of liver damage and inflammation. We studied miRNA-122, which is abundant in hepatocytes, and miR-155, -146a, and -125b, which regulate inflammation in immune cells in mouse models of alcoholic liver disease (ALD), drug (acetaminophen, APAP)-induced liver injury (DILI), and Toll-like receptor (TLR) 9+4 ligand-induced inflammatory cell-mediated liver damage. We found that serum/plasma miR-122 correlated with alanine aminotransferase (ALT) increases in the liver damage caused by alcohol, APAP, and TLR9 (CpG)+4 (LPS) ligands. MiR-155, a regulator of inflammation, was increased in serum/plasma in alcoholic and inflammatory liver injury. Alcohol failed to increase serum miR-122 in TLR4-deficient and p47phox-deficient mice that were protected from ALD. We found the most robust increase in plasma miR-122 in DILI and it correlated with the highest ALT levels. Consistent with the massive inflammatory cell infiltration in the liver, plasma miR-155 and miR-146a were significantly elevated after CpG+LPS administration. We show for the first time that, depending on the type of liver injury, circulating miRNAs are associated either with the exosome-rich or protein-rich compartments. In ALD and in inflammatory liver injury, serum/plasma miR-122 and miR-155 were predominantly associated with the exosome-rich fraction, whereas in DILI/APAP injury these miRNAs were present in the protein-rich fraction. Our results suggest that circulating miRNAs may serve as biomarkers to differentiate between hepatocyte injury and inflammation and the exosome versus protein association of miRNAs may provide further specificity to mechanisms of liver pathology.


[A tumor-like lymphocytis mastitis].
A 44-year-old woman presenting with an inflammatory and palpable firm breast lump underwent surgical excision. Intraoperative frozen section analysis showed an extensive lesion consisting of ducts with intraluminal "necrosis". In addition, a very dense stromal inflammation was observed around these ducts, suggesting an invasive ductal carcinoma with predominant intraductal proliferation. However, on paraffin sections, epithelial cells close to the lymphocytic infiltrate were rare, subatrophic, without any neoplastic feature. The density and architecture of the lymphocytic infiltrate mimicked a breast lymphoma. However, immunochemistry and molecular biology investigation favored the diagnosis of a tumor-like lymphocytic mastitis. Although extremely rare, this particular form of lymphocytic mastitis, a diagnostic pitfall particularly during peroperative examination, should be recognized by pathologists.