Non-specific blood tests as proxies for COVID-19 hospitalisation: are there plausible associations after excluding noisy predictors?

This study applied causal criteria in directed acyclic graphs for handling covariates in associations for prognosis of severe coronavirus disease 2019 (COVID-19) cases. To identify non-specific blood tests and risk factors as predictors of hospitalisation due to COVID-19, one has to exclude noisy predictors by comparing the concordance statistics (area under the curve - AUC) for positive and negative cases of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Predictors with significant AUC at negative stratum should be either controlled for their confounders or eliminated (when confounders are unavailable). Models were classified according to the difference of AUC between strata. The framework was applied to an open database with 5644 patients from Hospital Israelita Albert Einstein in Brazil with SARS-CoV-2 reverse transcription - polymerase chain reaction (RT-PCR) exam. C-reactive protein (CRP) was a noisy predictor: hospitalisation could have happened due to causes other than COVID-19 even when SARS-CoV-2 RT-PCR is positive and CRP is reactive, as most cases are asymptomatic to mild. Candidates of characteristic response from moderate-to-severe inflammation of COVID-19 were: combinations of eosinophils, monocytes and neutrophils, with age as risk factor; and creatinine, as risk factor, sharpens the odds ratio of the model with monocytes, neutrophils and age.

Long-term analgesic effect of a single dose of anti-NGF antibody on pain during motion without notable suppression of joint edema and lesion in a rat model of osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) patients experience exaggerated pain during movements such as walking. Anti-nerve growth factor (NGF) antibodies have recently shown analgesic effects in OA patients. We examined the effect of a single dose of anti-NGF antibody on pain during motion, joint edema and lesion in a rat model of OA to determine whether the analgesic effect demonstrated in clinical studies can be translated to a preclinical model. METHODS: Sodium monoiodoacetate (MIA)-induced arthritic rats that develop a right-left gait imbalance when walking as an index of pain during motion. This imbalance was assessed using a gait analysis system called "CatWalk". Edema size and lesion score in the relevant knee joint were also measured. The effect of a single intravenous injection of an anti-NGF monoclonal antibody AS2886401-00 on these parameters was assessed. RESULTS: AS2886401-00 administered at 0.3 or 1 mg/kg on Day 3 post-MIA injection resulted in a statistically significant improvement in gait imbalance even on Day 35. When gait measurement was set on Week 3 post-MIA administration, administration of the antibody at a timing close to the gait measurement, i.e., 1 or 24 h prior to the measurement, was less effective. AS2886401-00 did not suppress either edema or lesion. CONCLUSIONS: A single dose of anti-NGF antibody exerts a long-lasting analgesic effect on pain during motion in a rat model of OA. This finding could be associated with the analgesic efficacies that anti-NGF antibodies have exhibited in clinical studies. It appears unlikely that analgesia is secondary to inhibition of joint edema and lesion.

Note: Absolute detection efficiency of a tapered microchannel plate for Ne⁺ ions.

The absolute detection efficiency of a tapered microchannel plate with an open-area ratio of 90% was measured for Ne(+) with energies up to 5 keV, and comparison with the results for Xe(+) was made. As in the case of Xe(+), the maximum detection efficiency was 90%. The energy dependence of the efficiency curves normalized with respect to the open-area ratios was examined based on the scaling law proposed previously.

Automated measurement of spontaneous pain-associated limb movement and drug efficacy evaluation in a rat model of neuropathic pain.

BACKGROUND: The withdrawal response elicited by a nociceptive stimulus, i.e., evoked pain measure, is commonly used as an efficacy endpoint in neuropathic pain animal models. It, however, has several limitations, which highlight the importance of examining spontaneous pain. The present study describes an automated method for measuring spontaneous pain behaviour in a rat model of neuropathic pain caused by chronic constriction injury (CCI) of sciatic nerve. METHODS: After CCI surgery, a small magnet was implanted into the operated limb. The rat was placed in a test chamber that was surrounded by wire coil. Limb movements, including lifting/guarding, flinching/shaking, licking and walking in the operated limb, caused changes in the electromagnetic field, including a change in voltage and transformed into a signal via an amplifier. RESULTS: CCI rats consistently showed more frequent limb movement than sham rats. There was no significant correlation between the frequency of spontaneous pain behaviour and the evoked pain symptoms. Treatment with duloxetine (30 mg/kg p.o.) and amitriptyline (30 and 100 mg/kg p.o.) significantly reduced this frequency. Pregabalin at 30 mg/kg p.o. tended to reduce the frequency, and diclofenac up to 10 mg/kg p.o. had no effect. CONCLUSION: A non-subjective automated method for measuring spontaneous pain behaviour in an animal model of neuropathic pain was established. It is expected that the current system will greatly enhance the analysis of spontaneous pain-related behaviour, which is a predominant symptom in patients with neuropathic pain. The current system may also be valuable in the screening of potential analgesic treatments.

Endothelial expression of Fc gamma receptor IIb in the full-term human placenta.

In the third trimester, human placental endothelial cells express Fc gamma receptor IIb (FcgammaRIIb). This expression is unique because FcgammaRIIb is generally expressed on immune cells and is typically undetectable in adult endothelial cells. Recently, we found a novel FcgammaRIIb-defined, IgG-containing organelle in placental endothelial cells; this organelle may be a key structure for the transcytosis of IgG across the endothelial layer. In this study, we verify the expression of FcgammaRIIb in endothelial placenta cells and use reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing analyses to define the expressed FCGR2B mRNA transcript variant. We also investigated the distribution of FCGR2B mRNA and protein within the vascular tree of the full-term human placenta by RT-PCR and quantitative microscopy. The mRNA sequence of FCGR2B expressed specifically in placental endothelial cells is that of transcript variant 2. FcgammaRIIb expression and synthesis occur throughout the placental vascular tree but do not extend into the umbilical cord. This study provides additional information on FcgammaRIIb expression in the human placenta.

Proteome analysis of human placentae: pre-eclampsia versus normal pregnancy.

Although placental proteins play multiple roles in fetal and placental development and in the maintenance of pregnancy, many remain inadequately characterized. In the present study, we comprehensively analyzed these proteins by using a proteomic approach. Samples were denatured with guanidine hydrochloride, which was found to be superior to the commonly used urea for the present purpose, and subjected to 2-dimensional (2D) electrophoresis (2-DE) to obtain placental proteome maps. The identified protein spots (ca. 60% of the total) on the proteome maps included several pregnancy-related proteins (PRPs). Furthermore, a novel 2D immunoblotting (2-DI) analysis of molecules related to pre-eclampsia revealed three immunopositive spots that appeared to correspond to dynactin p-50, a protein related to cell turn-over. The rate of positivity for dynactin p-50-reactive antibodies was significantly (P=0.0024) higher in 26 pre-eclamptic women than in 58 normally pregnant women. These results indicate that dynactin p-50 may be involved in the pathophysiology of pre-eclampsia.

A candidate autonomous version of the wheat MITE Hikkoshi is present in the rice genome.

A miniature inverted-repeat transposable element (MITE), designated as Hikkoshi, was previously identified in the null Wx-A1 allele of Turkish bread wheat lines. This MITE is 165 bp in size and has 12-bp terminal inverted repeats (TIRs) flanked by 8-bp target site duplications (TSDs). Southern and PCR analyses demonstrated the presence of multiple copies of Hikkoshi in the wheat genome. Database searches indicated that Hikkoshi MITEs are also present in barley, rice and maize. A 3.4-kb element that has Hikkoshi-like TIRs flanked by 8-bp TSDs has now been identified in the rice genome. This element shows high similarity to the 5' subterminal region of the wheat Hikkoshi MITE and contains a transposase (TPase) coding region. The TPase has two conserved domains, ZnF_TTF and hATC, and its amino acid sequence shows a high degree of homology to TPases encoded by Tip100 transposable elements belonging to the hAT superfamily. We designated the 3.4-kb element as OsHikkoshi. Several wheat clones deposited in EST databases showed sequence similarity to the TPase ORF of OsHikkoshi. The sequence information from the TPase of OsHikkoshi will thus be useful in isolating the autonomous element of the Hikkoshi system from wheat.

Fetal circulatory responses to maternal blood loss.

We examined the fetal circulatory responses to maternal blood loss in pregnant women during the third trimester. Seven healthy women with placenta previa and singleton pregnancies underwent phlebotomies in an autologous donation program. Four hundred milliliters of blood was collected within 15 min at 34 and 35 weeks of gestation. Continuous electric recordings of fetal heart rate were performed during the first blood collection, and the maternal uterine artery (UtA), umbilical artery (UmA) and fetal middle cerebral artery (MCA) Doppler velocity waveforms were recorded before, immediately after and 24 h after the second collection in each patient. The average fetal heart rate, maternal UtA and UmA pulsatility indices did not change measurably during or after maternal blood collections. However, the average fetal MCA pulsatility index decreased significantly 24 h after maternal blood loss. The observation of a decrease in fetal MCA pulsatility index may indicate delayed fetal asphyxia following mild maternal hemorrhage.

Effect of a novel anti-inflammatory compound, YM976, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets.

We evaluated the effects of YM976, a selective inhibitor of phosphodiesterase type 4, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets. In rats, YM976 inhibited the accumulation of eosinophils at an oral ED(50) value of 1.7 mg/kg, and in C57Black/6 mice, exhibited a dose-dependent inhibition at an ED(50) value of 5.8 mg/kg. In the same dose range in the same mouse model, YM976 suppressed interleukin-5 production. We then compared the inhibitory effect of chronic administration with that of single administration in another rat model of eosinophilia induced by repeated antigen exposure. YM976 administered chronically offered more potent inhibition (ED(50) = 0.32 mg/kg p.o.) than a single dose (1.4 mg/kg p.o.). These results indicated that chronic administration is more effective in antigen-induced eosinophilia than a single administration. Emetogenicity is known to be a major adverse effect of phosphodiesterase type 4 inhibitors. We compared the anti-inflammatory activity of YM976 with its emetic activity in ferrets, in which it dose dependently suppressed eosinophil infiltration at an ED(50) value of 1.2 mg/kg, but induced no emesis at 10 mg/kg. This suggested that the compound exhibits a considerable dissociation between its anti-inflammatory and emetic effects. In summary, YM976 inhibited eosinophil infiltration in a dose-dependent manner in rats, mice, and ferrets. In ferrets, it suppressed antigen-induced eosinophil infiltration without emesis. Additionally, we demonstrated that the inhibitory effect on eosinophil infiltration was increased by chronic administration. In conclusion, YM976 is a promising drug for the treatment of diseases involving eosinophil activity, such as asthma.

Prediction of uterine dehiscence by measuring lower uterine segment thickness prior to the onset of labor: evaluation by transvaginal ultrasonography.

OBJECTIVE: Lower uterine segment thickness was measured by transvaginal ultrasound examination and its correlations with the occurrence of uterine dehiscence and rupture was examined. METHODS: The thickness of the muscular layer of the lower uterine segment was measured in 186 term gravidas with previous uterine scars and its correlation with uterine dehiscence/rupture was investigated. RESULTS: Uterine dehiscence was found in 9 cases or 4.7%. There were no cases of the uterine rupture. The thickness of the lower uterine segment among the gravidas with dehiscence was significantly less in than those without dehiscence (p< 0.01). The cut-off value for the thickness of the lower uterine segment was 1.6 mm as calculated by the receiver operating characteristic curve. The sensitivity was 77.8%; specificity 88.6%; positive predictive value 25.9%; negative predictive value 98.7%. CONCLUSION: Measurement of the lower uterine segment is useful in predicting the absence of dehiscence among gravidas with previous cesarean section. If the thickness of the lower uterine segment is more than 1.6 mm, the possibility of dehiscence during the subsequent trials of labor is very small.

Involvement of tyrosine kinase and phosphatidylinositol 3-kinase in phagocytosis by ascidian hemocytes.

It has been proposed that protein tyrosine phosphorylation plays important roles in signal transduction in mammalian T- and B-cells and monocytes. During our investigations on the ascidian host defense system, we have shown that the monoclonal antibody A74 strongly inhibits both phagocytosis of sheep red blood cells (SRBCs) by hemocytes and hemocyte aggregation, and that the A74 antigen protein has two immunoreceptor tyrosine-based activation motifs and several other motifs that are thought to function in signal transduction in mammals. In this study, we found that the A74 antibody strongly inhibited phagocytosis by ascidian hemocytes of yeast cells, as strongly as that of SRBCs, but not that of latex beads. We also found that herbimycin A and an erbstatin analog, tyrosine kinase inhibitors, and wortmannin, a specific inhibitor for phosphatidylinositol 3-kinase (PI3-kinase), inhibited the phagocytosis of yeast cells. We investigated which hemocyte proteins were specifically tyrosine-phosphorylated during phagocytosis by ascidian hemocytes and found that a protein with a molecular mass of 100 kDa was specifically tyrosine-phosphorylated upon phagocytosis; its tyrosine phosphorylation was inhibited by the A74 antibody. These results strongly suggest that both tyrosine kinase and PI3-kinase play important roles in phagocytosis by ascidian hemocytes.

B-cell-type malignant lymphoma with placental involvement.

We present here a case of B-cell-type mediastinal malignant lymphoma during pregnancy complicated by placental involvement. In this case, some nodular high-echo patterns were recognized in the placenta by ultrasonography. A cesarean section and resection of the mediastinal tumor were performed at 33 weeks and 6 days of gestation due to the deterioration of the dyspnea. A female infant weighing 1,868 g was delivered and she is now a healthy 2-year-old. The mother, however, died of the disease 1 month after surgery, due to progression of the tumor. The placenta showed numerous white firm nodules varying from 3 mm to 3 cm in diameter. The pathologic findings of both the mediastinal tumor and the placenta indicated primary mediastinal (thymic) B-cell lymphoma.

Primary structure and function of superoxide dismutase from the ascidian Halocynthia roretzi.

A protein with a molecular weight of 17K, immunoreactive with the S-1B2 antibody, has been isolated from hemocytes of Halocynthia roretzi. Its amino acid sequence has been determined by sequential Edman degradation analysis of peptide fragments derived from proteolytic fragmentation. The 17K protein is a single chain protein consisting of 151 amino acids with an acylated N-terminal serine. A comparison of the amino acid sequence of H. roretzi 17K protein with those of other proteins reveals that the 17K protein is Cu,Zn-SOD. The protein was found to have a KCN-inhibited SOD activity. Cu,Zn-SOD has been purified from H. roretzi plasma. The molecular weight is 17K and the activity is inhibited with KCN and diethyldithiocarbamate. It has been demonstrated that it can enhance phagocytosis by H. roretzi hemocytes. Thus, plasma Cu,Zn-SOD plays a role in H. roretzi as a defense molecule.

Iatrogenic monoamniotic twin gestation with progressive twin-twin transfusion syndrome.

OBJECTIVE: Intentional puncture of the membrane has been reported to be a promising new method for the management of twin-twin transfusion syndrome. CASE REPORT: Treatment of twin-twin transfusion syndrome with serial amniocenteses resulted in unintentional puncture of the dividing membrane at 24 weeks of gestation. Fetal growth discordance increased, and twin-twin transfusion did not improve following the puncture. Intrauterine death of both fetuses at 27 weeks of gestation occurred. CONCLUSION: Amniotic septostomy for the treatment of twin-twin transfusion syndrome should be performed with serious consideration.

Analgesia after upper abdominal surgery with extradural buprenorphine with lidocaine.

PURPOSE: To determine whether the continuous low thoracic extradural administration of the same dose of lidocaine at low concentration with a high infusion rate or at high concentration with a low infusion rate in combination with a fixed dose of buprenorphine (0.4 mg.day-1) modifies postoperative pain relief. METHODS: Twenty-eight patients undergoing elective upper abdominal surgery were randomly allocated to one of two groups to receive lidocaine 2%--buprenorphine at a rate of 6.3 ml.hr-1 (2% group, n = 13) or lidocaine 6%-buprenorphine at a rate of 2.1 ml.hr-1 (6% group, n = 15). During suture of the peritoneum, mepivacaine 2% (8 ml) with 0.1 mg (0.5 ml) buprenorphine was infused extradurally. After extubation, the continuous extradural infusion was initiated. Patients were assessed for the level of analgesia with the 10 cm VAS score at rest and with the Prince Henry Pain Scale (PHPS) at 3, 6, 9, 12, 18, and 24 hr postoperatively. RESULTS: The visual analogue scale (VAS) scores at rest did not differ between the two groups except at 18 hr after surgery. The Prince Henry Pain Scale (PHPS) scores were not different between the two groups postoperatively. CONCLUSION: There was no difference in analgesia produced by the continuous extradural infusion of lidocaine 2%-buprenorphine at a rate of 6.3 ml.hr-1 and that of lidocaine 6%-buprenorphine at a rate of 2.1 ml.hr-1 following upper abdominal surgery.

Analgesia after upper abdominal surgery using extradural administration of a fixed dose of buprenorphine in combination with lignocaine given at two infusion rates: a comparative study.

BACKGROUND: Extradural administration of combinations of local anaesthetics and opioids are frequently employed for postoperative pain relief. There is a scarcity of data on the analgesic effects of variations of the dose of local anaesthetic drug admixed to a fixed dose of opioid. METHODS: Twenty-four patients were investigated after elective upper abdominal surgery. During closure of the abdomen, 2% mepivacaine (8 ml) with buprenorphine 0.1 mg (0.5 ml) was given extradurally. After extubation, patients were randomly allocated to receive continuous extradural infusion of a fixed dose of buprenorphine (0.017 mg/h) in combination with 2% lignocaine at either 2.1 ml/h (low rate group, n = 14) or 6.3 ml/h (high rate group, n = 10). Postoperative pain at rest was assessed using visual analogue scale (VAS) scores and pain at movement by Prince Henry Pain Scale (PHPS) scores. Venous plasma lignocaine concentrations were measured. RESULTS: VAS scores at rest were similar in the two groups at 3 h postoperatively, whereas at 6-24 h postoperatively, VAS scores were higher in the low rate group than in the high rate group. PHPS scores were similar in the two groups at 3 h and at 18 h postoperatively, whereas at 6, 9, 12 and 24 h postoperatively, PHPS scores were higher in the low rate group than in the high rate group. Plasma lignocaine concentrations were higher at 23 h postoperatively in the high rate group than at 16 h in both groups, and at 23 h in the low rate group. At 3 h postoperatively, both the systolic and diastolic arterial pressures were higher in the low rate group than control values obtained on admission. Side effects were observed in one patient in the low rate group who complained of dizziness, and in one patient in the high rate group who complained of nausea. CONCLUSIONS: When added to a fixed dose of buprenorphine, continuous extradural infusion of 2% lignocaine at high rate provides better postoperative analgesia than when given at low rate without producing significant side effects.

The combination of external high-frequency oscillation and pressure support ventilation in acute respiratory failure.

BACKGROUND: Effective gas exchange can be maintained in animals by using external high-frequency oscillation (EHFO). The present study evaluates the effect of relatively long-term duration EHFO combined with pressure support ventilation (PSV) in patients with acute respiratory failure. METHODS: Twelve patients were ventilated with EHFO combined with PSV for 8 h at 60 oscillations.min-1, with a cuirass pressure of 36 cm H2O: -26 to +10 cm H2O (27 mm Hg: -19.5 to +7.5 mm Hg) and an inspiratory-to-expiratory ratio of 1:1. Blood gas values and hemodynamic parameters were measured. RESULTS: Significant increases were noted in cardiac index (3.0 +/- 0.7 to 3.2 +/- 0.7 1.min-1.m-2, P < 0.05) and stroke volume index (32 +/- 14 to 35 +/- 13 ml.m-2, P < 0.05) without changes in pulmonary artery wedge pressure at 1 h after EHFO. PaO2 (kPa)/FiO2 and PaCO2 improved from 21.9 +/- 7.5 to 26.8 +/- 8.0 (P < 0.05) at 2 h and from 6.9 +/- 1.7 to 6.1 +/- 0.9 (P < 0.01) at 30 min after EHFO, respectively. Breath sounds could be heard well throughout the lung fields after institution of EHFO. The mucous rales also decreased. CONCLUSIONS: As a method of ventilation for patients with acute respiratory failure, EHFO combined with PSV may have potential advantages over conventional mechanical ventilation when drainage of secretions if facilitated. Beneficial effects of EHFO may appear after several hours.

Continuous brachial plexus infusion of butorphanol-mepivacaine mixtures for analgesia after upper extremity surgery.

We have recently reported that continuous administration of butorphanol into the brachial plexus neurovascular sheath provided superior analgesia compared with that obtained with continuous i.v. administration. Furthermore, we found that analgesia was most pronounced when a mixture of mepivacaine and butorphanol was given and that butorphanol alone ranked next. In this study, we increased the dose of butorphanol, compared with that used in our previous reports, and an initial bolus dose of butorphanol was administered into the brachial plexus neurovascular sheath just after surgery had ended. Thereafter, postoperative pain relief was estimated. In patients undergoing upper extremity surgery with continuous axillary brachial plexus block, group A received a bolus of 1 ml of physiological saline with 1.5% mepivacaine, 10 ml into the brachial plexus sheath followed by a continuous brachial plexus infusion of 0.5% mepivacaine with butorphanol 6 mg at a rate of 144 ml/ 72 h. Group B was given a bolus of butorphanol 1 mg (1 ml) with 1.5% mepivacaine, 10 ml into the brachial plexus sheath and a continuous brachial plexus infusion of 0.5% mepivacaine with butorphanol 6 mg at a rate of 144 ml/72 h. After operation, VAS scores did not differ between the two groups. The time to first use of supplementary analgesia did not differ significantly between the two groups and there were no significant differences in the number of patients who required supplementary analgesia. These results indicate that continuous butorphanol 2 mg day-1 with 0.5% mepivacaine provided sufficient postoperative analgesia after upper limb surgery.

Cloning and tyrosine phosphorylation of a novel invertebrate immunocyte protein containing immunoreceptor tyrosine-based activation motifs.

Immunoreceptor tyrosine-based activation motif (ITAM) plays an important role in signal transduction through mammalian T-cell and B-cell antigen receptors and Fc receptors. The ITAM has been found only in vertebrate immunocytes. Ascidians are intriguing invertebrates from the viewpoint of the evolution of immune systems because they are considered to be ancestors of the vertebrates. We have previously shown that the monoclonal antibody A74 inhibits cellular defense reactions of the ascidian. In the present studies, we found that the A74 antigen protein has two ITAMs and several motifs that are proposed to function in signal transduction. The A74 protein is tyrosine-phosphorylated and associated with other proteins in the initial stages of cellular defense reactions. The ITAMs of the A74 protein are tyrosine-phosphorylated by a c-Src kinase in vitro. The A74 protein provides a key to the understanding of the origin of vertebrate immune systems.