[Diurnal rhythm in salamanders].
1. The locomotor activity of European salamanders differs from species to species. At all stages of development Triturus vulgaris is more light-active, Salamandra salamandra is dark-active, while Triturus alpestris and cristatus occupy an intermediate position. 2. The activity of the larvae is high but the rhythm is not very pronounced. Triturus larvae are less dark-active than adults (Fig. 2). 3. Periodism disappears completely during metamorphosis but after some weeks of terrestrial life a diurnal rhythm reappears (Fig. 3). 4. Adults of Triturus species show an increased activity during their aquatic life in spring: they are active by day and night, maxima occurring in twilight or darkness. 5. Terrestrial adults leave their hiding places only during twilight or darkness. Triturus vulgaris and alpestris display locomotor activity in twilight only whereas Triturus cristatus and Salamandra salamandra are also active in the dark (Figs. 5, 6).


[Surgical procedures to improve cleansing of the root surface and reduce pocket depth].
In recent years numerous reports have appeared in the dental literature comparing different methods of treating periodontitis. These researches have not indicated that surgical procedures have particular advantages over thorough hygiene therapy. This review considers several relevant hypotheses and the results of clinical research into this topic. Particular note has been taken of the research of Ramfjord et al. (1987) whose conclusions are typical of many others. This review discusses such conclusions from several standpoints and shows that there is a need for further research. It is derived from a review by the same authors in the journal of the Swedish Dental Association, Tandläkartidingen.


The sonographic approach to the detection of fetal cardiac anomalies in early pregnancy.
Transvaginal sonography enables imaging of the fetal heart in various planes and directions in early pregnancy. This study summarizes our experience in early detection of fetal cardiac anomalies. Transvaginal sonographic examination was performed in 36 323 consecutive fetuses in both high- and low-risk pregnancies. More than 99% of cases were evaluated at 14-16 weeks' gestation. Examination of the cardiovascular system did not rely on still images of the classic views but instead was performed in a dynamic mode visualizing the heart and great vessels from different directions and in various scanning planes. Cardiac anomalies were detected in 173 fetuses, giving an overall incidence of 1 in 210 pregnancies. In 44% of these, the cardiac anomaly was isolated. An abnormal karyotype was detected in 27 of the 72 cases that underwent chromosomal analysis. An abnormal nuchal translucency finding was observed in 59 fetuses. The sonographic diagnosis was confirmed after delivery or at postmortem in 90 cases. Ten fetuses had a cardiac anomaly which differed from the anomaly suggested by sonography. In the remaining cases, a postmortem examination was not possible because termination of pregnancy was performed by dilatation and curettage. In four cases we did not detect the cardiac anomaly in early pregnancy. Two of them were detected at rescanning in mid-pregnancy. Early detection of fetal cardiac anomalies is now possible. Most anomalies occur in low-risk pregnancies. We suggest performing a detailed early multidirectional dynamic continuous sweep ultrasound examination of the fetal cardiovascular system in all pregnancies.


Influence of the respiratory flow pattern on rebreathing in Mapleson A and D circuits.
In a lung model the rebreathing effects of different respiratory flow patterns (RFP) were studied in the coaxial Mapleson A (Lack) and D (Bain, Coax-II) systems during spontaneous breathing. In the Mapleson A system RFP was not found to have any impact. In the D systems FACO2 was higher with an RFP typical of halothane-anaesthetized patients than with an RFP with an exponentially decreasing expiratory flow and an end-expiratory flow pause (FTEP). The difference in FACO2 was 26% with a VF corresponding to 100 ml X min-1 X kg-1 body weight. The RFP in a non-anaesthetized volunteer was intermediate between these two patterns. Rebreathing decreased in the D systems with prolongation of FTEP and when a decelerating expiratory flow was used.


CDX2 downregulation in mouse mural trophectoderm during peri-implantation is heteronomous, dependent on the YAP-TEAD pathway and controlled by estrogen-induced factors.
To investigate the transition of CDX2 expression patterns in mouse trophectoderm (TE) and its regulatory mechanisms during implantation. Mouse E3.5-4.5 blastocysts were used to immunostain CDX2, YAP, TEAD4, and ESRRB. Endogenous estrogen signaling was perturbed by administrating estrogen receptor antagonist ICI 182,780 or ovariectomy followed by administration of progesterone and β-estradiol to elucidate the relationship between the transition of CDX2 expression patterns and ovarian estrogen-dependent change in the uterine environment. CDX2 expression was gradually downregulated in the mural TE from E4.0 in vivo, whereas CDX2 downregulation was not observed in blastocysts cultured in KSOM. Fetal bovine serum (FBS) supplementation in KSOM induced CDX2 downregulation independently of blastocyst attachment to dishes. CDX2 downregulation in the mural TE was repressed by administration of ICI 182,780 or by ovariectomy, and administration of β-estradiol into ovariectomized mice retriggered CDX2 downregulation. Furthermore, Cdx2 expression in the mural TE might be controlled by the YAP-TEAD pathway. CDX2 downregulation was induced heteronomously in the mural TE from E4.0 by uterus-derived factors, the secretion of which was stimulated by ovarian estrogen.


The role of biomarkers in dilated cardiomyopathy: Assessment of clinical severity and reverse remodeling.
Biomarkers in dilated cardiomyopathy (DCM) reflect various pathobiological processes, including neurohormonal activation, oxidative stress, matrix remodeling, myocyte injury and myocyte stretch. We assessed the role of biomarkers in clinical and echocardiographic parameters and in left ventricular (LV) reverse remodeling (LVRR). In this prospective study of 50 DCM patients (28 men, aged 59±10 years) with LV ejection fraction (LVEF) <40%, LVRR was defined as an increase of >10 U in LVEF after optimal medical therapy. Baseline LVEF was 25.4±9.8% and LV end-diastolic diameter (LVEDD)/body surface area (BSA) was 34.2±4.5 mm/m2. LVRR occurred in 34% of patients within 17.6±15.6 months. No correlation was found between B-type natriuretic peptide (BNP), 25-hydroxyvitamin D (25(OH)D), CA-125, high-sensitivity C-reactive protein (hs-CRP), lipoprotein(a) [Lp(a)], noradrenaline, adrenaline, renin or aldosterone and LVRR. Patients in NYHA class III or IV, with pulmonary congestion or ankle edema, had higher CA-125, cystatin C, BNP and hs-CRP levels (p<0.05). CA-125 was correlated with BNP (r=0.61), hs-CRP (r=0.56) and uric acid (r=0.52) (all p=0.01). BNP correlated directly with LVEDD (r=0.49), LV volumes (r=0.51), pulmonary artery systolic pressure (PASP) (r=0.43) and E/e' (r=0.31), and was inversely correlated with LVEF (r=-0.50) and e' velocity (r=-0.32) (p<0.05). CA-125 was positively correlated with left atrial volume/BSA (r=0.46), E/A ratio (r=0.60) and PASP (r=0.49) (p<0.05). No correlation was found between biomarkers and LVRR, but CA-125, BNP and hs-CRP were predictors of clinical severity and congestion. BNP correlated with parameters of systolic and diastolic dysfunction, while CA-125 correlated with measures of diastolic dysfunction.


Whole Body Vibration Improves Insulin Resistance in db/db Mice: Amelioration of Lipid Accumulation and Oxidative Stress.
Insulin resistance (IR) is the hallmark of type 2 diabetes mellitus (T2DM), which is one of the most important chronic noncommunicable diseases. Effective and feasible strategies to treat IR are still urgently needed. Previous research studies reported that whole body vibration (WBV) was beneficial for IR in clinical; however, its underlying mechanisms remains unknown. In the present study, db/db mice were treated with WBV administration 60 min/day for 12 weeks and the impaired insulin sensitivity was improved. Besides, liver steatosis was also ameliorated. Further explorations revealed that WBV could reduce the expression of SREBP1c and increase the expression of GSH-Px and consequently suppress oxidative stress. In conclusion, WBV attenuates oxidative stress to ameliorate liver steatosis and thus improves insulin resistance in db/db mice. Therefore, WBV administration is a promising treatment for individuals who suffered from central obesity and IR.


HIF1A-AS2 induces osimertinib resistance in lung adenocarcinoma patients by regulating the miR-146b-5p/IL-6/STAT3 axis.
Although epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) show efficacy in lung adenocarcinoma (LUAD) patients, TKI resistance inevitably develops, limiting long-term results. Thus, there is an urgent need to address drug resistance in LUAD. Long non-coding RNA (lncRNA) HIF1A-AS2 could be a critical mediator in the progression of various tumor types. We examined the function of HIF1A-AS2 in modifying tumor aggravation and osimertinib resistance in lung adenocarcinoma. Using clinical samples, we showed that HIF1A-AS2 was upregulated in LUAD specimens, predicting poorer overall survival and disease-free survival. HIF1A-AS2 silencing inhibited the proliferation, migration, and tumorigenesis of LUAD cells and therapeutic efficacy of osimertinib against tumor cells in vitro and in vivo. RNA precipitation assays, western blotting, luciferase assays, and rescue experiments demonstrated that HIF1A-AS2 sponged microRNA-146b-5p (miR-146b-5p), promoting interleukin-6 (IL-6) expression, activating the IL-6/STAT3 pathway, and leading to LUAD progression. miR-146b-5p and IL-6 levels were correlated with the prognosis of LUAD patients. Our results indicated that HIF1A-AS2 functions as an oncogenic factor in adenocarcinoma cells by targeting the miR-146b-5p/IL-6/STAT3 axis and may be a prognostic indicator of survival. Moreover, it can be a potential therapeutic target to enhance the efficacy of osimertinib in LUAD patients.


Kindling causes persistent in vivo changes in firing rates and glutamate sensitivity of central piriform cortex neurons in rats.
The present experiments were undertaken to study whether amygdala kindling induces persistent alterations in the functional status of neurons of the central piriform cortex, a subregion of the piriform cortex identified previously as a site involved in the kindling process. Extracellular, single-unit recordings of piriform cortex neurons were made in anesthetized fully kindled rats at an interval of at least five weeks after the last seizure. Electrode implanted but not kindled rats served as sham controls. An additional group of non-implanted rats was used as naive controls. Spontaneously firing piriform cortex neurons were characterized in all groups by smooth, sharp, biphasic (i.e. positive/negative) action potentials with a duration of 0.8-1.8 ms, and were primarily located at the border between piriform cortex layers II and III. In kindled rats, neurons in the central piriform cortex exhibited a significantly higher firing rate compared to controls. Based on median group values, the increase in basal activity in kindled rats averaged about 90%. The responsiveness of piriform cortex neurons to neurotransmitters was tested by microiontophoretic application of glutamate, N-methyl-D-aspartate and GABA. Piriform cortex neurons of kindled rats exhibited a significantly lower responsiveness to the excitatory effect of glutamate than naive controls. A lowered glutamate responsiveness was also seen in sham controls. No significantly altered transmitter sensitivities of piriform cortex neurons from kindled rats were seen with N-methyl-D-aspartate or GABA. The data indicate that amygdala kindling causes persistent interictal changes in both basal activity and glutamate responsiveness of central piriform cortex neurons which could contribute to the abnormal hyperexcitability characteristic of kindling.


External transcutaneous ultrasound technique in the equine cricoarytenoideus dorsalis muscle: Assessment of muscle size and echogenicity with resting endoscopy.
Recent studies have assessed the cricoarytenoideus dorsalis muscle (CAD) using transoesophageal ultrasonography in equine recurrent laryngeal neuropathy (RLN). We assessed the CAD using the external transcutaneous ultrasound technique, which may constitute an easier method in horses. To evaluate ultrasonographic imaging of the left cricoarytenoideus dorsalis muscle (LCAD) and right cricoarytenoideus dorsalis muscle (RCAD) as a diagnostic tool for RLN using the transcutaneous ultrasound technique. Cross-sectional study. The axial plane thickness, cross-sectional area and echogenicity of the LCAD and RCAD were measured using transcutaneous ultrasonography in 164 horses. Assessments of LCAD were compared with those of RCAD. The LCAD:RCAD ratios in thickness and area were compared between control horses (resting grades 1 and 2) and horses with resting laryngeal grades 3 and 4 using the Havemeyer 4-point grading system with subgrades. The LCAD:RCAD ratios for thickness and area were 0.69 and 0.66 in horses with resting grades 3 and 4 respectively; LCAD was more hyperechogenic than RCAD in resting grades 3 and 4. LCAD:RCAD ratios for thickness and area in grades 3.II, 3.III and 4 were significantly lower than those in control horses. Thickness and area of the LCAD were negatively correlated with resting laryngeal grade MAIN LIMITATIONS: Overground endoscopy was not performed in this study. There were some differences in methodology: measurement of the physical thickness of the LCAD and clipping of hair at the laryngeal region were only performed in horses that underwent laryngoplasty. Results of ultrasonographic assessments of the CAD using transcutaneous ultrasonography were similar to those obtained by transoesophageal ultrasonography. This technique enables a simple, noninvasive, direct and easy examination. Assessment of the CAD using transcutaneous ultrasonography may be a useful technique and a potential option for determining whether to perform nerve graft or laryngoplasty.


[Corrections on medicinal resource of Gramineae in Guizhou province and Guiyang city].
To confirm the medicinal plants of Gramineae and their distribution in Guiyang city. Through field investigations and comparing the collected speciments and literatures, the geographical distribution and functions of the medicinal species were investigated. 24 new medicinal species of Gramineae were found in Guizhou, while 5 species were absent in Guizhou. And 1 was first recorded for medicinal uses, 3 species newly added, and the latin name of 1 species was corrected. There are 72 medicinal species and 4 varieties in Guiyang.


Within-patient comparison between [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy and [99mTc]Tc-tilmanocept lymphoscintigraphy for sentinel lymph node detection in oral cancer: a pilot study.
To compare sentinel lymph node (SLN) identification using [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy to [99mTc]Tc-tilmanocept lymphoscintigraphy (including SPECT/CT) in early-stage oral cancer. Furthermore, to assess whether reliable intraoperative SLN localization can be performed with a conventional portable gamma-probe using [99mTc]Tc-tilmanocept without the interference of [68Ga]Ga-tilmanocept in these patients. This prospective within-patient comparison pilot study evaluated SLN identification by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy compared to conventional lymphoscintigraphy using [99mTc]Tc-tilmanocept (~ 74 MBq) in 10 early-stage oral cancer patients scheduled for SLN biopsy. After conventional [99mTc]Tc-tilmanocept lymphoscintigraphy, patients underwent peritumoral administration of [68Ga]Ga-tilmanocept (~ 10 MBq) followed by PET/CT acquisition initiated 15 min after injection. Intraoperative SLN localization was performed under conventional portable gamma-probe guidance the next day; the location of harvested SLNs was correlated to both lymphoscintigraphic images in each patient. A total of 24 SLNs were identified by [99mTc]Tc-tilmanocept lymphoscintigraphy, all except one were also identified by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy. [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy identified 4 additional SLNs near the injection site, of which two harbored metastases. Lymphatic vessels transporting [68Ga]Ga-tilmanocept were identified by PET/CT lymphoscintigraphy in 80% of patients, while draining lymphatic vessels were visualized by [99mTc]Tc-tilmanocept lymphoscintigraphy in 20% of patients. Of the 33 SLNs identified by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy, 30 (91%) were intraoperatively localized under conventional gamma-probe guidance. [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy provided more accurate identification of SLNs and improved visualization of lymphatic vessels compared to [99mTc]Tc-tilmanocept lymphoscintigraphy. When combined with peritumoral administration of [99mTc]Tc-tilmanocept, SLNs detected by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy can be reliably localized during surgery under conventional gamma-probe guidance.


Substantia innominata projection to caudate nucleus in macaque monkeys.
The distribution of the cells of origin projecting from the substantia innominata to the caudate nucleus was studied in macaque monkeys by means of the retrograde axonal transport of horseradish peroxidase (HRP). The HRP was injected, after callosotomy, into the exposed head of the caudate nucleus. Labeled cells appeared in the ipsilateral substantia innominata, extending rostrally to the level of the optic chiasma.


Effects of successful parathyroidectomy on altered arterial reactivity in patients with hypercalcaemia: results of a 3-year follow-up study.
Serum calcium was found to be an independent, prospective risk factor for myocardial infarction. We have previously shown that altered arterial reactivity in the course of primary hyperparathyroidism, a disease characterized by hypercalcaemia, may predominantly involve the arterial media and not the endothelium as observed in patients with various stages of atherosclerosis. The present study was performed to test whether successful parathyroidectomy can improve vascular reactivity in patients with primary hyperparathyroidism. Endothelium-dependent, flow-mediated and endothelium-independent, nitroglycerin-induced dilatation were assessed by brachial artery ultrasound (7 MHz) in 18 patients with primary hyperparathyroidism (mean +/- SD; age, 55.1 +/- 12.6) prior to and 3 years after successful parathyroidectomy. Parathyroidectomy resulted in significant decreases of PTH (242 +/- 186 vs. 34 +/- 24 ng/l, P = 0. 0001) and serum calcium levels (2.8 +/- 0.3 vs. 2.4 +/- 0.1 mm/l, P = 0.00001) and in an increase of serum phosphate levels (0.78 +/- 0. 23 vs. 1.17 +/- 0.18 mm/l, P = 0.00001). However, normalization of hormone and electrolyte levels did not lead to an improvement of flow-mediated dilatation (12.1 +/- 3.1 vs. 11.0 +/- 5.4&, P = 0.49) or nitroglycerin-induced dilatation (12.5 +/- 3.1 vs. 13.2 +/- 6.8%, P = 0.68) within the follow-up period. No changes were observed with respect to the risk factor profile, vessel size and blood flow. These data suggest that restoration of normocalcaemia by parathyroidectomy cannot improve vascular reactivity in patients with primary hyperparathyroidism but may prevent further progression of vascular disease within this period of time.


Treatment of bowel obstruction after operation for colorectal carcinoma.
Operative therapy is beneficial in patients with bowel obstruction after operation for colorectal carcinoma. The cause of the bowel obstruction is more likely to be benign following colorectal carcinoma than following other malignancies. Also, the period of preoperative nasogastric suction can safely be extended to 3 to 4 days in these patients, since a resolution rate of 28 percent can be achieved with minimal risk of strangulation.


Differential glucocorticoid regulation of collagen mRNAs in human dermal fibroblasts. Keloid-derived and fetal fibroblasts are refractory to down-regulation.
Abnormal regulation of collagen synthesis has been observed in fibroblasts from keloids, benign collagenous tumors that develop as a result of an inherited defect in dermal wound healing. Hydrocortisone reduces the rate of collagen synthesis in fibroblasts from normal adult dermis and scars, but fails to down regulate collagen synthesis in keloid-derived fibroblasts. We show here that loss of glucocorticoid control of collagen synthesis in keloid cells is due to an inability of hydrocortisone to reduce the levels of types I, III, and V collagen mRNA, whereas it coordinately lowers these RNAs in normal adult cells. The defective regulatory mechanism is expressed only in fibroblasts from the lesion. Fibroblasts from uninvolved dermis respond normally to hydrocortisone. Not all glucocorticoid-modulated matrix proteins are abnormally regulated in this disorder; fibronectin mRNA is induced to a similar extent in normal and keloid cells. The failure of hydrocortisone to reduce collagen gene expression is also seen in fibroblasts from fetal dermis. We have reported similarities between keloid and fetal cells with regard to growth factor requirements and growth response to hydrocortisone. Thus, keloids may be due to the inappropriate expression of a pattern of growth and matrix production that is developmentally regulated.


Posttransfusion purpura with antibodies against human platelet antigen-4a following checkpoint inhibitor therapy: a case report and review of the literature.
Posttransfusion purpura (PTP) is a rare condition characterized by severe thrombocytopenia following receipt of blood products. Most reported PTP cases involve alloantibodies directed against human platelet antigen (HPA)-1a. We present a case of PTP-mediated severe thrombocytopenia associated with alloantibodies directed against HPA-4a in the setting of combination checkpoint inhibitor therapy. A 62-year-old woman with rectal melanoma that progressed on combination checkpoint inhibitors (ipilimumab and nivolumab) was admitted for abdominoperineal resection. She received multiple blood products during surgery, and between the sixth and eighth days post-surgery her platelet (PLT) count decreased from 126 × 109 /L to a nadir of 1 × 109 /L. She received intravenous immunoglobulin (IVIG), steroids, and romiplostim with eventual recovery of her PLT count to 50 × 109 /L 20 days after surgery. She tested positive for anti-HPA-4a and was shown not to express HPA-4a, confirming a diagnosis of PTP. Alloantibodies strongly reactive to HPA-4a were detected in this patient who received multiple blood products during abdominoperineal resection surgery. Her thrombocytopenia improved with prompt administration of IVIG, steroids, and romiplostim. PTP must always be considered in patients with acute severe thrombocytopenia after receipt of blood products, and treatment should not be delayed while awaiting laboratory confirmation. To our knowledge, this is the second reported case of PTP with antibodies against HPA-4a.


Factors associated with infants' sunlight exposure among mothers attending the EPI unit of Wolkite University Specialized Hospital.
Infant sunlight exposure in their early infancy is essential for the cutaneous synthesis of vitamin D. Vitamin D deficiency is highly prevalent due to inadequate exposure to sunlight. In Ethiopia, one in thirteen children had rickets, which could be prevented by sunlight exposure or supplementation. This study aimed to identify the practice of infants' sunlight exposure and associated factors among mothers attending the Expanded program immunization unit of Wolkite University Specialized Hospital. This study employed an institutional-based cross-sectional study design to collect data. Data were collected from 220 mothers using an interviewer-administered questionnaire. The study employed a systematic random sampling technique to reach the study participants. The collected data were entered into a computer using the software Epidata 3.1 version and exported to SPSS version 23 for statistical analysis. Descriptive and inferential analysis was conducted. Logistic regression analysis was done, and a statistical association was declared at a p-value < 5% and a 95% confidence interval(CI). Then the results were presented using a frequency table, figures, and description. A total of 220 infant-coupled mothers who visited the Expanded program immunization unit were included in the study. According to the current study, 67.3% of mothers had good practice with infants' sunlight exposure. Mothers' practice of infant sunlight exposure was affected by age of mothers 30-34 years, [AOR = 3.10, 95%CI (1.13, 8.51)], and age ≥35 years, [AOR = 4.49, 95%CI (1.20, 16.86)], and living in urban, [AOR = 1.94, 95%CI (1.053, 3.57)]. The current study showed that two-thirds (67.3%) of mothers had good practice of sunlight exposure to their infants. Factors that affect mothers' practice of infants' sunlight exposure are age and place of residence. Health professionals should provide health education for mothers on the benefits of infants' sunlight exposure.


Less is more: clinical impact of decreasing pneumoperitoneum pressures during robotic surgery.
The objective of this study was to investigate the effects of decreasing insufflation pressure during robotic gynecologic surgery. The primary outcomes were patient-reported postoperative pain scores and length of stay. Secondary outcomes include surgical time, blood loss, and intraoperative respiratory parameters. This is a retrospective cohort study of patients undergoing robotic surgery for benign gynecologic conditions by a single minimally invasive surgeon at an academic hospital between 2014 and 2017. Patients were categorized by the maximum insufflation pressure reached during the surgery as either 15, 12, 10, or 8 mmHg. Continuous variables were compared using analysis of variance and χ2 test was used for categorical variables. 598 patients were included in this study with no differences in age, BMI, race, prior abdominal surgeries, or specimen weight between the four cohorts. When comparing cohorts, each decrease in insufflation pressure correlated with a significant decrease in initial pain scores (5.9 vs 5.4 vs 4.4 vs. 3.8, p ≤ 0.001), and hospital length of stay (449 vs 467 vs 351 vs. 317 min, p ≤ 0.001). There were no differences in duration of surgery (p = 0.31) or blood loss (p = 0.09). Lower operating pressures were correlated with significantly lower peak inspiratory pressures (p < 0.001) and tidal volumes (p < 0.001). Surgery performed at lower-pressure pneumoperitoneum (≤ 10 mmHg) is associated with lower postoperative pain scores, shorter length of stay, and improved intraoperative respiratory parameters without increased duration of surgery or blood loss. Operating at lower insufflation pressures is a low-cost, reversible intervention that should be implemented during robotic surgery as it results in the improved pain scores and shorter hospital stays.


The hinge region of the scaffolding protein of cell contacts, zonula occludens protein 1, regulates interacting with various signaling proteins.
Zonula occludens protein 1 (ZO-1) is a ubiquitous scaffolding protein, but it is unknown why it functions in very different cellular contacts. We hypothesized that a specific segment, the unique hinge region, can be bound by very different regulatory proteins. Using surface plasmon resonance spectroscopy and binding assays to peptide libraries, we show, for the first time, that the hinge region directly interacts with disparate signal elements such as G-proteins alpha 12 and alpha i2, the regulator of G-protein signaling 5, multifunctional signaling protein ahnak1, and L-type Ca2+-channel beta-2-subunit. The novel binding proteins specifically bound to a coiled coil-helix predicted in the hinge region of ZO-. The interactions were modulated by phosphorylation in the hinge helix. Activation of the G-proteins influenced their association to ZO-1. In colon cells, G alpha i2 and ZO-1 were associated, as shown by coimmunoprecipitation. After cotransfection in kidney cells, G alpha i2 barely colocalized with ZO-1; the colocalization coefficient was significantly increased when epinephrine activated G-protein signaling. In conclusion, proteins with different regulatory potential adhere to and influence cellular functions of ZO-proteins, and the interactions can be modulated via its hinge region and/or the binding proteins.


An expanded access program of risdiplam for patients with Type 1 or 2 spinal muscular atrophy.
The US risdiplam expanded access program (EAP; NCT04256265) was opened to provide individuals with Type 1 or 2 spinal muscular atrophy (SMA) who had no satisfactory treatment options access to risdiplam prior to commercial availability. The program was designed to collect safety data during risdiplam treatment. Patients were enrolled from 23 non-preselected sites across 17 states and treated with risdiplam orally once daily. Eligible patients had a 5q autosomal recessive Type 1 or 2 SMA diagnosis, were aged ≥2 months at enrollment, and were ineligible for available and approved SMA treatments or could not continue treatment due to a medical condition, lack/loss of efficacy, or the COVID-19 pandemic. Overall, 155 patients with Type 1 (n = 73; 47.1%) or 2 SMA (n = 82; 52.9%) were enrolled and 149 patients (96.1%) completed the EAP (defined as obtaining access to commercial risdiplam, if desired). The median treatment duration was 4.8 months (range, 0.3-9.2 months). The median patient age was 11 years (range, 0-50 years), and most patients (n = 121; 78%) were previously treated with a disease-modifying therapy. The most frequently reported adverse events were diarrhea (n = 10; 6.5%), pyrexia (n = 7; 4.5%), and upper respiratory tract infection (n = 5; 3.2%). The most frequently reported serious adverse event was pneumonia (n = 3; 1.9%). No deaths were reported. In the EAP, the safety profile of risdiplam was similar to what was reported in pivotal risdiplam clinical trials. These safety data provide further support for the use of risdiplam in the treatment of adult and pediatric patients with SMA.


Treatment options in primary mediastinal B cell lymphoma patients, retrospective multicentric analysis; a Turkısh oncology group study.
Primary mediastinal B-cell lymphomas (PMBL) are aggressive B- cell lymphomas. Although the initial treatment models vary in PMBL, appropriate treatment methods are not known. We aim to show real-life data on health outcomes in adult patients with PMBL who received various type of chemoimmunotherapies in Turkey. We analyzed the data of 61 patients who received treatments for PMBL from 2010 to 2020. The overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) of the patients were evaluated. 61 patients were observed in this study. The mean age of the study group was 38.4 ± 13.5 years. From among them, 49.2% of the patients were female (n = 30). For first-line therapy, 33 of them had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen (54%). Twenty-five patients had received rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH-R) regimen. The ORR was 77%. The median OS and PFS were as follows: 25 months (95% CI: 20.4-29.4) and 13 months (95% CI: 8.6-17.3), respectively. The OS and PFS at 12 months were 91.3% and 50%, respectively. The OS and PFS at five years were 64.9% and 36.7%, respectively. Median follow-up time period was 20 months (IQR 8.5-38.5). R-CHOP and DA-EPOCH-R showed good results in PMBL. These remain one of the best determined systemic treatment options for first-line therapy. Also, the treatment was associated with good efficacy and tolerability.


Correction to: Structural and solution chemistry, antiproliferative effects, and serum albumin binding of three pseudohalide derivatives of auranofin.
In the initial online publication, the given name of the first author was incorrectly displayed and should have read Damiano. The original article has been corrected and the proper representation of the authors' names and their affiliation is also listed here.


Comparison of sutured versus sutureless scleral-fixated intraocular lenses.
To compare the intermediate-term anatomic and visual results of scleral-fixated intraocular lens (IOL) implantation using 4-point suture fixation or transscleral sutureless fixation. Tertiary referral eye care center in South India. Retrospective case series. Medical records of consecutive patients who had scleral-fixated IOL surgery from January 1, 2010, to March 31, 2014, with more than 1 year of follow-up were retrospectively analyzed. Indication for scleral-fixated IOL implantation was aphakia after cataract extraction or trauma. The surgical technique was based on individual surgeon preference. The uncorrected distance visual acuity (UDVA), previous surgery, type of trauma, surgical technique, and complications were analyzed. One hundred nine cases were analyzed. The mean follow-up was 18.9 months ± 8.7 (SD). The majority of eyes experienced an improvement in UDVA after surgery; 93 eyes (86%) had a Snellen equivalent corrected distance visual acuity of 6/12 or better. The baseline characteristics and final visual outcomes in the sutured scleral-fixated IOL group (n = 52) and sutureless scleral-fixated IOL group (n = 59) were comparable. Patients with previous trauma (n = 52) were predominantly men and were significantly younger than those in the cataract group. The visual and refractive outcomes were comparable between eyes with previous trauma and eyes with previous cataract surgery. Transient cystoid macular edema was the most common complication (12%); retinal detachment occurred in 5 cases (4.5%). Scleral-fixated IOLs provided excellent visual rehabilitation of aphakic eyes without capsular support. The sutured technique and sutureless technique appear to be equally good in eyes with aphakia after cataract surgery or trauma. No author has a financial or proprietary interest in any material or method mentioned.


Image quality of two different mobile cone beam computed tomographs for maxillofacial surgery.
We evaluated two mobile cone beam computed tomographs (mCBCT) comparing image quality with respect to radiation dosage. Image quality was analyzed by using different scanning modes. The skulls of three human cadavers were scanned by use of conventional Computed Tomography (CT) as well as with two mobile cone beam computed tomographs (Siemens Arcadis Orbic 3D and Ziehm Vision Vario 3D). Six different acquisition modes with different radiation dosages were used. The axial views of all scans were evaluated by five medical doctors regarding image quality by identifying predefined anatomical structures of the skull. A five-point ranking scale was used. The inter-rater reliability was statistically depicted by Cohen's Kappa coefficient. A Wilcoxon signed rank test was used to evaluate the rater's results. For evaluating the signal-to-noise ratio (SNR) a Catphan 600 reference body with two different inlays was used. Comparing the mCBCTs, the image quality of the Siemens Arcadis Orbic 3D in high-dosage mode received the best score (median: 2.27). The inter-rater reliability was fair (Kappa=-0.030 to 0.328). The Wilcoxon test showed significant (p<0.05) different median rating values in 18 out of 21 imaging modes. The SNR was higher (better) in the high-dosage modes. Intra-operative 3D imaging by using mCBCT for maxillofacial surgery in low-dose mode acquisition is adequate in terms of signal-to-noise ratio and image quality. The image quality does not correlate in a linear manner with a higher radiation dosage. Surgeons using this technique should gather their own experience with the different acquisition modes.


National trends in primary cesarean delivery, labor attempts, and labor success, 1990-2010.
The national primary cesarean delivery rate increased until 2004, but after 2004, this rate cannot be tracked using Vital Statistics data. Additionally, it is unknown whether changes in the primary cesarean delivery rate reflect changes in the rate of labor attempts, labor success, or both. Here, using hospital discharge data, we examined national trends in primary cesarean deliveries, labor attempts, and labor success among women without prior cesarean delivery between 1990 and 2010. This analysis of serial cross-sectional data from the National Hospital Discharge Survey used Joinpoint regression to assess trends over time and logistic regression with marginal effects to identify rates of change over time and adjust for demographic and clinical factors. The primary cesarean delivery rate declined 0.2 percentage points per year (95% confidence interval [CI], 0.1-0.3) between 1990 and 1999, increased 1.0 percentage point per year (95% CI, 0.8-1.2) between 1999 and 2004, and increased 0.3 percentage points (95% CI, 0.1-0.6) per year from 2004 until 2010. Between 1998 and 2005, the rate of labor attempts declined 0.4 percentage points (95% CI, 0.3-0.5) per year. No changes in the labor attempt rate occurred between 2005 and 2010. Labor success rates increased 0.2 percentage points (95% CI, 0.1-0.3) per year between 1990 and 1998 but then declined 0.5 (95% CI, 0.5-0.8) percentage points per year from 1998 to 2010. Adjusted results were similar. The primary cesarean delivery rate continued to increase after 2004. Increases in the primary cesarean delivery rate after 2005 were driven by declines in labor success rates.


Treatment of the syndrome of knee pain and meniscal tear in middle-aged and older persons: A narrative review.
To summarize the literature investigating management, treatment strategies, short- and longer-term outcomes of treatment for meniscal tear in middle-aged and older adults. We performed a literature search using PubMed to identify relevant articles and selected 15 for a narrative summary on the available evidence. The literature suggests that middle-age and older adults with meniscal tear may benefit from initial physical therapy (PT) potentially followed by arthroscopic partial meniscectomy (APM) for those who do not experience sufficient benefit after PT and in whom other sources of pain are deemed unlikely. There is moderate evidence to suggest that some factors at baseline, such as radiographic OA, meniscal tear type, and pain at baseline may influence outcomes after APM. Over time, APM appears to increase the risk of degenerative changes in cartilage, bone, and other knee structures as evidenced by radiograph and MRI-based assessments. Evidence from research investigating outcomes of treatment for meniscal tear in middle-aged and older adults demonstrates that PT is a reasonable initial treatment. More research is needed to investigate the best treatment for those who do not benefit substantially from initial PT. The evidence also demonstrates that APM may be associated with greater risk of radiographic osteoarthritic changes, though more research and the addition of enhanced quantitative MRI-assessments are needed to further detail any compositional changes in the knee. Focusing on these areas of further study will clarify whether these imaging findings are clinically meaningful.


Application of new phenolic antioxidants for cryopreservation of sturgeon sperm.
Heterocyclic derivatives of butylated hydroxytoluene (BHT) were studied as cryoprotectants of the basic media for cryopreservation of the Russian sturgeon sperm. Rates of lipid peroxidation of sturgeon sperm before and after cryopreservation were reduced in the presence of the studied compounds, exceeding the effects of BHT and water-soluble analogue of vitamin E, trolox. The most efficient antioxidant has the effective concentration of 0.1 mM. Novel antioxidant agents as cryomedium supplements not only reduced the level of lipid peroxidation, but also enhanced the translational motility of the sperm of the Russian sturgeon after defrosting.


Trail Use, Motivations, and Environmental Attitudes of 3780 European Mountain Bikers: What Is Sustainable?
The extent to which mountain biking impacts upon the environment is largely determined by rider behaviours. The purpose of this study was to gain a better understanding of how mountain bikers interact with the natural environment and explore their attitudes towards sustainability. 3780 European mountain bikers completed an online cross-sectional survey. Connection to nature was an important source of motivation and the use of mountain bike trails has increased rider's appreciation of and willingness to protect nature, with a large majority having taken direct action to do so. Mountain bikers are prepared to contribute towards trail maintenance through the provision of labour or financially. Although most mountain bikers make use of wet trails and illegal trails, incidence of conflict is relatively low. A range of characteristics were identified as being fundamental elements of sustainable trails, both in relation to the sustainability of the trail itself and in terms of wider environmental sustainability. European mountain bikers care about the sustainability of the natural environment. Self-reported attitudes and behaviours suggest a willingness to reduce environmental impact and actively protect nature.


The Palomo procedure in the treatment of boys with varicocele: a retrospective study of testicular growth and fertility.
The Palomo procedure has often been criticized with regard to possible atrophy of the testis. Measuring the testicular volume is mainly used in pre- and postoperative assessment. Evidence concerning fertility remains unclear. The aim of this study was to learn whether now-adult former patients had any disturbance of their testicular growth and/or fertility. Out of 79 patients operated upon with Palomo's procedure between 1979 and 1990, 33 could be evaluated. They all had grade II or III left-sided varicoceles. Investigations consisted of: the patient's history, testicular-volume measurement by means of an orchidometer (OM) (Prader) and ultrasonography (US), and semen analysis (27/33) 6-17 years after surgery. No recurrence of grade II varicoceles was observed. Only 1 of the 33 patients might have had testicular atrophy, yet he had already fathered 3 children! Twenty-three had a normal sperm count and 24/27 showed normal sperm motility. Eight hydroceles were either present at the time of investigation or had been operated upon in the past. Estimations of testicular volume by OM and US showed significant differences between the two methods concerning volume and relation of right to left side. In general, the volume was overestimated by the OM. The study shows that in boys the simple surgical technique proposed by Palomo has - in the long run - no disadvantages for testicular development and sperm production. Fertility should therefore not be compromised.


Intraocular pressure and blood flow of the optic disk: a fluorescent blood cell angiography study.
The damage to disk microcirculation in glaucoma and ocular hypertension is correlated with the damage to the neuronal tissue. However, it is not clear whether the primary damage is vascular or neurogenic. We have developed a new method which allows in vivo observation of the retinal capillary blood cell flow and the plasma flow, separately. The method was used to examine the blood cell flow in the optic disks of cats' eyes. The intraocular pressure was controlled by extra-fine intraocular canula at the anterior chamber. It was found that blood cell flow became stagnant in a few capillaries at the optic disk with an intraocular pressure of 30-45% of the systemic mean blood pressure. When an induced IOP increase to 45% of systemic mean blood pressure was sustained for 30 minutes, microcirculatory blood flow recovery was complete two hours later. When this pressure was sustained for 120 minutes, the recovery was incomplete two hours later. This work represents a new tool in the research of retinal and disk hemodynamics and microvascular pathologies. The results presented in this paper support the hypothesis that early ischemic microdamage might be the basis of the pathogenesis of the chronic glaucomas.


Chemical hypoxia increases cytosolic Ca2+ and oxygen free radical formation.
'Chemical hypoxia' was produced in isolated rat hepatocytes. The cells were immobilized in agarose gel threads and perfused with Krebs-Henseleit bicarbonate buffer equilibrated with 95% O2 + 5% CO2 or 95% air + 5% CO2. During 'chemical hypoxia', 2 mM KCN + 0.5 mM iodoacetate (CN-IAA) were added to the perfusate for 30 min. Cytosolic ionized Ca2+ (Cai2+) was measured with aequorin, the formation of oxygen free radicals by lucigenin-enhanced chemiluminescence and cell injury by the rate of LDH released by the cells in the effluent perfusate. As soon as the cells were exposed to CN-IAA in the presence of 95% O2 + 5% CO2, Cai2+ increased rapidly to reach 1.5 microM within 10 min, and oxygen free radical formation increased 5-fold. The increase in LDH release was temporally delayed and occurred only during the recovery phase. The results were not significantly different when the cells were perfused with KHB equilibrated with 95% air + 5% CO2, except that oxygen free radical formation increased 13-fold. These results suggest that both a rise in Cai2+ and a formation of reactive oxygen species could be responsible for the cell injury and the cell death induced by CN-IAA poisoning.


Acute abdominal conditions in patients with leukemia.
Acute abdominal abnormalities are relatively uncommon during the treatment of leukemia. Over a 22 1/2 year period, acute abdominal abnormalities were diagnosed in 22 of 412 patients (5.3 percent) with acute leukemia and in 9 of 343 patients (2.6 percent) with chronic leukemia. Five patients with acute leukemia and two patients with chronic leukemia were treated medically, and all died within 1 week of diagnosis. Operative mortality decreased from 50 percent during the first half of the study period to 12.5 percent during the last half and was not related to the preoperative white blood cell count, platelet count, age of the patient, type of leukemia, or state of relapse or remission. Postoperative survival averaged 23 months in the patients with chronic leukemia and 5 months in those with acute leukemia, approximating the length of survival of patients with uncomplicated acute or chronic leukemia. Indications for operation in patients with leukemia are the same as for other patients and should be based on careful physical examination.


Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise.
An active lifestyle is crucial to maintain health into old age; inversely, sedentariness has been linked to an elevated risk for many chronic diseases. The discovery of myokines, hormones produced by skeletal muscle tissue, suggests the possibility that these might be molecular mediators of the whole body effects of exercise originating from contracting muscle fibers. Even though less is known about the sedentary state, the lack of contraction-induced myokines or the production of a distinct set of hormones in the inactive muscle could likewise contribute to pathological consequences in this context. In this review, we try to summarize the most recent developments in the study of muscle as an endocrine organ and speculate about the potential impact on our understanding of exercise and sedentary physiology, respectively. This article is part of a Special Issue entitled "Muscle Bone Interactions".


Measuring various drug use dimensions with a calendar method.
This note presents a technique used to acquire a variety of time-specific data on drug use. The calendar technique involves self-reported patterns of consumption and any changes therein, including cessation. Advantages of this technique over other approaches are discussed, and examples of the variety of use measures that can be derived from the calendar method are illustrated.


Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain.
Applications of RNA interference for neuroscience research have been limited by a lack of simple and efficient methods to deliver oligonucleotides to primary neurons in culture and to the brain. Here, we show that primary neurons rapidly internalize hydrophobically modified siRNAs (hsiRNAs) added directly to the culture medium without lipid formulation. We identify functional hsiRNAs targeting the mRNA of huntingtin, the mutation of which is responsible for Huntington's disease, and show that direct uptake in neurons induces potent and specific silencing in vitro. Moreover, a single injection of unformulated hsiRNA into mouse brain silences Htt mRNA with minimal neuronal toxicity. Thus, hsiRNAs embody a class of therapeutic oligonucleotides that enable simple and straightforward functional studies of genes involved in neuronal biology and neurodegenerative disorders in a native biological context.


Association between body mass index and clinical outcomes after new-generation drug-eluting stent implantation: Korean multi-center registry data.
It is unclear whether the obesity paradox is still apparent in the new-generation drug-eluting stent (DES) era. Therefore, we assessed the impact of body mass index (BMI) on clinical outcome after percutaneous coronary intervention (PCI) with new-generation DESs. A total of 5264 consecutive patients from 4 new-generation DES registries were divided into 4 categories according to BMI: 1) underweight (BMI<18.5 kg/m2, n = 130), 2) normal weight (18.5 ≤ BMI <25 kg/m2, n = 2943), 3) overweight (25 ≤ BMI<30 kg/m2, n = 1932), and 4) obese (BMI≥30 kg/m2, n = 259). The primary endpoint was the occurrence of major adverse cardiac and cerebrovascular event (MACCE) at 12 months, including all-cause mortality, nonfatal myocardial infarction, stroke, and target-vessel revascularization. The 12-month MACCE rates decreased according to increasing BMI categories. (underweight, 13.1%; normal, 6.0%; overweight, 4.8%; obese, 4.2%; p < 0.001). After adjustment for other confounders, the underweight group had significantly higher MACCE rates than the normal-weight (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.33-0.99; p = 0.049), overweight (HR, 0.49; 95% CI, 0.27-0.88; p = 0.017), and obese (HR, 0.41; 95% CI, 0.18-0.98; p = 0.044) groups. These differences were mainly driven by all-cause mortality and target-vessel revascularization. When BMI was treated as a continuous variable, BMI per 1 kg/m2 was also an independent predictor for MACCE (HR, 0.95; 95% CI, 0.91-0.99; p = 0.008) and a MACE increase began below a BMI of 24 kg/m2. Lower BMI was significantly associated with higher rates of MACCE and all-cause mortality after PCI. The obesity paradox is manifested in Korean patients in the new-generation DES era.


Experience with an adult alcohol withdrawal syndrome practice guideline in internal medicine patients.
To standardize treatment of alcohol withdrawal syndrome (AWS) in internal medicine patients using an adult AWS practice guideline with a symptom-triggered management approach. Prospective interventional (pilot group) and retrospective (control group). University teaching hospital. Thirty-two internal medicine patients identified as being at risk for AWS and treated according to the AWS practice guideline who were compared with 49 internal medicine patients managed with nonstandardized approaches. Patients in the pilot group were assessed using the AWS type indicator. They received lorazepam, clonidine, or haloperidol, based on AWS type indicator assessment and adult AWS practice guideline criteria. Data collected and analyzed were drugs administered to control AWS symptoms, use of sitters and physical restraints, length of hospital stay, and discharge from hospital receiving tapered drug therapy. Pilot patients received 46.6% less benzodiazepine (p=0.001), 20% more clonidine (p=0.01), and 18.2% more haloperidol (p=0.002) than control patients. No drug therapy was required in 19% of pilot patients compared with 2% of controls (p=0.01). Significantly more control (71.4%) than pilot patients (18.8%) were discharged with tapered benzodiazepine therapy (p<or=0.01). No significant differences were found between groups for sitters, restraints, or hospital length of stay. This pilot project suggests that internal medicine patients at risk for AWS can be managed with a standardized, symptom-triggered approach using decreased amounts of benzodiazepine in combination with adjunctive agents to treat adrenergic hyperactivity and delirium. Further data are necessary to determine the impact of the practice guideline on patient outcome measurements.


Interactome and interface protocol (2IP): a novel strategy for high sensitivity topology mapping of protein complexes.
A few well-characterized protein assemblies aside, little is known about the topology and interfaces of multiconstituent protein complexes. Here we report on a novel indirect strategy for low-resolution topology mapping of protein complexes. Following crosslinking, purified protein complexes are subjected to chemical cleavage with cyanogen bromide (CNBr) and the resulting fragments are resolved by 2-D electrophoresis. The side-by-side comparison of a thus generated and a 2-D CNBr fragment map obtained from uncrosslinked material reveals candidate gel spots harboring crosslinked CNBr fragments. In-gel trypsinization and MALDI MS analysis of these informative spots identify the underlying crosslinked CNBr fragments based on unmodified tryptic peptides. Matching the cumulative theoretical molecular mass and predicted pI of these crosslinked CNBr fragments with original gel spot coordinates is required for confident crosslink assignment. The above strategy was successfully validated with the Escherichia coli RNA polymerase (RNAP) core complex and subsequently applied to query the quaternary structure of components of the yeast Skp1-Cdc53/Cullin-F box (SCF) ubiquitin ligase complex. This protocol requires low picomole sample quantities, can be applied to multisubunit protein complexes, and does not rely on specialized data mining software.


Polyphasic Characterization of Lysobacter maris sp. nov., a Bacterium Isolated from Seawater.
A strictly aerobic, Gram-negative, apricot-pigmented, non-motile, rod-shaped strain designated KMU-14(T) was isolated from seawater collected from the coastal zone of Yokji Island, Gyeongsangnam-do, Republic of Korea. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the genus Lysobacter within the class Gammaproteobacteria and that it showed the highest sequence similarity (97.1 %) to Lysobacter concretionis Ko07(T). The hybridization value for DNA-DNA relatedness between the strains of KMU-14(T) and L. concretionis Ko07(T) was 34.8 %, which was lower than 70 %, the recommended delineation value for differentiation of species. The DNA G+C content of strain KMU-14(T) was 64.9 mol%. The major respiratory quinone was ubiquinone 8 (Q-8), and iso-C15:0, iso-C16:0, and 10-methyl C16:0 and/or iso-C17:1 ω9c were the major (>10 %) cellular fatty acids. A polar lipid profile was present consisting of diphosphatidylglycerol, phosphatidylethanolamine, an unidentified phosphoglycolipid, two unidentified aminophospholipids, and two unidentified phospholipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel species for which the name Lysobacter maris sp. nov. is proposed. The type strain of L. maris sp. nov. is KMU-14(T) (=KCTC 42381(T) =NBRC 110750(T)).


Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease.
Treatment targeted to achieve reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) improves outcomes in human congestive heart failure (CHF) patients. A pre-specified therapeutic algorithm that increased diuretic or pimobendan usage will reduce plasma NT-proBNP concentrations in dogs with CHF secondary to myxomatous mitral valve disease (MMVD). Twenty-six dogs with clinically stable CHF secondary to MMVD. Prospective, controlled before-and-after study. Dogs were examined up to 3 times over 21 days. Treatment was prescribed based on NT-proBNP as follows: <1500 pmol/L at baseline, no treatment adjustment at any point during the study (group 1); ≥1500 pmol/L and creatinine ≤3.0 mg/dL at baseline or SC visits, treatment escalated according to the algorithm (group 2); ≥1500 pmol/L at baseline, no treatment adjustment (group 3). N-terminal pro-B-type natriuretic peptide decreased significantly in group 2 (mean change = -1736 pmol/L (95% CI, -804 to -2668), P < .001) but not in groups 1 or 3 (623 pmol/L [-631 to 1877 pmol/L], P = .14 and 685 pmol/L [-304 to 1068 pmol/L], P = .46, respectively). Serum BUN and creatinine did not change significantly between visit 0 and visit 2 in group 1 (median = 23 mg/dL [range 13-32] versus 19 mg/dL [12-38], P = .72 and 1.15 mg/dL [0.70-1.40] versus 0.95 mg/dL [0.70-1.10], P = .10, respectively) or group 2 (28 mg/dL [18-87] versus 43.5 mg/dL [21-160], P = .092 and 1.10 mg/dL [0.90-2.50] versus 1.55 mg/dL [0.90-3.30], P = .062, respectively). Use of this treatment escalation algorithm allows effective targeting of treatment for CHF in dogs against an objective criterion.


Histopathology and cytotoxicity as biomarkers in treated rats with cadmium and some therapeutic agents.
The present study aimed to investigate the protective role of ascorbic acid (vitamin C) and zinc (Zn) against cadmium (Cd) induced histopathological changes in tissues of liver, kidney, lung and testis of rats as well as chromosomal aberrations. For this purpose, 60 male albino rats were divided into six groups; each group contained 10 animals. The first group served as control and was given only distilled water. The second and third groups received distilled water supplemented with 2 g ascorbic acid/l and 500 mg Zn/l, respectively. The fourth group received a daily oral dose containing 3 mg Cd/kg b.w. (1/30 LD50). The fifth group received Cd + ascorbic acid (3 mg Cd/kg b.w. + 2 g ascorbic acid/l), while the sixth group received Cd + Zn (3 mg Cd/kg b.w. +500 mg Zn/l). The treatment in all groups lasted for 90 consecutive days. Rats exposed to cadmium showed severe histopathological changes in the liver, kidney, lung and testicular tissues as well as chromosomal aberrations such as: break, ring, centromeric separation and polyploidy. Co-treatment with zinc partially improved the histopathological changes and chromosomal aberrations while co-treatment with vitamin C exhibited a more protective role and markedly reduced tissues damage induced by Cd.


Prognostic significance of computed tomography in resected N2 lung cancer.
We reviewed 124 patients from 1982 to 1988 who had a resected primary non-small cell lung cancer metastatic to mediastinal (N2) lymph nodes and a preoperative assessment of the mediastinum with computed tomography of the chest. Sixty-three patients studied had computed tomographic evidence of mediastinal lymph node enlargement. In these patients the survival at 5 years was only 6.6%, compared with the 5-year survival of 13.5% in 61 patients in whom the mediastinum was normal. Plain chest roentgenography with evidence of mediastinal adenopathy did not predict a poorer outcome. In addition, patients with tumors located in the left upper lobe were found to have an improved survival. These patients had a 5-year survival of 20.8%. Tumor histology, central location of the tumor, extranodal extension, and type of resection did not result in a significant survival difference.


Short-term plasticity of Bergmann glial cell extrasynaptic currents during parallel fiber stimulation in rat cerebellum.
Bergmann glial cells (BGC) enclose the synapses of Purkinje neurons (PN) and interneurons in the molecular layer of the cerebellar cortex. During synaptic transmission, glutamate evokes inward currents in the glia by activation of Ca2+-permeable aminohydroxymethylisoxazole propionic acid receptors (AMPAR) and electrogenic transporters. We describe the plasticity of BGC currents during paired-pulse and repetitive stimulation of parallel fibers in cerebellar slices. Paired-pulse facilitation (PPF) of BGC AMPAR currents was 4-fold, twice that of PN PPF. Experiments with a low-affinity AMPAR antagonist showed an increase in extrasynaptic glutamate concentration during the second pulse of the pair. PPF of glial transporter currents was 1.8-fold, similar to synaptic PPF. Tetanic stimulation revealed that facilitation of BGC AMPAR currents is not sustained during high-frequency stimulation, and substantial depression is observed after a few pulses. Consequently, Ca2+ influx through glial AMPARs would initially be facilitated but subsequently depressed, generating a transient Ca2+ influx in response to a sustained tetanus. This pattern of plasticity may be important in enabling Bergmann glial cell processes to detect and support synapses with high-frequency input. Finally, a new current was observed in BGC during repetitive stimulation. It was blocked by NBQX and intracellular GDP-beta-S, increased by glutamate uptake inhibition, had PPF similar to synaptic PPF, and was unaffected by an inhibitor of fast glial AMPAR currents. The evidence suggests that activation of neuronal AMPARs causes the release of a paracrine messenger to activate a G-protein coupled receptor in the BGC.


2,2-Dimethyl-4-(4-methoxy-phenoxy) butanoate and 2,2-dimethyl-4-azido butanoate: two new pivaloate-ester-like protecting groups.
The title compounds were developed to extend the available orthogonalities within the class of protecting groups removed by assisted cleavage. The mild, complementary (oxidative vs reductive) reaction conditions for the removal, together with their pivaloate-like character, were exploited, in combination with a levulinoyl-ester functioning as a third orthogonal protecting group, in the assembly of a Streptococcus mutans hexasaccharide built up from a oligorhamnose backbone featuring β-glucosyl appendages.


Light-adaptation attenuates the effects of phosphodiesterase blackade by Zaprinast in the isolated rat retina.
The effect of the type V/VI-selective phosphodiesterase inhibitor, Zaprinast, (200 microM) on the light-evoked extracellular field potential (EFP) in the isolated rat retina was tested under dark- and light-adapted conditions at two different temperatures. Peak enhancement EFP in dark- (344 +/- 70%; mean +/- SEM) and light-adapted (182 +/- 31%) retina at 37 degrees C was reached within 3 min of treatment with Zaprinast (200 microM) followed by a slower decrease to a level of 85 +/- 14 and 26 +/- 7% in dark- and light-adapted retina, respectively. The effect of Zaprinast (20 microM) on the pharmacologically-isolated photoreceptor component of the EFP was lost with increasing levels of background light. This may suggest that there is a slow time scale (minutes) shift in the steady state level of cGMP during light-adaptation.


Pain May Promote Tumor Progression via Substance P-Dependent Modulation of Toll-like Receptor-4.
In a previous study, persistent pain was suggested to be a risk factor for tumor patients. However, the mechanism underlying this phenomenon is still unclear. Substance P (SP), a pain-related neuropeptide secreted by the neural system and the immune system, plays an important role in the induction and maintenance of persistent pain. In this study, in order to explore whether SP participates in the influence of pain on tumor progression, the serum samples of lung cancer and breast cancer patients were collected and tested. An elevated expression of SP was found in patients with pain. Cell pharmacological experiments revealed that SP can upregulate the expression of Toll-like receptor-4 (TLR-4) in tumor cells and increase the proliferation, migration, and invasive activity of tumor cells. As high expression of TLR-4 has the ability to enhance the biological activity of tumor cells, TLR-4 is thought to be involved in SP-induced tumor proliferation, migration, and invasion. Treatment of tumor cells with Aprepitant, a specific blocker of the NK-1 receptor, could reduce the expression of TLR-4 and reduce the proliferation, invasion, and migration activities of tumor cells; further proof of the influence of SP on TLR-4 expression depends on the NK-1 receptor located in tumor cells. Based on the results above, we proposed a possible mechanism underlying pain affecting tumor progression: The presence of pain increases the content of SP in patients' blood, and elevated SP increases the expression of tumor TLR-4 by acting on the NK-1 receptor, which ultimately affects the biological activity of the tumor.


Interleukin-1beta modulates proinflammatory cytokine production in human epithelial cells.
Periodontitis is a chronic human inflammatory disease initiated and sustained by dental plaque microorganisms. A major contributing pathogen is Porphyromonas gingivalis, a gram-negative bacterium recognized by Toll-like receptor 2 (TLR2) and TLR4, which are expressed by human gingival epithelial cells (HGECs). However, it is still unclear how these cells respond to P. gingivalis and initiate inflammatory and immune responses. We have reported previously that HGECs produce a wide range of proinflammatory cytokines, including interleukin-6 (IL-6), IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha (TNF-alpha), and IL-1beta. In this study, we show that IL-1beta has a special role in the modulation of other inflammatory cytokines in HGECs challenged with P. gingivalis. Our results show that the increased production of IL-1beta correlates with the cell surface expression of TLR4, and more specifically, TLR4-normal HGECs produce fourfold more IL-1beta than do TLR4-deficient HGECs after challenge. Moreover, blocking the IL-1beta receptor greatly reduces the production of "secondary" proinflammatory cytokines such as IL-8 or IL-6. Our data indicate that the induction of IL-1beta plays an important role in mediating the release of other proinflammatory cytokines from primary human epithelial cells following challenge with P. gingivalis, and this process may be an inflammatory enhancement mechanism adopted by epithelial cells.


[Unilateral lung aplasia--on the danger of diagnostic-therapeutic erroneous assessment. A case report].
A 6 month old infant with recurrent respiratory infections showed a strange chest x-ray film. After axial CT of the chest and bronchoscopy the diagnosis of aplasia of the right lung was established. The case report illustrates the high risk of malpractise in patients suspected of hypogenetic lung syndrome.


Cyproterone acetate-promoted prevention of renal cortical necrosis following testosterone and vasopressin administration.
Bilateral focal renal cortical necrosis was observed after vasopressin administration in rats pretreated for 10 days with testosterone phenyl propionate. When the androgen-receptor blocking-agent cyproterone acetate was administered together with the testosterone, the subsequent vasopressin treatment did not cause renal cortical necrosis. The results suggest the role of the androgen receptors in the kidney in the induction of the phenomenon.


Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS.
We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS). Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2. Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy versus placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; p = 0.0359) and 28.6% (WB; p = 0.0286); month 24, 40.2% (CGM; p = 0.0416) and 43.0% (WB; p < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (p = 0.0004) and 47.3% (p < 0.0001) during years 1-2, respectively, and 6.6% (p = 0.0570) and 35.9% (p = 0.0250) during years 1-5. In patients with the least (bottom quartile) versus most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; p = 0.0024) and 58% (WB; p = 0.0028) during years 1-2, and 42% (CGM; p = 0.0138) and 29% (WB; p = 0.1912) during years 1-5. These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.


Anomalies of cyclic AMP excretion in some abnormal offenders.
It is now well established that the metabolic sequeale of catecholamine secretion are mediated via cyclic nucleotides. Recent studies have indicated changes in the pattern of catecholamine secretion correlating with convictions for violence in maximum security hospital detainees. This study of the excretion rate of urinary cyclic AMP in this group of patients failed to show a correlation between adrenaline or noradrenaline and cyclic AMP secretion. However, subjects convicted of sexual offences showed a significantly greater cyclic AMP excretion than other patients and normal controls. These results are discussed in terms of the possible modification of receptor sensitivity and influence of alternative agonists such as testosterone.


Identification of major immunogenic proteins of Mycoplasma synoviae isolates.
Mycoplasma synoviae isolates differ in patterns of immunogenic proteins, but most of them have not been identified yet. The main aim of this study was their identification in two closely related M. synoviae isolates, ULB 02/P4 and ULB 02/OV6, recovered recently from chickens in Slovenia. N-terminal sequencing identified 17 M. synoviae proteins. Amongst them were 14 major, highly expressed but previously unidentified proteins, including enzymes, chaperones and putative lipoproteins. ULB 02/P4 proteins with increasing molecular weight (M(w)) in the region above the lipoprotein MSPB (approximately 40 kDa) were elongation factor EF-Tu, enolase, NADH oxidase, haemagglutinin MSPA, ATP synthase beta chain, trigger factor, pyruvate kinase and chaperone DnaK. Enolase (approximately 47 kDa) seemed to be immunogenic for chickens infected with M. synoviae, whereas EF-Tu, which might cross-react with antibodies to the P1 adhesin of Mycoplasma pneumoniae, was not. ULB 02/OV6 synthesized several immunogenic proteins and those with M(w) of approximately 70, 78, 82, 90, 110 and 160 kDa, cross-reacted with antibodies to Mycoplasma gallisepticum. They remain to be identified, because besides putative lipoproteins, protein bands of 78, 82, 85 and 110 kDa contained also dehydrogenase PdhD, elongation factor EF-G, enzyme PtsG and putative neuraminidase, respectively.


Early life microbial exposures and allergy risks: opportunities for prevention.
Allergies, including asthma, food allergy and atopic dermatitis, are increasing in prevalence, particularly in westernized countries. Although a detailed mechanistic explanation for this increase is lacking, recent evidence indicates that, in addition to genetic predisposition, lifestyle changes owing to modernization have an important role. Such changes include increased rates of birth by caesarean delivery, increased early use of antibiotics, a westernized diet and the associated development of obesity, and changes in indoor and outdoor lifestyle and activity patterns. Most of these factors directly and indirectly impact the formation of a diverse microbiota, which includes bacterial, viral and fungal components; the microbiota has a leading role in shaping (early) immune responses. This default programme is markedly disturbed under the influence of environmental and lifestyle risk factors. Here, we review the most important allergy risk factors associated with changes in our exposure to the microbial world and the application of this knowledge to allergy prevention strategies.


The structural and functional effects of Hg(II) and Cd(II) on lipid model systems and human erythrocytes: A review.
The anthropogenic mobilization of mercury and cadmium into the biosphere has led to an increased and ineludible entry of these metals into biological systems. Here we discuss the impact of Hg(II) and Cd(II) on lipid model systems and human erythrocytes from a biophysical perspective. After a brief introduction to their implications on human health, studies that have investigated the effects of Hg(II) and Cd(II) on lipid model systems and human erythrocytes are discussed. In terms of lipids as toxicological target sites, predominantly variations in lipid head groups have been the source of investigation. However, as research in this field progresses, the effects of Hg(II) and Cd(II) on other structural features, such as acyl chain length and unsaturation, and other important lipid components and complex biomimetic lipid mixtures, will require further examinations. This review provides an analysis of what has been learned collectively from the diverse methodologies and experimental conditions used thus far. Consequently, there is a need for more comprehensive and thorough investigations into the effects of Hg(II) and Cd(II) on lipid membranes under consistent experimental conditions such as pH, ionic strength, temperature, and choice of lipid model system.


Neuroprotective role of quercetin in locomotor activities and cholinergic neurotransmission in rats experimentally demyelinated with ethidium bromide.
The purpose of this study was to investigate whether the flavonoid quercetin can prevent alterations in the behavioral tests and of cholinergic neurotransmission in rats submitted to the ethidium bromide (EB) experimental demyelination model during events of demyelination and remyelination. Wistar rats were randomly distributed into four groups (20 animals per group): Control (pontine saline injection and treatment with ethanol), Querc (pontine saline injection and treatment with quercetin), EB (pontine 0.1% EB injection and treatment with ethanol), and EB+Querc (pontine 0.1% EB injection and treatment with quercetin). The groups Querc and Querc+EB were treated once daily with quercetin (50mg/kg) diluted in 25% ethanol solution (1ml/kg) and the animals of the control and EB groups were treated once daily with 25% ethanol solution (1ml/kg). Two stages were observed: phase of demyelination (peak on day 7) and phase of remyelination (peak on day 21 post-injection). Behavioral tests (beam walking, foot fault and inclined plane test), acetylcholinesterase (AChE) activity and lipid peroxidation in pons, cerebellum, hippocampus, hypothalamus, striatum and cerebral cortex were measured. The quercetin promoted earlier locomotor recovery, suggesting that there was demyelination prevention or further remyelination velocity as well as it was able to prevent the inhibition of AChE activity and the increase of lipidic peroxidation, suggesting that this compound can protect cholinergic neurotransmission. These results may contribute to a better understanding of the neuroprotective role of quercetin and the importance of an antioxidant diet in humans to provide benefits in neurodegenerative diseases such as MS.


Study on the physiology of diapause, cold hardiness and supercooling point of overwintering pupae of the pistachio fruit hull borer, Arimania comaroffi.
The pistachio fruit hull borer, Arimania comaroffi (Ragonot) (Lepidoptera: Pyralidae), is a key pest of pistachio orchards in Iran. This pest passes the winter as diapausing pupae. In this study, some physiological changes in relation to environmental temperature were investigated in field collected pupae. The relationship between supercooling point, cold hardiness and physiological changes of a wild population of this pest was also investigated. The glycogen content decreased with decrease in environmental temperature. Decrease in glycogen content was proportional to increase in total body sugar, trehalose, myo-inositol and sorbitol contents. In January with mean ambient temperature of 5.4°C, glycogen (5 mg/g fresh body weight) content was at the lowest level whereas total body sugar (10.3 mg/g fresh body weight), trehalose (8.6 mg/g fresh body weight), myo-inositol (5.3 mg/g fresh body weight) and sorbitol (2.6 mg/g fresh body weight) were at the highest levels. Total body sugar, trehalose, myo-inositol and sorbitol contents increased as mean temperature decreased from 22.7°C in October to 5.4°C in January. Total body lipid decreased during overwintering and reached to the lowest level at the end of March. Supercooling points were decreased from October to January and reached to the lowest level (-16°C) in January with minimum ambient temperature of -10°C. Survival at low temperature after 24 h was also greatest in January with 72% survival at -10°C, 39% survival at -15°C and 0% survival at -20°C. Increase in temperature from February onward, was proportional with increase in supercooling points and decrease in survival rate. Regardless of sampling date, all pupae died after 24 h at -20°C, whereas none pupae died after 24 h at -5°C. This indicates that this insect is freeze-intolerant.


Thrombin stimulates release of endothelin and vasopressin, but not substance P, from isolated rabbit tracheal epithelial cells.
Release of endothelin, vasopressin and substance P from isolated rabbit tracheal epithelial cells was monitored after incubation for 2 h with thrombin (10 U/ml) in the presence and absence of cycloheximide (100 micrograms/ml) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC, 0.6 mM). Thrombin stimulated the release of endothelin and vasopressin. Inhibition of the thrombin-stimulated release of endothelin and vasopressin by cycloheximide (44 and 56%, respectively) and NCDC (59 and 88%, respectively) indicates that the release of these peptides is at least partially dependent on the ability of thrombin to stimulate protein synthesis and activate the phospholipase C pathway. Substance P, which is also present in tracheal epithelial cells, was not released by thrombin.


Anti-hyperlipidemia on rats in vivo and new compounds from the seeds of Psoralea corylifolia.
In this study, it was confirmed at first time that the crude extracts of Psoralea corylifolia seeds (PCE34) can reduce serum lipids (AST, ALT, TG, TC, LDL, ALP, ACP and LDH), body weight and serum sugar, increase HDL and serum insulin in hyperlipidemic wistar rat induced by high-fat diet in vivo. Furthermore, eight new chalcones 1-8, one new flavanone 12, one new coumarin 14, three new meroterpenes 15-17 and one new bakuchiol 20 together with seven known compounds (9-11, 13, 18-19 and 21) were isolated from the PCE34. Their structures were elucidated based on analyses of their spectroscopic (UV, CD, NMR and HREIMS) data. All the isolates were evaluated for in vitro inhibitory activity against DGAT1/2, PTP1B and α-Glucosidase. Among them, compounds 1-3, 8-11, 14-17, 19 and 20 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 66.7 ± 1.2 to 87.2 ± 1.3 μM; 1, 8-12, 14 and 20 has the best inhibit active on PTP1B with IC50 values ranging from 13.8 ± 1.1 to 19.1 ± 1.6 μM; 1-12 and 14 displayed the significant inhibitory activities on α-Glucosidase with IC50 values ranging from 29.1 ± 1.2 to 79.4 ± 1.2 μM.


Small-molecule-induced polymerization triggers degradation of BCL6.
Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets1-3, but a substantial subset of proteins are resistant to targeted degradation using existing approaches4,5. Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL66. We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand-protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology.


Clinical Case Seminar: Postmenopausal androgen excess-challenges in diagnostic work-up and management of ovarian thecosis.
Postmenopausal hyperandrogenism can be tumour- or non-tumour-related, with pathology residing either in the ovary or adrenal gland(s). The tempo of investigation is determined by the clinical severity of hyperandrogenism (presence/absence of actual virilisation) and degree of serum testosterone elevation. When clinical or biochemical hyperandrogenism is severe, rapidly developing, or associated with hypercortisolism, screening for adrenocortical or ovarian carcinoma with cross-sectional imaging should be prioritised over detailed biochemical evaluation. Adrenal hyperandrogenism is readily characterised, both biochemically and radiologically. By contrast, even a combination of high-resolution imaging with laboratory evaluation, including dynamic endocrine testing, often cannot distinguish between ovarian hyperthecosis (OH) and virilising ovarian tumour (VOT); a definitive diagnosis usually emerging only after histological examination of excised ovaries. VOTs are typically below the resolution-limit of current imaging modalities and exhibit suppression of gonadotropin-dependent androgen secretion with GnRH-analogue therapy. Thus, for well-characterised ovarian hyperandrogenism, laparoscopic bilateral salpingo-oophorectomy may serve both as a diagnostic and therapeutic procedure. Nevertheless, women unable or unwilling to undergo ovarian surgery can be reassured that malignant VOTs are exceedingly rare and that long-term medical therapy with oral antiandrogens or GnRH-analogues is safe and well-tolerated. OH is strongly associated with insulin-resistance, with hyperinsulinaemia acting synergistically with raised gonadotropin levels to stimulate thecal cell hyperplasia and androgen secretion by the postmenopausal ovary, which lacks granulosa cell aromatase activity and thus cannot convert testosterone to 17 beta estradiol. Thus, features of metabolic syndrome may indicate OH, and significant reductions in androgens can thereby potentially be achieved with lifestyle measures and/or insulin-sensitising drugs.


The antimicrobial activity of Cbf-K16 against MRSA was enhanced by β-lactamantibiotics through cell wall non-integrity.
Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the most important pathogens both in health care and in community-onset infections. Cbf-K16, a cathelicidin-like antimicrobial peptide, presented broad antimicrobial activity during our previous studies. We evaluated the potential for synergy of Cbf-K16 with ceftazidime/ampicilin against MRSA, which was resistant to these two antibiotics with the minimum inhibitory concentration more than 64 μg/ml. The combinations showed a synergistic effect by a checkerboard assay with a fractional inhibitory concentration index ≤0.5. The killing curves of the combination treatment against MRSA showed that CFU counts decreased rapidly within 4 h by almost five logs, while single medication groups and the control group exhibited little inhibitory effect. In addition, in a mice bacteremia model, studies indicated that the combination treatment significantly prolonged the survival time of mice infected with MRSA, with a death protection rate of 80 %. Flow cytometry analysis and transmission electron microscopy indicated that combination-treated MRSA was completely ruptured with the cellular contents leaked out. The synergistic effect showed that Cbf-K16 selectively killed cells with non-integrity induced by cell wall inhibition antibiotics, suggesting that Cbf-K16 is a potential therapeutic agent and adjuvant for antimicrobial chemotherapy.


Posterior pubo-urethral ligaments in normal and genuine stress incontinent women.
Specimens of the posterior pubo-urethral ligament were taken from 10 continent females (7 at post mortem and 3 at gynaecological surgery) and from 9 genuine stress incontinent patients. They were examined and compared using light and electron microscopy and neuro-histochemistry. The morphology of all specimens was similar in that they contained dense connective tissue elements enclosing smooth muscle bundles which were associated with numerous nerves, the enzyme content and fine structure of which were similar to those believed to represent cholinergic autonomic nerves. There was no difference in the morphology, histochemistry and fine structure of the specimens of the ligaments from the control and incontinent patients. Therefore, it is suggested that altered morphology of the posterior pubo-urethral ligaments is unlikely to be an etiological factor in genuine stress incontinence. It is postulated that the ligaments may play a role in stabilising the proximal urethra or assist in bladder-neck opening during voiding.


Aromatase overexpression transgenic mice model: cell type specific expression and use of letrozole to abrogate mammary hyperplasia without affecting normal physiology.
Our recent studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in female mammary glands and gynecomastia and testicular cancer in male aromatase transgenic mice. Both aromatase mRNA and protein are overexpressed in transgenic mammary glands and its expression is not limited to epithelial cells. However, it is more in epithelial than in stromal cells. Our results also indicate aromatase overexpression-induced changes in mammary glands can be abrogated with very low concentrations of the aromatase inhibitor, letrozole. Low concentration of letrozole had no effect on normal physiology as indicated by no significant change in the circulating levels of estradiol and follicle stimulating hormone as well as no change in estrogen responsive genes such as the progesterone receptor and lactoferrin in the uterine tissue. These observations indicate that the expression of aromatase in both epithelial and stromal cells can influence the complex interactions of biochemical pathways leading to mammary carcinogenesis and that the aromatase inhibitor, letrozole can be used as chemopreventive agents without affecting normal physiology.


An incarcerated Spigelian hernia with the appendix in the sac passing though all layers of the abdominal wall: an unusual cause for chronic right iliac fossa pain.
Abdominal wall hernias are a common pathology and source of morbidity including chronic pain. They occur in various anatomical areas; amongst the rarest locations is the Spigelian hernia accounting for <2% of all abdominal hernias. We present a case report of a patient with chronic right iliac fossa pain caused by an incarcerated Spigelian hernia containing her appendix within the hernial defect. Rarer still is that her hernial defect penetrated all three layers of anterior abdominal wall, typically a Spigelian hernia would only pass through transversus abdominis and internal oblique layers.


Pure skin perforator flap for microtia and congenital aural atresia using supermicrosurgical techniques.
Microtia or pinna deformities with congenital aural atresia are severe conditions that significantly affect the quality of life. Although several surgical treatments have been proposed for aural atresia, revision surgery is often required to address complications associated with the initial procedure, which include external auditory canal stenosis, lateralization of the tympanic membrane and chronic recurrent otorrhea. However, such problems may be addressed by using vascularized skin. We herein report a new method of reconstruction for congenital aural atresia in three cases using the superficial circumflex iliac artery as a pure skin perforator flap. The branch of the superficial circumflex iliac artery perforator was traced distally to a point where it penetrated the dermis. After identifying the branch of the perforator penetrating the dermis (termed the "pure skin perforator"), the pure skin perforator flap was elevated. A new external auditory canal was then created by drilling through the mastoid air cells and atresia plate. The pure skin perforator flap was folded into a 1.5×3 cm sac, which was placed into the external auditory canal. The superficial circumflex iliac artery and the superficial circumflex iliac vein were anastomosed to the superficial temporal artery and the superficial temporal vein, respectively. All of the pure skin perforator flaps survived. The flap sizes varied from 10×2.5 to 10×4 cm (average area of 32.5 cm2). These skin perforator flaps were all 2 mm thick. Pure skin perforator flaps fed only by the dermal subpapillary plexus survived, regardless of the presence of the subdermal plexus. The pure skin perforator flap can be as thin as a skin graft and it has the possibility to reduce the complications that frequently occur when the previously reported procedures are used.


Discovery of a novel marker for human granulocytes and tissue macrophages: RTL1 revisited.
Here, retrotransposon-like 1 (RTL1) is introduced as a marker for circulating and tissue neutrophils, tissue macrophages, and tumor-associated macrophages (TAM) and neutrophils (TAN). Anti-RTL1 polyclonal and monoclonal antibodies were produced, and their reactivity was examined by Western blotting (WB), ELISA, and immunostaining of human normal and cancer tissues. The reactivity of the anti-RTL1 antibodies with peripheral blood leukocytes and a panel of hematopoietic cell lines was examined. The generated antibodies specifically detected RTL1 in the WB of the placenta and U937 cells. The polyclonal antibody showed excellent reactivity with tissue-resident macrophages, Hofbauer cells, alveolar and splenic macrophages, Kupffer cells, and inflammatory cells in the tonsil, appendix, and gallbladder. In vitro GM-CSF-differentiated macrophages also showed a high level of intracellular RTL1 expression. TAM and TAN also showed excellent reactivity with this antibody. Almost all circulating granulocytes but not lymphocytes or monocytes expressed RTL1 at their surface. Serial sections of the appendix stained with CD15 and RTL1 and placenta stained with CD68 and RTL1 showed a considerable overlap in RTL1 expression in CD15+ granulocytes and CD68+ macrophages. A small percentage of myelomonocytic cell lines was positive for surface RTL1, while promyelocytic, monocytic, megaloblastic, and lymphoblastic cell lines were negative. Endothelial cells of normal and cancer tissues highly expressed RTL1. RTL1 could be considered a new marker for different normal tissue macrophages, TAM, circulating and tissue neutrophils, and TAN.


Effects of ethanol and ethionine on DNA synthesis during experimental liver regeneration.
Ethanol reversed the ethionine-induced inhibition of 3H-thymidine incoroporation into hepatic DNA in the male and female rat after partial hepatectomy.


New Method for Assessment of Levator Avulsion Injury: A Comparative Elastography Study.
The aim of this study was to introduce elastography as a new method for sonographic assessment of postpartum pelvic floor trauma. We examined 86 postpartum primiparous women, of whom 43 had undergone primary caesarean section (group_CS) and 43 vaginal delivery (group_VD). In a puborectal-symphysis plane, B-mode and elastographic ultrasonography were used to evaluate pelvic floor trauma. The strain value of left and right puborectal muscle was assessed close to the symphysis (Trauma_Elastography). The strain ratio maximum of this measurement was stored (Trauma_Index). The elastographic evaluation revealed more trauma-suspicious lesions than the B-mode investigation (60.5% versus 39.5%; P < .001). The median Trauma_Index was higher in group_VD compared to group_CS (1.63 versus 1.18; P < .001). Sonographic elastography assessment in a new examination plane shows postpartum trauma of the pelvic floor in women after vaginal delivery. This new method may help to identify women with a higher risk of postpartum pelvic floor disorders.


Application of pattern recognition techniques to the analysis of protein crystal structure data. I. Characteristics of per-residue side chain contact frequency distributions.
A statistical study of amino acid side chain contact interactions was carried out using a data set based on 36 protein structures. For each type of amino acid, a distribution of per-residue inter-side-chain contacts was obtained, over the observed span of zero to 11 contacts per residue. Significant observations included the following: 1) The mean number of inter-side-chain contacts is proportional to side chain surface area with the exception of Lys and Arg. 2) The mean number of contacts was greater for amino acids in beta-sheet relative to alpha-helical regions. 3) The more polar or surface-loving amino acids exhibited non-normal distributions, whereas distributions for the non-polar or interior-loving amino acids fell within accepted limits of normality.


A rapid and efficient method for the detection of point mutations of the human prion protein gene (PRNP) by direct sequencing.
Creutzfeldt-Jakob disease (CJD) and related disorders occur in sporadic, acquired and inherited forms. In sporadic, iatrogenic and new variant CJD the polymorphic codon 129 of the prion protein gene (PRNP) plays an important role for the susceptibility to the disease and for the clinical and neuropathological manifestations. All the inherited forms of CJD and related disorders are linked to point or insert mutations of PRNP. The analysis of PRNP is therefore important for a correct classification of these disorders and for the identification of novel mutations. The aim of the present study is to describe a fast and easy to perform method for the direct sequencing of the PCR amplified PRNP open reading frame, by using M13 tailed primers which allow a direct and rapid method of sequencing. The goodness of this method is demonstrated in the analysis of three sporadic CJD patients with different genotypes at codon 129 and three inherited cases bearing different point mutations of PRNP: the Pro102Leu mutation linked to Gerstmann-Sträussler-Scheinker-syndrome, the Val210Ile mutation and a novel mutation at codon 211 (Gln211Glu) both associated to familial CJD.


The burden of COVID-19 infection in a rural Tamil Nadu community.
There have been over 30 million cases of COVID-19 in India and over 430,000 deaths. Transmission rates vary from region to region, and are influenced by many factors including population susceptibility, travel and uptake of preventive measures. To date there have been relatively few studies examining the impact of the pandemic in lower income, rural regions of India. We report on a study examining COVID-19 burden in a rural community in Tamil Nadu. The study was undertaken in a population of approximately 130,000 people, served by the Rural Unit of Health and Social Affairs (RUHSA), a community health center of CMC, Vellore. We established and evaluated a COVID-19 PCR-testing programme for symptomatic patients-testing was offered to 350 individuals, and household members of test-positive cases were offered antibody testing. We also undertook two COVID-19 seroprevalence surveys in the same community, amongst 701 randomly-selected individuals. There were 182 positive tests in the symptomatic population (52.0%). Factors associated with test-positivity were older age, male gender, higher socioeconomic status (SES, as determined by occupation, education and housing), a history of diabetes, contact with a confirmed/suspected case and attending a gathering (such as a religious ceremony, festival or extended family gathering). Amongst test-positive cases, 3 (1.6%) died and 16 (8.8%) suffered a severe illness. Amongst 129 household contacts 40 (31.0%) tested positive. The two seroprevalence surveys showed positivity rates of 2.2% (July/Aug 2020) and 22.0% (Nov 2020). 40 tested positive (31.0%, 95% CI: 23.02 - 38.98). Our estimated infection-to-case ratio was 31.7. A simple approach using community health workers and a community-based testing clinic can readily identify significant numbers of COVID-19 infections in Indian rural population. There appear, however, to be low rates of death and severe illness, although vulnerable groups may be under-represented in our sample. It's vital these lower income, rural populations aren't overlooked in ongoing pandemic monitoring and vaccine roll-out in India.


Two new species of Asellota (Crustacea, Isopoda) from coral reefs on Iriomote Island, Okinawa, Japan.
Pleurocope iriomotensis sp. n. and Prethura tuberculata sp. n. are described from Iriomote Island, Ryukyu Archipelago, southern Japan. These are the first records of Pleurocope from the Pacific and of Prethura from the Asian Pacific coast. Pleurocope iriomotensis differs from its congeners in having lateral spine-like processes on pereonite 4 and coxal plates of pereonite 7. Prethura tuberculata can be distinguished from its single congener in having a lateral short projection of protopod of pleopod 2.