[Surgical treatment of ulcerative colitis and familial adenomatous polyposis: recent developments].
Reconstructive surgery for ulcerative colitis and familial adenomatous polyposis nowadays usually takes the form of an ileoanal pouch, involving making a reservoir of the terminal portion of the ileum which subsequently is anastomosed to the anal canal. This method results in definite cure in many cases, but is associated with a morbidity of 15-30% and fails in 10%. A new surgical treatment includes complete removal of the affected large bowel mucosa, guaranteeing oroanal intestinal continuity, limiting complications and providing good function of the reservoir or of the new rectum. In creation of an ileoneorectal anastomosis, complete removal of the affected mucous membrane is followed by preparing a functional 'neorectum' by means of pedicle grafting of ileal mucous membrane on to the uncovered muscular wall of the rectum. This operation gave good results in a small-scale clinical trial.


Fundamental fluid transport mechanisms through articular cartilage.
A unified self-consistent set of equations governing the fundamental fluid transport mechanisms through articular cartilage is described. These equations include Darcy's law for fluid flow through a permeable medium and Biot's consolidation equations for a fluid-filled elastically deformable permeable solid matrix. Kinematical, mechanical, and geometrical parameters which are important in the understanding of the biomechanics of normal and pathological articular cartilage are identified. Clearly, the present investigation is inchoate in that many of the mechanical and physical constants associated with articular cartilage are as yet unknown and imprecisely defined. Thus only a parametric study has been reported. It was found that in normal, healthy human articular cartilage during normal function the mechanical pumping mechanism dominated the processes of interstitial fluid transport, with the direct fluid pressure mechanism being the mode of fluid transport in the transitory phase of flow reversal. Further, upon load application the interstitial fluid was exuded across the articular surface directly under the load, and upon load removal the fluid was then imbibed under the load. Finally it was found that after one complete cycle there was a very small amount of net flux of fluid into the tissue.


Metallomic analysis of macrophages infected with Histoplasma capsulatum reveals a fundamental role for zinc in host defenses.
The fungal pathogen Histoplasma capsulatum evades the innate and adaptive immune responses and thrives within resting macrophages. Cytokines that induce antimicrobial activity, such as granulocyte macrophage colony-stimulating factor (GM-CSF), inhibit H. capsulatum growth in macrophages. Conversely, interleukin 4 inhibits the killing of intracellular pathogens. Using inductively coupled plasma mass spectrometry, we examined alterations in the metal homeostasis of murine H. capsulatum-infected macrophages that were exposed to activating cytokines. Decreases in the levels of iron (Fe(2+) and Fe(3+)) and zinc (Zn(2+)) were observed in infected, GM-CSF-treated macrophages compared with those in infected controls. Interleukin 4 reversed the antifungal activity of GM-CSF-activated macrophages and was associated with increased intracellular Zn(2+) levels. Chelation of Zn(2+) inhibited yeast replication in both the absence of macrophages and the presence of macrophages. Treatment of cells with GM-CSF altered the host Zn(2+) binding species profile. These results establish that Zn(2+) deprivation may be a host defense mechanism utilized by macrophages.


Dynamic testicular adhesion junctions are immunologically unique. II. Localization of classic cadherins in rat testis.
In the seminiferous epithelium, morphologically diverse junctions mediate inter-Sertoli and Sertoli-germ cell adhesive contact and likely transmit signals between contacting cells. Defining the molecular composition of testicular cell-cell junctions is an important step in determining their function. Proteins belonging to the cadherin superfamily are important mediators of cell-cell adhesion, as well as cell signaling. Here, we determined the spatial and temporal protein expression of four classic cadherins in rat testis: N-cadherin, cadherin-6, cadherin-11, and a cadherin defined by an antiserum generated against a conserved classic cadherin peptide (L4). Through Western blot analysis, all antibodies recognized unique proteins. Similarly, each cadherin displayed unique, cell-type specific immunostaining patterns. Whereas N-cadherin, cadherin-11, and L4-positive cadherin were expressed from Postnatal Day 7 through adulthood, cadherin-6 protein was not present at Postnatal Day 7 and first appeared at Day 21. Immunostaining of testis cryosections on Postnatal Days 7, 21, 31, 43, and those of adults indicated that cadherin-11 localized to peritubular cell junctions. N-cadherin immunostaining localized to basal inter-Sertoli junctions, Sertoli-spermatocyte junctions, and at about stages I-VII in Sertoli-elongate spermatid junctions. Cadherin-6 immunostaining was restricted to Sertoli-round spermatid and in Sertoli-elongate spermatid junctions at approximately stages XII-I. Finally, L4-positive immunostaining also detected Sertoli-round spermatid junctions in addition to Sertoli-elongate spermatid junctions at approximately stages XII-I. These data show that the various testicular cell-cell junctions are molecularly unique and dynamic complexes.


L-Lysine α-Oxidase: Enzyme with Anticancer Properties.
L-lysine α-oxidase (LO), one of L-amino acid oxidases, deaminates L-lysine with the yield of H2O2, ammonia, and α-keto-ε-aminocaproate. Multiple in vitro and in vivo studies have reported cytotoxic, antitumor, antimetastatic, and antitumor activity of LO. Unlike asparaginase, LO has a dual mechanism of action: depletion of L-lysine and formation of H2O2, both targeting tumor growth. Prominent results were obtained on murine and human tumor models, including human colon cancer xenografts HCT 116, LS174T, and T47D with maximum T/C 12, 37, and 36%, respectively. The data obtained from human cancer xenografts in immunodeficient mice confirm the potential of LO as an agent for colon cancer treatment. In this review, we discuss recently discovered molecular mechanisms of biological action and the potential of LO as anticancer enzyme.


Salmonella enterica Optimizes Metabolism After Addition of Acyl-Homoserine Lactone Under Anaerobic Conditions.
Acyl-homoserine lactones (AHLs) are quorum sensing (QS) signaling molecules that mediate cell-to-cell communication in Gram-negative bacteria. Salmonella does not produce AHL, however, it can recognize AHLs produced by other species through SdiA protein modulating important cellular functions. In this work, the influence of the N-dodecanoyl-DL-homoserine lactone (C12-HSL) on glucose consumption, metabolic profile, and gene expression of Salmonella throughout the cultivation time in Tryptic Soy Broth (TSB) under anaerobic conditions was evaluated. Analysis of the supernatant culture in high-performance liquid chromatography (HPLC) revealed lower glucose uptake after 4 and 6 h of the addition of C12-HSL. Gas chromatography-mass spectrometry (GC-MS) based analysis of the intracellular metabolites revealed C12-HSL perturbation in the abundance levels of metabolites related to the metabolic pathways of glycerolipids, purines, amino acids, and aminoacyl-tRNA biosynthesis. The real-time quantitative PCR (RT-qPCR) indicated that Salmonella increase expression of genes associated with nucleoside degradation and quantification of metabolites supported the induction of pentose phosphate pathway to ensure growth under lower glucose consumption. The obtained data suggest an important role of C12-HSL in the optimization of metabolism at a situation of high population densities.


Serial immunological investigations in a patient who had a life-threatening reaction to intravenous protamine.
Reactions to intravenous protamine include rash, urticaria, bronchospasm, hypotension, and/or pulmonary artery pressure elevation. We have previously shown that in diabetic patients receiving daily protamine-insulin injections, the presence of anti-protamine IgE or IgG antibodies are significant risk factors for acute, life-threatening reactions when protamine is given intravenously. To study protamine reactions further, we measured serum anti-protamine IgE and IgG antibody levels, in-vitro basophil histamine release and intracutaneous skin testing to protamine serially in an NPH-insulin dependent diabetic who had a severe, protracted anaphylactic reaction to protamine. At the time of his protamine reaction, his serum contained 8.5 ng/ml of anti-protamine IgE and 1.3 micrograms/ml of anti-protamine IgG antibody. One month following the reaction both anti-protamine IgE and IgG increased to 16 ng/ml (twofold rise) and 90.5 micrograms/ml (70-fold rise), respectively. With time, both anti-protamine IgE and IgG antibody declined. Serial intradermal skin tests using protamine sulphate did not discriminate between the protamine reactor and nine normal control subjects who had no prior exposure nor any demonstrable serum IgE antibody to protamine. In-vitro basophil histamine release to protamine sulphate was inconclusive in discriminating between the protamine reactor and normal control subjects. We postulate that protamine may be an incomplete or univalent antigen that must first combine with a tissue macromolecule or possibly heparin to become a complete multivalent antigen capable of eliciting IgE antibody-dependent mediator release.


Sorption of volatile flavor compounds by microcellular cereal starch.
Wheat starch based microcellular foam (MCF) forms of (dry) starch possess a significant percentage of micropores in the range of 5-14 A. The present study confirmed earlier preliminary studies that MCF starch (in a 0.25-1.0 mm diameter bead form) is effective in sorbing and lowering the headspace partial pressure of many volatile compounds in a manner similar (although less efficient) to that exhibited by other microcavity sorbants such as charcoal. It was found that the proportion of polar compounds sorbed was much greater than the proportion of nonpolar compounds. A major portion of the sorbed volatile compound was readily displaced from the MCF microcellular starch by the addition of water. These properties make this form of edible starch a potential useful carrier of flavor compounds for dried foods.


Human Amniotic Epithelial Stem Cells: A Promising Seed Cell for Clinical Applications.
Perinatal stem cells have been regarded as an attractive and available cell source for medical research and clinical trials in recent years. Multiple stem cell types have been identified in the human placenta. Recent advances in knowledge on placental stem cells have revealed that human amniotic epithelial stem cells (hAESCs) have obvious advantages and can be used as a novel potential cell source for cellular therapy and clinical application. hAESCs are known to possess stem-cell-like plasticity, immune-privilege, and paracrine properties. In addition, non-tumorigenicity and a lack of ethical concerns are two major advantages compared with embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). All of the characteristics mentioned above and other additional advantages, including easy accessibility and a non-invasive application procedure, make hAESCs a potential ideal cell type for use in both research and regenerative medicine in the near future. This review article summarizes current knowledge on the characteristics, therapeutic potential, clinical advances and future challenges of hAESCs in detail.


The effect of intramedullary cement on intercalary allograft reconstruction of bone defects after tumour resection: a pilot study.
A pilot study to evaluate the surgical and functional results of resection and reconstruction of diaphyseal bone tumours with cemented and uncemented intercalary allografts. A retrospective case series. A quaternary care unit within a teaching hospital. Twenty-two patients with diaphyseal bone tumours treated between 1988 and 1992, with mean follow-up of 38 months (range from 20 to 70 months). Diagnostic biopsy in all patients. Preoperative and postoperative chemotherapy in patients with high-grade sarcoma. En-bloc excision of all tumours. Reconstruction of the defect with cemented (15 patients) or uncemented (7 patients) intercalary allografts. Nonunion at one or both osteosynthesis sites, death from systemic disease, amputation. Six of the 22 patients died of systemic disease with the graft intact, and 3 subsequently had amputation for either local recurrence (2 patients) or failure of free tissue transfer (1 patient), leaving 13 patients alive with the allograft in situ at an average of 36 months (range from 24 to 64 months). There were no revision procedures to remove or replace the original allograft. Five patients had nonunion at one or more osteosynthesis sites on plain radiographs 9 months after resection. Four patients with nonunion were in the cemented group of 13 patients available for assessment at 9 months, and 1 was in the uncemented group of 5 patients available for assessment at 9 months. There were two graft fractures, both in the uncemented group. The results of this pilot study offer guarded support for the use of pressurized cement in allografts prior to reconstruction of intercalary defects.


Abdominal Sepsis - Current Definitions and Practice.
Abdominal sepsis remains the second most common source of sepsis, a life-threatening condition that became a global health priority in the medical field research. Open abdomen is part of the damage control surgery, a life-saving strategy in a well-selected group of surgical patients with severe abdominal sepsis and intra-abdominal hypertension. Definitions and recommendations in the management of abdominal sepsis and open abdomen have gradually evolved, as a reflection of the progress of both the comprehension of physiopathological mechanisms involved in sepsis and the technology of different temporary abdominal closure systems. The aim of this paper is to make an up-to-date literature narrative review of the definitions and current practice guidelines in abdominal sepsis, with illustration of clinical experience in the management of open abdomen wounds. In the past decades, progress has been made in the management of abdominal sepsis, with greatly ameliorated survival rates. Rapid diagnosis, extensive comprehension of the physiopathological mechanisms of sepsis, adapted fluid resuscitation, antimicrobial therapy and damage-control surgery, orchestrated by a multy-disciplinary team, play an equally important role in the prognosis of a patient.


On Farm Emergency Slaughter and Emergency Killing of Acutely Injured Cattle: Analysis of Guidelines From Five Jurisdictions.
In July 2009, the Farm Animal Welfare Advisory Council (FAWAC) in the Republic of Ireland published Animal Welfare Guidelines for the Management of Acutely Injured Animals on Farm in support of a new Irish regulation designed to permit on-farm emergency slaughter (OFES) of cattle. The purpose of this study was to evaluate the FAWAC guidelines, to determine if they remain fit for purpose by comparing them with five guidelines on the management of acutely injured cattle from four jurisdictions purposively selected because of their relevance to OFES, and to represent geographical and organisational diversity; The United Kingdom, Australia, New Zealand and British Columbia/Canada. Content and Thematic Analysis were used to compare the incidence and frequency of themes in the six guidelines using NVIVO 12. Humane killing and slaughter of animals and the prevention of unnecessary suffering at time of killing were emphasised in all guidelines. Thematic Analysis identified seven primary themes ("parent nodes"): animal welfare; decision tree; certification; legislation; stakeholders; transport and; veterinary ethics. Parent nodes encompassed 26 secondary themes ("child nodes") including casualty slaughter, on-farm emergency slaughter, euthanasia, unnecessary suffering, animal owner, private veterinary practitioner, official veterinarian and fitness for transport. Guidelines outlined stakeholders' roles in relation to all aspects of managing acutely injured cattle. Results showed similarities between FAWAC, the British Cattle Veterinary Association and the British Columbian/Canadian guidelines in relation to OFES as a method to address acutely injured cattle. OFES is not allowed in Australia or New Zealand as a method of managing acutely injured cattle. Animal welfare guidelines play a pivotal role in informing all stakeholders involved in the management of acutely injured cattle. Guidelines vary from prescriptive standard operating procedures on actions that should be undertaken for food safety reasons, to descriptive guidance upholding practicalities in relation to equipment and methods to be used in managing acutely injured cattle not meant for human consumption. The FAWAC guidelines remain substantially relevant today and consistent with other welfare guidelines published in the jurisdictions that formed part of the study. However, they need to be reviewed to align with current regulations.


Mutations in the COL18A1 gen associated with knobloch syndrome and structural brain anomalies: a novel case report and literature review of neuroimaging findings.
. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found. Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism without the brain malformations typically reported in patients with Knobloch syndrome.


Pseudotumor cerebri: CT findings and correlation with vision loss.
The purpose of this study was to determine if orbital and cerebral CT can be used to distinguish normal patients from those with pseudotumor cerebri, and to correlate CT findings with the severity of visual impairment. Seventeen patients with a clinical diagnosis of pseudotumor cerebri were compared with 20 age- and sex-matched control subjects. Thin-section coronal and axial CT scans of the orbit and whole-brain axial CT scans were available for all subjects. The diameter of the optic nerve sheath, the degree of reversal of the optic nerve head, the presence and degree of empty sellae, and ventricular and sulcal sizes were evaluated without knowledge of whether or not the subject had pseudotumor cerebri. The same parameters were compared for two subgroups of patients with pseudotumor cerebri: those with mild vision loss and those with severe vision loss. Patients with pseudotumor cerebri had significantly larger optic nerve sheaths than did control subjects (6.5 +/- 0.83 mm vs 5.4 +/- 0.69 mm). Radiologic evidence of papilledema with reversal of the optic nerve head was found in 12 of 17 patients compared with one of 20 control subjects. An empty sella was seen more frequently and to a greater degree in patients with pseudotumor cerebri than in control subjects (16 vs seven). Eight of nine patients with severe vision loss and four of eight patients with mild to moderate vision loss had reversal of the optic nerve head; the degree was greater in the group with severe vision loss. No difference in ventricular size or sulcal enlargement was seen between any of the groups. The opening CSF pressures of the two groups with vision loss were not significantly different (348 +/- 80 mm H2O vs 391 +/- 98 mm H2O). In addition to the role of CT in excluding intracranial disease as a basis for the clinical syndrome of pseudotumor cerebri, thin-section CT of the orbits reveals a constellation of findings, including enlarged optic nerve sheaths, reversal of the optic nerve head, and empty sellae in patients with pseudotumor cerebri. Furthermore, severe vision loss in these patients correlates with more frequent and more severe reversal of the optic nerve head.


Nuclear magnetic resonance solution structure of the growth factor receptor-bound protein 2 Src homology 2 domain.
A family of NMR solution structures of the growth factor receptor-bound protein 2 (Grb2) SH2 domain has been determined by heteronuclear multidimensional NMR. Proton, nitrogen, and carbon chemical shift assignments have been made for the SH2 domain of Grb2. Assignments were made from a combination of homonuclear two-dimensional and 15N- and 13C-edited three-dimensional spectra at pH 6.2 and 298 K. Structure-induced proton and carbon secondary shifts were calculated and used to facilitate the spectral assignment process. NOE, scalar coupling, secondary chemical shift, and amide proton exchange data were used to characterize the secondary structural elements and hydrogen-bonding network in the Grb2 SH2 domain. The three-dimensional structure of the Grb2 SH2 domain was calculated using 1112 restraints obtained from NOE, coupling constant, and amide proton exchange data. The rmsd for the 24 calculated structures to the mean structure of the Grb2 SH2 domain was 0.75 A for backbone and 1.28 A for all heavy atoms. The three-dimensional fold of the Grb2 SH2 domain is similar to that observed for other SH2 domains and consists of two alpha-helical segments and eight beta-strands, six strands that make up two contiguous antiparallel beta-sheets, and two strands that form two short parallel beta-sheets. The structure of the phosphotyrosine binding pocket of Grb2 is similar to that observed for other SH2 domains. The hydrophobic binding pocket of Grb2 is similar to that observed for Src with the exception that tryptophan 121 of Grb2 occupies part of the pY+3 binding pocket. Structural implications for the Grb2 SH2 domain selectivity at the pY+2 and pY+3 sites are discussed.


Signaling system for multiple-access laser communications and interference protection.
Signaling by spatial coding is proposed for asynchronous multiple-access free-space optical communications and interference mitigation. The large spatial bandwidth (e.g., 10(6) pixels) of each laser transmitter aperture is utilized for user coding, while the transmitter temporal bandwidth is preserved for information signals. Signal recovery is based on incoherent optical detection, spatial sampling, and electronic or optical matched filtering of the remotely received transmit optical beam Fresnel or Fraunhofer diffraction pattern. The proposed signaling method is appropriate for multiple-access free-space laser links involving multiple transmitters that use a common receiver. With electronic filtering, low-to-medium (e.g., 3 Mbits/s) data-rate users are appropriate. With a lenslet-array-based incoherent optical correlator, higher (e.g., 100 Mbits/s) data rates can be achieved. Improved interference protection is achieved cby spatially distributed bit-duration-based processing. Preliminary simulation results are carried out to demonstrate operating principles.


Salvage of Infected Breast Implants.
Implant-based breast reconstruction is being performed more frequently, and implants are associated with an increased risk of infection. We reviewed the clinical features of cases of implant infection and investigated the risk factors for breast device salvage failure. We retrospectively analyzed 771 patients who underwent implant-based breast reconstruction between January 2010 and December 2016. Age, body mass index, chemotherapy history, radiation exposure, and smoking history were assessed as potential risk factors for postoperative infection. We also evaluated the presence and onset of infection symptoms, wound culture pathogens, and other complications, including seroma, hematoma, and mastectomy skin necrosis. Additionally, we examined the mastectomy type, the use of acellular dermal matrix, the presence of an underlying disease such as hypertension or diabetes, and axillary node dissection. The total infection rate was 4.99% (58 of 1,163 cases) and the total salvage rate was 58.6% (34 of 58). The postoperative duration to closed suction drain removal was significantly different between the cellulitis and implant removal groups. Staphylococcus aureus infection was most frequently found, with methicillin resistance in 37.5% of the cases of explantation. Explantation after infection was performed more often in patients who had undergone 2-stage expander/implant reconstruction than in those who had undergone direct-to-implant reconstruction. Preventing infection is essential in implant-based breast reconstruction. The high salvage rate argues against early implant removal. However, when infection is due to methicillin-resistant S. aureus and the patient's clinical symptoms do not improve, surgeons should consider implant removal.


A Smart Wireless Ear-Worn Device for Cardiovascular and Sweat Parameter Monitoring During Physical Exercise: Design and Performance Results.
Wearable biomedical technology has gained much support lately as devices have become more affordable to the general public and they can easily interact with mobile phones and other platforms. The feasibility and accuracy of the data generated by these devices so as to replace the standard medical methods in use today is still under scrutiny. In this paper, we present an ear-worn device to measure cardiovascular and sweat parameters during physical exercise. ECG bipolar recordings capture the electric potential around both ears, whereas sweat rate is estimated by the impedance method over one segment of tissue closer to the left ear, complemented by the measurement of the lactate and pH levels using amperiometric and potentiometric sensors, respectively. Together with head acceleration, the acquired data is sent to a mobile phone via BLE, enabling extended periods of signal recording. Results obtained by the device have shown a SNR level of 18 dB for the ECG signal recorded around the ears, a THD value of -20.46 dB for the excitation signal involved in impedance measurements, sweat conductivity of 0.08 S/m at 1 kHz and sensitivities of 50 mV/pH and 0.8 μA/mM for the pH and lactate acquisition channels, respectively. Testing of the device was performed in human subjects during indoors cycling with characteristic level changes.


Experience with salvage regimens at M.D. Anderson Hospital.
With the intent of using active regimens in the front-line setting, new combinations of chemotherapy have been tested as salvage treatment in lymphoma patients at M.D. Anderson Hospital. Combinations based on ifosfamide plus etoposide, including IMVP-16 (ifosfamide/methotrexate/etoposide) and MIME (methyl-GAG/ifosfamide/methotrexate/etoposide) resulted in overall and complete responses (CRs) of 60 and 25%, respectively. Long-term follow-up of MIME indicates a 25% cure rate in intermediate-grade lymphoma patients who achieve CR. The in vitro synergism of platinum and high-dose cytarabine recently has been confirmed clinically. A study is currently under way to evaluate the effect of integrating MINE (mesna/ifosfamide/mitoxantrone/etoposide) and ESHAP (etoposide/methyl prednisolone/cytarabine/platinum) into one protocol.


3,5-diiodo-L-thyronine stimulates type 1 5'deiodinase activity in rat anterior pituitaries in vivo and in reaggregate cultures and GH3 cells in vitro.
Local deiodination of L-thyroxine (T4) to the active thyroid hormone T3 via two 5'deiodinase isoenzymes (5'DI and 5'DII) plays an important role for various T3-dependent functions of the anterior pituitary (AP). Recently, it was reported that 3,5-T2, the 5'deiodination product of T3, acts as a specific agonist in the feedback mechanism on TSH secretion at the pituitary level. We now examined the effects of 3,5-T2 on pituitary 5'deiodinase activities in vivo in male, adult rats and in vitro using rat AP reaggregate cultures and the somatomammotroph cell line GH3. 5'DI activity in the AP was transiently increased after a single injection of 3,5-T2. Serum TSH levels declined, and 24 h after 3,5-T2 application, betaTSH steady-state mRNA levels in the APs were markedly lower. In reaggregate cultures of the AP, 3,5-T2 stimulated 5'DI activity 24 h after application, dose-dependently. Compared with 5'DI activities, those of 5'DII were an order of magnitude lower, in vivo as well as in vitro, and were rapidly and transiently decreased by the higher dose of 3,5-T2. GH3 cells responded to 3,5-T2 and T3 by an 1.7-fold stimulation of 5'DI activity. Stimulation of DNA-binding was demonstrated in electrophoretic mobility shift assays for a specific RXR-containing protein complex with a DR+4 thyroid hormone response element of the human type 1 5'DI promoter using nuclear extracts from GH3 cells treated with 3,5-T2. In summary, 3,5-T2 and T3 exert direct thyromimetic effects on 5'DI activity and TSHbeta expression at the pituitary level. 5'DI is regulated by its substrate(s) and/or products and may serve an important function within the modulation of thyroid hormone-dependent gene expression in the AP.


Medical care provision at the venue of the weightlifting event of the Tokyo 2020 Olympic Games.
This study aimed to investigate the medical care provided at the venue of the weightlifting event of the Tokyo 2020 Olympic Games. We retrospectively evaluated athletes who availed of medical services at the venue during the weightlifting event of the Tokyo 2020 Olympic Games. In total, 194 athletes participated in the weightlifting competition.Injuries and illnesses were classified into cases handled without physician or cases requiring medical examination by a physician. These were tabulated for each examination location (athlete medical station, field of play [FOP], first-aid station of training floor or warm-up area). Throughout the event, a cumulative total of 132 people used the venue medical services. Nine athletes required medical attention at the athlete medical stations. Of these nine cases, six occurred on the training floor. In the FOP, nine athletes were examined. Two experienced light-headedness, two had knee pain, and the rest had other symptoms. No athletes wanted to undergo medical examination at the athlete medical station. 89 medical procedures were performed in the first-aid station on the training floor, including 52 tapings and 37 ice compressions, and the most frequent body part which needed treatment was the knee, followed by the fingers. At the first-aid station on the match floor, 25 medical procedures were performed, including 17 ice compressions, 5 haemostasis, and 4 tapings. The body parts that most frequently needed treatment were the fingers, knees, and lower legs. Several athletes needed treatment; however, only a few required medical care from a physician.


Computational screening of metal-organic frameworks for large-molecule chemical sensing.
Grand canonical Monte Carlo simulations were performed to identify trends in low-pressure adsorption of a broad range of organic molecules by a set of metal-organic frameworks (MOFs). While previous simulation studies focused on the adsorption of small molecules such as carbon dioxide and methane, we consider more complicated organic molecules relevant to chemical sensing and detection: small aromatics (o-, m-, and p-xylene), polycyclic aromatic hydrocarbons (naphthalene, anthracene, phenanthrene), explosives (TNT and RDX), and chemical warfare agents (GA and VM). The framework materials include several Zn-IRMOFs (IRMOFs 1-3, 7, 8), a Cr-MOF (CrMIL-53lp), and a Cu-MOF (HKUST-1). A wide range of loading pressures is examined, extending from 100 ppm to 10 ppb in air, thus spanning the entire range of conditions relevant to chemical sensing for security, environmental, and industrial process monitoring. Our results are validated by comparing calculated adsorption energies with experimental values, where available. Many of the larger organics are significantly adsorbed by the target MOFs at low pressure, which is consistent with the high isosteric heats of adsorption (12 kcal mol(-1)-49 kcal mol(-1)) computed for these analytes. These adsorption energies are significantly large that interference from atmospheric components should not interfere with chemical detection at low pressures. We show that pi-pi stacking interactions are an important contributor to these high heats of adsorption. CrMIL-53lp shows the highest adsorption energy for all analytes, suggesting that this material may be suitable for detection of low-level organics. At higher loading pressures, the Zn-MOFs show a much higher volumetric uptake than either CrMIL-53lp or HKUST-1 for all types of analyte considered here. Within the Zn-IRMOF series, analyte loading is proportional to accessible free volume, and loading decreases with increasing analyte size due to molecular packing effects. Overall, the results demonstrate that atomistic simulation can be used as an efficient first step in the screening of MOFs for detection of large molecules. For example, at the 10 ppb level, all of the Zn-IRMOFs are able to distinguish between TNT and the structurally similar xylenes.


Assessment of clotrimazole gels for in vitro stability and in vivo retention in the frontal sinus of dogs.
To evaluate the stability and retention of viscous formulations of the antifungal drug clotrimazole in vitro and to evaluate retention times, absorption, and histologic response to these compounds when placed in the frontal sinus of dogs. 6 male Beagles. 1% clotrimazole gels were formulated with hydroxypropyl cellulose, poloxamer, and carboxymethylcellulose sodium bases. Commercially available 1% clotrimazole creams were also evaluated. Each compound was incubated at 37 degrees C in a funnel. Volume retained and clotrimazole stability were evaluated for 4 weeks. Six compounds were then chosen for in vivo evaluation. The frontal sinuses of 6 dogs were filled with 1 of the 6 compounds. Computed tomographic evaluation was performed weekly for up to 4 weeks to evaluate gel retention. Blood samples were collected to evaluate clotrimazole absorption. Following euthanasia, sinuses were examined histologically. Commercially available clotrimazole creams were not retained in funnels in vitro. In vivo, hydroxypropyl cellulose- and carboxymethylcellulose-based gels resulted in the most severe inflammatory response and were retained the longest. Poloxamer-based gels had a shorter retention time and were associated with less inflammation. Clotrimazole was minimally absorbed. Despite a marked inflammatory response to several of the clotrimazole-containing gels, no notable adverse clinical responses were observed. Poloxamer gels had the most promise for improving drug contact within the frontal sinus of dogs, while limiting the inflammatory response. Poloxamer gels have the additional benefit of improved handling as a result of reverse gelation (ie, they gel when warmed to 37 degrees C).


Molecular analysis of the thymidine kinase gene of thymidine kinase-deficient mutants of varicella-zoster virus.
Five thymidine kinase (TK)-deficient mutants of varicella-zoster virus derived from the Oka vaccine strain were examined to determine the state of transcription of the TK gene, and the DNA sequences of two of the mutants and the parent strain were investigated. Restriction endonuclease analysis revealed no major alteration of whole genome organization, but did reveal a minor change of the cleaved fragment in size. Northern blot analysis showed that the transcripts from the TK gene of all five mutants were of the same size as that of the parent strain (1.6 kb). DNA sequences of the TK gene of the parent strain and those of two mutants were determined. One had a base substitution (C to T) in the coding region of TK, resulting in the termination of amino acid elongation in the 68th amino acid of 341. The other had a two-base deletion (AT) in the coding region, resulting in a frame shift from the 126th amino acid and termination at the 162nd amino acid. Both mutants had premature stop codons which might result in the synthesis of nonfunctional TK polypeptides. Thus, the molecular basis of TK deficiency was determined.


Sentence interpretation in normal and aphasic Hindi speakers.
In interpreting a sentence, listeners rely on a variety of linguistic cues to assign grammatical roles such as agent and patient. The present study considered the relative ranking of three cues to agenthood (word order, noun animacy, and subject-verb agreement) in normal and aphasic speakers of Hindi. Because animacy plays a grammatical role in Hindi (determining the nature and acceptability of sentences without accusative marking), this language is relevant to the claim that Broca's aphasia involves a dissociation between grammar and semantics. Results of Study 1 with normal Hindi-dominant speakers showed that animacy is the strongest cue in this language, while agreement is the weakest cue. In Study 2, Hindi-English bilinguals were tested in both their languages. Most showed the normal animacy-dominant monolingual pattern in Hindi, with a mixture of strategies from both languages in their interpretation of English. A substantial minority showed mixed strategies in both languages. Only 5 of 48 subjects displayed a complete separation between languages, with animacy dominance in Hindi and word order dominance in English. In Study 3, two Hindi-English bilinguals with Broca's aphasia were tested in both languages. Results indicate (a) greater use of animacy in Hindi than in English and (b) greater use of word order in English than in Hindi. The strategies displayed by these patients fall well within the range observed among bilingual normals. We conclude that the use of animacy in sentence interpretation by these aphasic patients reflects preservation of normal, language-specific processing strategies; it cannot be interpreted as a nonlinguistic strategy developed to compensate for receptive agrammatism. Results are discussed in light of other cross-linguistic evidence on sentence comprehension in monolingual and bilingual aphasics.


The effect of substrate size on the locomotion and gait patterns of the kinkajou (Potos flavus).
Diagonal-sequence (DS) gaits, which are very rare among mammals, are common and well documented in primates and some arboreal marsupials. DS walking gaits have been reported in the kinkajou (Potos flavus), which shows ecological similarities with primates and arboreal opossums but lacks prehensile specializations of the hindfoot. Nevertheless, the actual frequency of DS gaits and the functional context in which these gaits occur in this highly arboreal mammal remain unknown. We examined the effect of substrate size on the locomotion and gait patterns of kinkajous by recording gaits in two individuals walking and running on poles of two different diameters and on a runway. Diagonality and limb duty factors were calculated for 534 gait cycles. Kinkajous relied mostly on DS gaits and trots during walking, and increased the diagonality of their gait patterns on thinner substrates. The proposed functional link between locomotion on thin branches and the presence of a grasping, primate-like hindfoot is not supported by these data. However, further analysis of kinkajou gait cycles showed that DS gaits may have advantages overlooked earlier. DS gaits, during walking, minimize the distance between two ipsilateral feet during short periods of unilateral bipedality, and per corollary maximize the distance between two contralateral feet during the much longer periods of diagonal bipedality. Such foot positioning during the gait cycle could be beneficial in walking on a relatively thin substrate and could explain why kinkajous adopt DS walking gaits, especially on thinner poles, despite lacking prehensile specializations of the hindfoot.


Digoxin in clinical practice: sorting out the facts.
The aim of this review is to sort out from the huge amount of facts related to digoxin in the literature those pertinent to current clinical practice. Seven aspects of digoxin are discussed: its mechanism of action, therapeutic controversy, clinical efficacy, avoidance of toxicity, manifestations of toxicity, indications, and its use in coronary artery disease.


Beam brilliance investigation of high current ion beams at GSI heavy ion accelerator facility.
In this work the emittance measurements of high current Ta-beam provided by VARIS (Vacuum Arc Ion Source) ion source are presented. Beam brilliance as a function of beam aperture at various extraction conditions is investigated. Influence of electrostatic ion beam compression in post acceleration gap on the beam quality is discussed. Use of different extraction systems (single aperture, 7 holes, and 13 holes) in order to achieve more peaked beam core is considered. The possible ways to increase the beam brilliance are discussed.


Matched filter optical processor.
A new tracking optical processor that uses a computer generated matched filter to process the synthetic aperture radar data is described. The general consideration in generating the matched filter is discussed in detail and some experimental results are presented.


Early Clinical and Radiological Outcomes of the Metaphyseally Fixed Totally Stabilized Knee Prosthesis in Primary Total Knee Arthroplasty.
The use of valgus-varus constrained (VVC) implant designs in primary total knee arthroplasty (TKA) is considered in situations of severe deformities, bone loss, and inadequate soft tissue balance. It is not known whether the use of such prosthesis designs may predispose to reduced function owing to its constraining design. The components are usually implanted with diaphyseal stem extensions to dissipate the increased forces. The totally stabilized (TS) implant is a contemporary VVC design with metaphyseal fixation only. It has a conforming articulation with increased rotational freedom compared with conventional VVC designs. The aim of this study was to assess whether the use of the contemporary TS implant with its metaphyseally fixed components would be associated with inferior outcomes compared with conventional standard primary posterior stabilized (PS) implants. We reviewed 38 consecutive complex primary TKAs performed using the metaphyseally fixed TS implant and 76 matched patients receiving primary PS TKA, at a minimum follow-up of 24 months. The mean follow-up was 61.1 months (24-102). Only patients with osteoarthritis were included. Clinical outcome was assessed using range of motion (ROM) and Oxford knee score (OKS). Radiographic assessment was performed using the femorotibial angle (FTA) at 6 weeks followed by assessment of bone-implant interface lucencies at final follow-up. There were no major early postoperative complications. The mean postoperative ROM in the TS and PS groups were 114.1 and 112.0, respectively. There was no difference in the mean ROM and OKS between the two groups. The mean FTA for patients in both groups was within 3° of the expected. There was no evidence of progressive lucencies or implant migration at final follow-up. The metaphyseally fixed TS knee design achieves comparable short-term functional outcomes when compared with conventional PS designs in primary knee arthroplasty. Long-term follow-up studies are required to assess survivorship.


Insight into formation propensity of pseudocircular DNA G-hairpins.
We recently showed that Saccharomyces cerevisiae telomeric DNA can fold into an unprecedented pseudocircular G-hairpin (PGH) structure. However, the formation of PGHs in the context of extended sequences, which is a prerequisite for their function in vivo and their applications in biotechnology, has not been elucidated. Here, we show that despite its 'circular' nature, PGHs tolerate single-stranded (ss) protrusions. High-resolution NMR structure of a novel member of PGH family reveals the atomistic details on a junction between ssDNA and PGH unit. Identification of new sequences capable of folding into one of the two forms of PGH helped in defining minimal sequence requirements for their formation. Our time-resolved NMR data indicate a possibility that PGHs fold via a complex kinetic partitioning mechanism and suggests the existence of K+ ion-dependent PGH folding intermediates. The data not only provide an explanation of cation-type-dependent formation of PGHs, but also explain the unusually large hysteresis between PGH melting and annealing noted in our previous study. Our findings have important implications for DNA biology and nanotechnology. Overrepresentation of sequences able to form PGHs in the evolutionary-conserved regions of the human genome implies their functionally important biological role(s).


[Decorative repair and reconstruction of subtotal thumb and finger defect with trimmed toe flap transfer].
In partial loss of distal finger segment, a corresponding part of the toe tissue compound is harvested and transplanted for repair or reconstruction. This new procedure gives forth a new concept and is called decorative repair or reconstruction. In a series of 77 patients with 88 thumb and/or finger subtotal defects in forms of lateral half, dorsal half or volar half composite tissue defects were reconstructed with lateral nail-skin flap, dorsal skin-nail flap or pulp flap taken from corresponding part of the toes. The blood circulations were re-established by anastomosing digital arteries of the toe transplants and fingers. In this series 75 patients with 78 fingers reconstructed are successful. The overall survival rate is 97.5%. Follow-up examinations made half to 12 years postoperatively showed the fingers are having a normal length, outward appearance and function. There are nails preserved. The pulps are full. Sweating function are present. Two-point-discrimination tests are between 4-6 mm. By decorative reconstruction of subtotal dorsal, lateral, or volar halves defect of thumb and/or fingers by transplanting corresponding part of soft tissue taken from the toe has the merit of repair of any parts of tissue loss precisely what is needed. This procedure is better than any traditional toe-to-hand transfer and realizing the exact meaning of decorative reconstruction.


P-Akt expression distinguishes two types of malignant rhabdoid tumors.
Highly aggressive pediatric malignant rhabdoid tumors (MRT) arise in the kidney and central nervous system (CNS) with no curative treatment available. Multiple studies have shown that inactivation of the SNF5 tumor suppressor gene occurs in virtually all MRTs. However, few studies have addressed whether additional genetic events may contribute to MRT development. In this report, we demonstrate that phosphorylated Akt (P-Akt) is expressed in a subpopulation of cells in at least 10% of primary rhabdoid tumors as well as at high levels in three MRT cell lines. Similar to other high P-Akt expressing tumor cell lines, MRTs have decreased sensitivity to p21 induced growth arrest. Therefore, P-Akt expression may distinguish between two types of MRTs. Because drugs directed against the PI3-K/Akt have shown promise in clinical trials for other tumor types, they may prove useful for treatment of patients with P-Akt positive MRTs. P-Akt expression also provides a potential mechanistic link between these pediatric tumors and adult malignancies.


The effects of primiparity on reproductive performance in the brown bear.
We studied the effects of primiparity on litter size, offspring size, and cub loss in brown bears (Ursus arctos) in two study areas (north, south) in Sweden from 1987 to 2006. Sexually selected infanticide (SSI) has been suggested previously as a mortality factor in our study populations. Females in the south became primiparous earlier than females in the north. Primiparous females had significantly smaller litters of cubs than multiparous females. We found no evidence that primiparity was costly in terms of the interlitter interval. Primiparous mothers had a higher probability of cub loss than multiparous mothers. The probability of cub loss was analyzed separately for the pre-mating and the mating season. The probability of cub loss by primiparous females in the pre-mating season increased with both increasing population density and deteriorating food conditions, whereas the probability of cub loss during the mating season decreased with increasing age of primiparity and increased with male turnover (a variable predicting SSI). The temporal patterns of cub loss by primiparous females suggested that the critical times for reproductive success by primiparous females were the pre-mating season (from birth to shortly after leaving the den) and the mating season. Cub loss in these periods was independent and caused by different factors. Cub loss before the mating season seemed to be most influenced by food conditions, whereas that during the mating season appeared to be caused by SSI.


Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates.
Osteonecrosis of the jaw is a well-documented side effect of bisphosphonate (BP) use. Attempts have recently been made to predict the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We prospectively investigated the predictive value of serum levels of C-terminal telopeptide of collagen I (CTX), bone-specific alkaline phosphatase, and parathyroid hormone for the development of BRONJ. Data on the demographics, comorbidities, and BP treatment were collected from 78 patients scheduled for dentoalveolar surgery. Of the 78 patients, 51 had been treated with oral BPs and 27 had been treated with frequent intravenous infusions of BPs. Blood samples for CTX, bone-specific alkaline phosphatase, and parathyroid hormone measurements were taken preoperatively. Surgery was performed conservatively, and antibiotic medications were prescribed for 7 days. Of the 78 patients, 4 patients taking oral BPs (7.8%) and 14 receiving intravenous BPs (51.8%) developed BRONJ. A CTX level less than 150 pg/mL was significantly associated with BRONJ development, with an increased odds ratio of 5.268 (P = .004). The bone-specific alkaline phosphatase levels were significantly lower in patients taking oral BPs who developed BRONJ. The parathyroid hormone levels were similar in patients who did and did not develop BRONJ. The incidence of BRONJ after oral surgery involving bone is greater among patients receiving frequent, intravenous infusions of BPs than among patients taking oral BPs. Although the measurement of serum levels of CTX is not a definitive predictor of the development of BRONJ, it might have an important role in the risk assessment before oral surgery.


Pseudomonas fluorescens Filamentous Hemagglutinin, an Iron-Regulated Protein, Is an Important Virulence Factor that Modulates Bacterial Pathogenicity.
Pseudomonas fluorescens is a common bacterial pathogen to a wide range of aquaculture animals including various species of fish. In this study, we employed proteomic analysis and identified filamentous hemagglutinin (FHA) as an iron-responsive protein secreted by TSS, a pathogenic P. fluorescens isolate. In vitro study showed that compared to the wild type, the fha mutant TSSfha (i) exhibited a largely similar vegetative growth profile but significantly retarded in the ability of biofilm growth and producing extracellular matrix, (ii) displayed no apparent flagella and motility, (iii) was defective in the attachment to host cells and unable to form self-aggregation, (iv) displayed markedly reduced capacity of hemagglutination and surviving in host serum. In vivo infection analysis revealed that TSSfha was significantly attenuated in the ability of dissemination in fish tissues and inducing host mortality, and that antibody blocking of the natural FHA produced by the wild type TSS impaired the infectivity of the pathogen. Furthermore, when introduced into turbot as a subunit vaccine, recombinant FHA elicited a significant protection against lethal TSS challenge. Taken together, these results indicate for the first time that P. fluorescens FHA is a key virulence factor essential to multiple biological processes associated with pathogenicity.


HIV criminal prosecutions and public health: an examination of the empirical research.
To review the extant literature on HIV criminal laws, and to determine the impact of these laws on public health practice. The available research on this topic was obtained and reviewed. The extant literature addressed three main topics: people's awareness of HIV criminal laws; people's perceptions of HIV criminal laws; and the potential effects of HIV criminal laws on people's sexual, HIV-status disclosure and healthcare-seeking practices. Within these categories, the literature demonstrated a high level of awareness of HIV criminal laws, but a poor comprehension of these laws. For perceptions, on the whole, the quantitative research identified support for, while the qualitative literature indicated opposition to, these laws. Lastly, the behavioural effects of HIV criminal laws appear to be complex and non-linear. A review of the extant literature from a public health perspective leads to the conclusion that HIV criminal laws undermine public health.


Mutually exclusive binding of APPL(PH) to BAR domain and Reptin regulates β-catenin dependent transcriptional events.
Reptin functions in a wide range of biological processes including chromatin remodelling, nucleolar organization and transcriptional regulation of WNT signalling. As β-catenin dependent transcriptional repression and activation events involve binding of Reptin and histone deacetylase 1 to APPL endocytic proteins, this complex has become an important target to identify molecules governing endocytic processes and WNT signalling. Here, we describe the structural basis of APPL binding to Reptin to explore their mode of binding in context with APPL1/APPL2 dimerization. There is an evidence that both PH and BAR domains of APPL proteins exhibit alternately conserved regions involved in hetero-dimerization process and our in-silico data also corroborate this fact. Moreover, APPL2(PH) domain binds to the BAR domain region encompassing a nuclear localization signal. We conclude that APPL(PH) binding to BAR domain and Reptin is mutually exclusive which regulates the nucleocytoplasmic shuttling of Reptin. Furthermore, Reptin is unable to bind with membrane-associated APPL proteins. These observations were further expanded by experimental approaches where we identified a novel point mutation D316N lying in the APPL1(PH) domain which resulted in a significantly reduced binding with Reptin. By luciferase assays, we observed that overexpression of APPL1(D316N) and APPL1(WT) stimulated β-catenin/TCF dependent transcriptional activity in a similar manner which suggested that binding of Reptin to APPL1 is not necessary for β-catenin dependent target gene expression. Overall, our data attempt to highlight a comparative role of APPL proteins in controlling β-catenin dependent transcription mechanism which may improve our understanding of gene regulation.


A reappraisal of macrophage polarization in glioblastoma: Histopathological and immunohistochemical findings and review of the literature.
The survival rate in glioblastoma multiforme patients has scarcely improved in the last decades; however, many new therapeutic strategies have been theorized or developed for these neoplasias. Recently, the inverse correlation observed between patient prognosis and tumor-associated macrophages (TAMs) density in solid tumors has encouraged the development of anti-tumor strategies aiming to target TAMs. As expected, TAMs polarization is influenced by both macrophage localization and tumor microenvironment signals, resulting in a more complex scenario than the simple M1/M2 activation status. Macrophage polarization in glioblastoma has not yet been fully elucidated, and most results have been obtained in experimental non-human settings, with some apparent contradiction. The authors performed a histopathological and immunohistochemical study of 37 cases of glioblastoma in order to characterize the M1 and M2 macrophage populations within TAMs. A high prevalence of CD163+ M2-polarized macrophages was detected in this cohort, whereas iNOS+ macrophages were rarely found. The down-regulation of CD68 expression in microglia/macrophage infiltrating glioblastomas is also reported for the first time. Such a finding is associated with a specific location of TAMs within the lesion, as confirmed by the fact that CD68 staining was lower than CD163, mainly in perivascular areas. The authors discuss the recent literature about the global scenario of macrophage plasticity and polarization in glioblastoma, and suggest some pivotal points for therapeutic applications.


The prevalence of intellectual disability in Limburg, the Netherlands.
Current changes in care philosophy and diversity in care arrangements caused the need for a new estimate of the number of people with intellectual disability (ID), based on recent data. Previous estimates were based on client registrations, which was thought unreliable at this time. This manuscript studies the question how many people with ID can be found in (part of) the Netherlands. Identification of people with ID through a combination of general practice (GP) data bases and service registrations in the province of Limburg. The prevalence of people with ID appeared to be between 0.64% and 0.70%. About 0.21-0.27% were living with family or on their own; 55% of them did not use common ID services. Results are based on a combination of identification methods. Thirteen per cent of uncertain cases led to minimum and maximum estimates of the population. Limitations of the method and alternative ways of data collection are discussed.


Direct detection of Brucella spp. in raw milk by PCR and reverse hybridization with 16S-23S rRNA spacer probes.
The 16S-23S rRNA spacer regions of Brucella abortus, B. melitensis, and B. suis were cloned and subcloned after PCR amplification. Sequence analysis of the inserts revealed a spacer of about 800 bp with very high ( > 99%) homology among the three species examined. Two genus-specific primer pairs, BRU-P5-BRU-P8 and BRU-P6-BRU-P7, that could be used in a nested PCR format and three genus-specific DNA probes, BRU-ICG2, BRU-ICG3, and BRU-ICG4, were deduced from this spacer. The specificity and sensitivity of both primer sets and probes were examined by testing them against a collection of 18 Brucella strains and 56 strains from other relevant taxa by using PCR and the Line Probe Assay (LiPA), respectively. A method for direct detection of Brucella spp. in 1 ml of raw milk was developed on the basis of enzymatic treatment of the milk components and subsequent PCR and LiPA hybridization. After a single PCR, sensitivities of 2.8 x 10(5) and 2.8 x 10(4) CFU/ml were obtained for detection by agarose gel electrophoresis and LiPA, respectively. Nested PCR yielded a sensitivity of 2.8 x 10(2) CFU/ml for both methods.


Pathologic changes in the small airways of the guinea pig after amosite asbestos exposure.
To determine whether asbestos dust produces pathologic changes in the small airways, and to determine where the anatomic lesions of asbestosis commence, the authors examined lungs from guinea pigs exposed to 10 or 30 mg of amosite asbestos by intratracheal instillation and sacrificed 6 months later. Measurement of airway wall thickness revealed that membranous and respiratory bronchioles of all sizes in exposed animals were significantly thicker than those of controls. Amosite fibers were found embedded in the walls of bronchi and in membranous and respiratory bronchioles; where these fibers penetrated the airway walls, an interstitial inflammatory and fibrotic reaction (asbestosis) occurred. It is concluded that 1) amosite asbestos produces diffuse abnormalities throughout the noncartilagenous airways and possibly the cartilagenous airways as well; 2) this effect is independent of interstitial fibrosis of the parenchyma (classical asbestosis); 3) asbestosis, at least that induced by amosite, commences at any site in the parenchyma to which the asbestos fibers can gain access, either by deposition in alveoli and alveolar ducts or by direct passage of fibers through the walls of all types and sizes of small airways.


Hypoxia regulate developmental coronary angiogenesis potentially through VEGFR2- and SOX17-mediated signaling.
Coronary vessels in embryonic mouse heart arises from multiple progenitor population including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is shown to regulate coronary growth from SV pathway within the subepicardium, whereas VEGF-A/VEGF-R2 pathways is implicated to regulate coronary growth from endocardium pathway. Our previous study show hypoxia as a potential signaling cue to stimulate overall coronary growth and expansion within the myocardium. However, the role of hypoxia and its downstream signaling pathways in the regulation of coronary vessel development is not known. In this study, we investigated the role of hypoxia in coronary vessel development and have identified SOX17- and VEGF-R2-mediated signaling as a potential downstream pathway of hypoxia in the regulation of coronary vessel development. We show that hypoxia gain-of-function in the myocardium through upregulation of HIF-1α disrupts the normal pattern of coronary angiogenesis in developing mouse hearts and displays phenotype that is reminiscent of accelerated coronary growth. We show that VEGF-R2 expression is increased in coronary endothelial cells under hypoxia gain-of-function in vivo and in vitro . Furthermore, we show that SOX17 expression is upregulated in developing mouse heart under hypoxia gain-of-function conditions, whereas SOX17 expression is repressed under hypoxia loss-of-function conditions. Furthermore, our results show that SOX17 loss-of-function disrupts normal pattern of coronary growth. Collectively, our data provide strong phenotypic evidence to show that hypoxia might regulate coronary growth in the developing mouse heart potentially through VEGF-R2- and SOX17-mediated downstream signaling pathways.


Asymmetric Bálint's syndrome with multimodal agnosia, bilateral agraphesthesia, and ineffective kinesthetic reading due to subcortical hemorrhage in the left parieto-occipito-temporal area.
We report a patient with asymmetric Bálint's syndrome (predominantly right-sided oculomotor apraxia and simultanagnosia and optic ataxia for the right hemispace), and multimodal agnosia (apperceptive visual agnosia and bilateral associative tactile agnosia) with accompanying right hemianopia, bilateral agraphesthesia, hemispatial neglect, global alexia with unavailable kinesthetic reading, and lexical agraphia for kanji (Japanese morphograms), after hemorrhage in the left parieto-occipito-temporal area. The coexistence of tactile agnosia, bilateral agraphesthesia, and ineffective kinesthetic reading suggests that tactile-kinesthetic information can be interrupted because of damage to the fiber connection from the parietal lobe to the occipito-temporal area, leading to these tactually related cognitive impairments.


Oncostatin-M: a new bone active cytokine that activates osteoblasts and inhibits bone resorption.
Osteoblasts and their precursors respond to specific cytokines, growth factors, and hormones. One facet of this response includes the secretion of additional cytokines, some of which are part of the circuitry involved in the regulation of osteoblast and osteoclast function. Therefore, understanding which cytokines are able to activate osteoblastic cells and the consequences of that activation are central to understanding normal and pathologic bone remodeling. Oncostatin M (OSM) is a glycoprotein belonging to a new subfamily of cytokines related by sequence and structural homology and the use of the signal transducing receptor component gp130. Osteoblastic cells secrete and respond to leukemia-inhibiting factor (LIF) both in vitro and in vivo, suggesting that LIF is an autocrine regulatory factor. OSM is closely related to LIF, and therefore we hypothesized that OSM should regulate the function of cells in the osteoblastic lineage. Primary neonatal murine or fetal rat calvarial osteoblastic cultures were treated with OSM or LIF and a series of biochemical and biological parameters were determined. In these cultures, OSM induced proliferation, collagen synthesis, and interleukin-6 secretion, whereas it inhibited alkaline phosphatase activity. Bone resorption was also inhibited by OSM. These data represent the first report of OSM's effects on bone cell function and indicate that, like some other members of the LIF/interleukin-6 subfamily, OSM has potent bone regulatory activity.


Kidney rupture: an unusual and oligosymptomatic complication in a dialysis patient with acquired cystic disease.
Acquired cystic kidney disease (ACKD) is a complication of end-stage renal disease, the prevalence of which is related to dialysis duration; incidence of ACKD and associated conditions (neoplasia, hemorrhage) have decreased with improvements in renal transplantation and with the ageing of the dialysis population. This report regards spontaneous kidney rupture in a 57-year old patient, on home hemodialysis for 11 years, with ACKD for 5 years. At the end of a dialysis session, the patient reported sudden onset of colicky flank pain, followed by macrohematuria. Pain remitted with low doses of pain relievers, leaving dull flank discomfort. The patient self diagnosed a renal colic, and called the hospital two days later. At referral, two large hemorrhagic renal masses (7 and 2.8 cm) were found at ultrasound and CT scan. At surgery, kidney rupture was diagnosed. This case highlights the life threatening complications associated with ACKD, and underlines that massive renal hemorrhage may occur with relatively minor symptoms.


High urine concentrations of basic fibroblast growth factor in dogs with bladder cancer.
Because dogs with bladder cancer often have advanced disease at the time of diagnosis, the identification and use of a tumor marker that could facilitate earlier diagnosis is a valid approach to improve prognosis. The objective of this study was to determine if urine concentrations of the proangiogenic peptide, basic fibroblast growth factor (bFGF), are high in dogs with bladder cancer compared with normal dogs and dogs with urinary tract infection. We used a commercially available enzyme-linked immunosorbent assay test kit to quantitate bFGF in the urine of 17 normal dogs, 10 dogs with urinary tract infection, and 7 dogs with locally active transitional cell carcinoma of the urinary bladder. In normal dogs, the median urine bFGF concentration was 2.23 ng/g creatinine (quartile range, 1.53 to 5.12 ng/g creatinine). The median urine bFGF concentration in dogs with urinary tract infection did not differ significantly from normal dogs. Dogs with bladder cancer had significantly higher urine bFGF concentrations than normal dogs (P < .002) and dogs with infection (P < .02). The median urine bFGF concentration in dogs with transitional cell carcinoma was 9.86 ng/g creatinine (quartile range, 7.40 to 21.63 ng/g creatinine). Six of 7 dogs with bladder cancer had urine bFGF concentrations that were up to 7.4 times the 90th percentile value for normal dogs. Only 1 of 10 dogs with infection had a urine bFGF concentration that exceeded the 90th percentile of normal. These data suggest that canine bladder cancers export bFGF, and that urine bFGF may be useful as a diagnostic tumor marker or noninvasive indicator of treatment response.


Dogs with cognitive dysfunction syndrome: a natural model of Alzheimer's disease.
In the search for appropriate models for Alzheimer's disease (AD) involving animals other than rodents, several laboratories are working with animals that naturally develop cognitive dysfunction. Among the animals tested, dogs are quite unique in helping to elucidate the cascade of events that take place in brain amyloid-beta (Aβ)deposition aging, and cognitive deficit. Recent innovative research has validated human methods and tools for the analysis of canine neuropathology and has allowed the development of two different approaches to investigate dogs as natural models of AD. The first approach relates AD-like neuropathy with the decline in memory and learning ability in aged housed dogs in a highly controlled laboratory environment. The second approach involves research in family-owned animals with cognitive dysfunction syndrome. In this review, we compare the strengths and limitations of housed and family-owned canine models, and appraise their usefulness for deciphering the early mechanisms of AD and developing innovative therapies.


Limiting step involved in the thermal growth of silicon oxide films on silicon carbide.
Thermal growth of silicon oxide films on silicon carbide in O2 was investigated using oxygen isotopic substitution and narrow resonance nuclear reaction profiling. This investigation was carried out in parallel with the thermal growth of silicon oxide films on Si. Results demonstrate that the limiting steps of the thermal oxide growth are different in these two semiconductors, being diffusion limited in the case of Si and reaction limited in the case of SiC. This fact renders the growth kinetics of SiO2 on SiC very sensitive to the reactivity of the interface region, whose compositional and structural changes can affect the electrical properties of the structure.


High-resolution, human-bovine comparative mapping based on a closed YAC contig spanning the bovine mh locus.
A closed YAC contig spanning the mh locus was assembled by STS content mapping with seven microsatellite markers, eight genes or EST, and nine STS corresponding to YAC ends. The contig comprises 27 YACs, has an average depth of 4.3 YACs, and spans an estimated 1.2 Mb. A linkage map was constructed based on five of the microsatellite markers anchored to the contig and shown to span 7 cM, yielding a ratio of 160 kb/1 cM for the corresponding chromosome region. Comparative mapping data indicate that the constructed contig spans an evolutionary breakpoint connecting two chromosome segments that are syntenic but not adjacent in the human. Consolidation of human gene order by means of whole genome radiation hybrids and its comparison with the bovine order as inferred from the contig confirm conservation of gene order within segments.


Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously expressed in human cells.
Cytochrome b-type NAD(P)H oxidoreductases are involved in many physiological processes, including iron uptake in yeast, the respiratory burst, and perhaps oxygen sensing in mammals. We have identified a cytosolic cytochrome b-type NAD(P)H oxidoreductase in mammals, a flavohemoprotein (b5+b5R) containing cytochrome b5 (b5) and b5 reductase (b5R) domains. A genetic approach, using BLAST searches against DBEST for FAD-, NAD(P)H-binding sequences followed by reverse transcription-PCR, was used to clone the complete cDNA sequence of human b5+b5R from the hepatoma cell line Hep 3B. Compared with the classical single-domain b5 and b5R proteins localized on endoplasmic reticulum membrane, b5+b5R also has binding motifs for heme, FAD, and NAD(P)H prosthetic groups but no membrane anchor. The human b5+b5R transcript was expressed at similar levels in all tissues and cell lines that were tested. The two functional domains b5* and b5R* are linked by an approximately 100-aa-long hinge bearing no sequence homology to any known proteins. When human b5+b5R was expressed as c-myc adduct in COS-7 cells, confocal microscopy revealed a cytosolic localization at the perinuclear space. The recombinant b5+b5R protein can be reduced by NAD(P)H, generating spectrum typical of reduced cytochrome b with alpha, beta, and Soret peaks at 557, 527, and 425 nm, respectively. Human b5+b5R flavohemoprotein is a NAD(P)H oxidoreductase, demonstrated by superoxide production in the presence of air and excess NAD(P)H and by cytochrome c reduction in vitro. The properties of this protein make it a plausible candidate oxygen sensor.


Modeling and control of a brushless DC axial flow ventricular assist device.
This article presents an integrated model of the human circulatory system that incorporates circulatory support by a brushless DC axial flow ventricular assist device (VAD), and a feedback VAD controller designed to maintain physiologically sufficient perfusion. The developed integrated model combines a network type model of the circulatory system with a nonlinear dynamic model of the brushless DC pump We show that maintaining a reference differential pressure between the left ventricle and aorta leads to adequate perfusion for different pathologic cases, ranging from normal heart to left heart asystole, and widely varying physical activity scenarios from rest to exercise.


The relationship between AIDS dementia complex and the presence of macrophage tropic and non-syncytium inducing isolates of human immunodeficiency virus type 1 in the cerebrospinal fluid.
We sought to determine the clinical significance of macrophage tropic and non-syncytium inducing isolates of human immunodeficiency virus type 1 (HIV-1) in the cerebrospinal fluid (CSF) of patients with and without AIDS dementia complex (ADC). HIV-1 was isolated from the CSF of 31 patients with and without ADC. The isolates were then characterised as to the degree of macrophage tropism by quantitation of p24 production and the presence of syncytium inducing (SI) or non-syncytium inducing (NSI) isolates by MT2 assay and SupT1 coculture. The degree of macrophage tropism varied according to the donor macrophage that was used except in strongly macrophage tropic isolates. Moderate and severe ADC (stage > or = 2) was associated with the presence of highly macrophage tropic isolates in the CSF (P = 0.01). The sensitivity and specificity values of a highly macrophage tropic isolate in the CSF for ADC stage > or = 2 were 82% and 66% respectively while the predictive value was 64%. Three of four asymptomatic patients with such highly macrophage tropic isolates in the CSF subsequently developed ADC after an average of 4 months. Twenty-eight isolates from the CSF and 23 from the blood were NSI regardless of the presence or absence of ADC. The predictive value of an SI isolate in the blood reflecting an SI isolate in the CSF was 37.5% while the predictive value of an NSI isolate in the blood reflecting an NSI in the CSF was 100%. These data suggest that host factors are essential in determining the degree of macrophage tropism in HIV-1 and that such tropism is important for the presence and possibly subsequent development of ADC. The CSF usually has NSI isolates regardless of the presence of ADC and irrespective of the presence of such isolates in the blood thereby suggesting that the CSF is behaving virologically as a separate compartment to the blood.


Expression of the glutathione S-transferase placental form in human lung carcinomas.
Expression of glutathione S-transferase placental form (GST-pi) in human lung carcinoma tissue taken at autopsy or biopsy was investigated immunohistochemically. All of 34 cases of squamous cell carcinomas, including poorly, moderately and well-differentiated examples were shown to stain positively for GST-pi. Poorly differentiated adenocarcinomas were, however, negatively stained (0/5 cases), while moderately and well differentiated adenocarcinomas were found to stain with GST-pi at rates of 69% (9/13 cases) and 71% (5/7 cases), respectively. Six cases of small cell carcinomas examined were all negative. The results indicate that GST-pi may be a useful marker for non-small cell type lung cancer, especially squamous cell carcinoma which is in agreement with findings for rat lung neoplastic lesions reported previously.


Nutritional support of the pediatric intensive care unit patient.
Nutritional support of the critically ill or postoperative pediatric patient continues to develop as a clinical science in the face of technologic, pharmacologic, and nutritional science advances. For ethical and logistical reasons, however, clinical trials of new technologies and interventions often are performed first in adult subjects, and the pediatric intensivist and nutritionist are thereby left to draw conclusions from this literature. This review summarizes recent developments in the clinical nutrition literature concerning the nutritional care of intensive care unit patients, emphasizing experience with pediatric patients when possible. The central role of estimating energy requirements in the intensive care unit, the development of enteral formulas with nutritional as well as possible immunologic properties, the use of anabolic hormones to attenuate the catabolic response to illness, the concept of "conditionally essential" amino acids, and the propensity to use the parenteral route of nutrition when the enteral route is still available are discussed. Future directions in nutritional support, including the development of nutritional pharmacotherapy, are also considered.


Peripheral selection of the T cell repertoire.
T lymphocytes undergo selection events not only in the thymus, but also after they leave the thymus and reside in the periphery. Peripheral selection was found to be dependent on T cell receptor (TCR)-ligand interactions but to differ from thymic selection with regard to specificity and mechanism. Unlike thymic selection, peripheral selection required binding of antigen to the TCR, and it induced expansion of T cell clones. Tolerance to self antigens that are restricted to the periphery occurred through the elimination of self-reactive T cells and by the clonal anergy, which was associated with down-regulation of the alpha beta TCR and CD8.


Extremely rare case of successful treatment of metastatic ovarian undifferentiated carcinoma with high-dose combination cytotoxic chemotherapy: A case report.
Ovarian undifferentiated carcinomas are significantly rare and have an aggressive clinical course. Surgical resection is the only curative treatment in early-stage ovarian undifferentiated carcinomas that has a favorable prognosis. In case of recurrent and metastatic disease, palliative chemotherapy is the only available treatment. However, the effectiveness of standard chemotherapy regimen is not well-known, specifically in the case of extra-ovarian spread. We report an ovarian undifferentiated carcinoma of recurrent and inoperable advanced stage that was successfully treated with high-dose combination chemotherapy. A 52-year-old woman presented with a 1-mo history of right lower quadrant and epigastric pain. A computed tomography (CT) scan of the abdomen revealed a multicystic mass with extensive internal necrosis of the right ovary without evidence of metastatic disease. A total hysterectomy with bilateral salpingo-oophorectomy and omentectomy was performed, but the surgery had a positive resection margin. Pathologically, it was diagnosed as ovarian undifferentiated carcinoma with sarcomatoid change. Although adjuvant chemotherapy was planned, it was delayed for 6 wk because of postoperative recovery, and the patient complained of abdominal pain. A CT scan and positron emission tomography-CT revealed a huge mass with multiple nodules in the pelvic cavity and para-aortic lymph node metastasis. Instead of standard therapy such as paclitaxel and platinum, combined chemotherapy with etoposide, ifosfamide, and cisplatin was administered. The patient experienced no recurrence for 5 years. This is a case of metastatic ovarian undifferentiated carcinoma with sarcomatoid change that was successfully treated with high-dose combination cytotoxic chemotherapy.


Economic burden of Alzheimer disease and managed care considerations.
Alzheimer disease is the most common cause of dementia and the fifth leading cause of death in adults older than 65 years. The estimated total healthcare costs for the treatment of Alzheimer disease in 2020 is estimated at $305 billion, with the cost expected to increase to more than $1 trillion as the population ages. Most of the direct costs of care for Alzheimer disease are attributed to skilled nursing care, home healthcare, and hospice care. Indirect costs of care, including quality of life and informal caregiving, are likely underestimated and are associated with significant negative societal and personal burden. Managed care organizations are in a unique position to develop utilization strategies that would positively impact early diagnosis and treatment to lead to better outcomes and lower costs for patients, caregivers, and the healthcare system. Additionally, the recent inclusion of Alzheimer disease diagnoses into risk corridor calculations by the Centers for Medicare & Medicaid Services may encourage Medicare Advantage organizations to invest in programs that aid in its early detection and diagnosis.


Current and emerging therapies for the treatment of multiple sclerosis: focus on cladribine.
Multiple Sclerosis (MS) is a chronic inflammatory, immune-mediated, demyelinating disorder of the central nervous system with a heterogeneous clinical presentation and pathology in which activated lymphocytes play an important role in mediating tissue damage. Until recently, all first line therapies for MS were injectable. Several oral medications have been studied for preventative treatment of MS. Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog that has been used for the treatment of several hematologic neoplasms, with a unique lymphcytotoxic mechanism of action. Cladribine has been investigated as treatment of MS for more than 15 years. A recent placebo-controlled, double-blind study of cladribine, CLARITY, showed decreased relapse rates, risk of disability progression and MRI measures of disease activity at 96 weeks. Cladribine's strengths included high efficacy and convenient, biannual oral dosing. However, concerns about safety prevented the FDA from approving cladribine in 2011. Thus, use of cladribine for treatment of relapsing and remitting multiple sclerosis will remain off-label.


Effects of aluminum and extremely low frequency electromagnetic radiation on oxidative stress and memory in brain of mice.
This study was aimed to investigate the effect of aluminum and extremely low-frequency magnetic fields (ELF-MF) on oxidative stress and memory of SPF Kunming mice. Sixty male SPF Kunming mice were divided randomly into four groups: control group, ELF-MF group (2 mT, 4 h/day), load aluminum group (200 mg aluminum/kg, 0.1 ml/10 g), and ELF-MF + aluminum group (2 mT, 4 h/day, 200 mg aluminum/kg). After 8 weeks of treatment, the mice of three experiment groups (ELF-MF group, load aluminum group, and ELF-MF + aluminum group) exhibited firstly the learning memory impairment, appearing that the escaping latency to the platform was prolonged and percentage in the platform quadrant was reduced in the Morris water maze (MWM) task. Secondly are the pathologic abnormalities including neuronal cell loss and overexpression of phosphorylated tau protein in the hippocampus and cerebral cortex. On the other hand, the markers of oxidative stress were determined in mice brain and serum. The results showed a statistically significant decrease in superoxide dismutase activity and increase in the levels of malondialdehyde in the ELF-MF group (P < 0.05 or P < 0.01), load aluminum group (P < 0.01), and ELF-MF + aluminum group (P < 0.01). However, the treatment with ELF-MF + aluminum induced no more damage than ELF-MF and aluminum did, respectively. In conclusion, both aluminum and ELF-MF could impact on learning memory and pro-oxidative function in Kunming mice. However, there was no evidence of any association between ELF-MF exposure with aluminum loading.


Heparin and liver heparan sulfate can rescue hepatoma cells from topotecan action.
Topotecan (TpT) is a major inhibitory compound of topoisomerase (topo) I that plays important roles in gene transcription and cell division. We have previously reported that heparin and heparan sulfate (HS) might be transported to the cell nucleus and they can interact with topoisomerase I. We hypothesized that heparin and HS might interfere with the action of TpT. To test this hypothesis we isolated topoisomerase I containing cell nuclear protein fractions from normal liver, liver cancer tissues, and hepatoma cell lines. The enzymatic activity of these extracts was measured in the presence of heparin, liver HS, and liver cancer HS. In addition, topo I activity, cell viability, and apoptosis of HepG2 and Hep3B cells were investigated after heparin and TpT treatments. Liver cancer HS inhibited topo I activity in vitro. Heparin treatment abrogated topo I enzyme activity in Hep3B cells, but not in HepG2 cells, where the basal activity was higher. Heparin protected the two hepatoma cell lines from TpT actions and decreased the rate of TpT induced S phase block and cell death. These results suggest that heparin and HS might interfere with the function of TpT in liver and liver cancer.


Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis.
A hyperdiploid karyotype is found in 30% of B-cell precursor acute lymphoblastic leukemias in childhood. The time of nondisjunction of chromosomes leading to hyperdiploidy during leukemogenesis is unknown. We used the 3 clonotypic immunoglobulin heavy chain (IgH) gene rearrangements as molecular markers for each of the 3 chromosomes 14 in a case with hyperdiploid acute lymphoblastic leukemia to define the order of events-namely, somatic recombination and nondisjunction of chromosomes-during leukemia development. A partial sequence homology of the incomplete DJ(H) rearrangement with 1 of the 2 nonfunctional VDJ(H) rearrangements suggests that the doubling of chromosomes had occurred after this DJ(H) rearrangement and thus during early B-cell differentiation. The occurrence of the nondisjunction of chromosomes as well as ongoing rearrangement processes in utero were confirmed by the presence of all 3 IgH rearrangements in neonatal blood spots, providing the first evidence that hyperdiploidy formation is an early event in leukemogenesis in these leukemias.


Modulation of transcription factor NF-kappa B binding activity by oxidation-reduction in vitro.
NF-kappa B is a widely used regulator of inducible and tissue-specific gene control. In the cytosol, when complexed to an inhibitory molecule, I kappa B, NF-kappa B is in an inactive form and cannot bind DNA. Activation of cells with appropriate stimuli results in the dissociation of NF-kappa B from I kappa B and its translocation to the nucleus as an active binding protein. We now demonstrate that NF-kappa B binding in vitro can be inhibited by agents that modify free sulfhydryls. Binding is eliminated after treatment with N-ethylmaleimide, an alkylating agent, and diamide, an oxidizing agent. The diamide effect can be reversed by 2-mercaptoethanol. Further, 2-mercaptoethanol acts synergistically with deoxycholate plus Nonidet P-40 in converting inactive cytosolic NF-kappa B to an active DNA-binding form. It is therefore possible that modulation of the redox state of NF-kappa B could represent a post-translational control mechanism for this factor.


Exertional Dyspnoea in Chronic Respiratory Diseases: From Physiology to Clinical Application.
Dyspnoea is a complex, highly personalized and multidimensional sensory experience, and its underlying cause and mechanisms are still being investigated. Exertional dyspnoea is one of the most frequently encountered symptoms of patients with cardiopulmonary diseases, and is a common reason for seeking medical help. As the symptom usually progresses with the underlying disease, it can lead to an avoidance of physical activity, peripheral muscle deconditioning and decreased quality of life. Dyspnoea is closely associated with quality of life, exercise (in)tolerance and prognosis in various conditions, including chronic obstructive pulmonary disease, heart failure, interstitial lung disease and pulmonary hypertension, and is therefore an important therapeutic target. Effective management and treatment of dyspnoea is an important challenge for caregivers, and therapeutic options that attempt to reverse its underlying cause have been only partially successful This "review" will attempt to shed light on the physiological mechanisms underlying dyspnoea during exercise and to translate/apply them to a broad clinical spectrum of cardio-respiratory disorders.


Insulin Protects Hepatic Lipotoxicity by Regulating ER Stress through the PI3K/Akt/p53 Involved Pathway Independently of Autophagy Inhibition.
The detrimental role of hepatic lipotoxicity has been well-implicated in the pathogenesis of NAFLD. Previously, we reported that inhibiting autophagy aggravated saturated fatty acid (SFA)-induced hepatotoxicity. Insulin, a physiological inhibitor of autophagy, is commonly increased within NAFLD mainly caused by insulin resistance. We therefore hypothesized that insulin augments the sensitivity of hepatocyte to SFA-induced lipotoxicity. The present study was conducted via employing human and mouse hepatocytes, which were exposed to SFAs, insulin, or their combination. Unexpectedly, our results indicated that insulin protected hepatocytes against SFA-induced lipotoxicity, based on the LDH, MTT, and nuclear morphological measurements, and the detection from cleaved-Parp-1 and -caspase-3 expressions. We subsequently clarified that insulin led to a rapid and short-period inhibition of autophagy, which was gradually recovered after 1 h incubation in hepatocytes, and such extent of inhibition was insufficient to aggravate SFA-induced lipotoxicity. The mechanistic study revealed that insulin-induced alleviation of ER stress contributed to its hepatoprotective role. Pre-treating hepatocytes with insulin significantly stimulated phosphorylated-Akt and reversed SFA-induced up-regulation of p53. Chemical inhibition of p53 by pifithrin-α robustly prevented palmitate-induced cell death. The PI3K/Akt pathway blockade by its special antagonist abolished the protective role of insulin against SFA-induced lipotoxicity and p53 up-regulation. Furthermore, we observed that insulin promoted intracellular TG deposits in hepatocytes in the present of palmitate. However, blocking TG accumulation via genetically silencing DGAT-2 did not prevent insulin-protected lipotoxicity. Our study demonstrated that insulin strongly protected against SFA-induced lipotoxicity in hepatocytes mechanistically through alleviating ER stress via a PI3K/Akt/p53 involved pathway but independently from autophagy.


Octreotide for the treatment of systemic lupus erythematosus: clinical effects and an in vitro study on its therapeutic mechanism.
Increased serum growth hormone (GH), together with high expression of growth hormone receptor on peripheral blood mononuclear cells (PBMCs), correlates with systemic lupus erythematosus (SLE) activity, suggesting that modulation of GH signaling may affect SLE activity. We explored the effects of octreotide (OCT), an analog of somatostatin that suppresses the release of GH, in SLE. The objectives of the study were to investigate effects of OCT on the proliferative capacity and cytokine expression of PBMCs from patients with SLE and to investigate therapeutic effects of OCT in patients with SLE. PBMCs from 13 active/inactive SLE patients and 11 controls were pretreated with or without GH and cultured with OCT. The proliferation of PBMCs was assessed by MTT assay and cytokines were quantified by ELISA. We compared the clinical response of 12 patients with SLE treated with OCT (100 µg twice daily) with 12 patients treated with prednisone over three months. OCT inhibited PBMC proliferation in a dose-dependent manner and decreased the secretion of interleukin-6 (IL-6), interleukin-10 (IL-10), and interferon-gamma (IFN-γ). Patients treated with OCT demonstrated improvements in SLEDAI, dsDNA titer, complement levels, and erythrocyte sedimentation rate (ESR). OCT inhibited PBMC proliferation and PBMC secretion of IL-6, IL-10 and IFN-γ stimulated by GH. Treatment of patients with OCT resulted in clinical improvement in SLE.


Methodological considerations for the development of new treatments for bipolar disorder.
Lithium has been the drug of choice in treating bipolar disorder for 50 years and, therefore, patterns of response associated with its use define what we expect from treatment. Although efforts to establish some other agents as antimanic have been successful, it is difficult to assess their overall efficacy in relation to that of lithium without a better understanding of inclusion/exclusion criteria, subtypes, definitions of remission, relapse and recurrence, and duration of study. All of these factors need to be carefully addressed to identify the most important clinical targets for new drug development. Additional relevant information emerges from studies on combinations of mood stabilisers, efficacy of antimanic agents in different patient populations, analysis of rates of drop-out, non-compliance, suicide, drug abuse, and discontinuation especially with long-term treatment. Agents other than lithium that are effective in the acute phase treatment are still not well characterised as mood stabilisers. New agents need to be evaluated in the context of long-term treatment and the targeting of specific components of the syndrome beyond mania.


Acidic tumor microenvironment downregulates hMLH1 but does not diminish 5-fluorouracil chemosensitivity.
Human DNA mismatch repair (MMR) recognizes and binds 5-fluorouracil (5FU) incorporated into DNA and triggers a MMR-dependent cell death. Absence of MMR in a patient's colorectal tumor abrogates 5FU's beneficial effects on survival. Changes in the tumor microenvironment like low extracellular pH (pHe) may diminish DNA repair, increasing genomic instability. Here, we explored if low pHe modifies MMR recognition of 5FU, as 5FU can exist in ionized and non-ionized forms depending on pH. We demonstrate that MMR-proficient cells at low pHe show downregulation of hMLH1, whereas expression of TDG and MBD4, known DNA glycosylases for base excision repair (BER) that can remove 5FU from DNA, were unchanged. We show in vitro that 5FU within DNA pairs with adenine (A) at high and low pH (in absence of MMR and BER). Surprisingly, 5FdU:G was repaired to C:G in hMLH1-deficient cells cultured at both low and normal pHe, similar to MMR-proficient cells. Moreover, both hMSH6 and hMSH3, components of hMutSα and hMutSβ, respectively, bound 5FU within DNA (hMSH6>hMSH3) but is influenced by hMLH1. We conclude that an acidic tumor microenvironment triggers downregulation of hMLH1, potentially removing the execution component of MMR for 5FU cytotoxicity, whereas other mechanisms remain stable to implement overall 5FU sensitivity.


A comparative study of hepatic and colonic metabolic enzymes in inbred mouse lines before and after treatment with the colon carcinogen, 1,2-dimethylhydrazine.
1,2-Dimethylhydrazine (DMH) is an organotropic colon carcinogen that undergoes metabolic activation to DNA-reactive metabolites. Twenty hours after parenteral treatment of AKR/J (colon tumor resistant) and SWR/J (susceptible) mice with DMH.2HCl (70 mg/kg), functional levels of Cyp1a1 and Cyp2e1 were examined by measuring O-deethylation of ethoxyresorufin (EROD) and hydroxylation of p-nitrophenol, respectively. In control animals, SWR/J mice exhibited higher hepatic EROD activity (1.4-fold) when compared with AKR/J mice. In carcinogen-treated animals, EROD activity was decreased 20-30% in both mouse lines. Hepatic p-nitrophenol hydroxylase activity, similar in control animals of both strains, was reduced comparably (45-50% of control) after DMH administration. In liver, a decrease in immunoreactive Cyp2e1 protein paralleled the decline in enzyme activity, whereas in the colon, no significant treatment-related differences were detected in either strain. In liver and colon cytosols, alcohol dehydrogenase activity was not significantly different in either mouse line, both in control and DMH-treated animals. Glutathione levels were elevated (1.7-fold) in livers of AKR/J mice after DMH administration. Total glutathione-S-transferase (GST) activity was significantly increased (1.8-fold) in the colons of SWR/J mice and in the livers (1.4-fold) of AKR/J mice. Furthermore, the GST isoform, GST-Yp, was reduced 40% in the SWR/J colon. These data demonstrate the importance of metabolic capacity as a factor in conferring differential tumor susceptibility in a murine cancer model to the indirect-acting colon carcinogen, DMH.


Intravenous pulse methylprednisolone in chronic idiopathic thrombocytopenia.
Two children with chronic idiopathic thrombocytopenic purpura unresponsive to either standard corticosteroid treatment or high dose intravenous gammaglobulin, or both, were treated with intravenous methylprednisolone (15 mg/kg/day) given in pulses over three consecutive days. Both children showed a positive response and are still in remission after three months.


Seasonality of suicide in Shandong China, 1991-2009: associations with gender, age, area and methods of suicide.
Whether suicide in China has significant seasonal variations is unclear. The aim of this study is to examine the seasonality of suicide in Shandong China and to assess the associations of suicide seasonality with gender, residence, age and methods of suicide. Three types of tests (Chi-square, Edwards' T and Roger's Log method) were used to detect the seasonality of the suicide data extracted from the official mortality data of Shandong Disease Surveillance Point (DSP) system. Peak/low ratios (PLRs) and 95% confidence intervals (CIs) were calculated to indicate the magnitude of seasonality. A statistically significant seasonality with a single peak in suicide rates in spring and early summer, and a dip in winter was observed, which remained relatively consistent over years. Regardless of gender, suicide seasonality was more pronounced in rural areas, younger age groups and for non-violent methods, in particular, self-poisoning by pesticide. There are statistically significant seasonal variations of completed suicide for both men and women in Shandong, China. Differences exist between residence (urban/rural), age groups and suicide methods. Results appear to support a sociological explanation of suicide seasonality.