Robotic-Assisted Transabdominal Inferior Retroperitoneal Approach: an Alternative to Cattell-Braash Maneuver.
The Cattell-Braasch maneuver has been widely used to provide adequate exposure for aorto-caval space (ACS) since the 1960s. Given its requirement of complex visceral mobilization and significant physiological disturbance, we proposed a new alternative surgical technique to access ACS: the transabdominal inferior retroperitoneal approach (TIRA) with robotic assistance. Patients were placed in the Trendelenburg position, and the retroperitoneum was accessed from the iliac artery level and dissected toward the 3rd and 4th portion of the duodenum along the anterior surface of IVC and aorta. TIRA has been used in 5 consecutive patients at our institution whose tumors were located in the ACS below the level of SMA origin. The tumor sizes ranged from 1.7 to 5.6 cm. The median OR time was 192 min with a median EBL of 5 ml. Four out of the five patients passed flatus before or on post operative day (POD) 1, and the other patient passed flatus at POD2. The shortest length of stay was < 24 h, and the longest was 8 days due to pre-existing pain (the median length of stay was 4). The proposed robotic-assisted TIRA procedure is designed for tumors in the inferior portion of ACS, specifically for the tumor involving D3, D4, para-aortic, para-caval, and kidney regions. Since this approach does not involve organ mobilization and all the dissections are following an avascular plane, it can be easily adapted to laparoscopic and/or open surgery setting.


Retropharyngeal abscess: recent trends.
Retropharyngeal abscess (RPA) is relatively rare today. A study of 17 cases of RPA treated at our hospital in the past 10 years showed a shift in the disease from children below 6 years of age (41%) to older children and adults (58%). Upper respiratory tract infection (URTI) was found to be the commonest (52%) aetiological predisposing factor in all age groups. Other aetiological factors were septicaemia (11%) in children below the age of 6 years and trauma due to foreign body (35%) in the older children and adult age groups. Klebsiella, Staphylococcus and Streptococcus were the commonest species of microorganisms grown from pus. The changing clinical trends, microbiology, choice of antibiotics, usefulness of radiology, and complications of this potentially fatal illness are discussed.


The Effect of Ethnicity on Human Axillary Odorant Production.
Previous findings from our laboratory highlighted marked ethnic differences in volatile organic compounds (VOCs) from cerumen among individuals of Caucasian, East Asian, and African-American descent, based, in part, on genetic differences in a gene that codes for a transport protein, which is a member of the ATP-binding cassette transporter, sub-family C, member 11 (ABCC11). In the current work, we hypothesized that axillary odorants produced by East Asians would differ markedly from those obtained from individuals of European or African descent based on the pattern of ethnic diversity that exists in ABCC11. Using gas chromatography/mass spectrometry (GC/MS) we examined differences in axillary odorant VOCs among 30 individuals of African-American, Caucasian, and East Asian descent with respect to their ABCC11 genotype. While no qualitative differences in the type of axillary odorants were observed across ethnic groups, we found that characteristic axillary odorants varied quantitatively with respect to ethnic origin. We propose that ABCC11 is not solely responsible for predicting the relative amounts of volatiles found in axillary secretions and that other biochemical pathways must be involved.


Cortical dynamics of figure-ground segmentation: shine-through.
The shine-through effect occurs when a brief offset vernier target is followed by a grating of non-offset vernier elements. Rather than mask the target, this stimulus sequence produces a percept of the target vernier occluding the mask elements. We analyzed the dynamics of the 3D LAMINART model of depth perception and found that it explains the appearance of shine-through for these stimuli. The model explanation proposes that shine-through is due to a combination of false binocular disparity matches between the target and the central element of the mask, and a weakening of between disparity competition due to spatial competition and boundary grouping. Simulations of the model demonstrate that its behavior closely matches empirical data on the properties of shine-through. The model is contrasted with an alternative explanation of shine-through, and novel mask conditions are studied that allow for empirical tests of the model hypotheses.


[Identification of the cells expressing neural markers in normal and pathological human dental pulp].
This work presents the results of a immunohistochemical study, performed in order to identify the cells in human dental pulp which express neural markers. Population of cells expressing neuron-specific enolase, synaptophysin, and chromogranin A, which were stained by paraldehyde-fuchsin, was demonstrated in subodontoblastic layer of the dental pulp. Changes the number, morphological and functional characteristics during development of caries and pulpitis in combination with periodontitis are described.


Safety of free fibula flap harvest in IIIA and IIIB tibio-peroneal trunk variations.
In head and neck cancer malignancies, free fibula flap is the gold standard for reconstruction of segmental bone defects owing to its predictable anatomy, long bone length, and feasibility for multiple osteotomies. However, sometimes because of variations in anatomy of tibio-peroneal trunk, it is a dilemma for the surgeons to use free fibula flap for reconstruction. This case series aimed to evaluate the safety of harvest of fibula in such cases in terms of acute and chronic donor-site complications. A retrospective study was conducted from January 2018 to May 2021. All the patients with tibio-peroneal trunk anomaly, diagnosed during surgery, who underwent successful harvest of the free fibula were included in the study and analyzed for the early major and minor donor wound complications, long-term donor complications, and late functional deficit using the Foot and Ankle Disability Index (FADI). Out of 714 free fibulae operated, 26 patients (3.6%) had such tibio-peroneal trunk variations: 22 (2.9%) cases of type III A and B anomalies and 4 (0.56%) cases of type III C anomalies. The average FADI score was 95.3%. No one had any difficulty in personal care and activity of daily living. The free fibula flap can be safely harvested in patients with type III A and B anomalies if vascularity of foot after clamping of peroneal vessels is good and anterior tibial vessels are normal.


Evolution, ecology and management of resistance in Helicoverpa spp. to Bt cotton in Australia.
Prior to the widespread adoption of two-gene Bt cotton (Bollgard II®) in Australia, the frequency of resistance alleles to one of the deployed proteins (Cry2Ab) was at least 0.001 in the pests targeted namely, Helicoverpa armigera and Helicoverpa punctigera. In the 7 years hence, there has been a statistically significant increase in the frequency of alleles conferring Cry2Ab resistance in field populations of H. punctigera. This paper reviews the history of deploying Bt cotton in Australia, the characteristics of the isolated Cry2Ab resistance that likely impact on resistance evolution, aspects of the efficacy of Bollgard IIχ, and the behavioural ecology of Helicoverpa spp. larvae as it pertains to resistance management. It also presents up-to-date frequencies of resistant alleles for H. punctigera and reviews the same information for H. armigera. This is followed by a discussion of current resistance management strategies. The consequences of the imminent release of a third generation product that utilizes the novel vegetative insecticidal protein Vip3A are then considered. The area planted to Bt-crops is anticipated to continue to rise worldwide and many biotechnical companies intend to add Vip3A to existing products; therefore the information reviewed herein for Australia is likely to be pertinent to other situations.


Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Talaromyces marneffei and Cytomegalovirus Infections in an HIV-Infected Patient.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening syndrome led by a highly stimulated but invalid immune response, and Talaromyces marneffei (T. marneffei) is an opportunistic infection with high mortality commonly among acquired immunodeficiency syndrome (AIDS) patients. Here is a rare case, in which secondary HLH is caused by dual infections of T. marneffei and cytomega-lovirus (CMV). A 15 year old man with a 20-day history of fatigue and intermittent fever (maximum 41.0℃) was admitted to the department of infectious diseases. Marked hepatosplenomegaly and pulmonary infection were detected by computed tomography. Examination of peripheral blood and bone marrow (BM) smears provided clues pointing toward T. marneffei infection, and indicated prominent hemophagocytosis. Cytomegalovirus (CMV) and T. marneffei infections were confirmed by CMV quantitative nucleic acid testing and culture of blood and bone marrow, respectively. A diagnosis of acquired HLH caused by dual infections of T. marneffei and CMV was established because 5 of the 8 HLH diagnostic criteria were met. The case highlights the contribution of the morphological examination on peripheral blood and bone marrow smears in the diagnosis, which sometimes are the only locations that HLH and T. marneffei can be diagnosed.


Detection of phylogenetically informative polymorphisms in the entire euchromatic portion of human Y chromosome from a Sardinian sample.
Next-Generation Sequencing methods have led to a great increase in phylogenetically useful markers within the male specific portion of the Y chromosome, but previous studies have limited themselves to the study of the X-degenerate regions. DNA was extracted from peripheral blood samples of adult males whose paternal grandfathers were born in Sardinia. The DNA samples were sequenced, genotyped and subsequently analysed for variant calling for approximately 23.1 Mbp of the Y chromosome. A phylogenetic tree was built using Network 4.6 software. From low coverage whole genome sequencing of 1,194 Sardinian males, we extracted 20,155 phylogenetically informative single nucleotide polymorphisms from the whole euchromatic region, including the X-degenerate, X-transposed, and Ampliconic regions, along with variants in other unclassified chromosome intervals and in the readable sequences of the heterochromatic region. The non X-degenerate classes contain a significant portion of the phylogenetic variation of the whole chromosome and their inclusion in the analysis, almost doubling the number of informative polymorphisms, refining the known molecular phylogeny of the human Y chromosome.


Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo.
Once programmed to acquire a specific identity and function, cells rarely change in vivo. Neurons of the mammalian central nervous system (CNS) in particular are a classic example of a stable, terminally differentiated cell type. With the exception of the adult neurogenic niches, where a limited set of neuronal subtypes continue to be generated throughout life, CNS neurons are born only during embryonic and early postnatal development. Once generated, neurons become permanently post-mitotic and do not change their identity for the lifespan of the organism. Here, we have investigated whether excitatory neurons of the neocortex can be instructed to directly reprogram their identity post-mitotically from one subtype into another, in vivo. We show that embryonic and early postnatal callosal projection neurons of layer II/III can be post-mitotically lineage reprogrammed into layer-V/VI corticofugal projection neurons following expression of the transcription factor encoded by Fezf2. Reprogrammed callosal neurons acquire molecular properties of corticofugal projection neurons and change their axonal connectivity from interhemispheric, intracortical projections to corticofugal projections directed below the cortex. The data indicate that during a window of post-mitotic development neurons can change their identity, acquiring critical features of alternative neuronal lineages.


The action of purified lysophospholipases on microsomal membrane-bound lysophosphatidylcholine.
Rat liver membranes were labelled by intraperitoneal injection of [Me-14C]choline chloride. Isolated microsomal membranes were briefly treated with pancreatic phospholipase A2 to produce different levels of membrane-bound lysophosphatidylcholine. The hydrolysis of this lysophosphatidylcholine by two purified lysophospholipases from beef liver was studied. The specific activity of enzyme I at saturating membrane concentrations appeared to increase linearly with the lysophosphatidylcholine level in the membranes until the lysoderivative represented 15% of the original phosphatidylcholine. In contrast, the specific activity of enzyme II was independent of the lysophosphatidylcholine level, at least in the range of 4.9-34.0% tested. These different kinetics are discussed in terms of the possible functions of both enzymes in liver.


Nuclear translocation of the heterotrimeric CCAAT binding factor of Aspergillus oryzae is dependent on two redundant localising signals in a single subunit.
The CCAAT-binding complex in the Aspergillus species, also known as the Hap complex, consists of at least three subunits, namely HapB, HapC and HapE. Each Hap subunit contains an evolutionary conserved core domain. Recently, we have found that the HapC and HapE subunits do not carry a nuclear localisation signal. Furthermore, when in complex with HapB, they are transported into the nucleus via a 'piggy back mechanism' in A. nidulans. To extend our findings to other filamentous fungi, we examined the nuclear localisation of the A. oryzae Hap subunits by analysing several GFP fusion proteins with these Hap subunits in the hap deletion strains of A. nidulans. The nuclear translocation of the A. oryzae complex was found to be dependent on two redundant localising signals in HapB.


Effects of depressant amino acids and antagonists on an in vitro spinal cord preparation from the adult rat.
A mature sacrococcygeal in vitro spinal preparation from the rat has been used to demonstrate effects of neutral amino acids and their antagonists. gamma-Aminobutanoate (GABA), glycine and taurine (0.5-5 mM) produced dose-dependent depression of spontaneous paroxysmal activity generated in Mg2+ -free medium. The depressant effect of GABA was antagonised selectively by picrotoxin (25-50 microM) and the depressant effects of glycine and taurine were antagonised selectively by strychnine (0.2 microM). Glycine (0.5-5 mM) had a dose-dependent depolarizing action which was present at the central ends of isolated ventral roots. gamma-Aminobutanoate and taurine, had only weak depolarizing actions on ventral root fibres. Depolarizing responses to glycine showed a marked fading. Reduction in the fading appeared to be responsible for a paradoxical potentiation of glycine-induced depolarizations, which occurred in the presence of strychnine (0.2-2 microM). Strychnine (2-10 microM), picrotoxin (10-50 microM) or bicuculline (10 microM) had little or no effect on the amplitude, duration or latency of the monosynaptic component of ventral root reflexes evoked by supramaximal stimulation of dorsal roots (DR-VRP). However all three antagonists introduced slow, NMDA receptor mediated, components to these ventral root potentials. Picrotoxin and bicuculline, but not strychnine, reversibly depressed the dorsal root potential evoked from an adjacent dorsal root (DR-DRP). The depressant actions of 2-amino-5-phosphonopentanoate (AP5), kynurenate and 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) revealed both NMDA and non-NMDA receptor mediated components in the dorsal root potential.


Multicenter Study on COVID-19 Lung Computed Tomography Segmentation with varying Glass Ground Opacities using Unseen Deep Learning Artificial Intelligence Paradigms: COVLIAS 1.0 Validation.
Variations in COVID-19 lesions such as glass ground opacities (GGO), consolidations, and crazy paving can compromise the ability of solo-deep learning (SDL) or hybrid-deep learning (HDL) artificial intelligence (AI) models in predicting automated COVID-19 lung segmentation in Computed Tomography (CT) from unseen data leading to poor clinical manifestations. As the first study of its kind, "COVLIAS 1.0-Unseen" proves two hypotheses, (i) contrast adjustment is vital for AI, and (ii) HDL is superior to SDL. In a multicenter study, 10,000 CT slices were collected from 72 Italian (ITA) patients with low-GGO, and 80 Croatian (CRO) patients with high-GGO. Hounsfield Units (HU) were automatically adjusted to train the AI models and predict from test data, leading to four combinations-two Unseen sets: (i) train-CRO:test-ITA, (ii) train-ITA:test-CRO, and two Seen sets: (iii) train-CRO:test-CRO, (iv) train-ITA:test-ITA. COVILAS used three SDL models: PSPNet, SegNet, UNet and six HDL models: VGG-PSPNet, VGG-SegNet, VGG-UNet, ResNet-PSPNet, ResNet-SegNet, and ResNet-UNet. Two trained, blinded senior radiologists conducted ground truth annotations. Five types of performance metrics were used to validate COVLIAS 1.0-Unseen which was further benchmarked against MedSeg, an open-source web-based system. After HU adjustment for DS and JI, HDL (Unseen AI) > SDL (Unseen AI) by 4% and 5%, respectively. For CC, HDL (Unseen AI) > SDL (Unseen AI) by 6%. The COVLIAS-MedSeg difference was < 5%, meeting regulatory guidelines.Unseen AI was successfully demonstrated using automated HU adjustment. HDL was found to be superior to SDL.


Several variables of importance in the use of the cold pressor as a noxious stimulus in behavioral research.
To examine the effects of subject's sex, hand dominance, and spatial summation on cold pressor tolerance and discomfort, 80 subjects were randomly assigned to one of eight conditions using a 2 x 2 x 2 design. Analysis showed that females immersing the hand tolerated the stimulus significantly less time than males immersing the hand, females immersing the finger, or males immersing the finger. Female subjects reported significantly more pain than males, and subjects who immersed the hand reported significantly more pain than subjects who immersed the finger only. Implications are discussed.


Conducting ethical research in pediatrics: a brief historical overview and review of pediatric regulations.
Achieving proper balance between the social good that comes from performing research that involves children and offering the appropriate level of protection to children who participate in research is a significant challenge. As investigators design and implement research protocols, they should be aware of the ethical and legal requirements that govern research with human participants. This is especially true of research that involves children and other vulnerable groups. The welfare of children participating in research depends on knowledgeable, caring, and responsible investigators who place the well-being of the research participant above all other aspects of the research project. The purpose of this article is to provide a brief overview of the history of research involving children, to provide a basis for understanding the context within which the current federal regulations were written, and to provide an overview of the regulatory requirements that relate to research involving children. Good research is ethical research, and that requires investigators who take seriously the importance of participant welfare, meaningful informed consent, and respect for research participants.


GnRH agonist triggering: recent developments.
The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin(HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages, including virtually complete prevention of ovarian hyperstimulation syndrome(OHSS), the introduction of a surge of FSH in addition to the LH surge and finally the possibility to individualize luteal-phase supplementation based on ovarian response to stimulation. We maintain that the automatic HCG triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients.


The sealing effect of a fibrin tissue patch on the esophageal perforation area in primary repair.
The aim of this study was to investigate the efficacy of the fibrin tissue patch and to analyze its use in patients with esophageal perforation. We studied 28 patients who were diagnosed with esophageal perforation between January 1990 and January 2006 at Akdeniz University Hospital. Sixteen (57.14%) were male. The average age was 59 +/- 9 years. We performed surgery and primary repair reinforcement even if the diagnosis of esophageal perforation was late. Twenty-three (82.14%) perforations were the result of endoscopic instruments; spontaneous perforations occurred in three (10.71%) patients. Postoperative complication (Heller myotomy) caused perforation in one patient (3.57%) and blunt trauma in one patient (3.57%). Three (10.71%) patients had cervical perforation, and 25 (89.29%) patients had thoracic esophageal perforation. Twelve (42.86%) patients underwent emergency surgery (within the first 24 h). Ten (35.71%) patients underwent surgery within 48 h, and the remaining 6 (21.43%) underwent surgery after 48 h. Nine (32.14%) patients had primary repair, 7 (25%) had reinforcement of the primary repair with fibrin tissue patch, 7 (25%) had esophagectomy and gastric pull-up, and 2 (7.14%) had drainage and placement of metallic stents. In four patients of the nine who had primary repair, fistula complication was detected, whereas in only one of the seven who had reinforcement of the primary repair with fibrin tissue patch was a fistula detected. Three patients (10.71%), two of whom had Boerhaave's syndrome, died. Surgical primary repair with fibrin tissue patch is the most successful treatment option in the management of esophageal perforation.


Trace element levels in hashimoto thyroiditis patients with subclinical hypothyroidism.
The present study was conducted to evaluate the serum copper, zinc, magnesium, and selenium levels in patients with subclinical hypothyroidism in the iodine-rich region of Ankara, Turkey. The effects of hormone replacement therapy on these elements were also studied in these patients. Basal levels of selenium and iron in patients were significantly lower than control group (67.7 +/- 10.4 vs. 83.7 +/- 17.3 microg/dl, p = 0.02; 55.7 +/- 38 vs 275.7 +/- 24, P = 0.03 microg/dl). Serum magnesium levels were significantly higher in patient group (2.16 +/- 0.31 vs 1.95 +/- 0.13 mg/dl, P < 0.0001). There was a correlation between selenium levels with hsCRP (r = -0.408, p = 0.007). HsCRP levels in patients with selenium levels <80 microg/l (n = 31) was significantly higher than hsCRP levels in patients with selenium levels >80 microg/l (n = 12; 1.99 +/- 1.0; 1.02 +/- 0.9, p = 0.014). None of these biochemical risk factors and trace elements have changed after euthyroidism in patients with SH when compared to pretreatment levels. Selenium deficiency may contribute to cardiovascular disease risk in these patients.


Multiple distinct assemblies reveal conformational flexibility in the small heat shock protein Hsp26.
Small heat shock proteins are a superfamily of molecular chaperones that suppress protein aggregation and provide protection from cell stress. A key issue for understanding their action is to define the interactions of subunit domains in these oligomeric assemblies. Cryo-electron microscopy of yeast Hsp26 reveals two distinct forms, each comprising 24 subunits arranged in a porous shell with tetrahedral symmetry. The subunits form elongated, asymmetric dimers that assemble via trimeric contacts. Modifications of both termini cause rearrangements that yield a further four assemblies. Each subunit contains an N-terminal region, a globular middle domain, the alpha-crystallin domain, and a C-terminal tail. Twelve of the C termini form 3-fold assembly contacts which are inserted into the interior of the shell, while the other 12 C termini form contacts on the surface. Hinge points between the domains allow a variety of assembly contacts, providing the flexibility required for formation of supercomplexes with non-native proteins.


Echocardiography during submaximal isometric exercise in children with repaired coarctation of the aorta compared with controls.
Patients with repaired coarctation (RCoA) remain at higher risk of cardiac dysfunction, initially often only detected during exercise. In this study, haemodynamics of isometric handgrip (HG) and bicycle ergometry (BE) were compared in patients with RCoA and matched controls (MCs). Case-control study of 19 children with RCoA (mean age 12.9±2.3 years; mean age of repair 7 months) compared with 20 MC. HG with echocardiography followed by BE was performed in both groups. During HG (blood pressure) BP increased from 114±11/64±4 mm Hg to 132±14/79±7 mm Hg, without significant differences. During HG as well as BE, HR increased less in patients with RCoA. There were no significant differences in (left ventricle) LV dimensions or LV mass.The RCoA group had diastolic dysfunction: both at rest and during HG they had significantly higher transmitral E and A velocities and lower tissue Doppler E' and A' velocities. E/E' was higher, reaching statistical significance during HG (p<0001).Conventional parameters of systolic function (FS and EF) were similar at rest and HG. More sensitive tissue Doppler S' was significantly lower at rest in CoA subjects (5.1±1.5 cm/s vs 6.5±1±1 cm/s; p<0.01), decreasing further during HG by 5% in the CoA group (NS) while unchanged in controls. We provide first evidence that HG with echocardiography is feasible, easy and patient-friendly. A decreased systolic (tissue Doppler) and impaired diastolic LV function was measured in the RCoA group, a difference that tended to increase during HG.


Reference intervals for free thyroxine, total triiodothyronine, thyrotropin and thyroglobulin for Quebec newborns, children and teenagers.
Paediatric reference values, although essential for interpreting patients' results, are scarce. Moreover, they are often population- and instrument-dependent. We have measured free thyroxine (Free T(4)), total triiodothyronine (Total T(3)), thyroglobulin (Tg) and thyrotropin (TSH) in samples obtained from groups of newborns, children and adolescents. Blood samples collected from healthy children and teenagers (100 girls and 100 boys) of age groups ranging between 9-10, 11-14 and 15-17 years and selected randomly from a cohort representative of the Quebec population, were used. Samples from infants of age ranging between 1 day and 2 years (n = 99) were obtained from a hospital-based population with benign conditions unlikely to affect thyroid function. Variables were measured on the Access 2 immunosystem. Free T(4), Tg and TSH levels declined significantly with age. However, Total T(3) level presented a nonlinear variation with age, being lower in the first month of life.


Release of antibiotic resistant bacteria and genes in the effluent and biosolids of five wastewater utilities in Michigan.
The purpose of this study was to quantify the occurrence and release of antibiotic resistant genes (ARGs) and antibiotic resistant bacteria (ARB) into the environment through the effluent and biosolids of different wastewater treatment utilities including an MBR (Membrane Biological Reactor) utility, conventional utilities (Activated Sludge, Oxidative Ditch and Rotatory Biological Contactors-RBCs) and multiple sludge treatment processes (Dewatering, Gravity Thickening, Anaerobic Digestion and Lime Stabilization). Samples of raw wastewater, pre- and post-disinfected effluents, and biosolids were monitored for tetracycline resistant genes (tetW and tetO) and sulfonamide resistant gene (Sul-I) and tetracycline and sulfonamide resistant bacteria. ARGs and ARB concentrations in the final effluent were found to be in the range of ND(non-detectable)-2.33 × 10(6) copies/100 mL and 5.00 × 10(2)-6.10 × 10(5) CFU/100 mL respectively. Concentrations of ARGs (tetW and tetO) and 16s rRNA gene in the MBR effluent were observed to be 1-3 log less, compared to conventional treatment utilities. Significantly higher removals of ARGs and ARB were observed in the MBR facility (range of removal: 2.57-7.06 logs) compared to that in conventional treatment plants (range of removal: 2.37-4.56 logs) (p < 0.05). Disinfection (Chlorination and UV) processes did not contribute in significant reduction of ARGs and ARB (p > 0.05). In biosolids, ARGs and ARB concentrations were found to be in the range of 5.61 × 10(6)-4.32 × 10(9) copies/g and 3.17 × 10(4)-1.85 × 10(9) CFU/g, respectively. Significant differences (p < 0.05) were observed in concentrations of ARGs (except tetW) and ARB between the advanced biosolid treatment methods (i.e., anaerobic digestion and lime stabilization) and the conventional dewatering and gravity thickening methods.


Dissolved black carbon enhanced the aquatic photo-transformation of chlortetracycline via triplet excited-state species: The role of chemical composition.
Dissolved black carbon (DBC), widely distributed in the aquatic environments, can accelerate sunlight-driven photo-transformation of micropollutants, however the photosensitization mechanisms are not clear. Herein, the DBC was extracted from bamboo biochar and fractionated by molecular weight (i.e. <10 k, <3 k, and <1 k Da). The effects of DBC on chlortetracycline (CTC) photolysis behaviors, and the role of chemical composition (i.e., molecular weight and chemical structure) in DBC-mediated photo-transformation were investigated. The results showed that DBC could accelerate CTC photodegradation significantly. At low DBC concentrations (<6.0 mg C/L), the photodegradation rate constant of CTC increased from 0.0299 to 0.0416 min-1 with the increasing DBC concentration. Via quenching experiment, the triplet excited-state of DBC was identified as the dominant reactive intermediate with >90% contribution to total CTC photodegradation. In addition, it was found that the photosensitive efficiency of DBC increased as the molecular weight decreased, and the stronger photosensitization ability exhibited in DBC with low-molecular weight was potentially attributed to its higher content of carbonyl compounds. The observed photosensitive efficiency of DBC sharply decreased after reduction by NaBH4, further confirming the key role of carbonyl compounds in the photosensitization process. Moreover, based on the result of photoproducts, the amidogen in CTC was verified to be susceptible to react with 3DBC*.


Differentiation without mitosis in Dictyostelium discoideum.
Dictyoselium discoideum Ax-2 amoebae incubated in the presence of the microtubule inhibitor nocodazole, irreversibly lost their ability to multiply. Nocodazole-treated cells remained viable and RNA and protein synthesis continued for at least 48 h. When nocodazole-treated amoebae were allowed to develop on Millipore filters or on agar slides they differentiated with some delay when compared with controls. These results show that mitosis, naturally present during the developmental cycle of Dictyostelium discoideum Ax-2, is not indispensible for differentiation.


The structure and function of plant hemoglobins.
Plants, like humans, contain hemoglobin. Three distinct types of hemoglobin exist in plants: symbiotic, non-symbiotic, and truncated hemoglobins. Crystal structures and other structural and biophysical techniques have revealed important knowledge about ligand binding and conformational stabilization in all three types. In symbiotic hemoglobins (leghemoglobins), ligand binding regulatory mechanisms have been shown to differ dramatically from myoglobin and red blood cell hemoglobin. In the non-symbiotic hemoglobins found in all plants, crystal structures and vibrational spectroscopy have revealed the nature of the structural transition between the hexacoordinate and ligand-bound states. In truncated hemoglobins, the abbreviated globin is porous, providing tunnels that may assist in ligand binding, and the bound ligand is stabilized by more than one distal pocket residue. Research has implicated these plant hemoglobins in a number of possible functions differing among hemoglobin types, and possibly between plant species.


Effect of sex sorting on stallion spermatozoa: Heterologous oocyte binding, tyrosine phosphorylation and acrosome reaction assay.
The interest on sex sorting by flow cytometry on the equine industry has been increasing over the years. In this work, three different tests were performed in order to evaluate the membrane status of sorted stallion spermatozoa: assessment of binding ability to porcine oocytes, evaluation of acrosome integrity after stimulation with A23187, and detection of tyrosine phosphorylation. These evaluations were made after incubation for 0h, 1.5h and 3h in a capacitating medium. Sorted stallion spermatozoa attached similarly to the porcine oocytes, when compared with control samples. Sorted spermatozoa were more prone to undergo acrosome reaction (P<0.05), at the beginning and after 1.5h and 3h of incubation, and also had higher tyrosine phosphorylation of the tail (P<0.001), only at the beginning of the incubation period. Apparently sex sorted stallion spermatozoa are in a more advanced status of membrane destabilization, which could be associated with capacitation, although similar binding ability to porcine oocytes is maintained.


Neurocognitive testing in a murine model of mucopolysaccharidosis type IIIA.
Mucopolysaccharidosis type IIIA (MPS IIIA) is an inherited metabolic disorder caused by a lysosomal enzyme deficiency resulting in heparan sulphate (HS) accumulation and manifests with a progressive neurodegenerative phenotype. A naturally occurring MPS IIIA mouse model is invaluable for preclinical evaluation of potential treatments but the ability to effectively assess neurological function has proved challenging. Here, the aim was to evaluate a set of behaviour tests for their reliability in assessing disease progression in the MPS IIIA mouse model. Compared to wild-type (WT) mice, MPS IIIA mice displayed memory and learning deficits in the water crossmaze from mid-stage disease and locomotor impairment in the hind-limb gait assessment at late-stage disease, supporting previous findings. Declined wellbeing was also observed in the MPS IIIA mice via burrowing and nest building evaluation at late-stage disease compared to WT mice, mirroring the progressive nature of neurological disease. Excessive HS accumulation observed in the MPS IIIA mouse brain from 1 month of age did not appear to manifest as abnormal behaviours until at least 6 months of age suggesting there may be a threshold of HS accumulation before measurable neurocognitive decline. Results obtained from the open field and three-chamber sociability test are inconsistent with previous studies and do not reflect MPS IIIA patient disease progression, suggesting these assessments are not reliable. In conclusion, water cross-maze, hind-limb gait, nest building and burrowing, are promising assessments in the MPS IIIA mouse model, which produce consistent results that mimic the human disease.


Chemotherapy and antiangiogenesis--drug-specific, dose-related effects.
Dose-response effects of fluorouracil, paclitaxel, doxorubicin, cisplatin, methotrexate, cyclophosphamide and etoposide on VEGF165/164-mediated angiogenesis using the rat mesenteric-window angiogenesis assay are reported. VEGF is a pivotal pro-angiogenic factor in most tumors. Microvessel spatial extension, density, pattern formation and segment length were assessed quantitatively and objectively. A single i.v. injection of each drug was given at a low, intermediate or high dose, 7 days before sacrifice. All the drugs elicited significant responses in terms of one or more measured variables. Only paclitaxel, doxorubicin and cyclophosphamide significantly suppressed the overall angiogenic response (p < or = 0.0001, p < or = 0.0002 and p < or = 0.05, respectively), however. Taking toxicity into account, paclitaxel was more potent in inhibition of angiogenesis than the other agents. No clear correlation was found between drug half-life, the degree of toxic effects (in terms ofbody weight changes) and the antiangiogenic effect. The antiangiogenic effects were distinctly drug specific.


The economic impact of noise control.
This article has briefly summarized the cost of noise control for two standards under consideration by OSHA. Readers are encouraged to find ways to protect the hearing of workers in any way it can be done.


Wild-type amyloid beta 1-40 peptide induces vascular smooth muscle cell death independently from matrix metalloprotease activity.
Cerebral amyloid angiopathy (CAA) is an important cause of intracerebral hemorrhages in the elderly, characterized by amyloid-β (Aβ) peptide accumulating in central nervous system blood vessels. Within the vessel walls, Aβ-peptide deposits [composed mainly of wild-type (WT) Aβ(1-40) peptide in sporadic forms] induce impaired adhesion of vascular smooth muscle cells (VSMCs) to the extracellular matrix (ECM) associated with their degeneration. This process often results in a loss of blood vessel wall integrity and ultimately translates into cerebral ischemia and microhemorrhages, both clinical features of CAA. In this study, we decipher the molecular mechanism of matrix metalloprotease (MMP)-2 activation in WT-Aβ(1-40) -treated VSMC and provide evidence that MMP activity, although playing a critical role in cell detachment disrupting ECM components, is not involved in the WT-Aβ(1-40) -induced degeneration of VSMCs. Indeed, whereas this peptide clearly induced VSMC apoptosis, neither preventing MMP-2 activity nor hampering the expression of membrane type1-MMP, or preventing tissue inhibitors of MMPs-2 (TIMP-2) recruitment (two proteins evidenced here as involved in MMP-2 activation), reduced the number of dead cells. Even the use of broad-range MMP inhibitors (GM6001 and Batimastat) did not affect WT-Aβ(1-40) -induced cell apoptosis. Our results, in contrast to those obtained using the Aβ(1-40) Dutch variant suggesting a link between MMP-2 activity, VSMC mortality and degradation of specific matrix components, indicate that the ontogenesis of the Dutch familial and sporadic forms of CAAs is different. ECM degradation and VSMC degeneration would be tightly connected in the Dutch familial form while being two independent processes in sporadic forms of CAA.


[Wilson's disease in a black patient. Case report and brief literature review].
A Black patient with Wilson's disease is described. Clinical symptomatology and laboratory findings are reported and diagnosis, pathology, clinical picture and treatment of the disease are discussed.


Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells.
The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin-sensitive (MDA-MB-435) and -resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P-glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA-MB-435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [14C]paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [14C]paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [14C]paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors.


Initial and maintenance naltrexone treatment for alcohol dependence using primary care vs specialty care: a nested sequence of 3 randomized trials.
Naltrexone may improve success in primary care treatment of alcohol dependence (AD). This study tests naltrexone and primary care management (PCM) vs naltrexone and cognitive behavior therapy (CBT) and tests naltrexone maintenance among patients who respond to an initial course of naltrexone combined with PCM vs CBT. A nested sequence of 3 randomized trials was conducted. In study 1, 197 subjects with AD participated in a 10-week comparison of PCM and naltrexone (50 mg/d) vs CBT and naltrexone (50 mg/d). In study 2, 53 PCM responders from study 1 continued in a 24-week placebo-controlled study of maintenance naltrexone. In study 3, 60 CBT responders from study 1 continued in a 24-week placebo-controlled study of maintenance naltrexone and CBT. Study 1: No difference in the response to treatment; 84.1% (74/88) of the PCM patients and 86.5% (77/89) of the CBT patients avoided persistent heavy drinking. Percentage of days abstinent (PDA) declined over time for PCM vs CBT (P =.03). Study 2: Higher response maintenance for PCM and naltrexone (21/26, 80.8%) vs PCM and placebo (14/27, 51.9%; P =.03) and PDA declined more for the placebo group (P =.02). Study 3: The differences between naltrexone vs placebo on maintenance of response (25/30, 83.3% vs 21/30, 70.0%) or PDA did not reach statistical significance. Naltrexone yielded comparable results during the initial 10 weeks of treatment when combined with PCM or CBT. Maintenance of improvement was enhanced by continued naltrexone treatment in the PCM but not in the CBT arm.


[Bilateral traumatic carotid-cavernous fistula treated using an inflatable and detachable balloon].
The authors report a case of traumatic bilateral carotid-cavernous fistula successfully treated by inflatable and detachable balloon.


Influence of feeding formula and breast milk fortifier on lymphocyte subsets in very low birth weight premature newborns.
It is well known that breast-feeding protects the newborn from infectious diseases. This is especially important for very low birth weight preterm infants, whose immune systems are immature. In this study we investigated how a milk fortifier and replacement formula affected lymphocyte subsets in preterm infants. The study assessed the effects of different types of feeding (human milk, n = 14; fortified human milk, n = 16; formula, n = 14) on lymphocyte subsets in 44 very low birth weight preterm infants. For each baby, two consecutive blood samples were collected 7-10 days apart during the full enteral feeding period. For each sample, the percentages of CD3+ (pan-T), CD19+ (B-cell), CD4+ (T-helper), CD8+ (T-suppressor), and CD3-CD16/56+ (natural killer cell) lymphocytes were measured in a flow cytometer, and the absolute count for each subset was calculated based on the total lymphocyte count. Within each feeding group, the absolute numbers of each lymphocyte subset in the two consecutive samples were compared. Also, the mean absolute counts for each cell type were compared among the 3 groups for the first set of blood samples, and the same comparisons were made for the second set. The mean number of CD3-CD16/56+ cells in the formula-fed infants was significantly lower than the corresponding means in the groups fed human milk alone and fortified human milk (p = 0.037). The findings suggest that babies fed formula have different lymphocyte subset compositions than those fed breast milk or fortified breast milk.


Phenotype, growth regulation and cytokine transcription in Ovine Herpesvirus-2 (OHV-2)-infected bovine T-cell lines.
The causal agent of sheep-associated malignant catarrhal fever (MCF), Ovine Herpesvirus-2 (OHV-2), can be propagated in IL-2-dependent lymphoblastoid cell lines derived from diseased cattle and deer providing a useful model for the investigation of the pathogenesis of MCF. In this study, five interleukin-2 (IL-2)-dependent cell lines were established from affected cattle to examine their growth regulation and cytokine transcription. All cell lines expressed CD2, CD5 and CD25. Three of the cell lines were CD4+ and one CD8+, whereas one cell was of mixed CD4 and CD8 phenotye. The growth of these cell lines was reduced when cultured with antibody against CD25, the IL-2 receptor alpha subunit. All cell lines showed a lack of response to Con A and their cell growth was inhibited by Cyclosporin A which is known to inhibit cytokine promoters. It was decided therefore, to examine the cell lines for the presence of mRNA of different cytokines. The results showed that the cell lines transcribed message for IFNgamma, TNFalpha, IL-4 and IL-10 whereas no mRNA for IL-2 or IL-1beta was detected. In conclusion, the OHV-2-immortalised cell lines resemble anergic T-cells which may be activated giving rise to the characteristic lesions of MCF.


Decreased ventilation in preterm infants during oral feeding.
As respiratory difficulty may accompany nipple feeding in preterm neonates, we studied the effect of oral feeding on ventilation in 23 preterm infants. The infants composed two groups based on their postconceptional age at the time of study: Group A comprised 12 infants 34 to 35.9 weeks of age, and group B, 11 infants 36 to 38 weeks. Ventilation was measured via a nasal mask pneumotachometer, and sucking pressure via a nipple that also permitted milk delivery; transcutaneous PO2 and PCO2 were continuously monitored. The feeding pattern comprised an initial period of continuous sucking of at least 30 seconds, followed by intermittent sucking bursts for the remainder of the feed. When compared with an initial semi-upright control period, minute ventilation (V1) during continuous sucking fell by 52 +/- 6% (P less than 0.001) and 40 +/- 2% (P less than 0.001) in groups A and B, respectively. This was the result of a decrease in respiratory frequency and tidal volume and was associated with a fall in TcPO2 of 13 +/- 4 mm Hg (P less than 0.01) in group A and 10 +/- 2 mm Hg (P less than 0.01) in group B. During intermittent sucking, V1 and TcPO2 recovered partially only in the more mature infants (group B). At the end of the feed, TcPCO2 have risen by 3 +/- 1 mm Hg (P less than 0.001) in group A and by 2 +/- 2 mm Hg (P less than 0.05) in group B. Thus oral feeding results in an impairment of ventilation during continuous sucking and the subsequent recovery during intermittent sucking is dependent on postconceptional age.


Activity-dependent differences between rat fast and slow neuromuscular systems.
Activity-dependent pharmacologic differences between the fast tibialis anterior and slow soleus neuromuscular systems of the rat were studied. The tibialis anterior was more sensitive than the soleus to d-tubocurarine tetanic fade (50 Hz), as determined from recordings of compound muscle action potentials. Pre-treatment with physostigmine prevented curare-induced tetanic fade in the tibialis anterior, but not the soleus. Additionally, when contractile tension was 80% blocked by d-tubocurarine, the tibialis anterior was more responsive than the soleus to the decurarizing action of tetanic stimulation (25, 50 and 100 Hz). These results disclose that activity-dependent pharmacologic differences exist between neuromuscular systems. Further, they indicate that the tibialis anterior and the soleus differ in their processes of transmitter release. It is speculated that differences in nerve terminal Ca2+ account for the observed pharmacologic differences between the tibialis anterior and soleus.


Lumbar lateral interbody cage with plate augmentation: in vitro biomechanical analysis.
Many studies have concluded that stand alone cages provide limited stabilization to the spine, and this primary stabilization decreases postoperatively due to various factors. A supplemental fixation may, therefore, be needed to improve the stability. Extensive biomechanical analysis was performed in the present study to further evaluate the stabilization achieved by a laterally inserted cage and the role of an anterior lateral supplemental fixation. Eight human cadaver functional spinal units were subjected sequentially to four different test conditions: (1) intact, (2) instrumented laterally with a long cylindrical threaded cage, (3) the same cage supplemented with a lateral fixation plate, the plate being firmly connected to the cage, and (4) removal of the connection between the plate and the cage. Pure moments were applied to each specimen in a quasi static manner, ranging from -7 Nm to 7 Nm in flexion/extension, lateral bending and axial rotation. Three-dimensional segmental motions were simultaneously recorded under each loading condition. Statistical analysis was carried out on the motion parameters, including the range of motion (ROM) and the neutral zone (NZ). Inter-group comparisons were made using the Friedman test and the Wilcoxon test. The results showed that the stand alone lateral cage provided stabilization by increasing segmental stiffness above that of the intact spine. The stiffness increase ratios were: 1.6 in flexion/extension ( P=0.07), 1.3 in lateral bending ( P=0.4) and 1.0 in axial rotation ( P=0.67). A supplemental plate provided significant reinforcement of the stabilization. The stiffness increase ratios relative to the intact spine were: 3.1 in flexion/extension ( P=0.012), 5.0 in lateral bending ( P=0.012) and 2.3 in axial rotation ( P=0.012). After removal of the connection between the cage and the plate, the stiffness ratios were: 2.7 in flexion/extension ( P=0.027), 4.6 in lateral bending ( P=0.027) and 2.1 in axial rotation ( P=0.027). Globally, the cage alone increased the segmental stiffness above that of the intact spine by a factor of 1.1 ( P=0.39), with the supplemental plate, segmental stiffness increased by a factor of 3.1 ( P<0.01), and the unconnected cage/plate increased stiffness by a factor of 3.0 ( P=0.02). Supplementation of the lateral cage with an anterolateral plate was thus shown to provide significant additional stabilization in all directions, which may potentially compensate for the postoperative decrease in segmental stability.


Blocking of oestrogen signals improves anti-tumour effect regardless of oestrogen receptor alpha expression in cancer cells.
Anti-oestrogenic therapy has been used for breast cancer patients with oestrogen susceptibility cancer cells. However, little has been known about its potential role for immune cell biology within TME, particularly in cancer patients without oestrogen sensitivity of tumour cells. Therefore, we aimed to study the effect of oestrogen on immunity within TME. Using a clinical dataset, immune cells of humans and mice, female mice with and without ovaries, and several murine ERα-negative cancer cell lines, we evaluated the effect of oestrogen on immunity in TME. Clinical data analysis suggested oestrogen's suppressive efficacy against CTLs. Additionally, in vitro and in vivo experiments revealed intra-tumoural CTLs' direct repressive action by oestrogen in both mice and humans; blockade of oestrogen signals cancelled its immunosuppression resulting in tumour growth reduction in vivo. Most notably, immunotherapy (immune checkpoint inhibitor; ICI) combined with anti-oestrogenic therapy exhibited a dramatic anti-tumour effect. This study provides novel insights into how oestrogen contributes to tumour progression and a therapeutic rationale for blocking oestrogen signalling to boost the anti-tumour effect of ICI, regardless of tumour cells' ERα expression.


Cellular trafficking of the glypican Dally-like is required for full-strength Hedgehog signaling and wingless transcytosis.
Hedgehog (Hh) and Wingless (Wg) morphogens specify cell fate in a concentration-dependent manner in the Drosophila wing imaginal disc. Proteoglycans, components of the extracellular matrix, are involved in Hh and Wg stability, spreading, and reception. In this study, we demonstrate that the glycosyl-phosphatidyl-inositol (GPI) anchor of the glypican Dally-like (Dlp) is required for its apical internalization and its subsequent targeting to the basolateral compartment of the epithelium. Dlp endocytosis from the apical surface of Hh-receiving cells catalyzes the internalization of Hh bound to its receptor Patched (Ptc). The cointernalization of Dlp with the Hh/Ptc complex is dynamin dependent and necessary for full-strength Hh signaling. We also demonstrate that Wg is secreted apically in the disc epithelium and that apicobasal trafficking of Dlp allows Wg transcytosis to favor Wg spreading along the basolateral compartment. Thus, Dlp endocytosis is a common regulatory mechanism of both Hh and Wg morphogen action.


An automatic method for determination of glycosylated hemoglobins using low-pressure liquid chromatography.
Several studies have revealed a correlation between blood levels of glucose and hemoglobin A1c (HbA1c), a minor form of hemoglobin (Hb) present at elevated concentrations in patients with diabetes mellitus. To facilitate a clinical study of the level of circulating HbA1c we have developed an automatic chromatographic system. An efficient separation of HbA1c from HbA0 and other rapid hemoglobins (HbA1a, HbA1b) was achieved on Bio-Rex-70 columns using three buffers. This system allows the daily analysis of 40 samples. The mean level of HbA1c in normal subjects was 5.4 +/- 0.4%. The method also detects the presence of elevated levels of HbF and the most frequent forms of abnormal hemoglobin (HbS, HbC).


Human cytomegalovirus infant infection adversely affects growth and development in maternally HIV-exposed and unexposed infants in Zambia.
Human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) coinfections have been shown to increase infant morbidity, mortality, and AIDS progression. In HIV-endemic regions, maternal HIV-exposed but HIV-uninfected infants, which is the majority of children affected by HIV, also show poor growth and increased morbidity. Although nutrition has been examined, the effects of HCMV infection have not been evaluated. We studied the effects of HCMV infection on the growth, development, and health of maternally HIV-exposed and unexposed infants in Zambia. Infants were examined in a cohort recruited to a trial of micronutrient-fortified complementary foods. HIV-infected mothers and infants had received perinatal antiretroviral therapy to prevent mother-to-child HIV transmission. Growth, development, and morbidity were analyzed by linear regression analyses in relation to maternal HIV exposure and HCMV infection, as screened by sera DNA for viremia at 6 months of age and by antibody for infection at 18 months. All HCMV-seropositive infants had decreased length-for-age by 18 months compared with seronegative infants (standard deviation [z]-score difference: -0.44 [95% confidence interval {CI}, -.72 to -.17]; P = .002). In HIV-exposed infants, those who were HCMV positive compared with those who were negative, also had reduced head size (mean z-score difference: -0.72 [95% CI, -1.23 to -.22]; P = .01) and lower psychomotor development (Bayley test score difference: -4.1 [95% CI, -7.8 to -.5]; P = .03). HIV-exposed, HCMV-viremic infants were more commonly referred for hospital treatment than HCMV-negative infants. The effects of HCMV were unaffected by micronutrient fortification. HCMV affects child growth, development, and morbidity of African infants, particularly in those maternally exposed to HIV. HCMV is therefore a risk factor for child health in this region.


Assessment of fetal risk in postdate pregnancies.
To assess postdate fetal risk, pregnancies in which menstrual history was confirmed by early ultrasound examination were reviewed; 5915 pregnancies within 1 week of term, 1408 1 to 2 weeks postdate, and 340 at least 2 weeks postdate. Fetal distress and meconium release were twice as frequent and meconium aspiration eight times as frequent postterm. Birth asphyxia was unrelated to gestational age. Fractures and palsies were more frequent because of primiparity and macrosomia. Only one antepartum fetal death occurred in 1748 postdate pregnancies. Review of 674 perinatal deaths at 37 plus weeks in Quebec showed no increase in deaths postterm. The increase in fetal distress and meconium aspiration postterm without an increase in birth asphyxia or fetal death may reflect greater responsiveness of the more mature fetus to mild asphyxic insults. Findings of this study could not justify increased fetal monitoring in postdate pregnancies.


Lower Maternal Chronic Physiological Stress and Better Child Behavior at 18 Months: Follow-Up of a Cluster Randomized Trial of Neonatal Intensive Care Unit Family Integrated Care.
To assess whether Family Integrated Care (FICare) in the neonatal intensive care unit improves maternal chronic physiological stress and child behavior at 18 months of corrected age for infants born preterm. Follow-up of a multicenter, prospective cluster-randomized controlled trial comparing FICare and standard care of children born at <33 weeks of gestation and parents, stratified by tertiary neonatal intensive care units, across Canada. Primary outcomes at 18 months of corrected age were maternal stress hormones (cortisol, ie, hair cumulative cortisol [HCC], dehydroepiandrosterone [DHEA]) assayed from hair samples. Secondary outcomes included maternal reports of parenting stress, child behaviors (Internalizing, Externalizing, Dysregulation), and observer-rated caregiving behaviors. Outcomes were analyzed using multilevel modeling. We included 126 mother-child dyads from 12 sites (6 FICare sites, n = 83; 6 standard care sites, n = 43). FICare intervention significantly lowered maternal physiological stress as indicated by HCC (B = -0.22 [-0.41, -0.04]) and cortisol/DHEA ratio (B = -0.25 [-0.48, -0.02]), but not DHEA (B = 0.01 [-0.11, 0.14]). Enrollment in FICare led to lower child Internalizing (B = -0.93 [-2.33, 0.02]) and Externalizing behavior T scores (B = -0.91 [-2.25, -0.01]) via improvements to maternal HCC (mediation). FICare buffered the negative effects of high maternal HCC on child Dysregulation T scores (B = -11.40 [-23.01, 0.21]; moderation). For mothers reporting high parenting stress at 18 months, FICare was related to lower Dysregulation T scores via maternal HCC; moderated mediation = -0.17 (-0.41, -0.01). FICare has long-term beneficial effects for mother and child, attenuating maternal chronic physiological stress, and improving child behavior in toddlerhood. NCT01852695.


Advances in Metabolic Engineering of Plant Monoterpene Indole Alkaloids.
Monoterpene indole alkaloids (MIAs) encompass a diverse family of over 3000 plant natural products with a wide range of medical applications. Further utilizations of these compounds, however, are hampered due to low levels of abundance in their natural sources, causing difficult isolation and complex multi-steps in uneconomical chemical syntheses. Metabolic engineering of MIA biosynthesis in heterologous hosts is attractive, particularly for increasing the yield of natural products of interest and expanding their chemical diversity. Here, we review recent advances and strategies which have been adopted to engineer microbial and plant systems for the purpose of generating MIAs and discuss the current issues and future developments of manufacturing MIAs by synthetic biology approaches.


Efficacy and safety of aclidinium/formoterol versus monotherapies and aclidinium versus placebo in Chinese and other Asian patients with moderate-to-severe COPD: The AVANT Phase 3 study.
AVANT was a Phase 3, 24-week, randomized, parallel-group, double-blind, double-dummy, placebo-controlled study to assess the efficacy and safety of aclidinium/formoterol 400 μg/12 μg combination vs monotherapies and aclidinium vs placebo (1:1:1:1) in Asian patients (∼70% of whom were Chinese) with moderate-to-severe stable chronic obstructive pulmonary disease. Endpoints were analyzed hierarchically to incorporate type I error control. At Week 24, aclidinium/formoterol demonstrated improvements from baseline in 1-h morning post-dose forced expiratory volume in 1 s (FEV1) vs aclidinium (least squares [LS] mean 92 mL; 95% confidence interval [CI] 60, 124 mL; p < 0.001), and in trough FEV1 vs formoterol (LS mean 85 mL; 95% CI 53, 117 mL; p < 0.001). Furthermore, aclidinium provided improvements in trough FEV1 vs placebo (LS mean 134 mL; 95% CI 103, 166 mL; p < 0.001). There was an improvement in transition dyspnea index focal score at Week 24 for aclidinium/formoterol vs placebo (LS mean 0.8; 95% CI 0.2, 1.3; p = 0.005) but not for aclidinium vs placebo (LS mean 0.4; 95% CI -0.1, 1.0; p = 0.132). Improvements in St George's Respiratory Questionnaire total scores occurred for aclidinium/formoterol vs placebo (LS mean -4.0; 95% CI -6.7, -1.4; p = 0.003) and aclidinium vs placebo (LS mean -2.9; 95% CI -5.5, -0.3; p = 0.031). Aclidinium/formoterol and aclidinium were well tolerated and safety findings were consistent with known profiles; rates of treatment-emergent adverse events (AEs) (aclidinium/formoterol: 54.8%; aclidinium: 47.4%; placebo: 53.9%), serious AEs (7.2, 7.9, and 7.8%, respectively), and AEs leading to discontinuation of study medication (2.3, 1.5, and 2.2%, respectively) were similar between groups.


Use of 'tidal volume challenge' to improve the reliability of pulse pressure variation.
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .


Effects of charged drugs on the phase transition temperatures of phospholipid bilayers.
An approach is presented which allows the description of drug binding to lipid bilayers, when the drug is present in both charged and uncharged forms. Binding is described by Langmuir adsorption isotherms, with the maximum number of binding sites being 1/60 A2. An estimate of the change in drug pK on binding is necessary, and is close to zero for most drugs binding to dipalmitoyl phosphatidylcholine, although delta pK = 1.0 for procaine. From the binding curves it is possible to calculate the drug-induced decreases in lipid phase transition temperature, assuming ideal behaviour. Good fits between experiment and theory are possible, giving values for the dissociation constant describing drug binding to the membrane.


Evolutionary change in the insulin receptors of hystricomorph rodents.
INSULIN receptors have been thought to have remained unaltered despite evolutionary changes in the hormone(1). Because insulins from hystricomorph rodents are known to be highly substituted compared with other mammalian insulins, we decided to investigate the insulin receptor of some hystricomorphs to determine whether evolutionary change had occurred within the receptor itself. Here we present the first evidence that hystricomorph rodent insulin receptors have undergone evolutionary change.


The primary structure of carboxypeptidase S3 from Penicillium janthinellum IBT 3991.
The complete amino acid sequence of penicillopeptidase S3, a serine carboxypeptidase isolated from Penicillium janthinellum IBT 3991, has been determined. The enzyme consists of 481 amino acids arranged in a single polypeptide chain. Six glycosylation sites were established in positions 41, 218, 256, 326, 384 and 392. The molecule contains six cysteinyl residues among which disulfide bridges was established between Cys-71-Cys-333 and Cys-233-Cys-289. Carboxypeptidase S3 is homologous to carboxypeptidase PEPF (or carboxypeptidase I) from Aspergillus niger (67% identical positions). It is proposed that these enzymes form a separate sub-family among the serine carboxypeptidases.


Consensus and Meta-analysis regulatory networks for combining multiple microarray gene expression datasets.
Microarray data is a key source of experimental data for modelling gene regulatory interactions from expression levels. With the rapid increase of publicly available microarray data comes the opportunity to produce regulatory network models based on multiple datasets. Such models are potentially more robust with greater confidence, and place less reliance on a single dataset. However, combining datasets directly can be difficult as experiments are often conducted on different microarray platforms, and in different laboratories leading to inherent biases in the data that are not always removed through pre-processing such as normalisation. In this paper we compare two frameworks for combining microarray datasets to model regulatory networks: pre- and post-learning aggregation. In pre-learning approaches, such as using simple scale-normalisation prior to the concatenation of datasets, a model is learnt from a combined dataset, whilst in post-learning aggregation individual models are learnt from each dataset and the models are combined. We present two novel approaches for post-learning aggregation, each based on aggregating high-level features of Bayesian network models that have been generated from different microarray expression datasets. Meta-analysis Bayesian networks are based on combining statistical confidences attached to network edges whilst Consensus Bayesian networks identify consistent network features across all datasets. We apply both approaches to multiple datasets from synthetic and real (Escherichia coli and yeast) networks and demonstrate that both methods can improve on networks learnt from a single dataset or an aggregated dataset formed using a standard scale-normalisation.


DNA flow cytometry of canine mammary tumours: the relationship of DNA ploidy and S-phase fraction to clinical and histological features.
The DNA ploidy status and S-phase fraction (SPF) of benign proliferative lesions (BPL) and malignant tumours (MT) in the mammary glands of dogs were determined by flow cytometric analysis and the results were related to their clinical and histological features. Seven (14.3 per cent) of 49 BPL and 16 (48.5 per cent) of 33 primary MT had aneuploid G0,1 peaks (P < 0.001). Hypodiploid G0,1 peaks were found in one BPL and in five primary MT. The DNA ploidy status of primary MT was not found to be associated with their size, nodal status, grade of histological malignancy or nuclear grade. In several cases there was intra-tumour heterogeneity in ploidy status independent of histological heterogeneity. The SPF was significantly higher in 27 primary MT than in 45 BPL when diploid and aneploid cases were combined for comparison (P < 0.05), but not when only diploid cases were compared. Among the primary MT the SPF was higher in aneuploid than in diploid tumours (P < 0.05) and it was higher in five MT from five dogs with regional disease than in 22 MT from 19 dogs with local disease (P < 0.05). The SPF was positively correlated with the grade of histological malignancy (P < 0.05) but not with nuclear grade.


Redescription of the percoid fish Symphysanodon andersoni Kotthaus (Symphysanodontidae) from the northwestern Indian Ocean, based on the holotype and the second known specimen.
Symphysanodon andersoni was described in 1974 from a single specimen collected southwest of Socotra Island, near the entrance to the Gulf of Aden. A more recent report (2003) of its capture in the Gulf of Kutch, Arabian Sea, was based on a misidentification. The second known specimen of the Bucktoothed Slopefish, S. andersoni, (at 204 mm SL the largest known specimen of the genus Symphysanodon) was collected off the south coast of Oman, Arabian Sea, in April 2014. Symphysanodon andersoni is distinguishable from its congeners by number of tubed scales in the lateral line, 60 to 65 versus 42 to 59 in the other species of the genus. In view of the fact that S. andersoni is poorly known, we redescribe it based on the holotype and the new specimen collected off Oman and provide the first color photograph of the species.


Morphology of smooth muscle cells in the rat thoracic duct. A scanning and transmission electron-microscope study.
The three-dimensional cytoarchitecture and ultrastructure of the smooth muscle cells in the wall of the rat thoracic duct were investigated by scanning and transmission electron microscopy. The muscle layer basically consists of a single layer of circularly arranged cells. The smooth muscle cell is fusiform or ribbon-like in shape, as in veins or venules with a similar or smaller diameter. Connections by spinous processes are observed between adjacent muscle cells along their length. Spot-like membrane contacts frequently occur in areas where facing membranes are closely apposed. These are thought to be gap junctions and may be responsible for electrical coupling and mechanical attachment. Large invaginations arranged regularly in rows on the surface of the smooth muscle cells can be observed. These invaginations are closely associated with a flattened sarcoplasmic reticulum, and caveolae tend to open into the invaginations.


A model for spatiotemporal frequency responses in the X cell pathway of the cat's retina.
A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus at the cornea, to cones, to X-type ganglion cells. The model contains elements representing the eye's optics, phototransduction, gain control, spatiotemporal processing by cell layers, and pure delay. Centre-surround antagonism in the model arises through the presence of a centre element producing a small spatial spread of signals, and an antagonistic element producing a larger spread. Two arrangements were tried, feedforward and feedback, in which the antagonistic element's output was subtracted from the centre element's output, and input, respectively. The model was fitted to empirical spatial and temporal frequency responses collected by Frishman et al. (1987), and accounted qualitatively for these data in the feedback, but not the feedforward, arrangement. The model's centre pathway comprises a cascade of low-pass spatial filters, as does the surround pathway. As a consequence, the spatial frequency responses for these two pathways closely approximate Gaussian functions of spatial frequency, and the spatial frequency response of the complete model at low temporal frequency closely matches that of the difference of Gaussians model.


Neurofibromatosis.
The "neurofibromatoses" are a set of distinct genetic disorders that have in common the occurrence of tumors of the nerve sheath. They include NF1, NF2, and schwannomatosis. All are dominantly inherited with a high rate of new mutation and variable expression. NF1 includes effects on multiple systems of the body. The major NF1-associated tumor is the neurofibroma. In addition, clinical manifestations include bone dysplasia, learning disabilities, and an increased risk of malignancy. NF2 includes schwannomas of multiple cranial and spinal nerves, especially the vestibular nerve, as well as other tumors such as meningiomas and ependymomas. The schwannomatosis phenotype is limited to multiple schwannomas, and usually presents with pain. The genes that underlie each of the disorders are known: NF1 for neurofibromatosis type 1, NF2 for neurofibromatosis type 2, and INI1/SMARCB1 for schwannomatosis. Genetic testing is possible to identify mutations. Insights into pathogenesis are beginning to suggest new treatment strategies, and therapeutic trials with several new forms of treatment are underway.


[Does low-risk delivery exist?].
The main objective of our study is to evaluate the rate of call of the obstetrician during childbirth supposed in low-risk and compare it to high-risk deliveries in a maternity service level II. The secondary objective is to assess the level of intervention of the obstetrician with the patient in both groups. This is a prospective study of 490 patients including 259 classified as low risk based on obstetric criteria of Bourgogne Perinatal Network. The criteria considered for the call and/or intervention of the obstetrician were the following: altered fetal heart rate, lactate scalp, instrumental delivery, cesarean section, complete or complicated perineal, serious event during labor (cord prolapse, uterine rupture…), postpartum hemorrhage treated by prostaglandin ocytocic. The high-risk group is taken as reference for the calculation of confidence intervals. The rate of call of the obstetrician in the low versus high risk are: 37% [95% CI: 0.98-2.11] and 29% [95% CI: 1.00] (P=0.0587). The rate of intervention of the obstetrician in the low versus high risk is 21% [95% CI: 1.15-3.07] and 12% [95% CI: 1.00] (P=0.0109). The delivery process is unpredictable and potentially risky. Thirty-seven percent of patients classified as low risk at the beginning of labour have required intervention of the obstetrician and 21% of them his intervention.


Does intraoperative aneurysm rupture influence outcome? Analysis of 169 patients.
The aim of this study was to evaluate the prognostic value of intraoperative aneurysm rupture (IAR) in patients with subarachnoid hemorrhage (SAH) undergoing surgery for cerebral aneurysms. Between July 1997 and April 2000, 292 consecutive patients were admitted to our institution with SAH due to ruptured intracranial aneurysms. Of these, 169 patients were treated surgically according to standard microsurgical procedures and were included in this study. Mean age was 47 years. Initial clinical state was graded according to the classification of Hunt and Hess (HH). Outcome was classified according to the Glasgow Outcome Scale as favorable (grades IV and V) and unfavorable (grades I-III). Outcome of patients with intraoperative ruptured and non-ruptured aneurysms was analyzed in correlation to the preoperative clinical state and with respect to the time of surgery and to aneurysm localization. Different rupture rates were observed with respect to the localization of the aneurysm: anterior circulation (n=69) 39.1%, middle cerebral artery (n=46) 34.8%, internal carotid artery (n=48) 31.2%, and posterior circulation (n=6) 16.7%. Patients with HH-grades I-III showed a favorable outcome in 72.2% (61 of 84 patients) without intraoperative rupture and in 71.7% (33 of 46 patients) with intraoperative aneurysm rupture. The corresponding values for patients with HH-grades IV/V were: favorable outcome in 34.6% (9 of 26 patients) and 23.1% (3 of 13 patients), respectively. Poor initial clinical condition (HH IV and V) as well as the initial Fisher grades III and IV were strongly associated with poor clinical outcome. Intraoperative aneurysm rupture has no impact on the outcome, neither in patients with good initial condition nor for poor grades patients.


Serum and urinary ribonuclease in children with schistosomal hepatic fibrosis.
Serum and urinary RNase activity was determined in 15 normal children and in 52 children in various clinical stages of schistosomal hepatic fibrosis. The activity of serum RNase was compared with that of serum GOT, GPT and AP. The activity of serum and urinary RNase in the different schistosomal groups was significantly higher than in healthy children. The elevated levels of serum and urinary RNase activity were possibly due to malnutrition with tissue catabolism, zinc-deficiency and liver cell injury. Treatment with Astiban and protein-rich diet resulted in a significant decrease in serum and urinary RNase activity and an in significant drop in serum GOT, GPT and AP. Serum and urinary RNase appear to be more sensitive indices for evaluating the early metabolic disturbances in schistosomal patients than GOT, GPT or AP. Our findings also showed that the severity of cases could be graded according to the level of urinary RNase.


[Effectiveness of Integrated Psychological Therapy for schizophrenia patients. A meta-analysis including 28 independent studies].
Over the past 24 years, research groups in eight different countries have conducted 28 independent evaluation studies on Integrated Psychological Therapy (IPT) including 1,329 schizophrenia patients. The present study examines the effectiveness of IPT under different treatment conditions by means of a meta-analytic review. The most salient results indicate favourable mean effect sizes for IPT in comparison to control groups (placebo-attention conditions, standard care). Moreover, the superiority of IPT continues to increase during an average catamnestic phase of 8.1 months. The method obtains similarly favourable effects in different functional areas (neurocognition, social behaviour, psychopathology) and different assessment formats (expert ratings, self-reports, psychological tests). The comparison of different settings of IPT and control groups shows the superiority of IPT in any given therapy or site condition. The analysis of subsamples of inpatients, outpatients, and patients in varying rehabilitation phases reveals similarly favourable effects. Comparing only high-quality studies yields comparable results. In summary, the present meta-analysis corroborates evidence that IPT is an 'empirically validated treatment' according to American Psychiatric Association guidelines.


Overview of randomized clinical trials in acute heart failure syndromes.
Acute heart failure syndromes (AHFS) are among the most frequent causes of hospitalizations in the United States and Europe. Despite current therapies, patients with AHFS have high readmission and mortality rates. The randomized, controlled clinical trial is the standard by which contemporary therapies are evaluated, yet this tool of clinical science only recently has been rigorously applied to the development of novel therapies for patients with AHFS. This review briefly discusses some of the challenges presented in designing a clinical trial of therapies for AHFS and to describe some of the recent trials with respect to these issues in established drugs (such as milrinone, dobutamine, nitroglycerin, nitroprusside, and nesiritide) that have been approved by the US Food and Drug Administration (FDA). Recent trials of current investigational agents, such as levosimendan (the Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Versus Placebo in the Short-Term Treatment of Decompensated Heart Failure [REVIVE], the Calcium Sensitizer or Inotrope or None in Low-Output Heart Failure [CASINO] study, and the Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support [SURVIVE] trial), tezosentan (the Randomized Intravenous Tezosentan [RITZ] study and the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies [VERITAS]), and tolvaptan (the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure [ACTIV-CHF] study), are also discussed.


Supramolecular isomerism of a metallocyclic dipyridyldiamide ligand metal halide system generating isostructural (Hg, Co and Zn) porous materials.
We show how crystallisation of supramolecular isomers of a dynamic coordination system generates a series of isostructural porous materials. These mercury, cobalt and zinc metallocyclic materials show permanent porosity and exhibit single-crystal-to-single-crystal transformations.


Enhanced platelet adhesion in essential thrombocythemia after in vitro activation.
Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by elevated platelet counts and increased risk of thrombosis. Ex vivo data suggest increased platelet reactivity in agreement with the increased thrombosis risk, while in vitro tests often detect decreased platelet activity. The present study aimed to investigate adhesion of ET-platelets in vitro, which is an aspect of platelet function that has been addressed in only a few studies on ET patients. The study included 30 ET patients and 14 healthy controls. Platelet adhesion was measured with a static platelet adhesion assay. The main finding was that ET-platelets were more readily activated by adhesion-inducing stimuli in vitro than control platelets. This was particularly evident in elderly patients and when using multiple stimuli, such as surfaces of collagen or fibrinogen combined with addition of adenosine 5'-diphosphate or ristocetin. Such multiple stimuli resulted in adhesion above the control mean +2 standard deviations for approximately 50% of the patients. The results are in accordance with the concept of increased platelet activity in ET, but opposite to most other in vitro studies. We suggest that the conditions in the adhesion assay might mimic the in vivo situation regarding the presence of chronic platelet activation.


Carcinoma of the cervix uteri: an assessment of tumour proliferation using the monoclonal antibody Ki67.
Thirty-one cervical biopsies of invasive carcinoma have been studied by immunohistochemical means using the monoclonal antibody Ki67 to determine tumour cell proliferation rates. A wide range (10-50%) in the extent of Ki67 staining (expressed as the percentage of labelled tumour cells) was observed indicating considerable variation on tumour growth rates. There was no significant relationship between the percentage of positive cells and conventional histological parameters such as cell type or tumour differentiation. Immunostaining with monoclonal antibody Ki67 therefore provides a new approach to the assessment of cervical tumour biopsies which will require long term clinical follow-up to establish its prognostic significance.


Induction of Epstein-Barr virus early antigens by tumor promoters of the diterpene ester type in Raji cells and specific (receptor) binding as compared to irritant and promoting activities.
Sixteen new diterpene esters (DTE) of the tigliane, ingenane, daphnane, and 1 alpha-alkyldaphnane types were investigated in two in vitro assays: as inhibitors of specific binding of 3H-labeled 12-O-tetradecanoylphorbol 13-acetate (TPA) to protein kinase C in a receptor preparation from mouse brain, and as inducers of Epstein-Barr virus (EBV) early antigens in Raji cells. Inhibition of binding of [3H]TPA to the receptor preparation by tigliane and ingenane DTE correlates with irritant activity in vivo, while some daphnane and 1 alpha-alkyldaphnane DTE inhibit binding of [3H]TPA in a less pronounced manner but still are very irritant. Tumor-promoting activity does not correlate consistently with the receptor-binding data. To test the hypothesis that early antigen induction in Raji cells by DTE is coupled to functional DTE receptors (protein kinase C), the latter were searched on these Raji cells by a 'cold acetone-filter assay' and shown to be present. The dependence of the early antigen induction rate on the concentration of the DTE tested was demonstrated. At a given concentration of DTE, differences in the induction rate between various DTE are seen. However, a clear quantitative correlation either between early antigen induction and receptor binding data in vitro, or early-antigen-inducing activity in vitro versus irritancy and tumor-promoting activity in vivo was not observed.


Hypothetical superparamagnetic magnetometer in a pigeon's upper beak probably does not work.
We reanalysed the role of superparamagnetic magnetite clusters observed in a pigeon's upper beak to decide if this matter can be a component of some sort of pigeon magnetometer for Earth orientation. We investigated the mutual interaction of the magnetite clusters induced by the geomagnetic field. The force sensitivity of the hypothetical magnetometer in a pigeon's upper beak was estimated considering the previously presented threshold magnetic sensitivity of pigeons, measured in electrophysiological and behavioural investigations. The typical intercluster magnetic force seems to be 10(-19)N well above the threshold magnetic sensitivity. To strengthen our results, we measured the magnetic susceptibility of superparamagnetic magnetite using a vibrating sample magnetometer. Finally we performed theoretical kinematic analysis of the motion of magnetite clusters in cell plasma. The results indicate that magnetite clusters, constituted by superparamagnetic nanoparticles and observed in a pigeon's upper beak, may not be a component of a measuring system providing the magnetic map.


Precise prenatal diagnosis of tuberous sclerosis by sequencing the TSC2 gene.
The presumptive prenatal diagnosis of tuberous sclerosis (TSC) previously depended upon fetal imaging. Cloning of the two TSC genes (TSC1 and TSC2) now enables precise molecular diagnosis by gene sequencing. We used this approach for the prenatal diagnosis of a fetus showing multiple intracardiac tumors. DNA extracted from cultivated amniotic fluid cells underwent sequencing of all coding regions and exon-intron boundaries of the TSC1 and TSC2 genes. A mutation (R611Q) was found in exon 16 of the TSC2 gene. Thus far, neither clinically unaffected parents has provided blood samples for mutation analysis. For the first time, mutation analysis of a TSC gene enabled a precise prenatal diagnosis.


Systematic identification of pharmacogenomics information from clinical trials.
Recent progress in high-throughput genomic technologies has shifted pharmacogenomic research from candidate gene pharmacogenetics to clinical pharmacogenomics (PGx). Many clinical related questions may be asked such as 'what drug should be prescribed for a patient with mutant alleles?' Typically, answers to such questions can be found in publications mentioning the relationships of the gene-drug-disease of interest. In this work, we hypothesize that ClinicalTrials.gov is a comparable source rich in PGx related information. In this regard, we developed a systematic approach to automatically identify PGx relationships between genes, drugs and diseases from trial records in ClinicalTrials.gov. In our evaluation, we found that our extracted relationships overlap significantly with the curated factual knowledge through the literature in a PGx database and that most relationships appear on average 5 years earlier in clinical trials than in their corresponding publications, suggesting that clinical trials may be valuable for both validating known and capturing new PGx related information in a more timely manner. Furthermore, two human reviewers judged a portion of computer-generated relationships and found an overall accuracy of 74% for our text-mining approach. This work has practical implications in enriching our existing knowledge on PGx gene-drug-disease relationships as well as suggesting crosslinks between ClinicalTrials.gov and other PGx knowledge bases.


Chrysophanol, a main anthraquinone from Rheum palmatum L. (rhubarb), protects against renal fibrosis by suppressing NKD2/NF-κB pathway.
Chronic kidney disease (CKD), characterized as renal dysfunction and multi-system damage, has become a serious public health problem with high prevalence and mortality. Rheum palmatum L. (rhubarb) is one of the most widely used Chinese herb with renal protective activity. However, the active components and underlying mechanisms of rhubarb remain unknown. In this work, we tried to explore the pharmacological mechanism of chrysophanol, a main anthraquinone from rhubarb, against CKD by in vivo and in vitro models. The therapeutic effect of chrysophanol and its underlying mechanism were investigated using CKD mouse model induced by unilateral ureteral occlusion (UUO), and human kidney 2 (HK-2) cells stimulated by TGF-β1 in vivo. The impact of chrysophanol on renal function, inflammation, fibrosis of CKD mice were evaluated. Then, the protein expressions of FN1, collagen ɑI, α-SMA, NF-κB and naked keratinocyte homolog 2 (NKD2) were investigated. In vitro studies, the inhibition on inflammation and fibrogenesis by chrysophanol was further validated in TGF-β1-stimulated HK2 cells, and the regulation of chrysophanol on NKD2/NF-κB pathway was analyzed. Moreover, NKD2 was overexpressed in HK-2 cells to confirm the role of NKD2/NF-κB pathway in chrysophanol-mediated efficacy. Finally, the binding mode of chrysophanol with NKD2 was studied using in silico molecular docking and microscale thermophoresis (MST) assay. Chrysophanol could significantly improve the kidney dysfunction, alleviate renal pathology, and reverse the elevated levels of renal fibrosis markers such as FN1, collagen ɑI and α-SMA. Furthermore, chrysophanol effectively inhibited TNF-α, IL-6, and IL-1β production, and suppressed NF-κB activation and NKD2 expression. The findings of in vitro study were consistent with those of animal expriment. Using NKD2-overexpressing HK-2 cells, we also demonstrated that overexpression of NKD2 significantly compromised the anti-fibrotic effects of chrysophanol. In addition, molecular docking and MST analysis revealed that NKD2 was a direct target of chrysophanol. Together, our work demonstrated for the first time that chrysophanol could effectively ameliorate renal fibrosis by inhibiting NKD2/NF-κB pathway. Chrysophanol can potentially prevent CKD by suppressing renal NKD2 expression directly.


Risk of CKD Following Detection of Microscopic Hematuria: A Retrospective Cohort Study.
Microscopic hematuria is an uncertain risk factor for chronic kidney disease (CKD). We investigated the association between persistent or single episodes of microscopic hematuria and the development of incident CKD, overall and separately among men and women. Retrospective cohort study. A total of 232,220 Korean adults without CKD at baseline who underwent repeated regular health examinations at Kangbuk Samsung Health Study formed the study cohort. Microscopic hematuria was defined by≥5 red blood cells per high-power field. Participants were categorized into 1 of 4 groups according to the presence of hematuria at 2 consecutive examinations: (1) no hematuria at both examinations (reference group); (2) hematuria followed by no hematuria (regressed hematuria group); (3) no hematuria followed by hematuria (developed hematuria group); and (4) hematuria at both examinations (persistent hematuria group). CKD was defined as an estimated glomerular filtration rate<60mL/min/1.73m2 or proteinuria (1+or more on dipstick examination). Semiparametric proportional hazards models were used to estimate hazard ratios. During a 4.8-year median follow-up period, 2,392 participants developed CKD. Multivariable-adjusted hazard ratios for incident CKD, comparing the regressed, developed, and persistent hematuria groups to the no-hematuria group were 1.85 (95% CI, 1.35-2.53), 3.18 (95% CI, 2.54-3.98), and 5.23 (95% CI, 4.15-6.59), respectively. The association between persistent hematuria and incident CKD was stronger in men than women (P for interaction<0.001), although a statistically significant association was observed in both sexes. Lack of albuminuria and inability to consider specific glomerular diseases. Men and women with microscopic hematuria, especially persistent hematuria, may be at increased risk of CKD.


Negation interacts with motivational direction in understanding action sentences.
Linguistic negation acts by inhibiting the representation of information under its scope, often leading to the representation of positive alternative states of affairs. Motivational direction refers to approach/avoidance intentionality in our interactions with environmental stimuli expressed by means of verbs (e.g., "accept" vs "reject"). We consider it plausible that negation interacts with direction to represent the true motivation of the protagonist in sentence understanding (e.g., if an approach action is negated it is represented as avoidance). In the first study, we examine this interaction offline by asking participants to judge approach or avoidance meaning of affirmative (e.g., "he/she included/excluded meat") and negative sentences ("he/she did not include/exclude meat"). Results support that negation reversed participants' interpretation of sentence motivational direction. In a further study, we carried out two probe recognition experiments to examine the interaction during sentence comprehension; in both, the critical probe was the word referring to the target of the action (e.g., "meat"). In the first experiment, participants had to recognize the probe word presented 1500 milliseconds after sentence offset, while for the second one, the delay was 500 milliseconds. Results showed that at 1500 ms, target recognition took significantly more time for negated avoidance sentences than for the other conditions. Therefore, representing negated avoidance sentences seems to imply more complex processing, as avoidance verbs would be implicitly negative. By contrast, at the 500 ms delay, negation impaired target recognition for both approach and avoidance sentences, suggesting an unspecific inhibitory effect of negation at that sentence processing stage. Implication of these results for both research on negation and in action understanding are discussed.


Sugar beet BAC library construction and assembly of a contig spanning Rf1, a restorer-of-fertility gene for Owen cytoplasmic male sterility.
Rf1 is a nuclear gene that controls fertility restoration in cases of cytoplasmic male sterility caused by the Owen cytoplasm in sugar beet. In order to isolate the gene by positional cloning, a BAC library was constructed from a restorer line, NK198, with the genotype Rf1Rf1. The library contained 32,180 clones with an average insert size of 97.8 kb, providing 3.4 genome equivalents. Five AFLP markers closely linked to Rf1 were used to screen the library. As a result, we identified eight different BAC clones that were clustered into two contigs. The gap between the two contigs was filled by chromosome walking. To map the Rf1 region in more detail, we developed five cleaved amplified polymorphic sequence (CAPS) markers from the BAC DNAs identified, and carried out genotyping of 509 plants in the mapping population with the Rf1-flanking AFLP and CAPS markers. Thirteen plants in which recombination events had occurred in the vicinity of the Rf1 locus were identified and used to map the molecular markers relative to each other and to Rf1. In this way, we were able to restrict the possible location of the Rf1 gene to a minimum of six BAC clones spanning an interval of approximately 250 kb.


Patient-Perceived Outcomes of Recovery After Trigger Digit Release.
Trigger finger release (TFR) is one of the most commonly performed hand surgeries; nevertheless, the time until patients subjectively feel recovered has not been well documented. The limited literature on patient perceptions of recovery after any type of surgery has described that patients and surgeons may have differing views on the time until full recovery. Our primary study question was to determine how long it takes for patients to subjectively feel fully recovered after TFR. In this prospective study, patients who underwent isolated TFR completed questionnaires before surgery and at multiple time points following surgery until they reported full recovery. Patients completed visual analog scale (VAS) pain scores and QuickDASH (Disabilities of the Arm, Shoulder, and Hand) and were asked if they felt fully recovered at 4 weeks, 6 weeks, and 3, 6, 9, and 12 months. The average time to self-reported full recovery was 6.2 months (SD 2.6), and the median time to self-reported full recovery was 6 months (IQR 4 months). At 12 months, four out of 50 patients (8%) did not feel fully recovered. QuickDASH and VAS pain scores improved significantly from preoperative assessment to final follow-up. All patients reported improvement in both VAS pain scores and QuickDASH scores greater than the minimal clinically important difference between 6 weeks and 3 months after surgery. Higher preoperative VAS and QuickDASH scores were associated with failure to fully recover by 12 months after surgery. The length of time after surgery until patients felt fully recovered after isolated TFR is longer than the senior authors' expectations. This suggests that patients and surgeons may consider distinctly different parameters when discussing recovery. Surgeons should be aware of this discrepancy when discussing recovery after surgery. Prognostic II.


Use of a metallochromic indicator to study intracellular calcium movements in skeletal muscle.
The transient increase in free myoplasmic calcium concentration due to depolarization of a skeletal muscle fibre is the net result of the release of calcium from the sarcoplasmic reticulum (SR) and its simultaneous removal by binding to various sites and by reuptake into the SR. We review here procedures recently developed in this laboratory for empirically characterizing the calcium removal processes in voltage-clamped fibres and for using such characterization to determine the time course of SR calcium release during a depolarizing pulse.


Antiserum against Cl- pump complex recognizes 51 kDa protein, a possible catalytic unit in the rat brain.
We purified Cl- pump in the rat brain and obtained 520 or 580 kDa protein complexes which consisted of 62, 60, 55 and 51 kDa proteins. An antiserum against 520 kDa protein complex recognized 51 kDa protein in both 520 and 580 kDa complexes, and reduced both Cl(-)-ATPase and Cl(-) pump activities. Such an immunoreactive 51 kDa protein was found in the brain, spinal cord and kidney. When incubated with [gamma-(32)P]ATP, the protein complex yielded phosphorylated 51 kDa protein, the label being hydroxylamine-sensitive and increased in the presence of Cl- and/or an inhibitor of Cl- pump, ethacrynic acid. Thus, the antibody appears to recognize a possible catalytic subunit of Cl- pump, 51 kDa protein, in the rat.