Lnc-MEG3 inhibits invasion, migration, and epithelial- mesenchymal transition of nasopharyngeal carcinoma cells by regulating sequestosome 1.
Long non-coding RNAs regulate malignant behaviors of nasopharyngeal carcinoma (NPC). We aim to investigate the roles and mechanisms of long non-coding RNA maternally expressed gene 3 (lnc-MEG3) in NPC. The expression levels of lnc-MEG3 and sequestosome 1 (SQSTM1) in NPC tissues and cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell invasion and migration abilities were evaluated using transwell and wound healing assays, respectively. Downregulated lnc-MEG3 expression and upregulated SQSTM1 expression were found in NPC tissues and cells. Overexpression of lnc-MEG3 inhibited invasion, migration, and epithelial-mesenchymal transition in NPC cells. Overexpression of lnc-MEG3 reduced the expression level of SQSTM1, and SQSTM1 expression was inversely correlated with lnc-MEG3 level in NPC tissues. Besides, overexpression of SQSTM1 reversed the effects of lnc-MEG3 overexpression. Moreover, knockdown of lnc-MEG3 enhanced NPC progression while its effects were eased by SQSTM1 silence. Lnc-MEG3 inhibits malignant behaviors by regulating SQSTM1 expression. It may serve as a therapeutic target to treat NPC.


Interleukin-35 regulates the balance of Th17 and Treg responses during the pathogenesis of connective tissue diseases.
Interleukin (IL)-35 belongs to the IL-12 cytokine family and is a heterodimer of the p35 and Epstein-Barr virus-induced gene 3 (EBI3) subunits. Functionally, IL-35 can promote the proliferation and activation of regulatory T cells (Tregs) and suppress the function of T helper 17 (Th17) cells and other inflammatory cells to inhibit immune responses. In recent years, an abnormal IL-35 expression causing a Th17/Treg imbalance has been associated with the development and progression of several connective tissue diseases (CTDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis (DM)/polymyositis (PM), and primary Sjögren's syndrome (pSS). Here, we review the role of IL-35 in regulating the balance of Th17/Treg responses in different types of CTDs and provide new insights into the role of IL-35 in these diseases.


[To the process of registration of ageing process (author's transl)].
A cybernetical scheme and a corresponding system of differential equations, describing the dehydration and the diminishing metabolism rate of the aging cell as well as of the whole of the organism, are generalised to adapt them also to other phenomena of aging. The resulting expressions are tested by comparison with a number of representative theoretical and experimental dates of various aging processes.


Cell dynamics of calretinin-immunoreactive neurons in the rostral migratory stream after ibotenate-induced lesions in the forebrain.
It is now apparent that adult neurogenesis is taking place during life in the olfactory bulb (OB) of the rodent brain. In the olfactory nervous system, the precursor cells of the subventricular zone are known to continually proliferate, migrate through the rostral migratory stream (RMS) and differentiate into the bulbar neurons. The RMS, consisting of heterogeneous cell populations of the neural and neuronal precursor cells, is the unique forebrain structure that provides a long-distance migratory route for the precursor cells. The present study was undertaken to examine whether neuronal regeneration, focusing on calretinin-immunoreactive (+) cells, may proceed in the RMS following lesions induced by an excitotoxin. Two days after ibotenate injections, massive degeneration of calretinin (+) cells occurred in the RMS and its adjacent forebrains. Thereafter, calretinin (+) cells gradually increased in the RMS and reached above their control value 2 weeks after ibotenate injections. Removal of the OB also produced a marked increase in calretinin (+) cells in the RMS. Autoradiographic experiments using (3)H-thymidine showed that calretinin (+) cells were continually generated in the RMS and underwent neuronal turnover within 8 weeks in a normal condition. The results indicate that, in terms of calretinin (+) cells, neuronal differentiation and replacement is continually taking place within the RMS, and that the RMS is capable of repopulating those cells which were injured by ibotenate.


Arctigenin inhibits proliferation of ER-positive breast cancer cells through cell cycle arrest mediated by GSK3-dependent cyclin D1 degradation.
Estrogen receptor (ER) positive accounts for a large proportion of breast cancer. Although there are many targeted therapeutic drugs, the emergence of drug resistance urgently requires the development of new drugs. Arctigenin (Arc), a lignan found in certain plants of the Asteraceae, has the effect on inhibiting breast cancer, but its molecular mechanism has not been clear. To this end, the current study focuses on understanding the mechanism of Arc on ER-positive breast cancer cells. Colony formation experiments and sulforhodamine B methods were used to determine the growth-inhibitory effect of Arc. The cell cycle and apoptosis were analyzed by flow cytometry. Alterations of signaling proteins were measured by Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. The experimental results show that Arc did not induce apoptosis in ER-positive breast cancer cell, rather caused G1 cycle arrest by decreasing cyclin D1 levels without effect on altering CDK4/6 levels. Moreover, we have demonstrated that Arc decreases cyclin D1 levels through prompting Akt/GSK3β-mediated degradation. These findings warrant the potential of Arc as a candidate treatment for ER-positive breast cancer.


Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, RB, and E2F.
p53 is a well-established critical cell cycle regulator. By inducing transcription of the gene encoding p21, p53 inhibits cyclin-dependent kinase (CDK)-mediated phosphorylation of cell cycle inhibitor retinoblastoma (RB) proteins. Phosphorylation of RB releases E2F transcription factor proteins that transactivate cell cycle-promoting genes. Here, we sought to uncover the contribution of p53, p21, CDK, RB, and E2F to the regulation of ferroptosis, an oxidative form of cell death. Our studies have uncovered unexpected complexity in this regulation. First, we showed that elevated levels of p53 enhance ferroptosis in multiple inducible and isogenic systems. On the other hand, we found that p21 suppresses ferroptosis. Elevation of CDK activity also suppressed ferroptosis under conditions where p21 suppressed ferroptosis, suggesting that the impact of p21 must extend beyond CDK inhibition. Furthermore, we showed that overexpression of E2F suppresses ferroptosis in part via a p21-dependent mechanism, consistent with reports that this transcription factor can induce transcription of p21. Finally, deletion of RB genes enhanced ferroptosis. Taken together, these results show that signals affecting ferroptotic sensitivity emanate from multiple points within the p53 tumor suppressor pathway.


Darurah (Necessity) and Its Application in Islamic Ethical Assessment of Medical Applications: A Review on Malaysian Fatwa.
The discovery and invention of new medical applications may be considered blessings to humankind. However, some applications which might be the only remedy for certain diseases may contain ingredients or involve methods that are not in harmony with certain cultural and religious perspectives. These situations have raised important questions in medical ethics; are these applications completely prohibited according to these perspectives, and is there any room for mitigation? This paper explores the concept of darurah (necessity) and its deliberation in the formulation of fatwas on medicine issued by the National Fatwa Council of Malaysia. Darurah has explicitly been taken into consideration in the formulation of 14 out of 45 fatwas on medicine thus far, including one of the latest fatwas regarding uterine donation and transplantation. These fatwas are not only limited to the issues regarding the use of unlawful things as remedies. They include issues pertaining to organ transplantation, management of the corpse and treatment of brain dead patients. While deliberation of darurah in medicine may vary from issue to issue, darurah applies in a dire situation in which there are no lawful means to prevent harm that may be inflicted upon human life. Nevertheless, other aspects must also be taken into the deliberation. For example, consent must be obtained from the donor or his next of kin (after his death) to conduct a cadaveric organ transplantation.


The spectrum of ectopic thymomas.
Thymomas are rare tumors that usually manifest in the anterosuperior mediastinum. Occasionally, thymomas may also originate from ectopically dispersed thymic tissue and can arise in locations such as the neck, lung, or pleura or other locations in the thoracic cavity. The occurrence of thymomas in these ectopic locations can cause substantial diagnostic difficulty as the entity is almost never included in the differential diagnosis and its biphasic morphology can cause further complications during the diagnostic process. In this review, we summarize the clinical and pathological spectrum of ectopic thymomas and discuss the histogenesis, treatment, and prognosis of these extraordinary tumors.


Knee osteoarthritis pre-screening questionnaire (KOPS): cross-cultural adaptation and measurement properties of the brazilian version-KOPS Brazilian version.
Despite the criteria already established for the classification of knee osteoarthritis (OA), a radiographic and/or clinical knee OA diagnosis usually occurs in cases of fully manifest or more advanced disease, which can make health promotion, prevention, and functional rehabilitation in more advanced stages of the disease less effective. In addition, radiographic knee OA can generate more financial costs for health services. Therefore, developing and validating screening instruments to assess the probability of development and progression of knee OA would be of great value for both clinical practice and science. To cross-culturally adapt and investigate the measurement properties of the Knee OA Pre-screening Questionnaire Brazilian version. A total of 250 individuals of both sexes aged between 35 and 92 years [(mean (standard deviation): 63 (11) years old; 74.1 (15.1) kg; 1.59 (0.09) m; 29.38 (5.44) kg/m2] participated in this study. The cross-cultural adaptation and analyses of the measurement properties of the KOPS Brazilian version included: (1) assessment of conceptual and item equivalence; (2) assessment of semantic equivalence; (3) assessment of operational equivalence; and (4) assessment of measurement equivalence, reliability, and validity. Cronbach's alpha for the internal consistency among the six components of the KOPS Brazilian version was 0.71. The test-retest 72 h apart for each component resulted in a coefficient correlation intraclass ranging from 0.74 to 1.00. The probability of an individual randomly chosen from the population having KL ≥ 1 and KOPS Brazilian version ≥ 21 points was 0.74 (area under the curve of the Receiver Operating Characteristic - AUC of ROC); furthermore, the AUC for KL ≥ 2 and the KOPS Brazilian version ≥ 23 points was 0.77. The KOPS Brazilian version is a reliable and valid instrument for early screening of knee OA in individuals aged 35 years and over in the Brazilian context.


Survey from skills-based hands on learning courses demonstrates increased laparoscopic caseload and clinical laparoscopic suturing.
To evaluate the impact of the American Urological Association Hands on Laparoscopy course on the participants' practices. Many urologists without fellowship training perform laparoscopy, but do not advance beyond hand-assisted, extirpative laparoscopy. The American Urological Association Hands on Laparoscopy course was designed to help these practitioners advance their skills. A total of 68 urologists, aged 31 to 61 years (mean 46.6), participated in one of the four courses given between August 2002 and March 2004. The 2-day course included performing standardized tasks under videotape analysis and participating in porcine and pelvic trainer laboratory sessions. Surveys were sent by regular and electronic mail in September 2004 to assess the courses' impact. The mean follow-up was 15.2 months (range 7 to 25). Of the 68 surveys mailed, 54 were returned (79%). Most respondents were in private practice and had had prior experience with extirpative laparoscopy. Of the respondents, 41 (76%) reported that their laparoscopic practice had expanded after taking the course, with 34% performing at least 2 cases per month. Also, 33 respondents (61%) reported performing laparoscopic suturing after taking the course, with 35% having sutured a bleeding vessel. Of the respondents, 85% reported that the video mentoring during the course was helpful. Of those who purchased a pelvic trainer, 90% reported practicing on it regularly. The Hands on Laparoscopy course appeared to contribute to expansion of laparoscopic practices. Experience gained from skills-based lectures, videotape analysis of pelvic trainer performance, and a mentored porcine laboratory resulted in most (61%) participants expanding their practice to include clinical laparoscopic suturing.


Anti-thyroperoxidase antibodies from patients with Hashimoto's encephalopathy bind to cerebellar astrocytes.
A cohort of 10 Hashimoto's encephalopathy (HE) patients, 33 patients with unrelated neurological symptoms, 12 Hashimoto's thyroiditis patients and 4 healthy adult donors was studied to explore the neurological targets of anti-thyroperoxidase (TPO) autoantibodies (aAb) in HE. High levels of anti-TPO aAb were only detected in HE group's cerebrospinal fluids. In immunofluorescence assays on monkey brain cerebellum sections, both HE patients' sera and anti-TPO monoclonal antibodies (mAb) were able to bind cerebellar cells expressing glial fibrillary acid protein. Normal human astrocytes from primary cultures also reacted with anti-TPO mAb. Specific astrocyte binding of anti-TPO aAb suggests a role of these aAb in the HE pathogenesis.


Abortive long-lasting sporogony of two Haemoproteus species (Haemosporida, Haemoproteidae) in the mosquito Ochlerotatus cantans, with perspectives on haemosporidian vector research.
Haemoproteus spp. are cosmopolitan vector-born haemosporidian parasites, some species of which cause diseases in non-adapted birds. Recent polymerase chain reaction (PCR)-based studies have detected mitochondrial cytochrome b gene lineages of these Haemoproteus parasites in blood-sucking mosquitoes and speculated about possible involvement of these insects in transmission of avian haemoproteids. However, development of Haemoproteus lineages has not been documented in mosquitoes. We infected 304 individuals of Ochlerotatus cantans, a widespread Eurasian mosquito, with Haemoproteus tartakovskyi (lineage hSISKIN1) and Haemoproteus balmorali (lineage hROBIN1). Mosquitoes were allowed to take non-infected and infected blood meals and maintained in the laboratory until 17 days post-infection (dpi). They were tested for presence of sporogonic stages by microscopic and PCR-based methods. Microscopic examination revealed partial development of both parasites in the infected insects. Numerous ookinetes were seen in the gut area and adjacent tissues located in the head, thorax and abdomen of mosquitoes between 1 and 5 dpi. Numerous oocysts were seen in the midgut wall between 4 and 15 dpi; they were also present in the head and thorax of infected mosquitoes testifying to the active movement of ookinetes throughout the body. Oocysts degenerated between 11 and 17 dpi. Sporozoites were not seen in oocysts or mosquito salivary glands, indicating abortive sporogonic development at the oocyst stage. In accordance with microscopy data, PCR and sequencing revealed presence of the lineages hSISKIN1 and hROBIN1 in experimental mosquitoes as long as 15 and 17 dpi, respectively, demonstrating relatively long survival of Haemoproteus parasites in the resistant insects without DNA degeneration. The present study shows that PCR-based diagnostics should be carefully used in vector studies of haemosporidians because it detects parasites in insects for several weeks after initial infection, but does not distinguish abortive parasite development. Demonstration of infective sporozoites in insects is essential for definitively demonstrating the insects are vectors.


Multicentre study on inflammatory skin diseases from The International Confocal Working Group: specific confocal microscopy features and an algorithmic method of diagnosis.
The real value of reflectance confocal microscopy (RCM) for the evaluation of inflammatory skin conditions remains unclear. A project on RCM for inflammatory skin diseases involving international centres was designed by a coordinating centre and executed under the supervision of the International Confocal Working Group. To identify specific confocal features useful for distinction between the three main groups of superficial inflammatory skin diseases. Nineteen different RCM features were evaluated in a total of 155 lesions, diagnosed as spongiotic (45), interface (52) or psoriasiform (58) dermatitis, collected by a consortium of 19 different centres. Univariate and multivariate analysis identified RCM descriptors for the three main superficial inflammatory disease groups. Later, a multivariate method was employed to define a scoring system to be applied on an algorithmic method of analysis for fast clinical application. Our preliminary evaluation supports the use of RCM for the identification of confocal patterns consistent with the major features of the diagnostic groups of inflammatory skin diseases. Moreover, an efficient multivariate method for clinical in vivo RCM diagnosis using a tree decision diagram has been established.


[Possibilities for surgical correction of an anastomotic stricture after radical prostatectomy].
Anastomotic strictures following radical prostatectomy for prostate cancer are reported in about 1-8% of all patients. Endourologic management usually does not result in very high cure rates but is associated with very high rates of recurrences. There is no standard management of these postoperative long-term complications and quite often the patient ends up having a transurethral or suprapubic catheter as a simple long-term solution. Twenty-four patients with recurrent anastomotic strictures and a mean of 3.5 (2-9) previous transurethral surgical interventions were operated between 2004 and 2011. All patients underwent perineal bladder neck closure and a continent vesicostomy with either an appendiceal or an ileal stoma implanted in the bladder. The mean OR time was 125 (100-195) min, and the mean time of hospitalisation was 12.5 (9-27) days. There were no significant intra- or perioperative complications. Three patients developed a significant urinary tract infection, two patients had to be treated for the development of a paralytic ileus and one patient needed to undergo revision surgery for a urethral fistula. After a mean follow-up of 37 (10-78) months, two patients developed a stomal stenosis which was corrected surgically. Based on our experience, bladder neck closure and continent vesicostomy represent a valuable therapeutic option in the management of recurrent anastomotic strictures following radical prostatectomy.


Characteristics of pediatric emergency patients in a Turkish tertiary-level hospital: A 1-year cross-sectional study.
Overcrowding in pediatric emergency departments negatively affects the quality of care. Investigating the characteristics of the patients admitted to PEDs will provide valuable information to increase the satisfaction of patients and healthcare staff. This research aimed to investigate the characteristics of pediatric emergency patients in a foundation university hospital in Ankara. This is a retrospective, descriptive, single-center, cross-sectional study, which was conducted with 6550 patients who were admitted to the pediatric emergency department of a foundation university hospital in Ankara, and got diagnosed with one of the 15 most common diseases between 1 August 2017 and 31 July 2018. The associations between the demographics and clinical features of the patients and their diagnoses were evaluated. For comparisons, frequencies, percentages, crosstabs, and chi-square tests were used. While none of the patients had a red triage level, 19% had a yellow triage level, and 81% had a green triage level. The three most common diagnoses were fever of unknown origin, cough, and nausea and vomiting. Despite the 0-28 days of age group having the lowest admission rate of 5%, they had the highest usage rate of yellow triage level (66.5%). However, it was the opposite for the 19 months to 5 years of age group with the highest rate of admissions of 49% and the lowest usage rate of yellow triage level (12.8%). The reasons for admitting to pediatric emergency department differ according to some contextual variables. Being aware of the current situation is the first step in planning for better pediatric emergency service.


Nonresonant quadrupolar second-harmonic generation in isotropic solids by use of two orthogonally polarized laser beams.
We demonstrate an experimental technique for isolating and enhancing quadrupolar second-harmonic generation in isotropic materials by using two orthogonally polarized laser beams that create wavelength-scale, forward-radiating gradients in the second-harmonic polarization.


Identification of C-21 steroidal glycosides from the roots of Cynanchum chekiangense by high-performance liquid chromatography/tandem mass spectrometry.
High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC/ESI-MS/MS) was used to identify C-21 steroidal glycosides with immunological activities in roots of Cynanchum chekiangense. In the MS/MS spectra, fragmentation reactions of the [M+Na]+ were recorded to provide structural information about the glycosyl and aglycone moieties. To further confirm the fragments structures, off-line Fourier transform ion cyclotron resonance tandem mass spectrometry (FT-ICR-MS/MS) was also performed. In the study, four known steroidal glycosides cynascyroside C, chekiangensosides A and B, glaucoside H, and four novel steroidal glycosides chekiangensosides C, D, E and chekiangensoside A isomer were identified based on mass spectral data, NMR spectral data and standards. This is the first report on identifying steroidal glycosides in roots of C. chekiangense by HPLC/ESI-MS/MS directly, which could save time and material consuming efforts in traditional phytochemistry analysis.


Lasting Hb F reactivation and Hb A2 reduction induced by the treatment of Hodgkin's disease in a woman heterozygous for beta-thalassemia and the Swiss type of the heterocellular hereditary persistence of Hb F.
A remarkable augmentation of Hb F and a reduction of Hb A2 were observed in a Sicilian woman during and after a course of treatment for Hodgkin's disease. An inverse correlation between the proportion of Hb F and Hb A2 was found over an 8-year period, as well as in populations of red blood cells fractionated by density gradient. She exhibited two genetic defects, the Swiss type of heterocellular hereditary persistence of fetal hemoglobin and a beta-thalassemia trait, which were confirmed by the study of the hemoglobin synthesis and by a family study. The lasting reactivation of Hb F synthesis is attributable to the interaction of several acquired and inherited factors.


The value of intravascular ultrasound in the treatment of central venous obstructions in hemodialysis patients.
Digital subtraction angiography (DSA) is the gold standard in diagnosis and treatment of central venous obstructions (CVOs) in hemodialysis access. However, growing data suggest that DSA might underestimate the degree and morphology of venous outflow stenosis. This could lead to inappropriate CVO management. Intravascular ultrasound (IVUS) has been shown to identify lesion characteristics remaining obscure with angiography. With the current study we suggest IVUS as an eminent imaging modality in CVO management. Twelve patients (8 male, mean age 62.4 ± 9 years) were analyzed for suspicion of symptomatic CVO. Both angiography and IVUS evaluation were performed to determine the degree of obstruction before and after PTA. Stent placement was indicated when significant residual stenosis (>50% lumen reduction) was suspected. Conventional plain angiography determined 8 out of 12 central venous lesions significant. Secondary signs of obstruction, i.e., collateral filling, was present in all 12 cases. After PTA, persistent significant stenosis was observed in 3 out of 12 patients. IVUS showed significant lumen reduction in all 12 cases. Additionally, IVUS showed a median cross-sectional area of 24 ± 12 mm2 before PTA and 37 ± 23 mm2 after PTA (NS). Furthermore, IVUS showed signs of intraluminal fibrotic trabeculations in 9 patients. Stenting was performed in 10 patients with >50% lumen reduction on IVUS after PTA. Conventional angiography seems unreliable to identify all significant aspects of a central venous outflow obstruction. Additional use of IVUS might aid in the decision-making process and select the optimal treatment strategy.


Site and size of multiple sclerosis lesions predict enhanced or decreased female orgasmic function.
Neuroimaging identified brain areas involved in female orgasm. In women with multiple sclerosis (MS), associations between orgasmic function and the site and size of MS-related magnetic resonance imaging (MRI) changes are undetermined. This study intended to correlate MS-associated cerebral lesion load and location with clinical scores of female orgasmic function. In 50 women with MS (mean age 37.0 ± 9.9 years), we assessed Female Sexual Function Index (FSFI) scores for orgasmic frequency, difficulty and satisfaction. We determined disease duration, Expanded Disability Status Scale (EDSS) scores, and cerebral MS-lesion load and location using T2-weighed 1.5 T MRIs. We correlated FSFI scores for orgasm with patient age, disease duration, EDSS scores, and cerebral MS-lesion load (Spearman rank correlation; significance: p < 0.05). FSFI scores for orgasm correlated inversely with MS-lesion load in the left temporal periventricular white matter and right middle-inferior occipital area, but directly with MS-lesion load in the right frontal primary motor cortex, left prefrontal/inferior frontal cortex, right amygdala, left temporal middle-inferior and fusiform areas, and midbrain. FSFI scores for orgasm did not correlate with patient age, disease duration and EDSS scores (p > 0.05). In conclusion, our results indicate that MS-lesions in left temporal periventricular and right visual association areas deteriorate orgasmic function. In contrast, direct correlations between frontotemporal or midbrain lesions and higher FSFI scores, indicating enhanced or disinhibited orgasmic function, suggest that these brain regions normally buffer orgasmic responses. Moreover, our results indicate that orgasmic dysfunction in women with MS evolves independently of disease duration and physical disability.


State-of-the-Art in Ankle Fracture Management in Chile.
The ankle represents the most commonly injured weightbearing joint in the human body. They are typically the result of low-energy, rotational injury mechanisms. However, ankle fractures represent a spectrum of injury patterns from simple to very complex, with varying incidence of posttraumatic arthritis. Stable injury patterns can be treated nonoperatively; unstable injury patterns are typically treated operatively given that they could lead to severe arthritis if not properly addressed.


The Combination of Lithium and ACE Inhibitors: Hazardous, Critical, Possible?
Lithium is a well established therapeutic agent in the treatment of uni- and bipolar affective disorders. Angiotensin-converting enzyme (ACE) inhibitors are the most frequently used class of drugs in the treatment of cardiovascular diseases. Combination therapy with both may be considered in clinical practice on occurrence of arterial hypertension after years of successful lithium therapy, yet an increased risk of lithium intoxication in combination with ACE inhibitors has been described and thus the combination has been warned against. We describe three cases in which enalapril, lisinopril or ramipril was combined with lithium. Either additional co-medication with hydrochlorothiazide or dehydration rather than co-medication with ACE inhibitors could be identified as necessary factors for lithium intoxication. These cases suggest that a combination of lithium with ACE inhibitors is possible when sufficient hydration is ensured and a combination with hydrochlorothiazide is avoided. Lithium concentration should be controlled on a regular level.


The -670G>A polymorphism in the FAS gene promoter region influences the susceptibility to systemic sclerosis.
To evaluate the role of the single-nucleotide polymorphism (SNP) at position -670 in the FAS gene promoter (FAS-670G>A) in influencing the susceptibility, clinical features and severity of systemic sclerosis (SSc). 350 white Italian SSc patients (259 with limited cutaneous SSc (lcSSc) and 91 with diffuse cutaneous SSc (dcSSc)) and 232 healthy individuals were studied. Patients were assessed for the presence of autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70) antibodies), interstitial lung disease (ILD), pulmonary arterial hypertension and scleroderma renal crisis. FAS-670G>A SNP was genotyped by PCR restriction fragment length polymorphism assay. Serum levels of soluble FAS (sFAS) were analysed by ELISA. A significant difference in FAS-670 genotype distribution was observed between SSc patients and healthy individuals (p = 0.001). The frequency of the FAS-670A allele was significantly greater in SSc than in controls (p = 0.001). No significant difference in genotype distribution and allele frequencies was observed between lcSSc and dcSSc, although a greater frequency of the FAS-670A allele was found in dcSSc. The FAS-670AA genotype significantly influenced the predisposition to SSc (OR 1.97, 95% CI 1.35 to 2.88, p = 0.001) and to both lcSSc (OR 1.84, 95% CI 1.23 to 2.75, p = 0.003) and dcSSc (OR 2.37, 95% CI 1.41 to 3.99, p = 0.001). FAS-670A allele frequency was greater, although not significantly, in anti-Scl-70 antibody-positive dcSSc and ILD dcSSc. sFAS was significantly higher in patients and controls carrying the FAS-670AA genotype compared with those carrying the FAS-670GG genotype (p = 0.003 in SSc, p = 0.004 in controls). The FAS-670A allele is significantly associated with susceptibility to SSc, suggesting a role for a genetic control of apoptosis in the pathogenesis of the disease.


Intracellular calcium homeostasis and its dysregulation underlying epileptic seizures.
Biological activities require a delicate balance between excitatory and inhibitory signals in the brain. Disruption of this balance could lead to neurological disorders, such as epilepsydue to a relative enhancement of excitatory signals. In general, cytosolic calcium plays a key role in the transmission of excitatory signals mainly by promoting the release of synaptic vesicles containing neurotransmitters. A series of molecular components responsible for maintaining intracellular calcium homeostasis, including voltage-gated calcium (CaV) channels, the endoplasmic reticulum (ER) calcium sensor stromal interaction molecule (STIM), the PM calcium channel Orai, ER-resident inositol trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), sarco-endoplasmic reticulum calcium ATPase (SERCA), and transmembrane and coiled-coil domains 1 (TMCO1), have been demonstrated to be involved in calcium dysregulation that underlies epileptic seizures. More importantly, epileptic phenotypes were confirmed in several molecular components by transgenic animal models, including CACNA1A, CACNA1E, CACNA1G, CACNA2D1, ORAI1 and IP3R1. Calcium-binding proteins (CaBPs), such as calmodulin, parvalbumin, calretinin, and calbindin, provide an additional layer of defense by acting as calcium reservoirs to buffer rapid increases in cytosolic calcium concentrations and participate in cellular functions by regulating the activities of ion channels or acting as calcium-modulated sensors, and a series of lines of evidence support their implication with epileptic activities. Overall, stroke represents the most common environmental cause of acquired epilepsy in older adults, and preventing calcium disruption due to reperfusion injury might be an effective way to treat acute symptomatic seizures and decrease the risk for acquired poststroke epilepsy.


Skin disease in pregnancy: The approach of the obstetric medicine physician.
This review presents the approach of the obstetric medicine physician to skin disease in pregnancy. It elaborates on common skin-related problems during gestation, such as pruritus, with or without eruption, and drug eruptions. An algorithmic approach to the differential diagnosis of pruritus in pregnancy is outlined. Also, the review focuses on how to diagnose promptly endocrinopathies presenting with skin manifestations in pregnancy, such as Addison disease, diabetes, and hyperthyroidism. The prompt diagnosis of endocrine disorders can help to optimize management and improve outcomes. Finally, the authors outline their approach to minimizing maternal and fetal risks associated with skin disease. The risks associated with obstetric cholestasis, pemphigoid gestationis, and impetigo herpetiformis are discussed. Prompt diagnosis helps to minimize the serious risks associated with certain infections. Preconception counseling and a multidisciplinary approach are crucial to preventing risks associated with rheumatic skin disease and genodermatoses. Challenging, real-life obstetric medicine cases are discussed.


Asp746 to glycine change may have a greater influence than Cys751 to serine change in accounting for ligand selectivity between EGFR and HER-2 at the ATP site.
We have carried out up to 8.0 ns molecular dynamics simulation on the ATP-bound complexes of EGFR and HER-2 (homology model) receptor kinase domains to explore the possible consequences of amino acid residue changes in or close to the ATP site that might provide insights for selectivity of these kinases towards ATP site inhibitors. The simulation results show the formation of a channel under Thr766 following the movement of the side chain of Gln767 away from the hinge in EGFR. In HER-2, a similar movement of Gln799 occurs, but a simultaneous movement of Arg784 towards the hinge region occurs that tends to close the channel. The movement of Arg784 in HER-2 appears to result from the absence of an anchoring residue like Asp746 in EGFR, which has been changed to Gly778 in HER-2. In EGFR, this Arg784 is held away from the hinge region by interaction with Asp746, thereby leaving the channel open. This might be an important contributory factor to differences in selectivity of the ligands between the two kinases, probably more so than the conservative change of Cys751 of EGFR to serine in HER-2 at the ATP site.


A versatile tag for simple preparation of cutinase towards enhanced biodegradation of polyethylene terephthalate.
Enzymatic degradation of polyethylene terephthalate (PET) suffered from challenges such as complex and costly enzyme preparation, difficult access to PET substrates, poor reusability of free enzymes and sometimes MHET inhibitions. Herein, we propose an "all-in-one" strategy to address these issues with a well-designed elastin-like polypeptides (ELPs) tag. The preparation of the ELPs-tagged cutinase (ET-C) was efficient and easy to scale up by centrifugation, with an activity recovery of 57.55 % and a yield of 160 mg/L. Besides, the activity of the ET-C was 1.3 and 1.66-fold higher in degrading PET micro- and macro-plastics compared to wild-type cutinase. The self-immobilized cutinase (ET-C@SiO2) obtained by the ELPs-mediated biosilicification exhibited high loading capacity, activity, and thermostability and maintained 77.65 % of the original activity after 10 reuses. Interestingly, the product of the ET-C was TPA, whereas the wild-type was TPA and MHET. This is a simple way to release the intermediates inhibition compared with the existing methods. Our results demonstrated the feasibility of the versatile ELPs tag, which will pave an alternative economic way for scalable PET biodegradation.


Autonomic nervous system functioning associated with psychogenic nonepileptic seizures: Analysis of heart rate variability.
Psychogenic nonepileptic seizures (PNESs) resemble epileptic seizures but originate from psychogenic rather than organic causes. Patients with PNESs are often unable or unwilling to reflect on underlying emotions. To gain more insight into the internal states of patients during PNES episodes, this study explored the time course of heart rate variability (HRV) measures, which provide information about autonomic nervous system functioning and arousal. Heart rate variability measures were extracted from double-lead electrocardiography data collected during 1-7days of video-electroencephalography monitoring of 20 patients with PNESs, in whom a total number of 118 PNESs was recorded. Heart rate (HR) and HRV measures in time and frequency domains (standard deviation of average beat-to-beat intervals (SDANN), root mean square of successive differences (RMSSD), high-frequency (HF) power, low-frequency (LF) power, and very low-frequency (VLF) power) were averaged over consecutive five-minute intervals. Additionally, quantitative analyses of Poincaré plot parameters (SD1, SD2, and SD1/SD2 ratio) were performed. In the five-minute interval before PNES, HR significantly (p<0.05) increased (d=2.5), whereas SDANN (d=-0.03) and VLF power (d=-0.05) significantly decreased. During PNES, significant increases in HF power (d=0.0006), SD1 (d=0.031), and SD2 (d=0.016) were observed. In the five-minute interval immediately following PNES, SDANN (d=0.046) and VLF power (d=0.073) significantly increased, and HR (d=-5.1) and SD1/SD2 ratio (d=-0.14) decreased, compared to the interval preceding PNES. The results suggest that PNES episodes are preceded by increased sympathetic functioning, which is followed by an increase in parasympathetic functioning during and after PNES. Future research needs to identify the exact nature of the increased arousal that precedes PNES.


Incisional hernia rates following midline laparotomy in the obese patient: a retrospective review.
Incisional hernia is the most common complication of midline laparotomy. Although obesity is a known risk factor, the incidence of hernia formation in obese patients is not well defined. We sought to define the rate of incisional hernia formation in obese patients undergoing primary midline laparotomy in a large academic medical center. Obese patients (BMI ≥ 30 kg/m2) who underwent an elective or urgent primary midline laparotomy from 2017 to 2021 at our institution were retrospectively identified. A blinded hernia surgeon reviewed imaging to assess for incisional hernia formation, defined as a midline fascial defect with intra-abdominal contents herniated outside of the peritoneal cavity. A total of 2241 patients met inclusion criteria. Cross-sectional imaging was available for 914 (41%) of these patients. The median BMI for all patients was 34.3 kg/m2 (range 30.0-59.1). Median time to follow-up imaging was 316 days (181-957, IQR = 185) for all patients and 316 days (201-903, IQR = 184) for patients with incisional hernia. In total, 474 (51.9%) had radiographic evidence of an incisional hernia. Colorectal and General Surgery demonstrated the highest rate of incisional hernia (p < 0.001). During the study period, 138 patients (15.1%) underwent surgical repair of their hernia at our institution, with the highest percentage being Colorectal Surgery patients. There is a high rate of hernia formation and subsequent hernia repair in obese patients undergoing midline laparotomy. Most importantly, these findings demonstrate an immediate and pressing need to identify the patient risk factors and technical issues related to this rate of hernia formation.


Bone changes in the adult anophthalmic orbit influencing oculoplastic reconstructive considerations.
Decreased orbital development following enucleation is a well recognized condition in the young person and is lessened by orbital implantation at the time of inital surgery. Pfeiffer, some 30 years ago, suggested that bone changes as well as the soft tissue changes could also continue to take place in the adult resulting in added orbital changes. While this has been questioned, the findings originally reported by Pfeiffer are firmly substantiated by roentgenograms and documented in this report. If there has been a significant interval of time following the enucleation, careful roentgenographic evaluation prior to cosmetic oculoplastic revision of the orbit should be done even in the adult.


The effect of a simulated scaphoid malunion on wrist motion.
A scaphoid malunion results when a scaphoid fracture heals in a flexed position or when a scaphoid nonunion with carpal collapse is grafted without correction of the angular deformity. The effects of scaphoid malunion on wrist motion were simulated in a cadaveric study. It was found that the loss of wrist extension is proportional to the angular deformity. Loss of radiocarpal extension occurred at 15 degrees of angulation and loss of midcarpal extension occurred at 30 degrees of angulation.


A gene in the multidrug and toxic compound extrusion (MATE) family confers aluminum tolerance in sorghum.
Crop yields are significantly reduced by aluminum toxicity on highly acidic soils, which comprise up to 50% of the world's arable land. Candidate aluminum tolerance proteins include organic acid efflux transporters, with the organic acids forming non-toxic complexes with rhizosphere aluminum. In this study, we used positional cloning to identify the gene encoding a member of the multidrug and toxic compound extrusion (MATE) family, an aluminum-activated citrate transporter, as responsible for the major sorghum (Sorghum bicolor) aluminum tolerance locus, Alt(SB). Polymorphisms in regulatory regions of Alt(SB) are likely to contribute to large allelic effects, acting to increase Alt(SB) expression in the root apex of tolerant genotypes. Furthermore, aluminum-inducible Alt(SB) expression is associated with induction of aluminum tolerance via enhanced root citrate exudation. These findings will allow us to identify superior Alt(SB) haplotypes that can be incorporated via molecular breeding and biotechnology into acid soil breeding programs, thus helping to increase crop yields in developing countries where acidic soils predominate.


Use of Fortified Bread for Addressing Vitamin D Deficiency.
Vitamin D deficiency due to inadequate sun exposure and/or inadequate intake from food is very common worldwide, consisting a major public health problem. As prolonged exposure to ultraviolet radiation involves risks, food fortification of staple foods emerges as a favorable solution for addressing vitamin D deficiency. Bread is a suitable candidate for fortification as it is consumed often and is the main carbohydrate source in European countries.The purpose of this study was the evaluation of the bioavailability of vitamin D from a fortified Greek-type bread that was developed as a means for addressing vitamin D deficiency, by comparing the absorption curve of vitamin D in fortified bread in relation to that of plain vitamin supplementation. Two groups of clinically healthy volunteers consumed 25,000 international units (IU) of vitamin D3 (cholecalciferol) either in fortified bread (Group A) or in a plain supplement form (Group B). The baseline plasma concentrations of cholecalciferol were 8.1 ± 6.0 ng/mL and 6.8 ± 3.4 ng/mL in Groups A and B, respectively. After 12, 24, and 48 h, the concentrations of cholecalciferol in Group A were 16.7 ± 4.8, 15.3 ± 8.3 and 11.9 ± 6.0 ng/mL, respectively, and in Group B, 15.2 ± 3.3, 11.6 ± 2.4, and 9.6 ± 3.6 ng/mL, respectively. In both groups, the concentrations of cholecalciferol at 12 and 24 h were significantly higher than the baseline concentrations (p < 0.01). There were no statistically significant differences between the concentrations of cholecalciferol between Groups A and B, at each time point.Cholecalciferol is bioavailable from Greek-type fortified bread and bread could be used for addressing vitamin D deficiency.


ATP Hydrolysis Coordinates the Activities of Two Motors in a Dimeric Chromatin Remodeling Enzyme.
ATP-dependent chromatin remodelers are essential enzymes that restructure eukaryotic genomes to enable all DNA-based processes. The diversity and complexity of these processes arethe complexity of the enzymes that carry them out, making remodelers a challenging class of molecular motors to study by conventional methods. Here we use a single molecule biophysical assay to overcome some of these challenges, enabling a detailed mechanistic dissection of a paradigmatic remodeler reaction, that of sliding a nucleosome towards the longer DNA linker. We focus on how two motors of a dimeric remodeler coordinate to accomplish such directional sliding. We find that ATP hydrolysis by both motors promotes coordination, suggesting a role for ATP in resolving the competition for directional commitment. Furthermore, we show an artificially constitutive dimer is no more or less coordinated, but is more processive, suggesting a cell could modulate a remodeler's oligomeric state to modulate local chromatin dynamics.


AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo.
Vitiligo is an acquired depigmentation disorder largely caused by defective melanocyte- or autoimmunity-induced melanocyte destruction. The aryl hydrocarbon receptor (AHR) is essential for melanocyte homeostasis and immune process, and abnormal AHR was observed in vitiligo. We previously identified the T allele of AHR -129C > T variant as a protective factor against vitiligo. However, biological characterization underlying such effects is not fully certain, further validation by mechanistic research is warranted and was conducted in the present study. We showed that -129T allele promoted AHR transcriptional activity through facilitating its interaction with SP1 transcription factor (SP1) compared with -129C allele. We subsequently found reduced peripheral AHR and SP1 transcript expressions in vitiligo and a negative correlation of AHR level with disease duration. We also investigated AHR-related cytokines and observed increased serum TNF-α concentration and diminished serum levels of IL-10 and TGF-β1 in vitiligo. Further genetic analysis showed that -129T carriers possessed higher levels of AHR and IL-10 than -129C carriers. Therefore, our study indicates that the modulation of AHR transcription by a promoter variant has a profound influence on vitiligo, not only advancing our understanding on AHR function but also providing novel insight into the pathogenesis of degenerative or autoimmune diseases including vitiligo.


Comparing glucose and hemoglobin A1c diagnostic tests among a high metabolic risk Hispanic population.
Compare glycated hemoglobin (HbA1c ) diagnostic tests for prediabetes and diabetes with plasma glucose criteria and compare the metabolic profiles of people classified by HbA1c versus by glucose levels. Participants were recruited for the San Juan Overweight Adults Longitudinal Study. The participants were primarily Hispanic (98%), without previously diagnosed diabetes, and aged 40 to 65 years. Participants classified as normal glycemic, prediabetes, or diabetes on the basis of baseline HbA1c and plasma glucose criteria were compared with respect to baseline cardiometabolic factors. The 1342 participants had a mean age of 50.5 ± 6.8 years and 28% were men. Thirty-one percent were diagnosed with prediabetes by plasma glucose criteria and 53.4% by HbA1c , and 8.1% were diagnosed with diabetes by plasma glucose criteria and 6.3% by HbA1c ; overall concordance rate was 55.1%. The area under the receiver operating characteristic curve of HbA1c compared to plasma glucose criteria was 0.62 for impaired glucose and 0.76 for diabetes. A worse cardiometabolic profile was seen within subgroups that met HbA1c and plasma glucose criteria for diabetes or prediabetes. Those diagnosed with prediabetes by plasma glucose criteria had significantly higher systolic blood pressure and higher homeostatic model assessment than those diagnosed using HbA1c . Participants diagnosed with diabetes by plasma glucose criteria had lower body mass index, smaller waist circumference, and lower insulinogenic and disposition indices, but higher homeostatic model assessment of insulin resistance, than those diagnosed by HbA1c . Low concordance was seen between HbA1c and glucose measurements. The HbA1c is not a good test for prediabetes but shows reasonable validity for diabetes in this high-risk predominantly female Hispanic population. People classified by HbA1c , plasma glucose criteria, or both show different metabolic profiles; a combined test may be ideal.


Bioinspired mineralization of engineered living materials to promote osteogenic differentiation.
In this work, Engineered Living Materials (ELMs), based on the combination of genetically-modified bacteria and mineral-reinforced organic matrices, and endowed with self-healing or regenerative properties and adaptation to specific biological environments were developed. Concretely, we produced ELMs combining human mesenchymal stem cells (hMSCs) and Lactococcus lactis (L. lactis), which was specifically programmed to deliver bone morphogenetic protein (BMP-2) upon external stimulation using nisin, into mineralized alginate matrices. The hybrid organic/inorganic matrix was built through a protocol, inspired by bone mineralization, in which alginate (Alg) assembly and apatite (HA) mineralization occurred simultaneously driven by calcium ions. Chemical composition, structure and reologhical properties of the hybrid 3D matrices were dedicately optimized prior the incorportation of the living entities. Then, the same protocol was reproduced in the presence of hMSC and engineered L. lactis that secrete BMP-2 resulting in 3D hybrid living hydrogels. hMSC viability and osteogenic differentiation in the absence and presence of the bacteria were evaluated by live/dead and quantitative real-time polymerase chain reaction (qPCR) and immunofluorescence assays, respectively. Results demonstrate that these 3D engineered living material support osteogenic differentiation of hMSCs due to the synergistic effect between HA and the growth factors BMP-2 delivered by L. lactis.


Radioactive iodine therapy in poorly differentiated thyroid cancer.
A 55-year-old male was diagnosed with poorly differentiated thyroid cancer after total thyroidectomy, which was performed because of progressive enlargement of a dominant thyroid nodule. He developed an early cervical recurrence that was treated with modified neck dissection. He subsequently developed biopsy-proven progressive pulmonary metastases. Neck and chest CT scans, laboratory tests, CT-guided fine-needle aspiration biopsy, [18F]-2-fluoro-2-deoxy-D-glucose-PET scan, lesional dosimetry using 124I PET scan, diagnostic radioactive iodine (RAI) scanning, whole-body and blood RAI dosimetry, and single-photon-emission CT. Stage IV poorly differentiated thyroid cancer. Surgical resection of cervical recurrence, RAI therapy.


The effects of tertiapin-Q on responses of the sinoatrial pacemaker of the guinea-pig heart to vagal nerve stimulation and muscarinic agonists.
Using Langendorff preparations of the guinea-pig heart, we have examined the participation of the acetylcholine (ACh)-activated potassium channel, IK,ACh, in the bradycardia produced by electrical stimulation of the vagus (parasympathetic) nerve and muscarinic agonists (ACh and bethanecol, bolus i.a.). Hearts from young animals (160-250 g) were perfused with Krebs-Henseleit solution, and pacemaker frequency was determined from the P wave of an ECG. Tertiapin-Q was used to block IK,ACh. Vagal stimulation (10 s trains at 2, 5 and 10 Hz) produced graded reductions in atrial rate that were substantially attenuated, and to a similar extent, by 300 nm and 1 microm tertiapin-Q (to 0.42 +/- 0.12, mean +/- s.d., of the control values; P < 0.001). Acetylcholine (3 nmol) produced brief graded bradycardias that were also attenuated by tertiapin-Q (0.24 +/- 0.24; P = 0.006). Similar results were obtained when experiments were repeated in 2 mm Cs+ (to block the hyperpolarization-activated pacemaker current). Bethanecol (30, 50 and 70 nmol), a muscarinic agonist with no appreciable nicotinic activity, produced sustained bradycardias that were attenuated by 300 nm tertiapin-Q (0.36 +/- 0.21; P < 0.0001). The responses to vagal stimulation and ACh developed more slowly in tertiapin-Q, indicating that a rapidly acting mechanism had been blocked. Responses to vagal stimulation were faster in 2 mm Cs+. Together, these observations show that ACh released from parasympathetic nerve varicosities exerts a considerable part of its effect on the pacemaker by activating IK,ACh and acts in a manner not readily distinguishable from that of directly applied muscarinic agonists.


Antigenic and structural characteristics of an immunoglobulin-related peptide purified from marmoset T-lymphoma cells.
A 7800 Mr peptide, apparently derived from a 70,000 Mr immunoglobulin-related protein synthesized by a marmoset T-lymphoma cell line, bears immunoglobulin-related determinants apparently contained in a disulfide-bonded loop comparable to that of the VH fragment of classical H chain. A membrane-enriched, crude particulate fraction was prepared from marmoset T-lymphoma cells, and peptides generated by papain digestion of the particulate fraction were selectively purified by affinity chromatography using IgG purified from serum of a goat immunized with the Fab fragment of a human Waldenstrom macroglobulin. The smallest of the affinity-purified peptides was particularly reactive with unfractionated goat anti Fab (G alpha Fab) serum, purified IgG from G alpha Fab serum, and with antibodies affinity purified from G alpha Fab serum using Waldenstrom macroglobulins. Partial specificity of G alpha Fab antibodies was determined by competition radioimmunoassay and radioimmunoprecipitation assays. High-performance reverse-phase liquid chromatography was used for final purification of the smallest peptide which retained its reactivity with G alpha Fab serum and affinity-purified G alpha Fab antibodies. The apparent molecular weight of the peptide, determined by gel filtration in 6 M guanidine, was estimated at 3900 in its native state but increased to 7800 after reduction and alkylation, indicating a role for a disulfide bond in the tertiary structure of the peptide. The amino acid composition of the peptide was presented, and its possible relationship to immunoglobulin-like T-cell surface proteins was discussed.


Mycobacterium tuberculosis bacteremia in adults and children: a systematic review and meta-analysis.
SETTINGp: Among human immunodeficiency virus (HIV) infected adults living in tuberculosis (TB) endemic settings, Mycobacterium tuberculosis is a common cause of bloodstream infections. Although young children have an increased propensity for M. tuberculosis dissemination, M. tuberculosis bacteremia is infrequently described in children. To determine the prevalence of M. tuberculosis bacteremia in adult and pediatric patients and to examine sources of heterogeneity between estimates. Systematic review and meta-analysis. Of 1077 reviewed abstracts, 27 publications met the inclusion criteria, yielding 29 independent M. tuberculosis bacteremia prevalence estimates: 22 in adults, 6 in children, and 1 not stratified by age group. The random effects pooled M. tuberculosis bacteremia prevalence in adults was 13.5% (95%CI 10.8-16.2) and 0.4% (95%CI 0-0.9) in children (P for difference = 0.004). Restricting analyses to HIV-infected participants, pooled M. tuberculosis bacteremia prevalence from 21 adult studies was 15.5% (95%CI 12.5-18.5) and 0.8% (95%CI 0-1.8) in three pediatric studies (P = 0.001). Inclusion of pre-determined study-level confounders did not account for observed differences in M. tuberculosis bacteremia prevalence between age groups. While M. tuberculosis bacteremia appears relatively common in adults, particularly those with HIV infection, bloodstream M. tuberculosis appears to be rare in children.


[Response of ovarian steroid secretion to the intrinsic gonadotropin release caused by the administration of a synthetic luteinizing hormone-releasing hormone--the difference between the follicular and luteal phases].
During gynecologic laparotomy both ovarian and peripheral venous blood specimens were collected simultaneously, and follicle-stimulating hormone (FSH), luteinizing hormone (LH), pregnenolone (P5), 17 alpha-hydroxypregnenolone (17 alpha-OH-P5), dehydroepiandrosterone (DHA), progesterone (P4), 17 alpha-hydroxyprogesterone (17 alpha-OH-P4), delta 4-androstenedione (delta 4-A), estradiol (E2) and 20 alpha-dihydroprogesterone (20 alpha-OH-P4) were measured in each sample by means of the radioimmunoassay technique before and after the administration of synthetic LH-releasing hormone (LH-RH). Significantly higher concentrations of P5, 17 alpha-OH-P4 and E2 during the follicular phase and that of P5, DHA, P4, 17 alpha-OH-P4 and E2 during luteal phase were observed in the ovarian than in the peripheral venous blood. During the follicular phase, P5, DHA and E2 concentrations in ovarian vein blood increased significantly following LH-RH administration. It was observed that the delta 4-steroids and E2 concentrations during the luteal phase were higher than those during the follicular phase. During the luteal phase P4, 17 alpha-OH-P4, and E2 increased after LH-RH administration. Enzymes involved in the formation of these steroids may be stimulated by the intrinsic gonadotropin caused by LH-RH administration. The difference in steroidal profiles in ovarian vein blood and response to LH-RH in follicular and luteal phase were demonstrated.


Long term follow up of the cruciate fascial sling for women with genuine stress incontinence.
To determine the long term success of the cruciate fascial sling procedure for the treatment of genuine stress incontinence in women. In 1998, a pre-validated questionnaire was sent to all women who had a cruciate fascial sling between 1979 and 1996 under the care of the senior author at a District General Hospital and in private practice. Questionnaires were sent to 246 women; 198 (80%) were returned. Overall, 142 women felt that they were much improved or cured. The success rate was 74% (95% CI 70%-81%) in women having the sling as a primary procedure and 67% (95% CI 54%-81%) in women having the sling as a secondary procedure. There was no relationship between symptom severity score and age at time surgery, duration of follow up, current weight or body mass index, previous surgery for stress incontinence or concomitant surgery. Of the 103 women with six or more years of follow up, 29 felt that their operation had failed, 16 of whom thought that it lasted between five and 10 years. Urgency was experienced by 29% of women, three needed to perform intermittent self-catheterisation, and 9% found it difficult to empty their bladder. Thirty-seven women (19%) experienced problems that they attributed to the abdominal wound. Although inevitably there are some failures over time, the cruciate fascial sling has good long term success rates. Direct comparison with the literature is impossible, as few studies have relied on properly validated questionnaires.


Antidepressant response and intolerance to SSRI is not influenced by G-protein beta3 subunit gene C825T polymorphism in Japanese major depressive patients.
The G-protein beta3 subunit (GNB3) gene is a key modulator of signal transduction and is a major candidate for SSRIs response. The aim of the present study is to test a possible effect of the C825T polymorphism on the antidepressant response and intolerance to selective serotonin reuptake inhibitors (SSRIs) in 146 Japanese samples with major depression treated with paroxetine or fluvoxamine for 6 weeks. The severity of depression symptom was assessed using the 21-item Hamilton Rating Scale for Depression (HAM-D) and adverse drug reactions were evaluated bi-weekly. No association with SSRIs treatment response was observed in 107 completers also including HAM-D baseline scores, SSRI type or/and 5-HTTLPR variants in the model as covariates. Furthermore, no significant association could be observed with intolerance to SSRIs in the whole subjects. The result suggests that C825T variants of GNB3 cannot play a major role as a predictor of treatment response as well as intolerance to SSRIs in Japanese patients with major depression.


Falls and Fear of Falling After Stroke: A Case-Control Study.
Falls are common after stroke, with potentially serious consequences. Few investigations have included age-matched control participants to directly compare fall characteristics between older adults with and without stroke. Further, fear of falling, a significant psychological consequence of falls, has only been examined to a limited degree as a risk factor for future falls in a stroke population. To compare the fall history between older adults with and without a previous stroke and to identify the determinants of falls and fear of falling in older stroke survivors. Case-control observational study. Primary teaching hospital. Seventy-five patients with stroke (mean age ± standard deviation, 66 ± 7 years) and 50 age-matched control participants with no previous stroke were tested. Fall history, fear of falling, and physical, cognitive, and psychological function were assessed. A χ2 test was performed to compare characteristics between groups, and logistic regression was performed to determine the risk factors for falls and fear of falling. Fall events in the past 12 months, Fall Efficacy Scale-International, Berg Balance Scale, Functional Ambulation Category, Fatigue Severity Scale, Montreal Cognitive Assessment, and Patient Healthy Questionnaire-9 were measured for all participants. Fugl-Meyer Motor Assessment was used to quantify severity of stroke motor impairments. Twenty-three patients and 13 control participants reported at least one fall in the past 12 months (P = .58). Nine participants with stroke had recurrent falls (≥2 falls) compared with none of the control participants (P < .01). Participants with stroke reported greater concern for falling than did nonstroke control participants (P < .01). Female gender was associated with falls in the nonstroke group, whereas falls in the stroke group were not significantly associated with any measured outcomes. Fear of falling in the stroke group was associated with functional ambulation level and balance. Functional ambulation level alone explained 22% of variance in fear of falling in the stroke group. Compared with persons without a stroke, patients with stroke were significantly more likely to experience recurrent falls and fear of falling. Falls in patients with stroke were not explained by any of the outcome measures used, whereas fear of falling was predicted by functional ambulation level. This study has identified potentially modifiable risk factors with which to devise future prevention strategies for falls in patients with stroke. III.


Stable expression of silencing-suppressor protein enhances the performance and longevity of an engineered metabolic pathway.
Transgenic engineering of plants is important in both basic and applied research. However, the expression of a transgene can dwindle over time as the plant's small (s)RNA-guided silencing pathways shut it down. The silencing pathways have evolved as antiviral defence mechanisms, and viruses have co-evolved viral silencing-suppressor proteins (VSPs) to block them. Therefore, VSPs have been routinely used alongside desired transgene constructs to enhance their expression in transient assays. However, constitutive, stable expression of a VSP in a plant usually causes pronounced developmental abnormalities, as their actions interfere with endogenous microRNA-regulated processes, and has largely precluded the use of VSPs as an aid to stable transgene expression. In an attempt to avoid the deleterious effects but obtain the enhancing effect, a number of different VSPs were expressed exclusively in the seeds of Arabidopsis thaliana alongside a three-step transgenic pathway for the synthesis of arachidonic acid (AA), an ω-6 long chain polyunsaturated fatty acid. Results from independent transgenic events, maintained for four generations, showed that the VSP-AA-transformed plants were developmentally normal, apart from minor phenotypes at the cotyledon stage, and could produce 40% more AA than plants transformed with the AA transgene cassette alone. Intriguingly, a geminivirus VSP, V2, was constitutively expressed without causing developmental defects, as it acts on the siRNA amplification step that is not part of the miRNA pathway, and gave strong transgene enhancement. These results demonstrate that VSP expression can be used to protect and enhance stable transgene performance and has significant biotechnological application.


Bioprospecting of indigenous biosurfactant-producing oleophilic bacteria for green remediation: an eco-sustainable approach for the management of petroleum contaminated soil.
In the present study, the efficiency of four different strains of Pseudomonas aeruginosa and their biosurfactants in the bioremediation process were investigated. The strains were found to be capable of metabolizing a wide range of hydrocarbons (HCs) with preference for high molecular weight aliphatic (ALP) over aromatic (ARO) compounds. After treating with individual bacteria and 11 different consortia, the residual crude oils were quantified and qualitatively analyzed. The bacterial strains degraded ALP, ARO, and nitrogen, sulphur, oxygen (NSO) containing fractions of the crude oil by 73-67.5, 31.8-12.3 and 14.7-7.3%, respectively. Additionally, the viscosity of the residual crude oil reduced from 48.7 to 34.6-39 mPa s. Further, consortium designated as 7 and 11 improved the degradation of ALP, ARO, and NSO HCs portions by 80.4-78.6, 42.7-42.4 and 21.6-19.2%, respectively. Moreover, addition of biosurfactant further increased the degradation performance of consortia by 81.6-80.7, 43.8-42.6 and 22.5-20.7%, respectively. Gas chromatographic analysis confirmed the ability of the individual strains and their consortium to degrade various fractions of crude oil. Experiments with biosurfactants revealed that polyaromatic hydrocarbons (PAHs) are more soluble in the presence of biosurfactants. Phenanthrene had the highest solubility among the tested PAHs, which further increased as biosurfactant doses raised above their respective critical micelle concentrations (CMC). Furthermore, biosurfactants were able to recover 73.5-63.4% of residual oil from the sludge within their respective CMCs. Hence, selected surfactant-producing bacteria and their consortium could be useful in developing a greener and eco-sustainable way for removing crude oil pollutants from soil.


Recovery of high purity sulfuric acid from the waste acid in toluene nitration process by rectification.
Waste sulfuric acid is a byproduct generated from numerous industrial chemical processes. It is essential to remove the impurities and recover the sulfuric acid from the waste acid. In this study the rectification method was introduced to recover high purity sulfuric acid from the waste acid generated in toluene nitration process by using rectification column. The waste acid quality before and after rectification were evaluated using UV-Vis spectroscopy, GC/MS, HPLC and other physical and chemical analysis. It was shown that five nitro aromatic compounds in the waste acid were substantially removed and high purity sulfuric acid was also recovered in the rectification process at the same time. The COD was removed by 94% and the chrominance was reduced from 1000° to 1°. The recovered sulfuric acid with the concentration reaching 98.2 wt% had a comparable quality with commercial sulfuric acid and could be recycled back into the toluene nitration process, which could avoid waste of resources and reduce the environmental impact and pollution.


Shrimp carotenoids protect the developing rat cerebral cortex against the effects of ethanol on cortical spreading depression.
Cortical spreading depression is a neural phenomenon present in several animal species. Spreading depression features, like velocity of propagation, depends on several chemical and metabolic factors, as for example, anti-oxidants. Here we studied spreading depression-velocity changes in weaned rat-pups born from dams treated on a daily basis, either during gestation or lactation, with a carotenoid ethanolic extract (30 microg/kg/day) prepared from shrimp waste (heads). These pups were compared with age-mated ones, whose mothers were treated either with the vehicle (ethanol) or with distilled water. Compared to the distilled water-group (mean values, in mm/min, per hour of recording ranging from 3.02+/-0.26 to 3.15+/-0.27 [treatment during gestation; n=7], and from 3.03+/-0.25 to 3.22+/-0.30 [lactation; n=11]), ethanol-treated rats displayed higher spreading depression-velocities (from 3.74+/-0.06 to 3.82+/-0.08 [gestation; n=7], and from 4.26+/-0.32 to 4.33+/-0.34 [lactation; n=11]; p<0.05). Compared to the ethanol-group, carotenoid-treatment lead to lower spreading depression-velocities (p<0.05), ranging from 3.38+/-0.09 to 3.42+/-0.12, n=7 (gestation) and 3.58+/-0.13 to 3.62+/-0.17, n=12 (lactation). Carotenoid-treatment during lactation was shown to be significantly more effective than that during gestation (p<0.05), in lowering spreading depression-velocity. The results suggest a protective action of shrimp carotenoids against the ethanol effects on spreading depression. This protective effect could be related to the carotenoid antioxidant properties, as previously indicated by evidence showing spreading depression-effects of other antioxidants.


Prevention of rat fissure caries by sodium fluoride varnish (Duraphat) with different fluoride concentrations.
125 Osborne-Mendel rats were weaned at 22-23 days, inoculated with Streptococcus sobrinus and fed a cariogenic diet for 40 days. The control group received no treatment; the study groups received applications of Duraphat containing 2.3, 1.1, or 0.6% fluoride or a placebo varnish on days 21-23. The placebo varnish had no effect on caries. Fissure caries was significantly reduced by the 2.3 and 1.1% fluoride varnishes, whereas the caries reduction found after treatment with the 0.6% fluoride varnish was not statistically significant. These results suggest that reducing the fluoride content of Duraphat by half does not significantly reduce its caries-preventive effect, but the progress of caries seems to be somewhat slower with the 2.3% fluoride varnish.


Bioselective detection in liquid chromatography by the use of immobilized enzymes.
The combination of liquid chromatography and immobilized enzyme reactors (LC/IMER) is a rapidly developing field of research. The enzymes are used to catalyse chemical reactions and thereby facilitate selective detection. In this instance the chemical derivatizations are performed in the post-column mode. The selectivity is demonstrated with respect to interfering compounds present in complex samples.


Prevalence and risk factors for IgG antibodies to Neospora spp. in three types of equids from Southern Punjab, Pakistan.
Equine hosts suffer from neurological disease, congenital infection, and reproductive problems associated with Neospora spp. infection. We conducted a cross sectional study using sera from 631 equids (324 horses, 218 donkeys and 89 mules) from the southern region of Punjab province, Pakistan to determine the prevalence of antibodies against Neospora spp. in this diverse group of equines. Fisk factors associated with seropositivity were evaluated statistically based on equine type, breed, age, husbandry, breeding methods, and reproductive history. Prevalence of antibodies to Neospora spp. was detected using a commercially available competitive ELISA kit. We detected IgG antibodies to Neospora spp. in 23.3% of the equids with prevalence by host being 16.0% in horses, 32.6% in donkeys and 26.9% in 89 mules. Statistically significant (P < 0.05) differences in prevalence were observed among these hosts. Prevalence ranged in breeds of horses from 3.7% in the Morna breed, 12.4% in breeding stock, 26.8% in draughting stock, to 31.4% in unknown breeds. No significant (P > 0.05) difference in prevalence was noted among age groups. Prevalence was significantly (P < 0.05) higher in female equines with a history of abortion than those with no history of abortion. This is the first report documenting Neospora spp. in equines from Pakistan and it provides evidence that Neospora spp. is associated with abortions in female equines in Pakistan.


Genomic comparison of Rickettsia helvetica and other Rickettsia species.
We report the complete and annotated genome sequence of Rickettsia helvetica strain C9P9, which was first isolated in 1979 from Ixodes ricinus ticks in Switzerland and is considered a human pathogen.


Neuroanatomical and neurochemical organization of projections from the central amygdaloid nucleus to the nucleus retroambiguus via the periaqueductal gray in the rat.
The periaqueductal gray (PAG)-nucleus retroambiguus (NRA) pathway has been known to be involved in the control of vocalization and sexual behavior. To know how the amygdaloid complex influences the PAG-NRA pathway, here we first examined the synaptic organization between the central amygdaloid nucleus (CeA) fibers and the PAG neurons that project to the NRA by using anterograde and retrograde tract-tracing techniques in the rat. After ipsilateral injections of biotinylated dextran amine (BDA) into the CeA and cholera toxin B subunit (CTb) into the NRA, the prominent overlapping distribution of BDA-labeled axon terminals and CTb-labeled neurons was found ipsilaterally in the lateral/ventrolateral PAG, where some of the BDA-labeled terminals made symmetrical synaptic contacts with somata and dendrites of the CTb-labeled neurons. After CTb injection into the lateral/ventrolateral PAG, CTb-labeled neurons were distributed mainly in the medial division of the CeA. After BDA injection into the lateral/ventrolateral PAG, BDA-labeled fibers were distributed mainly in and around the NRA within the medulla oblongata. Using a combined retrograde tracing and in situ hybridization technique, we further demonstrated that more than half of the CeA neurons labeled with Fluoro-Gold (FG) injected into the lateral/ventrolateral PAG were positive for glutamic acid decarboxylase 67 mRNA and that the vast majority of PAG neurons labeled with FG injected into the NRA expressed vesicular glutamate transporter 2 mRNA. The present results suggest that the glutamatergic PAG-NRA pathway is under the inhibitory influence of the GABAergic CeA neurons.


Study of the repercussions on blood of acute experimental inflammation in rats. I. Systemic effects induced by generalised inflammation with dextran.
Systemic effects resulting from dextran induced general inflammation in rats were studied. The phlogogenic agent was i.p. or i.v. injected. Dextran led to an increase in hematocrit values and erythrocyte counts. A decrease in blood total proteins, fibrinogen and sedimentation rate was observed, too. ADP mediated platelet aggregation was also decreased.


Intrapulmonary cystic lymphangioma: report of a case.
We describe herein the case of a 52-year-old man found to have a solitary pulmonary lymphangioma. Computed tomography (CT) scan demonstrated a nodule with homogeneous density and a well-defined border in the lower lobe of the right lung. T2-Weighted magnetic resonance imaging (MRI) revealed a nodule with homogeneously high signal intensity. The tumor was removed by partial resection, and pathologic examination confirmed a diagnosis of primary lymphangioma of the lung.


Modification of an arginine residue essential for the activity of NAD-malic enzyme from Ascaris suum.
Purified NAD-malic enzyme from Ascaris suum is rapidly inactivated by the arginine reagent, 2,3-butanedione, and this inactivation is facilitated by 30 mM borate. Determination of the inactivation rate as a function of butanedione concentration suggests a second-order process overall, which is first order in butanedione. A second-order rate constant of 0.6 M-1 s-1 at pH 9 is obtained for the butanedione reaction. The inactivation is reversed by removal of the excess reagent upon dialysis. The enzyme is protected against inactivation by saturating amounts of malate in the presence and absence of borate. The divalent metal Mg2+ affords protection in the presence of borate but has no effect in its absence. The nucleotide reactant NAD+ has no effect on the inactivation rate in either the presence or absence of borate. A dissociation constant of 24 mM is obtained for E:malate from the decrease in the inactivation rate as a function of malate concentration. An apparent Ki of 0.5 mM is obtained for oxalate (an inhibitor competitive vs malate) from E:Mg:oxalate while no significant binding is observed for oxalate using the butanedione modified enzyme. The pH dependence of the first-order rate of inactivation by butanedione gives a pKa of 9.4 +/- 0.1 for the residue(s) modified, and this pK is increased when NAD is bound. The arginine(s) modified is implicated in the binding of malate.


Synthetic analogs of growth hormone-releasing factor with antagonistic activity in vitro.
Analogs of human and rat growth hormone-releasing factor (hGRF and rGRF), related to [D-Arg2]hGRF(1-29)NH2, were synthesized by solid phase methodology. Their capacity to inhibit growth hormone secretion stimulated by hGRF(1-44)NH2 was tested on rat anterior pituitary cells in monolayer culture. Among the analogs of hGRF, [D-Arg2,29,Arg30]hGRF(1-30)NH2 showed the highest antagonistic potency of 3.64 relative to [D-Arg2]hGRF(1-29)NH2 = 1. However, the most potent analog synthesized thus far was [N-Ac-His1,D-Arg2,Ala15]rGRF(1-29)NH2, which showed a relative potency of 27.7.


The effects of methadone maintenance with opioid takers. A review and some findings from one British city.
Various benefits claimed for methadone maintenance in the treatment of opioid drug takers are reviewed. It is said to stop illicit drug use, maintain treatment contact, reduce morbidity, mortality and crime, and improve social adjustment. Little firm evidence is found to support these claims. Results are reported comparing 26 drug takers on methadone prescriptions with 16 illicit opioid takers. The measures used are Stimson's (1972) 'Patterns of Behaviour' questionnaire and direct behavioural measures of social functioning. The groups are found not to differ in terms of treatment contact, work status and involvement with other drug takers. There is some evidence that the methadone group is involved in less criminal activity. However, no association is found between amounts of drugs prescribed and numbers of local pharmacy thefts. It is concluded that the benefits of methadone maintenance have been exaggerated.


MRS algorithm: a new method for searching myocardial region in SPECT myocardial perfusion images.
First, the necessity of automatically segmenting myocardium from myocardial SPECT image is discussed in Section 1. To eliminate the influence of the background, the optimal threshold segmentation method modified for the MRS algorithm is explained in Section 2. Then, the image erosion structure is applied to identify the myocardium region and the liver region. The contour tracing method is introduced to extract the myocardial contour. To locate the centriod of the myocardium, the myocardial centriod searching method is developed. The protocol of the MRS algorithm is summarized in Section 6. The performance of the MRS algorithm is investigated and the conclusion is drawn in Section 7. Finally, the importance of the MRS algorithm and the improvement of the MRS algorithm are discussed.


Linear polymers of β and γ cyclodextrins with a polyglutamic acid backbone as carriers for doxorubicin.
Cyclodextrins have been used to encapsulate drugs improving their stability and efficiently regulating their release. Polymeric nanoparticles containing cyclodextrins are currently undergoing clinical trials as nanotherapeutics. In this context, we have synthesized new linear polymers based on polyglutamic acid with pendant β- or γ-cyclodextrins, using a high yield reaction route. The new polymers with an average number of about 17 cyclodextrin cavities were characterized (NMR, MALDI-MS, DLS) and tested as carriers of doxorubicin in human tumor cells. They can include doxorubicin, and the inclusion complexes show antiproliferative activity in human tumor cells.


[Analysis of influencing factors for curative effect of maxillofacial fractures].
To explore the influencing factors for curative effect of maxillofacial fractures. Retrospective analysis of the 86 patients for maxillofacial fractures from Jan. 2008 to Dec. 2010 in our hospital, to observe data, sex, type, reason, associated injury, methods of treatment, and so on. The success rate of curing was 95.35%. The length of stay for the 86 patients was from 7 days to 28 days, average 16. 8 days. The type, reason, associated injury, methods of treatment were the influencing factors for curative effect of for maxillofacial fracture. The success rate of curing for different ways of operation were different. Recovery rate of operation was 6.097%, it of expectant treatment was 75%, they were statistical different significantly (P < 0.05). The type, reason, associated injury, methods of treatment were the influencing factors for curative effect of for maxillofacial fracture.


For my wellness, not just my illness: North Americans' use of dietary supplements.
Passage of the DSHEA in 1994 created a new "liminal" category for the FDA: dietary supplements are regulated as neither food nor drugs. However, there appears to be a significant disconnect between the "official" discourse surrounding dietary supplements and supplement users' actual practices. Despite this discrepancy, and the inadequacy of surveys to capture the dynamics of pharmaceutical practice, there is little ethnographic information available on the ways that Americans think about or use dietary supplements. We offer some preliminary observations from a pilot ethnographic study of Americans' use of dietary supplements in which we consider not only the reasons why people are using supplements, but how they are using them, and how their experimentation has been influenced by the information they seek and receive from a variety of sources. We illustrate how anthropological studies of supplement related practice can help us better understand Americans' attraction to and use of dietary supplements, and suggest that anthropology can contribute to a more balanced perspective on supplement use-one that moves the study of supplements beyond surveys and randomized controlled studies of efficacy to considerations of patterns of use in context, user expectations, and measures of perceived effectiveness.


Prediction of Local Tumor Progression After Microwave Ablation in Colorectal Carcinoma Liver Metastases Patients by MRI Radiomics and Clinical Characteristics-Based Combined Model: Preliminary Results.
To investigate the predictability of local tumor progression (LTP) after microwave ablation (MWA) in colorectal carcinoma liver metastases (CRLM) patients by magnetic resonance imaging (MRI) radiomics and clinical characteristics-based combined model. Forty-two consecutive CRLM patients (67 tumors) with post-MWA complete response at 1st month MRI were included in this retrospective study. One hundred and eleven radiomics features were extracted for each tumor and for each phase by manual segmentation from pre-treatment MRI T2 fat-suppressed (Phase 2) and early arterial phase T1 fat-suppressed sequences (Phase 1). A clinical model was constructed using clinical data, two combined models were created with feature reduction and machine learning by combining clinical data and Phase 2 and Phase 1 radiomics features. The predicting performance for LTP development was investigated. LTP developed in 7 patients (16.6%) and 11 tumors (16.4%). In the clinical model, the presence of extrahepatic metastases before MWA was associated with a high probability of LTP (p < 0.001). The pre-treatment levels of carbohydrate antigen 19-9 and carcinoembryonic antigen were higher in the LTP group (p = 0.010, p = 0.020, respectively). Patients with LTP had statistically significantly higher radiomics scores in both phases (p < 0.001 for Phase 2 and p = 0.001 for Phase 1). The classification performance of the combined model 2, created by using clinical data and Phase 2-based radiomics features, achieved the highest discriminative performance in predicting LTP (p = 0,014; the area under curve (AUC) value 0.981 (95% CI 0.948-0.990). The combined model 1, created using clinical data and Phase 1-based radiomics features (AUC value 0,927 (95% CI 0.860-0.993, p < 0.001)) and the clinical model alone [AUC value of 0.887 (95% CI 0.807-0.967, p < 0.001)] had similar performance. Combined models based on clinical data and radiomics features obtained from T2 fat-suppressed and early arterial-phase T1 fat-suppressed MRI are valuable markers in predicting LTP after MWA in CRLM patients. Large-scale studies with internal and external validations are needed to come to a firm conclusion on the predictability of radiomics models in CRLM patients.


Enantioselective Total Synthesis of 3β-Hydroxy-7β-kemp-8(9)-en-6-one, a Diterpene Isolated from Higher Termites.
The first total synthesis of the title diterpene was accomplished starting from the Wieland-Miescher ketone. A diastereoselective sulfa-Michael addition enabled the generation of the delicate β,γ-unsaturated ketone moiety, while the tetracyclic kempane skeleton was readily constructed through domino metathesis.


Molecular evidence of Rickettsia spp. in ixodid ticks and rodents in suburban, natural and rural habitats in Slovakia.
Natural foci of tick-borne spotted fever group (SFG) rickettsiae of public health concern have been found in Slovakia, but the role of rodents in their circulation is unclear. Ticks (Ixodes ricinus, Ixodes trianguliceps, Dermacentor marginatus, Dermacentor reticulatus, Haemaphysalis concinna and Haemaphysalis inermis) and tissues of rodents (Apodemus flavicollis, Apodemus sylvaticus, Myodes glareolus, Microtus arvalis, Microtus subterraneus and Micromys minutus) were examined for the presence of SFG rickettsiae and Coxiella burnetii by molecular methods. Suburban, natural and rural habitats were monitored to acquire information on the role of ticks and rodents in the agents' maintenance in various habitat types of Slovakia. The overall prevalence of rickettsial infection in questing I. ricinus and D. marginatus was 6.6% and 21.4%, respectively. Rickettsia helvetica, R. monacensis and non-identified rickettsial species were detected in I. ricinus, whereas R. slovaca and R. raoultii were identified in D. marginatus. Rickettsia spp.-infected I. ricinus occurred during the whole tick questing period. Rickettsia helvetica dominated (80.5%) followed by R. monacensis (6.5%). The species were present in all studied habitats. Rickettsia slovaca (66.7%) and R. raoultii (33.3%) were identified in D. marginatus from the rural habitat. Apodemus flavicollis was the most infested rodent species with I. ricinus, but My. glareolus carried the highest proportion of Rickettsia-positive I. ricinus larvae. Only 0.5% of rodents (A. flavicollis) and 5.2% of engorged I. ricinus removed from My. glareolus, A. flavicollis and M. arvalis were R. helvetica- and R. monacensis-positive. Coxiella burnetii was not detected in any of the tested samples. We hypothesize that rodents could play a role as carriers of infected ticks and contribute to the maintenance of rickettsial pathogens in natural foci. Long-term presence of SFG Rickettsia spp. was confirmed in questing ticks from different habitat types of Slovakia. The results suggest a human risk for infection with the pathogenic R. helvetica, R. monacensis, R. slovaca and R. raoultii.


HFrEF subphenotypes based on 4210 repeatedly measured circulating proteins are driven by different biological mechanisms.
HFrEF is a heterogenous condition with high mortality. We used serial assessments of 4210 circulating proteins to identify distinct novel protein-based HFrEF subphenotypes and to investigate underlying dynamic biological mechanisms. Herewith we aimed to gain pathophysiological insights and fuel opportunities for personalised treatment. In 382 patients, we performed trimonthly blood sampling during a median follow-up of 2.1 [IQR:1.1-2.6] years. We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, LVAD implantation, and heart transplantation) or censoring, and applied an aptamer-based multiplex proteomic approach. Using unsupervised machine learning methods, we derived clusters from 4210 repeatedly measured proteomic biomarkers. Sets of proteins that drove cluster allocation were analysed via an enrichment analysis. Differences in clinical characteristics and PEP occurrence were evaluated. We identified four subphenotypes with different protein profiles, prognosis and clinical characteristics, including age (median [IQR] for subphenotypes 1-4, respectively:70 [64, 76], 68 [60, 79], 57 [47, 65], 59 [56, 66]years), EF (30 [26, 36], 26 [20, 38], 26 [22, 32], 33 [28, 37]%), and chronic renal failure (45%, 65%, 36%, 37%). Subphenotype allocation was driven by subsets of proteins associated with various biological functions, such as oxidative stress, inflammation and extracellular matrix organisation. Clinical characteristics of the subphenotypes were aligned with these associations. Subphenotypes 2 and 3 had the worst prognosis compared to subphenotype 1 (adjHR (95%CI):3.43 (1.76-6.69), and 2.88 (1.37-6.03), respectively). Four circulating-protein based subphenotypes are present in HFrEF, which are driven by varying combinations of protein subsets, and have different clinical characteristics and prognosis. ClinicalTrials.gov Identifier: NCT01851538https://clinicaltrials.gov/ct2/show/NCT01851538. EU/EFPIA IMI2JU BigData@Heart grant n°116074, Jaap Schouten Foundation and Noordwest Academie.


Effects of the major histocompatibility complex loci and T-cell receptor beta-chain repertoire on Theiler's virus-induced demyelinating disease.
We have investigated the potential effects of H-2 and T-cell receptor (TCR) V beta family genes on induction of T-cell immunity and susceptibility to virally induced demyelinating disease by using BALB.S (H-2K(s)A(s)D(s)) and BALB.S 3 R (H-2K(s)A(s)D(d)/L(d)) mice. These parameters were compared with those of highly susceptible SJL/J (H-2K(s)A(s)D(s)) mice that contain only one-half of TCR V beta family genes compared with the above-mentioned strains. Our results demonstrate that BALB.S but not BALB.S 3 R mice are susceptible similar to SJL/J mice. Although the level of CD4(+) T-cell infiltration to the CNS was elevated in susceptible mice, virus-specific immune responses restricted with H-2(s) were similar in these mice. No preferential use of V beta families associated with differences in the major histocompatibility complex (MHC) components was apparent. However, the pattern and sequence of CDR 3 distribution shows T-cell clonal accumulation in the CNS associated with the H-2 components. Further anti-CD8 antibody treatment of resistant BALB.S 3 R mice abrogated resistance to demyelinating disease, indicating that CD8(+) T cells restricted with H-2D(d)/L(d) are most likely to exert resistance in BALB.S 3 R mice. These studies indicated that TCR V beta and MHC class II genes are the secondary to a particular MHC class I gene expression in susceptibility to virally induced demyelinating disease.


Patient-reported outcomes in immunotherapy for head and neck cancer.
Data about patient-reported outcomes (PROs) among patients with head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoint inhibitors are sparse. Our exploratory study evaluated PROs in patients with HNSCC starting treatment with immune checkpoint inhibitor monotherapy or combination therapy with cetuximab. Patients were recruited prior to receipt of their first checkpoint inhibitor therapy infusion. Participants completed measures of checkpoint inhibitor toxicities and quality of life (QOL) at on-treatment clinic visits. Among patients treated with checkpoint inhibitor monotherapy (n = 48) or combination therapy (n = 38) toxicity increased over time (p < 0.05), while overall QOL improved from baseline to 12 weeks, with stable or declining QOL thereafter (p < 0.05). There were no group differences in change in toxicity index or QOL. Toxicity index scores were significantly higher in the combination group at 18-20 weeks and 6 months post-initiation of immune checkpoint inhibitor (p < 0.05). There were no significant group differences at baseline, the 6-8 week (p = 0.13) or 3-month (p = 0.09) evaluations. The combination group reported better emotional well-being at baseline than the monotherapy group (p = 0.04), There were no other group differences QOL at baseline or later timepoints. Despite increasing patient-reported toxicity, checkpoint inhibitor monotherapy and combination therapy were associated with similar transient improvements, then worsening, of QOL in patients with HNSCC.


Computational markers of risky decision-making predict for relapse to alcohol.
Relapse remains the major challenge in treatment of alcohol use disorder (AUD). Aberrant decision-making has been found as important cognitive mechanism underlying relapse, but factors associated with relapse vulnerability are unclear. Here, we aim to identify potential computational markers of relapse vulnerability by investigating risky decision-making in individuals with AUD. Forty-six healthy controls and fifty-two individuals with AUD were recruited for this study. The risk-taking propensity of these subjects was investigated using the balloon analog risk task (BART). After completion of clinical treatment, all individuals with AUD were followed up and divided into a non-relapse AUD group and a relapse AUD group according to their drinking status. The risk-taking propensity differed significantly among healthy controls, the non-relapse AUD group, and the relapse AUD group, and was negatively associated with the duration of abstinence in individuals with AUD. Logistic regression models showed that risk-taking propensity, as measured by the computational model, was a valid predictor of alcohol relapse, and higher risk-taking propensity was associated with greater risk of relapse to drink. Our study presents new insights into risk-taking measurement and identifies computational markers that provide prospective information for relapse to drink in individuals with AUD.


Bereavement. Part 1: Theories of bereavement.
Bereavement is often accompanied by a deterioration in physical and emotional well-being. Nurses often find it difficult to deal with bereaved people, and avoid involvement with them. Understanding the bereavement process can help nurses to provide effective care and support for bereaved people.


[Post-traumatic subperiosteal chondroma of the hand. Clinical case].
The authors report a case of rapidly developing periosteal chondroma of the fifth metacarpal. No erosion of the bone cortex could be observed radiographically. The development of the tumor appears to follow a violent trauma without skeletal lesions occurred seven months before.


Survival of worm masses of Onchocerca ochengi in gerbils and hamsters: implications for the development of an in vivo macrofilaricide screening model.
Onchocerciasis, the second leading infectious cause of blindness, afflicts approximately 21 million people globally. Its control is limited to the use of the microfilaricidal drugs, ivermectin and moxidectin. Both drugs are unable to kill the adult worms which can survive for up to 15 years in patients, justifying the urgent need for potent and novel macrofilaricides that kill adult worms. The development of such drugs has been hindered by the lack of an appropriate small laboratory animal model to evaluate potential drug candidates in vivo. This study assessed the survival of O. ochengi female worms and their embryos over time in two laboratory rodents: gerbils and hamsters and tested using "proof-of-concept" studies, whether known macrofilaricidal drugs can kill these worms. Animals were surgically implanted with mechanical or collagenase-liberated O. ochengi worm masses, and necropsied at various time points to test for survival. Recovered worm masses were assessed for viability by biochemical analysis (MTT/formazan assay) or fecundity (embryogram). Flubendazole (FBZ) administered at 20 mg/kg body weight was used to validate both rodent models. By day 26 post-implantation of 15 worm masses, a median of 7.00 (4.00-10.00) was recovered from hamsters, and 2.50 (2.00-4.00) from gerbils. Worm masses recovered from gerbils were mostly disintegrated or fragmented, with significantly higher fragmentation observed with collagenase-liberated worm masses. FBZ had no significant effect on the number of worm masses recovered, but enhanced embryo degradation in gerbils and reduced worm mass viability in hamsters. This exploratory study has revealed the gerbil and hamster as permissible rodents to adult female worms of O. ochengi. The hamsters appeared to maintain the worms longer, compared to gerbils.