Computed tomography of posterior fossa ependymomas in childhood.
In reviewing 10 children with surgically proven posterior fossa ependymomas, various computed tomographic representations were seen. Calcification, seen in 50% of the cases, was the single most important finding suggesting the diagnosis of ependymoma. The appearance of two of our ependymomas mimicked the "typical" appearance of medulloblastomas. A case of calcified brainstem ependymoma is presented, to our knowledge, the first such case studied with computed tomography.


Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus.
Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.


Nonalcoholic Fatty Liver Disease Is Associated With Coronary Artery Calcification Development: A Longitudinal Study.
Nonalcoholic fatty liver disease (NAFLD) is associated with coronary artery calcification (CAC) in cross-sectional studies. However, whether NAFLD itself affects CAC development or progression remains unknown. This study investigated the longitudinal association between NAFLD and CAC score. This study is a longitudinal cohort study performed in a healthcare center. Among 1732 subjects who underwent serial CAC evaluation, we evaluated 846 subjects with NAFLD and 886 subjects without NAFLD, as diagnosed via ultrasonography. CAC score was compared at baseline and follow-up. In subjects without calcification (CAC score = 0) at baseline, any incidental calcification (CAC score >0) at follow-up was defined as development of CAC. In subjects with CAC (CAC score > 0) at baseline, confirmed CAC aggravation was defined as progression. Logistic regression analysis was performed. More subjects with NAFLD than without showed CAC development or progression (48.8 vs 38.4%; P < .001). The impact of NAFLD on a change in CAC score significantly differed according to the CAC score at baseline. In subjects without calcification at baseline, NAFLD significantly affected the development of calcification (odds ratio, 1.49; 95% confidence interval, 1.01-2.21; P = .045) after adjusting for traditional metabolic risk factors. However, in subjects with baseline CAC, NAFLD did not significantly affect progression (P = .734). Additionally, the severity of NAFLD was important. The severity of NAFLD was dose-dependently associated with the development of CAC (P for trend = .043). NAFLD plays a role in the early development of CAC, but not the progression. Ultrasonographic severity of NAFLD is dose-dependently associated with CAC development in subjects with a CAC score of 0 at baseline, independent of traditional risk factors.


Bouveret syndrome: A challenging case of impacted gallstone within the fourth part of the duodenum.
Bouveret syndrome is a rare condition characterised by gastric outlet obstruction secondary to a gallstone fistulating into the proximal duodenum or pylorus. Although rare, this condition carries a high mortality rate and no current standardised guidelines for management. We present a case of a patient in their 60s with recurrent small bowel obstruction secondary to a cholecysto-duodenal fistula and large gallstone which became impacted in the fourth part of the duodenum. The patient had a P-POSSUM Score of 14% mortality and 60% morbidity risk, had multiple co-morbidities, was bedbound, BMI 59 and had been deemed high risk for general anaesthetic at oncology centre for a 10 × 10 cm likely gynaecological malignancy a month prior to this admission. In contrast to existing literature, endoscopic lithotripsy was considered but not attempted due to unavailability of this service locally. Surgical intervention was decided based on radiological features of impending duodenal perforation on CT imaging and multiple disciplinary team discussion. The patient was managed with open enterolithotomy at the duodeno-jejunal (DJ) flexure and discharged 3 weeks post-operatively at her pre-operative baseline. This is the first report to our knowledge to describe successful surgical management of a gallstone impacted in the fourth part of the duodenum. In cases where anatomical location of impaction precludes retrieval via simple gastrostomy, we suggest using high pressure flush to mobilise the stone to more favourable location distally. We emphasise that stone size should be considered when planning surgical management.


Characterization, identification, and cloning of the S-layer protein from Cytophaga sp.
We characterized, identified, and cloned a major protein which comprised 16% of the total proteins from Cytophaga sp. cell lysate. After French pressing, the fraction of cell envelope was treated with 0.2% Triton X-100 to remove cell membranes. Subsequent SDS-PAGE analysis of the Triton X-100-insoluble cell wall revealed a protein of 120 kDa with a pI of 5.4, which was identified by gold immunostaining as the surface (S)-layer protein of this soil bacterium. The nucleotide sequence of the cloned S-layer protein gene (slp) encoding this protein consisted of 3144 nucleotides with an ORF for 1047 amino acids, which included a typical 32-amino acid leader peptide sequence. Amino acid sequence alignment revealed 29-48% similarity between this protein and the S-layer proteins from other prokaryotic organisms. The 120-kDa protein from the Cytophaga sp. cell lysate has been characterized as a member of the S-layer proteins, and the slp gene was cloned and expressed in Escherichia coli. E. coli harboring the plasmid containing the 600- or 800-bp DNA fragment upstream of the initiation codon of the slp gene, in the presence of the reporter gene rsda (raw starch digesting amylase), showed amylase activity in starch containing plate. The putative promoter region of slp located 600 bp upstream of the initiation codon might be used for foreign gene expression.


Medical treatment of acute spinal cord injuries.
The injury was performed with 600 g-cm/weight on the spinal cord of 40 cats with T8-9 laminectomy in this study. Ten cats were given 10 mg/kg naloxone i.v. 1 h after injury. Ten cats were given 2 mg/kg thyrotropin-releasing hormone (TRH) i.v. 1 h after injury followed by 1 mg/kg per hour for 4 h. Intravenous lidocaine was begun 30 min after injury in ten cats, administered as 1.5 mg/kg over the initial 5 min, 3 mg/kg over the next 30 min and 1 mg/kg every 30 min for 4 h. The remaining ten cats were given only saline (control group). TRH-treated cats showed significantly better histopathological scores than either naloxone- or lidocaine-treated animals (KW:13.65, P less than 0.50).


Utilization of CS2 as a source of C1 chemistry for the generation of methyldithioformate.
Insertion of CS(2) into the Ru-H bond of cis-[(dppe)(2)Ru(H)(2)] takes place to afford the hydride dithioformate complex trans-[(dppe)(2)Ru(H)(SC(S)H)]. The hydride dithioformate complex reacts under very mild conditions with MeX (X = OTf, I) to give the hydride methyldithioformate derivative trans-[(dppe)(2)Ru(H)(SC(SMe)H)][X]. Three different pathways have been found to cleave off the ester moiety from the metal complex. A method to recover the ruthenium starting material upon elimination of the methyldithioformate is presented. This is a novel case of C(1) chemistry using carbon disulfide.


Excitation of upper cervical inspiratory neurons by inspiratory neurons of the nucleus retroambigualis in the cat.
The experiments reported here examined inputs from inspiratory neurons of the nucleus retroambigualis to upper cervical inspiratory neurons. Antidromic mapping in contralateral C1 demonstrated the existence of axon collaterals for 9 of 19 nucleus retroambigualis axons tested (47%). Forty nucleus retroambigualis neurons were tested with antidromic mapping for a projection to the ipsilateral C1 segment; 9/40 (22%) had an ipsilateral axon (8 of these also projected contralaterally), and 2/40 (5%) had an axon collateral in ipsilateral C1. Cross-correlation histograms suggested monosynaptic excitation of an upper cervical inspiratory neuron by a contralateral nucleus retroambigualis neuron in 4/69 cases (6%) and common input to the pair in 2/69 cases (3%). Six of the 69 cross-correlograms were computed during antidromic activation of the nucleus retroambigualis neuron, and one of these six demonstrated direct excitation of the upper cervical inspiratory neuron by the retroambigualis neuron. We concluded that at least some upper cervical inspiratory neurons receive monosynaptic excitation from the contralateral, and possibly the ipsilateral, nucleus retroambigualis inspiratory neurons. These results, together with those published elsewhere for inputs from inspiratory neurons in the contralateral ventrolateral nucleus tractus solitarius, suggest that the rhythmic, inspiratory firing pattern of the upper cervical inspiratory neurons is due to excitatory inputs from these two inspiratory bulbospinal neuron populations.


Role of the lateral mammillary nucleus in the rat head direction circuit: a combined single unit recording and lesion study.
We recorded head direction (HD) cells from the lateral mammillary nucleus (LMN) and anterior thalamus (ATN) of freely behaving rats and also made bilateral lesions of LMN while recording HD cells from ATN. We discovered that the tuning functions of LMN HD cells become narrower during contraversive head turns, but not ipsiversive head turns, compared to when the head is not turning. This narrowing effect does not occur for ATN HD cells. We also found that the HD signal in LMN leads that in ATN by about 15-20 ms. When LMN was lesioned bilaterally, HD cells in ATN immediately lost their directional firing properties and never recovered them. Based on these findings, we argue that LMN may be an essential component of an attractor-integrator network that participates in generating the HD signal.


Exogenous human surfactant for treatment of severe respiratory distress syndrome: a randomized prospective clinical trial.
We performed a randomized, prospective clinical trial comparing intratracheal administration of human surfactant with conventional treatment with intermittent mandatory mechanical ventilation alone for treatment of severe respiratory distress syndrome in preterm infants of less than 30 weeks gestation. Twenty-two infants (mean gestational age 27.0 weeks, mean birth weight 987 gm) were given surfactant, and 23 infants (mean gestational age 27.2 week, mean birth weight 1055 gm) received intermittent mandatory ventilation. Infants given surfactant required less FiO2 during the first week, had lower mean airway pressure during the first 48 hours, and had improved ventilatory index and a/A PO2 ratio. Death or the occurrence of bronchopulmonary dysplasia was significantly less among infants given surfactant (P = 0.019). Pneumothorax, pulmonary interstitial emphysema, and need for FiO2 greater than or equal to 0.3 for greater than 30 days was significantly less in the surfactant group. This trial confirms the efficacy of treatment with human surfactant in preterm infants with severe respiratory distress syndrome.


Enzymic determination of plasma cholesterol on discrete automatic analysers.
Enzymic procedures for the determination of plasma cholesterol, using cholesterol esterase and cholesterol oxidase, have been adapted to the Vickers D-300, Vickers M,-300, and Vitatron AKES discrete analysers. The results obtained by these methods have been compared to those obtained by manual and continuous flow Liebermann-Burchard methods. The enzymic methods were found to be accurate, precise and of adequate sensitivity.


Rate hysteresis pacing: how valuable is it? A comparison of the stimulation rates of 70 and 50 beats per minute and rate hysteresis in patients with sinus node disease.
The main disadvantages of VVI pacing are absence of acceleration of the heart rate and loss of atrial synchronization. The alternatives to AAI and DDD pacing are stimulation at a low rate or hysteresis in order to decrease pacing time and thus reduce AV asynchrony. Nine patients who suffered from sinus node disease and who had been given a multiprogrammable pacemaker were monitored at each of three stimulation rates: 70, 50, and 70 bpm with an inhibition rate of 50 bpm (hysteresis). The total pacing time was shortest (p less than 0.05) for the stimulation rate of 50 bpm as compared to 70 bpm and hysteresis. It was also shorter for the hysteresis mode than for the 70 bpm mode (p less than 0.05). Only for hysteresis pacing was there a significant reduction in the number of changes from conducted cardiac rhythm to pacemaker-induced rhythm. Most patients found the 50 bpm mode preferable. None favored the hysteresis mode. In patients with sinus node disease and intermittent bradycardia being permanently paced, the periods of AV-conducted rhythm may be lengthened by reducing the stimulation rate from 70 bpm, with or without hysteresis pacing, to 50 bpm. In paced patients with sinus node disease and symptoms due to AV asynchrony, it might be worth trying a decrease in the stimulation rate before resorting to other pacemaker systems.


The effects of amiloride and age on oxygen consumption coupled to electrogenic sodium transport in the human sigmoid colon.
Aerobic metabolism is necessary for ion transport in many transporting epithelia, including the human colonic epithelium. We assessed the effects of the epithelial sodium channel blocker, amiloride, on oxygen consumption and short-circuit current of the human sigmoid epithelium to determine whether these effects were influenced by the age of the subject. Segments of the sigmoid colon were obtained from the safety margin of resections performed in patients of 62-77 years of age. Isolated mucosa preparations were obtained and mounted in airtight Ussing chambers, fit for simultaneous measurement of short-circuit current and oxygen concentration, before and after blocking epithelial sodium channels with amiloride (0.1 mmol/L). Regression analyses were performed to assess the associations between short-circuit current, oxygen consumption, and age of the subject as well as to define the relationship between the decreases in short-circuit current and oxygen consumption after blockade. Epithelial sodium channel blockade caused an 80% reduction in short-circuit current and a 26% reduction in oxygen consumption. Regression analysis indicated that both changes were significantly related (r = 0.884;P = 0.0007). Oxygen consumption decreased by 1 m mol/h/cm2 for each 25 m A/cm2 decrease in short-circuit current. Neither short-circuit current nor oxygen consumption had any significant relationship with the age of the subjects. The decrease in epithelial oxygen consumption caused by amiloride is proportional to the decrease in short-circuit current and independent of the age of the subject.


X-linked hypophosphatemic rickets: Description of seven new variants in patients followed up in reference hospitals in Rio de Janeiro.
X-linked hypophosphatemic rickets (XLHR) is a rare genetic disease, often delayed in diagnosis due to the low degree of suspicion and limited access to sophisticated diagnostic tools that confirm the diagnosis, such as genetic testing. Through a cross-sectional and observational study, 26 patients with a previously presumptive diagnosis of X-linked hypophosphatemic rickets (based on clinical history, laboratory findings, and physical examination), were followed for approximately 12 months. During 12 months of follow-up, only 16 patients underwent genetic testing and enrolled in the study. Previous data were analyzed, such as clinical history (e.g., gender, current age, age of clinical diagnosis, age of admission to hospital, family history, and previous orthopedic surgery), physical exam, imaging tests (e.g., radiological changes) and laboratory tests (e.g., tubular maximum reabsorption rate of phosphate to glomerular filtration rate, alkaline phosphatase, and phosphate levels) at the time of the patient's admission to IEDE and UFRJ, to corroborate and substantiate our research. These data were extracted from the medical records of the patients. Among the 16 patients analyzed by molecular biology techniques, the new generation sequencing (NGS), using DNA samples from oral swabs, we obtained seven variants never previously described, which were verified by Sanger sequencing. Among the seven variants never previously described, the most common coding impact was the nonsense mutation. We found two frameshift, one intronic splicing variant, three nonsense, and one deletion splice junction loss. Among patients with new mutations who presented data in the medical record, 100% showed a reduction in TmP/GFR (average of 1.98 mg/dl), the most sensitive laboratory parameter at the time of diagnosis, as well as serum phosphorus (100% had hypophosphatemia on arrival at the referral hospitals--average of 2.4 mg/dl and median 2.3 mg/dl). We also performed NGS on three mothers of the patients with identified mutations. Among these mothers, only one tested negative for the mutation and no family history was reported as well. This mother had serum phosphate of 3.5 mg/dl (normal range: 2.5-4.5 mg/dl) at the time of genetic test collection. The others had a positive test, low serum phosphorus at the time of the molecular test, in addition to a positive family history. This study describes seven new variants in the PHEX gene and aims to increase the knowledge of the scientific community about the types of mutations involving this gene, increasing information on the genetic basis of this condition, enabling future considerations about genotype-phenotype correlation, in addition to diagnosis accurate and early.


A new sample preparation approach for the analysis of 98 current-use pesticides in soil and herbaceous vegetation using HPLC-MS/MS in combination with an acetonitrile-based extraction.
A simple acetonitrile-based extraction method for the determination of 98 current-use pesticides (CUPs) in soil and herbaceous vegetation using HPLC-ESI-MS/MS is reported. The method was optimized in terms of extraction time, buffer (ammonium formate) ratio, and graphitized carbon black (GCB) ratio for the clean-up of vegetation. The validated method yielded accuracy in terms of percentage recovery of 71-125% (soil) and 70-117% (vegetation) for the majority of 98 CUPs. The precision in terms of relative standard deviation was at 1-14% (soil), and 1-13% (vegetation). Matrix-matched calibration curves exhibited good linearities (R2 > 0.99). The limits of quantitation ranged between 0.008 and 21.5 μg kg-1 in soil and vegetation. The reported method was applied to soils and vegetation from 13 agricultural sites across Germany. Overall, 44 of the 98 common CUPs were detected in our samples and the qualitative load is well above the average for arable soils in the EU.


Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells.
Muscarinic acetylcholine receptors (mAchRs) are guanosine nucleotide-binding protein (G protein) coupled receptors that crosstalk with receptor tyrosine kinases (RTKs) to signal mitogenic pathways. In particular, mAchRs are known to couple with RTKs for several growth factors to activate the mammalian target of rapamycin (mTOR)/Akt pathway, a regulator of protein synthesis. The RTK for the vascular endothelial growth factor (VEGF), VEGFR2, can signal protein synthesis but whether it cooperates with mAchRs to mediate mTOR activation has not been demonstrated. Using serum starved SK-N-SH neuroblastoma cells, we show that the muscarinic receptor agonists carbachol and pilocarpine enhance the activation of the mTOR substrate p70 S6 Kinase (S6K) and its target ribosomal protein S6 (S6) in a VEGFR2 dependent manner. Treatments with carbachol increased VEGFR2 phosphorylation, suggesting that mAchRs stimulate VEGFR2 transactivation to enhance mTOR signaling. Inhibitor studies revealed that phosphatidylinositol 3 kinase resides upstream from S6K, S6 and Akt phosphorylation while protein kinase C (PKC) functions in an opposing fashion by positively regulating S6K and S6 phosphorylation and suppressing Akt activation. Treatments with the phosphatase inhibitors sodium orthovanadate and okadaic acid increase S6, Akt and to a lesser extent S6K phosphorylation, indicating that tyrosine and serine/threonine dephosphorylation also regulates their activity. However, okadaic acid elicited a far greater increase in phosphorylation, implicating phosphatase 2A as a critical determinant of their function. Finally, pilocarpine but not carbachol induced a time and dose dependent cell death that was associated with caspase activation and oxidative stress but independent of S6K and S6 activation through VEGFR2. Accordingly, our findings suggest that mAchRs crosstalk with VEGFR2 to enhance mTOR activity but signal divergent effects on survival through alternate mechanisms.


The structure and specificity of endothelin receptors: their importance in physiology and medicine.
In addition to involvement in vascular endothelium-smooth muscle communication, the secretion of and receptors for, endothelins are widely distributed. Two cloned receptor subtypes are G-protein-coupled to several intracellular messengers, predominantly inositol phosphates. From a knowledge of structure-activity relationships and peptide conformations, details of receptor architecture and selective agents, including nonpeptides and antagonists, have been discovered. From the nature of the actions of endothelins, receptor distributions (including CNS) and plasma levels, it is concluded that they are paracrine factors normally involved in long-term cellular regulation, but which may be important in several pathologies, many of which are stress-related.


Embryology and endocrinology of genital development.
In the human male fetus, testes develop by the 7th week and begin to secrete two hormones: anti-müllerian hormone (AMH) induces the regression of müllerian ducts, the anlagen of the uterus, fallopian tubes and upper vagina, upon binding to a specific membrane receptor, whereas testosterone induces the differentiation of the wolffian ducts into the epididymes, vasa deferentia and seminal vesicles. In some target tissues, testosterone is converted to dihydrotestosterone, which is responsible for masculinization of the urogenital sinus and external genitalia. Both androgens act upon binding to the same nuclear receptor. In the absence of AMH and androgen action, or example in the female or in abnormal male differentiation, the internal and external genital primordia differentiate following the female pathway, even in the absence of ovaries. In males, an impaired function of the AMH-dependent pathway results in the persistent müllerian duct syndrome, a disorder characterized by the presence of uterus and fallopian tubes in otherwise normally virilized boys. Several mutations found in the AMH and AMH-receptor genes explain the pathophysiology of this syndrome.


[Phytopathological and molecular genetic identification of brown rust resistance genes in common wheat accessions with alien genetic material].
Brown rust resistance genes were sought in 23 resistant common wheat accessions with alien genetic material of Aegilops speltoides, Ae. triuncialis, and Triticum kiharae from the Arsenal collection. The genes were identified by common phytopathological tests and PCR analysis with STS markers directed to the known Lr genes. None of the methods identified the resistance genes in two accessions. In the other accessions, the combination of the two methods broadened the spectrum of detectable genes and, in some cases, allowed double verification of the presence of a resistance gene. Most accessions proved to contain several brown rust resistance genes, combining juvenile and adult plant ones. The accessions were found to contain gene combinations that ensured field resistance and immunity under the conditions of the Non-Chernozem region (Lr13 + Lr10 and Lr12 + Lr34). Accessions with alien genetic material contained a unique combination of five or six resistance genes. Since the accessions were rich in brown rust resistance genes, including effective ones, and carried rare combinations of these genes, they were proposed as donors to be universally employed in breeding for immunity in all regions of Russia.


Olive pulp and its effluents suitability for soil amendment.
Olive pulp (OP) and its effluents produced after digestion processes were characterised and their suitability as soil amendment materials were investigated. Results showed that OP and its effluent for hydrogen (EH2) and methane production (ECH4) contain high amount of organic matter, remarkable concentration of nutrients and negligible content of heavy metals. Decreasing concentrations of low molecular weight phenols (monomeric phenols) and increasing amount of humic-like materials were found passing from OP to EH2 and ECH4. The effects on both wheat seed germination and seedlings growth were also investigated. Addition of OP at the highest doses delayed both seed germination and seedling growth. These effects decreased when the OP and its effluents were incorporated into the soil. On the contrary an enhancement of seedlings growth was detected by addition of EH2 and ECH4. Enhancement effects also were found out by addition of lower OP concentrations. The phytotoxic effects decreased when the products were incorporated into the soil.


Rickets with alopecia: an inborn error of vitamin D metabolism.
Rickets with alopecia, an inborn error of vitamin D metabolism, is described in two sisters. The rachitic disorder began during the first year of life and was refractory to 50,000 IU of vitamin D2/day. Surprisingly, both children had marked elevations in serum concentrations of 1,25-(OH)2D. Although the molecular basis for this disorder is not evident to date, intestinal end-organ unresponsiveness to exceedingly high levels of 1,25-(OH)2D was present, in addition to hyporesponsiveness of bone to these high levels of the hormone, since normocalcemia was maintained despite elevated serum levels of PTH. Therapy with oral 1,25-(OH)2D3 failed to reverse the disorder, but oral phosphorus supplements resulted in significant radiographic and clinical improvement.


Ultrasound diagnosis of fetal diaphragmatic hernia and complex congenital heart disease at 12 weeks' gestation--a case report.
Congenital diaphragmatic hernia is commonly associated with congenital heart disease. Their coexistence indicates a poor prognosis. Prenatal diagnosis of these conditions in early pregnancy allows the option of pregnancy termination. We present a case of left-sided fetal diaphragmatic hernia and complex congenital heart disease diagnosed by ultrasound examination at 12 weeks' gestation.


Fetal heart rate and activity patterns in growth-retarded fetuses: changes after vibratory acoustic stimulation.
Seventeen pregnant women who subsequently were delivered of infants with birth weights less than the third percentile were studied for examination of fetal heart rate and fetal activity patterns before and after a 5-second external vibratory acoustic stimulation. None of the fetuses was acidotic at birth. A reduced time was noted during which accelerations in heart rate occurred (50% less) and long-term fetal heart rate variability (25% less) in small for gestational age fetuses compared with age-matched, normally grown fetuses. The incidence of gross fetal body movements was significantly lower (40% less) in small for gestational age fetuses than in those who were appropriate for gestational age. Fetal heart rate and fetal activity patterns after stimulation with the electronic artificial larynx in small for gestational age fetuses were similar to those of appropriate for gestational age fetuses.


Optimization of process parameters for reduction of gossypol levels in cottonseed meal by Candida tropicalis ZD-3 during solid substrate fermentation.
The objective of this work is to optimize the process parameters for detoxification of gossypol in cottonseed meal (CSM) by Candida tropicalis ZD-3 during solid substrate fermentation (SSF). The maximum detoxification efficiency of gossypol was achieved by employing the substrate, which consists of 70% of CSM, 20% of corn flour and 10% of wheat bran. The optimum fermentation conditions for gossypol detoxification are incubation period of 48h, incubation temperature at 30 degrees Celsius, inoculum level 5% v/w, moisture content of solid substrate 50% and pH in nature. Adding minerals solution to CSM substrate benefit fermentation detoxification.


Bacterial and archaeal communities in the acid pit lake sediments of a chalcopyrite mine.
Bacterial and archaeal community structures and diversity of three different sedimentary environments (BH1A, BH2A and BH3A) in the acid pit lake of a chalcopyrite mine at Touro (Spain) were determined by 16S rRNA gene PCR-DGGE and sequencing of clone libraries. DGGE of bacterial and archaeal amplicons showed that the sediments harbor different communities. Bacterial 16S rRNA gene sequences were assigned to Acidobacteria, Actinobacteria, Cyanobacteria, Planctomycetes, Proteobacteria, Chloroflexi and uncultured bacteria, after clustering into 42 operational taxonomic units (OTUs). OTU 2 represented approximately 37, 42 and 37 % of all sequences from sediments BH1A, BH2A and BH3A, respectively, and was phylogenetically related to uncultured Chloroflexi. Remaining OTUs were phylogenetically related to heterotrophic bacteria, including representatives of Ferrithrix and Acidobacterium genera. Archaeal 16S rRNA gene sequences were clustered into 54 OTUs. Most of the sequences from the BH1A sediment were assigned to Euryarchaeota, whereas those from BH2A sediment were assigned to Crenarchaeota. The majority of the sequences from BH3A sediment were assigned to unclassified Archaea, and showed similarities to uncultured and unclassified environmental clones. No sequences related to Acidithiobacillus and Leptospirillum, commonly associated with acid mine drainage, were detected in this study.


The effect of relaxin treatment on skeletal muscle injuries.
Injured skeletal muscle can repair itself via spontaneous regeneration; however, the overproduction of extracellular matrix and excessive collagen deposition lead to fibrosis. Neutralization of the effect of transforming growth factor-beta 1, a key fibrotic cytokine, on myogenic cell differentiation after muscle injury can prevent fibrosis, enhance muscle regeneration, and thereby improve the functional recovery of injured muscle. The hormone relaxin, a member of the family of insulin-like growth factors, can act as an antifibrosis agent and improve the healing of injured muscle. Controlled laboratory study. In vitro: Myoblasts (C2C12 cells) and myofibroblasts (transforming growth factor-beta 1-transfected myoblasts) were incubated with relaxin, and cell growth and differentiation were examined. Myogenic and fibrotic protein expression was determined by Western blot analysis. In vivo: Relaxin was injected intramuscularly at different time points after laceration injury. Skeletal muscle healing was evaluated via histologic, immunohistochemical, and physiologic tests. Relaxin treatment resulted in a dose-dependent decrease in myofibroblast proliferation, down-regulated expression of the fibrotic protein alpha-smooth muscle actin, and promoted the proliferation and differentiation of myoblasts in vitro. Relaxin therapy enhanced muscle regeneration, reduced fibrosis, and improved injured muscle strength in vivo. Administration of relaxin can significantly improve skeletal muscle healing. These findings may facilitate the development of techniques to eliminate fibrosis, enhance muscle regeneration, and improve functional recovery after muscle injuries.


Nuclear speckles are involved in nuclear aggregation of PABPN1 and in the pathophysiology of oculopharyngeal muscular dystrophy.
Nuclear speckles are essential nuclear compartments involved in the assembly, delivery and recycling of pre-mRNA processing factors, and in the post-transcriptional processing of pre-mRNAs. Oculopharyngeal muscular dystrophy (OPMD) is caused by a small expansion of the polyalanine tract in the poly(A)-binding protein nuclear 1 (PABPN1). Aggregation of expanded PABPN1 into intranuclear inclusions (INIs) in skeletal muscle fibers is the pathological hallmark of OPMD. In this study what we have analyzed in muscle fibers of OPMD patients and in primary cultures of human myoblasts are the relationships between nuclear speckles and INIs, and the contribution of the former to the biogenesis of the latter. While nuclear speckles concentrate snRNP splicing factors and PABPN1 in control muscle fibers, they are depleted of PABPN1 and appear closely associated with INIs in muscle fibers of OPMD patients. The induction of INI formation in human myoblasts expressing either wild type GFP-PABPN1 or expanded GFP-PABPN1-17ala demonstrates that the initial aggregation of PABPN1 proteins and their subsequent growth in INIs occurs at the edges of the nuclear speckles. Moreover, the growing of INIs gradually depletes PABPN1 proteins and poly(A) RNA from nuclear speckles, although the existence of these nuclear compartments is preserved. Time-lapse experiments in cultured myoblasts confirm nuclear speckles as biogenesis sites of PABPN1 inclusions. Given the functional importance of nuclear speckles in the post-transcriptional processing of pre-mRNAs, the INI-dependent molecular reorganization of these nuclear compartments in muscle fibers may cause a severe dysfunction in nuclear trafficking and processing of polyadenylated mRNAs, thereby contributing to the molecular pathophysiology of OPMD. Our results emphasize the potential importance of nuclear speckles as nuclear targets of neuromuscular disorders.


Monochorionic monoamniotic twin pregnancies.
Monoamniotic twin pregnancies are rare, but early diagnosis of such pregnancies is critical, as the incidence of complications in these pregnancies is much higher than in diamniotic or dichorionic twin pregnancies. Overall, only 70% of all monoamniotic twins will survive. Furthermore, approximately half of fetal deaths in these pregnancies are because of the high incidence of fetal anomalies (15%-25%), such as twin reversed arterial perfusion sequence and conjoined twinning. Therefore, early anatomy screening in the first trimester of pregnancy is recommended. Other causes of fetal death in these pregnancies include twin-twin transfusion syndrome, tight cord entanglement, or acute hemodynamic imbalances through the large placental vascular anastomoses. After viability, fetal surveillance can be intensified, as this decreases the risk of in utero death. Both inpatient and outpatient surveillance are reasonable. If otherwise uncomplicated, monoamniotic twins should be delivered at 33 to 34 weeks' gestation. Most centers will deliver by cesarean delivery, but some continue to advocate for vaginal delivery. Lastly, neonatal morbidity is high in monoamniotic twin pregnancies and is mainly related to prematurity.


Analysis of fractured dental implant body from five different implant systems: a long-term retrospective study.
The aim of this study was to perform an analysis of the incidence of implant body fracture and to identify possible risk factors. A long-term follow-up retrospective evaluation of 3477 patients who received 8588 implants from five implant systems was performed. Overall, 2810 patients who received 7502 implants, with an average follow-up of 6.9 years, were included in the analysis. The overall body fracture rate was 0.49% (37/7502), among which 32.4% (12/37) were implants with a reduced diameter. The estimated cumulative fracture rate was 1.24%. Fractures were observed in two patients with three Brånemark implants, 13 patients with 15 Nobel Replace implants, eight patients with eight Camlog implants, eight patients with 11 Ankylos implants, and none of the patients with Thommen implants. Most fractures occurred in the molar region (29/37) and in single implant-supported restorations (30/37). The results showed significant differences between splinted and unsplinted restorations (P = 0.005) and between regular and narrow diameter implants (P = 0.009). Within the limitations of this retrospective analysis, a narrow implant diameter is a potential risk factor for implant body fracture in the posterior region. Furthermore, unsplinted restorations appear to be associated with a higher rate of implant fracture.


γ-Aromatic Butenolides of Microbial Source - A Review of Their Structures, Biological Activities and Biosynthesis.
γ-Aromatic butenolides (γ-AB) are an important type of structures found in many bioactive microbial secondary metabolites (SMs). γ-AB refer to a group of natural products (NPs) containing five-membered (unsaturated) lactones with 3-phenyl and 4-benzyl substituents. Their wide-range biological activities have inspired pharmaceutical chemists to explore its biosynthesis mechanisms and design strategies to construct the γ-AB skeleton. Recently, there are a great deal of interesting research progress on the structures, biological activities and biosynthesis of γ-AB. This review will focus on these aspects and summarize the important achievements of γ-AB from 1975 to 2021.


A randomized controlled trial of an appearance-focused intervention to prevent skin cancer.
Skin cancer represents a significant health threat with over 1.3 million diagnoses, 8000 melanoma deaths, and more than $1 billion spent annually for skin cancer healthcare in the US. Despite findings from laboratory, case-control, and prospective studies that indicate a link between youthful indoor tanning (IT) and skin cancer, IT is increasing among US youth. Appearance-focused interventions represent a promising method to counteract these trends. A total of 430 female indoor tanners were randomized into intervention or no intervention control conditions. Intervention participants received an appearance-focused booklet based on decision-theoretical models of health behavior. Outcome variables included self-reports of IT behavior and intentions, as well as measures of cognitive mediating variables. Normative increases in springtime IT rates were significantly lower (ie, over 35%) at 6-month follow-up in intervention versus control participants with similar reductions in future intentions. Mediation analyses revealed 6 cognitive variables (IT attitudes, fashion attitudes, perceived susceptibility to skin cancer and skin damage, subjective norms, and image norms) that significantly mediated change in IT behavior. The appearance-focused intervention demonstrated strong effects on IT behavior and intentions in young indoor tanners. Appearance-focused approaches to skin cancer prevention need to present alternative behaviors as well as alter IT attitudes. Mediational results provide guides for strengthening future appearance-focused interventions directed at behaviors that increase risk of skin cancer.


Stimulating beta cell replication and improving islet graft function by GPR119 agonists.
G protein-coupled receptor 119 (GPR119) is predominantly expressed in β cells and intestinal L cells. In this study, we investigated whether oleoylethanolamide (OEA), a GPR119 endogenous ligand, and PSN632408, a GPR119 synthetic agonist, can stimulate β-cell replication in vitro and in vivo and improve islet graft function in diabetic mice. We found that OEA and PSN632408 significantly increased numbers of insulin(+)/5-bromo-2'-deoxyuridine (BrdU)(+) β cells in cultured mouse islets in a dose-dependent manner. All diabetic recipient mice, given marginal syngeneic islet transplants with OEA or PSN632408 or vehicle, achieved normoglycemia at 4 weeks after transplantation. However, normoglycemia was achieved significantly faster in OEA- or PSN632408-treated diabetic mice than in vehicle-treated diabetic mice (P < 0.05). The percentage of insulin(+)/BrdU(+) β cells in islet grafts in OEA- and PSN632408-treated mice was significantly higher than in vehicle-treated mice (P < 0.01). Our data demonstrated that OEA and PSN632408 can stimulate β-cell replication in vitro and in vivo and improve islet graft function. Targeting GPR119 is a novel therapeutic approach to increase β-cell mass and to improve islet graft function by stimulating β-cell replication.


Allosteric positive interaction of thymol with the GABAA receptor in primary cultures of mouse cortical neurons.
Thymol is a naturally occurring phenolic monoterpene known for its anti-microbial and anti-oxidant properties. It is used in dental practice and in anaesthetic halothane preparations. Recent studies have reported enhanced GABA(A) receptor-operated chloride channel activity and increased binding affinity of [(3)H]flunitrazepam in the presence of thymol. In the present work, we more closely examined the pharmacological action of thymol on the native GABA(A) receptor by using primary cultures of cortical neurons. Thymol enhanced GABA-induced (5 microM) chloride influx at concentrations lower than those exhibiting direct activity in the absence of GABA (EC(50) = 12 microM and 135 microM, respectively). This direct effect was inhibited by competitive and non-competitive GABA(A) receptor antagonists. Thymol increased [(3)H]flunitrazepam binding (EC(50) = 131 microM) and showed a tendency to increase [(3)H]muscimol binding. These results confirm that thymol is a positive allosteric modulator of the GABA(A) receptor. The thymol structural analogues menthol and cymene, which lack an aromatic ring or a hydroxyl group, did not affect [(3)H]flunitrazepam binding. Using a pharmacophoric model that includes a hydrogen bond donor group as well as an aromatic ring with two aliphatic substituents, we propose to demonstrate the molecular essential features of these compounds to interact with GABA(A) receptors. Thymol (0-1 mM) did not affect cellular viability.


Pediatric Oncology Providers' Attitudes and Practice Patterns Regarding Fertility Preservation in Adolescent Male Cancer Patients.
The aim of this study was to evaluate pediatric oncology providers' attitudes toward fertility preservation (FP), their use of educational materials, their approach to FP discussion, and their FP knowledge specifically pertaining to adolescent males. A 40-item online survey was distributed to physicians, advanced practice nurses (APN), and nurses within pediatric oncology. About 78.7% of physicians, 81.4% of APN, and 51.9% of nurses reported high levels of comfort in discussing FP options with adolescent males (P<0.05). Fifty-one percent of physicians and 54.2% of APN reported using educational materials, compared with 38.9% of nurses (P<0.05). Regarding knowledge of FP technologies, 48.7% of physicians, 52.5% of APN, and 81.1% of nurses reported being unfamiliar with intracytoplasmic sperm injection (P<0.05). An overwhelming majority (92.9%) of respondents reported having no formal training in discussing FP. Finally, 84.8% of respondents believed formal training on this issue would be useful to them. This study illustrates an unmet need in the education of pediatric oncology providers, as knowledge gaps and discomfort are common themes reported by health care professionals within the context of adolescent male FP care. In addition, this study reveals a high level of receptiveness to FP training by these same providers.


Classification of substandard factors in perinatal care: development and multidisciplinary inter-rater agreement of the Groningen-system.
Perinatal audit is an established method for improving the quality of perinatal care. In audit meetings substandard factors (SSF) are identified in cases of perinatal mortality and morbidity. To our knowledge there is no classification system specifically designed for the classification of substandard factors. Such a classification may help to standardise allocation of substandard factors to categories. This will help to prioritise, guide and implement actions in quality improvement programs. A classification system of 284 substandard factors (SSF) identified in perinatal audit meetings between 2007 and 2011 was drawn up using the WHO Conceptual Framework for the International Classification for Patient Safety as a starting point. Discussions were held on inter-rater disagreements, inclusion of items, format and organisation and definitions of the main- and subcategories. A guideline was developed. An independent multidisciplinary group tested the classification. Independent of inter-rater agreement the allocations to categories were counted. For the counts in the subcategories one and two, we used the allocations in the main category as reference. The chance corrected agreement between classifiers was tested with Cohen's kappa statistic. The classification consists of 9 main categories with one or two subcategories. The main categories are (1) Equipment and Materials, (2) Medication, (3) Additional tests/ investigations, (4) Transportation , (5) Documentation, (6) Communication, (7) Medical practice, (8) Other and (9) non classifiable. Of 3663 allocations by 13 classifiers 1452 SSF's were allocated (40%) to 'medical practice' and 1247 (34%) to 'documentation'. 118 (3%) times SSF's were not classifiable, mainly due to unclear phrasing of the SSF. The chance corrected agreement of 284 substandard factors in the main category was 0.68 (95% CI 0.66-0.70) and 0.57 (95% CI 0.54-0.59) for the CDG and the IGD respectively. Classifying substandard factors has given insight into problem area's in perinatal care and can give direction to medical, political and financial quality improvement measures. The Groningen-system has well defined categories and subcategories and the guidelines and examples are clear. The multidisciplinary inter-rater agreement is moderate to good. Improvement of the phrasing of the substandard factors is expected to improve inter-rater agreement.


Gender-Affirming Surgery of the Mandible: Lower Jaw Feminization and Masculinization.
For patients with gender dysphoria, gender-affirming surgery of the face has been shown to vastly improve quality of life. The mandible is one area of the face that has distinct feminine and masculine presentations. This article will review gender-affirming surgery of the lower jaw, both for feminization and masculinization. Techniques for bony contouring and soft tissue manipulation will be discussed.


Intracranial cholesteatoma in the thalamus: Uncommon location and atypical imaging findings.
Intracranial cholesteatoma is an uncommon condition that can occur anywhere in the intracranial cavity, but its occurrence in the thalamus is exceedingly rare. We present a case of thalamic cholesteatoma with atypical imaging findings and review the previous literature to explore the pathophysiological basis of these findings. A 55-year-old male presented to the hospital with right upper limb weakness and right ear hearing loss for more than 2 years. Imaging studies of the brain were performed, revealing a mixed density mass in the left thalamic region with calcification at the margin. Magnetic resonance imaging revealed a mixed signal intensity on T1-weighted and T2-weighted images, diffusion limitation on diffusion-weighted images, and ring enhancement on enhanced T1-weighted images. The mass caused mild obstructive hydrocephalus due to compression of the 3 ventricles and midbrain aqueduct. Thalamic cholesteatoma is an uncommon and often misdiagnosed lesion due to its unusual location and imaging characteristics. The pathophysiological basis of the atypical imaging findings associated with intracranial cholesteatoma is not well understood but may be related to the keratinization of the cyst lining or the presence of cholesterol crystals. Thalamic cholesteatoma should be considered in the differential diagnosis of thalamic lesions, especially in cases with calcifications or cystic components. Further studies are needed to better understand the pathophysiology of intracranial cholesteatoma and its associated atypical imaging findings.


Heterogeneous distribution of Fusobacterium nucleatum in the progression of colorectal cancer.
Fusobacterium nucleatum (Fn) is involved in colorectal cancer (CRC) growth and is a biomarker for patient prognosis and management. However, the ecology of Fn in CRC and the distribution of intratumoral Fn are unknown. We evaluated Fn and the status of KRAS and BRAF in 200 colorectal neoplasms (118 adenomas and 82 cancers) and 149 matched adjacent normal mucosas. The differentiation status between "surface" and "deep" areas of cancer tissue and matched normal mucosa were analyzed in 46 surgical samples; the Ki-67 index was also evaluated in these samples. Fusobacterium nucleatum presence in the tumor increased according to pathological stage (5.9% [adenoma] to 81.8% [stage III/IV]), while Fn presence in normal mucosa also increased (7.6% [adenoma] to 40.9% [stage III/IV]). The detection rates of Fn on the tumor surface and in deep areas were 45.7% and 32.6%, while that of normal mucosa were 26.1% and 23.9%, respectively. Stage III/IV tumors showed high Fn surface area expression (66.7%). Fn intratumoral heterogeneity (34.8%) was higher than that of KRAS (4.3%; P < 0.001) and BRAF (2.2%; P < 0.001). The Ki-67 index in Fn-positive cases was higher than that in negative cases (93.9% vs 89.0%; P = 0.01). Fusobacterium nucleatum was strongly present in CRC superficial areas at stage III/IV. The presence of Fn in the deep areas of adjacent normal mucosa also increased. The intratumoral heterogeneity of Fn is important in the use of Fn as a biomarker, as Fn is associated with CRC proliferative capacity.


Tumor size and surgical margins are important prognostic factors of synovial sarcoma - A retrospective study.
Synovial Sarcoma (SS) is a rare soft tissue sarcoma. Mean time to get a SS diagnosis from the onset of symptoms is 10 years, furthermore, SS is associated with late metastasis. Surgery is the main treatment option, whose quality deeply affects SS outcomes, and it can be associated to preoperative or post-operative radiotherapy. Chemotherapy is considered very effective in Children, while in adults its efficacy is still under debate. The aim of this study was to investigate the oncologic results in SS treatment and to identify the risk factors for local and systemic control of the disease. From 1994 to 2018, 211 patients affected by SS were treated in 3 Referral Centres of Orthopaedic Oncology. One hundred seventy-seven patients were included in the study, the median follow-up length was 96 months (5-374). Overall Survival on the Kaplan Meier Analyses was 80%, 70% and 56% at 5, 10 and 20 years. In multivariate analyses, OS correlated with tumour size and negative surgical margins. Chemotherapy use wasn't associated with better survival although patients who underwent CT had bigger and more aggressive tumours. Our findings suggests that surgery with negative margins is the most important factor in Synovial Sarcoma. Adjuvant treatments as chemotherapy and radiation therapy didn't change the disease's course.


A global health delivery framework approach to epilepsy care in resource-limited settings.
The Global Health Delivery (GHD) framework (Farmer, Kim, and Porter, Lancet 2013;382:1060-69) allows for the analysis of health care delivery systems along four axes: a care delivery value chain that incorporates prevention, diagnosis, and treatment of a medical condition; shared delivery infrastructure that integrates care within existing healthcare delivery systems; alignment of care delivery with local context; and generation of economic growth and social development through the health care delivery system. Here, we apply the GHD framework to epilepsy care in rural regions of low- and middle-income countries (LMIC) where there are few or no neurologists.


Effect of maternal methionine pre-treatment on alcohol-induced exencephaly and axial skeletal dysmorphogenesis in mouse fetuses.
Alcohol is known to induce folate deficiency and impair methionine synthase activity. Exogenous folic acid (FA) administered periconceptionally has been shown to prevent the first occurrence and recurrence of neural tube defects (NTD) in humans. Since folate, vitamin B(12) and methionine are metabolically interrelated, it was decided to determine the effect of methionine pre-treatment on alcohol-induced NTD and axial skeletal defects in mouse embryos. Following administration of a single dose of 70 or 150 mg/kg of methionine, 0.03 ml/g body weight of ethanol solution (25% v/v of absolute alcohol in saline) was injected intraperitoneally into pregnant mice at critical stages of neural tube development. The controls were either non-treated or saline treated and pair-fed and pair-watered. Fetuses were collected on gestation day 18. Alcohol and methionine plus alcohol numerically enhanced embryonic resorption and induced a significant reduction in fetal body weight. Alcohol alone caused a 3-fold increase in the background frequency of exencephaly in gestation days 7 and 8 treatment groups. The low dose of methionine only numerically reduced the spontaneous exencephaly. Pre-treatment with methionine only produced a numerical but not statistically significant reduction in alcohol-induced exencephaly. The higher dose of methionine did not produce a particularly beneficial effect on embryonic survival, fetal body weight and occurrence of exencephaly. Alcohol-induced cleft palate and limb malformations were ameliorated by methionine pre-treatment. Craniofacial skeleton, vertebrae and ribs were extensively malformed both in the alcohol and methionine plus alcohol groups indicating a lack of rescue effects of methionine. Whereas supernumerary ribs and extra sternal ribs were augmented by methionine, occipitalization of the atlas vertebra was a malformation unique to the pre-treatment group. Plasma levels of several amino acids including that of methionine were significantly lowered by alcohol. Pre-treatment with methionine produced a dose dependent enhancement of only methionine concentration. These data suggest that pre-administration of methionine only rescues mouse embryos of certain non-neural malformations and that the lack of ameliorative effect on NTD and axial skeletal defects may be due to the fact that alcohol lowers the concentration of a number of amino acids and therefore, supplementation should comprise a mixture of these amino acids and possibly FA and vitamin B(12).


Fatal home accidents--a product database.
A computer-based "Home Accident Deaths Database" has been developed to permit analysis of the consumer products and articles or features of the home involved in fatal domestic accidents in England and Wales. It makes use of information already recorded for other purposes, which is either manually coded or converted by computer to a standard format. Rapid interrogation and analysis (in the form of tables or easily readable case listings) is possible, and the format of the database permits direct comparison with statistics for nonfatal hospital-treated accidents recorded by the Home Accident Surveillance System. Such comparison reveals considerable differences between the products and articles most frequently involved in fatal accidents and those most common in nonfatal cases, so that neither provides an adequate indication of hazards on its own. There are some limitations, including a variation in the level of detail recorded between different types of accident, less than perfect matching of sources for deaths in fires, and a long delay in getting cases onto the database, but with the experience that has now been gained it is hoped to develop a new reporting system that will overcome these problems and will, additionally, cover "leisure" accidents.


Successful and safe use of 2 min cold atmospheric argon plasma in chronic wounds: results of a randomized controlled trial.
The development of antibiotic resistance by microorganisms is an increasing problem in medicine. In chronic wounds, bacterial colonization is associated with impaired healing. Cold atmospheric plasma is an innovative promising tool to deal with these problems. The 5-min argon plasma treatment has already demonstrated efficacy in reducing bacterial numbers in chronic infected wounds in vivo. In this study we investigated a 2-min plasma treatment with the same device and the next-generation device, to assess safety and reduction in bacterial load, regardless of the kind of bacteria and their resistance level in chronic wounds. Twenty-four patients with chronic infected wounds were treated in a prospective randomized controlled phase II study with 2 min of cold atmospheric argon plasma every day: 14 with MicroPlaSter alpha device, 10 with MicroPlaSter beta device (next-generation device) in addition to standard wound care. The patient acted as his/her own control. Bacterial species were detected by standard bacterial swabs and bacterial load by semiquantitative count on nitrocellulose filters. The plasma settings were the same as in the previous phase II study in which wounds were exposed for 5 min to argon plasma. Analysis of 70 treatments in 14 patients with the MicroPlaSter alpha device revealed a significant (40%, P<0.016) reduction in bacterial load in plasma-treated wounds, regardless of the species of bacteria. Analysis of 137 treatments in 10 patients with the MicroPlaSter beta device showed a highly significant reduction (23.5%, P<0.008) in bacterial load. No side-effects occurred and the treatment was well tolerated. A 2-min treatment with either of two cold atmospheric argon plasma devices is a safe, painless and effective technique to decrease the bacterial load in chronic wounds.


Perioperative Factors Affecting the Length of Hospitalization After Shoulder Arthroplasty.
To determine factors related to length of hospitalization after shoulder arthroplasty. A retrospective review identified patients who underwent shoulder arthroplasty between 2009 and 2012 at our institution. Factors were evaluated for their association with hospitalization length in a univariate model. Diagnoses were categorized into four groups: (1) osteoarthritis, cuff tear arthropathy, massive rotator cuff tear, or osteonecrosis; (2) acute fracture or fracture sequelae; (3) inflammatory arthropathy; and (4) failed shoulder arthroplasty. Significant factors were then evaluated using a multivariate model. Four hundred twenty-five shoulder arthroplasties were identified (average age, 66.9 years). Arthroplasty type significantly affected hospitalization length. Significant factors for increased hospitalization using multivariate analysis were diabetes mellitus, American Society of Anesthesiologists score of 3 or 4, acute fracture or fracture sequelae diagnosis, inflammatory arthropathy, and a blood transfusion. Independent factors using multivariate analysis are diabetes, an American Society of Anesthesiologists score ≥3, fracture or fracture sequelae, inflammatory arthritis, and a perioperative blood transfusion. Level III therapeutic study.


Arginine-rich membrane-permeable peptides are seriously toxic.
The membrane-permeable peptides (MPP) such as undecapeptides TAT (YGRKKRRQRRR) and CTP (YGRRARRRRRR) have been receiving much attention for delivering various kinds of low membrane-permeability materials in vitro and in vivo. We have successfully used MPP in carrying various proteins through blood-brain barrier (BBB) in treatment of many kinds of nervous diseases. However, people always concentrate their mind on the efficacy and the mechanism of permeation of the conjugates across BBB, but overlook the toxicity of the membrane-permeable peptide itself. Once we injected intravenously not very large amounts of gamma-aminobutyric acid-MPP (GABA-MPP) to the mice, to our great surprise, the mice died within seconds with seizure, whereas the GABA control mice well survived. Thus, the importance of the toxicity of MPPs and their conjugates comes into the field of our vision. The low LD50 values of arginine-rich TAT (27.244 mg kg-1 ) and CTP (21.345 mg kg-1 ) per se in mice indicate that they all fall within the range of highly toxic chemicals. Among the arginine-rich peptides, R11 (RRRRRRRRRRR), a peptide composed purely of arginine residues, has the lowest LD50 value (16.5 mg kg-1 ) and manifests the highest toxicity, whereas TD (ACSSSPSKHCG), a peptide without arginine residue, shows a much lower toxicity and higher survival rate in mice. The mass percentage of arginine-rich MPP in the conjugate is critically important, the mass radio of arginine in the MPP appears a linear correlation with the toxicity. Thus we conclude, the arginine-rich MPPs are more suitable for using in the macro-molecular conjugates, but not in the small-molecular one.


Enhanced stability of C-phycocyanin colorant by extrusion encapsulation.
C-phycocyanin (C-PC) a blue color phycobiliproteins used as a food colorant, therapeutics, medicines, health food and biomarkers. In the present study, morphological property of encapsulated C-PC and its stability under various conditions like temperature, pH conditions are discussed. Microencapsulated droplets formed by extrusion found to be spherical with average size 1.2 ± 0.1 mm. SEM micrographs of freeze dried encapsulate confirmed the spherical shape. The effect of droplet formation with varying alginate percentage (1.5%, 2.0% and 2.5% w/v) was studied. In the stability test at 70 °C and 80 °C relative concentration (CR %) was found to be 86.89 and 88.19%, respectively. The encapsulated C-PC showed a slow degradation at higher temperature compared to without encapsulated C-PC which was confirmed by UV-visible absorbance. At 45 °C and 55 °C temperatures the stability was studied at various pH conditions (pH 4.5, 5.5, 6.5, and 7.0) and reported. Aggregation of C-PC protein will not change during encapsulation was confirmed by SDS-PAGE. FTIR analysis of encapsulate and the alginate depicted similar characteristics of the compound compared to that of native C-phycocyanin colorant. Microencapsulation improves the stability and increases the shelf life of colorant.


Femoral neck shortening and varus collapse after navigated fixation of intracapsular femoral neck fractures.
Assessing femoral neck shortening (FNS) and varus collapse after internal fixation of femoral neck fractures using computerized navigation (CN). Retrospective cohort study. Academic Level I trauma center. Forty-one patients who had healed femoral neck fractures treated with CN between the years 2003 and 2008. Average age was 65 years (range, 14-91 years). Thirty-six patients had nondisplaced fractures and five had displaced fractures. Screws were placed using CN in an inverted triangle formation Follow-up films were digitized into a PACS system, calibrated, and analyzed using CAD software. The following parameters were recorded: abductor lever arm shortening (termed x), corresponding vertical femur shortening (termed y), and the resultant femoral neck shortening vector (z). Fifteen patients were available for clinical outcome measures by the means of SF-12 survey Significant FNS of the x component (greater than 5 mm) occurred in 30 of 42 (71%) patients with severe shortening (greater than 10 mm) in 25% of the patients. Significant y shortening occurred in 43% of the patients and severe shortening in 17%. Overall (z) femoral neck shortening occurred in 56% of the patients with severe shortening in 22% of patients. Varus collapse (greater than 5°) did not occur in any patient. Screw pullout (greater than 5 mm) occurred in 17 (41%) patients. Seven patients required late (greater than 6 months) arthroplasty postoperatively. FNS did not significantly correlate with fracture type, quality of reduction, age, or neck shaft angle. SF-12 results were negatively correlated with overall FNS. Our results show a high degree of FNS associated with the use of CN for fixation of femoral neck fractures, similar to recently published series using nonnavigated implants. However, no varus collapse occurred in our series. Our preliminary clinical data show a trend toward an adverse effect of FNS on quality-of-life measures.


Cordyceps militaris induces the IL-18 expression via its promoter activation for IFN-gamma production.
Cordyceps militaris, one of traditional herbal ingredient in oriental medicine, has been known to promote anticancer and immunomodulatory activities in vitro and in vivo. However, the biological mechanism of anticancer activity has been unknown. To investigate the effect of Cordyceps militaris extract on expression of interferon gamma (IFN-gamma) through interlukin-18 (IL-18) induction and its biological mechanism in vitro and in vivo. Mice were administrated orally with solution extracted from Cordyceps militaris. The transcription level of IL-18 and IFN-gamma production were measured by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. RAW 264.7 cells were transiently transfected with pCATp1 and pCATp2 for IL-18 promoter functional analysis. Cordyceps militaris extracts treatment significantly induced level of IL-18 transcription in mouse brain and liver and enhanced IL-18 transcription level and activated the IFN-gamma production in RAW 264.7 cells. Furthermore, Cordyceps militaris extract led to increase the activity of pCATp1 construct containing the 5' franking region of IL-18 promoter in RAW 264.7 cells. Cordyceps militaris extract induced IL-18 mRNA level via enhancing of P1 promoter region result in activation of IFN-gamma production, indicating its potential as an immune activator or anticancer drug.


Mechanisms of ageing: public or private?
Ageing--the decline in survival and fecundity with advancing age is caused by damage to macromolecules and tissues. Ageing is not a programmed process, in the sense that no genes are known to have evolved specifically to cause damage and ageing. Mechanisms of ageing might therefore not be expected to be as highly conserved between distantly related organisms as are mechanisms of development and metabolism. However, evidence is mounting that modulators of the rate of ageing are conserved over large evolutionary distances. As we discuss in this review, this conservation might stem from mechanisms that match reproductive rate to nutrient supply.


Understanding the Benefit of Magnetic Resonance-guided Adaptive Radiotherapy in Rectal Cancer Patients: a Single-centre Study.
Neoadjuvant chemoradiotherapy followed by surgery is the mainstay of treatment for patients with rectal cancer. Standard clinical target volume (CTV) to planning target volume (PTV) margins of 10 mm are used to accommodate inter- and intrafraction motion of target. Treating on magnetic resonance-integrated linear accelerators (MR-linacs) allows for online manual recontouring and adaptation (MRgART) enabling the reduction of PTV margins. The aim of this study was to investigate motion of the primary CTV (CTVA; gross tumour volume and macroscopic nodes with 10 mm expansion to cover microscopic disease) in order to develop a simultaneous integrated boost protocol for use on MR-linacs. Patients suitable for neoadjuvant chemoradiotherapy were recruited for treatment on MR-linac using a two-phase technique; only the five phase 1 fractions on MR-linac were used for analysis. Intrafraction motion of CTVA was measured between pre-treatment and post-treatment MRI scans. In MRgART, isotropically expanded pre-treatment PTV margins from 1 to 10 mm were rigidly propagated to post-treatment MRI to determine overlap with 95% of CTVA. The PTV margin was considered acceptable if overlap was >95% in 90% of fractions. To understand the benefit of MRgART, the same methodology was repeated using a reference computed tomography planning scan for pre-treatment imaging. In total, nine patients were recruited between January 2018 and December 2020 with T3a-T4, N0-N2, M0 disease. Forty-five fractions were analysed in total. The median motion across all planes was 0 mm, demonstrating minimal intrafraction motion. A PTV margin of 3 and 5mm was found to be acceptable in 96 and 98% of fractions, respectively. When comparing to the computed tomography reference scan, the analysis found that PTV margins to 5 and 10 mm only acceptably covered 51 and 76% of fractions, respectively. PTV margins can be reduced to 3-5 mm in MRgART for rectal cancer treatment on MR-linac within an simultaneous integrated boost protocol.


A Ukrainian infant with giant coronary aneurysms: A case report and literature review.
COVID may manifest multisystem inflammatory syndrome in children (MIS-C) which mimics Kawasaki disease (KD). Differentiating KD and MIS-C is difficult. Immunomodulatory treatment should be initiated promptly without accurate diagnosis. A febrile Ukrainian infant developed giant aneurysms in coronary arteries. Differentiating between Kawasaki disease and multisystem inflammatory syndrome in children was difficult. In both illnesses, coronary aneurysm may develop unless treated promptly. Therefore, guidelines should synthesize these clinical entities so that treatment can be initiated before rigorous diagnosis.


Motion aftereffect with flickering test stimuli depends on adapting velocity.
Temporal tuning property of motion aftereffect (MAE) with flickering test stimuli (flicker MAE) was examined. Using sinusoidal gratings of several spatial frequencies (SF), MAE strength was measured for various adapting temporal frequencies (TF). Unlike the traditional MAE with static test field, the results indicated that flicker MAE did not depend on TF. Rather, when plotted as a function of velocity, the peaks had approximately the same adapting velocity of 5-8 deg/sec for all SF conditions tested, suggesting velocity dependence. This is further support of the idea that the two kinds of MAE are of different origin and suggests a higher origin of flicker MAE, perhaps in the area MT or MST.


What every otolaryngologist should know about hearing aids.
The otolaryngologist does not have to fit hearing aids, but he does have to know with a broad encompassing view what is being done by the hearing aid dispenser and the audiologist in regards to hearing aid fitting and selection. The acquisition of a hearing aid is part of the general care for the hard of hearing. In this particular case, the otolaryngologist should always be the "Captain of the Ship." With him, as paramedical advisors and assistors, are the audiologist and the hearing aid dispenser. The ultimate responsibility of the members of this team to see that the patient is properly fitted and cared for is with the otolaryngologist. When problems exist with improper diagnosis or care, the medical-legal responsibility falls on the shoulders of the otolaryngologist. Having an audiologist work with the otolaryngologist is most desirable for the measurement and recommendations for the hearing aid. The new FDA regulations require an otolaryngologic examination prior to fitting hearing aids, except for personal and religious reasons. Children under 18 years of age require both a medical and audiologic examination. To simplify conversation with other members of this team, one should have some basic concepts clarified: 1) The nature of a hearing aid. 2) The concepts and nomenclature used in and for probably 90% of all descriptions regarding hearing aids. 3) Types of aids. 4) Coupling methods which involve ear molds, tubes, vents, and inserts. 5) Types of fittings, whether cross, bi-cross, monaural, etc. 6) Distortion. 7) Measurements. 8) Problems in fitting of hearing aids. It is reasonable to assume that adequate background in these simple basic concepts regarding hearing aids will permit the otolaryngologist to supervise and understand the nature of some of the complaints made by patients. It is totally desirable that a patient be seen by an otolaryngologist prior to being fit with a hearing aid. This can be accomplished by education of the public by the otolaryngologist.


Study of an Arctic blowing snow-induced bromine explosion event in Ny-Ålesund, Svalbard.
Bromine explosion events (BEEs) are important processes that influence the atmospheric oxidation capacity, especially in the polar troposphere during spring. Although sea ice surface is thought to be a significant bromine source, bromine release mechanisms remain unclear. High-resolution ground-based observations of reactive bromine, such as BrO, are important for assessing the potential impacts on tropospheric ozone and evaluating chemical models. However, previous model studies paid little attention to Svalbard, which is surrounded by both open ocean and sea ice. In this paper, we present continuous BrO slant column densities and vertical column densities derived by Multi-Axis Differential Optical Absorption Spectroscopy deployed at Ny-Ålesund (78.92°N, 11.93°E) in March 2017. We focused on one BEE in mid-March, during which the vertical column densities of BrO surged from 4.26 × 1013 molecular cm-2 to the peak at 1.23 × 1014 molecular cm-2 on March 17, surface ozone depleted from a background level of 46.25 parts per billion by volume (ppbv) to 13.9 ppbv. This case study indicates that the BEE was strongly associated with blowing snow induced by the cyclone systems that approached Svalbard from March 14 to 18. By considering meteorological conditions, sea ice coverage, and airmass trajectory history, we demonstrate that sea salt aerosols (SSAs) from blowing snow on sea ice, rather than from open ocean, are attributed to the occurrence of this BEE. Model results from a parallelized-tropospheric offline model of chemistry and transport (p-TOMCAT) indicate that this BEE was mainly triggered by a blowing snow event associated with a low-pressure cyclone system. The concentration of blowing-snow-sourced SSAs surged to peak when the airmass pass across the sea-ice-covered area under high wind speed, which is a critical factor in the process of bromine explosion observed in Ny-Ålesund. Due to the coarse resolution, the possible delayed timing of bromine release from SSA and the model-data discrepancies still exist.


Extracellular superoxide dismutase polymorphism in mice.
In this study, we describe a previously unrecognized murine extracellular superoxide dismutase (ecSOD) allele and examine its distribution among various strains and its effect on the ecSOD phenotype. Polymerase chain reaction analysis of genomic and cDNA from apolipoprotein E/LDLR-/- mice indicates the presence of 2 distinct transcripts for this enzyme independent of the extent of atherosclerosis or age. Sequencing and genotyping analyses reveal the presence of 2 alleles for ecSOD. One is a short variant with a 10-base pair deletion in the 3'UTR, accompanied by a single nucleotide substitution (position 61) found in the 129P3/J strain of mice. By contrast, all other strains examined carry the long form. Both free and heparin-releasable ecSOD activities in the 129P3/J strain are more than 3-fold higher than those in the C57Bl/6 mice. Corresponding differences in plasma enzyme mass are observed by immunoblotting. A clear allele dose effect can be observed in F2 hybrids of these 2 strains; free and total ecSOD activities in mice homozygous for the short allele are twice those of mice homozygous for the long allele, with the heterozygote values in between. These data clearly demonstrate the allele-specific effects on the ecSOD phenotype independent of other strain-specific factors and underline the need for backcrossing of genetically modified mice.


Association between the presence of protein bands in ram seminal plasma and sperm tolerance to freezing.
This study evaluated associations between the presence of protein bands in ram seminal plasma and the quality of sperm frozen with distinct extenders. Ejaculates were frozen in a Tris-egg yolk based extender, including either 5% glycerol or 100mM trehalose. Seminal plasma samples were submitted to unidimensional electrophoresis. Pre-freezing and post-thawing sperm quality was similar between extenders (P>0.05). A total of 26 bands were identified in ram seminal plasma. Pre-freezing sperm motility was increased when the 15, 19 and 80kDa bands were present in seminal plasma (P<0.05). The presence of an 11kDa band in seminal plasma was associated with reduced pre-freezing membrane integrity (P<0.05). After thawing, both sperm motility and membrane integrity were reduced when a 24kDa band was present in seminal plasma (P<0.05). Post-thawing acrosome integrity was greater in the presence of a 31kDa band in seminal plasma (P<0.05). Regardless of the cryoprotectant included in the freezing extender, these six bands may be potential markers for ram sperm tolerance to freezing.


Orange juice and its major polyphenol hesperidin consumption do not induce immunomodulation in healthy well-nourished humans.
Polyphenols exert a variety of biological properties, including antioxidant, immunomodulatory and antigenotoxic effects. In a randomized crossover study in healthy men, we investigated the effects of orange juice and its major polyphenolic compound hesperidin on a panel of immune cell functions, including cytokine secretion by leukocytes, lytic activity of NK cells, and the Reactive Oxygen Species (ROS) burst by polymorphonuclear neutrophil cells (PMN). The protocol design was divided into three 4-week treatment periods separated by 3-week wash-out intervals, for total study duration of 18 weeks. During treatment periods, volunteers (n = 24) consumed daily 500 mL of orange juice, or an isocaloric control beverage with hesperidin (292 mg in a capsule), or of the same control beverage with a placebo. Whatever the intake was, no variations were recorded on leukocyte subset distributions (PMN, B and T lymphocytes, NK cells and monocytes), ROS production by stimulated PMNs, lytic activity of NK cells or cytokine production capacity of leukocytes in well-nourished healthy volunteers. We show that consumption within the usual daily intake range of orange juice and its major polyphenol hesperidin do not induce immunomodulation of cell immune function in healthy well-nourished humans.


Perioperative risk factors predict one-year mortality in patients with acute type-A aortic dissection.
The goal of this study was to analyze perioperative risk factors to predict one- year mortality after operation for acute type A aortic dissection (AAD). A total of 121 consecutive patients undergoing Stanford type A AAD surgery in Beijing Anzhen Hospital were enrolled. Preoperative clinical and laboratory data from patients were collected. Multivariable Cox regression analysis showed that significant factors associated with increased one-year mortality were elder age (year) (hazard ratio (HR) 1.0985; 95% confidence interval (CI) 1.0334-1.1677), intraoperative blood transfusion ≥2000 mL (HR 8.8081; 95% CI 2.3319-33.2709), a higher level of serum creatinine (μmol/L) at postoperative one day (HR 1.0122; 95% CI 1.0035-1.0190) and oxygenation index (OI) < 200 (mmHg) at the end of surgery (HR 5.7575; 95% CI 1.1695-28.3458). In this study, perioperative risk factors to predict one-year prognosis are age, intraoperative blood transfusion ≥2000 mL, postoperative OI < 200 mmHg and level of postoperative serum creatinine. The results aid in the comprehension of surgical outcomes and assist in the optimization of treatment strategies for those with perioperative risk factors to decrease one-year mortality.


Assumptions on decision making and environment can yield multiple steady states in microbial community models.
Microbial community simulations using genome scale metabolic networks (GSMs) are relevant for many application areas, such as the analysis of the human microbiome. Such simulations rely on assumptions about the culturing environment, affecting if the culture may reach a metabolically stationary state with constant microbial concentrations. They also require assumptions on decision making by the microbes: metabolic strategies can be in the interest of individual community members or of the whole community. However, the impact of such common assumptions on community simulation results has not been investigated systematically. Here, we investigate four combinations of assumptions, elucidate how they are applied in literature, provide novel mathematical formulations for their simulation, and show how the resulting predictions differ qualitatively. Our results stress that different assumption combinations give qualitatively different predictions on microbial coexistence by differential substrate utilization. This fundamental mechanism is critically under explored in the steady state GSM literature with its strong focus on coexistence states due to crossfeeding (division of labor). Furthermore, investigating a realistic synthetic community, where the two involved strains exhibit no growth in isolation, but grow as a community, we predict multiple modes of cooperation, even without an explicit cooperation mechanism. Steady state GSM modelling of microbial communities relies both on assumed decision making principles and environmental assumptions. In principle, dynamic flux balance analysis addresses both. In practice, our methods that address the steady state directly may be preferable, especially if the community is expected to display multiple steady states.


Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat.
Impaired intestinal barrier function is observed in type 1 diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type 1 diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model. DP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose-mannitol test and ex vivo by measuring transepithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. Ileal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction-related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf-ß (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR. The HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered. Improved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect.


Persistence of maternal effects in baboons: Mother's dominance rank at son's conception predicts stress hormone levels in subadult males.
Dominance status and reproductive experience are maternal characteristics that affect offspring traits in diverse taxa, including some cercopithecine primates. Maternal effects of this sort are widespread and are sources of variability in offspring fitness. We tested the hypothesis that maternal dominance rank and reproductive experience as well as a male's own age and dominance rank predicted chronic fecal glucocorticoid (fGC) concentrations in 17 subadult wild male baboons, Papio cynocephalus (median age 6.5 years), in the Amboseli basin, Kenya. Among these variables, maternal dominance rank at a subadult male's conception was the sole significant predictor of the male's fGC and accounted for 42% of fGC variance; sons of lower ranking mothers had higher fGC than did those of high-ranking mothers. This result is striking because subadult male baboons are approximately 4-6 years past the period of infant dependence on their mothers, and are larger than and dominant to all adult females. In addition, many males of this age have survived their mothers' death. Consequently, the influence of maternal dominance rank persisted well beyond the stage at which direct maternal influence on sons is likely. Persistence of these major maternal influences from the perinatal period may signal organizational effects of mothers on sons' HPA axis. Although short-term, acute, elevations in GC are part of adaptive responses to challenges such as predators and other emergencies, chronically elevated GC are often associated with stress-related pathologies and, thereby, adverse effects on fitness components.


Synthesis and gastric antisecretory properties of allenic 16-phenoxy-omega-tetranor prostaglandin E analogs.
In order to improve the modest oral activity of PGE2 as an inhibitor of gastric acid secretion, analogs were prepared and tested orally in histamine-challenged rats. Insertion of a double bond at C-4, resulting in the 4,5-allene analog of PGE1, gave a small increase in activity. Introduction of the omega-tetranor-16-phenoxy lower sidechain, a modification known to enhance activity in the PGF series, gave an eight-fold increase in activity. The analog having both modifications (enprostil, 2) showed a six hundred-fold increase in oral antisecretory activity over PGE2, which may reflect a potentiation effect. Modification of enprostil at C-1 (various esters) and at C-11 (11-methyl, 11-deoxy) generally resulted in compounds of high activity while modifications at other sites generally resulted in significant reductions in activity.


Behavior problems, foster home integration, and evidence-based behavioral interventions: What predicts adoption of foster children?
Adoption is particularly important for foster children with special mental health needs who are unable to return home, as adoption increases parental support often critically needed by youth with mental health issues. Unfortunately, significant behavior problems frequently inhibit foster parents from adopting, and little is known about factors that predict adoption when a child has behavior problems. Previous research suggests that foster parent behavioral training could potentially increase rates of successful adoptions for pre-school-aged foster children with behavior problems (Fisher, Kim, & Pears, 2009), but this has not been previously tested in older samples. In older children, effective treatment of behavior problems might also increase adoption by reducing the interference of behavior problems and strengthening the child's foster home integration. This pilot study focused on this question by testing associations between behavior problems, foster home integration, an evidence-based foster parent intervention, and adoption likelihood. This study used an intent-to-treat design to compare foster home integration and adoption likelihood for 31 foster children with histories of abuse and neglect whose foster parents received a foster behavioral parenting intervention (see Chamberlain, 2003) or usual services. Random effect regression analyses were used to estimate outcomes across four time points. As expected, externalizing behavior problems had a negative effect on both integration and adoption, and foster home integration had an independent positive effect on adoption. Internalizing behavior problems (e.g., depression/anxiety) were not related to adoption or integration. However, the intervention did not have a direct effect on either foster home integration or adoption despite its positive effect on behavior problems. Results from this preliminary study provide further evidence of the negative effect of externalizing behavior problems on adoption. Its findings also suggest that foster home integration is an important dimension of foster home adaptation that appears particularly relevant to chances for adoption. While behavior problems appear to weaken foster home integration, integration is also an independent predictor of adoption likelihood. If these results are replicated in a larger study, consideration of foster home integration in case planning and future intervention studies focused on increasing permanency could potentially improve outcomes for foster children with behavior problems.


Flow-dependent regulation of angiopoietin-2.
Endothelial cells are constantly exposed to high or low shear stress in arteries and veins by the flowing blood. Angiopoietin-2 (Ang-2) is acting as a critical regulator of vessel maturation and endothelial cell quiescence. In this study, flow-dependent regulation of Ang-2 was analyzed in vitro and in vivo. Ang-2 mRNA, protein expression and release was upregulated by 24 h of low (1 dyne/cm(2)), but downregulated by high flow (30 dyne/cm(2)) in human endothelial cells. Increased endothelial NO synthase expression and NO formation was not affecting regulation of Ang-2 by low or high flow. Low and high flow increased VEGF-A expression. Inhibition of VEGFR-2 prevented upregulation of Ang-2 by low flow, but not downregulation of Ang-2 by high flow. Furthermore, upregulation of Ang-2 by VEGF was reduced by application of high flow. Forkhead box O (FOXO) transcription factor FOXO1 has been shown to regulate Ang-2 expression in endothelial cells. FOXO1 binding activity was reduced by high flow. Nuclear localization of transcription factor FOXO1 was not changed by low flow, but reduced by high flow. In vivo, Ang-2 was higher expressed in veins compared to arteries. Arterial ligation augmented Ang-2 expression in distal arterial low flow areas. Our results support a VEGF-dependent induction of Ang-2 in low flow areas, and FOXO1-dependent downregulation of Ang-2 in high flow areas. These data suggest a new mechanism of flow-dependent regulation of vessel stability and differentiation.


Functional characteristics of rat gastrocnemius and tibialis anterior muscles during growth.
Several morphological and functional characteristics of the rat gastrocnemius medialis and tibialis anterior muscle were studied in young, adult, and old rats to assess the influence of growth. Antagonist muscles were studied to determine how changes of muscle architecture and functional characteristics are influenced by the demands of increased body weight and by the specific roles of these muscles in locomotion. Both muscles change drastically, for instance, in muscle length, volume, physiological cross-sectional area aponeurosis length, and their muscular geometry changes allometrically for both muscles. The relationships between muscle length, distance between origin and insertion, tendon length, and tibial length also change with growth. Both muscles are rather pennate, so that the increase of physiological cross-sectional area is a major factor in the determination of muscle length. No significant difference could be shown for fundamental physiological characteristics (i.e., functional characteristics normalized for muscular dimensions such as maximal work per unit volume). The changes of morphological and functional variables of both muscles parallel each other as is apparent from the index of antagonist characteristics, which is constant for all variables studied with the exception of muscle volume and tendon length. Consequently, the considerable and similar changes of TA and GM morphology and functional characteristics that take place during growth from approximately four weeks postnatally is not caused by changes of muscular material but by changes of the amount and architectural arrangement of the material involved.


Isolation and electrophoretic identification of exogenous histone from rat blood plasma.
Histone fractions H1, (H2b+H2a) and H4 were isolated from rat blood plasma and electrophoretically identified 5 min after i.v. exogenous histone application.


Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment.
Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-exenatide antibodies and potential effects on efficacy and safety. Data from intent-to-treat patients in 12 controlled (n = 2225,12-52 weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30 weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52 weeks) were analysed. Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, exenatide BID; -1.6% and -1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres. Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide.


Combined surgical and endovascular removal of thrombus entirely occluding a bifurcated aortic stent-graft.
To explore a method combining interventional, endovascular, and conventional surgical techniques for treating a completely occluded bifurcated stent-graft after endovascular aortic aneurysm repair. A 60-year-old patient underwent endovascular repair of an abdominal aortic aneurysm (AAA) with a Talent bifurcated stent-graft. Five months later, after chronic thrombotic occlusion of the right iliac limb, he presented with acute occlusion of the entire stent-graft. Local intra-arterial infiltration thrombolysis successfully reconstituted flow through the main aortic segment and left iliac limb. With a combination of conventional surgical and intraoperative endovascular procedures, thrombectomy and recanalization of the right iliac limb was completed by stenting a severe stenosis of the proximal iliac limb. A combination of techniques may be essential for successful management of thrombotic complications after endovascular AAA repair.


Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids.
Anti-inflammatory glucocorticoids inhibit prostaglandin (PG) biosynthesis by preventing arachidonic acid release from phospholipids rather than inhibiting the cyclooxygenase. As in other cells, this steroid action depends on receptor occupation and de novo protein/RNA biosynthesis. We have previously shown in guinea pig perfused lungs and rat peritoneal leukocytes that the effect of steroids in PG generation is mediated by an uncharacterized 'second messenger'. Now, we report that this factor (which we have named 'macrocortin') is an intracellular polypeptide whose release and synthesis are stimulated by steroids. Macrocortin derived from rat peritoneal leukocytes is very similar to that released from guinea pig lungs.