Pulmonary involvement in catastrophic antiphospholipid syndrome: A descriptive analysis from the "CAPS Registry".
To describe the pulmonary involvement in patients with catastrophic antiphospholipid syndrome (CAPS), focusing on its relationship with extrapulmonary involvement, laboratory, radiological, and pathological findings. This retrospective cross-sectional study includes all patients grouped in the "CAPS Registry". All cases were reviewed, and those with pulmonary thromboembolism (PE) and/or diffuse alveolar hemorrhage (DAH) were selected. Data on pulmonary and extrapulmonary clinical presentation, radiologic patterns, laboratory findings, associated autoimmune diseases, treatments, and outcomes were analyzed. Frequency distribution and measures of central tendency were used to describe the cohort. Comparison between groups regarding qualitative variables was undertaken by chi-square or Fisher exact test, while T-test for independent variables was used to compare groups regarding continuous variables. IBM-SPSS v.22 was used for data analysis. PE was reported in 129 (48.6 %) episodes, DAH in 75 (28.3 %) episodes, and overlap (DAH plus PE) in 7 (2.6 %) episodes. Bronchoalveolar lavage (BAL) was performed in 35 (4.9 %) CAPS episodes, and lung pathology samples were obtained in 84 (10.5 %) episodes (including autopsies). A significant relationship was observed between DAH and laboratory features of thrombotic microangiopathy (TMA). A meaningful relationship was also found between triple antiphospholipid antibody positivity and pathological TMA (26.5 %) as well as hypocomplementemia and DAH (24 %). Pulmonary involvement may include both TMA and non-thrombotic inflammation, which can be differentiated into three patterns: PE, DAH with systemic TMA with hypocomplementemia or DAH without systemic TMA with/without hypocomplementemia.


A prospective cohort study of patients with transient ischemic attack to identify high-risk clinical characteristics.
The occurrence of a transient ischemic attack (TIA) increases an individual's risk for subsequent stroke. The objectives of this study were to determine clinical features of patients with TIA associated with impending (≤7 days) stroke and to develop a clinical prediction score for impending stroke. We conducted a prospective cohort study at 8 Canadian emergency departments for 5 years. We enrolled patients with a new TIA. Our outcome was subsequent stroke within 7 days of TIA diagnosis. We prospectively enrolled 3906 patients, of which 86 (2.2%) experienced a stroke within 7 days. Clinical features strongly correlated with having an impending stroke included first-ever TIA, language disturbance, longer duration, weakness, gait disturbance, elevated blood pressure, atrial fibrillation on ECG, infarction on computed tomography, and elevated blood glucose. Variables less associated with having an impending stroke included vertigo, lightheadedness, and visual loss. From this cohort, we derived the Canadian TIA Score which identifies the risk of subsequent stroke≤7 days and consists of 13 variables. This model has good discrimination with a c-statistic of 0.77 (95% confidence interval, 0.73-0.82). Patients with TIA with their first TIA, language disturbance, duration of symptoms≥10 minutes, gait disturbance, atrial fibrillation, infarction on computed tomography, elevated platelets or glucose, unilateral weakness, history of carotid stenosis, and elevated diastolic blood pressure are at higher risk for an impending stroke. Patients with vertigo and no high-risk features are at low risk. The Canadian TIA Score quantifies the impending stroke risk following TIA.


Improvement of water-soluble cephalosporin derivatives having antibacterial activity against methicillin-resistant Staphylococcus aureus.
We evaluated a series of novel cephem antibiotics, N-alkylpyridinium (alkyl group), N-carboxyethylpyridinium (carboxylic group), N-sulfoethylpyridinium (sulfonic group) and N-alkylquaternary ammonium salts (ammonioethyl group), N-alkyl-aromatic-quaternary ammonium salts and N-alkyl-heterocyclic quaternary ammonium salts (cyclic group) as vinylthio pyridinium derivatives at the C-3 position and hydroxyiminoaminothiazol at the C-7 position, for their activity against methicillin-resistant Staphylococcus aureus (MRSA) and their solubility, by measuring the minimum inhibitory concentrations (MICs) and the dissolving test in phosphate buffer. All tested compounds, except for the alkyl group, showed good solubility (>10%) in 1/15 M phosphate buffer (pH 7.2). The concentrations required to inhibit 80% of the bacterial strains (MIC80s) of the alkyl group, carboxylic group, sulfonic group, ammonioethyl group and cyclic group against MRSA were 1.56, 12.5-25, 6.25, 1.56 and 1.56 microg/ml, respectively. These results indicated that the ammonioethyl and cyclic groups yield the maximum anti-MRSA and anti-Enterococcus faecalis activity, and also good water solubility.


Balanced Crystalloids versus Normal Saline in Adults with Sepsis: A Comprehensive Systematic Review and Meta-Analysis.
The crystalloid fluid of choice in sepsis remains debatable. We aimed to perform a comprehensive meta-analysis to compare the effect of balanced crystalloids (BC) vs. normal saline (NS) in adults with sepsis. A systematic search of PubMed, EMBASE, and Web of Sciences databases through 22 January 2022, was performed for studies that compared BC vs. NS in adults with sepsis. Our outcomes included mortality and acute kidney injury (AKI), need for renal replacement therapy (RRT), and ICU length of stay (LOS). Pooled risk ratio (RR) and mean difference (MD) with the corresponding 95% confidence intervals (CIs) were obtained using a random-effect model. Fifteen studies involving 20,329 patients were included. Overall, BC showed a significant reduction in the overall mortality (RR 0.88, 95% CI 0.81-0.96), 28/30-day mortality (RR 0.87, 95% CI 0.79-0.95), and AKI (RR 0.85, 95% CI 0.77-0.93) but similar 90-day mortality (RR 0.96, 95% CI 0.90-1.03), need for RRT (RR 0.91, 95% CI 0.76-1.08), and ICU LOS (MD -0.25 days, 95% CI -3.44, 2.95), were observed between the two groups. However, subgroup analysis of randomized controlled trials (RCTs) showed no statistically significant differences in overall mortality (RR 0.92, 95% CI 0.82-1.02), AKI (RR 0.71, 95% CI 0.47-1.06), and need for RRT (RR 0.71, 95% CI 0.36-1.41). Our meta-analysis demonstrates that overall BC was associated with reduced mortality and AKI in sepsis compared to NS among patients with sepsis. However, subgroup analysis of RCTs showed no significant differences in both overall mortality and AKI between the groups. There was no significant difference in the need for RRT or ICU LOS between BC and NS. Pending further data, our study supports using BC over NS for fluid resuscitation in adults with sepsis. Further large-scale RCTs are necessary to validate our findings.


Isomerization of the uncomplexed actinidin molecule: kinetic accessibility of additional steps in enzyme catalysis provided by solvent perturbation.
The effects of increasing the content of the aprotic dipolar organic co-solvent acetonitrile on the observed first-order rate constant (k(obs)) of the pre-steady state acylation phases of the hydrolysis of N-acetyl-Phe-Gly methyl thionester catalysed by the cysteine proteinase variants actinidin and papain in sodium acetate buffer, pH 5.3, were investigated by stopped-flow spectral analysis. With low acetonitrile content, plots of k(obs) against [S]0 for the actinidin reaction are linear with an ordinate intercept of magnitude consistent with a five-step mechanism involving a post-acylation conformational change. Increasing the acetonitrile content results in marked deviations of the plots from linearity with a rate minimum around [S]0=150 microM. The unusual negative dependence of k(obs) on [S]0 in the range 25-150 microM is characteristic of a rate-determining isomerization of the free enzyme before substrate binding, additional to the five-step mechanism. There was no evidence for this phenomenon nor for the post-acylation conformational change in the analogous reaction with papain. For this enzyme, however, acetonitrile acts as an inhibitor with approximately uncompetitive characteristics. Possible mechanistic consequences of the differential solvent-perturbed kinetics are indicated. The free enzyme isomerization of actinidin may provide an explanation for the marked difference in sensitivity between this enzyme and papain of binding site-catalytic site signalling in reactions of substrate-derived 2-pyridyl disulphide reactivity probes.


Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells.
Bi-allelic-inactivating mutations of the VHL tumor suppressor gene are found in the majority of clear cell renal cell carcinomas (VHL(-/-) RCC). VHL(-/-) RCC cells overproduce hypoxia-inducible genes as a consequence of constitutive, oxygen-independent activation of hypoxia inducible factor (HIF). While HIF activation explains the highly vascularized nature of VHL loss lesions, the relative role of HIF in oncogenesis and loss of growth control remains unknown. Here, we report that HIF plays a central role in promoting unregulated growth of VHL(-/-) RCC cells by activating the transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGF-R) pathway. Dominant-negative HIF and enzymatic inhibition of EGF-R were equally efficient at abolishing EGF-R activation and serum-independent growth of VHL(-/-) RCC cells. TGF-alpha is the only known EGF-R ligand that has a VHL-dependent expression profile and its overexpression by VHL(-/-) RCC cells is a direct consequence of HIF activation. In contrast to TGF-alpha, other HIF targets, including vascular endothelial growth factor (VEGF), were unable to stimulate serum-independent growth of VHL(-/-) RCC cells. VHL(-/-) RCC cells expressing reintroduced type 2C mutants of VHL, and which retain the ability to degrade HIF, fail to overproduce TGF-alpha and proliferate in serum-free media. These data link HIF with the overproduction of a bona fide renal cell mitogen leading to activation of a pathway involved in growth of renal cancer cells. Moreover, our results suggest that HIF might be involved in oncogenesis to a much higher extent than previously appreciated.


Exhaled leukotrienes and prostaglandins in asthma.
Most of the studies investigating the role of leukotrienes (LTs) and prostaglandins (PGs) in asthma have used invasive (eg, bronchoalveolar lavage fluid) or semi-invasive (eg, sputum induction) techniques. Others have measured eicosanoids in plasma or urine, probably reflecting systemic rather than lung inflammation. Collection of exhaled breath condensate (EBC) is a noninvasive method to collect airway secretions. We sought to investigate whether eicosanoids are measurable in EBC, to show possible differences in their concentrations in asthmatic patients and healthy subjects, and to investigate whether exhaled eicosanoids correlate with exhaled nitric oxide (NO), a marker of airway inflammation. Twelve healthy nonsmokers and 15 steroid-naive patients with mild asthma were studied. Subjects attended on one occasion for pulmonary function tests, collection of EBC, and exhaled NO measurements. Exhaled LTB(4)-like immunoreactivity, LTE(4)-like immunoreactivity, PGE(2)-like immunoreactivity, PGD(2)-methoxime, PGF(2)(alpha)-like immunoreactivity, and thromboxane B(2)-like immunoreactivity were measured by means of enzyme immunoassays. LTE(4)-like immunoreactivity and LTB(4)-like immunoreactivity were detectable in EBC in healthy subjects, and their levels in asthmatic patients were increased about 3-fold (P <.0001) and 2-fold (P <.0005), respectively. Exhaled NO was increased in asthmatic patients compared with healthy subjects (P <.0001). There was a correlation between exhaled LTB(4) and exhaled NO (r = 0.56, P <.04) in patients with asthma. When measurable, prostanoid levels were similar in asthmatic patients and control subjects. Exhaled LTE(4) and LTB(4) are increased in steroid-naive patients with mild asthma. EBC may be proved to be a novel method to monitor airway inflammation in asthma.


Analysis of expressed sequence tags from the harmful alga, Prymnesium parvum (Prymnesiophyceae, Haptophyta).
A cDNA library was constructed from late log-phase cultures of the ichthyotoxin-producing haptophyte, Prymnesium parvum. Approximately 6,300 single-pass 5' nucleotide sequences (out of nearly 8,000 randomly isolated clones) achieved length and quality criteria for incorporation into an expressed sequence tag (EST) database. Collectively, 3,415 unique genes (tentative unigenes [TUGs]) were assembled. Database searches revealed approximately 1,100 TUG (34%) that encode proteins of known or putative function (expect values E < or = 1.0 x 10(-10)), representing most functional classes of proteins and many metabolic pathways. In addition to proteins involved in photosynthesis and protein synthesis/degradation, one of the most frequently encountered transcripts putatively encodes an ABC-type phosphate transport system component. Active (and efficient?) phosphate transport may correlate with rapid growth, perhaps explaining how this alga out-competes other species when it blooms and becomes toxic under low-phosphate conditions. The majority of TUGs, including 12 of the 50 most commonly encountered transcripts, encode potentially novel proteins, some of which are probably involved in synthesis and secretion of the unique prymnesin toxins. This work suggests that future studies on the expression of many of these genes during rapid growth should provide insight into the genetic basis of bloom formation and toxicity.


Reactive nanostructured membranes for water purification.
Many current treatments for the reclamation of contaminated water sources are chemical-intensive, energy-intensive, and/or require posttreatment due to unwanted by-product formation. We demonstrate that through the integration of nanostructured materials, enzymatic catalysis, and iron-catalyzed free radical reactions within pore-functionalized synthetic membrane platforms, we are able to conduct environmentally important oxidative reactions for toxic organic degradation and detoxification from water without the addition of expensive or harmful chemicals. In contrast to conventional, passive membrane technologies, our approach utilizes two independently controlled, nanostructured membranes in a stacked configuration for the generation of the necessary oxidants. These include biocatalytic and organic/inorganic (polymer/iron) nanocomposite membranes. The bioactive (top) membrane contains an electrostatically immobilized enzyme for the catalytic production of one of the main reactants, hydrogen peroxide (H(2)O(2)), from glucose. The bottom membrane contains either immobilized iron ions or ferrihydrite/iron oxide nanoparticles for the decomposition of hydrogen peroxide to form powerful free radical oxidants. By permeating (at low pressure) a solution containing a model organic contaminant, such as trichlorophenol, with glucose in oxygen-saturated water through the membrane stack, significant contaminant degradation was realized. To illustrate the effectiveness of this membrane platform in real-world applications, membrane-immobilized ferrihydrite/iron oxide nanoparticles were reacted with hydrogen peroxide to form free radicals for the degradation of a chlorinated organic contaminant in actual groundwater. Although we establish the development of these nanostructured materials for environmental applications, the practical and methodological advances demonstrated here permit the extension of their use to applications including disinfection and/or virus inactivation.


Susceptibility of the Algal Toxin Microcystin-LR to UV/Chlorine Process: Comparison with Chlorination.
Microcystin-LR (MC-LR), an algal toxin (cyanotoxin) common in sources of drinking water, poses a major human health hazard due to its high toxicity. In this study, UV/chlorine was evaluated as a potentially practical and effective process for the degradation of MC-LR. Via mass spectrometry analysis, fewer chlorinated-MC-LR products were detected with UV/chlorine treatment than with chlorination, and a transformation pathway for MC-LR by UV/chlorine was proposed. Different degrees of rapid degradation of MC-LR were observed with varying pH (6-10.4), oxidant dosage (0.5-3 mg L-1), natural organic matter (0-7 mg L-1), and natural water sources. In contrast to the formation of primarily chloroform and dichloroacetic acid in deionized water where MC-LR serves as the only carbon source, additional chlorinated disinfection byproducts were produced when sand filtered natural water was used as a background matrix. The UV/chlorine treated samples also showed quantitatively less cytotoxicity in vitro in HepaRG human liver cell line tests than chlorination treated samples. Following 16 min (96 mJ cm-2) of UV irradiation combined with 1.5 mg L-1 chlorine treatment, the cell viability of the samples increased from 80% after exposure to 1 mg L-1 MC-LR to 90%, while chlorination treatment evidenced no reduction in cytotoxicity with the same reaction time.


[Results and progress of scanning- and analytical electron microscopy in dermatology].
This is a review of the achievements of scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM) and ultrastructural x-ray microanalysis in Dermatology. Eight years after its introduction, the scanning electron microscope opened new possibilities for qualitative and semi-quantitative ultrastructural analysis of human skin, nails and hairs and provided new valuable information in clinical dermatology and dermatopathology. Considerable work has been done on the spatial architecture of normal skin, hair, hyperkeratotic conditions, psoriasis, hair abnormalities, fungus infections, dermal collagen in normal and diseased skin, and the surfaces of cutaneous vascular endothelia. Recently, x-ray microanalysis has been applied for the first time in dermatological research. Subcellular particles, the products of cytochemical reactions and tracer substances, such as heavy metals, can now be analyzed by SEM and STEM techniques. Keratohyaline granules do show a sulfur peak by means of this technique and lipoid droplets fail to demonstrate the peaks of sulfur and chloride. X-ray-microanalysis of ATPase and AChE-reactions in human skin facilitates the indentification and the localization of the reaction product in tissue, whereas the penetration of mercury compounds can be followed more precisely by this technique.


Psychologic functioning and physical health: a paradigm of flexibility.
Recent evidence suggests that positive psychologic factors may be protective against coronary artery disease (CAD). We consider this possibility through a paradigm that explores three interrelated factors that may promote healthy psychologic functioning: vitality, emotional flexibility, and coping flexibility. Vitality is a positive and restorative emotional state that is associated with a sense of enthusiasm and energy. Flexibility is related both to the ability to regulate emotions effectively and cope effectively with challenging daily experiences. A variety of factors may diminish vitality, including chronic stress and negative emotions. Pathophysiologically, chronic stress and negative emotional states can both invoke a "chronic stress response" characterized by increased stimulation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, with resultant peripheral effects, including augmented heart rate and blood pressure responsiveness and delayed recovery to stressful stimuli. Research indicates a wide array of stressful conditions--associated with either elements of relative inflexibility in psychologic functioning and/or relatively unabated stressful stimulation--that are associated with this type of exhausting hyperarousal. Conversely, new data suggest that positive psychologic factors, including positive emotions, optimism, and social support, may diminish physiological hyperresponsiveness and/or reduce adverse clinical event rates. Still other positive factors such as gratitude and altruistic behavior have been linked to a heightened sense of well-being but have not yet been tested for beneficial physiological effects. Pending further study, these observations could serve as the basis for expanding the potential behavioral interventions that may be used to assist patients with psychosocial risk factors for CAD.


Digoxin is not a substrate for organic anion-transporting polypeptide transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but is a substrate for a sodium-dependent transporter expressed in HEK293 cells.
Digoxin, an orally administered cardiac glycoside cardiovascular drug, has a narrow therapeutic window. Circulating digoxin levels (maximal concentration of ∼1.5 ng/ml) require careful monitoring, and the potential for drug-drug interactions (DDI) is a concern. Increases in digoxin plasma exposure caused by inhibition of P-glycoprotein (P-gp) have been reported. Digoxin has also been described as a substrate of various organic anion-transporting polypeptide (OATP) transporters, posing a risk that inhibition of OATPs may result in a clinically relevant DDI similar to what has been observed for P-gp. Although studies in rats have shown that Oatps contribute to the disposition of digoxin, the role of OATPs in the disposition of digoxin in humans has not been clearly defined. Using two methods, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Solvo observed that digoxin is not a substrate of OATP1A2, OATP1B1, OATP1B3, and OATP2B1. However, digoxin inhibited the uptake of probe substrates of OATP1B1 (IC(50) of 47 μM), OATP1B3 (IC(50) > 8.1 μM), and OATP2B1 (IC(50) > 300 μM), but not OATP1A2 in transfected cell lines. It is interesting to note that digoxin is a substrate of a sodium-dependent transporter endogenously expressed in HEK293 cells because uptake of digoxin was significantly greater in cells incubated with sodium-fortified media compared with incubations conducted in media in which sodium was absent. Thus, although digoxin is not a substrate for the human OATP transporters evaluated in this study, in addition to P-gp-mediated efflux, its uptake and pharmacokinetic disposition may be partially facilitated by a sodium-dependent transporter.


[Micro-endoscopy of the uterine cervix (author's transl)].
Since 1978 micro-endoscopy of the uterine cervix was added to routine colposcopic and cytologic evaluation of the cervix for the purpose of early diagnosis of cancer. Especially, in cases of a typical transformation zones important diagnostic information about the malignity or benignity of the lesion can be obtained. Under colposcopic guidance a suspect point is vitally stained with Cresyl violet acetate 10% solution. Colposcopy is not only supplemented by micro-endoscopy, but colposcopy with the micro-endoscope. The new micro-endoscope gives a magnification of 130 times, a diameter of 5 mm, a length of 200 mm and in a fibre-optic light cable a light source of 280 volts with 150 watts/second from a Xenon Arc Lamp, focal depth of 0.8 mm, an internal visual field of 35 mm. In 356 micro-endoscopies 3.92% showed positive findings, 12.75% showed suspicious findings, 73.04% showed negative findings and 10.29% showed other findings such as necrotic cells, bleeding or were impossible to evaluated with the micro-endoscope.


[Electrophysiological study of the anomalous innervation of the hand].
The innervation of the hand frequently differs from the usual description that we can find in text books. The most frequent anomalies consist on communications among the median and cubital nerves at level of either forearm (Martin-Gruber anastomosis) or to more distal level (Richie-Cannieu anastomosis), although they are not the only possibilities. To study from a electrophysiological point of view or the variants of the normality in the innervation of the hand and to define their functional characteristics. We performed an electromyographic and electroneurographic studies on patients that suffered wounded (fundamentally) or other pathologies in the forearm. The presence of double innervation in abductor pollicis brevis and opponens pollicis muscles has been verified in 2.48% of the patients. Although, it has not been possible to determine the prevalence of other anomalies, the presence of several types of anastomosis has been observed: Martin-Gruber types I and III, as well as the incomplete innervation on the part of the cubital nerve of the muscles of the tenar muscles (only of the opponens pollicis). The correct methodology is fundamental in the electrophysiological study, so several pitfalls can take place. It would be desirable to employ techniques that minimize the problems of dispersion of the current, by means of needles. It is very important to keep in mind these variations of the normality in the innervation of the hand, specially when pronostic and surgical treatment are considered.


Wavefront aberrations following laser in situ keratomileusis and refractive lens exchange for hypermetropia.
To compare the magnitude of aberrations in eyes after elective hypermetropic laser in situ keratomileusis (LASIK) and refractive lens exchange (clear lens replacement). Forty-nine patients (92 eyes) had hypermetropic LASIK and 28 (48 eyes) had refractive lens exchange; 23 hypermetropic subjects (41 eyes) were the control group. LASIK was performed with the Nidek EC-5000 excimer laser; ablation zones 5.5 to 6.0-mm in diameter with transition zones 7.5 to 8-mm in diameter. For refractive lens exchange, all but four IOLs were made of foldable acrylic. Aberrations and corneal topography were measured with the Nidek OPD-Scan model ARK-10000 more than 12 months after surgery. The higher-order root-mean-square (HORMS) wave aberrations for combined third to sixth Zernike aberration orders and the Zernike spherical aberration coefficient C(0)(4) at both 4.2-mm and 6.0-mm pupil sizes were calculated. For the LASIK group, surgical refractive change correlated significantly with total, corneal, and internal HORMS and spherical aberrations (except with internal spherical aberration for a 4.2-mm diameter pupil). For the refractive lens exchange group, there were no significant correlations of surgical refractive change with any of these factors. Similarly, there were no significant correlations of refraction with any of these factors for the control group. For a 3-diopter change in refraction with 6-mm pupils, LASIK doubled the total HORMS aberrations. LASIK changed the sign of spherical aberration from positive to negative by increasing the negative asphericity of the anterior cornea. Taking age differences between groups into account, refractive lens exchange increased the total HORMS aberrations by 40% compared with that of the control group, but this was not statistically significant. However, refractive lens exchange significantly increased total spherical aberration. Refractive lens exchange was a better refractive procedure than LASIK for minimizing total higher order optical aberrations that accompany hypermetropic refractive surgery.


Herbal medicine as adjunctive therapy with antidepressants for post-stroke depression: a systematic review and network meta-analysis of randomized controlled trials.
Background: Herbal medicine can provide adjunctive therapy for adults with post-stroke depression. This study summarizes the latest evidence regarding the harms and benefits of herbal antidepressants. Methods: The literature searched from the Cochrane Library (using the OVID platform), Embase, PubMed, the China National Knowledge Infrastructure (CNKI), the Wan Fang Data Knowledge Service Platform, and the China Scientific Journal Database (VIP) from their inception to 18 August 2021, for randomized controlled trials of herbal medicine in adults with post-stroke depression, were included in this systematic review and network meta-analysis. The search was updated on 1 December 2022. To summarize the evidence, the frequentist random-effect network meta-analyses were conducted. To categorize interventions, rate the certainty of the evidence, and present the findings, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks were carried out. The registration number of this study on PROSPERO website is CRD 42021273956. Findings: Of 1132 citations identified from the search, 51 randomized clinical trials, totaling 4,507 participants, met the inclusion criteria for this study. For response rate, Shugan Jieyu capsule (SJC) plus selective serotonin reuptake inhibitors (SSRI), Jie-Yu Pills plus SSRI, and Wuling capsule plus SSRI were shown to be among the most effective with moderate certainty of evidence (RR: 1·45, 95%CI: 1·23 to 1·7; RR: 1·35, 95%CI: 1·09 to 1·68; RR: 1·32, 95%CI: 1·09 to 1·59). In terms of mean changes in Hamilton depression scale (HAMD) score after the completion of treatment, Wuling capsule plus Hypericum and Wuling capsule plus SSRI were found to be among the most effective in reducing symptoms of depression with moderate certainty of evidence (MD: 10·12, 95%CI: -17·25 to -2·99; MD: -3·81, 95%CI: -6·19 to -1·42). The network meta-analysis (NMA) showed that SJC may be a safer intervention than SSRI in terms of both total gastrointestinal and total nervous system events with moderate certainty of evidence (RR:0.34, 95%CI:0.18, 0.62 and RR: 0.11, 95%CI: 0.03, 0.35, respectively). Interpretation: SJC plus SSRI, Jie-Yu Pills plus SSRI, and Wuling capsule plus SSRI were among the most effective in terms of HAMD score reduction response rates. Low to very low certainty of evidence revealed no increased risk of gastrointestinal and nervous system events. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=273956; Identifier: CRD42021273956.


Yellow-Green Leaf 19 Encoding a Specific and Conservative Protein for Photosynthetic Organisms Affects Tetrapyrrole Biosynthesis, Photosynthesis, and Reactive Oxygen Species Metabolism in Rice.
Chlorophyll is the main photosynthetic pigment and is crucial for plant photosynthesis. Leaf color mutants are widely used to identify genes involved in the synthesis or metabolism of chlorophyll. In this study, a spontaneous mutant, yellow-green leaf 19 (ygl19), was isolated from rice (Oryza sativa). This ygl19 mutant showed yellow-green leaves and decreased chlorophyll level and net photosynthetic rate. Brown necrotic spots appeared on the surface of ygl19 leaves at the tillering stage. And the agronomic traits of the ygl19 mutant, including the plant height, tiller number per plant, and total number of grains per plant, were significantly reduced. Map-based cloning revealed that the candidate YGL19 gene was LOC_Os03g21370. Complementation of the ygl19 mutant with the wild-type CDS of LOC_Os03g21370 led to the restoration of the mutant to the normal phenotype. Evolutionary analysis revealed that YGL19 protein and its homologues were unique for photoautotrophs, containing a conserved Ycf54 functional domain. A conserved amino acid substitution from proline to serine on the Ycf54 domain led to the ygl19 mutation. Sequence analysis of the YGL19 gene in 4726 rice accessions found that the YGL19 gene was conserved in natural rice variants with no resulting amino acid variation. The YGL19 gene was mainly expressed in green tissues, especially in leaf organs. And the YGL19 protein was localized in the chloroplast for function. Gene expression analysis via qRT-PCR showed that the expression levels of tetrapyrrole synthesis-related genes and photosynthesis-related genes were regulated in the ygl19 mutant. Reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide accumulated in spotted leaves of the ygl19 mutant at the tillering stage, accompanied by the regulation of ROS scavenging enzyme-encoding genes and ROS-responsive defense signaling genes. This study demonstrates that a novel yellow-green leaf gene YGL19 affects tetrapyrrole biosynthesis, photosynthesis, and ROS metabolism in rice.


Medium- to Long-Term Results of the Nexgen Legacy Posterior Stabilized Fixed-Bearing Knee Replacement.
The NexGen legacy posterior stabilized (LPS) prosthesis was introduced in 1997 after many design changes to its predecessor, the Insall-Burstein II prosthesis. However, there have been no reported long-term studies on the performance of this implant. Prospectively, collected data from a local database comprising primary total knee replacements (TKRs) with LPS between 1997 and 2002 was analyzed. All implants were fixed with cement. Patients were followed up at 1, 3, 5, 7, and 10 years, with patient satisfaction, range of movement, and Knee Society score (KSS) assessed. A total of 621 primary TKRs were analyzed with an average follow-up of 11.25 years (9.15-14.55). The mean age was 69.53 years. The mean KSS was 88.97 and mean flexion increased from 88.3 to 103.5 degrees at 10 years. Kaplan-Meier's analysis revealed a survivorship of 96.5% with revision for any reason as the end point and 98.9% if aseptic loosening was the reason for revision at 14 years. This study revealed excellent mid- to long-term results with the NexGen LPS prosthesis.


Commensal bacteria augment Staphylococcus aureus infection by inactivation of phagocyte-derived reactive oxygen species.
Staphylococcus aureus is a human commensal organism and opportunist pathogen, causing potentially fatal disease. The presence of non-pathogenic microflora or their components, at the point of infection, dramatically increases S. aureus pathogenicity, a process termed augmentation. Augmentation is associated with macrophage interaction but by a hitherto unknown mechanism. Here, we demonstrate a breadth of cross-kingdom microorganisms can augment S. aureus disease and that pathogenesis of Enterococcus faecalis can also be augmented. Co-administration of augmenting material also forms an efficacious vaccine model for S. aureus. In vitro, augmenting material protects S. aureus directly from reactive oxygen species (ROS), which correlates with in vivo studies where augmentation restores full virulence to the ROS-susceptible, attenuated mutant katA ahpC. At the cellular level, augmentation increases bacterial survival within macrophages via amelioration of ROS, leading to proliferation and escape. We have defined the molecular basis for augmentation that represents an important aspect of the initiation of infection.


CD28 costimulation inhibits TCR-induced apoptosis during a primary T cell response.
Murine splenic T cells undergo apoptosis when the TCR complex is re-cross-linked in the absence of costimulation during a primary immune response. However, if the CD28 complex is also cross-linked, growth continues without induction of apoptosis. Prevention of apoptosis by CD28 costimulation was associated with increased expression of bcl-xL, while overexpression of bcl-2 in T cells from bcl-2 transgenic mice was not protective. In both situations, surviving cells can be recovered in a growth arrested state following the primary response, many more if CD28 was also religated. When these cells were restimulated in secondary response, those surviving TCR religation without CD28 costimulation could not be induced to proliferate further. In contrast, cells given CD28 costimulation during the primary response proliferated well after restimulation. Thus, the CD28 signaling pathway may function not only in the initial activation of naive T cells, but also in maintaining their viability and responsiveness during a primary immune response. In addition, the results further suggest that bcl-2 and bcl-xL regulate T cell survival under different conditions, with bcl-xL being perhaps more important in maintaining viability of activated T cells traversing the cell cycle.


As Verified with the Aid of Biotinylated Spermine, the Brain Cannot Take up Polyamines from the Bloodstream Leaving It Solely Dependent on Local Biosynthesis.
The importance of polyamines (PAs) for the central nervous system (CNS) is well known. Less clear, however, is where PAs in the brain are derived from. Principally, there are three possibilities: (i) intake by nutrition, release into the bloodstream, and subsequent uptake from CNS capillaries, (ii) production by parenchymatous organs, such as the liver, and again uptake from CNS capillaries, and (iii) uptake of precursors, such as arginine, from the blood and subsequent local biosynthesis of PAs within the CNS. The present investigation aimed to unequivocally answer the question of whether PAs, especially the higher ones like spermidine (SPD) and spermine (SPM), can or cannot be taken up into the brain from the bloodstream. For this purpose, a biotin-labelled analogue of spermine (B-X-SPM) was synthesized, characterized, and used to visualize its uptake into brain cells following application to acute brain slices, to the intraventricular space, or to the bloodstream. In acute brain slices there is strong uptake of B-X-SPM into protoplasmic and none in fibrous-type astrocytes. It is also taken up by neurons but to a lesser degree. Under in vivo conditions, astrocyte uptake of B-X-SPM from the brain interstitial fluid is also intense after intraventricular application. In contrast, following intracardial injection, there is no uptake from the bloodstream, indicating that the brain is completely dependent on the local synthesis of polyamines.


Efficient enrichment cloning of TAL effector genes from Xanthomonas.
Many plant-pathogenic xanthomonads use a type III secretion system to translocate Transcription Activator-Like (TAL) effectors into eukaryotic host cells where they act as transcription factors. Target genes are induced upon binding of a TAL effector to double-stranded DNA in a sequence-specific manner. DNA binding is governed by a highly repetitive protein domain, which consists of an array of nearly identical repeats of ca. 102 base pairs. Many species and pathovars of Xanthomonas, including pathogens of rice, cereals, cassava, citrus and cotton, encode multiple TAL effectors in their genomes. Some of the TAL effectors have been shown to act as key pathogenicity factors, which induce the expression of susceptibility genes to the benefit of the pathogen. However, due to the repetitive character and the presence of multiple gene copies, high-throughput cloning of TAL effector genes remains a challenge. In order to isolate complete TAL effector gene repertoires, we developed an enrichment cloning strategy based on •genome-informed in silico optimization of restriction digestions,•selective restriction digestion of genomic DNA, and•size fractionation of DNA fragments. Our rapid, cheap and powerful method allows efficient cloning of TAL effector genes from xanthomonads, as demonstrated for two rice-pathogenic strains of Xanthomonas oryzae from Africa.