[Efficacy of rituximab therapy for 10 patients suffering from systemic lupus erythematosus with intestinal involvement].

We retrospectively analyzed therapy efficacy and the adverse reactions of 10 patients suffering from systemic lupus erythematosus (SLE) with intestinal involvement treated with rituximab (RTX). Patients were hospitalized in the Department of Rheumatology and Immunology of the First Medical Center of PLA General Hospital from January 2015 to January 2023. Among the 10 patients, two were men and eight were women. The age of the cohort was (41.9±8.8) years. The age at disease onset was (28.8±9.2) years. The total course of the SLE diagnosis was(109.6±59.9) months. The course of the diagnosis of SLE with intestinal involvement was (89.3±50.2) months. The time from the appearance of intestinal symptoms to the diagnosis of SLE with intestinal involvement was 1.5 (1.0,8.0) months. The time from the diagnosis of SLE with intestinal involvement to RTX use was 13.0 (1.0,46.3) months. Follow-up duration after application of RTX treatment was (55.3±28.4) months. There were five cases of abdominal pain, four cases of abdominal distension, nine cases of diarrhea, three cases of nervous-system involvement, nine cases of lupus nephritis, and seven cases of serositis. All 10 patients underwent computed tomography and radiology of the abdomen. Eight patients had intestinal-wall edema, seven suffered intestinal dilation, four had target signs, three suffered congestion of mesenteric blood vessels, eight had increased mesenteric-fat density, and six had false intestinal obstruction. All 10 patients showed a low level of complement C3 (250-750 mg/L). Nine cases showed a low level of complement C4 (10-90 mg/L). The SLE disease activity index 2000 (SLEDAI-2K) at baseline in 10 patients was 20.5 (17.8, 30.0). After receiving RTX (0.5 g: day 1, day 14, or 375 mg/m2: day 1, day 14) induction treatment, the intestinal symptoms of 10 cases were relieved completely. Four patients had adverse reactions, of which three received a high-dose glucocorticoid combined with RTX treatment simultaneously. Adverse reactions manifested mainly as a reduced level of IgG and infection with herpes simplex virus in one case, reduced level of IgG and lung infection in one patient, lung infection in one case, and reduced IgG level in one patient. RTX may an efficacious treatment strategy for patients suffering from refractory SLE with intestinal involvement.

[Efficacy and safety of half-dose rituximab in the treatment of 23 cases with lupus nephritis].

The study aimed to analyze the efficacy and safety of rituximab in the treatment of 23 cases of lupus nephritis and explore the prospect of half-dose rituximab in lupus nephritis treatment. Twenty-three patients with lupus nephritis hospitalized in the Department of Rheumatology and Immunology at the First Medical Center of the PLA General Hospital from May 2013 to December 2021 were selected. Eighteen patients received rituximab 375 mg/m2 on the first and 14th days, 5 patients received 500 mg of rituximab on the first and 14th days, and rituximab was used as needed 6 months later. Methylprednisolone (80-120 mg) was given together with rituximab. Afterward, 1 mg/kg prednisone was used for 4 weeks, which was progressively tapered to maintenance doses or discontinued. B lymphocyte level, renal function, 24-h urine protein level, and systemic lupus erythematosus (SLE) disease activity index 2000 (SLEDAI2K) score before and after treatment were recorded. The efficacy and adverse reactions were analyzed. The results showed that 11 patients suffered from renal insufficiency [creatinine (162.7±58.6) µmol/L ] at baseline, while the creatinine level of 9 patients returned to normal 12 months after the treatment [ (66.3±10.1)µmol/L ]. Normal renal function of the other 12 patients was maintained during treatment. After 12 months, the 24-h urine protein level decreased from 4.00 (2.00,6.80) g in the baseline period to 0.10 (0.08,0.40) g. SLEDAI2K score decreased from 22 (18,26) in the baseline period to 3 (0,6) 12 months after the treatment. The B lymphocyte level reached 0.00 (0.00,0.01)% at 3 months. Of 23 patients, 13 patients achieved complete remission, and 7 patients achieved partial remission after 6 months of rituximab treatment. Five patients experienced adverse reactions related to rituximab, including 1 case of transfusion reaction, 1 case of perioral herpes with pulmonary infection, and 3 cases of decreased IgG levels. Therefore, rituximab regimen used in this study can be an effective treatment strategy for lupus nephritis.

Impact of brain injury on functional measures of amplitude-integrated EEG at term equivalent age in premature infants.

OBJECTIVE: To evaluate the association between qualitative and quantitative amplitude-integrated EEG (aEEG) measures at term equivalent age (TEA) and brain injury on magnetic resonance imaging (MRI) in preterm infants. STUDY DESIGN: A cohort of premature infants born at <30 weeks of gestation and with moderate-to-severe MRI injury on a TEA MRI scan was identified. A contemporaneous group of gestational age-matched control infants also born at <30 weeks of gestation with none/mild injury on MRI was also recruited. Quantitative aEEG measures, including maximum and minimum amplitudes, bandwidth span and spectral edge frequency (SEF90), were calculated using an offline software package. The aEEG recordings were qualitatively scored using the Burdjalov system. MRI scans, performed on the same day as aEEG, occurred at a mean postmenstrual age of 38.0 (range 37 to 42) weeks and were scored for abnormality in a blinded manner using an established MRI scoring system. RESULTS: Twenty-eight (46.7%) infants had a normal MRI or mild brain abnormality, while 32 (53.3%) infants had moderate-to-severe brain abnormality. Univariate regression analysis demonstrated an association between severity of brain abnormality and quantitative measures of left and right SEF90 and bandwidth span (ß=-0.38, -0.40 and 0.30, respectively) and qualitative measures of cyclicity, continuity and total Burdjalov score (ß=-0.10, -0.14 and -0.12, respectively). After correcting for confounding variables, the relationship between MRI abnormality score and aEEG measures of SEF90, bandwidth span and Burdjalov score remained significant. CONCLUSION: Brain abnormalities on MRI at TEA in premature infants are associated with abnormalities on term aEEG measures, suggesting that anatomical brain injury may contribute to delay in functional brain maturation as assessed using aEEG.

Early hyperoxia burden detected by cerebral near-infrared spectroscopy is superior to pulse oximetry for prediction of severe retinopathy of prematurity.

OBJECTIVE: Fractional tissue oxygen extraction (FTOE) is a measure derived from cerebral near-infrared spectroscopy (NIRS) and simultaneous pulse oximetry (SpO2), capturing the proportion of oxygen delivered in arterial blood that is used by the target tissue. FTOE may provide a better proxy measurement of retinal hyperoxia than pulse oximetry alone and could provide insight into the risk for retinopathy of prematurity (ROP). In this study, we directly compared hyperoxia burden calculated from FTOE with hyperoxia burden calculated from SpO2 alone in order to assess the strength of association between hyperoxia and severe ROP. STUDY DESIGN: Infants born before <30 weeks and weighing <1500 g underwent synchronized SpO2 and FTOE recording over the first 4 days following birth. After error correction of the raw recording, hyperoxia burden was calculated as the percentage of the total SpO2 or FTOE recording with measurements exceeding defined thresholds (90/93/95% and 20/15/10%, respectively) and was compared with the outcome of severe ROP, defined as ROP requiring laser therapy, after controlling for important covariates. RESULT: A total of 63 infants were included with a mean±s.d. gestational age of 25.8±1.5 weeks and birth weight of 898.5±206.9 g; 13/63 (20%) had severe ROP. SpO2 hyperoxia burden was not associated with severe ROP at any threshold. FTOE hyperoxia burden was associated with severe ROP at the 15% (P=0.04) and 10% (P=0.03) thresholds. Infants with severe ROP spent 20% and 50% more time exceeding the 15% and 10% thresholds, respectively, as compared with those without severe ROP. CONCLUSION: In the first 96 h of life, FTOE but not SpO2 hyperoxia burden is associated with severe ROP. These preliminary results suggest that NIRS may be a viable alternative technology for targeted oxygen saturation guidelines.

Response to dopamine in prematurity: a biomarker for brain injury?

OBJECTIVE: To identify factors associated with responsiveness to dopamine therapy for hypotension and the relationship to brain injury in a cohort of preterm infants. STUDY DESIGN: The pharmacy database at St Louis Children's Hospital was retrospectively queried to identify infants who (a) were born <28 weeks gestation between 2012 and 2014, (b) received dopamine and (c) had blood pressure measurements from an umbilical arterial catheter. A control group was constructed from contemporaneous infants who did not receive dopamine. Mean arterial blood pressure (MABP) at baseline, 1 h and 3 h after initiating dopamine were obtained for each dopamine-exposed infant. MABP measurements at matched time points were obtained in the control group. RESULT: Sixty-nine dopamine-treated and 45 control infants were included. Mean ΔMABP at 3 h was 4.5±6.3 mm of Hg for treated infants vs 1±2.9 for the control. Median dopamine starting dose was 2.5 µg kg(-1) min(-1). Dopamine-treated infants were less mature and of lower birth weight while also more likely to be intubated at 72 h, diagnosed with intraventricular hemorrhage (IVH) and to die. Failure to respond to dopamine was associated with greater likelihood of developing IVH (odds ratio (OR) 5.8, 95% confidence interval (CI) 1.1-42.3), while a strong response (ΔMABP>10 mm Hg) was associated with a reduction in risk of IVH (OR 0.1, 95% CI 0.01-0.8). CONCLUSION: Low-moderate dose dopamine administration results in modest blood pressure improvements. A lack of response to dopamine is associated with a greater risk of IVH, whereas a strong response is associated with a decreased risk. Further research into underlying mechanisms and management strategies is needed.

Is there a duty to share genetic information?

A number of prominent bioethicists, such as Parker, Lucassen and Knoppers, have called for the adoption of a system in which by default genetic information is shared among family members. This paper suggests that a main reason given in support of this call to share genetic information among family members is the idea that genetic information is essentially familial in nature. On examining this "familial nature of genetics" argument, the paper shows that most genetic information is only shared in a weaker way among family members and does not necessarily lead to the actual manifestation of particular diseases. The upshot is that the idea that genetic information is familial in nature does not provide sufficient ground for moving towards a system in which by default genetic information is shared among family members.

Unintended changes in cognition, mood, and behavior arising from cell-based interventions for neurological conditions: ethical challenges.

The prospect of using cell-based interventions (CBIs) to treat neurological conditions raises several important ethical and policy questions. In this target article, we focus on issues related to the unique constellation of traits that characterize CBIs targeted at the central nervous system. In particular, there is at least a theoretical prospect that these cells will alter the recipients' cognition, mood, and behavior-brain functions that are central to our concept of the self. The potential for such changes, although perhaps remote, is cause for concern and careful ethical analysis. Both to enable better informed consent in the future and as an end in itself, we argue that early human trials of CBIs for neurological conditions must monitor subjects for changes in cognition, mood, and behavior; further, we recommend concrete steps for that monitoring. Such steps will help better characterize the potential risks and benefits of CBIs as they are tested and potentially used for treatment.

Cell-based interventions for neurologic conditions: ethical challenges for early human trials.

BACKGROUND: Attempts to translate basic stem cell research into treatments for neurologic diseases and injury are well under way. With a clinical trial for one such treatment approved and in progress in the United States, and additional proposals under review, we must begin to address the ethical issues raised by such early forays into human clinical trials for cell-based interventions for neurologic conditions. METHODS: An interdisciplinary working group composed of experts in neuroscience, cell biology, bioethics, law, and transplantation, along with leading disease researchers, was convened twice over 2 years to identify and deliberate on the scientific and ethical issues raised by the transition from preclinical to clinical research of cell-based interventions for neurologic conditions. RESULTS: While the relevant ethical issues are in many respects standard challenges of human subjects research, they are heightened in complexity by the novelty of the science, the focus on the CNS, and the political climate in which the science is proceeding. CONCLUSIONS: Distinctive challenges confronting US scientists, administrators, institutional review boards, stem cell research oversight committees, and others who will need to make decisions about work involving stem cells and their derivatives and evaluate the ethics of early human trials include evaluating the risks, safety, and benefits of these trials, determining and evaluating cell line provenance, and determining inclusion criteria, informed consent, and the ethics of conducting early human trials in the public spotlight. Further study and deliberation by stakeholders is required to move toward professional and institutional policies and practices governing this research.

[Cluster analysis of Dendrobium by RAPD and design of specific primer for Dendrobium candidum].

OBJECTIVE: To analyze the genetic relationship of Dendrobium and design a specific primer to differentiate Dendrobium candidum effectively. METHOD: Random amplified polymorphic DNA (RAPD) technique was used to analyze the genetic relationships of 26 species of Dendrobium and one species of Ephemerantha. Dendrogram was constructed by UPGMA. According to the sequence of DNA fragment selected, Sangon 18 primer had been extended from 3' extreme to 20 bp in order to form a specific primer. RESULT AND CONCLUSION: This primer can be used to distinguish Dendrobium candidum from other Dendrobium effectively. Such a technique provides a new way for the identification of Chinese traditional medicines.

IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex.

Here we report the identification of a novel PMA-inducible IkappaB kinase complex, distinct from the well-characterized high-molecular weight IkappaB kinase complex containing IKKalpha, IKKbeta, and IKKgamma. We have characterized one kinase from this complex, which we designate IKKepsilon. Although recombinant IKKepsilon directly phosphorylates only serine 36 of IKBalpha, the PMA-activated endogenous IKKepsilon complex phosphorylates both critical serine residues. Remarkably, this activity is due to the presence of a distinct kinase in this complex. A dominant-negative mutant of IKKepsilon blocks induction of NF-kappaB by both PMA and activation of the T cell receptor but has no effect on the activation of NF-KB by TNFalpha or IL-1. These observations indicate that the activation of NF-kappaB requires multiple distinct IkappaB kinase complexes, which respond to both overlapping and discrete signaling pathways.

Temporal regulation of RNA polymerase II by Srb10 and Kin28 cyclin-dependent kinases.

Two cyclin-dependent kinases have been identified in yeast and mammalian RNA polymerase II transcription initiation complexes. We find that the two yeast kinases are indistinguishable in their ability to phosphorylate the RNA polymerase II CTD, and yet in living cells one kinase is a positive regulator and the other a negative regulator. This paradox is resolved by the observation that the negative regulator, Srb10, is uniquely capable of phosphorylating the CTD prior to formation of the initiation complex on promoter DNA, with consequent inhibition of transcription. In contrast, the TFIIH kinase phosphorylates the CTD only after the transcription apparatus is associated with promoter DNA. These results reveal that the timing of CTD phosphorylation can account for the positive and negative functions of the two kinases and provide a model for Srb10-dependent repression of genes involved in cell type specificity, meiosis, and sugar utilization.

Association of an activator with an RNA polymerase II holoenzyme.

RNA polymerase II holoenzymes have been described that consist of RNA polymerase II, a subset of general transcription factors, and four SRB proteins. The SRB proteins, which were identified through a selection for genes involved in transcription initiation by RNA polymerase II in vivo, are a hallmark of the holoenzyme. We report here the isolation and characterization of additional SRB genes. We show that the products of all nine SRB genes identified thus far are components of the RNA polymerase II holoenzyme and are associated with a holoenzyme subcomplex termed the mediator of activation. The holoenzyme is capable of responding to a transcriptional activator, suggesting a model in which activators function, in part, through direct interactions with the holoenzyme. Immunoprecipitation experiments with anti-SRB5 antibodies demonstrate that the acidic activating domain of VP16 specifically binds to the holoenzyme. Furthermore, the holoenzyme and the mediator subcomplex bind to a VP16 affinity column. These results provide a more complete description of the RNA polymerase II holoenzyme and suggest that this form of the transcription apparatus can be recruited to promoters via direct interactions with activators.

A kinase-cyclin pair in the RNA polymerase II holoenzyme.

The RNA polymerase II holoenzyme consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins. The genes encoding SRB proteins were isolated as suppressors of mutations in the RNA polymerase II carboxy-terminal domain (CTD). The CTD and SRB proteins have been implicated in the response to transcriptional regulators. We report here the isolation of two new SRB genes, SRB10 and SRB11, which encode kinase- and cyclin-like proteins, respectively. Genetic and biochemical evidence indicates that the SRB10 and SRB11 proteins form a kinase-cyclin pair in the holoenzyme. The SRB10/11 kinase is essential for a normal transcriptional response to galactose induction in vivo. Holoenzymes lacking SRB10/11 kinase function are strikingly deficient in CTD phosphorylation. Although defects in the kinase substantially affect transcription in vivo, purified holoenzymes lacking SRB10/11 kinase function do not show defects in defined in vitro transcription systems, suggesting that the factors necessary to elicit the regulatory role of the SRB10/11 kinase are missing in these systems. These results indicate that the SRB10/11 kinase is involved in CTD phosphorylation and suggest that this modification has a role in the response to transcriptional regulators in vivo.

RNA polymerase II carboxy-terminal domain contributes to the response to multiple acidic activators in vitro.

The largest subunit of RNA polymerase II contains a unique carboxy-terminal domain (CTD) that consists of repeats of the heptapeptide YSPTSPS. RNA polymerase II CTD truncation mutations affect the ability to induce transcription of a subset of yeast genes in vivo, and the lack of response to induction maps to the upstream activating sequences of these genes. Here, we report that progressive truncation of the yeast RNA polymerase II CTD causes progressive loss of trans-activator-dependent transcription in nuclear extracts but has little effect on elongation or termination. Specific transcription, which is reduced by up to 50-fold in these assays, can be restored in the defective nuclear extracts by adding purified wild-type RNA polymerase II. The defects in factor-dependent transcription are observed with templates that are assembled into nucleosomes as well as with templates that are not so assembled. Defects in factor-independent transcription are also observed, but these are not as profound as those observed in the presence of trans-activators. These results indicate that the RNA polymerase II CTD functions during transcription initiation and is required for normal levels of activated transcription in vitro.

RNA polymerase II subunit composition, stoichiometry, and phosphorylation.

RNA polymerase II subunit composition, stoichiometry, and phosphorylation were investigated in Saccharomyces cerevisiae by attaching an epitope coding sequence to a well-characterized RNA polymerase II subunit gene (RPB3) and by immunoprecipitating the product of this gene with its associated polypeptides. The immunopurified enzyme catalyzed alpha-amanitin-sensitive RNA synthesis in vitro. The 10 polypeptides that immunoprecipitated were identical in size and number to those previously described for RNA polymerase II purified by conventional column chromatography. The relative stoichiometry of the subunits was deduced from knowledge of the sequence of the subunits and from the extent of labeling with [35S]methionine. Immunoprecipitation from 32P-labeled cell extracts revealed that three of the subunits, RPB1, RPB2, and RPB6, are phosphorylated in vivo. Phosphorylated and unphosphorylated forms of RPB1 could be distinguished; approximately half of the RNA polymerase II molecules contained a phosphorylated RPB1 subunit. These results more precisely define the subunit composition and phosphorylation of a eucaryotic RNA polymerase II enzyme.

Subunits shared by eukaryotic nuclear RNA polymerases.

RNA polymerases I, II, and III share three subunits that are immunologically and biochemically indistinguishable. The Saccharomyces cerevisiae genes that encode these subunits (RPB5, RPB6, and RPB8) were isolated and sequenced, and their transcriptional start sites were deduced. RPB5 encodes a 25-kD protein, RPB6, an 18-kD protein, and RPB8, a 16-kD protein. These genes are single copy, reside on different chromosomes, and are essential for viability. The fact that the genes are single copy, corroborates previous evidence suggesting that each of the common subunits is identical in RNA polymerases I, II, and III. Furthermore, immunoprecipitation of RPB6 coprecipitates proteins whose sizes are consistent with RNA polymerase I, II, and III subunits. Sequence similarity between the yeast RPB5 protein and a previously characterized human RNA polymerase subunit demonstrates that the common subunits of the nuclear RNA polymerases are well conserved among eukaryotes. The presence of these conserved and essential subunits in all three nuclear RNA polymerases and the absence of recognizable sequence motifs for DNA and nucleoside triphosphate-binding indicate that the common subunits do not have a catalytic role but are important for a function shared by the RNA polymerases such as transcriptional efficiency, nuclear localization, enzyme stability, or coordinate regulation of rRNA, mRNA, and tRNA synthesis.

[The function of 100% O2 suction key in Bennett 7200 microprocessor ventilator].

Tracheal suctioning of a patient on a ventilator may induce hypoxemia. Bennett 7200 microprocessor ventilator has an "100% O2 suction" key which is claimed to provide 100% oxygen for two minutes and switch back automatically when this function is set. Four 7200 ventilators were tested to verify this function. We found that the mean lag time varied from 20.1 seconds to 103.3 seconds and the mean recovery time varied from 33.0 seconds to 134.6 seconds according to the difference of initial tidal volume, ventilator rate and fractional inspired oxygen setting. When the ventilator was on "100% O2 suction", the delivered tidal volume was less than the preset tidal volume. In order to hyper-oxygenate and hyper-inflate the patient to prevent suction-induced hypoxemia, those finding should be taken into consideration when the clinicians apply this function in clinical situation.

Bacteriophage P22 Mnt repressor. DNA binding and effects on transcription in vitro.

We have examined the binding of Mnt repressor to operator DNA in vitro and have determined how this binding affects the level of transcription from two nearby promoters, Pant and Pmnt. Mnt binds to a region of DNA that overlaps the startpoint of transcription of Pant and the -35 region of Pmnt. Mnt represses transcription in vitro from Pant and enhances transcription from Pmnt. Protection and interference experiments show that Mnt binds to a single, 17 base-pair operator site. The operator sequence and the protein-DNA contacts are symmetric. Mnt makes major groove contacts on both faces of the operator DNA. At pH 7.5, 200 mM-KCl, 22 degrees C, the Mnt tetramer binds operator with high affinity (Kd = 2.2 X 10(-11M) and the protein-DNA complex is quite stable (t1/2 = 48 min). Operator binding shows large dependencies on pH, salt concentration, and temperature.