Renal protective effects of astragalus root in rat models of chronic kidney disease.
Astragalus root is a commonly used herb in traditional Chinese medicine. Although renoprotective effects have been reported in some clinical and experimental studies, the details remain unknown. We used 5/6 nephrectomized rats as chronic kidney disease (CKD) models. At 10 weeks, they were divided into four groups, namely, CKD, low-dose astragalus (AR400), high-dose astragalus (AR800), and sham groups. At 14 weeks, they were sacrificed for the evaluation of blood, urine, mRNA expression in the kidney, and renal histopathology. Kidney dysfunction was significantly improved following astragalus administration (creatinine clearance: sham group; 3.8 ± 0.3 mL/min, CKD group; 1.5 ± 0.1 mL/min, AR400 group; 2.5 ± 0.3 mL/min, AR800 group; 2.7 ± 0.1 mL/min). Blood pressure, urinary albumin, and urinary NGAL levels were significantly lower in the astragalus-treated groups than those in the CKD group. Excretion of urinary 8-OHdG, an oxidative stress marker, and intrarenal oxidative stress were lower in the astragalus-treated groups than those in the CKD group. Furthermore, the mRNA expression of NADPH p22 phox, NADPH p47 phox, Nox4, renin, angiotensin II type 1 receptor, and angiotensinogen in the kidney was lower in the astragalus-treated groups compared with the CKD group. This study suggests that astragalus root slowed CKD progression, possibly through the suppression of oxidative stress and the renin-angiotensin system.


Reimbursement of Digital Therapeutics: Future Perspectives in Korea.
Digital health is rapidly growing worldwide and its area is expanding from wellness to treatment due to digital therapeutics (DTx). This study compared DTx in the Korean context with other countries to better understand its political and practical implications. DTx is generally the same internationally, often categorized as software as a medical device. It provides evidence-based therapeutic interventions for medical disabilities and diseases. Abroad, DTx support entailed state subsidies and fundraising and national health insurance coverage. In the case of national health insurance coverage, most cases were applied to mental diseases. Moreover, in Japan, DTx related to hypertension will possibly be under discussion for national health insurance coverage in 2022. In overseas countries, coverage was decided only when the clinical effects were equivalent to those provided by existing technology, and in the UK, real usage data for DTx and associated evaluations were reflected by national health coverage determination. Prices were either determined through closed negotiations with health insurance operating agencies and manufacturers or established based on existing technology. Concerning the current situation, DTx dealing with various diseases including hypertension are expected to be developed near in the future, and the demand for use and compensation will likely increase. Therefore, it is urgent to define and prepare for DTx, relevant support systems, and health insurance coverage listings. Several support systems must be considered, including government subsidies, science/technology funds, and health insurance.


Using guinea pigs in studies relevant to asthma and COPD.
The guinea pig has been the most commonly used small animal species in preclinical studies related to asthma and COPD. The primary advantages of the guinea pig are the similar potencies and efficacies of agonists and antagonists in human and guinea pig airways and the many similarities in physiological processes, especially airway autonomic control and the response to allergen. The primary disadvantages to using guinea pigs are the lack of transgenic methods, limited numbers of guinea pig strains for comparative studies and a prominent axon reflex that is unlikely to be present in human airways. These attributes and various models developed in guinea pigs are discussed.


Environmental modulation of exopolysaccharide production in the cyanobacterium Synechocystis 6803.
Microorganisms produce extracellular polymeric substances (EPS, also known as exopolysaccharides) of diverse composition and structure. The biochemical and biophysical properties of these biopolymers enable a wide range of industrial applications. EPS from cyanobacteria are particularly versatile as they incorporate a larger number and variety of building blocks and adopt more complex structures than EPS from other organisms. However, the genetic makeup and regulation of EPS biosynthetic pathways in cyanobacteria are poorly understood. Here, we measured the effect of changing culture media on titre and composition of EPS released by Synechocystis sp. PCC 6803, and we integrated this information with transcriptomic data. Across all conditions, daily EPS productivity of individual cells was highest in the early growth phase, but the total amount of EPS obtained from the cultures was highest in the later growth phases due to accumulation. Lowering the magnesium concentration in the media enhanced per-cell productivity but the produced EPS had a lower total sugar content. Levels of individual monosaccharides correlated with specific culture media components, e.g. xylose with sulfur, glucose and N-acetyl-galactosamine with NaCl. Comparison with RNA sequencing data suggests a Wzy-dependent biosynthetic pathway and a protective role for xylose-rich EPS. This multi-level analysis offers a handle to link individual genes to the dynamic modulation of a complex biopolymer. KEY POINTS: • Synechocystis exopolysaccharide amount and composition depends on culture condition • Production rate and sugar content can be modulated by Mg and S respectively • Wzy-dependent biosynthetic pathway and protective role proposed for xylose-rich EPS.


Conservation of the 2-keto-3-deoxymanno-octulosonic acid (Kdo) biosynthesis pathway between plants and bacteria.
The increasing prevalence of multi-drug resistant bacteria is driving efforts in the development of new antibacterial agents. This includes a resurgence of interest in the Gram-negative bacteria lipopolysaccharide (LPS) biosynthesis enzymes as drug targets. The six carbon acidic sugar 2-keto-3-deoxymanno-octulosonic acid (Kdo) is a component of the lipid A moiety of the LPS in Gram-negative bacteria. In most cases the lipid A substituted by Kdo is the minimum requirement for cell growth, thus presenting the possibility of targeting either the synthesis or incorporation of Kdo for the development of antibacterial agents. Indeed, potent in vitro inhibitors of Kdo biosynthesis enzymes have been reported but have so far failed to show sufficient in vivo action against Gram-negative bacteria. As part of an effort to design more potent antibacterial agents targeting Kdo biosynthesis, the crystal structures of the key Kdo biosynthesis enzymes from Escherichia coli have been solved and their structure based mechanisms characterized. In eukaryotes, Kdo is found as a component of the pectic polysaccharide rhamnogalacturonan II in the plant primary cell wall. Interestingly, despite incorporating Kdo into very different macromolecules the Kdo biosynthesis and activation pathway is almost completely conserved between plants and bacteria. This raises the possibility for plant research to exploit the increasingly detailed knowledge and resources being generated by the microbiology community. Likewise, insights into Kdo biosynthesis in plants will be potentially useful in efforts to produce new antimicrobial compounds.


Pre-treatment of mice with tumor-conditioned media accelerates metastasis to lymph nodes and lungs: a new spontaneous breast cancer metastasis model.
Current spontaneous metastasis models require a long period of observation after establishment of primary tumors to see significant metastatic progression. The degree of metastasis is not consistent among animals: this is problematic since it requires the use of a large number of animals to obtain reliable statistics. Here we report that pre-treatment of animals with tumor-conditioned media (TCM) consistently accelerates spontaneous metastasis in breast cancer. An inguinal breast tumor model facilitated by TCM showed robust anterior metastasis to the axillary and brachial lymph nodes (LN), and the lungs compared to the serum-free media treated group. The LN in TCM-treated animals showed enhanced angiogenesis and lymphangiogenesis. Primary tumors and lungs in TCM-treated animals showed enhanced lymphangiogenesis with no significant change in angiogenesis. TCM-treated animals also showed metastatic dissemination to abdomen from the primary injection site: this would generally enhance metastasis to other organs. In sum, the addition of TCM pre-treatment to current metastasis models results in accelerated and robust metastasis which would enable more efficient evaluation of anti-metastatic agents.


Revascularization of the limbs with urokinase and TEC catheter endarterectomy for occluded bypass grafts.
Occlusion of a femoral-popliteal or a femoral-tibial bypass graft on a prior occluded superficial femoral artery or the popliteal artery (in cases of ischemia of the legs) creates a complicated problem that may result in limb loss. The revascularization of such limbs with a repeat femoral-tibial or peroneal bypass is difficult and results in a high rate of limb loss from failure of the repeat grafts. Therefore, attempts were made to re-open the grafts through urokinase administration and thrombolysis for the grafts. To address the distal critical stenosis, or occlusion, the urokinase administration and thrombolysis were followed by endovascular endarterectomy using a thromboembolytic catheter (TEC). From 1990 to 1992, the above protocol was followed with 15 patients. In all patients, the protocol included 24 to 48 hours of urokinase administration with 60,000 to 120,000 U of urokinase per hour. A distal pathology was detected in all 15 patients, of whom 8 had complete occlusion at the site of distal anastomosis, 7 had critical stenosis ranging from 90% to 99%, and 1 was found to have a proximal critical stenosis at the femoral-graft junction. TEC catheter endarterectomy was performed to address the problem of occlusion and critically stenosed distal anastomotic lesions; a 100% success rate was immediately achieved, with flow being re-established to the distal limb. Fourteen of 15 patients remained well revascularized for more than 1 year. One patient experienced re-occlusion after 8 months; the occlusion was re-opened using the same technique of urokinase administration and the use of the TEC catheter, in which case the graft subsequently remained open. The longest follow-up of one patient is more than 2 years, during which time the graft has stayed open. With the aforementioned results, after revascularization of the ischemic limbs from occluded bypass grafts, it is strongly recommended that urokinase administration, along with TEC endovascular endarterectomy, be used to establish the circulation when occluded grafts threaten limb loss.


Plasma short-chain fatty acids in fulminant hepatic failure.
The role of short-chain fatty acids in the pathogenesis of coma in patients with fulminant hepatic failure has been studied by gas-liquid chromatography. There was no correlation between the initial or the final plasma levels of short-chain fatty acids in these patients and the clinical outcome of their disease. A primary role for the short-chain fatty acids in the pathogenesis of coma in fulminant hepatic failure is unlikely.


A pH-responsive polymer-coated CaO2as oxygen-generating nanoparticlein situfor enhanced chemo-photodynamic synergistic therapy against tumors.
Photodynamic therapy (PDT) has emerged as an efficient strategy for tumor treatment. However, Insufficient amounts of inherent hypoxia and intrinsic hydrogen peroxide (H2O2) in the tumor microenvironment severely constrained PDT, as oxygen is the critical substrate for photosensitivity reaction. Here, a pH-responsive H2O2and O2self-supplying hybrid nanoparticle was designed. Through, the calcium peroxide (CaO2) as carriers loading a chemotherapeutic drug a photosensitizer 5,10,15,20-tetrakis(4-aminophenyl) porphyrin (TAPP) and doxorubicin (DOX), was covered with polyacrylic acid (PAA) to build up a feature material DOX-TAPP-CaO2@OA@PAA (denoted as DTCOP) through the reverse microemulsion method. In the acidic tumor microenvironment conditions exposing the water-sensitive CaO2nanocore to generate hydrogen peroxide (H2O2) and O2, the self-supplied O2alleviates hypoxia to enhance the PDT, and releasing DOX and TAPP. Synthetic characterization shows that the succeeded synthesized Nanocarriers could effectively carry DOX and TAPP to the tumor site and release O2at the low pH of TME. And the experimental results demonstrated that this interpose exogenous oxygen strategy is efficient at inhibition of tumor growth bothin vitroandin vivo. The nanocomposite exhibits excellent biocompatibility and the ability to inhibit tumor growth and has significant potential for the treatment of hypoxic tumors.


Biomarkers Associated with Lymph Nodal Metastasis in Endometrioid Endometrial Carcinoma.
Lymph node metastasis is determinant in the prognosis and treatment of endometrioid endometrial cancer (EEC) but the risk-benefit balance of surgical lymph node staging remains controversial. Describe the pathways associated with lymph node metastases in EEC detected by whole RNA sequencing. RNA-sequencing was performed on a retrospective series of 30 non-metastatic EEC. N+ and N- patients were matched for tumoral size, tumoral grade and myometrial invasion. Twenty-eight EECs were analyzable (16 N+ and 12 N-). Bioinformatics Unsupervised analysis revealed three patterns of expression, enriched in N+, mix of N+/N- and enriched in N-, respectively. The cluster with only N+ patient overexpressed extra cellular matrix, epithelial to mesenchymal and smooth muscle contraction pathways with respect to the N- profile. Differential expression analysis between N+ and N- was used to generate a 54-genes signature with an 87% accuracy. RNA-expression analysis provides a basis to develop a gene expression-based signature that could pre-operatively predict lymph node invasion.


Adrenalectomy and dexamethasone differentially affect postswim antinociception in mice selectively bred for high and low stress-induced analgesia.
The effects of dexamethasone and naloxone on analgesia induced by swimming (3 min, 20 degrees C) were studied in the 6th and 7th generations of adrenalectomized and intact mice selectively bred for high (HA) and low (LA) postswim analgesia. Swim-induced analgesia in intact HA animals was significantly reduced by naloxone and dexamethasone while in LA mice these two compounds were ineffective. Naloxone ability to reverse adrenalectomy-caused swim analgesia increase was much greater in HA than in LA mice. In both intact and adrenalectomized HA animals dexamethasone and naloxone decreased postswim analgesia to the level observed in LA mice. It is suggested that selective breeding for high and low swim analgesia modified the extent of pituitary-adrenal axis involvement in the generation of stress-induced analgesia.


Effects of Fluorosurfactant Structure and Concentration on Drug Availability and Biocompatibility in Water-in-Perfluorocarbon Emulsions for Pulmonary Drug Delivery.
The efficacy of inhaled antibiotics is often impaired by insufficient drug penetration into plugged and poorly ventilated airways. Liquid ventilation with perfluorocarbon (PFC) containing emulsified aqueous antibiotics, or antibacterial perfluorocarbon ventilation, could potentially improve treatment of respiratory infections when used as an adjunct therapy to inhaled antibiotics. The molecular structure and concentration of the fluorosurfactant used to stabilize such water-in-PFC emulsions will have significant effects on the efficacy and safety of the resulting treatment. In the present study, emulsions are formulated with tobramycin in the aqueous phase using two different fluorosurfactants (termed FSL-PEG+FSL and FSH-PEG) at varying concentrations (Cfs ). An aqueous gel is used to evaluate the availability of emulsified drug to diffuse into an aqueous interface (such as mucus or biofilm) for varying emulsion formulations. Lastly, the cytotoxicity of the fluorosurfactants is characterized using human alveolar basal epithelial cells. Results showed that tobramycin delivery is reduced at low Cfs due to inadequate drug emulsification and at large Cfs due to hindered drug availability. Thus, maximal delivery occurs at intermediate values of Cfs equal to 2 and 10 mg mL-1 for the FSH-PEG and FSL-PEG+FSL fluorosurfactants, respectively. The optimal emulsion formulation utilized FSH-PEG and demonstrated improved drug delivery relative to previously used formulations while exhibiting no cytotoxic effect. This work increases understanding of the physical means of pulmonary drug delivery via a water-in-PFC emulsion and represents a critical step in optimizing emulsion formulation for safe and effective treatment.


Electrocardiographic features of children with Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a clinically common X-linked recessive myopathy, which is caused by mutation of the gene encoding dystrophin on chromosome Xp21. The onset of heart injury in children with DMD is inconspicuous, and the prognosis is poor once it develops to the stage of heart failure. Cardiovascular complications remain an important cause of death in this patient population. At present, population and animal studies have suggested that Electrocardiogram (ECG) changes may be the initial manifestation of cardiac involvement in children with DMD. Relevant clinical studies have also confirmed that significant abnormal ECG changes already exist in DMD patients before cardiomegaly and/or LVEF decrease. With increases in age and decreases in cardiac function, the proportion of ECG abnormalities in DMD patients increase significantly. Some characteristic ECG changes, such as ST-segment changes, T wave inversion, Q wave at the inferolateral leads, LBBB and SDANN, have a certain correlation with the indexes of cardiac remodeling or impaired cardiac function in DMD patients, while VT and LBBB have demonstrated relatively good predictive value for the occurrence of long-term DCM and/or adverse cardiovascular events or even death in DMD patients. The present review discusses the electrocardiographic features in children with DMD.


Soil biogeochemistry and microbial community dynamics in Pinus pinaster Ait. forests subjected to increased fire frequency.
Fire frequency might increase in many fire-dominated ecosystems of the world due to the combined effects of global warming, land-use change and increased human pressures. Understanding how changes in fire frequency can affect the main soil biogeochemical dynamics, as well as the microbial community, in the long term is utmost important. Here we determined the effect of changes in fire frequency and other fire history characteristics on soil C and N dynamics and the main microbial groups (using soil fatty acid profiles), in Pinus pinaster forests from central Spain. Stands were chosen to differ in the number of fires (1 to 3) occurred between 1976 and 2018, in the time elapsed since the last fire and the interval undergone between the last two consecutive fires. We found that, in general, most of the studied biogeochemical and microbial variables showed clear differences between unburned and burned stands. The time elapsed since the last fire was the most important fire history covariable and governed the main soil nutrient dynamics and microbial groups. Recovery to pre-fire values took 30-40 years. Increased wildfire frequency only modified total C and nitrification rate, but results were not consistent between stands burned twice and thrice. The time interval (years) between the last two fires was not a significant covariable. The fact that some stands burnt up to thrice in a period of 43 years supports the strong capacity of this ecosystem to recover, even under an increased fire frequency.


Oral nifedipine in the long-term management of severe chronic heart failure.
We evaluated the hemodynamic effects of nifedipine in 10 symptomatic patients with chronic refractory heart failure due to idiopathic cardiomyopathy. Nifedipine significantly increased cardiac index (from 1.80 +/- 0.4 to 3 +/- 0.6 L/min/m2), stroke volume index (from 21 +/- 6 to 33 +/- 8 ml/beat/m2), and stroke work index (from 17.9 +/- 7 to 25.5 +/- 7 g-m/m2). The drugs also produced a significant decrease in left ventricular filling pressure (from 24.6 +/- 3 to 19 +/- 2 mm Hg), mean blood pressure (from 86 +/- 9 to 74 +/- 5 mm Hg), mean pulmonary arterial pressure (from 31.9 +/- 5 to 25.6 +/- 3 mm Hg), total systemic vascular resistance (from 2,104 +/- 329 to 1,088 +/- 249 dyn/s/cm-5), and pulmonary vascular resistance (from 200 +/- 71 to 107 +/- 50 dyn/s/cm-5). Heart rate remained unchanged. In all patients maintained on nifedipine therapy, repeat hemodynamic studies at 2 months revealed sustained effects, and all patients had symptomatic improvement of at least one New York Heart Association (NYHA) functional class. Long-term treatment was well tolerated. Forty-eight hours after discontinuation of nifedipine administration the hemodynamic benefits were lost. We conclude that nifedipine may be of value for long-term ambulatory therapy of severe chronic heart failure.


Extracellular Cl- regulates electrical slow waves and setting of smooth muscle membrane potential by interstitial cells of Cajal in mouse jejunum.
What is the central question of this study? The aim was to investigate the roles of extracellular chloride in electrical slow waves and resting membrane potential of mouse jejunal smooth muscle by replacing chloride with the impermeant anions gluconate and isethionate. What is the main finding and its importance? The main finding was that in smooth muscle cells, the resting Cl- conductance is low, whereas transmembrane Cl- movement in interstitial cells of Cajal (ICCs) is a major contributor to the shape of electrical slow waves. Furthermore, the data confirm that ICCs set the smooth muscle membrane potential and that altering Cl- homeostasis in ICCs can alter the smooth muscle membrane potential. Intracellular Cl- homeostasis is regulated by anion-permeable channels and transporters and contributes to excitability of many cell types, including smooth muscle and interstitial cells of Cajal (ICCs). Our aims were to investigate the effects on electrical activity in mouse jejunal muscle strips of replacing extracellular Cl- (Cl-o ) with the impermeant anions gluconate and isethionate. On reducing Cl-o , effects were observed on electrical slow waves, with small effects on smooth muscle membrane voltage (Em ). Restoration of Cl- hyperpolarized smooth muscle Em proportional to the change in Cl-o concentration. Replacement of 90% of Cl-o with gluconate reversibly abolished slow waves in five of nine preparations. Slow waves were maintained in isethionate. Gluconate and isethionate substitution had similar concentration-dependent effects on peak amplitude, frequency, width at half peak amplitude, rise time and decay time of residual slow waves. Gluconate reduced free ionized Ca2+ in Krebs solutions to 0.13 mm. In Krebs solutions containing normal Cl- and 0.13 mm free Ca2+ , slow wave frequency was lower, width at half peak amplitude was smaller, and decay time was faster. The transient hyperpolarization following restoration of Cl-o was not observed in W/Wv mice, which lack pacemaker ICCs in the small intestine. We conclude that in smooth muscle cells, the resting Cl- conductance is low, whereas transmembrane Cl- movement in ICCs plays a major role in generation or propagation of slow waves. Furthermore, these data support a role for ICCs in setting smooth muscle Em and that altering Cl- homeostasis in ICCs can alter smooth muscle Em .


Long-Term Outcome of Sustained Endocrine Monotherapy for Elderly Breast Cancer Patients.
Among elderly breast cancer patients, endocrine therapy may be chosen as definitive treatment by patients or physicians. This study investigated the efficacy of endocrine monotherapy (ET) in terms of avoidance of invasive local treatment. Elderly patients (≥70 years) with a diagnosis of estrogen receptor-positive breast cancer who underwent ET between 2008 and 2015 were identified through the Netherlands Cancer Registry. The primary outcome was the cumulative risk of undergoing invasive local treatment (radiotherapy or surgery) for the primary tumor. The secondary outcomes were development of uncontrolled local disease and overall survival (OS). Of the 105 patients (median age, 86 years) enrolled in this study, 91 (78 %) received ET as definitive treatment, whereas 14 received ET as a "bridge to surgery." For the 91 patients who used ET as intended definitive treatment, the 5-year cumulative risk of undergoing invasive local treatment and experiencing uncontrolled disease were respectively 28 % and 16 %. The 5-year cumulative OS was 42 %. Whereas 11 patients had metastatic or locally progressive breast cancer at the time of death, cardiovascular disease, infectious diseases, and old age or dementia were reported as contributing to the death of 39 patients. For a select group of elderly breast cancer patients who received sustained ET, the risk of undergoing invasive local treatment was surpassed by a twofold higher risk of dying. As an alternative to invasive local treatment, ET can be discussed as a safe and effective option for patients unwilling or unfit to undergo surgery.


Oestrogens and insulin secretion.
There is a persistent perception that oestrogens have an adverse effect on carbohydrate metabolism. It might therefore be expected that their use would result in a corresponding increase in the incidence of diabetes. Recent evidence from clinical trials suggesting that women on postmenopausal oestrogen hormone replacement therapy (HRT) have a reduced incidence of type 2 diabetes therefore appears paradoxical. Short-term supraphysiological oestrogen administration has an adverse effect on glucose tolerance, resulting from suppression of first-phase insulin secretion and increased insulin resistance. Oestrogen-induced increases in glucocorticoid activity could account for these effects. Oestrogen-induced deterioration in glucose tolerance is, however, accompanied by a reduction in fasting glucose, an effect that could be accounted for by glucagon antagonism. These short-term effects contrast with long-term preservation of insulin secretion and glucose homeostasis by oestrogens. In animal studies, ovariectomy is associated with decreased insulin secretion and increased risk of diabetes, whereas oestrogen administration protects against diabetes and increases the insulin response to glucose. The mechanism is uncertain, but direct effects on the pancreas via steroid receptors or indirect effects via oestrogen-induced glucagon antagonism and subclinical increases in glucocorticoids and growth hormone could all contribute. Recent evidence that HRT increases the risk of cardiovascular disease suggests that it should not be used for the prevention of diabetes, but the mechanism responsible for this benefit merits further investigation and might lead to new therapies.


Coronary Dissection and Right Heart Failure Salvaged by PCI With Percutaneous Intraluminal Microaxial RV-Assist Support.
Right heart failure is a dreaded sequelae of proximal right coronary artery occlusion that can complicate an angiogram or percutaneous coronary intervention. This case illustrates the use of a percutaneous intraluminal microaxial right ventricular assist device for high-risk percutaneous coronary intervention of an ostial right coronary artery dissection in refractory right heart failure. (Level of Difficulty: Advanced.).


Effect of a sustained-release formulation of trimazosin in mild to moderate hypertension.
A single-blind study was conducted to evaluate the blood pressure (BP) reduction and side effects of a sustained-release (SR) formulation of trimazosin in patients with mild to moderate hypertension. Eighteen individuals (age, 21-65 yr; mean diastolic BP, greater than 95 mm Hg) with essential hypertension were enrolled into the study. Each patient's dose was titrated to a range of 150-900 mg/d, with polythiazide added as necessary to achieve BP control. Four hours following the maximum titrated dose of trimazosin, mean standing and supine diastolic BPs were significantly lower than baseline readings. Supine systolic BP and supine and standing heart rate were not significantly lower than baseline. At 24 hours after administration of the maximum dose, there were no significant differences in heart rate of BP compared with baseline readings. Five of 16 patients responded to trimazosin therapy alone. Of the 11 treatment failures with trimazosin alone, five were therapeutic failures and six discontinued because of side effects. Only two of these 11 patients achieved satisfactory results with the combination therapy. Trimazosin SR acutely lowers BP three to six hours after administration. It appears to have a duration of action longer than six hours, but it is not sustained for 24 hours. The proportion of patients failing to respond in this sample was very high and suggests that for similar patients, the drug does not appear to be a very useful antihypertensive agent.


Testicular blood supply and growth in children with high cryptorchidism treated with gubernaculum preserving vs. cutting laparoscopic orchiopexy: A pilot trial.
It is still controversial whether the frenum of testis should be retained in laparoscopic testicular fixation. It is a prospective experiment to study testicular preservation on testicular growth in children with high cryptorchidism. From January 2018 to June 2020, 120 children with high cryptorchidism in Inner Mongolia Maternal and Child Health Care Hospital and The Fourth Hospital of Baotou were randomly divided into retention group (60 cases in group P, aged 1-3 years, average 1.85 ± 0.58) and cutting group (60 cases in group C, aged 1-3 years, average 1.75 ± 0.66) (P = 0.52). PSV, EDV, RI and testicular volume were measured by color Doppler ultrasound before operation and 1,3,6,12 months after operation. No, there was significant difference between the two groups (P > 0.05). There is no significant difference in testicular blood supply and growth between laparoscopic testicular fixation and frenulum amputation in children with high cryptorchidism.


Depression type and depression severity in relation to risk of violent suicide attempt.
Low levels of cerebrospinal fluid 5-hydroxyindoleacetic acid and a blunted thyroid-stimulating hormone response to thyrotropin-releasing hormone have been reported in depressed patients--in particular in those who have made violent suicide attempts. There are at least two conceivable explanations for these findings: The biological abnormalities relate to (1) disturbed aggression regulation or to (2) disturbed mood regulation (either type or severity). The second alternative presupposes that violent suicide attempts occur differentially in a particular depression type or differentially in severe depression. This study demonstrated that violent suicide attempts are "depression-specific," i.e., they relate to a particular depressive syndrome, that of vital depression, but not to the severity factor. Therefore, it is impossible to decide whether the biological abnormalities in depressed, violent suicide attempters relate to a particular type of mood disorder or to a distorted regulation of aggression.


Efficacy and safety of scheduled dosing of opioid analgesics: a quality improvement study.
Scheduled dosing of opioids is believed to provide more effective analgesia when compared to as needed (PRN) administration of the drug; however, few studies have evaluated the value of this approach. Therefore, a quality improvement study was conducted to determine the efficacy and safety of scheduled dosing of opioid analgesics, using a 2-group parallel design. One medical unit in a large urban academic medical center employed scheduled dosing, whereas a comparable unit used PRN dosing. The primary outcome indicators included pain intensity ratings and opioid doses, along with adverse events. Scheduled dosing was associated with decreased pain intensity ratings. There were no statistically significant differences in the amount of opioid ordered, or the amount administered when comparing scheduled vs. PRN dosing. However, when the amount of opioid given was expressed as a percentage of the amount ordered, the difference between scheduled (70.8%) and PRN (38%) dosing was statistically significant (P = .0001). There was no difference in adverse events between the 2 groups. These findings suggest that scheduled dosing of opioids in an inpatient medical population provides improved analgesia with no increased risk of adverse events. Scheduled dosing of opioids in an inpatient medical population improves analgesia, theoretically by overcoming barriers to drug administration, as well as providing more stable plasma levels of the opioid.


Effects of sustained-release isradipine on left ventricular anatomy and function in systemic hypertension.
With use of digitized M-mode echocardiograms and 24-hour noninvasive ambulatory blood pressure (BP) monitoring, the effects of chronic treatment with sustained-release isradipine on left ventricular (LV) morphology and function in hypertensive patients were evaluated. We selected 12 patients with LV hypertrophy and normal LV diastolic diameter. Echocardiograms and 24-hour BP monitoring were performed after 2 weeks of placebo and after 6 months of oral treatment with sustained-release isradipine (5 mg once daily). Therapy significantly reduced BP without changes in heart rate. LV mass decreased in all patients and peak lengthening rate of LV diameter, index of diastolic function, increased in all, with normalization in 7 of the 9 with basal diastolic impairment. Peak shortening rate of LV diameter, index of systolic function, was normal in all patients at basal evaluation and did not change after therapy. Reduction in LV mass significantly (p < 0.05) correlated with the decrease in average 24-hour and daytime systolic and diastolic BP. Sustained-release isradipine administered once daily is an effective antihypertensive agent; the drug also induces regression of LV hypertrophy, with significant improvement in LV diastolic function and no deterioration in systolic function.


Long-term outcomes following drug-eluting stents versus bare metal stents for primary percutaneous coronary intervention: A real-world analysis of 11,181 patients from the british columbia cardiac registry.
Drug eluting stents (DES) are associated with reduced risk of restenosis when compared with bare metal stents (BMS). Their use in ST-elevation myocardial infarction (STEMI) is debated, owing to concerns about stent thrombosis. There are limited real-world data comparing DES versus BMS in STEMI. We conducted an observational analysis in this setting and rigorously adjusted for treatment selection bias. We analyzed 11,181 consecutive patients with acute STEMI who received either DES or BMS during 2008-2014 in the British Columbia Cardiac Registry. We analyzed target vessel revascularization (TVR) and mortality at 2 years. Multivariable-adjusted, propensity-matched and inverse probability-treatment weighted analyses found DES to be associated with early and late survival up to 2 years but not TVR. However, when adjusting for measured and unmeasured confounders, instrumental variable (IV) analyses demonstrated that DES use was associated with reduced TVR up to 2 years (Δ = -6.7%, 95% CI: -10.0%, -3.4%, P < 0.001). DES use was not associated with mortality at 1 year (Δ = -2.3%, 95% CI: -5.0%, 0.4%, P = 0.100) but associated with reduced mortality at 2 years (Δ = -5.4%, 95% CI: -8.3%, -2.5%, P < 0.001). Stratified IV analyses indicated that this long-term survival benefit was largely attributable to the second generation DES. In this study of patients with STEMI, when adjusting for measured and unmeasured factors, DES use was associated with reduced TVR and long-term survival beyond 1 year. This long-term survival was largely attributable to the second generation DES. These real-world data are reassuring and support the use of DES for STEMI. © 2016 Wiley Periodicals, Inc.


Family dynamics and aggressive behavior in Latino adolescents.
Despite high prevalence rates and evidence that acculturation is associated with adolescent behavioral and mental health in Latino youth, little research has focused on aggressive behavior for this population. The aim of the current study was to fill this research gap by examining the influence of several aspects of family functioning, including parent-adolescent conflict, parent worry, and parent marital adjustment, on aggression among Latino adolescents. Data come from the Latino Acculturation and Health Project (LAHP), a longitudinal investigation of acculturation in Latino families in North Carolina and Arizona. Hierarchical linear modeling was used to estimate a longitudinal rater effects model of adolescent aggression as reported by 258 Latino adolescents each paired with 1 parent for a total of 516 participants across 4 time points over a span of 18 months. Results indicated a general decline in aggression over the study window. In addition, parent-adolescent conflict and parent worry predicted higher adolescent aggression whereas parent marital adjustment predicted lower adolescent aggression. The salience of family risk factors for aggression among Latino adolescents is discussed. (PsycINFO Database Record


Fabrication of uniform-sized poly-ɛ-caprolactone microspheres and their applications in human embryonic stem cell culture.
The generation of liquefied poly-ɛ-caprolactone (PCL) droplets by means of a microfluidic device results in uniform-sized microspheres, which are validated as microcarriers for human embryonic stem cell culture. Formed droplet size and size distribution, as well as the resulting PCL microsphere size, are correlated with the viscosity and flow rate ratio of the dispersed (Q d) and continuous (Q c) phases. PCL in dichloromethane increases its viscosity with concentration and molecular weight. Higher viscosity and Q d/Q c lead to the formation of larger droplets, within two observed formation modes: dripping and jetting. At low viscosity of dispersed phase and Q d/Q c, the microfluidic device is operated in dripping mode, which generates droplets and microspheres with greater size uniformity. Solutions with lower molecular weight PCL have lower viscosity, resulting in a wider concentration range for the dripping mode. When coated with extracellular matrix (ECM) proteins, the fabricated PCL microspheres are demonstrated capable of supporting the expansion of human embryonic stem cells.


Disappearance and reappearance of high endothelial venules and immigrating lymphocytes in lymph nodes deprived of afferent lymphatic vessels: a possible regulatory role of macrophages in lymphocyte migration.
Interruption of the afferent lymphatic vessels of the popliteal lymph node resulted in the disappearance of high endothelial venules (HEV) and immigrating lymphocytes within 3 weeks. HEV showed several characteristic morphological changes: the endothelial cells became flattened and less pyroninophilic, the chromatine became condensed and protein synthetizing and secretory cell organelles became scarce. At the same time the number of macrophages in the lymph node was severely reduced. Injection of sheep red blood cells into such lymph nodes, 6 weeks after operation, resulted in reappearance of HEV and immigrating lymphocytes, and development of many plasma cells and some germinal centres. Injection of lipopolysaccharide into the operated lymph nodes resulted in the appearance of many plasma cells and a few poorly developed germinal centres; HEV and immigrating lymphocytes, however, remained almost absent. The results show a relationship between the immigration of lymphocytes and the activity of the endothelial cells in the HEV. The activation of the latter may occur by mediators released by antigen-stimulated macrophages and T cells. Moreover, the morphological features of the HEV are independent of the presence of recirculating lymphocytes.


Idiopathic hypertrophy of the oesophagus in children. A case report and review of the literature.
Idiopathic hypertrophy of the oesophagus is a rare entity. Of approximately 50 cases reported in the literature, only 5 are in children. The case of an 8-year-old girl is presented and compared with those previously reported.


Genetic ablation of homeodomain-interacting protein kinase 2 selectively induces apoptosis of cerebellar Purkinje cells during adulthood and generates an ataxic-like phenotype.
Homeodomain-interacting protein kinase 2 (HIPK2) is a multitalented coregulator of an increasing number of transcription factors and cofactors involved in cell death and proliferation in several organs and systems. As Hipk2(-/-) mice show behavioral abnormalities consistent with cerebellar dysfunction, we investigated whether Hipk2 is involved in these neurological symptoms. To this aim, we characterized the postnatal developmental expression profile of Hipk2 in the brain cortex, hippocampus, striatum, and cerebellum of mice by real-time PCR, western blot analysis, and immunohistochemistry. Notably, we found that whereas in the brain cortex, hippocampus, and striatum, HIPK2 expression progressively decreased with age, that is, from postnatal day 1 to adulthood, it increased in the cerebellum. Interestingly, mice lacking Hipk2 displayed atrophic lobules and a visibly smaller cerebellum than did wild-type mice. More important, the cerebellum of Hipk2(-/-) mice showed a strong reduction in cerebellar Purkinje neurons during adulthood. Such reduction is due to the activation of an apoptotic process associated with a compromised proteasomal function followed by an unpredicted accumulation of ubiquitinated proteins. In particular, Purkinje cell dysfunction was characterized by a strong accumulation of ubiquitinated β-catenin. Moreover, our behavioral tests showed that Hipk2(-/-) mice displayed muscle and balance impairment, indicative of Hipk2 involvement in cerebellar function. Taken together, these results indicate that Hipk2 exerts a relevant role in the survival of cerebellar Purkinje cells and that Hipk2 genetic ablation generates cerebellar dysfunction compatible with an ataxic-like phenotype.


Diffusion tensor and perfusion imaging of brain tumors in high-field MR imaging.
Diffusion tensor imaging (DTI) and perfusion-weighted imaging (PWI) are essential tools for diagnosing, differentiating, and monitoring brain tumors. High-field MRI provides higher signal-to-noise ratio, shorter scan time, and better image quality. One-stop multiparametric study, including DTI and PWI, is possible with high-field MRI in brain tumors. DTI can be used for assessing spatial relationship between major white matter tract and tumor, differentiating gliomas from nonglial tumors, and postoperative evaluation. PWI provides reliable biomarkers for glioma grading, therapeutic responses, and differential diagnosis of various brain tumors. With higher field strength, better-quality DTI and PWI can raise the diagnostic accuracy in brain tumors.


The functional independence measure: its use to identify rehabilitation needs in stroke survivors.
To explore the potential of the Functional Independence Measure (FIM) as a prognostic indicator of outcome in stroke survivors, 113 consecutive patients were observed from admission until discharge. Patients received assessment and treatment by a multidisciplinary team in a regional tertiary care stroke-specific rehabilitation program. The FIM, Chedoke-McMaster Stroke Assessment, and discharge location were used as the main outcome measures. The results suggested that; (1) impairment variables alone are insufficient as prognostic indicators of outcome; (2) the absolute admission FIM score, not the change in the FIM score, is the best predictor of outcome disability and place of discharge; and (3) subgroups of stroke survivors with differing rehabilitation needs can be identified. The FIM allows us to classify stroke survivors according to their needs; therefore, attention should be redirected to the development of prognostic indicators for groups of stroke survivors.


Primary malignant lymphoma of the rectum.
A rare case of a primary malignant lymphoma of the rectum in a 7 year old girl is presented. Although rectal polyps in children are usually benign juvenile polyps, a rare possibility of malignancy should be kept in mind. An adequate histological examination is essential.


Androgen receptor is expressed in both X- and Y-carrier human spermatozoa.
To quantify the amount of AR messenger RNA (mRNA) and to analyze the presence and functionality of the AR protein in X- and Y-carrier human spermatozoa. A molecular and cellular research study. Academic research clinic and laboratories. Ten normozoospermic volunteers. Sperm were analyzed for expression of AR mRNA and protein. The functionality of AR protein was assessed after incubation with 1 nM of synthetic androgen. Reverse-transcription polymerase chain reaction (PCR), real-time PCR, Western immunoblotting, confocal immunofluorescence, and fluorescence in situ hybridization analysis were performed. A significant amount of AR mRNA (around 30% of that found in the testis) was found in sperm. Androgen receptor protein was found in both X- and Y-carrier spermatozoa and translocates into the nucleus in the presence of synthetic androgen. A functional AR is expressed in human sperm. In view of the fact that AR protein is found in both X- and Y-carrier spermatozoa, it most probably is translated in earlier steps of spermatogenesis and moves to Y-carrier spermatids through the cytoplasmic bridges.


Endocrine disrupting chemicals and metabolic disorders in the liver: What if we also looked at the female side?
Endocrine disrupting chemicals (EDCs) are linked to the worldwide epidemic incidence of metabolic disorders and fatty liver diseases, which affects quality of life and represents a high economic cost to society. Energy homeostasis exhibits strong sexual dimorphic traits, and metabolic organs respond to EDCs depending on sex, such as the liver, which orchestrates both drug elimination and glucose and lipid metabolism. In addition, fatty liver diseases show a strong sexual bias, which in part could also originate from sex differences observed in gut microbiota. The aim of this review is to highlight significant differences in endocrine and metabolic aspects of the liver, between males and females throughout development and into adulthood. It is also to illustrate how the male and female liver differently cope with exposure to various EDCs such as bisphenols, phthalates and persistent organic chemicals in order to draw attention to the need to include both sexes in experimental studies. Interesting data come from analyses of the composition and diversity of the gut microbiota in males exposed to the mentioned EDCs showing significant correlations with hepatic lipid accumulation and metabolic disorders but information on females is lacking or incomplete. As industrialization increases, the list of anthropogenic chemicals to which humans will be exposed will also likely increase. In addition to strengthening existing regulations, encouraging populations to protect themselves and promoting the substitution of harmful chemicals with safe products, innovative strategies based on sex differences in the gut microbiota and in the gut-liver axis could be optimistic outlook.


Predicting institutionalization after Subacute Stroke Rehabilitation using the 12-Item World Health Organization Disability Assessment Schedule.
To evaluate the utility of the 12-item World Health Organization Disability Assessment Schedule (WHODAS-12) in predicting institutionalization after subacute stroke rehabilitation. Prospective observational study. On a specialized rehabilitation ward, discharge WHODAS-12 scores of 156 consecutive patients (24-h National Institutes of Health Stroke Scale (NIHSS) ≥ 15) and assessment from their proxies were compared, and receiver operating characteristic curves for predicting institutionalization were generated. Clinician-rated assessments of functioning were applied for comparison. Thirty-three percent of the patients were unfit to respond, due to the consequences of major stroke. However, both patient and proxy WHODAS-12 sum scores differentiated the community (n = 70) and institution (n = 86) groups (p = 0.02 and p < 0.0001, respectively), the discriminative accuracy (area under the curve; AUC) being 0.63 and 0.79, respectively. In proxy assessments, the institutionalized patients were significantly more impaired in all item comparisons except for emotions and concentrating. Ability to participate differentiated the groups as accurately as activities (AUC 0.75 vs 0.78, respectively). The corresponding discriminative accuracy of the clinician-rated World Health Organization (WHO) minimal generic dataset sum score and modified Rankin Scale were 0.74 and 0.79 (p < 0.0001), respectively. Despite its brevity and subjectivity, the WHODAS-12 from proxies has shown high accuracy in predicting institutionalization after subacute rehabilitation of individuals with major stroke, the impact of participation being as relevant as that of activities.


The effect of normalization of ECW volume as a marker of hydration in peritoneal dialysis patients and controls.
We measured extraceLlular water (ECW) and intracellular water (ICW) volumes in peritoneal dialysis (PD) patients and controls to determine the effect of ICW variation on ECW/ICW ratio and to compare alternative ratios of ECW to height, height2, weight, and body surface area (BSA). We measured body water compartments by deuterium oxide and bromide dilution in 29 PD patients (14 M, 15 F) and 31 controls (15 M, 16 F). ECW was similar in PD patients (17.58 +/- 3.58 L) and controls (17.20 +/- 2.97 L), p = NS. ICW was nonsignificantly lowerin PD patients (17.58 +/- 4.88 L) than in controls (19.71 +/- 5.08 L), p = NS. ECW/ICW was greaterin PD patients (1.06 +/- 0.32) than in controls (0.92 +/- 0.25), p = 0.057, and was inversely correlated with ICW in PD patients (r = -0.733, p < 0.0001) and controls (r = -0.721, p < 0.0001). In contrast, ECW/height, ECW/height2, ECW/weight, and ECW/BSA were similar for the two groups. ECW/ICW is affected by changes in ICW as well as by ECW varying with hydration. ECW/ICW ratio leads to the spurious impression of overhydration in subjects with smaller ICW volumes. ECW/ICW does not reflect hydration alone and other methods of expressing ECW as a measure of hydration need further evaluation.


Assessment of early kidney injury caused by asymptomatic bacteriuria in children with type 1 diabetes.
Infection is one of the most frequent causes of morbidity and mortality in diabetic patients. Some microorganisms become more virulent in a high glucose concentration. Diabetics are more likely to have asymptomatic and symptomatic bacteriuria. NGAL is secreted in high concentrations into the blood and urine within two hours of AKI. The aim of the study is early detection of UTI in type1diabetic children through screening of their urine samples, and measurement of NGAL urinary levels in cases with asymptomatic bacteriuria for early detection of AKI to prevent serious complications. One thousand twenty-two known diabetic children on regular follow up in endocrine outpatient clinic at Minia Children University hospital were screened for UTI. From them only 52 diabetic children were diagnosed as asymptomatic bacteriuria (group I), 52 diabetic children with normal urine analysis (group II) and 52 apparently healthy children, age and sex matched, served as controls (group III). CBC, Renal function test, HbA1c, hs- CRP, Albumin/creatinine ratio, urine examination, urine culture, GFR and urinary NGAL were done to all children. Thirty-seven females (71.2%) had asymptomatic bacteriuria, Hs CRP and urinary NGAL were significantly higher, while GFR was significantly lower in diabetic children with bacteriuria than the other two groups. For diabetic children with bacteriuria, (AUC) for NGAL was 1 with optimal cutoff value of > 44.1 (Sensitivity 100% and Specificity 100%) while AUC for hsCRP was 0.887 with optimal cutoff value of > 1 (Sensitivity 82.69% and Specificity 90.38%). Routine urine analysis should be done for all diabetic children even if they are asymptomatic. NGAL and hsCRP are non-invasive methods that could detect early renal injury in these patients thus, early, and proper management of UTI should be started to prevent renal injury.


A social skills group for autistic children.
The evolution and preliminary evaluation of a social skills training group for 10 autistic children aged between 9 and 16 years was described. These children attended a special unit which aimed to integrate them into normal school provision. The paper consists of a description of the evolution of the group and the training methods employed and an evaluation of the effect of the group. This was accomplished by the use of a standard teacher's questionnaire. The results of the evaluation are described and the implications for further study of this means of helping autistic individuals discussed.


Effects of various antipsychotic drugs upon the striatal concentrations of para-hydroxyphenylacetic acid and meta-hydroxyphenylacetic acid in the mouse.
The endogenous concentrations of p- and m-hydroxyphenylacetic acid in the mouse caudate nucleus were determined by a gas chromatographic or a gas chromatographic-mass spectrometric technique and the concentrations were about 30 and 11 ng g-1 respectively. The subcutaneous administration of (+)-butaclamol (1 mg kg-1), haloperidol (5 mg kg-1), molindone (100 mg kg-1), sulpiride (50 mg kg-1) or chlorpromazine (20 mg kg-1) increased the concentration of mouse striatal p- and m-hydroxyphenylacetic acid; the effects were observed at 2 h after drug administration. Lower doses of chlorpromazine (2 mg kg-1), haloperidol (0.2 mg kg-1) and molindone (2 mg kg-1) did not affect p- or m-hydroxyphenylacetic acid concentrations. The time course for the concentration changes produced by chlorpromazine (20 mg kg-1) revealed that the formation of the metabolites occurred within 30 min after its administration and that their efflux from the caudate nucleus took at least 4 h for p-hydroxyphenylacetic acid and more than 8 h for m-hydroxyphenylacetic acid. Promethazine and (-)-butaclamol which have chemical structures related to chlorpromazine or (+)-butaclamol respectively but which lack antipsychotic activity, produced no effect on striatal p- or m-hydroxyphenylacetic acid concentrations. The results suggest that antipsychotic drugs increase the utilization of mouse striatal p- and m-tyramine and that after use the amines are metabolized by monoamine oxidase to form p- or m-hydroxyphenylacetic acid. The synthesis of the acid metabolites occurs within 30 min after chlorpromazine administration and their efflux from the caudate nucleus takes from 4-8 h.


Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1.
Two common features of dietary polyphenols have hampered our mechanistic understanding of their beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high-fat diet (HFD)-challenged male mice inhibits chylomicron secretion, associated with reduced expression of jejunal but not hepatic scavenger receptor class B type 1 (SR-B1). Intestinal mucosa-specific SR-B1-/- mice on HFD-challenge exhibit improved lipid homeostasis but show virtually no further response to REV-I. SR-B1 expression in Caco-2 cells cannot be repressed by pure resveratrol compound while fecal-microbiota transplantation from mice on REV-I suppresses jejunal SR-B1 in recipient mice. REV-I reduces fecal levels of bile acids and activity of fecal bile-salt hydrolase. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating FXR-stimulated gut SR-B1 elevation.


Gmelina arborea- an indigenous timber species of India with high medicinal value: A review on its pharmacology, pharmacognosy and phytochemistry.
Gmelina arborea Roxb.ex Smith, a fast-growing deciduous tree belongs to the family Lamiaceae, and is an important plantation species in many tropical areas around the world. The species is naturally distributed in semi-deciduous forests in tropical/subtropical regions of South East Asia. The tree is also an important medicinal plant in the Indian Systems of Medicine. The whole plant is used in medicine. It is astringent, bitter, digestive, cardiotonic, diuretic, laxative and pulmonary and nervine tonic. It improves digestion, memory, helps overcome giddiness and is useful in burning sensation, fever, thirst, emaciation, heart diseases, nervous disorders and piles. The roots are acrid, bitter-sweet in taste, stomachic, tonic, laxative, galactagogue and antihelmintic. The flowers are sweet, refrigerant, bitter, astringent and acrid, and are used in treating leprosy and skin diseases. The fruits are acrid, sour, sweet, refrigerant, bitter, astringent, aphrodisiac, trichogenous, alterant and tonic. Fruits are edible and also used for promoting hair growth and in treating anaemia, leprosy, ulcers, constipation, leucorrhoea and colitis. The leaves are a good fodder also. The major bioactive compounds extracted from different parts of G. arborea are arboreal, verbascoside, tyrosol, iridoids, phenylpropanoid glycoside, premnazole, martynoside, iridoid glycosides, balanophonin, gmelinol, isoarboreol apigenin, umbelliferone etc. AIM OF THE REVIEW: This review provides an insight into the medicinal aspects of G. arborea. It provides the latest information on phytochemistry, pharmacological activities and traditional uses of G.arborea. Information on G. arborea was gathered from various sources like textbooks, literature, databases such as PubMed, Science Direct, Wiley, Springer, Taylor and Francis, Scopus, Inflibnet, Sci-Finder and Google Scholar. Sixty-nine phytochemicals which include lignans, acylated iridoid glycosides, acylated rhamnopyranoses, flavonoids, flavones, flavone glycosides have been isolated. Many of them have been characterized for their pharmacological activity. Several researchers have identified bioactive phytochemicals like luteolin, iridoid alkaloids from the leaves, hentriacontanol and lignans such as arboreol, isoarboreol, arborone, gmelanone, gummadiol from the heartwood, flavon glycosides in roots. The extracts are reported to have wound-healing and antidiarrheal properties. Various studies demonstrated that G.arborea and its constituents possess several pharmacological activities like anti-oxidant, anti-diabetic, anti-inflammatory, antiulcer, analgesic, anti-nociceptive, anticancer and wound healing activities. G. arborea is a valuable medicinal plant used traditionally in the Indian Systems of Medicine (ISM - Ayurveda and Unani) to treat a wide variety of ailments. These phytochemicals are highly bioactive and exhibit various pharmacological activities. However, pharmacological activities of many compounds which have been identified, are yet to be understood.


Laminar cortical interactions during epileptic spikes studied with principal component analysis and physiological modeling.
The direct cortical responses (DCR) to electrical stimulation and electrically evoked interictal penicillin spikes (EIIS) were studied in the same rats using current source-density (CSD) analysis to directly compare regions of neuronal depolarization and hyperpolarization in neocortex. Principal component analysis (PCA) was further used to evaluate patterns of covariance in the CSD that were characteristic of interactions between pyramidal cell populations with spatially and temporally distinct transmembrane currents. A physical model was applied to the physiological interpretation of PCA results and the optimal model parameters used to estimate neuronal generators of recorded laminar field potentials. The data suggested that the DCR and EIIS were produced by the same neuronal circuit which could be represented by two anatomically distinct populations of pyramidal cells. The first of these populations was situated in the upper and middle layers (supragranular pyramidal neurons) and formed a dipolar CSD pattern that reversed polarity in layers II and III. The second deeper population (infragranular pyramidal neurons) extended throughout most of the cortical thickness and formed a dipolar CSD pattern that reversed polarity in layer V. We propose that excitatory intracortical connections of supragranular pyramidal cells may pathologically synchronize depolarization within the epileptic focus. In this way, supragranular pyramidal cells may provide a trigger mechanism for interictal spikes in neocortex.


[The function of enzymes for the antioxidative protection of the bone marrow cells in rats during irradiation, bone fracture and combined radiation injury].
The activity of superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione: dehydroascorbate oxidoreductase is lower in the bone marrow than in the liver. The changes in the cellular antioxidative enzymatic system during leg bones fracture and X-ray irradiation are more pronounced in the rat bone marrow, as compared to the liver. The data obtained are in keeping with selective bone-marrow radiosensitivity and with the effect of exogenous superoxide dismutase and glutathione as radioprotectors.


Evaluating the anticancer properties and real-time electrochemical extracellular bio-speciation of bis (1,10-phenanthroline) silver (I) acetate monohydrate in the presence of A549 lung cancer cells.
According to the American Cancer Society report (2019-2021), the majority (63%) of stage III non-small cell lung cancer (NSCLC) patients are prescribed with chemo and/or radiation therapies, with 5-year relative survival rates of just 19%. Thus, directed drug development, toward personalised cancer treatment, is widely recognised as a necessary strategy in drug discovery research. However, broad generalisations on the modes of action of bioinorganic compounds are not conducive to tailored drug design, hence, fundamental mechanistic research is essential in realising personalised healthcare. In this work, anticancer properties of bis (1,10-phenanthroline) silver (I) acetate monohydrate (Ag-Phen), toward A549 lung cancer cells are presented. Biological assays were carried out to evaluate the effect of Ag-Phen on cell viability, reactive oxygen species generation and mitochondrial membrane potentials. In tandem with the biological assays, electrochemistry was employed to determine the real-time concentrations of intact Ag-Phen and dissociated Ag+ in the extracellular medium using platinum microelectrodes, as a function of cellular exposure time. Observations from the assays conducted include, Ag-Phen induced cytotoxicity (IC50 4.5 μM at 72 h) and 2-fold ROS generation, and a 50% decrease in mitochondrial membrane potentials with respect to equivalent concentrations of Ag+ and 1,10-phenanthroline. Bio-speciation studies, conducted electrochemically at platinum microelectrodes, revealed almost 50% of the Ag-Phen had dissociated after 2 h. Significant reductions in concentrations of dissociated Ag+ (from 67.7 μM to 6.7 μM), and the Ag-Phen complex (from 50.2 μM to 11.7 μM) between 4 and 24 h from the extracellular medium, indicate cellular uptake of both. This novel method facilitates the real-time identification and quantification of electroactive species, both the intact Ag-Phen and Ag+, in the presence of A549 cells.


Overweight, obesity and related non-communicable diseases in Asian Indian girls and women.
The prevalence of obesity is rising globally and in India. Overweight, obesity and related diseases need to be delineated in Asian Indian women. A literature search was done using key words like 'obesity', 'Asian Indian women', 'body fat distribution', 'type 2 diabetes', 'fertility', 'polycystic ovarian disease', metabolic syndrome', 'cardiovascular disease', 'non-alcoholic fatty liver disease', 'gender', 'sex' and 'prevalence' up to September 2012 in Pubmed and Google Scholar search engines. This review highlights the Asian Indian body composition with regards to obesity and provides a collated perspective of gender-specific prevalence of the co-morbidities. Recent data show that women (range of prevalence of overweight and obesity from different studies 15-61%) have higher prevalence of overweight and obesity as compared with men (range of prevalence of overweight and obesity from different studies 12-54%) in India and that obesity is increasing in the youth. The prevalence of overweight and obesity in both men and women steeply rose in a Punjabi community from Jaipur. Importantly, prevalence of abdominal obesity has been consistently higher in women than in men. The lowest prevalence (6.0%) of type 2 diabetes mellitus in women is reported from South India (rural Andhra Pradesh; 2006) and the highest (14.0%) by the National Urban Diabetes Survey (2001). Although the clustering of cardiovascular disease risk factors was generally high, it increased further in post-menopausal women. There are a number of factors that predispose Indian women to obesity; sedentary behaviour, imbalanced diets, sequential and additive postpartum weight gain and further decrease in physical activity during this period and cultural issues. In view of these data, preventive measures should be specifically targeted to Indian women.


Comparing the effects of docosahexaenoic and eicosapentaenoic acids on cardiovascular risk factors: Pairwise and network meta-analyses of randomized controlled trials.
Evidence from clinical trial studies suggests that docosahexaenoic acids (DHA) may have greater potential effects on improving cardiovascular risk factors than eicosapentaenoic acid (EPA). However, this evidence has not yet been meta-analyzed and quantified. The aim of this study was to evaluate and compare the effect of DHA and EPA monotherapy on cardiovascular risk factors based on paired and network meta-analysis. Relevant articles published up to January 2022 were systematically retrieved from relevant databases. We included all Randomized Controlled Trials (RCTs) on adults that directly compared the effects of DHA with EPA and RCTs of indirect comparisons (DHA and EPA monotherapy compared to control groups). Data were pooled by pairwise and network meta-analysis and expressed as mean differences (MDs) with 95% CIs. The study protocol was registered with PROSPERO (Registration ID: CRD42022328630). Network meta-analysis of comparisons of DHA and EPA suggested significant comparable effects only on LDL-C (MD EPA versus DHA = -8.51 mg/L; 95% CI: -16.67; -0.35). However, the Network meta-analysis not show a significant effect for other risk factors. Furthermore, pairwise meta-analysis of direct comparisons of DHA and EPA showed significant difference in their effects on plasma glucose (MD EPA versus DHA = -0.31 mg/L; 95% CI: -0.60, -0.02), Insulin (MD EPA versus DHA = -2.14 mg/L; 95% CI: -3.26, -1.02), but the results were not significant for risk factors. Our findings suggest that both EPA and DHA act similarly on the markers under study, with slight changes in plasma glucose, insulin, and LDL-C.


Tumor vaccines: effects and fate of IL-2 transfected murine melanoma cells in vivo.
We have previously demonstrated the general usefulness of the adenovirus-enhanced transferrinfection (AVET) in the generation of IL-2 producing tumor vaccines. By optimizing different parameters of the transfection protocol we were able to transform the poorly immunogenic M-3 mouse melanoma cell line into a potent immunogen. A long-lasting immunity was demonstrated after administration of the IL-2 releasing vaccine, since immunized animals successfully rejected native M-3 melanoma cells even after a period of more than 6 months. We also demonstrated that in vivo administration of such a vaccine is safe since transmission of the transfected IL-2 gene in host organs was not detected. IL-2 production ceased 2 days after injection because the engineered cells were destroyed. However, RT-PCR analysis of the site of vaccine injection suggests that IL-2 exerts its effects not only directly but also by inducing a set of other immunomodulator cytokines in situ that are probably indispensable in inducing a host response. We conclude that AVET of IL-2 into tumor cells is a safe and efficient method for the generation of tumor vaccines.


Mechanisms of apoptotic phosphatidylserine exposure.
It has been a long-standing enigma which scramblase causes phosphatidylserine residues to be exposed on the surface of apoptotic cells, thereby facilitating the phagocytic recognition, engulfment and destruction of apoptotic corpses. In a recent paper in Science, Nagata and coworkers reveal that the scramblases Xkr8 and its C. elegans ortholog, CED-8, are activated by caspase cleavage in apoptotic cells.


Polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDD), dechlorane-related compounds (DRCs), and emerging brominated flame retardants (EBFRs) in foods: The levels, profiles, and dietary intake in Latvia.
This study was performed to assess the Latvian population exposure to polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDD), dechlorane-related compounds (DRCs), and emerging brominated flame retardants (EBFRs). Food items including fish, fish products, meat, dairy products, cereals and bread, eggs, vegetable oils, and sweets were analyzed for the content of these contaminants, followed by per capita intake calculations and risk assessment. The highest dietary exposure for general population was observed in the case of HBCDD, .reaching an estimated daily intake (EDI) value of 2.92 ng kg-1 b.w. (or 3.35 ng kg-1 b.w. if an outlying data point is included), followed by PBDEs with EDI of 1.24 ng kg-1 b.w., including ~25% contribution of PBDE-209 to the overall EDI from PBDEs. DRCs and EBFRs were secondary contributors to the total intake of selected flame retardants (FRs), with the observed EDIs of 0.46 and 0.47 ng kg-1 b.w, respectively. The obtained occurrence data and risk characterization according to the European Food Safety Authority (EFSA) approach showed the calculated margin of exposure (MOE) values higher than the critical values for PBDE-47, -99 and -153as well as for HBCDD, indicating that the estimated dietary exposures are unlikely to be of significant health concern for the Latvian population. At the same time, it should be pointed out that the risk assessment was performed only for five out of the twenty-five selected halogenated flame retardants (HFRs), while cumulative effects due to the potential presence of other HFRs and their biodegradation products were not considered.


The COOH terminus of synaptotagmin mediates interaction with the neurexins.
The interaction of the synaptic vesicle protein, synaptotagmin, and the presynaptic alpha-latrotoxin receptor, a neurexin, has been proposed to be involved in docking of synaptic vesicles at active sites or modulation of neurotransmitter release. Here I report the investigation of the domain of synaptotagmin responsible for this interaction. Pieces of synaptotagmin containing the carboxyl terminus are capable of purifying neurexins from solubilized brain homogenates. Pieces as small as a synthesized peptide corresponding to the COOH-terminal 34 amino acids are capable of enriching neurexins 100-fold. The binding of neurexins to synaptotagmin is calcium-independent and of moderate affinity. This COOH-terminal segment of synaptotagmin is conserved in all species characterized to date. Reflective of this, a synthetic peptide corresponding to the carboxyl terminus of Drosophila synaptotagmin is capable of purification of rat neurexins, suggesting the possibility that this interaction may also exist in Drosophila. I propose that the carboxyl terminus of synaptotagmin binds to the carboxyl terminus of the neurexins and that this interaction may mediate docking of synaptic vesicles or modulation of neurotransmitter release.


Relationship Between Third-Trimester Sonographic Estimate of Fetal Weight and Mode of Delivery.
Some have suggested, based on limited data, that knowledge of an estimated fetal weight from a sonogram in a low-risk population, particularly in the setting of a larger fetus, is associated with increased risk of cesarean delivery. We aimed to investigate, among women delivering neonates weighing greater than 3500 g, whether having had a sonographically estimated fetal weight in temporal proximity to delivery was associated with the risk of cesarean delivery. We conducted a retrospective cohort study of term nulliparous women delivering live-born, cephalic, singleton, nonanomalous fetuses with birth weights of greater than 3500 g. The study was powered to detect a 30% change in cesarean delivery frequency with the presence of a sonographic examination after 36 weeks' gestation. Of the 2099 women meeting inclusion criteria, 419 (20%) had a sonographic examination after 36 weeks' gestation. Women were similar with respect to demographic and obstetric characteristics regardless of whether they underwent sonography. There were no differences in rates of cesarean delivery regardless of whether women had or did not undergo sonography after 36 weeks (33.2% versus 29.4%, respectively; P = .13). There also were no differences in rates of chorioamnionitis, postpartum hemorrhage, episiotomy, third- or fourth-degree perineal laceration, or neonatal adverse outcomes based on sonographic status. Findings were similar in a multivariable analysis, as well as when the study population was restricted to those with birth weights of greater than 4000 and 4500 g. In this population of neonates weighing greater than 3500 g, the presence of a sonographic examination was not associated with the frequency of cesarean delivery.


Partial transition-state inhibitors of glyoxalase I from human erythrocytes, yeast and rat liver.
Glyoxalase I (lactoylglutathione lyase, EC 22.214.171.124) converts the hemithiolacetal of glutathione and an alpha-ketoaldehyde to S-D-lactoylglutathione which is hydrolysed under the catalytic influence of glyoxalase II to produce D-lactate and regenerate glutathione. There is much evidence that glyoxalase I operates via an enediol intermediate, and in this study a number of inhibitors are described which were designed based on the enediol moiety of this reactive intermediate. These enediol and paene-enediol moieties were combined with groups designed to make use of an adjacent hydrophobic site and can be described as partial transition-state analogues. Derivatives of lapachol and kojic acid were good competitive inhibitors of glyoxalase I from various sources unless the free hydroxy group was blocked or replaced. Flavones with strong inhibitors of glyoxalase I and gallocyanine (a dye) showed spectral changes on binding to glyoxalase I indicative of binding to a metal-ion site (probably Zn2+ or Mg2+). The use of the enediol-binding determinant to produce glyoxalase I inhibitors is discussed as a route to potential antitumour derivatives.


Hormonal correlates of migration and territorial behavior in juvenile willow tits during autumn.
This study compared plasma levels of dihydrotestosterone, testosterone, corticosterone, luteinizing hormone, growth hormone, and prolactin in migrating juvenile willow tits with those in territorial juveniles. Both categories of birds were caught in late September. Migrating juveniles had higher plasma levels of corticosterone than territorial juveniles. Only corticosterone secretion was affected by "handling stress" in both migrating and territorial juveniles. However, territorial birds showed a much stronger relationship between these two variables. It is suggested that high corticosterone levels are involved in the emigration of juveniles out of the coniferous forest. Only juveniles were found among the migrating willow tits, and these birds were not well adapted for migration. Migrating juvenile males had less fat stored than did territorial ones. Furthermore, migrating juvenile males had higher liver/somatic index and higher plasma levels of growth hormone than did territorial males. These results indicate that migrating males had been, or were, exposed to food restrictions. The same proportion of migrating and territorial juveniles, males as well as females, had high plasma levels of testosterone. We suggest that these high levels were caused by recent aggressive interactions. To test the hypothesis that high plasma levels of testosterone are important for a juvenile to become a member of a territorial winter group, we performed a field experiment in which juveniles were given testosterone implants (controls were given empty silastic tubes) at the beginning of the territorial establishment period. The same proportion of testosterone-implanted birds and control birds succeeded in becoming members of territorial winter groups. Thus, testosterone does not seem to play an essential role in autumn territoriality, and it does not prevent autumn migration.


Tear lipocalin is the major endonuclease in tears.
Human endonucleases are integral to apoptosis in which unwanted or potentially harmful cells are eliminated. The rapid turnover of ocular surface epithelium and microbial colonization of the eyelids are continual sources of DNA in tears. Here, we determine the principal sources of endonuclease activity in tears. Endonucleases in human tears were identified after Sephadex G100 gel filtration. DNA hydrolyzing activity was measured by the conversion pUC19 plasmid DNA to its circular form in agarose gels. Fractions with endonuclease activity were further isolated using a combination ConA-Sepharose DNA, oligo (dT) cellulose, and anion exchange chromatographies. The molecular weights of the DNA hydrolyzing proteins were estimated in zymograms and by calibration of size exclusion chromatography. DNase activities were characterized for activity at a variety of pH and ion concentrations as well as in the presence of inhibitors including NiCl(2), ZnCl(2), G-actin, and aurintricarboxylic acid (ATA). To determine the mode of hydrolysis, the cleaved ends of the DNA digested by tear DNases were analyzed by 3' and 5' end labeling using either terminal deoxynucleotidyl transferase or polynucleotide kinase with or without pretreatment with alkaline phosphatase. Tear lipocalin (TL) accounts for over 75% of the DNA catalytic activity in tears while a second endonuclease, approximately 34 kDa, is responsible for less than 24% of the activity. Both are Mg(2+) dependent enzyme endonucleases that are enhanced by Ca(2+), active at physiologic pH, inhibited by aurintricarboxylic acid, and catalyze hydrolysis of DNA to produce 3'-OH/5'P ends. However, the two enzymes can be distinguished by the inhibitory effect of NiCl(2) and the sizes of the cleaved DNA fragments. Two magnesium dependent extracellular endonucleases were identified in tears that are different from other major human extracellular nucleases. TL is the principal endonuclease in human tear fluid. Tear endonucleases have unique characteristics that differ from other known human endonucleases.


Spatial and temporal changes in cell proliferation in the chick jejunum during the folding of the ridges into zigzags.
Vilification in the chick gut involves the formation of longitudinal ridges, establishment of their zigzag pattern and emergence of individual villi. Although the morphological changes during vilification are well known in the chick gut, the pattern of cell proliferation during this process is poorly understood. The aim of the present study was to correlate spatial and temporal changes in cell proliferation to folding of the longitudinal ridges into zigzags. Embryos on the 13th pos-incubation day were injected with BrdU and sacrificed at 8 h intervals up to 64 h after injection. Spatial and temporal changes in cell proliferation were observed during the folding the longitudinal ridges into zigzags. Cell proliferation occurred throughout the epithelium of the folded ridges, was predominant in the epithelial cells at the sides of the zigzagging ridges, and finally appeared in the epithelial cells at the tips of the zigzag ridges. In conclusion, cell proliferation might be a requirement for the folding of the longitudinal ridges into zigzags.


Comparison of the fatty acid composition of human milk from mothers in Tanzania, Curacao and Surinam.
Fatty acid composition of mature human milk from Curacao (Netherlands Antilles), Surinam and Tanzania was determined by capillary gas chromatography. In the Curacaoan samples the cholesterol and alpha- and gamma-tocopherol concentrations were also determined. Remarkable differences were found in the fatty acid composition of breastmilk fat from the three countries. The differences in the levels of medium chain fatty acids between Curacao and Tanzania, and between Curacao and Surinam were significant. The mean sum of the essential fatty acids linoleic acid and linolenic acid showed the highest values in Curacao (16.1 g per cent). Mean values for Tanzania and Surinam were 14.9 and 12.7, respectively. The mean level of the docosahexaenoic acid was higher in the Curacaoan and Surinam samples compared with that from Tanzania. In the Curacaoan breastmilk samples the concentrations of cholesterol and alpha- and gamma-tocopherol were about twice as high as those reported for Western countries.


The effect of chronological and theoretical birth order on sexual attitudes and behaviors.
A survey designed to evaluate the impact that both chronological and theoretical birth order may have on sexual attitudes and behaviors was completed by 441 respondents (221 male, 220 female). The attitudes and behaviors investigated were aggressive sexual behavior, social relationship attitudes, emotional relationship attitudes, total heterosexual behavior, and total orgasmic behavior. The data revealed no difference between male and female in terms of total sexual behavior. However, males had significantly higher sexual aggression, social attitudes, emotional attitudes, and total orgasm scores. These results suggest that while there may be equity between the sexes in terms of heterosexual behavior, there are still significant differences between the sexes in terms of specific behaviors and attitudes. No differences were found on any of the scales based on either chronological or theoretical birth order. These results suggest that sexual behavior and attitudes may be influenced to a greater degree by biological and cohort factors than by sibling position.


The removal of reactive dyes from aqueous solutions using chemically modified mesoporous silica in the presence of anionic surfactant-the temperature dependence and a thermodynamic multivariate analysis.
The three-parameter Sips adsorption model was successfully employed to modeled equilibrium adsorption data of a yellow and a red dye onto a mesoporous aminopropyl-silica, in the presence of the surfactant sodium dodecylbenzenesulfonate (DBS) from 25 to 55 degrees C. The results were evaluated in relation to the previously reported surface tension measurements. The presence of curvatures of the van()t Hoff plots suggested the presence of non-zero heat capacities terms (Delta(ads)C(p)). For the yellow dye, it is observed that the values of Delta(ads)H are almost all positive and they decrease in endothermicity, in the absence and in the presence of DBS, from 25 to 55 degrees C. For the red dye, there is an increase in endothermicity in relation to the temperature increase. The negative Delta(ads)G values indicate spontaneous adsorption processes. Almost all adsorption entropy values (Delta(ads)S) were positive. This suggests that entropy is a driving force of adsorption. The adsorption thermodynamic parameters were also evaluated using a new 2(3) full factorial design analysis. The multivariate polynomial modelings indicated that the thermodynamic parameters are also affected by important interactive effects of the experimental factors and not by the temperature changes alone.


Serum desialotransferrin in the detection of alcohol abuse. Definition of a Tf index.
Different molecular forms of transferrin (Tf) have been separated in sera from alcoholics and controls by isoelectric focusing on ultrathin polyacrylamide gels using a semi narrow pH range. The main fraction focused at pH 5.4 (Tf5.4) and minor components appeared among controls at pH 5.7 (Tf5.7). This fraction was increased among alcoholics and was sometimes accompanied by a fraction focusing at pH 5.9 (Tf5.9). Fractions were quantified by densitometry following immunofixation. Significant differences in the ratios Tf5.4/Tf and Tf5.7/Tf between the groups were obtained, but no difference could be determined in the total Tf. We used the ratio Tf5.7/Tf5.4 called Tf index to distinguish alcoholics from controls. The sensitivity, the specificity and the global predictive value of this test were 0.82, 1 and 0.88 respectively. These results seems to indicate that the Tf index is more reliable for the detection of alcohol abuse than liver enzymes such as gammaglutamyl transferase (gamma GT) or glutamate dehydrogenase (GDH).


[Diagnosis and treatment of primary hyperparathyroidism].
To study the diagnosis and treatment of hyperparathyroidism. 37 patients with primary hyperparathyroidism (PHPT) were confirmed pathologically. The course of the disease varied, the longest one being 14 years and the shortest one 3 months. 35 patients had parathyroid adenoma, 1 hyperplasia of parathyroid, and 1 carcinoma of parathyroid. The main clinical manifestation was symmetrical pain of the supporting bones and joints, hypercalcemia, hypercalcinuria, hypophosphatemia, hyper-alkaline phosphatasemia, and increase of iPTH in peripheral blood. X-ray examination showed osteoporosis and decalcification, accompanied with multiple fracture occasionally, we injected (99m)Tc and MiBi into inferior thyroid artery as a demonstration for the diagnosis of tumor of parathyroid. The key procedure of the operation was to search for tumor of parathyroid. We used thymus-thyroid ligament as guide and injected methylene blue into the artery during operation to search thyroid.


Effect of nimesulide and indomethacin on contractility and the Ca2+ channel current in myometrial smooth muscle from pregnant women.
The non-steroidal anti-inflammatory drug (NSAID) indomethacin inhibits both constitutive and inducible forms of cyclo-oxygenase (COX-1 and COX-2, respectively), while nimesulide is a selective COX-2 inhibitor. Uterine COX-2 is upregulated before and during term and pre-term labour, and prostaglandins play a crucial role in parturition. We therefore evaluated the effects of these drugs on myometrial contractility and the voltage-gated Ca2+ channel current in tissue strips and isolated human myometrial smooth muscle cells (HMSMC) from myometrial biopsies taken with informed consent from women undergoing caesarean section at term (not in labour). Nimesulide and indomethacin caused almost complete inhibition of spontaneous myometrial contractions at concentrations of 100 and 300 microM, respectively. The Ca2+ channel current was inhibited in a concentration-dependent manner by both drugs, with a 40% reduction of the current at 100 microM nimesulide and 300 microM indomethacin. Nimesulide also accelerated the decay of the Ca2+ channel current. The inhibition of the Ca2+ channel current by 100 microM nimesulide and 300 microM indomethacin was unaffected by the presence of either PGF2alpha or PGE2 (30 microM), and was of similar magnitude whether 10 mM Ba2+ or 1.5 mM Ca2+ was used as the charge carrier. The concentrations of indomethacin and nimesulide required to suppress spontaneous contractility in human pregnant myometrium were much higher than those necessary to inhibit prostaglandin production. The results suggest that both nimesulide and indomethacin inhibit myometrial contractility via mechanisms independent of cyclo-oxygenase inhibition. Blockade of the Ca2+ current may contribute to this effect.


Modulation of granulosa cell function via CRISPR-Cas fuelled editing of BMPR-IB gene in goats (Capra hircus).
BMPs are multifunctional growth factors implicated in regulating the ovarian function as key intra-ovarian factors. Biological effects of BMPs are mediated through binding with membrane bound receptors like BMPR-IB and initiating downstream Smad signaling pathway. FecB mutation, regarded as a loss of function mutation in the BMPR-IB gene was identified in certain sheep breeds having high fecundity. Similar type of fecundity genes in goats have not been discovered so far. Hence, the current study was designed to investigate the effects of BMPR-IB gene modulation on granulosa cell function in goats. The BMPR-IB gene was knocked out using CRISPR-Cas technology in granulosa cells and cultured in vitro with BMP-4 stimulation for three different durations In addition, the FecB mutation was introduced in the BMPR-IB gene applying Easi-CRISPR followed by BMP-4/7 stimulation for 72 h. Steroidogenesis and cell viability were studied to explore the granulosa cell function on BMPR-IB gene modulation. BMPRs were found to be expressed stage specifically in granulosa cells of goats. Higher transcriptional abundance of R-Smads, LHR and FSHR indicating sensitisation of Smad signaling and increased gonadotropin sensitivity along with a significant reduction in the cell proliferation and viability was observed in granulosa cells upon BMPR-IB modulation. The inhibitory action of BMP-4/7 on P4 secretion was abolished in both KO and KI cells. Altogether, the study has revealed an altered Smad signaling, steroidogenesis and cell viability upon modulation of BMPR-IB gene in granulosa cells similar to that are documented in sheep breeds carrying the FecB mutation.


Biochemical changes associated with ascorbic acid-cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice.
Cisplatin is one of the well-established anticancer drugs being used against a wide spectrum of cancers. However, full therapeutic efficacy of the drug is limited due to development of various toxicities in the host. This study examines the comparative therapeutic effectiveness and toxicities of cisplatin alone and in combination of dietary ascorbic acid (AA) in ascites Dalton's lymphoma-bearing mice. The findings show that the combination treatment of mice with ascorbic acid plus cisplatin has much better therapeutic efficacy against murine ascites Dalton's lymphoma (DL) in comparison to cisplatin alone and this may involve a decrease in reduced glutathione (GSH), catalase activity and increased lipid peroxidation (LPO) in Dalton's lymphoma tumor cells. At the same time, combination treatment indicates a protective role of ascorbic acid against cisplatin-induced tissue toxicities (side effects) in the hosts. Cisplatin-induced histopathological changes in liver, kidney and testes were decreased after combination treatment. The analysis of renal function test (RFT), liver function test (LFT) and sperm abnormalities also suggest an improvement in these parameters after combination treatment. Therefore, it may be concluded that the increased GSH level, catalase activity and decreased LPO in the tissues, i.e., liver, kidney and testes after combination treatment may be involved in its protective ability against cisplatin-induced tissue toxicities in the host.


Post-tonsillectomy haemorrhage: reusable and disposable instruments compared.
The aim of this study was to determine if the introduction of disposable instruments for tonsillectomy resulted in a significant change in post-tonsillectomy haemorrhage rates. This is a prospective comparative study of haemorrhage rates for cold dissection (CD) tonsillectomy in adults using reusable instruments during 1999-2000 ( n=83) and disposable instruments between August and December 2001 ( n=111). Haemorrhage rates in children with reusable instruments ( n=156) and disposable instruments ( n=115) were also compared. Confidence intervals were established for the differences between study groups along with exact levels of significance. No difference was found in the overall reactionary haemorrhage rate [ P=0.32, Diff 0.9% (95% CI; -3.2 to +0.4)] or secondary haemorrhage rate [ P=1.00, Diff 3.4% (95% CI; -0.09 to +0.01)] between reusable and disposable instruments. The introduction of disposable instruments has not produced a statistically significant increase in post-tonsillectomy haemorrhage rates in our centre.


The effect of ketotifen on bronchial beta-adrenergic tachyphylaxis in normal human volunteers.
The effect of ketotifen on bronchial beta-adrenergic tachyphylaxis was studied in healthy volunteers. In a 2-week pilot study, 19 volunteers inhaled 300 micrograms of salbutamol, four times a day. Ten subjects became tachyphylactic to inhaled salbutamol, assessed by a dose-response curve, before and after the 2 weeks of treatment from a metered-dose inhaler. These 10 subjects were then involved in a double-blind, crossover study comparing the effect of ketotifen, 1 mg in the evening during 1 week, and 1 mg, twice daily, during 3 weeks, and placebo on the bronchial beta-adrenergic tachyphylaxis induced by the concomitant administration during the last 2 weeks of each treatment period of 300 micrograms of salbutamol, four times a day, from a metered-dose inhaler. The end of the pilot study preceded the double-blind study by at least 1 month. However, the salbutamol dose-response curve at the beginning of the double-blind study was still significantly decreased, compared to the dose-response curve before the pilot study. During placebo treatment, a further decrease in bronchial beta-adrenergic sensitivity was observed. Treatment with ketotifen prevented the induction of further beta-adrenergic tachyphylaxis. Each 2 weeks of treatment with inhaled salbutamol increased significantly the baseline specific airway conductance; therefore, based on the present data, it is impossible to determine whether ketotifen also restores the sensitivity of an already desensitized beta-adrenergic system in the airways.


Splicing mediates the activity of four putative cellular internal ribosome entry sites.
A growing number of cellular mRNAs are thought to possess internal ribosome entry sites (IRESs), sequences that permit translation of a transcript independent of its 5' end and cap structure. Although dicistronic assays are the canonical method of testing sequences for IRES activity, they may produce false-positive results if unanticipated monocistronic RNAs arise from the dicistronic construct used. Using a dicistronic reporter system and a green fluorescent protein-tagged retrovirus to evaluate six previously reported cellular IRESs, we found that four contain 3' splice sites whose activity was required for apparent IRES function and which resulted in formation of monocistronic transcripts by splicing. Bioinformatic analysis revealed that the 3' splice sites identified in three of these putative IRESs are used in their native mRNAs and that the fourth is likely an artifactual sequence created during cDNA cloning. Our findings demonstrate a need for reexamination of other reported cellular IRESs by using careful RNA structural analysis to rule out splicing as the source of perceived IRES activity.


Upregulated expression of S100A6 in human gastric cancer.
The expression of S100A6 (calcyclin), a member of the S100 calcium binding protein family, is elevated in a number of malignant tumors, but there have been few reports about its expression in gastric cancer. The aim of this study was to investigate its expression regulations in human gastric cancer and noncancerous mucosa, and the response to chemotherapeutic drugs in the gastric cancer cell line. In one matched gastric cancer sample pair, the serial analysis of gene expression (SAGE) experiment was conducted to compare the gene expression profiles between cancerous and adjacent tissues. To detect the expression regulations among more cancerous tissues, microarrays were carried out and real-time RT-PCR was conducted to validate the results. At the protein level, Western blot and tissue microarray (TMA) examination were further used to verify S100A6 expression. The regulation detection of S100A6 with flurouracil and doxorubicin at the mRNA and protein level was performed in the SGC7901 cell line. With the SAGE strategy, five times more S100A6 tags were identified in cancer tissues than in normal tissues. With the cDNA microarray, S100A6 was found to be significantly upregulated in 21 of 42 (50%) nonselective gastric cancers. In 10 other paired samples, the upregulation of S100A6 was consolidated with RT-PCR and Western blot analysis as well. A total of 14 endoscopy-sectioned gastric noncancerous lesions and corresponding normal gastric mucosa were also applied to profile the gene expression; both cDNA microarray and RT-PCR demonstrated no significant alterations of S100A6 at the mRNA level. TMA examination showed that 34 of 52 (65.4%) cancer samples were positively stained, while only 17 of 80 (21.3%) noncancerous lesions were positively detected and all nine normal mucosae were detected to be negative. An in vitro experiment showed that in the gastric cell line SGC-7901, S100A6 mRNA was detected to be upregulated from 24 to 72 h after treatment with 5 mg/L 5-flurouracil or 0.3 mg/L doxorubicin, and there were two wave upregulations of the S100A6 protein. The observed regulated expression of S100A6 suggests that it is associated with gastric cancer tumorigenesis and quantitation of S100A6 is a promising tool for diagnosis of gastric cancer.