Increased activity of the Na(+)-dependent Cl(-)-HCO3- anion exchanger in erythrocytes of patients with essential hypertension.
To study the activity of the Na(+)-dependent Cl(-)-HCO3- anion exchanger in erythrocytes of patients with essential hypertension. The study was performed in cells from 48 untreated essential hypertensive patients and 30 normotensive controls with similar age- and sex- distribution. The activity of the Na(+)-dependent anion exchanger was determined by measuring the 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) sensitive Li+ influx in fresh cells incubated into a medium containing Li2CO3. The DIDS-sensitive Li+ influx was higher in hypertensives than controls. With the 100% confidence (upper) limit of the normotensive population as a cut-off point, a subgroup of 11 hypertensives had an abnormally high activity of the Na(+)-dependent Cl(-)-HCO3- anion exchanger. Compared with patients with normal exchanger activity, patients with increased exchanger activity were characterized by the following: higher frequency of family history of hypertension; lower serum high-density lipoprotein cholesterol levels and higher plasma aldosterone concentrations. After multiple regression analysis, the DIDS-sensitive Li+ influx was inversely correlated with high-density lipoprotein cholesterol levels. These results show the presence of a new abnormality of erythrocyte Na+ transport in essential hypertension--increased activity of the Na(+)-dependent Cl(-)-HCO3- anion exchanger. In addition, our findings suggest that from the clinical point of view, patients with this transport abnormality represent a particular subset of essential hypertensives.


Stent intussusception after thromboaspiration through a platinum chrome stent: a particular case of longitudinal stent deformation.
The need to improve stent deliverability has led to the development of thinner and more flexible stents. However, there is concern about decreased longitudinal strength. The number of longitudinal stent deformation reports has dramatically increased. We report a case of stent longitudinal deformation after thromboaspiration through a new generation platinum chrome bare metal stent. Images show an "intussusception effect," an extreme form of the previously described "concertina deformation," as the mechanism of shortening. Since stent technology is constantly evolving, newer devices will probably be designed to have less susceptibility to longitudinal stent deformation.


Structural correlates of the creatine transporter function regulation: the undiscovered country.
Creatine (Cr) and phosphocreatine constitute an energy shuttle that links ATP production in mitochondria to subcellular locations of ATP consumption. Cells in tissues that are reliant on this energy shuttle, such as myocytes and neurons, appear to have very limited ability to synthesize creatine. Therefore, these cells depend on Cr uptake across the cell membrane by a specialized creatine transporter (CrT solute carrier SLC6A8) in order to maintain intracellular creatine levels. Cr supplementation has been shown to have a beneficial effect in numerous in vitro and in vivo models, particularly in cases of oxidative stress, and is also widely used by athletes as a performance enhancement nutraceutical. Intracellular creatine content is maintained within narrow limits. However, the physiological and cellular mechanisms that mediate Cr transport during health and disease (such as cardiac failure) are not understood. In this narrative mini-review, we summarize the last three decades of research on CrT structure, function and regulation.


MicroRNA-223 promotes mast cell apoptosis by targeting the insulin-like growth factor 1 receptor.
The present study aimed to examine the functional role of miR-223 in the regulation of mast cell apoptosis. Overexpressed miR-223 in mast cells transfected by Lipofectamine 2000 was used as a model, and miR-223 was found to promote mast cell apoptosis. To investigate the underlying mechanisms involved, the potential and putative target molecules of miR-223 were detected by bioinformatical analysis using predictive software, and western blotting. Insulin-like growth factor-1 receptor (IGF-1R) was found to be the functional target of miR-223 in the promotion of cell apoptosis. The downstream PI3K/protein kinase B (Akt) signaling pathway was also inhibited, and signaling was mediated by IGF-1R. Furthermore, the relative luciferase activity of the reporter containing the 3'-untranslated region (3'-UTR) of IGF-1R was significantly suppressed, while suppression of miR-223-inhibited IGF-1R protein expression was also observed. In conclusion, the results suggest that IGF-1R is the functional target for miR-223 promotion of cell apoptosis, and its downstream PI3K/Akt signaling pathway was suppressed by miR-223 through targeting of IGF-1R.


Variable incidence of cyclosporine and FK-506 neurotoxicity in hematopoeitic malignancies and marrow conditions after allogeneic bone marrow transplantation.
This study examines whether malignant disease under treatment influences the incidence of cyclosporine or FK-506 neurotoxicity after myeloablative conditioning and allogeneic bone marrow transplantation (allo-BMT). Review of 290 patients who received myeloablative conditioning prior to allo-BMT and cyclosporine/FK-506 identified 21 (7.2%) patients with neurotoxicity confirmed by computed tomography or magnetic resonance. Underlying malignancy necessitating allo-BMT included leukemias (67%), lymphoma (10%), myelodysplastic syndrome (10%), and multiple myeloma (MM). Frequency of neurotoxicity by disease was compared. The highest incidence of neurotoxicity was present with MM (25%), whereas the lowest incidence was present with lymphoma (2.7%). Other diseases demonstrated intermediate incidence, including acute leukemias (10%), myelodysplastic syndrome (6.4%), and chronic myelogenous leukemia (4.9%). Cyclosporine/FK-506 neurotoxicity varied according to the underlying malignancy. The variable susceptibility to the development of neurotoxicity in this population may depend on the interaction of host vasculature with disease specific factors. Understanding the cause of neurotoxicity could improve survival after allo-BMT.


Expression of phosphodiesterase 5 in maternal and fetal sheep.
Ovine pregnancy is associated with elevated levels of nitric oxide. Nitric oxide stimulates cyclic guanosine monophosphate (cGMP), which results in vascular smooth muscle relaxation/vasodilation. Phosphodiesterase type 5 regulates cGMP in the urogenital track. The present study was designed to determine message expression of phosphodiesterase type 5 in the myometrium, uterine vessels, and placentome of the sheep and phosphodiesterase type 5 protein expression in the maternal and fetal placentome. Tissue was collected from 5 nonpregnant and 5 pregnant anesthetized animals (gestational day = 134 +/- 4) and frozen at -80 degrees C. Optimized reverse transcription-polymerase chain reaction was performed on all tissues, and immunohistochemistry was performed on the placentome only. Phosphodiesterase type 5 messenger ribonucleic acid levels were significantly higher in the myometrium and placentome, compared with the maternal blood vessels. Phosphodiesterase type 5 protein was immuno-localized to the vascular smooth muscle of the maternal vessels, stroma, and placental capsule only. Although phosphodiesterase type 5 messenger ribonucleic acid was present in the fetal placenta, phosphodiesterase type 5 protein was expressed only in maternally derived placental tissue. This suggests that regulation of cGMP levels and vascular tone in the umbilical circulation differs from the uterine circulation.


Could calcitonin be a useful therapeutic agent for trigeminal neuralgia?
Trigeminal neuralgia (TN) has been recognized as one of the most common neurovascular syndromes caused by the vascular contact of the trigeminal nerve in its root entry zone (REZ) with a branch of the superior or anterior inferior cerebellar arteries, leading to a demyelinization of trigeminal sensory fibers within either the nerve root or, less commonly, the brainstem. There is a lack of certainty regarding the aetiology and pathophysiology of TN, therefore the treatment of trigeminal neuropathic pain disorders continues to be a major therapeutic challenge. The identification of novel therapeutic agents for the treatment of these disorders is important. Calcitonin (especially intranasal) provides an interesting analgesic effect in a series of painful conditions including reflex sympathetic dystrophy syndrome, adhesive capsulitis, ankylosing spondylitis, rheumatoid arthritis, vertebral crush fractures and metastasis, phantom limb pain, etc. Exogenous calcitonin is thought to cross the blood-brain barrier and to accumulate slowly in the brain, inducing analgesia once sufficient receptors are occupied. We hypothesize that calcitonin may has anti - trigeminal neuralgia properties. From the clinical point of use, the analgesic effect of calcitonin will be beneficial throughout the whole period of medical treatment of trigeminal neuralgia patients.


Apo A-I metabolism in cynomolgus monkeys: male-female differences.
Female cynomolgus monkeys have significantly higher plasma apo A-I concentrations than males (P = 0.04) and are able to maintain higher levels than the males even after consuming a high-cholesterol diet that severely depresses the apo A-I concentration in primates (P less than 0.05). The mechanism responsible for this difference was investigated by comparing apo A-I turnover (synthesis and catabolism) in males and females consuming monkey chow and in a separate group of males and females that had consumed the high-cholesterol diet for several weeks. The average length of time an apo A-I molecule remained in the plasma compartment of chow-fed monkeys was 2.62 days but decreased to 1.52 days (P less than 0.01) in animals fed the HC diet. There were no male-female differences in the residence times. The absolute turnover rate (mg/day) of apo A-I was not statistically affected by diet or sex; however, the females were substantially smaller than the males (3.8 vs. 4.8 kg; P less than 0.01) and their plasma volumes were significantly smaller than those of the males, even after correction for differences in body wt. (32.6 vs. 37.0 ml/kg, respectively; P less than 0.01). Taken together, the data indicate that females cynomolgus monkeys have higher apo A-I synthesis rates than males of comparable plasma volume (P = 0.03), which we would propose accounts for the higher plasma apo A-I concentrations evident in females.


Suppression of twins in b-oriented MFI molecular sieve films under microwave irradiation.
Twin growth in the synthesis of b-oriented MFI films is successfully suppressed by applying microwave irradiation on a b-oriented MFI seed layer, relying on the nucleation-related bottleneck effect. Electrochemical oxidation experiments demonstrated the importance of twin suppression in enhancing the diffusion of guest molecules in MFI films.


An improved technique for sequential R-, Q- and C-banding of bone marrow chromosomes.
A procedure for the sequential staining of metaphase cells to provide R-banding, Q-banding and C-banding of chromosomes is described. The combined techniques allow more precise identification of marker chromosomes and more accurate definition of breakpoints in the consistent chromosome translocations that are associated with certain human malignancies.


Development and testing of a new instrument to measure fluid intake, output, and urinary symptoms: the questionnaire-based voiding diary.
The purpose of this study was to develop a validated self-administered questionnaire to measure fluid intake, output, behavior, and urinary symptoms. Factor analysis identified 4 subscales in the new questionnaire. Ninety-two women completed the questionnaire, comprised of a 48-hour voiding diary and the Bristol Female Lower Urinary Tract Symptom-Scored form. The questionnaire was readministered after a 2-week period with no change in treatment and 2-3 months later after treatment of urinary symptoms. Correlation of items of the questionnaire with the 48-hour voiding diary in the 4 subscales was high (r = 0.55, 0.74. 0.68, and 0.47; P < .01). Subscale scores also correlated with the Bristol Lower Urinary Tract Symptom score (r = 0.68 and =0.87; P < .001). Comparisons of scores before and after treatment showed the ability of the questionnaire to respond to change. The new questionnaire is a valid and reliable means to assess fluid intake, output, behavior, and urinary symptoms.


An evaluation and education program for driving while intoxicated offenders.
This report addresses the development of a mandatory, inpatient, evaluation and education program aimed at reducing Driving While Intoxicated (DWI) at a major Army installation. The program was designed to provide extensive evaluation to all soldiers within a week of the DWI. The majority of soldiers are young males, a population known for heavy drinking and a disproportionate amount of both motor-vehicle accidents and fatalities. Among the initial 490 soldiers admitted to the program, 88% were found to meet DSM-III criteria for alcohol abuse or alcohol dependence. Factors associated with a diagnosis of abuse or dependence were age; scores on the Vaillant alcohol questionnaire, the MacAndrews and F scales of the MMPI, the Mortimer-Filkins questionnaire; BAC at time of arrest; a prior history of alcohol-related problems; and certain blood hematology and chemistry values. Results indicate that DWI is a marker for serious alcohol problems.


Quantitative Susceptibility Mapping and R2* Measured Changes during White Matter Lesion Development in Multiple Sclerosis: Myelin Breakdown, Myelin Debris Degradation and Removal, and Iron Accumulation.
Quantitative susceptibility mapping and R2* are sensitive to myelin and iron changes in multiple sclerosis lesions. This study was designed to characterize lesion changes on quantitative susceptibility mapping and R2* at various gadolinium-enhancement stages. This study included 64 patients with MS with different enhancing patterns in white matter lesions: nodular, shell-like, nonenhancing < 1 year old, and nonenhancing 1-3 years old. These represent acute, late acute, early chronic, and late chronic lesions, respectively. Susceptibility values measured on quantitative susceptibility mapping and R2* values were compared among the 4 lesion types. Their differences were assessed with a generalized estimating equation, controlling for Expanded Disability Status Scale score, age, and disease duration. We analyzed 203 lesions: 80 were nodular-enhancing, of which 77 (96.2%) were isointense on quantitative susceptibility mapping; 33 were shell-enhancing, of which 30 (90.9%) were hyperintense on quantitative susceptibility mapping; and 49 were nonenhancing lesions < 1 year old and 41 were nonenhancing lesions 1-3 years old, all of which were hyperintense on quantitative susceptibility mapping. Their relative susceptibility/R2* values were 0.5 ± 4.4 parts per billion/-5.6 ± 2.9 Hz, 10.2 ± 5.4 parts per billion/-8.0 ± 2.6 Hz, 20.2 ± 7.8 parts per billion/-3.1 ± 2.3 Hz, and 33.2 ± 8.2 parts per billion/-2.0 ± 2.6 Hz, respectively, and were significantly different (P < .005). Early active MS lesions with nodular enhancement show R2* decrease but no quantitative susceptibility mapping change, reflecting myelin breakdown; late active lesions with peripheral enhancement show R2* decrease and quantitative susceptibility mapping increase in the lesion center, reflecting further degradation and removal of myelin debris; and early or late chronic nonenhancing lesions show both quantitative susceptibility mapping and R2* increase, reflecting iron accumulation.


Intravitreal liposome-encapsulated drugs: a preliminary human report.
Intravitreal liposome-encapsulated antibiotics and antiviral drugs were used in patients with acute toxoplasmosis retinochoroiditis, presumed propionibacterium acne endophthalmitis after cataract surgery, and presumed cytomegalovirus retinitis associated with AIDS. A single intravitreal dose was effective in the treatment of all the conditions. Intravitreal liposomes may prove to be an advantageous drug delivery system for the treatment of chronic intraocular inflammatory disorders.


Trypanosoma cruzi: partial prevention of the natural infection of guinea pigs with a killed parasite vaccine.
Guinea pigs are natural reservoirs of Chagas' disease. Domestic breeding and local trade of these animals are common practices among andean communities in South America. Infection by Trypanosoma cruzi occurs when the animals live in triatomine-infested houses or yards. The preventive effect of a vaccine consisting of cultured T. cruzi killed by freezing and thawing plus saponin was tested both in mice and in the guinea pig ecosystem. Resistance against T. cruzi challenge in mice was improved by increasing the trypomastigote/epimastigote ratio in live attenuated vaccines but not in killed parasite vaccines. Although the killing of attenuated parasites sharply reduced their immunogenicity for mice, a protective effect against natural T. cruzi infection was detected in guinea pigs. A total of 88 guinea pigs were vaccinated in four intradermal sites on three occasions. Eighty controls received similar inoculations of culture medium plus saponin. All animals were kept in a triatomine-infested yard. Parasitemia was studied with the capillary microhematocrit method. After an exposure time averaging 4 months, natural T. cruzi infection occurred in 55% (44/80) of the controls and in 33% (29/88) of the vaccinated group (P less than 0.01). The number of highly parasitemic guinea pigs was also significantly decreased (6/80 vs 0/88, P less than 0.01). Thus, immunizing protocols which are only partially protective against artificial callenge with T. cruzi may nevertheless constrain the exchange of parasites between natural hosts and vectors.


Interleukin 2, soluble interleukin 2 receptor, and interferon-gamma in the suction blister fluids from psoriatic skin.
Psoriasis represents inflammatory skin disorders characterized by significant changes in cellular immunity, particularly exhibiting alterations in T lymphocyte-related functions. Early psoriatic lesions have been reported to show an infiltration of activated helper T cells. Elevated levels of interleukin 2 (IL-2), IL-2 receptor (IL-2R), and interferon-gamma (INF-gamma) are associated with an early activation of T cells. To examine local activation of T cells in psoriatic skin, the amounts of activated T cell products, IL-2, secretory form of IL-2R (sIL-2R) and INF-gamma were measured in the fluids of suction blisters raised on psoriatic skin. sIL-2R levels were significantly elevated in the suction blister fluids raised on psoriatic involved skin compared with those on normal and psoriatic uninvolved skin. On the other hand, neither IL-2 or IFN-gamma was detected in the suction blister fluids either from normal, psoriatic uninvolved, or involved skin. However, we could detect IFN-gamma and IL-2 in the psoriatic scale extracts. Although we failed to detect IL-2 and IFN-gamma in the suction blister fluids, the increased levels of sIL-2R in the suction blister fluids from the psoriatic lesional skin indicate local activation of T cells in psoriatic lesional skin.


Primary reverse total shoulder arthroplasty for fractures requires more revisions than for degenerative conditions 1 year after surgery: an analysis from the Dutch Arthroplasty Register.
Although reverse total shoulder arthroplasty (RTSA) is considered a viable treatment strategy for proximal humeral fractures, there is an ongoing discussion of how its revision rate compares with indications performed in the elective setting. First, this study evaluated whether RTSA for fractures conveyed a higher revision rate than RTSA for degenerative conditions (osteoarthritis, rotator cuff arthropathy, rotator cuff tear, or rheumatoid arthritis). Second, this study assessed whether there was a difference in patient-reported outcomes between these 2 groups following primary replacement. Finally, the results of conventional stem designs were compared with those of fracture-specific designs within the fracture group. This was a retrospective comparative cohort study with registry data from the Netherlands, generated prospectively between 2014 and 2020. Patients (aged ≥ 18 years) were included if they underwent primary RTSA for a fracture (<4 weeks after trauma), osteoarthritis, rotator cuff arthropathy, rotator cuff tear, or rheumatoid arthritis, with follow-up until first revision, death, or the end of the study period. The primary outcome was the revision rate. The secondary outcomes were the Oxford Shoulder Score, EuroQol 5 Dimensions (EQ-5D) score, numerical rating scale score (pain at rest and during activity), recommendation score, and scores assessing change in daily functioning and change in pain. This study included 8753 patients in the degenerative condition group (mean age, 74.3 ± 7.2 years) and 2104 patients in the fracture group (mean age, 74.3 ± 7.8 years). RTSA performed for fractures showed an early steep decline in survivorship: Adjusted for time, age, sex, and arthroplasty brand, the revision risk after 1 year was significantly higher in these patients than in those with degenerative conditions (hazard ratio [HR], 2.50; 95% confidence interval, 1.66-3.77). Over time, the HR steadily decreased, with an HR of 0.98 at year 6. Apart from the recommendation score (which was slightly better within the fracture group), there were no clinically relevant differences in the patient-reported outcome measures after 12 months. Patients who received conventional stems (n = 1137) did not have a higher likelihood of undergoing a revision procedure than those who received fracture-specific stems (n = 675) (HR, 1.70; 95% confidence interval, 0.91-3.17). Patients undergoing primary RTSA for fractures have a substantially higher likelihood of undergoing revision within the first year following the procedure than patients with degenerative conditions preoperatively. Although RTSA is regarded as a reliable and safe treatment option for fractures, surgeons should inform patients accordingly and incorporate this information in decision making when opting for head replacement surgery. There were no differences in patient-reported outcomes between the 2 groups and no differences in revision rates between conventional and fracture-specific stem designs.


[Light chain amyloidosis].
Light chain amyloidosis (AL) is a rare protein deposition disease. It is caused by a clonal plasma cell or B‑cell disease in the bone marrow. With the exception of the central nervous system, all organs can be affected by amyloid deposits. Cardiac involvement is the most frequent organ manifestation that leads to significantly increased mortality when it is diagnosed at an advanced stage. The causal treatment of AL amyloidosis is reduction of amyloidogenic light chains by chemotherapy. Early diagnosis of the disease is essential to reduce early mortality, to effectively treat patients and to prevent further deterioration of organ function. New treatment approaches for AL amyloidosis are aimed at inhibiting amyloid formation or degradation of amyloid in organs.


The effect of botulinum toxin A on fat graft survival.
Autologous fat grafting is a common procedure used in plastic surgery to correct soft tissue deficiency or depression deformity. However, absorption of grafted fat in the recipient area is unpredictable, and various methods for improving fat survival have been developed clinically. This study analyzed the changes and viability of injected fat in relation to the effects of botulinum neurotoxin type A (BoNTA). Fat tissue was harvested from the pre-urinary bladder cavity of four Sprague-Dawley rats and processed using the Coleman technique. The experiment was performed on the backs of eight BALB/c-nu mice. The injection of free fat grafts was performed on the bilateral side of the back of each mouse. The one side (experimental) was treated with 0.5 ml of a free fat injection combined with 0.5 IU of BoNTA in 0.1 ml of saline. The other side (control) was treated with 0.5 ml of free fat injection combined with 0.1 ml of saline. The mice were killed after 9 weeks, and the injected fat grafts were explanted, after which the weight and volume were measured. Histologic study was performed with hematoxylin and eosin staining. Statistical analysis of the weight and volume from both sides, the histologic parameters, and cellular integrity was performed. A difference in the weight, volume, and histologic parameters of the injected fat grafts was observed. The BoNTA-treated side exhibited a significantly higher survival rate than the control side. The histologic examination of the fat grafts also demonstrated that the grade scale of cellular integrity was higher for the BoNTA-treated sides. Botulinum toxin A significantly reduces the level of fat graft resorption. Therefore, an injected fat graft can be used in conjunction with botulinum toxin A and offers better volumetric improvement. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.


Codon Usage and mRNA Stability are Translational Determinants of Cellular Response to Canonical Ferroptosis Inducers.
Ferroptosis is a non-apoptotic cell death mechanism characterized by the generation of lipid peroxides. While many effectors in the ferroptosis pathway have been mapped, its epitranscriptional regulation is not yet fully understood. Ferroptosis can be induced via system xCT inhibition (Class I) or GPX4 inhibition (Class II). Previous works have revealed important differences in cellular response to different ferroptosis inducers. Importantly, blocking mRNA transcription or translation appears to protect cells against Class I ferroptosis inducing agents but not Class II. In this work, we examined the impact of blocking transcription (via Actinomycin D) or translation (via Cycloheximide) on Erastin (Class I) or RSL3 (Class II) induced ferroptosis. Blocking transcription or translation protected cells against Erastin but was detrimental against RSL3. Cycloheximide led to increased levels of GSH alone or when co-treated with Erastin via the activation of the reverse transsulfuration pathway. RNA sequencing analysis revealed early activation of a strong alternative splice program before observed changes in transcription. mRNA stability analysis revealed divergent mRNA stability changes in cellular response to Erastin or RSL3. Importantly, codon optimality biases were drastically different in either condition. Our data also implicated translation repression and rate as an important determinant of the cellular response to ferroptosis inducers. Given that mRNA stability and codon usage can be influenced via the tRNA epitranscriptome, we evaluated the role of a tRNA modifying enzyme in ferroptosis stress response. Alkbh1, a tRNA demethylase, led to translation repression and increased the resistance to Erastin but made cells more sensitive to RSL3.


Rolipram optimizes therapeutic effect of bevacizumab by enhancing proapoptotic, antiproliferative signals in a glioblastoma heterotopic model.
The unstable response to bevacizumab is a big dilemma in the antiangiogenic therapy of high-grade glioma that appears to be linked to an increase in the post-treatment intratumor levels of hypoxia-inducible factor 1 α (HIF1α) and active AKT. Particularly, a selective phosphodiesterase IV (PDE4) inhibitor, rolipram is capable of inhibiting HIF1α and AKT in cancer cells. Here, the effect of bevacizumab alone and in presence of rolipram on therapeutic efficacy, intratumor hypoxia levels, angiogenesis, apoptosis and proliferation mechanisms were evaluated. BALB/c mice bearing C6 glioma were received bevacizumab and rolipram either alone or combined for 30 days (n = 11/group). At the last day of treatments, apoptosis, proliferation and microvessel density, in xenografts (3/group) were detected by TUNEL staining, Ki67 and CD31 markers, respectively. Relative expression of target proteins was measured using western blotting. Bevacizumab initially hindered the tumor progression but its antitumor effect was weakened later despite the vascular regression and apoptosis induction. Unpredictably, bevacizumab-treated tumors exhibited the highest cell proliferation coupled with PDE4A, HIF1α and AKT upregulation and p53 downregulation and reversed by co-treatment with rolipram. Unlike a similar antivascular pattern to bevacizumab, rolipram consistently led to a more tumor growth suppression and proapoptotic effect versus bevacizumab. Co-treatment maximally hampered the tumor progression and elongated survival along with the major vascular regression, hypoxia, apoptosis induction, p53 and caspase activities. In conclusion, superior and persistent therapeutic efficacy of co-treatment provides a new insight into antiangiogenic therapy of malignant gliomas, suggesting to be a potential substitute in selected patients.


Clinical target promiscuity: lessons from ras molecular trials.
Mutated ras has been identified in approximately 30% of human tumors, and dysregulation of ras function and signal transduction pathways is a critical step in tumorigenesis. Herein, we review the early data that supports the concept that the intrinsic radiosensitivity of tumor cells can be altered by oncogenic ras expression and that this impacts the PI3K-dependent signaling cascade. This ras-induced radioresistance can be reversed using prenyl transferase inhibitors (PTIs.). We discuss the effects of PTIs as a radiosensitizer in both in vivo and in vitro studies and show that PTIs can lead to increased radiosensitization in vivo through a variety of potential mechanisms that enhance radiation-induced cell kill. We critically evaluate the use of ras biomarkers in predicting the clinical response to PTIs that may explain the mixed results seen thus far in clinical trials using PTIs as a clinical radiosensitizer. We conclude that Ras-mediated radioresistance is the result of multiple intercommunicating pathways functioning against a complex genetic background and a solitary biomarker may not be adequate to predict for PTI-mediated radiosensitization. Nonetheless, our knowledge of the ras-signaling pathway has led to development and testing of specific therapies directed against PI3K-AKT signaling pathways as a future approach towards clinical radiosensitization.


Isotopomer Spectral Analysis: Utilizing Nonlinear Models in Isotopic Flux Studies.
We present the principles underlying the isotopomer spectral analysis (ISA) method for evaluating biosynthesis using stable isotopes. ISA addresses a classic conundrum encountered in the use of radioisotopes to estimate biosynthesis rates whereby the information available is insufficient to estimate biosynthesis. ISA overcomes this difficulty capitalizing on the additional information available from the mass isotopomer labeling profile of a polymer. ISA utilizes nonlinear regression to estimate the two unknown parameters of the model. A key parameter estimated by ISA represents the fractional contribution of the tracer to the precursor pool for the biosynthesis, D. By estimating D in cells synthesizing lipids, ISA quantifies the relative importance of two distinct pathways for flux of glutamine to lipid, reductive carboxylation, and glutaminolysis. ISA can also evaluate the competition between different metabolites, such as glucose and acetoacetate, as precursors for lipogenesis and thereby reveal regulatory properties of the biosynthesis pathway. The model is flexible and may be expanded to quantify sterol biosynthesis allowing tracer to enter the pathway at three different positions, acetyl CoA, acetoacetyl CoA, and mevalonate. The nonlinear properties of ISA provide a method of testing for the presence of gradients of precursor enrichment illustrated by in vivo sterol synthesis. A second ISA parameter provides the fraction of the polymer that is newly synthesized over the time course of the experiment. In summary, ISA is a flexible framework for developing models of polymerization biosynthesis providing insight into pools and pathway that are not easily quantified by other techniques.


Influence of high pressure on the dimerization of ToxR, a protein involved in bacterial signal transduction.
High hydrostatic pressure (HHP) is suggested to influence the structure and function of membranes and/or integrated proteins. We demonstrate for the first time HHP-induced dimer dissociation of membrane proteins in vivo with Vibrio cholerae ToxR variants in Escherichia coli reporter strains carrying ctx::lacZ fusions. Dimerization ceased at 20 to 50 MPa depending on the nature of the transmembrane segments rather than on changes in the ToxR lipid bilayer environment.


Design of Novel Imidazopyrazine Derivative against Breast Cancer via Targeted NPY1R Antagonist.
Breast cancer is the most frequent malignancy in women with more than one in ten new cancer diagnoses each year. Synthetic products are a key source for the identification of new anticancer medicines and drug leads. Imidazopyrazine is a highly favored skeleton for the design of new anticancer drugs. In silico designed derivatives were screened using computer aided drug design techniques and validated using MTT assay. A template-based methodology was used in the current work to create novel Imidazopyrazine derivatives, targeting the NPY1R protein. Molecular docking, Diffusion docking, MD simulation, MM-GBSA and meta-dynamics techniques were followed. MTT assay was performed to validate the activity of principal compound. A docking score of -6.660 and MMGBSA value of -108.008 (+/-) 9.14 kcal/mol was obtained from the investigations conducted. In addition, molecular dynamics simulation was carried out for 500 ns, yielding a stable RMSD and value of 5.6 Å, thus providing insights on the stability of the protein conformation on interaction with the principal compound. Furthermore, the in vivo validation studies conducted via MTT assay showed an IC50 value of 73.45 (+/-) 0.45 μg /mL. The research has produced encouraging findings and can be applied as a model for precise enumerations in the future. It also encourages the study of novel synthetic compounds with potential anti-cancer properties.


Use of the Saccharomyces cerevisiae endopolygalacturonase promoter to direct expression in Escherichia coli.
In Saccharomyces cerevisiae, an endopolygalacturonase encoded by the PGL1 gene catalyzes the random hydrolysis of the α-1,4 glycosidic linkages in polygalacturonic acid. To study the regulation of the PGL1 gene, we constructed a reporter vector containing the lacZ gene under the control of PGL1 promoter. Surprisingly, when Escherichia coli DH5α was transformed by this vector, cells harboring the constructed plasmid produced blue colonies. Sequence analysis of this promoter revealed that E. coli consensus sequences required to express an in-frame lacZ alpha product were present. We next decided to investigate how the PGL1 promoter is regulated in E. coli compared to yeast. In this study, we examined the modulation of the PGL1 promoter in E. coli, and the results indicated that its activity is greatly induced by saturated digalacturonic acid and is indirectly regulated by the transcriptional regulators the 2-keto-3-deoxygluconate repressor. Moreover, PGL1 expression is enhanced under aerobic conditions. We found that β-galactosidase activity in E. coli could reach 180 units, which is 40-fold greater than the activity produced in S. cerevisiae, and greater than recombinant protein expression previously reported by other researchers. We thus demonstrate that this vector can be considered as a dual expression plasmid for both E. coli and S. cerevisiae hosts. So far, no modulation of endoPG promoters expressed in E. coli has been reported.


2-Methoxyphenyl isocyanate and 2-Methoxyphenyl isothiocyanate: conformers, vibration structure and multiplet Fermi resonance.
IR and Raman spectral measurements in the region 3500-400/50 cm(-1) have been made for the liquid samples of 2-Methoxyphenyl isocyanate and 2-Methoxyphenyl isothiocyanate. A complete assignment of the measured bands has been proposed as aided by conformational and vibration analyses at B3LYP/6-311++G** level of calculations. Three conformers for 2-Methoxyphenyl isocyanate and two for 2-Methoxyphenyl isothiocyanate have been determined. The tilt of the isocyanate (NCO) and isothiocyanate (NCS) moieties with respect to phenyl ring are in broad agreement with their parents. Stretching mode frequencies of methyl group (-OCH(3)) in 2-Methoxyphenyl isocyanate have been lowered in the 2900-2800 cm(-1); deformation asymmetric modes are IR strong and symmetric one Raman strong. In 2-Methoxyphenyl isothiocyanate, a similar pattern is true for stretching modes but deformation asymmetric modes are IR strong and symmetric mode has not been observed. Multiplet absorption band system near 2200 cm(-1) in 2-Methoxyphenyl isocyanate has been interpreted to be caused by Fermi resonance. A similar pattern in absorption near 2100 cm(-1) in 2-Methoxyphenyl isothiocyanate but more complex Raman band pattern has also been explained through Fermi resonance from heuristic stand-point. Many Raman modes in 1300-1100 cm(-1) are intensified apparently owing to isothiocyanate than isocyanate moiety. Phenyl ring breathing mode is shifted to 1040 cm(-1) as strong Raman; the symmetric stretching mode of O-CH(3) near 1023 cm(-1) as strong absorption.


New ultrastructural observations on the skeletal matrix of Tritrichomonas foetus.
Tritrichomonas foetus, a parasitic protozoon of the urogenital tract in cattle, presents a poorly known cytoskeleton, formed by rootlets and proteinaceous structures, many of which have not yet been characterized. Studies on its skeletal organization sheds light on the evolution of the matrix system, characteristic of higher eukaryotes. The skeletal matrix system of T. foetus in interphasic and dividing cells were studied using whole mount cell procedures observed either in field emission scanning electron microscopy (FESEM) or in transmission electron microscope (TEM) after the cell-sandwich technique, where the plasma membrane was mechanically removed. Three-dimensional-like images of the cell matrix were attained revealing a network of filaments that has not been described previously. Freeze-etching and cytochemistry using acridine orange for TEM, were also used. Membrane-skeleton interactions were examined in the hydrogenosomes, on the nuclear envelope at mitosis and interphase, and in the overall matrix filling of the cytoplasm and nucleoplasm. It was demonstrated that this eukaryote has a complex skeletal matrix other than just the rigid cytoskeletal structures. Our analysis indicated that the nucleus has a defined position, and fibrils perform an anchoring system for the nucleus. The possibility of a mechanism for nuclei fidelity migration during mitosis is discussed.


Mesohepatectomy as an option for the treatment of central liver tumors.
Despite substantial improvements in intra- and postoperative management of extended hemihepatectomy as the curative option for treatment of central liver tumors, the high morbidity and mortality rates accompanying the procedure still represent major obstacles. Mesohepatectomy preserves up to 35% more functional liver tissue than extended hepatectomy, but it has not been widely applied, perhaps because of its complexity as a resection method. Forty-eight consecutive patients (29 men and 19 women) with centrally located liver tumors underwent mesohepatectomy. Peri- and postoperative morbidity and mortality rates were prospectively evaluated and analyzed. Mean age of the patients was 60.7 years. Indications for mesohepatectomy were liver metastasis (n = 29), hepatocellular carcinoma (n = 5), gallbladder carcinoma (n = 4), cholangiocellular carcinoma (n = 4), hemangioma (n = 2), and other benign diseases (n = 4). Mean operative time was 238 minutes (range 65 to 480 minutes) and mean intraoperative blood loss was 1,120 mL (range 100 to 5,000 mL). Mean amount of intraoperative red blood cells and fresh frozen plasma transfusion was 3.6 U (range 1 to 12 U) and 3.8 U (range 2 to 14 U), respectively. Mean postoperative hospitalization was 15.8 days (range 6 to 104 days). Postoperative surgical complications were seen in 18.8% of patients (n = 9) and included liver failure (n = 1), intraabdominal abscess (n = 1), bilioma or bile leakage (n = 4), hemorrhage and hematoma (n = 2), peritonitis because of intestinal perforation (n = 1), and wound infection (n = 1). One patient (2%) died in the early postoperative phase from portal vein bleeding and disseminated intravascular coagulation, followed by liver failure. Compared with extended liver resection, mesohepatectomy clearly leads to less parenchymal loss. Although it is a technically difficult operation and requires special attention to prevent surgical complications, it is justified in selected patients with centrally located tumors and is a feasible and safe alternative to extended liver resection.


Identification of a Pivotal Period in the Oral Feeding Progression of Preterm Infants.
Preterm infants are at risk of encountering oral feeding difficulties which impede on the transition to independent oral feeds. The objective of this study was to identify a pivotal period where regressions are most likely to occur during their oral feeding progression. This is a retrospective study on 101 infants born <35 weeks' gestation. The sample was separated into two groups, infants who experienced a regression during their oral feeding progression and those who did not. A pivotal period was defined as a time frame where setbacks (a decrease in oral feed attempts by one) are most likely to occur at the start (1-2 oral feed attempts per day), middle (3-5 oral feed attempts per day), or end (6-8 oral feed attempts per day) of the oral feeding progression. Eighty-two percent of infants experienced setbacks; 45% of all setbacks occurred at the middle time frame (p = 0.03). Infants' degree of maturity and enteral tube feeding intolerances were associated with increased occurrence of setbacks (p = 0.04). The midpoint in the oral feeding progression is a pivotal period where setbacks are most likely to occur. This time frame can be used by clinicians to evaluate oral-motor skills for earlier provision of interventions to reduce the occurrence of oral feeding difficulties in this high-risk population.


Increasing amperometric biosensor sensitivity by length fractionated single-walled carbon nanotubes.
In this work the sensitivity-increasing effect of single-walled carbon nanotubes (SWCNTs) in amperometric biosensors, depending on their average length distribution, was studied. For this purpose the SWCNTs were oxidatively shortened and subsequently length separated by size exclusion chromatography. Transmission electron micrographs of different fractions of SWCNTs were collected. Diaphorase "wired" to an osmium redox polymer was blended with the shortened SWCNTs of different lengths. Depending on the average length of the SWCNTs the sensitivity of the amperometric biosensor model system towards oxidation of 1,4-dihydronicotinamide adenine dinucleotide (NADH) was increased by a factor of five. The best performance was achieved with SWCNTs of medium length. The linear range for NADH detection was between 5 microM and 7 mM, the maximum sensitivity was 47 nA microM(-1) cm(-2), and the detection limit was 1 microM. The biosensor exhibited excellent electrocatalytic properties. Even at relatively high NADH concentrations the oxidative current was limited by the diffusion rate of NADH.


A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.
Interleukin 17 (IL-17)-producing T helper 17 cells (T(H)-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T(H)-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1beta and IL-6) were all essential for human T(H)-17 differentiation. However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T(H)-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T(H)-17 differentiation and provide a framework for the global analysis of T helper responses.


Active range of motion outcomes after reconstruction of burned wrist and hand deformities.
This works aim is to evaluate the efficacy of skin grafts and flaps in reconstruction of post-burn hand and wrist deformities. A prospective study of 57 burn contractures of the wrist and dorsum of the hand was performed. Flaps were used only if there was a non-vascularized structure after contracture release, otherwise a skin graft was used. Active range of motion (ROM) was used to assess hand function. The extension deformity cohort uniformly underwent skin graft following contracture release with a mean improvement of 71 degrees (p<0.0001). The flexion deformity cohort was treated with either skin grafts (8 patients) or flaps (9 patients) with a mean improvement of 44 degrees (p<0.0001). Skin grafts suffice for dorsal hand contractures to restore functional wrist ROM. For flexion contractures, flaps were more likely for contractures >6 months. Early release of burn contracture is advisable to avoid deep structure contracture.


Overexpression of miR-484 and miR-744 in Vero cells alters Dengue virus replication.
Dengue is considered one of the world's most important mosquito-borne diseases. MicroRNAs (miRNAs) are small non-coding single-stranded RNAs that play an important role in the regulation of gene expression in eukaryotes. Although miRNAs possess antiviral activity against many mammalian-infecting viruses, their involvement in Dengue virus (DENV) replication remains poorly understood. To determine the role of miR-484 and miR-744 in DENV infection and to examine whether DENV infection alters the expression of both miRNAs. We used bioinformatics tools to explore the relationship between DENV and cellular miRNAs. We then overexpressed miR-484 or miR-744 in Vero cells to examine their role in DENV replication using flow cytometry, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), and western blotting. We found several cellular miRNAs that target a conserved region within the 3' untranslated region (3' UTR) of the genome of the four DENV serotypes and found that overexpression of miR-484 or miR-744 inhibits infection by DENV-1 to DENV-4. Furthermore, we observed that DENV RNA might be involved in the downregulation of endogenous miR-484 and miR-744. Our study identifies miR-484 and miR-744 as two possible restriction host factors against DENV infection. However, further studies are needed to directly verify whether miR-484 and miR-744 both have an anti-DENV effect in vivo.


Effects of diet, level of intake, sodium bicarbonate and monensin on urinary allantoin excretion in sheep.
The present experiment was designed to study the effects of factors likely to alter microbial purine yield from the rumen on urinary excretion of allantoin-nitrogen (UAN). Sixteen mature Clun Forest-Welsh crossbred wethers were used in a 2 x 2 x 2 x 2 factorial design to investigate the effects of (1) level of intake, (2) wheat:nutritionally improved straw (NIS) ratio, (3) sodium bicarbonate inclusion and (4) monensin inclusion on diet digestibilities, fractional outflow rates of solids and liquids from the rumen and urinary allantoin excretion. Each treatment occurred in each of two experimental periods. The treatments were designed to influence microbial purine yield via changes in rumen outflow rate and microbial maintenance coefficient. Increasing the proportion of NIS and increasing feeding level decreased digestibility and increased the fractional outflow rate of solids. Increasing the level of intake increased the fractional outflow rate of liquids. Urinary allantoin excretion (/kg live weight0.75 per d) was significantly increased by an increased proportion of wheat in the diet and increased level of intake, and significantly reduced by NaHCO3. There was a significant interaction effect such that increasing level of intake did not increase UAN with the high-NIS diet, despite an increased fractional outflow of solids from the rumen, in contrast to the increase observed with the high-wheat diet. Taken together with other observations it is suggested that high sodium concentrations in the diet reduce the efficiency of microbial synthesis, probably by increasing the energy cost of maintaining osmolarity.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis.
Currently, only a few specific blood pressure-lowering medications are recommended for migraine prevention. Whether benefits extend to other classes or drugs is uncertain. Embase, MEDLINE, and the Cochrane Central Registry of Controlled Trials were searched for randomized control trials on the effect of blood pressure-lowering medications compared with placebo in participants with episodic migraine. Data were collected on four outcomes - monthly headache or migraine days, and monthly headache or migraine attacks, with a standardised mean difference calculated for overall. Random effect meta-analysis was performed. In total, 50 trials (70% of which were crossover) were included, comprising 60 comparisons. Overall mean age was 39 years, and 79% were female. Monthly headache days were fewer in all classes compared to placebo, and this was statistically significant for all but one class: alpha-blockers -0.7 (95% CI: -1.2, -0.1), angiotensin-converting enzyme inhibitors -1.3 (95% CI: -2.9, 0.2), angiotensin II receptor blockers -0.9 (-1.6, -0.1), beta-blocker -0.4 (-0.8, -0.0) and calcium channel blockers -1.8 (-3.4, -0.2). Standardised mean difference was significantly reduced for all drug classes and was separately significant for numerous specific drugs: clonidine, candesartan, atenolol, bisoprolol, metoprolol, propranolol, timolol, nicardipine and verapamil. Among people with episodic migraine, a broader number of blood pressure-lowering medication classes and drugs reduce headache frequency than those currently included in treatment guidelines.Trial Registration: The study was registered at PROSPERO (CRD42017079176).


Hybrid allele-specific ChIP-seq analysis identifies variation in brassinosteroid-responsive transcription factor binding linked to traits in maize.
Genetic variation in regulatory sequences that alter transcription factor (TF) binding is a major cause of phenotypic diversity. Brassinosteroid is a growth hormone that has major effects on plant phenotypes. Genetic variation in brassinosteroid-responsive cis-elements likely contributes to trait variation. Pinpointing such regulatory variations and quantitative genomic analysis of the variation in TF-target binding, however, remains challenging. How variation in transcriptional targets of signaling pathways such as the brassinosteroid pathway contributes to phenotypic variation is an important question to be investigated with innovative approaches. Here, we use a hybrid allele-specific chromatin binding sequencing (HASCh-seq) approach and identify variations in target binding of the brassinosteroid-responsive TF ZmBZR1 in maize. HASCh-seq in the B73xMo17 F1s identifies thousands of target genes of ZmBZR1. Allele-specific ZmBZR1 binding (ASB) has been observed for 18.3% of target genes and is enriched in promoter and enhancer regions. About a quarter of the ASB sites correlate with sequence variation in BZR1-binding motifs and another quarter correlate with haplotype-specific DNA methylation, suggesting that both genetic and epigenetic variations contribute to the high level of variation in ZmBZR1 occupancy. Comparison with GWAS data shows linkage of hundreds of ASB loci to important yield and disease-related traits. Our study provides a robust method for analyzing genome-wide variations of TF occupancy and identifies genetic and epigenetic variations of the brassinosteroid response transcription network in maize.


Cannabis for morning sickness: areas for intervention to decrease cannabis consumption during pregnancy.
Cannabis use during pregnancy is increasing, with 19-22% of patients testing positive at delivery in Colorado and California. Patients report using cannabis to alleviate their nausea and vomiting, anxiety, and pain. However, preclinical and clinical data highlight harmful effects to offspring physiology and behavior following fetal cannabis exposure. This narrative review identifies potential areas for intervention to decrease cannabis consumption during pregnancy. A combination of keywords, including "cannabis", "cannabis", "weed", "pregnancy", "morning sickness", "child protective services", and "budtender" were searched in databases such as PubMed and Google Scholar, as well as in social media forums, governmental webpages, and other publicly available sources. The literature search identified several areas for intervention to reduce cannabis use during pregnancy, including physician and pharmacist training, engagement with pregnant patients, regulation of dispensary workers, and the role of child protective services. This comprehensive review identifies multiple areas for improvement to benefit pregnant patients. Recommendations are independent and can be implemented simultaneously by the identified groups. Limitations of this research includes the relatively limited availability of data focused specifically on cannabis consumption during pregnancy and the complexity of the sociopolitical field of substance use during pregnancy. Cannabis consumption during pregnancy is increasing and causes harm to the developing fetus. To educate pregnant patients about these risks, we must address the gaps in education from multiple contact points.


MARCH5-mediated quality control on acetylated Mfn1 facilitates mitochondrial homeostasis and cell survival.
Mitochondrial dynamics and quality control have a central role in the maintenance of cellular integrity. Mitochondrial ubiquitin ligase membrane-associated RING-CH (MARCH5) regulates mitochondrial dynamics. Here, we show that mitochondrial adaptation to stress is driven by MARCH5-dependent quality control on acetylated Mfn1. Under mitochondrial stress conditions, levels of Mfn1 were elevated twofold and depletion of Mfn1 sensitized these cells to apoptotic death. Interestingly, overexpression of Mfn1 also promoted cell death in these cells, indicating that a fine tuning of Mfn1 levels is necessary for cell survival. MARCH5 binds Mfn1 and the MARCH5-dependent Mfn1 ubiquitylation was significantly elevated under mitochondrial stress conditions along with an increase in acetylated Mfn1. The acetylation-deficient K491R mutant of Mfn1 showed weak interaction with MARCH5 as well as reduced ubiquitylation. Neither was observed in the acetylation mimetic K491Q mutant. In addition, MARCH5-knockout mouse embryonic fibroblast and MARCH5(H43W)-expressing HeLa cells lacking ubiquitin ligase activity experienced rapid cell death upon mitochondrial stress. Taken together, a fine balance of Mfn1 levels is maintained by MARCH5-mediated quality control on acetylated Mfn1, which is crucial for cell survival under mitochondria stress conditions.


Vibrational spectroscopic characterization of the phosphate mineral bermanite-Mn2+Mn2(3+)(PO4)2(OH)2·4(H2O).
Bermanite Mn(2+)Mn(2)(3+)(PO(4))(2)(OH)(2)·4(H(2)O) is a mixed valent hydrated hydroxy phosphate mineral. The mineral is reddish-brown and occurs in crystal aggregates and as lamellar masses. Bermanite is a common mineral in granitic pegmatites. The chemical composition of bermanite was obtained using EDS techniques. We have studied the molecular structure of bermanite using vibrational spectroscopy. The mineral is characterized by a Raman doublet at 991 and 999 cm(-1) attributed to the phosphate stretching mode of two non-equivalent phosphate units. Raman bands at 1071, 1117 and 1142 cm(-1) are assigned to the phosphate antisymmetric stretching modes. The hydroxyl stretching spectral region is complex with overlapping bands attributed to water and hydroxyl stretching vibrations. Vibrational spectroscopy proves most useful for the study of the mineral bermanite.


Vaginal microbicides: where are we and where are we going?
The epidemic of HIV has catalyzed the need for safe and effective prevention methods, particularly for women. Vaginal microbicides have been targeted because these methods can be controlled by women themselves. Microbicides have focused on preventing HIV as well as other sexually transmitted infections, because the acquisition of HIV is enhanced by the presence of many infections. Although many products show promise in preclinical trials, safety remains paramount. The importance of safety was exemplified by the nonoxynol-9 studies which showed actual harm. This experience catalyzed the development of criteria that should be used as safety standards in trials, including immune markers of the cervical epithelium, and colposcopy standards. Unfortunately, immune markers are in their infant stages of development and reliability and validity checks remain large challenges. There have been four recent phase IIb/III trials that had disappointing results. However, these trials offer an opportunity to develop new preclinical models and biomarkers. The search for new microbicides remains critical. Current microbicides in trials can be categorized into vaginal defense enhancers (which help maintain the vaginal pH or facilitate the colonization of vaginal lactobacilli); surfactants (or detergents) which disrupt viral membranes; HIV entry inhibitors; and HIV reverse transcriptase inhibitors. Even with a good product, acceptance by both partners will be essential for its success, and lack of acceptance is often not evident until large trials are completed.


AFM characterization of spin coated carboxylated polystyrene nanospheres/xyloglucan layers on mica and silicon.
Self-assembled nano-arrays have a potential application as solid-phase diagnostics in many biomedical devices. The easiness of its production is directly connected to manufacture cost reduction. In this work, we present self-assembled structures starting from spin coated thin films of carboxylated polystyrene (PSC) and xyloglucan (XG) mixtures on both mica and silicon substrates. AFM images showed PSC nanospheres on top of a homogeneous layer of XG, for both substrates. The average nanosphere diameter fluctuated for a constant speed and it was likely to be independent of the component proportions on the mixture within a range of 30-50% (v/v) PSC. It was also observed that the largest diameters were found at the center of the sample and the smallest at the border. The detected nanospheres were also more numerous at the border. This behavior presents a similarity to spin coated colloidal dispersions. We observed that the average nanosphere diameter on mica substrates was bigger than the nanosphere diameters obtained on top of silicon substrates, under the same conditions. This result seems to be possibly connected to different mixture-surface interactions.


Improving venous thromboembolism prevention processes and outcomes at a community hospital.
Venous thromboembolism (VTE) is a cause of significant morbidity and mortality in hospitalized patients in the United States. Quality improvement (QI) strategies to increase the rates of prophylaxis in patients at-risk for VTE have been shown to be successful. The development of a formal, active strategy addressing the prevention of VTE, as a written, institutionwide VTE prophylaxis policy, presents a challenge for hospitals In 2007 a multidisciplinary VTE committee was initiated to develop and implement a hospitalwide QI program to standardize VTE risk assessment and prophylaxis prescribing practices at Saint Francis Hospital (Tulsa, Oklahoma). The QI program included clinician education, VTE order set and electronic trigger implementation, and changes in mechanical prophylaxis usage. The VTE prophylaxis order set was successfully piloted and implemented hospitalwide within three months of the project's initiation. Standardization of VTE prophylaxis practices across surgical and medical specialties was the key aim of this QI program. As a result, patient-related outcomes were also improved. The number of hospital-acquired VTE events decreased from 123 (0.39%) in 2008 to 99 (0.32%) in 2009 and 87 (0.27%) in 2010, and a reduction in the VTE rate between 2008 and 2010 of 31.6%. There was a significant decrease between 2008 and 2010 in the number of hospital-acquired VTE events (p = .035). Keys to the success of this QI program included leveraging multidisciplinary VTE committee members, physician champions, multiple approaches to communication and education, and providing evidence to support the changes. Sharing the hospital's QI process may provide a model for other hospitals challenged with developing and sustaining positive outcomes in patients at risk for VTE.


Arc welders' respiratory health evolution over five years.
The respiratory health of 138 arc welders and 106 control subjects in the same company was studied in 1981 and in 1986. Most of the subjects welded mild steel using the Metal Inert Gas (MIG) process. The controls were workers in the same company, not exposed to any known pulmonary risk. The welders and controls in the analysis had not changed their professional activity nor their smoking habits during these five years. The examinations consisted of a questionnaire on respiratory symptoms, a thoracic auscultation, a chest X-ray and lung function tests: flow-volume curve and steady state CO transfer test. The examinations in 1986 confirmed the risk of non specific radiological impairment (pulmonary reticulo-micronodulation) and of obstruction in the small bronchi, which had already been observed in 1981 in the arc welders in this company. These impairments did not seem to have evolved more than in the controls, but do however justify regular surveillance of the respiratory health of arc welders.


Interaction of myelin basic protein, melittin and bovine serum albumin with gangliosides, sulphatide and neutral glycosphingolipids in mixed monolayers.
Some parameters that may regulate the miscibility and stability of mixed lipid-protein monolayers at the air-145 mM NaCl interface were studied employing six glycosphingolipids (acidic or neutral), three different types of proteins (soluble, extrinsic or highly amphipathic) and some phospholipids. The results obtained show that the percentage of the total area occupied by the protein at the interface is an important parameter leading to lateral phase separations; the amount and area contribution of the protein accepted in the film before the components become immiscible increase with the complexity of the polar head group of the glycosphingolipids. The interactions occur with progressive reductions of the intermolecular packing as the polar head group of the glycosphingolipid becomes more complex and this is accompanied by more negative values of the excess free energy of mixing. The lipid component seems to be the major responsible for the reduction in mean molecular area.


An in vitro injury model for SH-SY5Y neuroblastoma cells: effect of strain and strain rate.
There is a great need to have in vitro cell injury model wherein a wide range of strain (ɛ) and strain rate (ε˙) can be precisely and independently applied. Such a model will enable exploration of various biomechanical loading conditions cells normally encounter during either blunt or blast impact-induced traumatic brain injuries (TBIs). In combination with a highly automated data acquisition and analysis system, this method can quickly generate a large data set of experimental results to yield identification of bio-mechanical and chemical sequelae following injury. A proper understanding of these sequelae will enable the discovery of the time window of opportunity available for pharmacological interventions. In this study we present such an injury model, a modified version of the Cultured Axonal Injury (CAI) device, and demonstrate its efficacy through viability of SH-SY5Y cells at different ranges of strain (0-140%) and strain rate (15-68 s⁻¹). We identified three different regimes in the stretch-induced dose-response of curves of SH-SY5Y cells, with a very sharp decline from live to dead in a narrow range of strain (30-55%). The effect of strain rate is minimal when the final strain in the cells was fixed at 50%. The model further shows that time-after-injury plays a vital role in the determination of recovery-deterioration pathways and the biological selection depends on the severity of initial injury. These data point out the initial strain level is vital to the cell fate and emphasize the need to study the various mechanisms triggered by different magnitudes of initial injuries.


Hearing threshold and physical performance in older people: a cross-sectional study from the HUNT4 cohort.
To evaluate the association between increased hearing loss and reduced physical performance in older people. Cross-sectional population-based study using data from the fourth wave of the Trøndelag Health Survey (HUNT4) in Norway. Data were obtained from the subproject HUNT4 Hearing which collected audiometric data of people > 70 years (N = 13,197). Analyses were performed on all participants who had completed audiometry and measured balance using the Short Physical Performance Battery (SPPB), which was scored from 0 (worst score) to 12. The hearing threshold was expressed as a pure tone average (PTA). Associations between the hearing threshold for the best and worst ear and physical performance were analyzed by linear regression models adjusted for age, sex, education, diabetes, and cardiovascular disease. Hearing threshold was indicated with steps of 10 dB. Of 13,197 eligible participants, 4101 who completed audiometry and SPPB (52.3% women. mean age 76.3 years) were included. The analyses revealed an association between reduced SPPB and increased hearing threshold in the best ear (b = - 0.296; 95% CI - 0.343 to - 0. 249; P < 0.001) and the worst ear (b = - 0.229; 95% CI - 0.270 to - 0.189; P < 0.001). In this population study, we found that the increased hearing threshold was associated to reduced physical performance as measured by SPPB. The association seemed to be strongest for the best ear. The association between hearing threshold and physical performance illustrates the importance of assessing physical performance in people with hearing loss to prevent the risk of falls and disability. The underlying causes of the associations between hearing loss and poorer physical performance are not fully understood and should be further investigated. Level 3.


European aquatic ecological assessment methods: A critical review of their sensitivity to key pressures.
The European Union has embarked on a policy which aims to achieve good ecological status in all surface waters (i.e. rivers, lakes, transitional and coastal waters). In theory, ecological status assessment methods should address the effects of all relevant human pressures. In this study, we analyze the degree to which methods European countries use to assess ecological status tackle various pressures affecting European waters. Nutrient pollution is by far the best-covered pressure for all four water categories. Out of total of 423 assessment methods, 370 assess eutrophication and pressure-specific relationships have been demonstrated for 212 of these. "General degradation" is addressed by 238 methods, mostly validated by relationships to combined pressure indices. Other major pressures have received significantly less effort: hydromorphological degradation is assessed by 160 methods and pressure-specific relationships have been demonstrated for just 40 of these. Hydromorphological pressures are addressed (at least by one BQE) only by 25% countries for coastal waters and 70-80% for lakes and transitional waters. Specific diagnostic tools (i.e. single-pressure relationships) for hydromorphology have only been developed by a few countries: only 20% countries have such methods for lakes, coastal and transitional waters and less than half for rivers. Toxic contamination is addressed by 90 methods; however, pressure-specific relationships have been demonstrated for just eight of these. Only two countries have demonstrated pressure-specific acidification methods for rivers, and three for lakes. In summary, methods currently in use mostly address eutrophication and/or general degradation, but there is not much evidence that they reliably pick up the effects of other significant pressures such as hydromorphology or toxic contamination. Therefore, we recommend that countries re-examine: (1) those pressures which affect different water categories in the country; (2) relevant assessment methods to tackle those pressures; (3) whether pressure-response relationships have been developed for each of these.


Promoting β-cells function by the recapitulation of in vivo microenvironmental differentiation signals.
The study aims to transdifferentiate rat bone marrow-derived mesenchymal stem cells (BM-MSCs) more efficiently into islet-like cells and encapsulate and transplant them with vital properties like stability, proliferation, and metabolic activity enhanced for the treatment of T1DM. Trans-differentiation of BM-MCs into islet-like cells induced by high glucose concentration combined with Nicotinamide, ꞵ-Mercaptoethanol, ꞵ-Cellulin, and IGF-1. Glucose challenge assays and gene expression profiles were used to determine functionality. Microencapsulation was performed using the vibrating nozzle encapsulator droplet method with a 1% alginate concentration. Encapsulated ꞵ-cells were cultured in a fluidized-bed bioreactor with 1850 μL/min fluid flow rates and a superficial velocity of 1.15 cm/min. The procedure was followed by transplanting transdifferentiated cells into the omentum of streptozotocin (STZ)-induced diabetic Wistar rats. Changes in weight, glucose, insulin, and C-peptide levels were monitored for 2 months after transplantation. PDX1, INS, GCG, NKx2.2, NKx6.1, and GLUT2 expression levels revealed the specificity of generated β-cells with higher viability (about 20%) and glucose sensitivity about twofold more. The encapsulated β-cells decreased the glucose levels in STZ-induced rats significantly (P < 0.05) 1 week after transplantation. Also, the weight and levels of insulin and C-peptide reached the control group. In contrast to the treated, the sham group displayed a consistent decline in weight and died when loss reached > 20% at day ~ 55. The coated cells secrete significantly higher amounts of insulin in response to glucose concentration changes. Enhanced viability and functionality of β-cells can be achieved through differentiation and culturing, a promising approach toward insulin therapy alternatives.


Phospholipid metabolism in calcium-regulated differentiation in cultured murine keratinocytes.
The present findings associate phospholipid alteration, particularly the turnover of phosphatidylinositol, in Ca2+ induced differentiation of keratinocytes. These conclusions are based on the hydrolysis of 14C-AA from prelabeled PI and the accumulation 14C-DG and 14C-PA after cells are switched from low to normal concentrations of extracellular Ca2+. This novel finding implies that the biological changes which accompany keratinocyte differentiation after switch from low to normal extracellular medium may be due at least in part to increased accumulation of PA and DG which are major deacylation and reacylation products of phosphatidylinositol. A second interesting finding in these studies is the marked transformation of 14C-AA into lipoxygenase products by proliferating keratinocytes cultured in low Ca2+ medium when compared to differentiating cells cultured in normal Ca2+. The significance of decreased generation of lipoxygenase products in epidermal differentiation deserve further exploration.


Retrosplenial amnesia without topographic disorientation caused by a lesion in the nondominant hemisphere.
We report the case of a 68-year-old right-handed man who was admitted to our hospital because of sudden onset of headache. On admission, he presented with left homonymous hemianopsia, disorientation, and recent memory disturbance; however, he had normal remote memory and digit span. He was able to recall the room layout of his house and describe the route from the nearest station to his home on a map. However, at the hospital, he sometimes lost his way because of amnesia. Computed tomography (CT) and magnetic resonance imaging revealed a subcortical hematoma in the right occipital forceps and the parietal lobe, involving the cingulate isthmus. Single-photon emission CT imaging showed reduced perfusion not only in the retrosplenial region but also in the right thalamus. These findings suggested that the retrosplenial amnesia might have been caused by the interruption of hippocampal input into the anterior thalamus.


A detailed open access model of the PubMed literature.
Portfolio analysis is a fundamental practice of organizational leadership and is a necessary precursor of strategic planning. Successful application requires a highly detailed model of research options. We have constructed a model, the first of its kind, that accurately characterizes these options for the biomedical literature. The model comprises over 18 million PubMed documents from 1996-2019. Document relatedness was measured using a hybrid citation analysis + text similarity approach. The resulting 606.6 million document-to-document links were used to create 28,743 document clusters and an associated visual map. Clusters are characterized using metadata (e.g., phrases, MeSH) and over 20 indicators (e.g., funding, patent activity). The map and cluster-level data are embedded in Tableau to provide an interactive model enabling in-depth exploration of a research portfolio. Two example usage cases are provided, one to identify specific research opportunities related to coronavirus, and the second to identify research strengths of a large cohort of African American and Native American researchers at the University of Michigan Medical School.


On the programmed/non-programmed nature of ageing within the life history.
Understanding why and how senescence evolved is of great importance in investigating the multiple, complex mechanisms that influence the course of ageing in humans and other organisms. Compelling arguments eliminate the idea that death is generally programmed by genes for ageing, but there is still a widespread tendency to interpret data in terms of loosely defined 'age regulation', which does not usually make either evolutionary or mechanistic sense. This review critically addresses the role of natural selection in shaping ageing within the life history and examines the implications for research on genetic pathways that influence the life span. It is recognised that in exceptional circumstances the possibility exists for selection to favour limiting survival. In acknowledging that, at least in theory, ageing might occasionally be adaptive, however, the high barriers to validating actual instances of adaptive ageing are made clear.


Multiparent intercross populations in analysis of quantitative traits.
Most traits of interest to medical, agricultural and animal scientists show continuous variation and complex mode of inheritance. DNA-based markers are being deployed to analyse such complex traits, that are known as quantitative trait loci (QTL). In conventional QTL analysis, F2, backcross populations, recombinant inbred lines, backcross inbred lines and double haploids from biparental crosses are commonly used. Introgression lines and near isogenic lines are also being used for QTL analysis. However, such populations have major limitations like predominantly relying on the recombination events taking place in the F1 generation and mapping of only the allelic pairs present in the two parents. The second generation mapping resources like association mapping, nested association mapping and multiparent intercross populations potentially address the major limitations of available mapping resources. The potential of multiparent intercross populations in gene mapping has been discussed here. In such populations both linkage and association analysis can be conductted without encountering the limitations of structured populations. In such populations, larger genetic variation in the germplasm is accessed and various allelic and cytoplasmic interactions are assessed. For all practical purposes, across crop species, use of eight founders and a fixed population of 1000 individuals are most appropriate. Limitations with multiparent intercross populations are that they require longer time and more resource to be generated and they are likely to show extensive segregation for developmental traits, limiting their use in the analysis of complex traits. However, multiparent intercross population resources are likely to bring a paradigm shift towards QTL analysis in plant species.


Excitation Energies in Time-Dependent (Current-) Density-Functional Theory: A Simple Perspective.
This paper gives a simple and pedagogical explanation, using density matrices of two-level systems, how to calculate excitation energies with time-dependent density-functional theory. The well-known single-pole approximation for excitation energies is derived here in an alternative way and extended to time-dependent current-density-functional theory.


Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB.
Site-directed mutagenesis experiments have suggested a model for the inactivation mechanism of Shaker potassium channels from Drosophila melanogaster. In this model, the first 20 amino acids form a cytoplasmic domain that interacts with the open channel to cause inactivation. The model was tested by the internal application of a synthetic peptide, with the sequence of the first 20 residues of the ShB alternatively spliced variant, to noninactivating mutant channels expressed in Xenopus oocytes. The peptide restored inactivation in a concentration-dependent manner. Like normal inactivation, peptide-induced inactivation was not noticeably voltage-dependent. Trypsin-treated peptide and peptides with sequences derived from the first 20 residues of noninactivating mutants did not restore inactivation. These results support the proposal that inactivation occurs by a cytoplasmic domain that occludes the ion-conducting pore of the channel.


Molecular diagnosis of human cancer type by gene expression profiles and independent component analysis.
The precise diagnosis of cancer type based on microarray data is of particular importance and is also a challenging task. We have devised a novel pattern recognition procedure based on independent component analysis (ICA). Different from the conventional cancer classification methods, which are limited in their clinical applicability of cancer diagnosis, our method extracts explicitly, by ICA algorithm, a set of specific diagnostic patterns of normal and tumor tissues corresponding to a set of biomarkers for clinical use. We validated our procedure with the colon and prostate cancer data sets and achieved good diagnosis (>90%) on the data sets studied here. This technique is also suitable for the identification of diagnostic expression patterns for other human cancers and demonstrates the feasibility of simple and accurate molecular cancer diagnostics for clinical implementation.


Impacts of skin disorders associated with facial discoloration on quality of life: Novel insights explaining discordance between life quality scores and willingness to pay.
How diseases associated with skin discoloration affect the quality of life (QoL) has rarely been examined. In this study, we directly compared the QoL and willingness to pay (WTP) among patients with skin disorders associated with facial discoloration. A single-center, cross-sectional study consisting of patients seeking treatment for facial discoloration was performed. All patients completed the dermatology life quality index (DLQI) and the short form 36 (SF-36) health survey questionnaires. Additionally, information regarding monthly income and the WTP for a complete cure of the affected condition was obtained. Patients with melasma (58), lentigo (56), postinflammatory hyperpigmentation (5), vitiligo (51), acne-induced erythema (10), and rosacea (31) were enrolled. Vitiligo, acne-induced erythema, and rosacea patients reported significantly worse QoL compared to lentigines or melasma patients as evaluated by DLQI. Using SF-36, rosacea patients were affected mentally the most as they reported the worst mental component scores, and the scores were significantly worse than that of melasma patients (rosacea vs. melisma = 46.5 vs. 52.7, p = 0.007). Vitiligo patients had the worst general health scores. Although there were no differences in the WTP among different diseases, the vitiligo group had the highest percentage of patients willing to pay more than 40% of their monthly income for a complete cure. The impact on QoL is different among skin diseases associated with facial discoloration. Only vitiligo patients reported worse general health as compared to the general population, explaining the discordance between life quality scores and WTP in these patients.


P21 facilitates macrophage chemotaxis by promoting CCL7 in the lung epithelial cell lines treated with radiation and bleomycin.
Interstitial lung diseases (ILDs) can be induced and even exacerbated by radiotherapy in thoracic cancer patients. The roles of immune responses underlying the development of these severe lung injuries are still obscure and need to be investigated. A severe lung damage murine model was established by delivering 16 Gy X-rays to the chest of mice that had been pre-treated with bleomycin (BLM) and thus hold ILDs. Bioinformatic analyses were performed on the GEO datasets of radiation-induced lung injury (RILI) and BLM-induced pulmonary fibrosis (BIPF), and RNA-sequencing data of the severely damaged lung tissues. The screened differentially expressed genes (DEGs) were verified in lung epithelial cell lines by qRT-PCR assay. The injured lung tissue pathology was analyzed with H&E and Masson's staining, and immunohistochemistry staining. The macrophage chemotaxis and activity promoted by the stressed epithelial cells were determined by using a cell co-culture system. The expressions of p21 in MLE-12 and Beas-2B cells were detected by qRT-PCR, western blot, and immunofluorescence. The concentration of CCL7 in cell supernatant was measured by ELISA assay. In some experiments, Beas-2B cells were transfected with p21-siRNA or CCL7-siRNA before irradiation and/or BLM treatment. After the treatment of irradiation and/or BLM, the inflammatory and immune responses, chemokine-mediated signaling pathways were steadily activated in the severely injured lung, and p21 was screened out by the bioinformatic analysis and further verified to be upregulated in both mouse and human lung epithelial cell lines. The expression of P21 was positively correlated with macrophage infiltration in the injured lung tissues. Co-culturing with stressed Beas-2B cells or its conditioned medium containing CCL7 protein, U937 macrophages were actively polarized to M1-phase and their migration ability was obviously increased along with the damage degree of Beas-2B cells. Furthermore, knockdown p21 reduced CCL7 expression in Beas-2B cells and then decreased the chemotaxis of co-cultured macrophages. P21 promoted CCL7 release from the severely injured lung epithelial cell lines and contributed to the macrophage chemotaxis in vitro, which provides new insights for better understanding the inflammatory responses in lung injury.


Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.
The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.


Temperature-dependent CD and NMR studies on a synthetic oligonucleotide containing a B-Z junction at high salt.
It is now accepted that two or more conformations may exist within the same DNA molecule, thereby generating conformational junctions. The presence of B-Z junctions between right- and left-handed DNA conformations has been detected in plasmids by a number of techniques. Preliminary characterization of the first example of a B-Z junction is a short DNA oligonucleotide has recently been reported [Sheardy, R. D. (1988) Nucleic Acids Res. 16, 1153-1167]. We report additional CD and NMR data that support the existence of the junction in this model oligomer. These studies indicate that only three base pairs are involved in the junction and only one of these is dramatically distorted. Furthermore, the NMR saturation-transfer experiments suggest the junction's internal motion is temperature dependent.


Dscam in immunity: A question of diversity in insects and crustaceans.
In insects and crustaceans, thousands of Down syndrome cell adhesion molecules (Dscam) can be generated by alternative splicing of variable exons from a single-locus gene, Dscam-hv. This extraordinarily versatile gene (38,016 protein isoforms produced in Drosophila) was first proposed to be involved in exon guidance and subsequently implicated in immunity as a hypervariable immune molecule. Almost 20 y after discovery of Dscam-hv, there have been many studies in insects and crustaceans regarding roles of Dscam in immunity, with many similarities and concurrently, many differences. Here, we review the current status of Dscam-hv, presented as a comparison of similarities and differences in insects and crustaceans and discuss hypotheses of Dscam functions in immunity.


Simultaneously increased expression of microRNA-155 and suppressor of cytokine signaling 1 (SOCS1) gene in the peripheral blood mononuclear cells of patients with primary Sjögren's syndrome.
The microRNA-155 (miR-155) is regarded as a central modulator of T-cell responses and could be a potential therapeutic target for certain inflammatory diseases. In our present study we analyzed the expression rate of miR-155 and its functionally linked gene, the suppressor gene of cytokine signaling 1 (SOCS1) in primary Sjögren's syndrome (pSS). We enrolled 23 pSS patients and 10 healthy individuals in the study. The expression of miR-155 and SOCS1 gene were measured by real-time polymerase chain reaction. We observed the over-expression of miR-155 in the peripheral mononuclear cells of patients with pSS. Surprisingly, SOCS1 gene was also over-expressed in pSS patients. This unanticipated phenomenon might be a laboratory characteristic of Sjögren's syndrome, and presumably a consequence of the noteworthy difference in the pSS immune system reacting with Epstein-Barr virus.


Performance of the nitrogen removal, bioactivity and microbial community responded to elevated norfloxacin antibiotic in an Anammox biofilm system.
Antibiotic pollution in nitrogen contained wastewater is an urgent issue. In this study, the nitrogen removal, biofilm property and microbial community of Anammox system were investigated with elevated norfloxacin (NOR) feeding. Batch experiments were carried out to detect the specific anammox activity (SAA) in each phase. Anammox system could resist NOR in 0.001-50 mg L-1, in which the nitrogen removal was firstly limited to 0.220 from the initial 0.345 by NOR suppression and then regained to 0.354 kg m-3 d-1 after acclimatization. SAA decreased to 7.56 from the initial 10.84 and then climbed up to 11.01 mg g-1 SS, while the relative abundance of Candidatus Kuenenia decreased to 11.33% and then picked up to 25.28% from the initial 20.74%. The suppression threshold on Anammox was calculated as 50-100 mg L-1 NOR, the NRR, SAA and Candidatus Kuenenia abundance all recovered to almost the initial level when NOR feeding was terminated.


Animal models of depression and neuroplasticity: assessing drug action in relation to behavior and neurogenesis.
Depression is among the most prevalent forms of mental illness and a major cause of morbidity worldwide. Diagnosis of depression is mainly based on symptomatic criteria, and the heterogeneity of the disease suggests that multiple different biological mechanisms may underlie its etiology. Animal models have been important for recent advances in experimental neuroscience, including modeling of human mood disorders, such as depression and anxiety. Over the past few decades, a number of stress and neurobiochemical models have been developed as primary efficacy measures in depression trials, which are paving the way for the discovery of novel therapeutic targets. Recent data indicates that stress-related mood disorders have influence on neuroplasticity and adult neurogenesis. In this chapter, several currently available animal models are presented as powerful tools for both mechanistic studies into the neurobiology of the antidepressant response and for drug discovery.


Visual Training in Virtual Reality in Adult Patients with Anisometric Amblyopia.
Amblyopia is one of the most common childhood disease. The average prevalence of amblyopia in children is estimated at 2-5 %. It arises during the child development until the age of six, if not treated then, it persist throught adulthood. The aim of our work is to retrospectively analyze the results of treatment of anisometropic amblyopia using dichoptical training in virtual reality in adult amblyopic patients. Our group consisted of 84 amblyopic patients with anisometropic amblyopia with an average age of 33.8 ± 9.4 years. Patients played a video game twice a week in the Oculus Rift 3D virtual reality. Together they completed 8 visual trainings, with one training lasting 60 minutes. Before and after the training we evaluated the best corrected visual acuity (BCVA). Throughout the group, we observed an improvement of 0.1 BCVA from 0.48 to 0.58 Sloan table (p.


Placental Pathology and Its Associations With Clinical Signs in Different Subtypes of Fetal Growth Restriction.
We evaluated placental alterations in different subtypes of fetal growth restriction (FGR) to determine any clinical associations. FGR placentas classified according to the Amsterdam criteria were correlated with clinical findings. Percentage of intact terminal villi and villous capillarization ratio were calculated in each specimen. Correlations of placental histopathology and perinatal outcomes were studied. 61 FGR cases were studied. Early-onset-FGR was more often associated with preeclampsia and recurrence than late-onset-FGR; placentas from early-onset-FGR often had diffuse maternal (or fetal) vascular malperfusion and villitis of unknown etiology. Decreased percentage of intact terminal villi was associated with pathologic CTG. Decreased villous capillarization was associated with early-onset-FGR and birth weight below the second percentile. Avascular villi and infarction were more common when femoral length/abdominal circumference ratio was >0.26, and perinatal outcome was poor in this group. In early-onset-FGR and preeclamptic FGR, altered vascularization of villi may have a key role in pathogenesis, and recurrent FGR is associated with villitis of unknown etiology. There is an association between femoral length/abdominal circumference ratio >0.26 and histopathological alterations of placenta in FGR pregnancies. There are no significant differences in the percentage of intact terminal villi between different FGR subtypes by onset or recurrency.


Experiences in the molecular genetic and histopathological evaluation of calpainopathies.
Calpainopathy is mainly characterized by symmetric and progressive weakness of proximal muscles. Several reports showed that the most common LGMD subtype is LGMDR1 or calpainopathy, which had previously been defined as LGMD2A. Until now, more than 500 likely pathogenic/pathogenic variants in the CAPN3 gene have been reported. However, a clear genotype-phenotype association had not yet been established and this causes major difficulties in predicting the prognosis in asymptomatic patients and in providing genetic counseling for prenatal diagnosis. In this report, we aimed to add new data to the literature by evaluating 37 patients with likely pathogenic/pathogenic variants for the detected variants' nature, patients' phenotypes, and histopathological features. As a result, the general clinical presentation of the 23 different variants was presented, the high frequency of NM_000070.3:c.550delA mutation in Exon 4 was discussed, and some novel genotype-phenotype associations were suggested. We have underlined that calpainopathy can be misdiagnosed with inflammatory myopathies histopathologically. We have also emphasized that, in young or adult patients with mild to moderate proximal muscle weakness and elevated CK levels, calpainopathy should be the first suspected diagnosis.


Characterizing Marine Soundscapes.
The study of marine soundscapes is becoming widespread and the amount of data collected is increasing rapidly. Data owners (typically academia, industry, government, and defense) are negotiating data sharing and generating potential for data syntheses, comparative studies, analyses of trends, and large-scale and long-term acoustic ecology research. A problem is the lack of standards and commonly agreed protocols for the recording of marine soundscapes, data analysis, and reporting that make a synthesis and comparison of results difficult. We provide a brief overview of the components in a marine soundscape, the hard- and software tools for recording and analyzing marine soundscapes, and common reporting formats.


Phase II study of spirogermanium in patients with advanced colorectal carcinoma.
Twenty one evaluable patients with advanced colorectal carcinoma were treated with continuous infusion of spirogermanium at a median daily dose of 150 mg/m2 (range 120-210) for five consecutive days every 14 days. Treatments were accomplished by using outpatient infusion devices. Fifteen patients had not received any prior radiation therapy, immunotherapy, or chemotherapy. Nineteen patients were previously untreated with chemotherapy. Five patients had received prior immunotherapy with copovithane and only two patients had received radiation therapy prior to spirogermanium therapy. None of the patients achieved a complete or partial remission. Minor tumor regressions were observed in two patients, both were less than 12 weeks in duration. The major toxicities included nausea and vomiting and neurologic side effects; however, the toxicity was completely reversible. Spirogermanium is not effective in the treatment of patients with advanced colorectal carcinoma.