Progression to fusion after lumbar laminectomy for degenerative lumbar spondylolisthesis: Rate and risk-factors. A national database study.
Lumbar laminectomy is often utilized in the treatment of degenerative lumbar spondylolisthesis. Risk factors that contribute to reoperation rates, in particular to progression to fusion, are poorly understood. We aimed to identify rate and risk factors of lumbar fusion surgery following lumbar laminectomy for the treatment of degenerative lumbar spinal spondylolisthesis. Our sample was obtained from the national MarketScan Commercial Claims and Encounters Database. We reviewed patients undergoing lumbar laminectomy for stable degenerative lumbar spondylolisthesis (Grade-1) at one or two levels between January 2007 and December 2016. A total of 33,681 patients were included. By 2 years after the index operation, 2.48 % of patients had required lumbar fusion surgery. Female sex was associated with lower odds (OR 0.8, 95 %CI 0.7-0.9) of reoperation for fusion. Diabetes (OR 1.2, 95 %CI 1.1-1.4), rheumatoid arthritis (OR 1.5, 95 %CI 1.2-1.7) and clinical presentation with LBP (OR 2.1, 95 %CI 1.6-2.9), lower extremity weakness (OR 1.4, 95 %CI 1.1-1.5), as well as occurrence of a postoperative neurological complications (OR 2.0, 95 %CI 1.1-3.4) increased the odds ratio for requiring fusion surgery within two years after lumbar laminectomy. In this large cross-sectional sample of a national claims database consisting of lumbar laminectomy patients for the treatment of spondylolisthesis, approximately 2.5 % required subsequent lumbar fusion. Several modifiable risk factors for fusion progression were identified, which may guide clinicians in shared decision-making and to help identify patients with elevated post-operative risk providing potential leverage point for prevention.


Lack of insulinotropic effect of endogenous and exogenous cholecystokinin in man.
Intraduodenal phenylalanine administration (333 mg/min over 60 min) released endogenous cholecystokinin in healthy young subjects as demonstrated radioimmunologically and by intraduodenal bilirubin and pancreatic enzyme output. Concomitantly, there was only a small increase over basal in circulating immunoreactive-insulin and immunoreactive-C-peptide concentrations. In healthy volunteers intraduodenal infusions of saline (10 ml/min), glucose (333 mg/min) or phenylalanine (333 mg/min) were performed for 60 min when plasma glucose was clamped at approximately 8 mmol/l. Phenylalanine enhanced immunoreactive-insulin and immunoreactive-C-peptide responses three-fold more than did the same amount of glucose. Immuno-reactive gastric inhibitory polypeptide responses were small and not different after glucose and phenylalanine administration. Immunoreactive cholecystokinin was significantly stimulated to 9.4 +/- 1.4 pmol/l only by intraduodenal phenylalanine. Plasma phenylalanine concentrations increased into the supraphysiological range (approximately 1.5 mmol/l). Intravenous infusions of phenylalanine achieving plasma concentrations of 1.2 mmol/l stimulated insulin secretion at elevated plasma glucose concentrations (approximately 8 mmol/l clamp experiments), but had no effect at basal plasma glucose concentrations. A small increase in cholecystokinin also was observed. Intravenous infusions of synthetic sulphated cholecystokinin-8 leading to plasma concentrations in the upper postprandial range (8-12 pmol/l) did not augment the immunoreactive-insulin or immunoreactive-C-peptide levels during hyperglycaemic clamp experiments, in the absence or presence of elevated plasma phenylalanine concentrations. It is concluded that the augmentation of the glucose-induced insulin release by intraduodenal administration of phenylalanine cannot be related to cholecystokinin release, but rather is explained by the combined effects of elevated glucose and phenylalanine concentrations. In man, cholecystokinin does not augment insulin secretion caused by moderate hyperglycaemia, elevations of phenylalanine concentrations, or combinations thereof.


Improved quality control method for Fufang Danshen preparations through simultaneous determination of phenolic acids, saponins and diterpenoid quinones by HPLC coupled with diode array and evaporative light scattering detectors.
A herb-combined prescription, mainly derived from roots of Salvia miltiorrhiza and Panax notoginseng, has been widely used for improving coronary or cerebral circulation in China as well as in Western countries. Multiple commercially available preparations, known as Fufang Danshen preparations (FDPs), produced by various manufacturers with the raw materials from different sources, pose a serious challenge to the quality control of this herb medicine. Previous pharmacological studies identify three types of bioactive components correlated with the clinical effect of those herb preparations. Those mainly include four phenolic acids, four saponins and four diterpenoid quinones. In this report, by using high performance liquid chromatography (HPLC) coupled with diode array and evaporative light scattering detectors (DAD-ELSD), we developed an improved quality control method for those herb medicines. A simultaneous separation and quantification of the 12 components was performed on a C(18) column, in which the mobile phase consisted of (A) 0.1% aqueous formic acid and (B) acetonitrile using a gradient elution. The optimum detection wavelength was set at 281 nm, the drift tube temperature of ELSD was set at 113 degrees C, the nitrogen flow rate at 3.1L/min, and the gain=4. All calibration curves showed good linear regression (r(2)>0.9927) within test ranges. The method developed showed good precision and accuracy with overall intra- and inter-day variations of 0.64-4.79% and 0.69-4.96%, respectively, and the overall recoveries of 93.50-107.69% for the 12 compounds analyzed. This method was successfully applied to quantify the twelve components in ten commercial samples from three formulas by seven independent manufacturers. This readily available, low-cost and reliable HPLC-DAD-ELSD method improved the quality control of traditional Chinese medicinal preparations consisting of complex compounds with different structures such as FDPs.


Development of children with a chronic illness.
About 5 to 10 per cent of all children have sometime during childhood a moderately to severely handicapping long-term illness or disability. These children are at risk, not only medically, but for complex social, educational, and emotional difficulties. The potential interferences with normal development imposed by a chronic illness are varied but pervasive, and depend on the specific characteristics of the illness, the child, and the child's family. There are known psychological effects of illness on a child, which can best be understood within a developmental framework such as that outlined above. Optimal health care of these children and families depends on a knowledge of the risks to normal development that are regularly faced by these children at each stage of their development. Physicians, nurses, and other health care providers have the opportunity to be powerful advocates for children with a chronic illness. We thus have a responsibility to facilitate these children's negotiation of the challenges and crises of childhood, so they may enter their adult years with strength and security. Such guidance requires an understanding of children's development and the impact of illness on that process, and effective communication with both children and families.


Selective surgical resection in small cell carcinoma of the lung.
Surgical resection has failed notably as definitive treatment for small cell carcinoma of the lung. Newer treatment programs combining intensive chemotherapy with radiation therapy achieve a significant response in about 85 percent of cases, with about 50 percent of patients showing clinically complete remission. Long-term survival without recurrence has been the outcome in a small minority of cases. A frequent mode of failure after treatment of limited disease is recurrence within the chest. The course of one patient treated early in this series suggests that exclusion of initial surgical resection from programs of combined treatment may be a serious omission. Since that time, four patients have undergone initial resection, apparently with uniformly favorable courses to date. Selection criteria based on staging factors are proposed. Admittedly, only a minority of patients will be suitable for this treatment at the time of first diagnosis. Much opportunity exists for improvement in survival rates of patients, even those with limited disease.


Non-contiguous meningeal metastases of olfactory neuroblastoma.
Olfactory neuroblastoma (ONB) is a malignant neoplasm centered along the roof of the nasal cavity near the cribriform plate. Although metastasis of this tumor has been reported, non-contiguous spread to the dura is rare. Here, we report the largest series of intracranial meningeal metastases of ONBs from M.D. Anderson Cancer Center and the University of Toronto. The unique natural history and geographical distribution of these metastatic lesions suggest a common mechanism of tumor spread along the dural vascular arborization.


The mechanism of dorsal fracture dislocation of the fifth carpometacarpal joint.
Fracture dislocation at the base of the fifth metacarpal is a rare injury. Fewer than 25 cases have been published in the English-language literature. A force acting along the longitudinal axis of the fifth metacarpal causes a fracture dislocation at the base of the bone in a dorsal-ulnar direction, because of the anatomy of the joint and the mechanical properties of the bone and the intermetacarpal ligament. The mechanism of other types of injury to this joint, namely dorsal-radial or palmar-radial dislocation of the base of the fifth metacarpal is different. A case is presented which demonstrates the mechanism of the fracture dislocation.


Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer's disease.
Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer's disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.


Human BDNF isoforms are differentially expressed in cocaine addicts and are sorted to the regulated secretory pathway independent of the Met66 substitution.
Differential BDNF gene (BDNF) promoter use leads to protein isoforms differing by 8 or 15 N-terminal residues (BDNF1 and BDNF2) whose regulation and function are not completely understood versus the well-known 247-aa BDNF "short" form. To describe how BDNF isoform levels were regulated by chronic drug use, we measured BDNF isoform-specific mRNA levels in different human brain regions from cocaine addicts relative to age, race, and gender-matched controls. The cocaine group had threefold higher levels of exon 4-specific (BDNF Short) mRNAs in cerebellum versus controls (P < 0.01). In cortex, exon 4 and exon 1-specific BDNF mRNA levels (BDNF1) were significantly reduced in the cocaine group relative to controls (40%, P < 0.01). We also tested the hypothesis that the signal peptides of isoforms BDNF1 and BDNF2 confer different functional properties and determined if the functional Val66Met polymorphism influenced these functions. In contrast to transfected AtT-20 cells producing BDNF Short, regulated secretion of BDNF1 or BDNF2 was not affected by the Met66 substitution. Hippocampal neurons producing BDNF1 or BDNF2 on either the Val66 or Met66 background were similarly distributed in dendrites and had similar colocalization patterns with the secretory granule marker Sec II. This pattern differed from neurons producing BDNF Short Met66, which had impaired trafficking. Together, these findings support a mechanism by which variant BDNF proteins can overcome the functional defect of the Met66 substitution and suggest how functional differences in BDNF may impact brain responses in disease.


What is the role of the cys-his motif in retroviral nucleocapsid (NC) proteins?
Retroviruses encode a small, basic nucleocapsid (NC) protein that is found complexed to genomic RNA within the viral particle. The NC protein appears to function not only in a histone-like manner in packaging the RNA into the particle but also in specifically selecting the viral genomic RNA for packaging. A cysteine-histidine (cys-his) region, usually composed of 14 amino acids and reminiscent of the 'zinc fingers' of transcription factors, is the only highly conserved sequence element among the retroviral NC proteins. This review discusses the biochemical properties of NC, and its possible role(s) in retroviral replication. We also speculate on how the biochemical properties may relate to its function in RNA recognition and packaging.


Effect of in-situ biochemical modification on the synthesis, structure, and function of xanthan gum based bacterial cellulose generated from Tieguanyin oolong tea residue hydrolysate.
The effect of in-situ biochemical modification on the synthesis, structure, and function of xanthan gum based bacterial cellulose generated from Tieguanyin oolong tea residue hydrolysate was evaluated for the first time. This modification could overcome the inhibitory effect of the hydrolysate and the bacterial cellulose yield with 0.6% xanthan gum addition increased by 260.8% compared with that without xanthan gum addition. Bacterial cellulose and xanthan gum were combined by the in-situ modification and the alteration of fermentation medium rheological properties by xanthan gum addition might be beneficial for their combination. The average diameter of the bacterial cellulose microfibrils was increased by the modification, and it had a great influence on the crystalline structure of the bacterial cellulose. Additionally, both the water absorption and texture properties of the bacterial cellulose was strengthened by the modification. Overall, this modification showed great potential for efficient and effective xanthan gum based bacterial cellulose production.


Post-operative responses of paranasal Aspergillus granuloma to itraconazole.
Paranasal Aspergillus granuloma is an invasive infection, seen mainly in tropical countries, involving the paranasal sinuses, orbit and brain. Previously surgical excision has been followed by a high relapse rate, 80% in some series, and mortality. This study involved the use of post-operative therapy with oral itraconazole in doses of 200-300 mg daily. Twenty-two patients were treated for a mean period of 19.7 weeks. Of 19 patients for whom follow-up data were available, 12 (62%) were rated as being in complete remission in a mean period of 17.2 months after the end of therapy. Only one patient developed progressive disease during itraconazole therapy. No serious adverse effect was seen. Use of itraconazole shows promise as a means of preventing relapse after surgery in this progressive infection.


Identification of a fibroblast growth factor 6 (FGF6) gene in a non-mammalian vertebrate: continuous expression of FGF6 accompanies muscle fiber hyperplasia.
FGF6, a member of the fibroblast growth factor (FGF) family, is specifically expressed in developing skeletal muscle and may participate in muscle maintenance and regeneration. Until now, no convincing evidence for the existence of an FGF6 gene in non-mammalian vertebrates has been put forward. Only a hybrid growth factor containing features characteristic of both FGF4 and FGF6 has been identified in frogs and chickens, suggesting that the step of duplication which created FGF4 and FGF6 took place with the emergence of mammals. In this study, we report the isolation and characterization of a genomic clone encoding the trout (Oncorhynchus mykiss) fibroblast growth factor 6 (TFGF6). An initial cDNA clone was generated by PCR amplification using degenerate oligo primers corresponding to a conserved region of protein found in the mouse and human homologs. The screening of a genomic library with the cloned PCR product led to the isolation of a clone composed of three exons encoding a putative protein of 206 amino acids which exhibits a potential signal peptide and shows 64.6 and 63.6% similarity with mouse and human FGF6, respectively (77% over the carboxy two-thirds of the protein) and only 46.5% similarity with mouse and human FGF4 (62% over the carboxy two-thirds of the protein). The splice position of the three exons was found to be analogous to the human and mouse FGF6 and the start translation site of TFGF6 was preceded by a long stretch of nucleotides that is highly and specifically conserved in mammalian FGF6. Furthermore, a comparative reverse transcriptase-linked PCR assay revealed that the expression pattern of TFGF6 is close to that of mammals, TFGF6 transcripts being present in muscle (fast-twitch and to a lesser extent slow-twitch fibers), heart, testis and brain. Interestingly, the prolonged phase of muscle fiber hyperplasia which occurs in trout is accompanied by the lasting expression of TFGF6 up to the adult stage suggesting that TFGF6 may participate in the continuous generation of muscle fibers within the myotomal musculature of post larval animals.


Lactic acid bacteria: reviewing the potential of a promising delivery live vector for biomedical purposes.
Lactic acid bacteria (LAB) have a long history of safe exploitation by humans, being used for centuries in food production and preservation and as probiotic agents to promote human health. Interestingly, some species of these Gram-positive bacteria, which are generally recognized as safe organisms by the US Food and Drug Administration (FDA), are able to survive through the gastrointestinal tract (GIT), being capable to reach and colonize the intestine, where they play an important role. Besides, during the last decades, an important effort has been done for the development of tools to use LAB as microbial cell factories for the production of proteins of interest. Given the need to develop effective strategies for the delivery of prophylactic and therapeutic molecules, LAB have appeared as an appealing option for the oral, intranasal and vaginal delivery of such molecules. So far, these genetically modified organisms have been successfully used as vehicles for delivering functional proteins to mucosal tissues in the treatment of many different pathologies including GIT related pathologies, diabetes, cancer and viral infections, among others. Interestingly, the administration of such microorganisms would suppose a significant decrease in the production cost of the treatments agents since being live organisms, such vectors would be able to autonomously amplify and produce and deliver the protein of interest. In this context, this review aims to provide an overview of the use of LAB engineered as a promising alternative as well as a safety delivery platform of recombinant proteins for the treatment of a wide range of diseases.


Biocatalytic cascade process of islatravir: Analytical and regulatory control strategy of minor enantiomer.
Commercial process of islatravir (MK-8591, EFdA) utilizes biocatalytic cascade reactions to construct the ribose moiety of the molecule which bears three chiral centers. However, this biocatalytic process also brought analytical challenges where all stereoisomers and process related compounds are controlled in one isolated intermediate, the final drug substance. A chiral LC method was developed to resolve all those compounds from islatravir and its minor enantiomer by thorough column screening and careful optimization. Detail of designing key method validation components such as method linearity, precision and robustness is discussed, and their results were presented. The method was successfully validated to fulfill various expectation from each individual health authority including FDA, EMA, PMDA, and ANVISA.


Growth of tracheal anastomoses in lambs. Comparison of PDS and Vicryl suture material and interrupted and continuous techniques.
Tracheal anastomoses were performed in 19 lambs (mean age 4 weeks, mean weight 9.8 kg) to compare polydioxanone (PDS) and polyglactin 910 (Vicryl) suture material (Ethicon, Inc., Somerville, N.J.) and simple continuous and simple interrupted suture technique. Each animal had two anastomoses with full-thickness bites for both suture techniques. Animals were killed at 4 months (n = 6) or 8 months (n = 5). Eight animals died before they were scheduled to be put to death (mean 6 weeks postoperatively). Transverse sections of the trachea were taken at the level of the anastomoses and three tracheal rings above and below each anastomosis. The cross-sectional area of the tracheal lumen of these transverse sections was measured with a computerized digitizing tablet. A percent luminal area for each anastomosis was calculated relative to the mean tracheal area three rings above and three rings below the anastomosis. There was little difference between interrupted and continuous technique with either suture material (p = 0.94). In 10 animals that each served as its own control for suture material, PDS anastomotic area was 55.0% +/- 4.1% of mean tracheal luminal area compared with 45.4% +/- 7.1% for Vicryl anastomoses (p = 0.06). Histologic analysis revealed a more intense inflammatory reaction surrounding multifilament Vicryl sutures with more rapid resorption and greater subsequent fibrosis relative to the reaction seen with PDS sutures. A small clinical experience with seven infants has confirmed short-term satisfactory clinical performance of continuous PDS suture for tracheal anastomosis.


PTHrP-independent hypercalcemia with increased proinflammatory cytokines and bone resorption in two children with CD19-negative precursor B acute lymphoblastic leukemia.
Hypercalcemia in childhood acute lymphoblastic leukemia (ALL) is rare and occasionally associated with parathyroid hormone-related protein (PTHrP). However, the pathogenesis of PTHrP-independent hypercalcemia remains unclear. We report two children with precursor B ALL who had marked hypercalcemia (15.8 and 16.6 mg/dl, respectively) and disseminated osteolysis. Serum tumor necrosis factor-alpha (TNF-alpha) and IL-6 were markedly elevated, whereas 1,25(OH)(2) vitamin D(3), intact PTH and PTHrP were decreased or undetected. Analysis of urinary deoxypyridinoline (DPY) or bone biopsy of the osteolytic lesion showed an increased bone resorption, and administration of bisphosphonate improved the hypercalcemia. Patients had ALL with immunophenotype positive for CD10, CD34, and HLA-DR but negative for CD19 and obtained remission with chemotherapy. These findings suggest that increased osteoclastic bone resorption via stimulation with TNF-alpha and IL-6 may be mechanism causing PTHrP-independent hypercalcemia in some patients with precursor B ALL lacking CD19 expression.


A kind of planar waveguides for cheating the high-speed digital signals into misidentifying the characteristic impedance.
Since a planar periodic transmission line can suppress drastically the electromagnetic coupling, it would be advantageous to use such a kind of transmission lines in solving the problem of miniaturization of circuit area. By adjusting the lattice constants and geometric parameters of periodic microstrip lines, a time domain characteristic impedance that is the same as that of conventional microstrip lines (CMLs) can be achieved. Such periodic microstrip lines can therefore be used to trick high-speed digital signals, causing a digital signal to misjudge the time domain characteristic impedance of the transmission lines. The theoretical analysis has been verified by our experimental measurement results. Besides, a specific expression for the characteristic impedance of lossless periodic artificial materials is deduced by a circuit model and a standard of misidentification for the characteristic impedance of periodic microstrip lines is given for the digital signals.


Beneficial Effect of Combining Radiotherapy and Transarterial Chemoembolization on Patient Survival in Hepatocellular Carcinomas and Macrovascular Invasion Treated with Sorafenib.
Approximately 10-40% of hepatocellular carcinoma (HCC) patients have definite vascular invasion at the time of diagnosis. Without curative treatment options, these patients have an abysmal prognosis with a median survival of only a few months following systemic therapy. However, supportive evidence of combining multiple locoregional treatments with systemic therapy is limited. This study compared the outcomes of sorafenib alone versus multimodality therapy with sorafenib, radiotherapy (RT), and transarterial chemoembolization (TACE) in advanced HCC patients with macrovascular invasion (MaVI). The process took place over a nine-year period between March 2009 and October 2017, wherein 78 HCC patients with MaVI who underwent either sorafenib therapy alone (n = 49) or combined sorafenib/RT/TACE (n = 29) therapy were chosen for the retrospective study. We compared the overall survival (OS) between the two groups using the Cox regression hazard model and adjusted imbalances using propensity score matching (PSM). At the last follow-up, 76 patients had died, with a median follow-up time of 4.8 months for all patients and 31 months for those who were alive. Patients treated with sorafenib/RT/TACE had superior OS compared to those treated with sorafenib alone, showing a median survival of 9.3 vs. 2.7 months and a one-year survival of 37.1% vs. 6.1% (p < 0.001). In the multivariable analysis, new diagnosis or recurrence of HCC and treatment modalities (sorafenib alone vs. sorafenib/RT/TACE) were independent prognostic factors for OS. Compared to patients treated with sorafenib alone, significantly better OS was further verified using PSM (p < 0.001) in patients who received multiple therapeutic modalities. Multimodality therapy with sorafenib/RT/TACE increased OS threefold versus sorafenib therapy alone in HCC patients with MaVI. This study offers promising benefits of combined locoregional and systemic therapy for advanced HCC in current patient management and prospective clinical trials.


Bottle-feeding as a tool to reinforce breastfeeding.
Babies may need supplementation due to difficulty breastfeeding. Others must be fed by alternative feeding methods because they are separated from mothers who have returned to employment or school. Recognizing that mothers and caregivers are often not comfortable using other alternative feeding devices, the author endeavored to develop a method of bottle-feeding that would meet the needs of these mothers and their babies without causing suck confusion. The resulting bottle-feeding method requires babies to expend effort and use their oral anatomy in ways very similar to breastfeeding.


Lipidomics by HILIC-Ion Mobility-Mass Spectrometry.
Lipidomics is a rapidly growing field that enables the characterization of the entire lipidome in cells, tissues, or an organism. Changes in lipid metabolism and homeostasis caused by different disease states or drug treatments can be probed by lipidomics experiments, which can aid our understanding of normal physiology and disease pathology at the molecular level. While current technologies using liquid chromatography coupled with high-resolution mass spectrometry have greatly increased coverage of the lipidome, there are still limitations in resolving the large number of lipid species with similar masses in a narrow mass window. We recently reported that two orthogonal separation techniques, hydrophilic interaction liquid chromatography (HILIC) and ion mobility (IM), enhance the resolution of lipid species based on headgroup polarity and gas-phase size and shape, respectively, of various classes of glycerolipids, glycolipids, phospholipids, and sphingolipids. Here we describe the application of our HILIC-IM-MS lipidomics protocol to the analysis of lipid extracts derived from either tissues or cells, to identify significant changes in the lipidome in response to an internal or external stimulus, such as exposure to environmental chemicals.


Upper limb robotic therapy for children with hemiplegia.
Our aim was to examine the feasibility and effects of robotic therapy for children with cerebral palsy and upper limb hemiplegia. A single group within-subjects design was used. Twelve children aged 5-12 yrs with moderate to severe motor impairments participated in 1-hr robotic therapy sessions, 2 times per week for 8 wks. During each session, children used the paretic arm to perform 640 repetitive, goal-directed planar reaching movements, with robotic assistance as needed. Primary outcomes were the Quality of Upper Extremity Skills Test (QUEST) and the Fugl-Meyer Assessment upper limb subtest. Secondary outcomes were the Modified Ashworth Scale, peak isometric strength of shoulder and elbow muscles, and parent questionnaire scores. We found significant gains in total QUEST and Fugl-Meyer Assessment scores at discharge and follow-up and in isometric strength of elbow extensors at discharge. The parent questionnaire showed significant improvements in "how much" and "how well" children used the paretic arm during daily functional tasks at home. Robotic therapy can provide new opportunities for improving upper limb coordination and function in children with moderate to severe impairments due to cerebral palsy or stroke.


Giant aneurysm of anterior communicating artery simulating 3rd ventricular tumor.
This is a case report of an anterior communicating artery aneurysm simulating a 3rd ventricular tumor with obstructive hydrocephalus demonstrated on CT scan. Angiography showed the "tumor" to be an aneurysm. We believe that giant aneurysms of the anterior communicating artery should be included in the differential diagnosis of suspected 3rd ventricular tumors along with suprasellar masses as seen on CT scans.


The responses of plasma biochemical parameters to a 56-km race in novice and experienced ultra-marathon runners.
A number of blood biochemical parameters, including the activities of the plasma enzymes creatine kinase (CK), aspartate aminotransferase (ASAT), lactate dehydrogenase and alkaline phosphatase, were measured in 23 athletes before, and immediately after a 56-km running race. Of the 23 athletes, 18 had previously completed standard 42-km marathon or longer (up to 90-km) ultra-marathon races, whereas not one of the other five athletes had previously run in a long-distance race. After the race, plasma CK and ASAT activities had both risen at least 280% more in the novice runners despite their much slower mean running speed (9.8 +/- 0.4 vs. 13.8 +/- 0.3 hm/h). There were no other inter-group differences in the absolute levels of the other measured biochemical parameters, although the rise in plasma calcium during the race was significantly greater in the experienced marathon runners. This study shows that either higher levels of training, or previous ultra-marathon racing experience, or both, is associated with lower immediate post-exercise levels of plasma enzyme activity. This is compatible with the finding that physical training reduces post-exercise plasma enzyme levels.


Imaging cells in three-dimensional collagen matrix.
The use of in vitro three-dimensional (3-D) collagen matrices to mimic an in vivo cellular environment has become increasingly popular and is broadening our understanding of cellular processes and cell-ECM interactions. To study cells in in vitro 3-D collagen matrices, both cellular proteins and the collagen matrix must be visualized. In this unit, the authors describe the protocol and provide troubleshooting for immunolabeling of cells in 3-D collagen gels to localize and visualize cellular proteins with high-resolution fluorescence confocal microscopy. The authors then describe confocal reflection microscopy as a technique for direct imaging of 3-D fibrillar collagen matrices by discussing the advantages and disadvantages of the technique. They also provide instrument settings required for simultaneous imaging of cellular proteins with fluorescence confocal imaging and 3-D collagen fibrils with confocal reflection microscopy. Additionally, the authors provide protocols for a "cell sandwiching" technique to prepare cell cultures in 3-D collagen matrices required for high-resolution confocal imaging.


Characteristics and Effectiveness of Dedicated Care Programs for Patients Starting Dialysis: A Systematic Review.
Dedicated care programs that provide increased support to patients starting dialysis are increasingly being used to reduce the risk of complications. The objectives of this systematic review were to determine the characteristics of existing programs and their effect on patient outcomes. We searched Embase, MEDLINE, Web of Science, Cochrane CENTRAL, and CINAHL from database inception to November 20, 2019 for English-language studies that evaluated dedicated care programs for adults starting maintenance dialysis in the inpatient or outpatient setting. Any study design was eligible, but we required the presence of a control group and prespecified patient outcomes. We extracted data describing the nature of the interventions, their components, and the reported benefits. The literature search yielded 12,681 studies. We evaluated 66 full texts and included 11 studies (n=6812 intervention patients); eight of the studies evaluated hemodialysis programs. All studies were observational, and there were no randomized controlled trials. The most common interventions included patient education (n=11) and case management (n=5), with nurses involved in nine programs. The most common outcomes were mortality (n=8) and vascular access (n=4), with only three studies reporting on the uptake of home dialysis and none on transplantation. We identified four high-quality studies that combined patient education and case management; in these programs, the relative reduction in 90-day mortality ranged from 22% (95% CI, -3% to 41%) to 49% (95% CI, 33% to 61%). Pooled analysis was not possible due to study heterogeneity. Few studies have evaluated dedicated care programs for patients starting dialysis, especially their effect on home dialysis and transplantation. Whereas multidisciplinary care models that combine patient education with case management appear to be promising, additional prospective studies that involve patients in their design and execution are needed before widespread implementation of these resource-intensive programs.


Sertoli cell tumor of the testis. Report of a case with imprint cytology findings.
Sertoli cell tumor of the testis is a relatively rare neoplasm, and few reports concerning its cytologic findings have been previously documented. A 41-year-old male had Sertoli cell tumor in the left testis. An imprint smear revealed tumor cells showing a less cohesive or singly dispersed cell pattern. The cytoplasm was faintly stained, and most tumor cells were naked. The nuclei were oval or short and spindle in shape, and some of them showed coffee bean nuclei or nuclear indentation. Coffee bean nuclei can be observed in Sertoli cell tumor.


Characterization of the oat1 gene of Penicillium chrysogenum encoding an omega-aminotransferase: induction by L-lysine, L-ornithine and L-arginine and repression by ammonium.
The Penicillium chrysogenum oat1 gene, which encodes a class III omega-aminotransferase, was cloned and characterized. This enzyme converts lysine into 2-aminoadipic semialdehyde, and plays an important role in the biosynthesis of 2-aminoadipic acid, a precursor of penicillin and other beta-lactam antibiotics. The enzyme is related to ornithine-5-aminotransferases and to the lysine-6-aminotransferases encoded by the lat genes found in bacterial cephamycin gene clusters. Expression of oat1 is induced by lysine, ornithine and arginine, and repressed by ammonium ions. AreA-binding GATA and GATT sequences involved in regulation by ammonium, and an 8-bp direct repeat associated with arginine induction in Emericella (Aspergillus nidulans and Saccharomyces cerevisiae, were found in the oat1 promoter region. Deletion of the oat1 gene resulted in the loss of omega-aminotransferase activity. The null mutants were unable to grow on ornithine or arginine as sole nitrogen sources and showed reduced growth on lysine. Complementation of the null mutant with the oat1 gene restored normal levels of omega-aminotransferase activity and the ability to grow on ornithine, arginine and lysine. The role of the oat1 gene in the biosynthesis of 2-aminoadipic acid is discussed.


Molecular detection of pathogens in the ova and unfed larvae of Rhipicephalus annulatus and Haemaphysalis bispinosa ticks infesting domestic cattle of south India.
This study aimed to investigate the presence of pathogens in the engorged ticks infesting domestic cattle, their ova, and unfed larvae. The engorged female ticks infesting domestic cattle of Wayanad district of Kerala, south India were collected and kept for oviposition. The dead females after the complete oviposition, their egg masses, and unfed larvae were screened for the presence of various pathogens by specific PCRs. The presence of Babesia bigemina, Anaplasma marginale, A. phagocytophilum, and Rickettsia spp. similar to R. raoultii was confirmed in Rhipicephalus annulatus ticks, their egg masses, and unfed larvae. Theileria orientalis was detected in Rh. annulatus females, but not in their egg masses or progenies. The presence of A. phagocytophilum and Rickettsia spp. similar to R. raoultii was confirmed in Haemaphysalis bispinosa ticks, their egg masses, and unfed larvae too. The presence of coinfections of B. bigemina with A. phagocytophilum and A. marginale were detected in Rh. annulatus ticks and their progenies.


Association Between Stressful Life Events and Depression; Intersection of Race and Gender.
Although stressful life events (SLEs) and depression are associated, we do not know if the intersection of race and gender modifies the magnitude of this link. Using a nationally representative sample of adults in the USA, we tested if the association between SLE and major depressive episode (MDE) depends on the intersection of race and gender. Data came from the National Survey of American Life (NSAL), 2003, a cross-sectional survey that enrolled 5899 adults including 5008 Blacks (African-Americans or Caribbean Blacks), and 891 Non-Hispanic Whites. Logistic regression was used for data analysis. Stressful life events (past 30 days) was the independent variable, 12-month MDE was the dependent variable, and age, educational level, marital status, employment, and region of country were controls. In the pooled sample, SLE was associated with MDE above and beyond all covariates, without the SLE × race interaction term being significant. Among men, the SLE × race interaction was significant, suggesting a stronger association between SLE and MDE among White men compared to Black men. Such interaction between SLE × race could not be found among women. The association between SLE and depression may be stronger for White men than Black men; however, this link does not differ between White and Black women. More research is needed to better understand the mechanism behind race by gender variation in the stress-depression link.


Combining tau-PET and fMRI meta-analyses for patient-centered prediction of cognitive decline in Alzheimer's disease.
Tau-PET is a prognostic marker for cognitive decline in Alzheimer's disease, and the heterogeneity of tau-PET patterns matches cognitive symptom heterogeneity. Thus, tau-PET may allow precision-medicine prediction of individual tau-related cognitive trajectories, which can be important for determining patient-specific cognitive endpoints in clinical trials. Here, we aimed to examine whether tau-PET in cognitive-domain-specific brain regions, identified via fMRI meta-analyses, allows the prediction of domain-specific cognitive decline. Further, we aimed to determine whether tau-PET-informed personalized cognitive composites capture patient-specific cognitive trajectories more sensitively than conventional cognitive measures. We included Alzheimer's Disease Neuroimaging Initiative (ADNI) participants classified as controls (i.e., amyloid-negative, cognitively normal, n = 121) or Alzheimer's disease-spectrum (i.e., amyloid-positive, cognitively normal to dementia, n = 140), plus 111 AVID-1451-A05 participants for independent validation (controls/Alzheimer's disease-spectrum=46/65). All participants underwent baseline 18F-flortaucipir tau-PET, amyloid-PET, and longitudinal cognitive testing to assess annual cognitive changes (i.e., episodic memory, language, executive functioning, visuospatial). Cognitive changes were calculated using linear mixed models. Independent meta-analytical task-fMRI activation maps for each included cognitive domain were obtained from the Neurosynth database and applied to tau-PET to determine tau-PET signal in cognitive-domain-specific brain regions. In bootstrapped linear regression, we assessed the strength of the relationship (i.e., partial R2) between cognitive-domain-specific tau-PET vs. global or temporal-lobe tau-PET and cognitive changes. Further, we used tau-PET-based prediction of domain-specific decline to compose personalized cognitive composites that were tailored to capture patient-specific cognitive decline. In both amyloid-positive cohorts (ADNI [age = 75.99±7.69] and A05 [age = 74.03±9.03]), cognitive-domain-specific tau-PET outperformed global and temporal-lobe tau-PET for predicting future cognitive decline in episodic memory, language, executive functioning, and visuospatial abilities. Further, a tau-PET-informed personalized cognitive composite across cognitive domains enhanced the sensitivity to assess cognitive decline in amyloid-positive subjects, yielding lower sample sizes required for detecting simulated intervention effects compared to conventional cognitive endpoints (i.e., memory composite, global cognitive composite). However, the latter effect was less strong in A05 compared to the ADNI cohort. Combining tau-PET with task-fMRI-derived maps of major cognitive domains facilitates the prediction of domain-specific cognitive decline. This approach may help to increase the sensitivity to detect Alzheimer's disease-related cognitive decline and to determine personalized cognitive endpoints in clinical trials.


Reduced bioavailability of polycyclic aromatic hydrocarbons (PAHs) in sediments impacted by carbon manufacturing plant effluent: Evaluation by ex situ passive sampling method.
Potential risks of polycyclic aromatic hydrocarbons (PAHs) in sediments of a Japanese bay contaminated by carbon manufacturing plant effluent were evaluated by calculating toxicity units (TUs). TUs calculated from the measured whole-sediment concentrations (Cwhole) were often higher than or close to 1, signaling a possible toxicity concern to benthic organisms. In contrast, TUs based on the freely dissolved pore water concentrations (Cfree) measured by an ex-situ passive sampling method with polyethylene strips were 0.0007-0.005, much lower than 1, indicating no effect. We also found that the fractions of black carbon in sediments of the contaminated bay were significantly higher than those of reference sites. Overall, we conclude that carbon manufacturing plant effluent substantially increases Cwhole of PAHs in sediments but also increases the fraction of carbonaceous particles that strongly retain PAHs. As a combined result, bioavailable concentrations (as expressed by pore water Cfree) of PAHs do not increase as much as Cwhole. The results of this study indicate that ecotoxicological risks of PAH contamination by carbon manufacturing plants should be evaluated by directly measuring pore water Cfree instead of Cwhole.


Breeding signatures of rice improvement revealed by a genomic variation map from a large germplasm collection.
Intensive rice breeding over the past 50 y has dramatically increased productivity especially in the indica subspecies, but our knowledge of the genomic changes associated with such improvement has been limited. In this study, we analyzed low-coverage sequencing data of 1,479 rice accessions from 73 countries, including landraces and modern cultivars. We identified two major subpopulations, indica I (IndI) and indica II (IndII), in the indica subspecies, which corresponded to the two putative heterotic groups resulting from independent breeding efforts. We detected 200 regions spanning 7.8% of the rice genome that had been differentially selected between IndI and IndII, and thus referred to as breeding signatures. These regions included large numbers of known functional genes and loci associated with important agronomic traits revealed by genome-wide association studies. Grain yield was positively correlated with the number of breeding signatures in a variety, suggesting that the number of breeding signatures in a line may be useful for predicting agronomic potential and the selected loci may provide targets for rice improvement.


Endophytic Yeasts in Malus domestica and Pyrus communis Fruits under Anthropogenic Impact.
Yeast abundance and species diversity on the surface and in inner tissues of Malus domestica and Pyrus communis fruits under high anthropogenic impact in the city of Moscow (Russia) were studied. Results demonstrated that abundance of epiphytic yeasts on the fruits increased gradually, reaching the maximum of 3.2 × 10⁴ CFU/g on mature fruits. During summer, abundance of endophytes did not change significantly (variation near 2.5 × 10³ CFU/g) until complete maturation, while in September their numbers increased to 104 CFU/g. Basidiomycetous yeasts (Filobasidium wieringae, F. magnum, Rhodotorula glutinis, and Rhodosporidiobolus colostri) predominated on the fruit surface. Ascomycetous species were the most diverse group inside the fruits, which quantitatively increased through maturation. It was found that the share of opportunistic species Candida parapsilosis in internal tissues was significant during the entire period of fruit formation and development under anthropogenic impact in the city. Specific properties of epiphytic and endophytic yeast communities developing in natural ecological niches under synanthropic conditions and anthropogenic impact are discussed.


Assessing the cost-effectiveness of the rivastigmine transdermal patch for Alzheimer's disease in the UK using MMSE- and ADL-based models.
Assess long-term cost-effectiveness of rivastigmine patch in Alzheimer's disease (AD) management in the UK, using cognitive and functional models based on clinical trial efficacy data. Incremental costs and Quality Adjusted Life Years (QALYs) associated with rivastigmine patch and capsule treatment versus best supportive care (BSC) were calculated using two economic models, one based solely on Mini-Mental State Examination (MMSE) scores, and one also incorporating activities of daily living (ADL) scores. The clinical pathway was populated with data from a clinical trial of rivastigmine patch (9.5 mg/24 h) and capsules (12 mg/day) versus placebo. Costs were based on the UK health and social care costs and basic UK National Health Service (NHS) prices. Disease progression was modelled beyond the trial period over 5 years using published equations to predict natural decline in AD patients. Base case costing variables included drugs, clinical monitoring, and institutionalization. The MMSE model estimated incremental costs per QALY of £10 579 for rivastigmine patch and £15 154 for capsule versus BSC. The MMSE-ADL model estimated incremental costs per QALY of £9114 for rivastigmine patch and £13 758 for capsules. The main difference between the models was a greater number of institutionalized days avoided for rivastigmine versus BSC estimated by the MMSE-ADL model. Both the MMSE and MMSE-ADL models suggest that rivastigmine patch and capsules are cost-effective treatments versus BSC. Incorporating ADL evidence makes a marginal but important difference to estimates in this case. Future economic evaluations of AD treatment should include measures of both cognition and functioning.


[Surgical problems of iatrogenic esophagus perforations (author's transl)].
With increase of invasive investigations of the upper digestive tract an increase of complications is also expected. From 1968--1977 eleven patients with iatrogenic esophagus perforation were referred to the department of general surgery, University of Kiel. Symptoms, diagnosis and different treatment, depending on localization and time of perforation and underlying disease are described.


Dating Violence Attitudes Among Latino College Students: An Examination of Gender, Machismo, and Marianismo.
This study sought to fill a gap in the literature by exploring the association of gender, machismo and marianismo, and acculturation to dating violence (DV) attitudes among a sample of Latino college students. A total of 305 students were recruited from a Hispanic Serving Institution (HSI) located on the United States-Mexico border. Results showed significant differences in all forms of DV attitudes across gender. Separate regression models for men and women showed a pattern of endorsing the traditional gender role of machismo was predictive of tolerant DV attitudes for men and women. The marianismo dimension of chastity and virtuosity was associated to a decrease in tolerant DV attitudes among men. In addition, acculturation's relationship to DV attitudes and gender role ideology was not significant. Overall, the findings highlight the need for DV programs to address culturally-based understandings of gender roles and their association to DV attitudes.


Changes in sorbitol, myo-inositol and lipid inositol in dorsal root and sympathetic ganglia from streptozotocin-diabetic rats.
Sorbitol, fructose, myo-inositol and lipid inositol concentrations were measured in excised dorsal root and sympathetic ganglia from rats with streptozotocin-induced diabetes, both in the acute stage (1 and 2 weeks after the induction of diabetes) and chronically (after 2 months of diabetes). In comparison with age-matched controls, myo-inositol concentrations were decreased by 26-32% after 1 and 2 weeks but had returned to normal levels at 2 months. Lipid inositol concentrations were normal both in the acutely and chronically diabetic animals. Sorbitol was not detectable in ganglia from diabetic or control animals except for a small quantity (0.05 mumol/g wet weight) in dorsal root ganglia at the 2-month stage. Fructose was present in dorsal root ganglia (1.71-3.53 mumol/g wet weight) at all stages and in sympathetic ganglia (2.18 mumol/g wet weight) at the 8-week stage. The differences in these results from those obtained in peripheral nerve trunks are possibly related to the lack of a blood-nerve barrier in sensory and autonomic ganglia.


Mechanism of inhibition of malate dehydrogenase by thyroxine derivatives and reactivation by antibodies: homogeneous enzyme immunoassay for thryroxine.
Pig heart mitochondrial malate dehydrogenase (L-malate:NAD+ oxidoreductase, EC 184.108.40.206) is about 90% inhibited upon labelling an average of two amino groups per subunit with an active ester of thyroxine. Inhibition is probably associated primarily with thyroxine binding to one specific group which is normally unreactive but becomes activated upon noncovalent binding of thyroxine derivatives to the enzyme. Enzyme inhibition is due to a decrease in the rate of association of NAD. Antibodies to thyroxine induce a slow conformational change with partial reversal of inhibition of more heavily labelled conjugates. The antibody-induced activation is not cooperative and does not require bivalent association of the antibody. Activation can be blocked by the presence of free thyroxine and is the basis for a clinically useful assay for serum thyroxine.


Root hair systems biology.
Plant functional genomic studies have largely measured the response of whole plants, organs and tissues, resulting in the dilution of the signal from individual cells. Methods are needed where the full repertoire of functional genomic tools can be applied to a single plant cell. Root hair cells are an attractive model to study the biology of a single, differentiated cell type because of their ease of isolation, polar growth, and role in water and nutrient uptake, as well as being the site of infection by nitrogen-fixing bacteria. This review highlights the recent advances in our understanding of plant root hair biology and examines whether the root hair has potential as a model for plant cell systems biology.


Tyrosinemia type I and not treatment with NTBC causes slower learning and altered behavior in mice.
Tyrosinemia type I is a recessive inborn error of metabolism caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme in the metabolism of tyrosine. This renders FAH nonfunctional and without treatment, toxic metabolites accumulate causing liver and kidney damage. Introduction of the drug NTBC in 2002 offered a treatment which inhibits an upstream enzyme, preventing the production of the toxic metabolites. There is now a long-term survival rate of greater than 90 % in children, but there are reports of lower cognitive function and IQ as well as schooling and behavioral problems in these children. We studied a mouse model of tyrosinemia type I to gain insight into the effects of tyrosinemia type I and treatment with NTBC on mouse learning, memory, and behavior. In the Barnes maze, visual and spatial cues can be used by mice to remember the location of a dark escape box. The primary time, distance, and strategy taken by the mice to locate the escape box is a measure of learning and memory. Our findings show that mice with tyrosinemia type I were slower to learn than wild-type mice treated with NTBC and made more mistakes, but were capable of learning and storing long-term memory. After learning the location of the target hole, mice with tyrosinemia type I respond differently to a change in location and were less flexible in learning the new target hole location. Our findings suggest that this slower learning and cognitive difference is caused by tyrosinemia type I and not by the treatment with NTBC.


Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue.
A small amount of adipose tissue associated with small arteries and arterioles is encountered both in mice and man. This perivascular adipose tissue (PVAT) has a paracrine effect on the vascular tone regulation. PVAT is expanded in obesity and in diabetes. This expansion not only involves enlargement of fat cells, but also the accumulation of inflammatory cells and a shift in the production of adipokines and cytokines. This effect is illustrated in this review by the effect of PVAT-derived factors of insulin-mediated vasoregulation in mouse resistance arteries. Insulin sensitivity of endothelial cells is also involved in the insulin-mediated regulation of muscle glucose uptake. Insulin affects vasoregulation by acting on different signaling pathways regulating NO and endothelin-1 release. This process is influenced by various adipokines and inflammatory mediators released from PVAT, and is affected by the degree of expansion and content of inflammatory cells. It is modulated by adiponectin (via 5' adenosine monophosphate-activated protein kinase, AMPK), TNFα (via c-jun N-terminal kinase) and free fatty acids (via protein kinase C-θ). PVAT thus provides an important site of control of vascular (dys)function in obesity and type 2 diabetes. An altered profile of adipokine and cytokine production by PVAT of resistance arteries may also contribute to or modulate hypertension, but a causal role in hypertension has still to be established.


Comparison of haemodynamic effects of pethidine and anileridine in anaesthetised patients.
Haemodynamic effects of equianalgesic doses of pethidine (1 mk kg -1) and anileridine (0.25 mg kg -1) were compared in patients with coronary artery disease, after induction of anaesthesia with flunitrazepam - N2O - pancuronium. Contrary to previous findings made in conscious patients, these analgesics produced a moderate circulatory depression. Heart rate, cardiac index and rate-pressure product were decreased by both drugs, and anileridine alone decreased mean arterial pressure. The only statistically significant differences in the haemodynamic changes between the two groups were those in pulmonary capillary wedge pressure and rate pressure product, which were slightly lower after anileridine than after pethidine.


Pharmacotherapies and harm-reduction options for the treatment of tobacco dependence.
Tobacco dependence, a chronic relapsing condition, requires repeated interventions and multiple attempts to quit. Strategies for assisting smoking cessation include behavioural counselling and pharmacotherapy. Three drugs are currently used as first-line pharmacotherapy: nicotine replacement therapy (NRT), bupropion and varenicline. Compared to placebo, the drug effect varies from RR = 2.27 for varenicline, to 1.69 for bupropion, and 1.60 for any form of NRT. Cytisine (similar to varenicline) has a RR = 3.98 compared to placebo (two trials). Second-line pharmacotherapies include nortriptyline and clonidine. This review also offers an overview of pipeline developments. Effective medications exist, and clinicians should encourage and offer treatment to every smoker. However, most smokers try to quit by themselves, with only about 3% quitting successfully each year. Alternative interventions are needed. Harm reduction has not received much support to date. Safer alternative to tobacco smoking (smoke-free products, long-term use of cessation drugs, or electronic cigarettes) could save lives and reduce the burden of tobacco-related deaths and diseases. Despite some encouragement to develop a research agenda for e-cigarettes, particularly on the safety issues, too little attention has been brought to this area of research.


ras p21 protein promotes survival and fiber outgrowth of cultured embryonic neurons.
Although evidence obtained with the PC12 cell line has suggested a role for the ras oncogene proteins in the signal transduction of nerve growth factor-mediated fiber outgrowth, little is known about the signal transduction mechanisms involved in the neuronal response to neurotrophic factors in nontransformed cells. We report here that the oncogene protein T24-ras, when introduced into the cytoplasm of freshly dissociated chick embryonic neurons, promotes the in vitro survival and neurite outgrowth of nerve growth factor-responsive dorsal root ganglion neurons, brain-derived neurotrophic factor-responsive nodose ganglion neurons, and ciliary neuronotrophic factor-responsive ciliary ganglion neurons. The proto-oncogene product c-Ha-ras also promotes neuronal survival, albeit less strongly. No effect could be observed with truncated counterparts of T24-ras and c-Ha-ras lacking the 23 C-terminal amino acids including the membrane-anchoring, palmityl-accepting cysteine. These results suggest a generalized involvement of ras or ras-like proteins in the intracellular signal transduction pathway for neurotrophic factors.


A practical guide for generating unsupervised, spectrogram-based latent space representations of animal vocalizations.
The manual detection, analysis and classification of animal vocalizations in acoustic recordings is laborious and requires expert knowledge. Hence, there is a need for objective, generalizable methods that detect underlying patterns in these data, categorize sounds into distinct groups and quantify similarities between them. Among all computational methods that have been proposed to accomplish this, neighbourhood-based dimensionality reduction of spectrograms to produce a latent space representation of calls stands out for its conceptual simplicity and effectiveness. Goal of the study/what was done: Using a dataset of manually annotated meerkat Suricata suricatta vocalizations, we demonstrate how this method can be used to obtain meaningful latent space representations that reflect the established taxonomy of call types. We analyse strengths and weaknesses of the proposed approach, give recommendations for its usage and show application examples, such as the classification of ambiguous calls and the detection of mislabelled calls. What this means: All analyses are accompanied by example code to help researchers realize the potential of this method for the study of animal vocalizations.


Pre-labour fetal membranes overlying the cervix display alterations in inflammation and NF-kappaB signalling pathways.
To generate new insights into the process of fetal membrane rupture, we have developed a technique whereby fetal membranes overlying the cervix (i.e. supracervical site, SCS) are tagged in women undergoing term elective Caesarean section. The specific aim is to determine the effect of supracervical apposition on the release of inflammatory mediators and NF-kappaB signalling in pre-labour fetal membranes. Fetal membranes were collected from both the SCS and from a distal site (DS). The level of NF-kappaB proteins and its transcriptional co-activator protein CBP and p300 was determined by Western blotting and/or immunohistochemistry (IHC), and cytokine and prostaglandin release was quantified by enzyme immunoassay. Tissues obtained before labour at term possess an area of the fetal membranes (i.e. supracervical site) that exhibit decreased release of IL-1beta, IL-6, IL-8, TNF-alpha and PGE(2). IHC revealed that NF-kappaB signalling proteins, CBP and p300 were significantly increased in SC fetal membranes compared to distal membranes. In summary, data from this study confirm that supracervical fetal membranes display altered structural and biochemical characteristics.


Effect of breviscapine on CYP3A metabolic activity in healthy volunteers.
The purpose of this study was to investigate the influence of breviscapine on the pharmacokinetics of concomitantly administered midazolam (MID) and its associations with and effects on genetic polymorphism of the gene encoding cytochrome P450 3A5 (CYP3A5) in healthy volunteers. The study group comprised 17 healthy volunteers who had been genotyped for CYP3A5*3 prior to start of the study. These volunteers were given daily doses of 120 mg (40 mg, three times a day) of breviscapine or a placebo for 14 days, followed by 7.5 mg midazolam (MID) on day 15. The plasma concentrations of MID and the metabolite 1-hydroxy-midazolam (1-OH-MID) were determined by ultra-performance liquid chromatography-mass spectrometry for up to 12 h after drug administration. The pharmacokinetics of MID and 1-OH-MID were significantly different between the breviscapine and placebo groups, with a point estimate for MID AUC(0-12) of 1.56 (90% confidence interval 1.26, 1.87). The pharmacokinetics of MID and 1-OH-MID were not different among the CYP3A5 genotype groups, regardless of whether MID was coadministered with breviscapine or with placebo. These findings suggest that breviscapine inhibited the metabolism of CYP3A in the volunteers, with no interaction difference among the different CYP3A5 genotypes.


Mitochondrial dysfunction and type I interferon signaling induce anxiodepressive-like behaviors in mice with neuropathic pain.
Clinical evidence indicates that major depression is a common comorbidity of chronic pain, including neuropathic pain; however, the cellular basis for chronic pain-mediated major depression remains unclear. Mitochondrial dysfunction induces neuroinflammation and has been implicated in various neurological diseases, including depression. Nevertheless, the relationship between mitochondrial dysfunction and anxiodepressive-like behaviors in the neuropathic pain state remains unclear. The current study examined whether hippocampal mitochondrial dysfunction and downstream neuroinflammation are involved in anxiodepressive-like behaviors in mice with neuropathic pain, which was induced by partial sciatic nerve ligation (PSNL). At 8 weeks after surgery, there was decreased levels of mitochondrial damage-associated molecular patterns, such as cytochrome c and mitochondrial transcription factor A, and increased level of cytosolic mitochondrial DNA in the contralateral hippocampus, suggesting the development of mitochondrial dysfunction. Type I interferon (IFN) mRNA expression in the hippocampus was also increased at 8 weeks after PSNL surgery. The restoration of mitochondrial function by curcumin blocked the increased cytosolic mitochondrial DNA and type I IFN expression in PSNL mice and improved anxiodepressive-like behaviors. Blockade of type I IFN signaling by anti-IFN alpha/beta receptor 1 antibody also improved anxiodepressive-like behaviors in PSNL mice. Together, these findings suggest that neuropathic pain induces hippocampal mitochondrial dysfunction followed by neuroinflammation, which may contribute to anxiodepressive-behaviors in the neuropathic pain state. Improving mitochondrial dysfunction and inhibiting type I IFN signaling in the hippocampus might be a novel approach to reducing comorbidities associated with neuropathic pain, such as depression and anxiety.


Life-Threatening Cardiac Tamponade Secondary to COVID-19 Treated with Uniportal Video-Assisted Thoracoscopic Surgery: A Case Report.
BACKGROUND The COVID-19 outbreak emerged in December 2019 in Wuhan, China. COVID-19 is caused by the SARS-CoV-2 coronavirus and mostly affects the respiratory system but can also affect other organs, including the cardiovascular system. Furthermore, the most common cardiac complications include severe left ventricular dysfunction, acute myocardial injury, and arrhythmias. Life-threatening cardiac tamponade and large pericardial effusion are exceedingly rare complications in patients recovered from COVID-19. Previously, this condition was treated with pericardiocentesis, colchicine, and corticosteroids. CASE REPORT We present the case of a 54-year-old man who recovered from a SARS-CoV-2 infection 7 days before presentation and describe a complicated pericardial effusion with life-threatening cardiac tamponade. To the best of our knowledge, this is the first case of pericardial effusion with cardiac tamponade that was successfully treated with single port or uniportal video-assisted thoracoscopic surgery with an excellent outcome. CONCLUSIONS Life-threatening cardiac tamponade with pericardial effusion is an exceedingly rare complication in patients recovered from COVID-19. Generally, patients diagnosed with pericardial effusion undergo a pericardiocentesis procedure. Although there are multiple treatment options for draining pericardial effusion, the recurrence rate with surgical pericardial window formation is the lowest. However, our patient underwent surgery using a uniportal video-assisted thoracoscopic surgery with an excellent outcome.


Non-specific neck pain in schoolchildren: prognosis and risk factors for occurrence and persistence. A 4-year follow-up study.
This study investigated the natural course of neck pain (NP) in 9-12-year-olds during a 4-year follow-up. Risk factors for the occurrence and persistence of weekly NP were explored separately for boys and girls. At baseline, 1756 schoolchildren completed a questionnaire eliciting musculoskeletal pain symptoms, other physical, and psychological symptoms and frequency of physical activity, and were tested for joint hypermobility. Symptoms during the preceding three months were asked using a five-level frequency classification. Re-evaluation was performed after one and four years using identical questionnaires. During follow-up, 24% reported none, 71% fluctuating, and 5% persistent weekly NP. The frequency of NP at baseline was linearly related to weekly NP during follow-up in both genders (P<0.001). Furthermore, a significant increasing linear trend towards a more persistent course of NP was seen in children with weekly other musculoskeletal and/or other physical and psychological symptoms at baseline. Among originally neck pain-free pre-/early adolescents, weekly other musculoskeletal pain symptoms (only in girls) and other physical and psychological symptoms (in both genders) predicted the occurrence of weekly NP during follow-up. In conclusion, neck pain in schoolchildren tends to fluctuate, but there also seems to exist a subgroup (5%) with persistent NP already in pre-/early adolescents, or even earlier. Co-occurrence of frequent other musculoskeletal symptoms and/or markers of psychological stress with frequent NP are risk indicators for a more persistent course, at least within next few years. Since adult chronic NP problems might originate in childhood, further studies are needed, including preventive interventions.


Hemopoietic growth factors and oncogenes in myeloid leukemia development.
Most primary myeloid leukemias are dependent for proliferative stimulation on the glycoprotein colony-stimulating factors. These agents are therefore mandatory co-factors in the development of myeloid leukemia. The CSFs also modify oncogene transcription, and in model leukemogenesis experiments GM-CSF has been shown to be a proto-oncogene. However, most evidence is against an autocrine hypothesis of myeloid leukemia based solely on CSF production by emerging leukemic cells. Because the CSFs also have differentiation commitment actions, they can induce differentiation in myeloid leukemic cells, and G-CSF in particular has an impressive capacity to suppress myeloid leukemic populations by this action. The antagonistic actions of the CSFs on myeloid leukemic cells make it difficult to predict whether they will prove to be useful agents in the management of myeloid leukemias.


Attentional bias modification with a new paradigm: The effect of the Detection Engagement and Savoring Positivity (DESP) task on eye-tracking of attention.
We tested the effect of a new Attentional Bias Modification (ABM) task - the Detection Engagement and Savoring Positivity (DESP) task - on attentional biases. The DESP is innovative in that it involves a procedure of savoring the positivity of various pictures. Participants were randomly assigned to the DESP or to a placebo control condition (experiment 1; n = 38) or a condition controlling for savoring (experiment 2; n = 54) in a pre-post/training experimental design. During one week, the participants completed the DESP or the control task once a day between three and six times. We assessed the effects of the DESP task on various attentional biases (i.e. positive, negative and threat) by computing dwell time from an eye-tracking technology before and after the training, and also one week after the post-training session in experiment 2. In both experiments, the attentional bias toward positive stimuli between the pre- and the post-training increased significantly more in the DESP task condition than in the control conditions. Negative and threat attentional biases were not significantly affected by the experimental manipulations. Experiment 2 revealed that the DESP task - including the savoring instruction - increased significantly more the positive attentional bias than a task excluding this step and that this effect remained significant one week after the post-training session. Our samples were mainly composed of women participants. This prevents generalization of the findings. The DESP task offers promising perspectives for sustainably improving attention to positive information.


Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals ACTN2 mutation related to hypertrophic/dilated cardiomyopathy and a novel LZTR1 variant associated with Noonan syndrome.
Genetic cardiac diseases are the main trigger of sudden cardiac death (SCD) in young adults. Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiomyopathy and accounts for 0.5 to 1% of SCD cases per year. Herein, we report a family with a marked history of SCD focusing on one SCD young adult case and one pediatric case with HCM. For the deceased young adult, postmortem whole-exome sequencing (WES) revealed a missense variant in the ACTN2 gene: c.355G > A; p.(Ala119Thr) confirming the mixed hypertrophic/dilated cardiomyopathy phenotype detected in the autopsy. For the pediatric case, WES allowed us the identification of a novel frameshift variant in the LZTR1 gene: c.1745delT; p.(Val582Glyfs*10) which confirms a clinical suspicion of HCM related to Noonan syndrome. The present study adds further evidence on the pathogenicity of ACTN2: p. Ala119Thr variant in SCD and expands the mutational spectrum of the LZTR1 gene related to Noonan syndrome.


Synthesis and structural studies of N-p-toluensulfonyl cyclodipeptides.
In view of the chemical and structural interest of cyclopeptides bearing an electron withdrawing substituent directly bonded at the amide nitrogen atom, the two N-p-toluensulfonyl (N-tosyl) derivatives cyclo[-Phe(Tos)-D-Phe-] (I) and cyclo[-Phe(Tos)-D-Pro-] (II) have been synthesized and their stereochemistry defined. The molecular structure of I, as determined by x-ray diffraction analysis, is reported together with 1H-nmr parameters indicating the preferred rotameric conformation in chloroform solution. The N-tosyl group alters the geometry of the cyclodipeptide ring by lengthening both the N-C bonds departing from the tosylated nitrogen and reducing the corresponding ring angle. The 6-membered peptide ring adopts an unusual "sofa" conformation with the Tos-Phe C alpha atom deviating 0.230(3) A out of the mean plane of the other five ring atoms. One of the two S-O bonds forms a planar system that involves the tosylated nitrogen and the corresponding amide carbonyl. In the crystal, both the benzylic side chains are folded over the heterocyclic ring, whereas in chloroform solution, the benzylic side chain of the D-Phe prefers an extended conformation.


Therapeutic potential of cancer stem cells.
Cancer stem cells (CSCs) play an important role in cancer growth, self-renewal, metastasis, recurrence and radio/chemotherapy. However, the underlying mechanisms remain elusive. In this review, we explore the roles of CSCs in cancer's relapse and progression and discuss the biomarkers of CSCs to predict clinical outcome and their diagnostic potential. The different approaches of CSC therapies are also reviewed, including cytotoxic, radiation, differentiation and targeting signaling pathways. We also discuss the challenge of targeting CSCs in cancer therapy. In addition, non-coding RNAs in CSC therapies are also discussed.


A case of vasa previa diagnosed prenatally, and review of the literature.
The perinatal mortality rate of vasa previa is high if it is not prenatally diagnosed. In this report, a case of vasa previa diagnosed prenatally is presented. Antepartum hemorrhage at 24 weeks of gestation prompted a close investigation of the uterine cervix, internal os, and placenta. We detected a low-lying bilobed placenta with umbilical cord insertion in the lower uterine segment. Furthermore, one of the connecting vessels of the bilobed placenta passed directly above the internal os. Vasa previa was suspected and confirmed with color Doppler and MRI. The fetus was delivered uneventfully by planned Cesarean section at 38 weeks of gestation. It should be considered that placenta previa (including low-lying placenta), bilobed placenta, and umbilical cord insertion in the lower uterine segment are associated with high risk of vasa previa. Ultrasound screening for cord insertion and placenta around the internal os enables efficient and certain detection of vasa previa.


Evaluation of marine biotoxin's accumulation by Acanthocardia tuberculatum from Algarve, Portugal.
Acanthocardia tuberculatum is a bivalve mollusc that presents recurrent problems of paralytic shellfish poisoning (PSP) contamination in the Mediterranean coasts of Spain and Morocco. Although not commercially exploited from the Portuguese south coast, it represents an alternative for reducing the harvest pressure on species presently exploited. Evaluation of accumulation of marine biotoxins was carried out by HPLC in this species, harvested during a campaign carried out in April 2001 aimed at evaluating bivalve's resources that covered the entire Portuguese south coast.PSP toxins were studied by automated pre-column oxidation. Toxins were found in specimens from all stations, but always under the regulatory limit of 80 microg STX eq./100g. Saxitoxin and decarbamoyl-saxitoxin were the only PSP toxins unambiguously identified. In commercially exploited species, saxitoxin and analogues were not detected. The amnesic toxin domoic acid was found, but in levels similar to those found in species commercially exploited, and always under the regulatory limit of 20 microg/g. A fast elimination, and not a prolonged retention, of domoic acid seems to occur in A. tuberculatum in view of the levels close to or higher than 20 microg/g found in commercial bivalves harvested the two preceding months. The diarrhoeic toxin okadaic acid was found at trace levels much under the allowable level, similar to what was happening with other species harvested during the same period.


Epidemiology of adults' and childrens' burns in a Turkish burn center.
From 1 January 1979 to 1 January 1985, 4094 patients were treated for burn injury in our centre. Of these, 84.9 per cent were treated as outpatients and 617 (15.1 per cent) were hospitalized. Of the 617 patients, 56.7 per cent were under 15 years of age (birth to 6 years: 67.7 per cent; 7-15 years, 32.3 per cent) and 43.3 per cent were over 15 years. The causes of burns in the over 15 years group were: flame, 36.3 per cent; electrical, 28.0 per cent; scalding, 18.4 per cent; liquefied petroleum (LP) gas explosion, 11.0 per cent; and others, 6.3 per cent. The burn cases in the under 15 years group were: scalding, 58.0 per cent; flame, 24.6 per cent; electrical, 10.0 per cent; hot meals, 5.2 per cent; and others, 2.0 per cent. After being resuscitated, these patients were treated with systemic antibiotics, local chemotherapy and silver-nitrate-incorporated amniotic membrane. Despite all medical efforts, 217 (35.7 per cent) of the hospitalized patients died as a result of various complications. At the same time, 3477 patients were treated as outpatients: 72.0 per cent of these were under 15 years old (birth to 6 years, 82.9 per cent, 7-15 years, 18.8 per cent) and 28.0 per cent patients were over 15 years of age. The causes of burn injury in these patients were: hot liquids, 61.7 per cent; flame, 17.0 per cent; hot meals, 8.4 per cent; hot metal, 5.8 per cent; electrical, 3.6 per cent; and chemical, 1.7 per cent.


WITHDRAWN: Challenges for future caring science research: A response to Hallberg (2006).
The publisher regrets that this article is an accidental duplication of an article that has already been published in the International Journal of Nursing Studies, volume 45 (2008) 971-974, doi:10.1016/S0020-7489(08)00116-8. The duplicate article has therefore been withdrawn.


Effects of essential oil from Croton tiglium L. on intestinal transit in mice.
Croton tiglium (Croton tiglium L., Euphorbiaceae) is widely used as a herb for treatment of gastrointestinal disturbances. Previous studies established its purgative and inflammational properties. The present study aimed to investigate the effects of Croton tiglium oil (CO) on intestinal transit in mice. Gastrointestinal transit in mice and contractile characteristics of isolated intestinal strips from mice were evaluated. Intestinal inflammation was confirmed by histological examination. Low dose of CO increased the gastrointestinal transit of charcoal and barium meal as well as the production of fecal pellets in mice. In contrast, high dose exerted inhibitory effects. For normal colonic circular strips, both high and low dose of CO inhibited the contractile frequency. Low doses (0-20 microg/ml) of CO enhanced the phasic contractions, while high doses (>40 microg/ml) reduced them. Colonic longitudinal strips in CO-treated mice were less sensitive to electrical field stimulation than those in control mice. The contraction of colonic longitudinal, colonic and jejunal circular strips in CO-treated mice was more sensitive to atropine than that in control mice. CO might modulate gastrointestinal motility and induce intestinal inflammation related to immunological milieu and motor activity. Our findings may highlight the ethno-medical uses of Croton tiglium on intestinal disorders.


Zn(2+) -induced Ca(2+) release via ryanodine receptors triggers calcineurin-dependent redistribution of cortical neuronal Kv2.1 K(+) channels.
Increases in intracellular Zn(2+) concentrations are an early, necessary signal for the modulation of Kv2.1 K(+) channel localization and physiological function. Intracellular Zn(2+) -mediated Kv2.1 channel modulation is dependent on calcineurin, a Ca(2+) -activated phosphatase. We show that intracellular Zn(2+) induces a significant increase in ryanodine receptor-dependent cytosolic Ca(2+) transients, which leads to a calcineurin-dependent redistribution of Kv2.1 channels from pre-existing membrane clusters to diffuse localization. As such, the link between Zn(2+) and Ca(2+) signalling in this Kv2.1 modulatory pathway is established. We observe that a sublethal ischaemic preconditioning insult also leads to Kv2.1 redistribution in a ryanodine receptor-dependent fashion. We suggest that Zn(2+) may be an early and ubiquitous signalling molecule mediating Ca(2+) release from the cortical endoplasmic reticulum via ryanodine receptor activation. Sublethal injurious stimuli in neurons induce transient increases in free intracellular Zn(2+) that are associated with regulating adaptive responses to subsequent lethal injury, including alterations in the function and localization of the delayed-rectifier potassium channel, Kv2.1. However, the link between intracellular Zn(2+) signalling and the observed changes in Kv2.1 remain undefined. In the present study, utilizing exogenous Zn(2+) treatment, along with a selective Zn(2+) ionophore, we show that transient elevations in intracellular Zn(2+) concentrations are sufficient to induce calcineurin-dependent Kv2.1 channel dispersal in rat cortical neurons in vitro, which is accompanied by a relatively small but significant hyperpolarizing shift in the voltage-gated activation kinetics of the channel. Critically, using a molecularly encoded calcium sensor, we found that the calcineurin-dependent changes in Kv2.1 probably occur as a result of Zn(2+) -induced cytosolic Ca(2+) release via activation of neuronal ryanodine receptors. Finally, we couple this mechanism with an established model for in vitro ischaemic preconditioning and show that Kv2.1 channel modulation in this process is also ryanodine receptor-sensitive. Our results strongly suggest that intracellular Zn(2+) -initiated signalling may represent an early and possibly widespread component of Ca(2+) -dependent processes in neurons.


The influence of structural variations in the F- and FG-helix of the beta-subunit modified oxyHb-NES on the heme structure detected by resonance Raman spectroscopy.
The dispersion of the depolarization ratio of two prominent Raman lines (1,375 cm-1 and 1,638 cm-1) of oxyhemoglobin-N-ethyl succinimide have been examined for pH values between pH = 6.0 and 8.5. Both exhibit a significant pH dependence. Calculation of the Raman tensor in terms of a fifth-order time dependent theory provides information about the pH-dependence of parameters reflecting symmetry classified distortions of the prosthetic heme group. To correlate these distortions with the functional properties of the molecule the following protocol was used: 1) An allosteric model suggested by Herzfeld and Stanley (1974) has been applied to O2-binding curves measured at different pH values between 6.5 and 9.0. From this calculation one obtains both, the energy differences between different molecular conformations and the equilibrium constants of oxygen and proton binding. 2) A titration model was formulated relating each conformation of a molecule to a distinct set of distortion parameters of the heme group. 3) The distortion parameters resulting from the analysis of our Raman data were assigned as an effective value due to incoherent superposition of the distortion parameters related to the different titration states. The application of this procedure yields an excellent reproduction of the pH-dependent effective distortion parameters of both Raman lines investigated. It is shown that the protonation of two tertiary effector groups located in the beta-subunits affect the symmetry of the heme in a contrary manner: the protonation of a His-residue (pK = 8.2, probably His(FG4) beta) causes a symmetric position of the proximal imidazole thus lowering the perturbations of the heme core. Further it influences the interaction between amino acid residues of the heme cavity and pyrrole side chains (probably Val(FG5) beta-vinyl (pyrrole 3) thus causing a decrease of the distortions related to the peripheral part of the heme. In contrast, the protonation of Lys (EF6) beta causes a tilt position of the proximal imidazole and an increase of asymmetric perturbations of the heme core, whereas the interaction between the pyrrole side chains and the heme cavity is weakened. Our results are consistent with stereochemical predictions of Moffat (1971) concerning the existence of a H-bond between His(FG4) beta and Cys(F9) beta.


Implanted defibrillators in trouble: initial device misclassification leads to correct diagnosis-a case series.
Supraventricular tachycardia, mistakenly diagnosed as ventricular tachycardia, may lead to inappropriate ICD therapy. Inappropriate ICD therapy associates with increased morbidity and mortality. A reduction of inappropriate therapy is therefore desired. We present three different cases that beautifully illustrate the diagnostic possibilities of stored electrograms. Initial differential diagnoses in all three patients included ventricular tachycardia, focal atrial tachycardia, atrio-ventricular re-entry tachycardia, and atrio-ventricular nodal re-entry tachycardia. The first case was diagnosed as atrio-ventricular nodal re-entry tachycardia. In the second case, atrio-ventricular re-entry tachycardia was revealed. Ectopic atrial tachycardia was the reason for inappropriate therapy in the third patient. Thorough analysis of stored electrograms yielded correct diagnosis in all cases, which subsequently was confirmed by electrophysiological study.


Effect of deep hypothermia on cerebral hemodynamics during selective cerebral perfusion with systemic circulatory arrest.
We studied the effect of deep hypothermia on cerebral hemodynamics during selective cerebral perfusion with systemic circulatory arrest. Ten anesthesized pigs were placed on cardiopulmonary bypass and cooled to a rectal temperature of 22 degrees C (n = 5) or 15 degrees C (n = 5). During selective cerebral perfusion, the descending aorta was clamped and perfusion of the lower body was discontinued. As the pump flow was changed, we monitored the perfusion pressure, local cerebral blood flow, and local cerebral oxygenation using laser Doppler flowmetry and near-infrared spectroscopy. We also measured the free flow of the left internal thoracic artery during selective cerebral perfusion. Perfusion pressure and local cerebral blood flow decreased as the pump flow decreased. Oxygenated and deoxygenated hemoglobin in cerebral tissue remained unchanged at a perfusion flow of 10 ml/kg/min, whereas oxygenated hemoglobin decreased and deoxygenated hemoglobin increased progressively and reciprocally as the pump flow decreased. The pump flow for maintaining perfusion pressure above 35 mmHg with stabilized local cerebral oxygenation was significantly higher at 15 degrees C than at 22 degrees C. The internal thoracic artery free flow was higher at 15 degrees C than at 22 degrees C. Selective hypothermic cerebral perfusion with systemic circulatory arrest produces an extracranial shunt through the internal thoracic artery, especially under deep hypothermia. Our data suggests that selective cerebral perfusion during deep hypothermia is best managed by perfusion pressure control rather than by flow control.


Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part II, free fatty acid profiles.
In the second part of this study, the emphasis is on the free fatty acids during cervical carginogenesis, since they may reflect active cell metabolism during this disease process. Lipids were extracted from biopsies of normal epithelial tissue (N) (n=36), cervical intraepithelial lesions (CIL) (n=47), and infiltrating lesions (Ca) (n=47) of the cervix. Samples, from which the free fatty acid compositions were determined, were saponified, methylated and analysed by GLC. In accordance with results obtained on total fatty acid compositions, essential fatty acid deficiency (EFAD) in the intraepithelial lesions, compared with normal tissue (linoleic acid, P< 0.01), and infiltrating lesions compared with intraepithelial lesions (linoleic acid and arachidonic acid, P< 0.01) were observed. High levels of oleic acid were also observed when infiltrating lesions were compared with normal tissue (P < 0.01). As previously mentioned by us in part I of this study, with regard to possible disturbances in metabolic pathways based on the total fatty acid profiles during stages of cervical cancer, EFAD is prevalent during cervical carcinogenesis. This EFAD in cancer cells may result in many defective cell mechanisms, since fatty acids are associated with biochemical events such as lipid peroxidation, signal transduction and immune responses. The high level of oleic acid in cancer cells is known to activate PKC and thus contribute to the continous growth stimulus thought to exist in malignant cells. From a therapeutic viewpoint, substantial changes in the fatty acid composition of the membranes can be produced in cancer cells by selective fatty acid supplementation strategies. At present, modifications of the fatty acid compositions of cell membranes represent an experimental model that has promoted increased understanding of lipid transportation, membrane remodelling, and the relationship between membrane lipids and membrane function. By addressing factors responsible for insufficient essential fatty acid levels, carginogenesis may be prevented or treated. The clinical feasibility of using modification of fatty acids in tumours or cancer by diet or perfusion as an adjunct to standard therapies should be tested.


Diabetes-induced changes in endothelial mechanisms implicated in rabbit carotid arterial response to 5-hydroxytryptamine.
The influence of diabetes on endothelial mechanisms implicated in the response of isolated rabbit carotid arteries to 5-hydroxytryptamine (5-HT) was studied. 5-HT induced a concentration-dependent contraction that was potentiated in arteries from diabetic rabbits with respect to that in arteries from control rabbits. Endothelium removal potentiated 5-HT contractions in arteries from both control and diabetic rabbits but increased the maximum effect only in arteries from diabetic rabbits. Incubation of arterial segments with N(G)-nitro-L-arginine (L-NA) enhanced the contractile response to 5-HT. This L-NA enhancement was greater in arteries from diabetic rabbits than in arteries from control rabbits. Aminoguanidine did not modify the 5-HT contraction in arteries from control and diabetic rabbits. Indomethacin inhibited the 5-HT-induced response, and this inhibition was higher in arteries from control rabbits than in arteries from diabetic rabbits. In summary, diabetes enhances the sensitivity of the rabbit carotid artery to 5-HT. In control animals, the endothelium modulated the arterial response to 5-HT by the release of both nitric oxide (NO) and a vasoconstrictor prostanoid. Diabetes enhances endothelial constitutive NO activity and impairs the production of the endothelial vasoconstrictor.


Infection with a novel virus causes hemorrhagic fever in China.
Patients have been identified with hemorrhagic fever (HF) caused by Huaiyangshan virus (HYSV) infection since 2009. This study aimed to investigate the characteristics of clinical symptoms, laboratory examinations, epidemiological factors, and therapeutic responses in patients with Huaiyangshan hemorrhagic fever (HYSHF). A total of 57 patients with a suspected HF were admitted to the Department of Infectious Diseases, the Affiliated Union Hospital of Tongji Medical College between June 2009 and October 2010. A potential infection with HYSV was determined by indirect immunofluorescent assay and reverse-transcription (RT)-PCR. The clinical symptoms, epidemiological characteristics, laboratory examinations, and therapeutic responses of these patients were evaluated. Forty-eight out of 57 patients were diagnosed with HYSHF. They displayed diverse clinical symptoms, such as an acute febrile flu-like illness, and progressed to proteinuria, hemorrhagic manifestations, and encephalopathy. Some patients exhibited progressive leukopenia, thrombocytopenia, liver and kidney dysfunction, and systemic cell injury. Following symptom-specific treatment, 35 patients recovered completely and 13 patients died from severe complications, including central nervous system manifestations. Patients with HYSHF displayed diverse clinical symptoms and laboratory findings. Such patients should be treated immediately and closely monitored to prevent severe complications.


Treatment of erectile dysfunction with sildenafil.
To determine the efficacy of sildenafil for the treatment of erectile dysfunction (ED) in a clinical practice setting; to evaluate the correlation between patient and partner perceptions of treatment outcomes; and to assess the relation between the severity of ED and response to treatment. Among the first 100 men to receive sildenafil in a urology practice setting, 74 (mean + SD age 64+/-11 years) completed a validated sexual function questionnaire (International Index of Erectile Function [IIEF]) before and after a 4 to 6-week treatment period. A modified version of the same questionnaire was independently completed by partners. ED was categorized into a severity class of I to IV. Sildenafil treatment improved erections by 71% to 95%, according to responses in key IIEF questions 3 and 4. Overall, 57 (77%) of 74 patients desired to continue treatment after the test period. Patient score on the IIEF was correlated with partner score on the modified questionnaire before and after treatment (r = 0.67 to 0.81, P <0.01). IIEF scores were reflected in a simple severity classification system. Men with the best preservation of erections (severity class I) exhibited the best responses to sildenafil, whereas men with no erections (severity class IV) were much less likely to respond to the drug and desire continuation of treatment (P <0.01). Patients with a radical prostatectomy were relatively refractory to sildenafil, except for 2 of 5 who had undergone a nerve-sparing operation. In clinical practice, sildenafil is an effective treatment of ED, according to partner-validated questionnaire responses; and the results of treatment are predictable with an ED severity classification system.


Spinal cord stimulation for gait disturbances in Parkinson's disease.
Gait disturbances are a major contributor to the disability associated with Parkinson's disease. Although pharmacologic therapies and deep brain stimulation improve most motor parkinsonian features, their effects on gait are highly variable. Spinal cord stimulation, typically used for the treatment of chronic pain, has emerged as a potential therapeutic approach to improve gait disturbances in Parkinson's disease. The authors review the available evidence on the effects of spinal cord stimulation in patients with Parkinson's disease, targeting primarily gait abnormalities. They also discuss possible mechanisms, safety, and methodological implications for future clinical trials. This systematic review of originally published articles in English language was performed using The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).