Survey of nutritional management practices and metabolic disorders in West Virginia dairy herds.
Sixteen farmers, representing three major dairy counties in West Virginia, were interviewed to determine current dairy management practices. Herd health records were used to determine the incidence of metabolic and digestive disorders. All feedstuffs used on these farms were sampled for chemical analyses. The total number of cows on the 16 farms surveyed was 1870 with an average herd size of 117 and 6387 kg milk produced per cow per year. Fourteen of the 16 farmers used forage testing services, obtained professional advice on feeding and nutrition, and attempted to feed according to production. Eleven of sixteen farmers increased grain 2 weeks prior to calving and all gradually adjusted the intake of grain to cows recently freshened. Ration imbalance problems included both excesses and deficiencies of energy, protein, phosphorus, and calcium. Excess calcium, phosphorous, and crude protein were correlated (P less than .01, r2 = .74) with the incidence of fat cows. The incidence of metabolic disorders in these herds was low to average and the most prevalent management problem encountered was low butter fat.


Common gastroenterological problems. III. Chronic benign gastric ulcer.
A gastric ulcer is a lesion which needs to be treated with respect and should be followed to a satisfactory conclusion. The barium meal is still the mainstay of diagnosis but the accuracy of this examination is considerably improved when a double-contrast technique is used. Endoscopy is of value both to check the radiological findings and in particular to obtain biopsy material for histological examination. When the diagnosis has been established surgical intervention may be indicated, but if a course of medical treatment is thought to be justifiable the patient's progress must be closely followed radiologically and surgery reconsidered if there is no convincing evidence of ulcer healing.


Herpetic whitlow and ocular infection.
Herpes simplex virus can involve the mouth, nose, or skin in addition to the eye. A very rare form of herpes simplex involves the fingertips (herpetic whitlow) and can be a source of diagnostic confusion. Herpes simplex can be spread by direct contact from any of these sites to the eye by cross-infection or autoinoculation. The ophthalmologist should be aware of the nonocular forms of herpes simplex.


Evaluation of INK4A promoter methylation using pyrosequencing and circulating cell-free DNA from patients with hepatocellular carcinoma.
Hyper-methylation of CpG dinucleotides in the promoter region of inhibitor of cyclin-dependent kinase 4A (INK4A) has been reported in 60%-80% of hepatocellular carcinoma (HCC). As INK4A promoter hypermethylation event occurs early in HCC progression, the quantification of INK4A promoter methylation in blood sample may represent a useful biomarker for non-invasive diagnosis and prediction of response to therapy. We examined INK4A promoter methylation using circulating cell-free DNA (ccfDNA) in a total of 109 serum specimens, including 66 HCC and 43 benign chronic liver diseases. Methylation of the individual seven CpG sites was examined using pyrosequencing. Our results showed that there were significantly higher levels of methylated INK4A in HCC specimens than controls and that the seven CpG sites had different levels of methylation and might exist in different PCR amplicons. The area under receiver operating characteristic (ROC) curve was 0.82, with 65.3% sensitivity and 87.2% specificity at 5% (LOD), 39.0% sensitivity and 96.5% specificity at 7% LOD, and 20.3% sensitivity and 98.8% specificity at 10% LOD, respectively. Our results support additional studies incorporating INK4A methylation testing of ccfDNA to further validate the diagnostic, predictive, and prognostic characteristics of this biomarker in HCC patients. The knowledge of the existence of epi-alleles should help improve assay design to maximize detection.


Maternal transfer of nanoplastics to offspring in zebrafish (Danio rerio): A case study with nanopolystyrene.
Plastics are ubiquitous anthropogenic contaminants that are a growing concern in aquatic environments. The ecological implications of macroplastics pollution are well documented, but less is known about nanoplastics. The current study investigates the potential adverse effects of nanoplastics, which likely contribute to the ecological burden of plastic pollution. To this end, we examined whether a dietary exposure of adult zebrafish (Danio rerio) to polystyrene nanoparticles (PS NPs) could lead to the transfer of nanoplastics to the offspring, and whether nanoplastics exposure affects zebrafish physiology. Specifically, adult female and male zebrafish (F0 generation) were exposed to PS NPs via diet for one week and bred to produce the F1 generation. Four F1 groups were generated: control (unexposed females and males), maternal (exposed females), paternal (exposed males), and co-parental (exposed males and females). Co-parental PS NP exposure did not significantly affect reproductive success. Assessment of tissues from F0 fish revealed that exposure to PS NPs significantly reduced glutathione reductase activity in brain, muscle, and testes, but did not affect mitochondrial function parameters in heart or gonads. Assessment of F1 embryos and larvae revealed that PS NPs were present in the yolk sac, gastrointestinal tract, liver, and pancreas of the maternally and co-parentally exposed F1 embryos/larvae. Bradycardia was also observed in embryos from maternal and co-parental exposure groups. In addition, the activity of glutathione reductase and the levels of thiols were reduced in F1 embryos/larvae from maternal and/or co-parental exposure groups. Mitochondrial function and locomotor activity were not affected in F1 larvae. This study demonstrates that (i) PS NPs are transferred from mothers to offspring, and (ii) exposure to PS NPs modifies the antioxidant system in adult tissues and F1 larvae. We conclude that PS NPs could bioaccumulate and be passed on to the offspring, but this does not lead to major physiological disturbances.


Activation of the cnidarian oxidative stress response by ultraviolet radiation, polycyclic aromatic hydrocarbons and crude oil.
Organisms are continuously exposed to reactive chemicals capable of causing oxidative stress and cellular damage. Antioxidant enzymes, such as superoxide dismutases (SODs) and catalases, are present in both prokaryotes and eukaryotes and provide an important means of neutralizing such oxidants. Studies in cnidarians have previously documented the occurrence of antioxidant enzymes (transcript expression, protein expression and/or enzymatic activity), but most of these studies have not been conducted in species with sequenced genomes or included phylogenetic analyses, making it difficult to compare results across species due to uncertainties in the relationships between genes. Through searches of the genome of the sea anemone Nematostella vectensis Stephenson, one catalase gene and six SOD family members were identified, including three copper/zinc-containing SODs (CuZnSODs), two manganese-containing SODs (MnSODs) and one copper chaperone of SOD (CCS). In 24 h acute toxicity tests, juvenile N. vectensis showed enhanced sensitivity to combinations of ultraviolet radiation (UV) and polycyclic aromatic hydrocarbons (PAHs, specifically pyrene, benzo[a]pyrene and fluoranthene) relative to either stressor alone. Adult N. vectensis exhibited little or no mortality following UV, benzo[a]pyrene or crude oil exposure but exhibited changes in gene expression. Antioxidant enzyme transcripts were both upregulated and downregulated following UV and/or chemical exposure. Expression patterns were most strongly affected by UV exposure but varied between experiments, suggesting that responses vary according to the intensity and duration of exposure. These experiments provide a basis for comparison with other cnidarian taxa and for further studies of the oxidative stress response in N. vectensis.


Biodegradable microfabricated plug-filters for glaucoma drainage devices.
We report on the development of a batch fabricated biodegradable truncated-cone-shaped plug filter to overcome the postoperative hypotony in nonvalved glaucoma drainage devices. Plug filters are composed of biodegradable polymers that disappear once wound healing and bleb formation has progressed past the stage where hypotony from overfiltration may cause complications in the human eye. The biodegradable nature of device eliminates the risks associated with permanent valves that may become blocked or influence the aqueous fluid flow rate in the long term. The plug-filter geometry simplifies its integration with commercial shunts. Aqueous humor outflow regulation is achieved by controlling the diameter of a laser-drilled through-hole. The batch compatible fabrication involves a modified SU-8 molding to achieve truncated-cone-shaped pillars, polydimethylsiloxane micromolding, and hot embossing of biodegradable polymers. The developed plug filter is 500 μm long with base and apex plane diameters of 500 and 300 μm, respectively, and incorporates a laser-drilled through-hole with 44-μm effective diameter in the center.


Inducible nitric oxide synthase as a possible target in hypertension.
Nitric oxide (NO) is an important vasodilator produced by vascular endothelium. Its enzymatic formation is derived from three different synthases: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) synthases. While relatively small amounts of NO produced by eNOS are important to cardiovascular homeostasis, high NO levels produced associated with iNOS activity may have detrimental consequences to the cardiovascular system and contribute to hypertension. In this article, we reviewed current literature and found mounting evidence indicating that increased iNOS expression and activity contribute to the pathogenesis of hypertension and its complications. Excessive amounts of NO produced by iNOS up-regulation can react with superoxide anions forming peroxynitrite, thereby promoting nitrosative stress and endothelial dysfunction. In addition, abnormal iNOS activity can up-regulate arginase activity, allowing it to compete with eNOS for L-arginine, thereby resulting in reduced NO bioavailability. This may also lead to eNOS uncoupling with enhanced production of superoxide anions instead of NO. All these alterations mediated by iNOS apparently contribute to hypertension and its complications. We also reviewed current evidence showing the effects of iNOS inhibitors on different animal models of hypertension. iNOS inhibition apparently exerts antihypertensive effects, decreases oxidative and nitrosative stress, and improves vascular function. Together, these studies highlight the possibility that iNOS is a potential pharmacological target in hypertension.


Protein mass spectrometry detects multiple bloodmeals for enhanced Chagas disease vector ecology.
Chagas disease, a neglected tropical disease endemic in Latin America, is caused by the protozoan parasite Trypanosoma cruzi and is responsible for significant health impacts, especially in rural communities. The parasite is transmitted by insect vectors in the Triatominae subfamily and due to lack of vaccines and limited treatment options, vector control is the main way of controlling the disease. Knowing what vectors are feeding on directly enhances our understanding of the ecology and biology of the different vector species and can potentially aid in engaging communities in active disease control, a concept known as Ecohealth management. We evaluated bloodmeals in rural community, house-caught insect vectors previously evaluated for bloodmeals via DNA analysis as part of a larger collaborative project from three countries in Central America, including Guatemala. In addition to identifying bloodmeals in 100% of all samples using liquid chromatography tandem mass spectrometry (LC-MS/MS) (n = 50), strikingly for 53% of these samples there was no evidence of a recent bloodmeal by DNA-PCR. As individual vectors often feed on multiple sources, we developed an enhanced detection pipeline, and showed the ability to quantify a bloodmeal using stable-isotope-containing synthetic references peptides, a first step in further exploration of species-specific bloodmeal composition. Furthermore, we show that a lower resolution mass spectrometer is sufficient to correctly identify taxa from bloodmeals, an important and strong attribute of our LC-MS/MS-based method, opening the door to using proteomics in countries where Chagas disease is endemic.


The Uncinate Process First Approach in Laparoscopic Pancreaticoduodenectomy: A Single-institution Experience.
Limited studies regarding the uncinate process first in laparoscopic pancreaticoduodenectomy (LPD) have been reported. The objective of this study was to evaluate the feasibility, safety, and efficacy of LPD using the uncinate process first approach. This is a retrospective study of selected patients who underwent LPD using the uncinate process first approach at our center between between June 2015 and January 2017. Clinical characteristics and intraoperative and postoperative data were retrospectively analyzed. LPD was performed successfully in 45 patients. The median operative time was 410±68 minutes and the median loss of blood was 258±50 mL. Intraoperative frozen section histologic analyses revealed that margin-negative resections were negative in all cases. The median first flatus time was 2±1 day, and median diet start time was 3±1.5 day. The median postoperative hospital stay was 13±4 day. There were no deaths within 30 days following LPD. The mean number of lymph nodes removed was 20±5. The overall morbidity rate was 20%. LPD with the uncinate process first approach well combines the benefits of laparoscopy with low risk of postoperative complications and high rate of curative resection.


Potential therapeutic role of glutamate transporter 1 for the treatment of alcohol dependence.
Evidence has demonstrated that deficits in glutamate transmission impair neurocircuits involved in drug abuse or drug-seeking behaviour and affect many aspects of neuroplasticity associated with alcohol and drug addiction. Alcohol-seeking behaviour is promoted by increased glutamate transmission in key regions of the mesocorticolimbic reward circuit, including the nucleus accumbens and prefrontal cortex. Glutamate transmission or glutamate uptake is regulated by a number of glutamate transporters in the brain regions. Among these glutamate transporters, glutamate transporter 1 (GLT1; its human homolog is the excitatory amino acid transporter 2, EAAT2) regulates the removal of majority of the extracellular glutamate. The role of GLT1 has been tested in alcohol and other drugs of abuse models with dysfunction in glutamate transmission. We recently reported that treatment of alcohol-preferring rats with compounds ceftriaxone and GPI-1046, known to upregulate GLT1 levels, showed reduction in alcohol intake and attenuation of relapse-like ethanol-drinking behaviour. Furthermore, we demonstrated that upregulation of GLT1 was associated with attenuation of cue-induced cocaine relapse. Together, we suggest that GLT1 is considered as a potential therapeutic target for the treatment of drug dependence, including alcohol. The aim of this critical review was to discuss the potential therapeutic role of GLT1 for the treatment of alcohol dependence. Dysfunction of glutamate transmission has been suggested to impair neurocircuits involved in alcohol dependence, which affect neuroplasticity that is associated with ethanol intake.


Initiation and exacerbation of autoimmune demyelination of the central nervous system via virus-induced molecular mimicry: implications for the pathogenesis of multiple sclerosis.
Epidemiological studies indicate that infectious agents are important in the pathogenesis of multiple sclerosis (MS). Our previous reports showed that the infection of SJL mice with a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV) engineered to express a naturally occurring Haemophilus influenzae-encoded molecular mimic (HI574-586) of an immunodominant self-myelin proteolipid protein epitope (PLP139-151) induced a rapid-onset demyelinating disease associated with the activation of PLP139-151-specific Th1 responses. The current results extend our previous findings in four critical respects. We show that disease initiation by the H. influenzae mimic is prevented by tolerance to the self PLP139-151 epitope, definitively proving the occurrence of infection-induced molecular mimicry. We demonstrate that the H. influenzae mimic epitope can be processed from the flanking sequences within the native mimic protein. We show that the H. influenzae mimic epitope only induces an immunopathologic self-reactive Th1 response and subsequent clinical disease in the context of the TMEV infection and not when administered in complete Freund's adjuvant, indicating that molecular mimicry-induced disease initiation requires virus-activated innate immune signals. Lastly, we show that the infection of SJL mice with TMEV expressing the H. influenzae mimic can exacerbate a previously established nonprogressive autoimmune disease of the central nervous system. Collectively, these findings illustrate the evolving mechanisms by which virus infections may contribute to both the initiation and exacerbation of autoimmune diseases, and they have important implications for MS pathogenesis.


Guiding Binocular Saccades during Reading: A TMS Study of the PPC.
Reading is an activity based on complex sequences of binocular saccades and fixations. During saccades, the eyes do not move together perfectly: saccades could end with a misalignment, compromising fused vision. During fixations, small disconjugate drift can partly reduce this misalignment. We hypothesized that maintaining eye alignment during reading involves active monitoring from posterior parietal cortex (PPC); this goes against traditional views considering only downstream binocular control. Nine young adults read a text; transcranial magnetic stimulation (TMS) was applied over the PPC every 5 ± 0.2 s. Eye movements were recorded binocularly with Eyelink II. Stimulation had three major effects: (1) disturbance of eye alignment during fixation; (2) increase of saccade disconjugacy leading to eye misalignment; (3) decrease of eye alignment reduction during fixation drift. The effects depend on the side; the right PPC was more involved in maintaining alignment over the motor sequence. Thus, the PPC is actively involved in the control of binocular eye alignment during reading, allowing clear vision. Cortical activation during reading is related to linguistic processes and motor control per se. The study might be of interest for the understanding of deficits of binocular coordination, encountered in several populations, e.g., in children with dyslexia.


Liver membrane proteome glycosylation changes in mice bearing an extra-hepatic tumor.
Cancer is well known to be associated with alterations in membrane protein glycosylation (Bird, N. C., Mangnall, D., and Majeed, A. W. (2006) Biology of colorectal liver metastases: A review. J. Surg. Oncol. 94, 68-80; Dimitroff, C. J., Pera, P., Dall'Olio, F., Matta, K. L., Chandrasekaran, E. V., Lau, J. T., and Bernacki, R. J. (1999) Cell surface n-acetylneuraminic acid alpha2,3-galactoside-dependent intercellular adhesion of human colon cancer cells. Biochem. Biophys. Res. Commun. 256, 631-636; and Arcinas, A., Yen, T. Y., Kebebew, E., and Macher, B. A. (2009) Cell surface and secreted protein profiles of human thyroid cancer cell lines reveal distinct glycoprotein patterns. J. Proteome Res. 8, 3958-3968). Equally, it has been well established that tumor-associated inflammation through the release of pro-inflammatory cytokines is a common cause of reduced hepatic drug metabolism and increased toxicity in advanced cancer patients being treated with cytotoxic chemotherapies. However, little is known about the impact of bearing a tumor (and downstream effects like inflammation) on liver membrane protein glycosylation. In this study, proteomic and glycomic analyses were used in combination to determine whether liver membrane protein glycosylation was affected in mice bearing the Engelbreth-Holm Swarm sarcoma. Peptide IPG-IEF and label-free quantitation determined that many enzymes involved in the protein glycosylation pathway specifically; mannosidases (Man1a-I, Man1b-I and Man2a-I), mannoside N-acetylglucosaminyltransferases (Mgat-I and Mgat-II), galactosyltransferases (B3GalT-VII, B4GalT-I, B4GalT-III, C1GalT-I, C1GalT-II, and GalNT-I), and sialyltransferases (ST3Gal-I, ST6Gal-I, and ST6GalNAc-VI) were up-regulated in all livers of tumor-bearing mice (n = 3) compared with nontumor bearing controls (n = 3). In addition, many cell surface lectins: Sialoadhesin-1 (Siglec-1), C-type lectin family 4f (Kupffer cell receptor), and Galactose-binding lectin 9 (Galectin-9) were determined to be up-regulated in the liver of tumor-bearing compared with control mice. Global glycan analysis identified seven N-glycans and two O-glycans that had changed on the liver membrane proteins derived from tumor-bearing mice. Interestingly, α (2,3) sialic acid was found to be up-regulated on the liver membrane of tumor-bearing mice, which reflected the increased expression of its associated sialyltransferase and lectin receptor (siglec-1). The overall increased sialylation on the liver membrane of Engelbreth-Holm Swarm bearing mice correlates with the increased expression of their associated glycosyltransferases and suggests that glycosylation of proteins in the liver plays a role in tumor-induced liver inflammation.


Histological assessment of new bone formation with biomimetic scaffold in posterolateral lumbar spine fusion.
Spinal fusion procedures often require the use of bone grafts (autograft or allograft) to help bone healing and to increase stability. However, the application of autografts is frequently limited by donor site morbidity. In recent years, different synthetic bone substitutes have been introduced in the clinical practice to overcome these limitations. The purpose of this paper is to report a case where a biomimetic, synthetic and osteoconductive bone graft substitute was successfully implanted in a patient during lumbar spine arthrodesis. The case of a 58-year-old female subjected to lumbar spine arthrodesis with bone augmentation is described. The bone graft substitute RegenOss® (Finceramica, Faenza, Italy) was implanted during spinal arthrodesis. The successful bone integration was evaluated by X-rays. After 11 months, the patient underwent a second surgery due to spine imbalance; the debris of the bone graft was therefore collected and analyzed by macroscopic evaluation and by histology. The bone substitute was successfully implanted during a spinal arthrodesis procedure. Histologic evaluation of the removed bone graft debris showed the complete resorption of the implant and the formation of new bone, which was well integrated with the host bone. This bone substitute may represent a safe and effective alternative to autologous bone grafts, avoiding adverse events related to donor-site morbidity.


Changes in tibial bone density measured from standard radiographs in cemented and uncemented total knee replacements after ten years' follow-up.
Stress shielding resulting in diminished bone density following total knee replacement (TKR) may increase the risk of migration and loosening of the prosthesis. This retrospective study was designed to quantify the effects of the method of fixation on peri-prosthetic tibial bone density beneath cemented and uncemented tibial components of similar design and with similar long-term survival rates. Standard radiographs taken between two months and 15 years post-operatively were digitised from a matched group of TKRs using cemented (n = 67) and uncemented (n = 67) AGC tibial prostheses. Digital radiograph densitometry was used to quantify changes in bone density over time. Age, length of follow-up, gender, body mass index and alignment each significantly influenced the long-term pattern of peri-prosthetic bone density. Similar long-term changes in density irrespective of the method of fixation correlated well with the high rate of survival of this TKR at 20 years, and suggest that cemented and uncemented fixation are both equally viable.


Combined general and epidural anaesthesia versus general anaesthesia for radical cystectomy.
The basic objective of the study is to present the effects of two types of anesthesia, general and combined general and epidural, on intraoperative bleeding and to present the effect of epidural analgesia during the postoperative period in radical cystecomy. Subjects who received general and epidural anesthesia had on the average 28.5% less bleeding than those who only had general anesthesia. Patients who received postoperative epidural analgesia had statistically significantly better analgesia during the postoperative period than those who were administered Tramadol intramuscularly.


Environmental insights from high-resolution (SIMS) sulfur isotope analyses of sulfides in Proterozoic microbialites with diverse mat textures.
In modern microbial mats, hydrogen sulfide shows pronounced sulfur isotope (δ34 S) variability over small spatial scales (~50‰ over <4 mm), providing information about microbial sulfur cycling within different ecological niches in the mat. In the geological record, the location of pyrite formation, overprinting from mat accretion, and post-depositional alteration also affect both fine-scale δ34 S patterns and bulk δ34 Spyrite values. We report μm-scale δ34 S patterns in Proterozoic samples with well-preserved microbial mat textures. We show a well-defined relationship between δ34 S values and sulfide mineral grain size and type. Small pyrite grains (<25 μm) span a large range, tending toward high δ34 S values (-54.5‰ to 11.7‰, mean: -14.4‰). Larger pyrite grains (>25 μm) have low but equally variable δ34 S values (-61.0‰ to -10.5‰, mean: -44.4‰). In one sample, larger sphalerite grains (>35 μm) have intermediate and essentially invariant δ34 S values (-22.6‰ to -15.6‰, mean: -19.4‰). We suggest that different sulfide mineral populations reflect separate stages of formation. In the first stage, small pyrite grains form near the mat surface along a redox boundary where high rates of sulfate reduction, partial closed-system sulfate consumption in microenvironments, and/or sulfide oxidation lead to high δ34 S values. In another stage, large sphalerite grains with low δ34 S values grow along the edges of pore spaces formed from desiccation of the mat. Large pyrite grains form deeper in the mat at slower sulfate reduction rates, leading to low δ34 Ssulfide values. We do not see evidence for significant 34 S-enrichment in bulk pore water sulfide at depth in the mat due to closed-system Rayleigh fractionation effects. On a local scale, Rayleigh fractionation influences the range of δ34 S values measured for individual pyrite grains. Fine-scale analyses of δ34 Spyrite patterns can thus be used to extract environmental information from ancient microbial mats and aid in the interpretation of bulk δ34 Spyrite records.


SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities.
Traversal from G1 to S-phase in cycling cells of budding yeast is dependent on the destruction of the S-phase cyclin/CDK inhibitor SIC1. Genetic data suggest that SIC1 proteolysis is mediated by the ubiquitin pathway and requires the action of CDC34, CDC4, CDC53, SKP1, and CLN/CDC28. As a first step in defining the functions of the corresponding gene products, we have reconstituted SIC1 multiubiquitination in DEAE-fractionated yeast extract. Multiubiquitination depends on cyclin/CDC28 protein kinase and the CDC34 ubiquitin-conjugating enzyme. Ubiquitin chain formation is abrogated in cdc4ts mutant extracts and assembly restored by the addition of exogenous CDC4, suggesting a direct role for this protein in SIC1 multiubiquitination. Deletion analysis of SIC1 indicates that the N-terminal 160 residues are both necessary and sufficient to serve as substrate for CDC34-dependent ubiquitination. The complementary C-terminal segment of SIC1 binds to the S-phase cyclin CLB5, indicating a modular structure for SIC1.


Transferrin promotes chondrogenic differentiation in condylar growth through inducing autophagy via ULK1-ATG16L1 axis.
Skeletal mandibular hypoplasia (SMH) is one of the most common skeletal craniofacial deformities in orthodontics, which was often accompanied by impaired chondrogenesis and increasing apoptosis of condylar chondrocytes. Therefore, protecting chondrocytes from apoptosis and promoting chondrogenesis in condylar growth is vital for treatment of SMH patients. Transferrin (TF) was highly expressed in condylar cartilage of newborn mice and was gradually declined as the condyle ceased growing. Interestingly, serum level of TF in SMH patients was significantly lower than normal subjects. Hence, the aim of our study was to investigate the effect of TF on survival and differentiation of chondrocytes and condylar growth. First, we found that TF protected chondrogenic cell line ATDC5 cells from hypoxia-induced apoptosis and promoted proliferation and chondrogenic differentiation in vitro. Second, TF promoted chondrogenic differentiation and survival through activating autophagic flux. Inhibiting autophagic flux markedly blocked the effects of TF. Third, TF significantly activated ULK1-ATG16L1 axis. Silencing either transferrin receptor (TFRC), ULK1/2 or ATG16 significantly blocked the autophagic flux induced by TF, as well as its effect on anti-apoptosis and chondrogenic differentiation. Furthermore, we established an organoid culture model of mandible ex vivo and found that TF significantly promoted condylar growth. Taken together, our study unraveled a novel function of TF in condylar growth that TF protected chondrocytes from hypoxia-induced apoptosis and promoted chondrogenic differentiation through inducing autophagy via ULK1-ATG16L1 axis, which demonstrated that TF could be a novel growth factor of condylar growth and shed new light on developing treatment strategy of SMH patients.


Atypical presentation of pleural tuberculosis: CT findings.
Contrast enhanced CT examination of a 22-year-old male with pleuritic chest pain showed pleural-based nodular thickening and masses without any parenchymal involvement or mediastinal lymphadenopathy. Pathological examination following right parietal pleural decortication showed multiple granulomas with caseation necrosis typical of tuberculosis. Pleural tuberculosis presenting with multiple pleural nodules and masses without parenchymal involvement or lymphadenopathy has, to our knowledge, never been reported in the English literature.


Non-pharmacological therapies for pain management in Parkinson's disease: A systematic review.
Among the various non-motor symptoms of Parkinson's disease (PD), pain is often cited as the most common and debilitating feature. Currently, the literature contains gaps in knowledge with respect to the various forms of treatment available, particularly non-pharmacological therapies. Thus, the purpose of this systematic review is to provide an examination of the literature on non-pharmacological therapies for pain in PD. We compared the findings of research articles indexed within various literature databases related to non-pharmacological treatments of pain in PD patients. Our review identified five major non-pharmacological methods of pain therapy in PD: acupuncture, hydrotherapy, massage therapy, neuromodulation, and exercise. Treatments such as exercise therapy found a reduction in pain perception due to various factors, including the analgesic effects of neurotransmitter release during exercise and increased activity leading to a decrease in musculoskeletal rigidity and stiffness. By the same token, hydrotherapy has been shown to reduce pain perception within PD patients, with authors often citing a combined treatment of exercise and hydrotherapy as an effective treatment for pain management. Multiple methods of neurostimulation were also observed, including deep brain stimulation and spinal cord stimulation. Deep brain stimulation showed efficacy in alleviating certain pain types (dystonic and central), while not others (musculoskeletal). Hence, patients may consider deep brain stimulation as an additive procedure for their current treatment protocol. On the other hand, spinal cord stimulation showed significant improvement in reducing VAS scores for pain. Finally, although the literature on massage therapy and acupuncture effectiveness on pain management is limited, both have demonstrated a reduction in pain perception, with common reasons such as tactile stimulation and release of anti-nociceptive molecules in the body. Although literature pertaining to non-pharmacological treatments of pain in PD is sparse, there is copious support for these treatments as beneficial to pain management. Further exploration in the form of clinical trials is warranted to assess the efficacy of such therapies.


Reduced concentrations of arginine vasopressin and MHPG in lumbar CSF of patients with Korsakoff's psychosis.
The concentrations of arginine vasopressin (AVP), somatostatin (SS), and the primary brain metabolites of norepinephrine (MHPG), serotonin (5-HIAA), and dopamine (HVA) were measured in samples of lumbar CSF obtained from ten amnesics with Korsakoff's psychosis, four patients with a history of Korsakoff's psychosis who had recovered from the amnesic symptoms of this disease, and control subjects. Significant deficits were observed in the amnesic group for AVP and MHPG, but not for the other substances measured. Subjects who had recovered from the amnesic symptoms of Korsakoff's psychosis had increased concentrations of AVP and MHPG, but not of SS or the other monoamine metabolites.


Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes.
There is an active and growing interest in cannabis female inflorescence (Cannabis sativa) for medical purposes. Therefore, a definition of its quality attributes can help mitigate public health risks associated with contaminated, substandard, or adulterated products and support sound and reproducible basic and clinical research. As cannabis is a heterogeneous matrix that can contain a complex secondary metabolome with an uneven distribution of constituents, ensuring its quality requires appropriate sampling procedures and a suite of tests, analytical procedures, and acceptance criteria to define the identity, content of constituents (e.g., cannabinoids), and limits on contaminants. As an independent science-based public health organization, United States Pharmacopeia (USP) has formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key cannabis quality attributes. The consensus within the expert panel was that these specifications should differentiate between cannabis chemotypes. Based on the secondary metabolite profiles, the expert panel has suggested adoption of three broad categories of cannabis. These three main chemotypes have been identified as useful for labeling based on the following cannabinoid constituents: (1) tetrahydrocannabinol (THC)-dominant chemotype; (2) intermediate chemotype with both THC and cannabidiol (CBD); and (3) CBD-dominant chemotype. Cannabis plants in each of these chemotypes may be further subcategorized based on the content of other cannabinoids and/or mono- and sesquiterpene profiles. Morphological and chromatographic tests are presented for the identification and quantitative determination of critical constituents. Limits for contaminants including pesticide residues, microbial levels, mycotoxins, and elemental contaminants are presented based on toxicological considerations and aligned with the existing USP procedures for general tests and assays. The principles outlined in this review should be able to be used as the basis of public quality specifications for cannabis inflorescence, which are needed for public health protection and to facilitate scientific research on cannabis safety and therapeutic potential.


Adenylate cyclase activation shifts the phase of a circadian pacemaker.
Forskolin, a highly specific activator of adenylate cyclase, produced both delay and advance phase shifts of the circadian rhythm recorded from the isolated eye of the marine mollusk Aplysia. The phase dependence of the response to forskolin was identical to that with serotonin, which also stimulates adenylate cyclase in the eye. The ability of agents to activate adenylate cyclase in homogenates was correlated with their ability to shift the phase of the circadian oscillator. These results along with earlier findings show that adenosine 3',5'-monophosphate mediates the effect of serotonin on the rhythm and regulates the phase of the circadian pacemaker in the eye of Aplysia.


Optogenetics 2.0: challenges and solutions towards a quantitative probing of neural circuits.
To exploit the full potential of optogenetics, we need to titrate and tailor optogenetic methods to emulate naturalistic circuit function. For that, the following prerequisites need to be met: first, we need to target opsin expression not only to genetically defined neurons per se, but to specifically target a functional node. Second, we need to assess the scope of optogenetic modulation, i.e. the fraction of optogenetically modulated neurons. Third, we need to integrate optogenetic control in a closed loop setting. Fourth, we need to further safe and stable gene expression and light delivery to bring optogenetics to the clinics. Here, we review these concepts for the human and rodent brain.


Evidence-based medicine: a means of improving clinical outcome and cost-benefit ration.
Evidence-based medicine (EBM) is a new way of conceiving clinical practice based on the need to both improve the approach to the patient's care and rationalize the costs. EBM is thus defined as "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients". To realize this project a cultural change is mandatory, involving doctors, health planners, and users, whose empowerment seems pivotal. Reasoning in terms of efficacy or even better of cost-benefit ratio will certainly improve the clinical outcome and the allocation of resources.


Relationships between exterior views and nurse stress: an exploratory examination.
Examine the relationships between acute stress and alertness of nurse, and duration and content of exterior views from nurse work areas. Nursing is a stressful job, and the impacts of stress on performance are well documented. Nursing stress, however, has been typically addressed through operational interventions, although the ability of the physical environment to modulate stress in humans is well known. This study explores the outcomes of exposure to exterior views from nurse work areas. A survey-based method was used to collect data on acute stress, chronic stress, and alertness of nurses before and after 12-hour shifts. Control measures included physical environment stressors (that is, lighting, noise, thermal, and ergonomic), organizational stressors, workload, and personal characteristics (that is, age, experience, and income). Data were collected from 32 nurses on 19 different units at two hospitals (part of Children's Healthcare of Atlanta) in November 2006. Among the variables considered in the study view duration is the second most influential factor affecting alertness and acute stress. The association between view duration and alertness and stress is conditional on the exterior view content (that is, nature view, non-nature view). Of all the nurses whose alertness level remained the same or improved, almost 60% had exposure to exterior and nature view. In contrast, of all nurses whose alertness levels deteriorated, 67% were exposed to no view or to only non-nature view. Similarly, of all nurses whose acute stress condition remained the same or reduced, 64% had exposure to views (71% of that 64% were exposed to a nature view). Of nurses whose acute stress levels increased, 56% had no view or only a non-nature view. Although long working hours, overtime, and sleep deprivation are problems in healthcare operations, the physical design of units is only now beginning to be considered seriously in evaluating patient outcomes. Access to a nature view and natural light for care-giving staff could bear direct as well as indirect effects on patient outcomes.


Clinical experience with insulin detemir in patients with type 2 diabetes from the near East countries.
This study aimed at determining the clinical safety and efficacy of insulin detemir (IDet) in combination with oral anti-diabetic drugs (OADs) in type 2 diabetes (T2D) patients from four Near East Countries (Israel, Jordan, Pakistan and Lebanon). This prospective observational study included T2D patients previously on OADs and newly diagnosed patients initiating IDet with or without OADs, at the discretion of physicians. Safety objectives included evaluation of hypoglycemia and adverse drug reactions (ADRs) from baseline to Week 24. Efficacy outcomes included baseline to Week 24 changes in glucose control parameters (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG] and post-breakfast post-prandial plasma glucose [PPPG]). Change in body weight during this period was also assessed. A total of 2,155 patients (mean ± SD: age 57.1 ± 11.0 years, BMI 29.4 ± 5.1 kg/m(2), average diabetes duration 9.2 ± 5.4 years) were included. IDet dose at baseline was 0.20 ± 0.09 U/kg titrated up to 0.34 ± 0.14 U/kg by Week 24. From baseline to Week 24, the total number of hypoglycemic episodes increased from 1.30 to 1.37 events/patient-year, while major hypoglycemic episodes decreased from 0.15 to 0.02 events/patient-year. A total of 9 ADRs were reported, of which one event was a serious ADR. Statistically significant improvements in glucose control were reported from baseline to Week 24 (HbA1c: 9.6 ± 1.6% vs. 7.6 ± 1.1%; FPG: 201.5 ± 59.5 mg/dL vs. 124.9 ± 31.6 mg/dL; PPPG: 264.2 ± 65.7 mg/dL vs. 167.2 ± 36.8 mg/dL; all p < 0.0001). Body weight did not change significantly after 24 weeks of IDet therapy. IDet therapy in combination with OADs improved glycemic control without increasing the risk of hypoglycemia or weight gain.


[NO-Ergic transmission and NO as a volume transmitter. Effect of NO on mechanisms of synaptic plasticity and epileptogenesis].
Nitric oxide (NO) is a universal intercellular messenger and the only molecule known so far, which satisfies all requirements of the volume (extrasynaptic) neurotransmitter. The effect of NO on target cells is so read in the four-dimensional coordinate system by combining both the spatial and the temporal components of the nervous activity. In this review, the authors, based on literature data and own studies, present a detailed analysis of properties of NO as a volume neurotransmitter at formation of phenomena of synaptic plasticity in norm and pathology. An evaluation is given of cytotoxic and neuroprotective effects of NO under conditions of the brain tissue ischemia and phenomena of hyperexcitability in foci of epileptiform activity. It is emphasized that the long-term potentiation and long-term depression, phenomena of physiological plasticity, can be transformed into pathological plasticity at disturbances of equilibrium between neuroprotective and neurotoxic effects of NO.


Implementation of standards for individual monitoring in Europe.
A large number of standards are available for radiation protection and individual monitoring purposes. They are published by various organisations, international and national. Moreover, the increasing policy of "Quality" applied to individual monitoring requires the implementation of standards on Quality Assurance (QA) both in technical and management aspects of a dosimetric service. Implementation of standards is not mandatory; therefore, varying degrees of implementation can be found in different European countries. However, for a number of good reasons, a degree of harmonisation within the European Union (EU) of the requirements and procedures for individual monitoring would be desirable. Harmonisation as applied to dosimetric services does not mean that they should all follow exactly the same procedures, but that they should aim to meet the same general requirements, and their results should be comparable. This article aims to compile information on the use of all standards applied within individual monitoring practices, be it on the calibration of dosemeters or on the QA procedures to be applied to the overall dose evaluation process. Both "technical standards" and "quality standards" will be discussed. A list of documents of relevance to subjects such as recommendations and requirements in the field of individual monitoring, whose application could help in the harmonisation of procedures, will also be given. As it is agreed that implementation of quality standards is a relevant framework within which harmonisation can be achieved, guidance on the implementation of quality standards in a dosimetric service is given. Accreditation and approval of dosimetric services will be of relevance in the process of harmonisation of individual monitoring within the EU. In this article, a discussion of various procedures and the meaning of both forms of recognition is also provided. Although most of the text applies to the monitoring of internal and external exposure to ionising radiation, the emphasis of this practical guidance is on monitoring for external radiation with passive dosemeters.


High-throughput ultrasound neuromodulation in awake and freely behaving rats.
Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity.


Caspase-3 deficiency reveals a physiologic role for Smac/DIABLO in regulating programmed cell death.
Inhibitor of apoptosis protein (IAP)-binding proteins such as Grim, Reaper and HID have been shown to exert a critical role in regulating caspase activity in species such as D. Melanogaster. However, a comparable role for the mammalian homologue of second mitochondrial-derived activator of caspase/direct IAP-binding protein with low pI (Smac/DIABLO) has yet to be clearly established in vivo. Despite tremendous interest in recent years in the use of so-called Smac mimetics to enhance chemotherapeutic potency, our understanding of the true physiologic nature of Smac/DIABLO in regulating programmed cell death (PCD) remains elusive. In order to critically evaluate the role of Smac/DIABLO in regulating mammalian PCD, deficiency of caspase-3 was used as a sensitizing mutation in order to reduce aggregate levels of executioner caspase activity. We observe that combinatorial deletion of Diablo and Casp3, but neither alone, results in perinatal lethality in mice. Consistent with this, examination of both intrinsic and extrinsic forms of PCD in lines of murine embryonic fibroblasts demonstrate that loss of Smac/DIABLO alters both caspase-dependent and caspase-independent intrinsic PCD. Comparative small interfering RNA inhibition studies of X-linked inhibitor of apoptosis, cellular inhibitor of apoptosis (cIAP)-1, cIAP-2, caspase-6 and -7 in both wild-type and Casp3/Diablo DKO mouse embryonic fibroblast lineages, supports a model in which Smac/DIABLO acts to enhance the early phase executioner caspase activity through the modulation of inhibitory interactions between specific IAP family members and executioner caspases-3 and -7.


Incidence and Outcome of Neurologic Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Patients With Melanoma.
Neurological immune related adverse events (n-irAEs) reportedly occur in up to 8% of patients treated with immune-checkpoints inhibitors (ICI) of all age groups. We investigated the association between age and n-irAEs in patients treated with ICI, and examined the impact of n-irAEs on survival outcomes in a large cohort of melanoma patients. We conducted a retrospective analysis of advanced melanoma patients treated with ICI at Ella Institute for Immuno-oncology and Melanoma between 1/1/2015 and 20/04/2022. The outcomes of interest were defined as the investigation of age-related frequency and severity of n-irAE, the need for ICI interruption, the treatment required for n-irAE management, the safety of ICI reintroduction, and n-irAE's impact on survival. ICI was administered to 937 patients. At least one IrAE occurred in 73.5% (n=689) of them. Amongst the study population, 8% (n=76) developed a n-irAE, with a median age of 66 in females and 68 in males at onset. Median follow-up after n-irAE was 1,147 days (IQR: 1091.5 range: 3938). Fewer irAEs occurred in patients older than 70 years (median: 3 events, p=0.04, CI:2.5-4.7), while specifically colitis and pneumonitis were more common in the 18-60 age group (p=0.03 95% CI:0.8,0.38, p=0.009, 95% CI:0.06,0.2). Grade ≥ 3 toxicity was seen in 35.5% of patients across age groups. Median time from ICI administration to n-irAE development was 48 days across age groups. Common n-irAE phenotypes were myositis (44.7%), encephalitis (10.5%), and neuropathy (10.5%). N-irAE required hospitalization in 40% of patients, and steroids treatment in 46% with a median of 4 days from n-irAE diagnosis to steroids treatment initiation. Nine patients needed second-line immunosuppressive treatment. Rechallenge did not cause additional n-irAE in 71% of patients. Developing n-irAE (HR=0.4, 95% CI:0.32,0.77) or any irAE (HR=0.7195% CI:0.56,0.88) were associated with longer survival. Neurological-irAEs are a relatively common complication of ICI (8% of our cohort). Older age was not associated with its development or severity, in contrast with non-neurological-irAE which occurred less frequently in the elderly. Rechallenge did not result in life-threatening AEs. Development of any irAE was associated with longer survival, this association was stronger with n-irAE.


[Ultrasonographic screening of the cranium in risk newborn (author's transl)].
This article goes into the question whether prophylactic examination of the cranium of risk newborn via ultrasonography would be meaningful or not. A total of 443 patients was examined during the period January to September 1980. Of these, 160 had shown clinical signs, whereas the remaining 283 clinically apparently normal risk newborn were subjected to ultrasonography before discharge. In 21 cases, findings were pathological (7.4%). Ventricles which were pathologically deformed and of plump shape, represented the main group, followed by hydrocephalus, subdural effusion and intraventricular haemorrhage.


Endoscopic factors in the diagnosis of colorectal dysplasia in chronic inflammatory bowel disease.
Surveillance colonoscopy in inflammatory bowel diseases (IBDs) is advocated for early diagnosis of neoplasia but is imperfect because some patients develop cancer despite surveillance. We sought to determine if any endoscopic factors during surveillance colonoscopy were associated with the diagnosis of colorectal dysplasia before the development of cancer. We reviewed the Mayo Clinic endoscopic database and medical records of patients with IBD who underwent surveillance colonoscopy between January 2002 and November 2003. Associations were sought between endoscopic factors and the diagnosis of dysplasia. Among 635 IBD patients, 24 (3.8%) had flat dysplasia and 12 (1.9%) had IBD-related polypoid dysplasia. In 28 patients (4.4%), sporadic tubular adenoma was identified. Colonoscopies in which flat dysplasia was identified varied in duration from 7 to 81 minutes (median, 24.5 min) compared with 3 to 70 minutes (median, 22 min) for those in which dysplasia was not found. Using logistic regression analysis, we found that every additional minute in total colonoscopy time increased the flat dysplasia diagnosis rate by 3.5% (P = 0.0157). There was a significant correlation between median surveillance colonoscopy duration per endoscopist and flat dysplasia diagnosis rate (P = 0.0066). The number of biopsies taken during the procedures with flat dysplasia ranged from 6 to 36 (median, 28) compared with 2 to 54 (median, 25) in those without flat dysplasia. There was no significant effect of biopsy number of dysplasia diagnosis. Our results show that the practice of surveillance colonoscopy varies greatly among endoscopists, and longer procedure duration is significantly associated with the likelihood of dysplasia diagnosis.


Distinct subcellular localization and mRNA expression of neuronal nitric oxide synthase in the nucleus dorsalis and red nucleus and their correlation with inducible transcription factors after spinal cord hemisection.
We previously reported on the differential expression of neuronal nitric oxide synthase (nNOS) in neurons of the nucleus dorsalis (ND) and red nucleus (RN), as well as differential roles of nitric oxide (NO) in these two distinct groups' neurons characterized with different nNOS phenotypes after lower thoracic spinal cord hemisection. To further understand the enzyme, nNOS expression was studied at the subcellular and mRNA levels by using electron microscopic immunohistochemistry (EM-IHC) and in situ hybridization respectively. Possible transcriptional regulation by c-Jun or CREB in the differential nNOS expression in both ND and RN neurons was also studied. nNOS mRNA was not found in the normal ND neurons, but was shown in the normal RN neurons. After spinal cord hemisection, nNOS mRNA was induced in the ipsilateral ND, while upregulated on both sides of the RN, which preceded protein induction or upregulation. By EM-IHC, nNOS immunoreaction products were predominantly bound to the membrane of the mitochondria, rough endoplasmic reticulum (rER), Golgi apparatus, and nuclear envelope in the RN neurons of normal rats as well as rats subjected to spinal cord hemisection. In contrast, nNOS-immunoreactive deposits in the experimental ND neurons were found to be mainly granular, being dispersed throughout the cytoplasmic matrix. It is speculated that the differential subcellular localizationof nNOS indicates that axotomy may trigger different nNOS transcripts and lead to different nNOS isoform expression in the normally non-nNOS- and normally nNOS-containing neurons. c-Jun was induced in the ipsilateral ND neuronsand upregulated only in the contralateral RN neurons. Activation of CREB by phosphorylation was occasionally detectable in the ND neurons, but not in the RN neurons. Double-labeling data showed a large proportion of c-Jun and nNOS colocalization in neurons of the ipsilateral ND and contralateral RN after spinal cord hemisection. However, dissociation of nNOS expression kinetics with c-Jun was observed in the ipsilateral RN. The results implied that nNOS expression might not be under the direct transcriptional regulation by c-Jun, although it seemed to be closely related to the c-Jun expression.


SV40 deletion mutants lacking the 21-bp repeated sequences are viable, but have noncomplementable deficiencies.
We have constructed deletion mutants of simian virus 40 (SV40) lacking the two tandemly repeated copies or all three copies of the 21-bp repeated sequence located in the origin region. The mutants were viable, but had lower infectivities compared to the wild type. The mutant lacking two copies of the 21-bp repeat grew fairly well indicating that the one copy of the 21-bp repeat it contains is adequate. The other mutant lacking all the three copies of the 21-bp repeat was also viable but grew poorly. The viability of this mutant suggests that the upstream 72-bp repeated sequence compensates, though only partially, for the absence of the 21-bp repeat. The growth deficiencies of the deletion mutants could not be overcome by complementation with temperature-sensitive helper mutants providing either the early or the late functions of the virus, suggesting that the deficiencies lie in both early and late gene expression and/or in replication.


Association between conformational mutations in neuroserpin and onset and severity of dementia.
The aggregation of specific proteins is a common feature of the familial dementias, but whether the formation of neuronal inclusion bodies is a causative or incidental factor in the disease is not known. To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations. Five families with neurodegenerative disease and typical neuronal inclusions had biopsy or autopsy material available for further examination. Immunostaining confirmed that the inclusions were formed of neuroserpin aggregates, and the responsible mutations in neuroserpin were identified by sequencing of the neuroserpin gene (SERPINI1) in DNA from blood samples or from extraction of histology specimens. Molecular modelling techniques were used to predict the effect of the gene mutations on three-dimensional protein structure. Brain sections were stained and the topographic distribution of the neuroserpin inclusions plotted. Each of the families was heterozygous for an amino acid substitution that affected the conformational stability of neuroserpin. The least disruptive of these mutations (S49P), as predicted by molecular modelling, resulted in dementia after age 45 years, and presence of neuroserpin inclusions in only a few neurons. By contrast, the most severely disruptive mutation (G392E) resulted, at age 13 years, in progressive myoclonus epilepsy, with many inclusions present in almost all neurons. The findings provide evidence that inclusion-body formation is in itself a sufficient cause of neurodegeneration, and that the onset and severity of the disease is associated with the rate and magnitude of neuronal protein aggregation.


Effects of indole amides on lettuce and onion germination and growth.
Auxins, such as indole-3-acetic acid (IAA), are important in plant germination and growth, while physiological polyamines, such as putrescine, are involved in cell proliferation and differentiation, and their concentrations increase during germination. In this work, novel indole amides were synthesized in good yields by monoacylation of morpholine and unprotected symmetrical diamines with indole-3-carboxylic acid, a putative metabolite of IAA, possessing no auxin-like activity. These amides were tested for their effects on seed germination and growth of the radicles and shoots of Lactuca sativa (lettuce) and Allium cepa (onion) seedlings, at 100.0, 1.0, and 0.01 microM concentrations. Germination was generally stimulated, with the exception of amide 3, derived from morpholine, at 100 microM. On radicle and shoot growth, the effect of these compounds was predominantly inhibitory. Compound 3 was the best inhibitor of growth of lettuce and onion, at the highest concentration. Amides, such as propanil, among others, are described as having herbicidal activity.


Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation.
Metazoans viability depends on their ability to regulate metabolic processes and also to respond to harmful challenges by mounting anti-stress responses; these adaptations were fundamental forces during evolution. Central to anti-stress responses are a number of short-lived transcription factors that by functioning as stress sensors mobilize genomic responses aiming to eliminate stressors. We show here that increased expression of nuclear factor erythroid 2-related factor (Nrf2) in Drosophila activated cytoprotective modules and enhanced stress tolerance. However, while mild Nrf2 activation extended lifespan, high Nrf2 expression levels resulted in developmental lethality or, after inducible activation in adult flies, in altered mitochondrial bioenergetics, the appearance of Diabetes Type 1 hallmarks and aging acceleration. Genetic or dietary suppression of Insulin/IGF-like signaling (IIS) titrated Nrf2 activity to lower levels, largely normalized metabolic pathways signaling, and extended flies' lifespan. Thus, prolonged stress signaling by otherwise cytoprotective short-lived stress sensors perturbs IIS resulting in re-allocation of resources from growth and longevity to somatic preservation and stress tolerance. These findings provide a reasonable explanation of why most (if not all) cytoprotective stress sensors are short-lived proteins, and it also explains the build-in negative feedback loops (shown here for Nrf2); the low basal levels of these proteins, and why their suppressors were favored by evolution.


Two distinct but overlapping antibody binding sites in the pre-S(2) region of HBsAg localized within 11 continuous residues.
The fine specificity of the humoral immune response to the pre-S(2) region of the hepatitis B surface antigen was studied. It was demonstrated that the murine antibody response to the pre-S(2) region is focused on residues 133 through 143, and two distinct but overlapping epitopes were identified within 11 continuous residues. One epitope, defined by p133-139, is group specific, and the other epitope, defined by p137-143, is influenced by a subtype-dependent amino acid substitution at residue 141. However, the influence of residue 141 was "covert" in that it was only detected when synthetic antigens of 19 amino acids or smaller were used as the solid-phase ligand. The minimum size of both epitopes (p133-139 and p137-143) was seven amino acids. The physical and chemical form of the immunogen (i.e., protein vs peptide; conjugated vs free peptide) influenced antibody fine specificity. In quantitative antibody inhibition studies it was demonstrated that antibodies with nonoverlapping as well as overlapping fine specificities were capable of mutual inhibition. Finally, human HBV-infected, patient sera were shown to possess anti-pre-S(2) region antibodies that recognized sequences in common with the murine antisera. These results have implications relevant to the design of synthetic and recombinant second generation HBV vaccines and diagnostic reagents.


An In-Silico Evaluation of Anthraquinones as Potential Inhibitors of DNA Gyrase B of Mycobacterium tuberculosis.
The World Health Organization reported that tuberculosis remains on the list of the top ten threats to public health worldwide. Among the main causes is the limited effectiveness of treatments due to the emergence of resistant strains of Mycobacterium tuberculosis. One of the main drug targets studied to combat M. tuberculosis is DNA gyrase, the only enzyme responsible for regulating DNA topology in this specie and considered essential in all bacteria. In this context, the present work tested the ability of 2824 anthraquinones retrieved from the PubChem database to act as competitive inhibitors through interaction with the ATP-binding pocket of DNA gyrase B of M. tuberculosis. Virtual screening results based on molecular docking identified 7122772 (N-(2-hydroxyethyl)-9,10-dioxoanthracene-2-sulfonamide) as the best-scored ligand. From this anthraquinone, a new derivative was designed harbouring an aminotriazole moiety, which exhibited higher binding energy calculated by molecular docking scoring and free energy calculation from molecular dynamics simulations. In addition, in these last analyses, this ligand showed to be stable in complex with the enzyme and further predictions indicated a low probability of cytotoxic and off-target effects, as well as an acceptable pharmacokinetic profile. Taken together, the presented results show a new synthetically accessible anthraquinone with promising potential to inhibit the GyrB of M. tuberculosis.


Assessment of the usability of teleconsultations during the COVID-19 pandemic at a children's hospital.
Introduction. Usability in a telemedicine system directly affects the efficiency and effectiveness of remote health care. Objective. To assess the usability of teleconsultations during the COVID-19 pandemic. Population and method. This was a cross-sectional study. The caregivers of children aged 1 month to 12 years were included. Usability was assessed with the Telehealth Usability Questionnaire, adapted to Spanish. Socioeconomic data were also assessed. Results. The response rate was 70.2% (n = 221). Most responders were women whose average age was 33 years, had completed secondary education and had public health insurance. Of them, 87.8% selected telephone health care and 88.2% had their first teleconsultation. The overall satisfaction was high, with lower scores for ease of use and learning how to use video calls. Conclusion. Regardless of modality, the usability of teleconsultations by caregivers of children aged 1 month to 12 years was adequate.


Radical S-adenosylmethionine enzyme coproporphyrinogen III oxidase HemN: functional features of the [4Fe-4S] cluster and the two bound S-adenosyl-L-methionines.
The S-adenosylmethionine (AdoMet) radical enzyme oxygen-independent coproporphyrinogen III oxidase HemN catalyzes the oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX during bacterial heme biosynthesis. The recently solved crystal structure of Escherichia coli HemN revealed the presence of an unusually coordinated iron-sulfur cluster and two molecules of AdoMet. EPR spectroscopy of the reduced iron-sulfur center in anaerobically purified HemN in the absence of AdoMet has revealed a [4Fe-4S](1+) cluster in two slightly different conformations. Mössbauer spectroscopy of anaerobically purified HemN has identified a predominantly [4Fe-4S](2+) cluster in which only three iron atoms were coordinated by cysteine residues (isomer shift of delta = 0.43 (1) mm/s). The fourth non-cysteine-ligated iron exhibited a delta = 0.57 (3) mm/s, which shifted to a delta = 0.68 (3) mm/s upon addition of AdoMet. Substrate binding by HemN did not alter AdoMet coordination to the cluster. Multiple rounds of AdoMet cleavage with the formation of the reaction product methionine indicated AdoMet consumption during catalysis and identified AdoMet as a co-substrate for HemN catalysis. AdoMet cleavage was found to be dependent on the presence of the substrate coproporphyrinogen III. Two molecules of AdoMet were cleaved during one catalytic cycle for the formation of one molecule of protoporphyrinogen IX. Finally, the binding site for the unusual second, non iron-sulfur cluster coordinating AdoMet molecule (AdoMet2) was targeted using site-directed mutagenesis. All AdoMet2 binding site mutants still contained an iron-sulfur cluster and most still exhibited AdoMet cleavage, albeit reduced compared with the wild-type enzyme. However, all mutants lost their overall catalytic ability indicating a functional role for AdoMet2 in HemN catalysis. The reported significant correlation of structural and functional biophysical and biochemical data identifies HemN as a useful model system for the elucidation of general AdoMet radical enzyme features.


Prospecting for candidate molecules from Conus virgo toxins to develop new biopharmaceuticals.
A combination of pharmacological and biomedical assays was applied in this study to examine the bioactivity of Conus virgo crude venom in order to determine the potential pharmacological benefit of this venom, and its in vivo mechanism of action. Two doses (1/5 and 1/10 of LC50, 9.14 and 4.57 mg/kg) of the venom were used in pharmacological assays (central and peripheral analgesic, anti-inflammatory and antipyretic), while 1/2 of LC50 (22.85 mg/kg) was used in cytotoxic assays on experimental animals at different time intervals, and then compared with control and reference drug groups. The tail immersion time was significantly increased in venom-treated mice compared with the control group. Also, a significant reduction in writhing movement was recorded after injection of both venom doses compared with the control group. In addition, only the high venom concentration has a mild anti-inflammatory effect at the late inflammation stage. The induced pyrexia was also decreased significantly after treatment with both venom doses. On the other hand, significant increases were observed in lipid peroxidation (after 4 hours) and reduced glutathione contents and glutathione peroxidase activity, while contents of lipid peroxidation and nitric oxide (after 24 hours) and catalase activity were depleted significantly after venom administration. These results indicated that the crude venom of Conus virgo probably contain bioactive components that have pharmacological activities with low cytotoxic effects. Therefore, it may comprise a potential lead compound for the development of drugs that would control pain and pyrexia.


Infectious bovine rhinotracheitis virus infection in bulls, with special reference to preputial infection.
In an experiment with infectious bovine rhinotracheitis (IBR) virus in two bulls, observed over a period of 122 weeks, the pattern of virus release was studied. Recurrent, unprovoked release of virus was demonstrated after one year in a nasal washing from one of the bulls and in preputial washings of both on 13 and 4 occasions, respectively, and finally in weeks 113 and 110, although clinical disease was not observed. During periods of recurrent virus release, concentrations of virus in the prepuce were generally much lower than during the period of primary infection; usually, however, they were not of negligible titer. The frequency of such periods and the virus titers observed strongly suggest that an IBR antibody carrier should always be considered as a potential source of infection to other animals. When virus was demonstrated in semen an almost equal amount was found in the preputial washing (50 ml). In week 120, virus replication in the respiratory tract and prepuce was induced in both bulls by prednisolone injections. It is concluded that antibody carriers will rarely attain a state of absolute immunity.


Novel Insights into the PKCβ-dependent Regulation of the Oxidoreductase p66Shc.
Dysfunctional mitochondria contribute to the development of many diseases and pathological conditions through the excessive production of reactive oxygen species (ROS), and, where studied, ablation of p66Shc (p66) was beneficial. p66 translocates to the mitochondria and oxidizes cytochrome c to yield H2O2, which in turn initiates cell death. PKCβ-mediated phosphorylation of serine 36 in p66 has been implicated as a key regulatory step preceding mitochondrial translocation, ROS production, and cell death, and PKCβ thus may provide a target for therapeutic intervention. We performed a reassessment of PKCβ regulation of the oxidoreductase activity of p66. Although our experiments did not substantiate Ser36 phosphorylation by PKCβ, they instead provided evidence for Ser139 and Ser213 as PKCβ phosphorylation sites regulating the pro-oxidant and pro-apoptotic function of p66. Mutation of another predicted PKCβ phosphorylation site also located in the phosphotyrosine binding domain, threonine 206, had no phenotype. Intriguingly, p66 with Thr206 and Ser213 mutated to glutamic acid showed a gain-of-function phenotype with significantly increased ROS production and cell death induction. Taken together, these data argue for a complex mechanism of PKCβ-dependent regulation of p66 activation involving Ser139 and a motif surrounding Ser213.


Cross-National Variations in Student Employment and Academic Performance: The Roles of National Context and International Law.
Most existing research indicates that working students perform more poorly than do full-time students on standardized achievement tests. However, we know there are wide international variations in this gap. This article shows that national and international contexts help to explain the gap in the academic performance between working and non-working middle-school students. We combined data from the 2003 Trends in International Mathematics and Science Study (TIMSS) eighth-grade assessment with the country specific information on socioeconomic and educational conditions, as well as the timing of each country's ratification of an international treaty regulating child labor. Our multilevel analyses show that, while student employment was generally negatively associated with academic performance, this negative association is smaller in countries that by 1995 had ratified the International Labour Organization's Convention No. 138 on child labor. These findings highlight the role of national and international policy in structuring the consequences of student employment for academic performance.


Real-world outcomes in 2646 psoriasis patients: one in five has PASI ≥10 and/or DLQI ≥10 under ongoing systemic therapy.
Although biologics introduced a new era in psoriasis care when available a decade ago, it is unclear to what extent the available systemic treatments treat patients adequately. To analyse the clinical severity and quality of life of the psoriasis population in Sweden treated with systemics. Data included 2646 patients from the Swedish Registry for Systemic Treatment of Psoriasis. Average Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and EQ-5D were reported. A subgroup of persisting moderate-to-severe psoriasis as defined by PASI ≥10 and/or DLQI ≥10 after >12 weeks treatment was analysed. Mean (SD) PASI, DLQI and EQ-5D were 4.12 (4.57), 4.11 (5.24) and 0.79 (0.22). Eighteen percent had persisting moderate-to-severe psoriasis (n = 472). These patients were younger, had higher BMI, had psoriasis arthritis and were smoking to a larger extent (p < 0.01) compared with lower-severity patients (n = 2174). Mean (SD) EQ-5D was also considerably lower 0.63 (0.29) vs. 0.82 (0.19) (p < 0.01). Almost one in every five patients had persisting moderate-to-severe psoriasis, despite ongoing systemic treatment. Both comorbidities and life style factors were associated with persisting moderate-to-severe psoriasis. The considerably lower generic quality of life in these patients demonstrates an unmet need. Subsequently, improved access to biologics and continuous drug development is needed in psoriasis.


Human balancing of an inverted pendulum: is sway size controlled by ankle impedance?
Using the ankle musculature, subjects balanced a large inverted pendulum. The equilibrium of the pendulum is unstable and quasi-regular sway was observed like that in quiet standing. Two main questions were addressed. Can subjects systematically change sway size in response to instruction and availability of visual feedback? If so, do subjects decrease sway size by increasing ankle impedance or by some alternative mechanism? The position of the pendulum, the torque generated at each ankle and the soleus and tibialis anterior EMG were recorded. Results showed that subjects could significantly reduce the mean sway size of the pendulum by giving full attention to that goal. With visual feedback sway size could be minimised significantly more than without visual feedback. In changing sway size, the frequency of the sways was not changed. Results also revealed that ankle impedance and muscle co-contraction were not significantly changed when the sway size was decreased. As the ankle impedance and sway frequency do not change when the sway size is decreased, this implies no change in ankle stiffness or viscosity. Increasing ankle impedance, stiffness or viscosity are not the only methods by which sway size could be reduced. A reduction in torque noise or torque inaccuracy via a predictive process which provides active damping could reduce sway size without changing ankle impedance and is plausible given the data. Such a strategy involving motion recognition and generation of an accurate motor response may require higher levels of control than changing ankle impedance by altering reflex or feedforward gain.


Secretin-stimulated amylase release into blood is impaired in type 1 diabetes mellitus.
Prior studies have provided data indicating the existence of close interaction between pancreatic endocrine and exocrine function, but few clinical studies have explored this relationship in depth. We compared pancreatic exocrine function non-endoscopically in individuals with type 1 diabetes mellitus, type 2 diabetes mellitus, and normal glucose tolerant controls, to assess the importance of local insulin production to pancreatic exocrine function. The plasma amylase response to intravenous secretin challenge was measured in men with type 1 diabetes mellitus (n = 5), type 2 diabetes mellitus (n = 5), and normal controls (n = 3). Patients were characterized by their urinary excretion of c-peptide and albumin over 24 hours. Autonomic neuropathy was non-invasively assessed by measuring RR variation (with deep respiration on EKG). Post-secretin amylase responses were generally absent with low baseline levels in the patients with type 1 diabetes mellitus. Patients with type 2 diabetes mellitus and controls showed similar twofold increases over baseline after secretin administration. When normal glucose tolerant and type 2 diabetic patients were pooled and compared against type 1 diabetes mellitus, the differences were statistically significant (p < 0.03). Total amylase response correlated positively, but weakly, with 24 h urinary C-peptide excretion (r = 0.507; p < 0.112), but not with glycemic control, duration of diabetes, or indices of autonomic neuropathy. Patients with type 1 diabetes mellitus, but not type 2 diabetes mellitus, have reduced pancreatic exocrine function, supporting the concept of a local paracrine effect of insulin on pancreatic acinar cells. Further studies are needed to determine the clinical impact of this deficiency, and whether such patients with type 1 diabetes mellitus would benefit from therapy with pancreatic enzyme supplementation.


Comparison of in-house and commercial 16S rRNA sequencing with high-performance liquid chromatography and genotype AS and CM for identification of nontuberculous mycobacteria.
Sequencing of the 16S gene or other targets and line probe assay are in wide use for the identification of nontuberculous mycobacteria. We compared in-house and commercial sequencing with 3 sequence databases against high-performance liquid chromatography (HPLC) and line probe assay (HAIN Genotype AS and CM) for the identification of 84 reference, clinical, and unique strains representing 41 species. Consensus of methods was used as reference standard. Sequencing identification was more specific and flexible than HPLC, but it was limited by database content and quality as well as fragment length. No one database satisfied all requirements. In-house sequencing was lower in cost than commercial sequencing or line probe assay.


Isolation of Burkholderia pseudomallei from a case of septicaemia--a case report.
Meliodosis, an infectious disease caused by Burkholderia pseudomallei has been recognized as an emerging infectious disease in India. The infection is under diagnosed and underreported, and hence considered a rare disease. Majority of the cases have been documented from the states with heavy rainfall. The present case being reported is a middle-aged woman who had developed a fulminant infection following exposure to stagnant floodwater in the city of Hyderabad. To the best of our knowledge, this is the first case of Melioidosis being reported from this part of the country.


A topographic study of oscillatory potentials in man.
The purpose of this study was to evaluate the use of slow multifocal m-sequence stimulation in analyzing the topographic distribution and underlying mechanisms (including nonlinearities) of the retinal oscillatory potentials (OPs). In giving us access to the response topography and the nonlinear characteristics of the OPs, the m-sequence technique provides us with two important means for the identification and characterization of the signal sources. In this study, we analyzed the OPs into the first- and second-order components and investigated their topographies and luminance dependence. The distribution of both the first- and second-order OP components differed significantly from that of the flicker ERG investigated by Sutter and Tran (1992). At eccentricities and luminance levels favoring activity by both rods and cones, the second-order OPs were particularly prominent, showing the most clear-defined and complex waveform. The topographic distribution of the second-order OPs showed combined features of both rod and cone distributions. On a strong rod-bleaching background, the second-order OPs were eliminated and the first-order OPs showed a reduced amplitude and a shifted latency. These results are consistent with the notion that the second-order component of the OPs is dominated by contributions from rod-cone interactions.


Understanding the Magnitude of Hypocrisy in Moral Contradictions: The Role of Surprise at Violating Strong Attitudes.
Although two people could both enact similar forms of hypocrisy, one person might be judged as more hypocritical than the other. The present research advances a novel, theoretical explanation for a paradigmatic instance of this: the increased hypocrisy ascribed to contradicting a morally (vs. nonmorally) based attitude. In contrast to prior explanations, the present research shows that people infer targets holding morally (vs. nonmorally) based attitudes are more difficult to change. Consequently, when people are hypocritical on these stances, it elicits greater surprise, which amplifies the perceived hypocrisy. Through both statistical mediation and experimental moderation, we provide evidence for this process and show how our explanation generalizes to understanding heightened hypocrisy in other contexts, too (i.e., violating nonmoral attitudes held with certainty vs. uncertainty). Altogether, we provide an integrative, theoretical lens for predicting when moral and nonmoral acts of hypocrisy will be perceived as particularly hypocritical.


Cooperation between Polycomb and androgen receptor during oncogenic transformation.
Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development and function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell-like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous dedifferentiation.


Guillain-Barré-like axonal polyneuropathy associated with Toscana virus infection: A case report.
Numerous cases of post-infectious Guillain-Barré syndrome (GBS) have been reported in the literature. Toscana virus (TOSV) is an arthropod-borne emerging pathogen in the Mediterranean area. A 40-year-old male patient was admitted to hospital for acute facial weakness, associated to numbness paraesthesias at lower and upper limbs. The neurological examination revealed facial diplegia and reduced tendon reflexes. The nerve conduction studies documented an acute motor and sensory axonal neuropathy (AMSAN); the lumbar puncture detected albuminocytologic dissociation. Serology for human immunodeficiency virus (HIV), Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), mumps, and Borrelia was negative, as was cerebrospinal fluid (CSF) polymerase chain reaction assay for Herpes virus, Borrelia, Mycoplasma pneumoniae, Cryptococcus, and Mycobacterium tubercolosis. Positivity for TOSV IgG antibodies was found on both CSF and serum; the patient remembered being recently exposed to mosquitoes. The AMSAN subtype of GBS, subsequent to a TOSV infection, was diagnosed. The patient was treated with plasma-exchange with complete clinical recovery, but a relapse occurred 9 months later, when the nerve conduction studies confirmed the presence of an AMSAN, which benefited from oral steroids. A good clinical recovery was achieved after treatments. This is the first case, to the best of our knowledge, of a TOSV infection associated to a peripheral neuropathy mimicking a GBS syndrome, both clinically and electrophysiologically. The clinical spectrum of TOSV neurological complications seems to be wider than previously known: this should be taken into account by the scientific community and public health institutions.


Health and social behaviour through pandemic phases in Switzerland: Regional time-trends of the COVID-19 Social Monitor panel study.
Switzerland has a liberal implementation of Coronavirus mitigation measures compared to other European countries. Since March 2020, measures have been evolving and include a mixture of central and federalistic mitigation strategies across three culturally diverse language regions. The present study investigates a hypothesised heterogeneity in health, social behavior and adherence to mitigation measures across the language regions by studying pre-specified interaction effects. Our findings aim to support the communication of regionally targeted mitigation strategies and to provide evidence to address longterm population-health consequences of the pandemic by accounting for different pandemic contexts and cultural aspects. We use data from from the COVID-19 Social Monitor, a longitudinal population-based online survey. We define five mitigation periods between March 2020 and May 2021. We use unadjusted and adjusted logistic regression models to investigate a hypothesized interaction effect between mitigation periods and language regions on selected study outcomes covering the domains of general health and quality of life, mental health, loneliness/isolation, physical activity, health care use and adherence to mitigation measures. We analyze 2,163 (64%) participants from the German/Romansh-speaking part of Switzerland, 713 (21%) from the French-speaking part and 505 (15%) from the Italian-speaking part. We found evidence for an interaction effect between mitigation periods and language regions for adherence to mitigation measures, but not for other study outcomes (social behavior, health). The presence of poor quality of life, lack of energy, no physical activity, health care use, and the adherence to mitigation measures changed similarly over mitigation periods in all language regions. As the pandemic unfolded in Switzerland, also health and social behavior changed between March 2020 to May 2021. Changes in adherence to mitigation measures differ between language regions and reflect the COVID-19 incidence patterns in the investigated mitigation periods, with higher adherence in regions with previously higher incidence. Targeted communcation of mitigation measures and policy making should include cultural, geographical and socioeconomic aspects to address yet unknown long-term population health consequences caused by the pandemic.


Genetic and pharmacological factors that influence reproductive aging in nematodes.
Age-related degenerative changes in the reproductive system are an important aspect of aging, because reproductive success is the major determinant of evolutionary fitness. Caenorhabditis elegans is a prominent organism for studies of somatic aging, since many factors that extend adult lifespan have been identified. However, mechanisms that control reproductive aging in nematodes or other animals are not well characterized. To use C. elegans to measure reproductive aging, we analyzed mated hermaphrodites that do not become sperm depleted and monitored the duration and level of progeny production. Mated hermaphrodites display a decline of progeny production that culminates in reproductive cessation before the end of the lifespan, demonstrating that hermaphrodites undergo reproductive aging. To identify factors that influence reproductive aging, we analyzed genetic, environmental, and pharmacological factors that extend lifespan. Dietary restriction and reduced insulin/insulin-like growth factor signaling delayed reproductive aging, indicating that nutritional status and a signaling pathway that responds to environmental stress influence reproductive aging. Cold temperature delayed reproductive aging. The anticonvulsant medicine ethosuximide, which affects neural activity, delayed reproductive aging, indicating that neural activity can influence reproductive aging. Some of these factors decrease early progeny production, but there is no consistent relationship between early progeny production and reproductive aging in strains with an extended lifespan. To directly examine the effects of early progeny production on reproductive aging, we used sperm availability to modulate the level of early reproduction. Early progeny production neither accelerated nor delayed reproductive aging, indicating that reproductive aging is not controlled by use-dependent mechanisms. The implications of these findings for evolutionary theories of aging are discussed.


Ultrasound guidance for facet joint injections in the lumbar spine: a computed tomography-controlled feasibility study.
We conducted this study to develop an ultrasound-guided approach for facet joint injections of the lumbar spine. Five zygapophyseal joints (L1-S1) on each side of 5 embalmed cadavers were examined by ultrasound for a total of 50 examinations. The joint space was demonstrated under ultrasound guidance. The midpoint of the joint space, defined as the middle of its cranio-caudal extension on its dorsal surface, was taken as a reference point, and its position was computed from its depth and lateral distance from the spinous process. Forty-two of 50 approaches could be clearly visualized. Subsequently, these distances were compared to those obtained by computed tomography (CT). To assess the efficacy of ultrasound in the needle placement, all lumbar facet joints were approached in one embalmed cadaver. The exact placement of the needle tips was again evaluated by CT. Ultrasound and CT measurements showed the same mean depth and lateral distance to the reference point, 3.15 +/- 0.5 cm and 1.9 +/- 0.6 cm, respectively. Pearson's coefficient of correlation was 0.86 (P < 0.0001) between ultrasound and CT. All 10 needle tips were within the joint space during simulated facet joint injections. We conclude that ultrasound guidance might be a useful adjunct for facet joint injections in the lumbar spine. This study was designed to develop an ultrasound-guided approach to the facet joints of the lumbar spine and to assess its feasibility and accuracy by means of a comparison to computed tomography images. The imaging study demonstrated a significant correlation between ultrasound and computed tomography measurements. During simulated facet injection, ultrasound guidance consistently resulted in accurate needle placement.


[The description of Gyrodactylus mulli sp. n. (Monogenea: Gyrodactylidae) from the Black Sea blunt-snouted mullet Mullus barbatus ponticus].
A new species Gyrodactylus mulli sp. n. is described from the thorax fins of blunt-snouted mullet Mullus barbatus ponticus by the collections of B. E. Bychowsky made in 1947 near Karadag on the Black Sea. Gyrodactylus mulli sp. n. differs from G. alviga Dmitrieva et Gerasev, 2000 (described from blunt-snouted mullet too) in having another morphotype of the marginal hooks. The new species differs from G. proterorhini Ergens, 1967, which has the identical type of the marginal hooks, in having longer membrane of the ventral connective bar, longer point of the anchors, shorter marginal hooks, and lesser size of the cirrus.


Sustained cortical and subcortical neuromodulation induced by electrical tongue stimulation.
This pilot study aimed to show that information-free stimulation of the tongue can improve behavioral measures and induce sustained neuromodulation of the balance-processing network in individuals with balance dysfunction. Twelve balance-impaired subjects received one week of cranial nerve non-invasive neuromodulation (CN-NINM). Before and after the week of stimulation, postural sway and fMRI activation were measured to monitor susceptibility to optic flow. Nine normal controls also underwent the postural sway and fMRI tests but did not receive CN-NINM. Results showed that before CN-NINM balance-impaired subjects swayed more than normal controls as expected (p ≤ 0.05), and that overall sway and susceptibility to optic flow decreased after CN-NINM (p ≤ 0.005 & p ≤ 0.05). fMRI showed upregulation of visual sensitivity to optic flow in balance-impaired subjects that decreased after CN-NINM. A region of interest analysis indicated that CN-NINM may induce neuromodulation by increasing activity within the dorsal pons (p ≤ 0.01).


Pompe disease and physical disability.
This study describes the physical disability of 30 children and adolescents with Pompe disease (23 males, 7 females; mean age 7 years 7 months, SD 5 years 6 months; range 6 months to 22 years 1 month) using a disease-specific functional instrument. Data were collected by telephone interview with parents using a modified version of the Pediatric Evaluation of Disability Inventory. The sample included mostly males of Caucasian origin, recruited from several countries. Disability profiles in mobility and self-care skills were heterogeneous because functional status was not related to chronological age. Most children had severe functional deficits: nearly two-thirds of the sample was non-ambulatory and could not perform age-expected self-care skills. Three-quarters of the children used a ventilator. Two children were able to participate in age-appropriate sports and peer activities. Although the mean chronological age of the sample was 7 years 7 months, the mean age-performance for self-care skills was under 2 years 6 months and under 1 year 6 months for mobility. Implications of physical disability findings for individuals with Pompe disease are discussed.


[Pseudodementia in frontal tumours (author's transl)].
Our examinations have revealed personality changes in eighteen out of fifty patients with frontal tumour. The changes may be classified to a certain extent in the same symptomatological category as pseudodementia. In view of the site, size and histological structure of the tumours, the existence and severity of the disorders seem to be independent of tumour vascularization. Such personality changes may be the only pathological sign, even in the presence of large tumours. Earlier diagnostic difficulties (the group of patients dates back to the period prior to CAT scanning) may be largely overcome by the use of computerized axial tomography. Thus the duration of a case up to time of surgery can be reduced (hitherto as long as 10 years or more) and tumours may no longer grow to excessive size.


A first estimate of white shark, Carcharodon carcharias, abundance off Central California.
The decline of sharks in the global oceans underscores the need for careful assessment and monitoring of remaining populations. The northeastern Pacific is the home range for a genetically distinct clade of white sharks (Carcharodon carcharias). Little is known about the conservation status of this demographically isolated population, concentrated seasonally at two discrete aggregation sites: Central California (CCA) and Guadalupe Island, Mexico. We used photo-identification of dorsal fins in a sequential Bayesian mark-recapture algorithm to estimate white shark abundance off CCA. We collected 321 photographs identifying 130 unique individuals, and estimated the abundance off CCA to be 219 mature and sub-adult individuals ((130, 275) 95% credible intervals), substantially smaller than populations of other large marine predators. Our methods can be readily expanded to estimate shark population abundance at other locations, and over time, to monitor the status, population trends and protection needs of these globally distributed predators.


Cation-π binding ability of BN indole.
A BN indole-containing aromatic scaffold has been synthesized and the cation-π binding ability characterized by nuclear magnetic resonance (NMR) monitored titrations. The resulting chemical shifts were analyzed using a non-linear curve fitting procedure and the extracted association constants (Ka's) compared with the natural indole scaffold. Computations were also performed to support our findings. This work shows that incorporation of a B-N bond in place of a C-C bond in an aromatic system slightly lowers the cation-π binding ability of the arene's π-system with simple cations.