Inhibitory rTMS of secondary somatosensory cortex reduces intensity but not pleasantness of gentle touch.
Research suggests that the discriminative and affective aspects of touch are processed differently in the brain. Primary somatosensory cortex is strongly implicated in touch discrimination, whereas insular and prefronal regions have been associated with pleasantness aspects of touch. However, the role of secondary somatosensory cortex (S2) is less clear. In the current study we used inhibitory repetitive transcranial magnetic stimulation (rTMS) to temporarily deactivate S2 and probe its role in touch perception. Nineteen healthy adults received two sessions of 1-Hz rTMS on separate days, one targeting right S2 and the other targeting the vertex (control). Before and after rTMS, subjects rated the intensity and pleasantness of slow and fast gentle brushing of the hand and performed a 2-point tactile discrimination task, followed by fMRI during additional brushing. rTMS to S2 (but not vertex) decreased intensity ratings of fast brushing, without altering touch pleasantness or spatial discrimination. MRI showed a reduced response to brushing in S2 (but not in S1 or insula) after S2 rTMS. Together, our results show that reducing touch-evoked activity in S2 decreases perceived touch intensity, suggesting a causal role of S2 in touch intensity perception.


Test Characteristics of Emergency Medicine-Performed Point-of-Care Ultrasound for the Diagnosis of Acute Cholecystitis: A Systematic Review and Meta-analysis.
Acute cholecystitis accounts for up to 9% of hospital admissions for acute abdominal pain, and best practice entails early surgical management. Ultrasound is the standard modality used to confirm diagnosis. Our objective was to perform a systematic review and meta-analysis to determine the diagnostic accuracy of emergency physician-performed point-of-care ultrasound for the diagnosis of acute cholecystitis when compared with a reference standard of final diagnosis (informed by available surgical pathology, discharge diagnosis, and radiology-performed ultrasound). We completed a systematic review and meta-analysis, registered in PROSPERO, in adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched 7 databases as well as gray literature in the form of select conference abstracts from inception to February 8, 2023. Two independent reviewers completed study selection, data extraction, and risk of bias (QUADAS-2) assessment. Disagreements were resolved by consensus with a third reviewer. Data were extracted from eligible studies to create 2 × 2 tables for diagnostic accuracy meta-analysis. Hierarchical Summary Receiver Operating Characteristic models were constructed. Of 1855 titles/abstracts, 40 were selected for full-text review. Ten studies (n=2356) were included. Emergency physician-performed point-of-care ultrasound with final diagnosis as the reference standard (7 studies, n=1,772) had a pooled sensitivity of 70.9% (95% confidence interval [CI] 62.3 to 78.2), specificity of 94.4% (95% CI 88.2 to 97.5), positive likelihood ratio of 12.7 (5.8 to 27.5), and negative likelihood ratio of 0.31 (0.23 to 0.41) for the diagnosis of acute cholecystitis. Emergency physician-performed point-of-care ultrasound has high specificity and moderate sensitivity for the diagnosis of acute cholecystitis in patients with clinical suspicion. This review supports the use of emergency physician-performed point-of-care ultrasound to rule in a diagnosis of acute cholecystitis in the emergency department, which may help expedite definitive management.


Polymeric drug based on sulfanilamide: synthesis, antimicrobial and drug releasing studies.
N-((4-amino sulfonyl)phenyl)acrylamide (APA) was synthesized using sulfanilamide and acryloyl chloride in the presence of triethyl amine at 0-5 degrees C. Homo- and co-polymerization of 2-hydroxyethyl acrylate (HEA) and acrylic acid (AA) were done by adopting a solution polymerization technique using methyl ethyl ketone (MEK) as a solvent and benzoyl peroxide (BPO) as a free radical initiator at 70 +/- 1 degrees C. All the monomers and polymers were characterized by IR and NMR techniques. These monomers and polymers were tested for their antimicrobial activity against five different ATCC strain microorganisms (Escherichia coli (25922), Pseudomonas aeruginosa (27853), Klebsiella (70063), Salmonella typhi (6539) and Staphylococcus aureus (25923)). The effect of co-monomer, other than the active drug moiety present in the polymeric drug, is discussed. The antimicrobial activity of APA on Gram-positive bacteria was enhanced when copolymerized with AA and HEA. The polymer was made into a film form and that film was used for drug releasing study. The drug releasing rate was monitored by the absorption at 268 nm using a UV spectrophotometer. The effect of pH and the temperature on the drug releasing rate was monitored and found that the releasing rate was dependent on the co-monomer, pH and temperature of the medium.


Making the most of major histocompatibility complex molecule multimers: applications in type 1 diabetes.
Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producing β cells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.


Global cancer pain management: a systematic review comparing trials in Africa, Europe and North America.
Despite the rise in cancer survivorship, few reviews have examined the quality of studies of cancer pain management and practices around the globe. With a void in trials spanning multiple geographical settings, this review evaluates the quality of cancer trials across three continents. A literature review and search of established databases was conducted to identify eligible studies. The Cochrane method, the Jadad Score and a cancer pain-specific ad hoc tool were used to evaluate quality of studies. Eighteen studies representing a total of 4693 individuals were included in the review. Study quality correlated positively with study sample size and palliative care index. Trials in all three continents were prone to use opioids for pain management, whereas trials in Europe and North America utilized other adjuvant therapies such as antidepressants and steroids. This review underscores the need for better multidimensional quality assessment tools for cancer pain trials.


Results of Arthroscopic Repair of Peripheral Triangular Fibrocartilage Complex Tear With Exploration of Dorsal Sensory Branch of Ulnar Nerve.
Ulnar-sided approach in arthroscopic triangular fibrocartilage complex (TFCC) repair may jeopardize treatment success by exposing the dorsal sensory branch of ulnar nerve (DSBUN) in risk of injury. We aim to conduct a follow-up assessment of arthroscopic outside-in TFCC repair and efficacy of sensory nerve exploration. We conducted a retrospective chart review of 58 patients (59 wrists) who received arthroscopic repair of the peripheral attachment of the TFCC. Ulnar-sided skin incision and exploration of DSBUN were performed before arthroscopy setting. Arthroscopic outside-in repair through pullout suture ligation was performed. Functional survey at 6 months and 1 year postoperatively was based on Mayo Modified Wrist Score (MMWS), and compared to the preoperative assessment. A p-value of less than 0.05 was considered significant as calculated using paired t-test. Postoperative MMWS averaged 74.32±11.50 at 6 months, and 84.41±9.52 at one year; both showed significant difference as compared to preoperative status. Significant improvement was noted in all 4 individual items except motion retrieval between 6 months and 1 year. Totally, 45 (76%) cases achieved good or excellent results at one year; however, less patients resumed pre-injury activity level when treatment delay was more than 6 months than those treated earlier (41% vs. 57%). Complication included 6 transient paresthesia; 1 anchor migration and 1 distal radioulnar arthrosis. No more nerve complication was found after modification of perineural dissection. Arthroscopy is effective in obtaining both correct diagnosis and treatment of peripheral TFCC tear. Modified perineural dissection can minimize sensory nerve complications.


In vitro activities of 11 fluoroquinolones against 226 Campylobacter jejuni strains isolated from Finnish patients, with special reference to ciprofloxacin resistance.
Although Campylobacter jejuni is naturally susceptible to fluoroquinolones, the resistance to these antimicrobials has increased rapidly during the recent years. The aim of this study was to compare the activities of various older and newer fluoroquinolones towards C. jejuni, with special attention on ciprofloxacin-resistant strains. We analysed the in vitro activities of 11 fluoroquinolones against 226 C. jejuni strains collected from Finnish patients between 1995 and 2000. Of all 226 C. jejuni strains, 134 (59.3%) were resistant to ciprofloxacin (MIC > or = 4 mg/L), 1 (0.4%) was intermediately resistant (MIC = 2 mg/L) and 91 (40.3%) were ciprofloxacin-susceptible (MIC < or = 1 mg/L). The MIC50 and MIC90 values of ciprofloxacin for the 91 ciprofloxacin-susceptible strains were 0.25 and 0.5 mg/L, respectively. The corresponding MIC50 and MIC90 values of levofloxacin were 0.25 and 0.5 mg/L, and those of moxifloxacin were 0.125 and 0.25 mg/L, these being lower than those of norfloxacin and ofloxacin. The two newer fluoroquinolones, sitafloxacin and clinafloxacin, exhibited the lowest MIC50 and MIC90 values: 0.016 and 0.064 mg/L of sitafloxacin and 0.032 and 0.125 mg/L of clinafloxacin, respectively. Sitafloxacin and clinafloxacin exhibited the lowest MIC50 and MIC90 values also for the 134 ciprofloxacin-resistant C. jejuni strains: 0.25 and 1 mg/L of sitafloxacin and 1 and 4 mg/L of clinafloxacin, respectively. Of the newer fluoroquinolones presently under development, sitafloxacin is in vitro highly effective towards C. jejuni, with low MIC values also for the ciprofloxacin-resistant strains. Sitafloxacin might be a candidate for clinical trials on campylobacteriosis.


Differential Diagnosis between Primary Endocervical and Endometrial Adenocarcinoma using Immunohistochemical Staining of Estrogen Receptor, Vimentin, Carcinoembryonic Antigen and p16.
When clinical and histopathological evaluation is not effective in discriminating primary endocervical adenocarcinoma (ECAs) and endometrial adenocarcinoma (EMAs), an immunohistochemistry (IHC) method is regularly used in practice, which involves staining of estrogen receptor (ER), vimentin (Vim), monoclonal carcinoembryonic antigen (mCEA) and p16. To evaluate the performance of IHC markers, ER, Vim, mCEA and p16, in differentiating between primary ECAs and EMAs and to compare the performances of two-, three- and four-marker panels. Women with cervical or uterine cancers who were diagnosed with mucinous or endometrioid adenocarcinoma or adenocarcinoma of non-otherwise specified, after cervical biopsy, endometrial biopsy or curettage, and who underwent elective surgery at Rajavithi Hospital between January 1, 2011 and June 30, 2012 were retrospectively reviewed. Paraffin-embedded tissue sections from pre-operative specimens were reviewed and stained with ER, Vim, mCEA and p16. Postoperative pathologic slides was reviewed and installed as the reference standard. Of 110 cases, 44 were primary ECAs and 66 were primary EMAs. ER and Vim were significantly expressed in EMAs (p < 0.001), while mCEA and p16 were significantly expressed in ECAs (p < 0.001). From multivariable analysis, Vim and p16 were the significant markers for differentiating ECAs and EMAs. A comparison of different combinations showed that panels of Vim/p16, ER/Vim/p16, Vim/mCEA/p16 and ER/Vim/mCEA/p16 achieved the highest overall accuracy of97.9%. Vim and p16 are the significant IHC markers and a two-marker panel of Vim/p16 is recommended for using in differentiating primary ECAs and EMAs; which a pattern of negative Vim and positive p16 expression favors diagnosis of ECAs while the converse pattern of positive Vim and negative p16 staining points to diagnosis of EMAs.


Imbalance in the Th17/Treg and cytokine environment in peripheral blood of patients with adenocarcinoma and squamous cell carcinoma.
It has been reported that the imbalance of T helper IL-17-producing cells (Th17 cells)/regulatory T cells (Tregs) was closely associated with advanced tumor growth and poor prognosis in lung cancer, but little is known about whether this imbalance is existed in the peripheral blood of patients with non-small cell lung cancer (NSCLC). Here, the percentage of Treg and Th17 cells, and the expression of transcription factors RORγt and FoxP3 were studied by flow cytometry, real-time PCR, and Western blotting, respectively. Levels of serum cytokines (IL-6, IL-17, IL-10, and TGF-β1) were analyzed by ELISA. The results showed that there was an increase in the percentage of Tregs, the mRNA and protein expression of FoxP3, the level of Treg-related cytokines in patients with NSCLC while compared to that in healthy patients. Moreover, the percentage of Th17 cells, RORγt mRNA, and protein expression were decreased in peripheral blood of NSCLC patients. In addition, Th17/Treg ratio was decreased in lung cancer patients when compared with healthy patients and Th17/Treg ratio was negatively correlated with the stages. Our results indicate that the Th17/Treg balance is abnormal in peripheral blood, which may be important in the development of NSCLC.


Spontaneous fission-neutron fission xenon: a new technique for dating geological events.
A method for dating geological samples which uses fission product xenon in a manner similar to the use of radiogenic argon in the 40Ar-39Ar technique has been developed. The results of stepwise heating experiments for a zircon from the Ahaggar region in the Sahara are compared to the geochronology determined by the rubidiumstrontium, uranium-thorium-lead, and potassium-argon dating methods.


Myo-inositol facilitators IolT1 and IolT2 enhance D-mannitol formation from D-fructose in Corynebacterium glutamicum.
Reduction of D-fructose to D-mannitol by whole-cell biotransformation with recombinant resting cells of Corynebacterium glutamicum ATCC13032 requires the coexpression of mdh and fdh, which encode mannitol and formate dehydrogenases, respectively. However, d-mannitol formation is limited by the uptake of d-fructose in its unphosphorylated form, because additional expression of the sugar facilitator from Zymomonas mobilis resulted in a significantly increased productivity. Here we identified similarities of the myo-inositol transporters IolT1 and IolT2 of C. glutamicum to the sugar facilitator of Z. mobilis. The myo-inositol transporter genes were both individually overexpressed and deleted in recombinants expressing mdh and fdh. Biotransformation experiments showed that the presence and absence, respectively, of IolT1 and IolT2 significantly influenced D-mannitol formation, indicating a D-fructose transport capability of these transporters. For further evidence, a C. glutamicum Delta ptsF mutant unable to grow with D-fructose was complemented with a heterologous fructokinase gene. This resulted in restoration of growth with D-fructose. Using overexpressed iolT1, mdh and fdh, D-mannitol formation obtained with C. glutamicum was 34.2 g L(-1), as opposed to 16 g L(-1) formed by the strain overexpressing only mdh and fdh, showing the suitability of myo-inositol transporters for D-fructose uptake to obtain D-mannitol formation by whole-cell biotransformation with C. glutamicum.


Simulation of hard-disk flow in microchannels.
The dynamic flow behavior of a hard-disk fluid under external force field in two-dimensional microchannels is investigated using an event-driven molecular dynamics simulation method. Simulations have been carried out under laminar and subsonic conditions in both slip regime and transition regime, and the effects of three main factors, Knudsen number (Kn), force field intensity, and packing fraction, on flow and heat transfer behavior have been studied. It is shown that all the factors play important roles in the velocity distribution of the flow, and the temperature profile of the gas flow may exhibit a bimodal shape with a local minimum instead of a maximum in the center. These findings verify the predictions of nonequilibrium kinetic theories on the so-called "temperature dip." At high Kn, the two maxima of temperature shift to two walls and the temperature profile changes to a "parabola" opening upward with a minimum in the center. A slight setback of the temperature is also found before the fluid flow eventually arrives at a steady state when the shear rate is high enough.


The effect of ovariectomy, estradiol and progesterone on opioid modulation of feeding.
A number of lines of evidence have suggested that alterations in gonadal steroids may modulate opioid function. We report here the effects of manipulation of female gonadal steroids on the opioid feeding system. Naloxone produced a depression of feeding in all groups. Although the group X dosage interaction was not significant, an internally consistent tendency effect of naloxone among the different treatment groups was observed. Estradiol treated rats were 20 times less sensitive to naloxone's suppressive effects of feeding than ovariectomized animals. Sham operated controls and animals treated with estradiol and progesterone had sensitivities to naloxone which were intermediate to those seen in estradiol treated and ovariectomized animals. A significant drug X dosage interaction was present for the ketocyclazocine effects at 4 hours. Overall, ovariectomized animals were resistant to feeding induced by ketocyclazocine compared to the other groups. Ovariectomy significantly decreased ir-dynorphin levels in the cortex and these values were restored towards normal by a combination of estrogen and progesterone treatment. These studies add to the growing literature suggesting a role for the peripheral endocrine system in the modulation of opioid feeding system.


Team-based Medical Care for Cardiac Failure-The Pharmacist's Expected Role.
The pharmacist's role in home care is increasingly important. We are required to collaborate with multiple other professions. As home care pharmaceutical managers, pharmacists verify the timeline of side effects and the onset of expected effects. It is also important to verify all prescriptions from the pharmaceutical viewpoint, and to point out potential negative interactions or consequences of each prescribed medication, suggesting changes or dosage reduction in drugs as appropriate. Additionally, we verify the cause of unused drugs (i.e. patient non-compliance) and take action. As an effort to provide quality home care, pharmacists share information with other professions for collaborative management of a patient's needs. We act as a bridge between related government, agencies and citizens, assisting in creating a healthy lifestyle for the residents of our community. The days when pharmacists just sit in their pharmacies and dispense drugs are gone. Therefore, we need to collaborate more with medical, nursing care, and governmental professionals in our communities.


Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation.
The degeneration of articular cartilage as part of the clinical syndrome of osteoarthritis is one of the most common causes of pain and disability in middle-aged and older people. The strong correlation between increasing age and the prevalence of osteoarthritis, and recent evidence of important age-related changes in the function of chondrocytes, suggest that age-related changes in articular cartilage can contribute to the development and progression of osteoarthritis. Although the mechanisms responsible for osteoarthritis remain poorly understood lifelong moderate use of normal joints does not increase the risk. Thus, the degeneration of normal articular cartilage is not simply the result of aging and mechanical wear. However, high-impact and torsional loads may increase the risk of degeneration of normal joints, and individuals who have an abnormal joint anatomy, joint instability, disturbances of joint or muscle innervation, or inadequate muscle strength or endurance probably have a greater risk of degenerative joint disease. Recent work has shown the potential for the restoration of an articular surface. Currently, surgeons frequently debride joints and penetrate subchondral bone as well as perform osteotomies, with the intent of decreasing symptoms and restoring or maintaining a functional articular surface. The results of these procedures vary considerably among patients. Clinical and experimental work has shown the important influence of loading and motion on the healing of articular cartilage and joints. Experimental studies have revealed that transplantation of chondrocytes and mesenchymal stem cells; use of periosteal and perichondrial grafts, synthetic matrices, and growth factors: and other methods have the potential to stimulate the formation of a new articular surface. The long-term follow-up of small series of patients has shown that the transplantation of osteochondral autologous grafts and allografts can be effective for the treatment of focal defects of articular cartilage in selected patients. Thus far, none of these methods has been shown to predictably restore a durable articular surface to an osteoarthritic joint, and it is unlikely that any one of them will be uniformly successful. Rather, the available clinical and experimental evidence indicates that future optimum methods for the restoration of articular surfaces will begin with a detailed analysis of the structural and functional abnormalities of the involved joint and the patient's expectations for future use of the joint. On the basis of this analysis, the surgeon will develop a treatment plan that potentially combines correction of mechanical abnormalities (including malalignment, instability, and intra-articular causes of mechanical dysfunction), debridement that may or may not include hunted penetration of subchondral bone, and applications of growth factors of implants that may consist of a synthetic matrix that incorporates cells or growth factors or use of transplants followed by a postoperative course of controlled loading and motion.


Structural Characterization of Early Michaelis Complexes in the Reaction Catalyzed by (+)-Limonene Synthase from Citrus sinensis Using Fluorinated Substrate Analogues.
The stereochemical course of monoterpene synthase reactions is thought to be determined early in the reaction sequence by selective binding of distinct conformations of the geranyl diphosphate (GPP) substrate. We explore here formation of early Michaelis complexes of the (+)-limonene synthase [(+)-LS] from Citrus sinensis using monofluorinated substrate analogues 2-fluoro-GPP (FGPP) and 2-fluoroneryl diphosphate (FNPP). Both are competitive inhibitors for (+)-LS with KI values of 2.4 ± 0.5 and 39.5 ± 5.2 μM, respectively. The KI values are similar to the KM for the respective nonfluorinated substrates, indicating that fluorine does not significantly perturb binding of the ligand to the enzyme. FGPP and FNPP are also substrates, but with dramatically reduced rates (kcat values of 0.00054 ± 0.00005 and 0.00024 ± 0.00002 s-1, respectively). These data are consistent with a stepwise mechanism for (+)-LS involving ionization of the allylic GPP substrate to generate a resonance-stabilized carbenium ion in the rate-limiting step. Crystals of apo-(+)-LS were soaked with FGPP and FNPP to obtain X-ray structures at 2.4 and 2.2 Å resolution, respectively. The fluorinated analogues are found anchored in the active site through extensive interactions involving the diphosphate, three metal ions, and three active-site Asp residues. Electron density for the carbon chains extends deep into a hydrophobic pocket, while the enzyme remains mostly in the open conformation observed for the apoprotein. While FNPP was found in multiple conformations, FGPP, importantly, was in a single, relatively well-defined, left-handed screw conformation, consistent with predictions for the mechanism of stereoselectivity in the monoterpene synthases.


Treatment of a Mandibular Diastemal Fracture Using Locking Compression Plate and Cerclage Wire in a Mare.
This report describes the combination of two surgical fracture repair techniques and the postoperative management of a mandibular diastemal fracture in a two-year-old mare. The mare was referred to a veterinary hospital with a laceration over the body of the right mandible. Radiographic assessment revealed two mesial fracture lines involving the second premolar tooth and a ventrally displaced bone fragment. The mare was treated under general anesthesia and the fracture was corrected using open reduction and plate fixation. A 3.5 mm narrow 15-hole locking compression plate with seven locking screws were used in a bridge form. Cerclage wire was also used to anchor the incisor teeth to the second and third premolar teeth. The cerclage wire and incisor teeth were covered with polymethylmethacrylate to prevent implant failure and avoid injury to the oral mucosa. Implants were removed 55 days after surgery and the mare was discharged from hospital five days later. The mare returned for cerclage wire removal after 90 days and was allowed to resume exercise thereafter. The combination of two surgical techniques, proper implant choice and appropriate postoperative management, including use of pelleted feed, contributed to successful bone healing and return to function.


Synthesis, preclinical evaluation and antidepressant activity of 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides.
A series of phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides (TTa-TTg) were synthesized by the ring closure reaction of phenyl-1-(thiophen-2-yl) prop-2-en-1-ones with thiosemicarbazide in alcoholic basic medium. All the final derivatives were evaluated for their antidepressant and neurotoxicity screening. The structures of the compounds were characterized by IR, 1H NMR, 13C NMR, Mass and elemental analyses. Preclinical evaluation of the compounds were ascertained by in silico toxicity, blood-brain barrier and human oral absorption prediction. In this series, 5-(4-hydroxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1 carbothioamide (TTg) reduced immobility time 61.17 and 62.05 % in both force swimming and tail suspension test respectively at 10 mg/kg dose level when compared to the standard Imipramine without influencing the baseline locomotion. Moreover it was observed that the titled scaffold possessing electron withdrawing chlorine atom in the 4(th) position of aromatic ring of the scaffold also showed good the antidepressant activity. In conclusion, the behavioural investigation revealed that thiophene based pyrazolines having a carbothioamide tail unit in the N1 position may be therapeutically useful as potential antidepressant medications.


Peripheral and autonomic nerve function in long-term insulin-dependent diabetes.
In a cross sectional study, motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV), beat-to-beat variation (BBV) at rest and speed of pupillary dilatation (SPD) have been investigated in 127 nonketonuric long-term insulin-dependent diabetics aged 19-72 yr and in age-matched control subjects. 84% of the patients had electrophysiologic abnormalities, 58% had symptomatic peripheral neuropathy, 35% had abnormal cardiac parasympathetic tests and 26% had abnormal pupillary tests. The most frequent pathologic feature was a decreased sural SNCV (66%). Among the patients without symptomatic peripheral neuropathy, 71% showed electrophysiologic abnormalities. MNCV and SNCV in median, peroneal and sural nerves correlated with BBV (p less than 0.005), but only peroneal MNCV was related to SPD (p less than 0.005). There was also a relationship between BBV and SPD (p less than 0.05). Glycosylated hemoglobin (HbA1) levels correlated inversely with median MNCV (p less than 0.001), and SNCV (p less than 0.03), peroneal MNCV (p less than 0.05) and sural SNCV (p less than 0.05). Patients with abnormal peripheral or autonomic nerve function tests or symptomatic peripheral neuropathy had significantly higher HbA1 levels than those with normal tests (p less than 0.04) or asymptomatic patients (p less than 0.01). Median MNCV and SNCV, sural SNCV and BBV deteriorated with age (p less than 0.05) and median SNCV and peroneal MNCV deteriorated with the duration of diabetes (p less than 0.001). Our findings show an association between peripheral and autonomic nerve dysfunction in long-term insulin-dependent diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)


15.26Gb/s Si-substrate GaN high-speed visible light photodetector with super-lattice structure.
In this paper, we studied a series of high-speed photodetectors (PD) with different super-lattice interlayer periods and the scale of the effective area to examine their communication performance. The mini-PDs are designed with a single 1 mm × 1 mm effective area. The mini-PDs have three different super-lattice (SL) periods in the interlayer: 8, 15, and 32. The micro-PD sample has multiple 50um by 50um photosensitive areas that form a 4 × 4 receiver array, which shares a common N electrode. Its SL period is 26. The experiment shows that mini-PDs have the advantages such as better tolerance to beam spot deviation, larger field of view (FoV), higher responsibility, and wider peak width in spectral response. But micro-LED samples outperform the others in communication capacity and wavelength selectivity. The 8, 15, and 32 SL mini-PD samples achieve 6.6, 7.3, and 8.8 Gb/s data rates, respectively. The micro-PD gains the maximum data rate of 14.38Gb/s without applying waveform level post-equalization, and 15.26Gb/s after using an NN-based post-equalizer. This experiment shows that with proper DSP, GaN-based PD would be suitable for high-speed VLC systems, especially for the short wavelength spectrum in visible light.


Intravascular Large B-Cell Lymphoma: A Diagnostic Dilemma.
Intravascular large B-cell lymphoma is a rare malignancy characterized by the presence of lymphoma cells within the lumen of blood vessels. The annual incidence of cases is fewer than 0.5 cases per 1,000,000. It usually affects the elderly with an average age of diagnosis around 70 years. Due to the absence of lymphoma cells in the peripheral smear and lymphadenopathy, it is difficult to diagnose these cases. Although the central nervous system and skin are the commonly involved organs, they can involve any organ system. Prompt diagnosis and initiation of treatment are very crucial as it carries a high mortality. We describe two patients who presented with constitutional symptoms and fever of unknown origin, later diagnosed as intravascular large B- cell lymphoma. The diagnosis was difficult in both cases as the presenting symptoms were atypical. One of the patients was diagnosed at autopsy. The delay in diagnosis often leads to fatal outcomes as the disease is very aggressive. A high degree of clinical suspicion is the key to prompt diagnosis and improved outcomes.


L-serine and L-threonine dehydratase from Clostridium propionicum. Two enzymes with different prosthetic groups.
L-Serine dehydratase from the Gram-positive bacterium Peptostreptococcus asaccharolyticus is novel in the group of enzymes deaminating 2-hydroxyamino acids in that it is an iron-sulfur protein and lacks pyridoxal phosphate [Grabowski, R. and Buckel, W. (1991) Eur. J. Biochem. 199, 89-94]. It was proposed that this type of L-serine dehydratase is widespread among bacteria but has escaped intensive characterization due to its oxygen lability. Here, we present evidence that another Gram-positive bacterium, Clostridium propionicum, contains both an iron-sulfur-dependent L-serine dehydratase and a pyridoxal-phosphate-dependent L-threonine dehydratase. These findings support the notion that two independent mechanisms exist for the deamination of 2-hydroxyamino acids. L-Threonine dehydratase was purified 400-fold to apparent homogeneity and revealed as being a tetramer of identical subunits (m = 39 kDa). The purified enzyme exhibited a specific activity of 5 mu kat/mg protein and a Km for L-threonine of 7.7 mM. L-Serine (Km = 380 mM) was also deaminated, the V/Km ratio, however, being 118-fold lower than the one for L-threonine. L-Threonine dehydratase was inactivated by borohydride, hydroxylamine and phenylhydrazine, all known inactivators of pyridoxal-phosphate-containing enzymes. Incubation with NaB3H4 specifically labelled the enzyme. Activity of the phenylhydrazine-inactivated enzyme could be restored by pyridoxal phosphate. L-Serine dehydratase was also purified 400-fold, but its extreme instability did not permit purification to homogeneity. The enzyme was specific for L-serine (Km = 5 mM) and was inhibited by L-cysteine (Ki = 0.5 mM) and D-serine (Ki = 8 mM). Activity was insensitive towards borohydride, hydroxylamine and phenylhydrazine but was rapidly lost upon exposure to air. Fe2+ specifically reactivated the enzyme. L-Serine dehydratase was composed of two different subunits (alpha, m = 30 kDa; beta, m = 26 kDa), their apparent molecular masses being similar to the ones of the two subunits of the iron-sulfur-dependent enzyme from P. asaccharolyticus. Moreover, the N-terminal sequences of the small subunits from these two organisms were found to be 47% identical. In addition, 38% identity with the N-terminus of one of the two L-serine dehydratases of Escherichia coli was detected.


Mechanically and Electrically Robust Self-Assembled Monolayers for Large-Area Tunneling Junctions.
This paper examines the relationship between mechanical deformation and the electronic properties of self-assembled monolayers (SAMs) of the oligothiophene 4-([2,2':5',2″:5″,2‴-quaterthiophen]-5-yl)butane-1-thiol (T4C4) in tunneling junctions using conductive probe atomic force microscopy (CP-AFM) and eutectic Ga-In (EGaIn). We compared shifts in conductivity, transition voltages of T4C4 with increasing AFM tip loading force to alkanethiolates. While these shifts result from an increasing tilt angle from penetration of the SAM by the AFM tip for the latter, we ascribe them to distortions of the π system present in T4C4, which is more mechanically robust than alkanethiolates of comparable length; SAMs comprising T4C4 shows about five times higher Young's modulus than alkanethiolates. Density functional theory calculations confirm that mechanical deformations shift the barrier height due to changes in the frontier orbitals caused by small rearrangements to the conformation of the quaterthiophene moiety. The mechanical robustness of T4C4 manifests as an increased tolerance to high bias in large-area EGaIn junctions suggesting that electrostatic pressure plays a significant role in the shorting of molecular junctions at high bias.


Ethanol Extract of Oldenlandia diffusa Herba Attenuates Scopolamine-Induced Cognitive Impairments in Mice via Activation of BDNF, P-CREB and Inhibition of Acetylcholinesterase.
Though Oldenlandia diffusa Herba (ODH) has been known to exhibit anti-cancer and anti-inflammatory effects, its anti-amnestic effect has never been reported so far. The aim of this present study was to elucidate the anti-amnestic effect of ODH. ODH pretreatment significantly reduced escape latency of scopolamine treated Institute of Cancer Research (ICR) mice compared to untreated control groups in a Morris water maze test. Similarly, the passive avoidance test showed that ODH treatment recovered the scopolamine induced amnesia in the ICR mouse model. Concentration of Ach in brains of ODH treated mice was increased compared to that of scopolamine treated mice. In addition, activity of acetylcholinesterase (AChE) was notably decreased by ODH. The protein expression of brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding protein (p-CREB) (Ser133) was increased in ODH pretreated group compared to control group. Consistently, immunohistochemistry (IHC) revealed the elevated expression of brain-derived neurotrophic factor (BDNF) and p-CREB in brains of ODH treated mice compared to the control group. Overall, these findings suggest that ODH has anti-amnestic potential via activation of BDNF and p-CREB and inhibition of AChE in mice with scopolamine induced amnesia.


Berry phase for a spin 1/2 particle in a classical fluctuating field.
The effect of fluctuations in the classical control parameters on the Berry phase of a spin 1/2 interacting with an adiabatically cyclically varying magnetic field is analyzed. It is explicitly shown that in the adiabatic limit dephasing is due to fluctuations of the dynamical phase.


4D Printing of Biocompatible Scaffolds via In Situ Photo-crosslinking from Shape Memory Copolyesters.
The complexity of surgical treatments for large-area soft tissue injuries makes placing large implants into injury sites challenging. Aliphatic polyesters are often used for scaffold preparation in tissue engineering owing to their excellent biodegradability and biocompatibility. Scaffolds with shape-memory effect (SME) can also avoid large-volume trauma during the implantation. However, the complexity and diversity of diseases require more adaptable and precise processing methods. Four-dimensional (4D) printing, a booming smart material additive manufacturing technology, provides a new opportunity for developing shape memory scaffolds. With the aim of personalized or patient-adaptable soft tissues such as blood vessels, we developed a feasible strategy for fabricating scaffolds with fine architectures using 4D printing crosslinkable shape memory linear copolyesters using fused deposition modeling (FDM). To overcome the weak bonding strength of each printed layer during FDM, a catalyst-free photo-crosslinkable functional group derived from biocompatible cinnamic acid was embedded into the linear copolyesters as in situ crosslinking points during FDM printing. Under ultraviolet-assisted irradiation, the resulting 4D scaffold models demonstrated excellent SME, desirable mechanical performance, and good stability in a water environment owing to the chemical bonding between each layer. Moreover, the excellent biocompatibility of the scaffold was evaluated in vitro and in vivo. The developed composite scaffolds could be used for minimally invasive soft tissue repair.


AMPK activity and isoform protein expression are similar in muscle of obese subjects with and without type 2 diabetes.
Acute or chronic activation of AMP-activated protein kinase (AMPK) increases insulin sensitivity. Conversely, reduced expression and/or function of AMPK might play a role in insulin resistance in type 2 diabetes. Thus protein expression of the seven subunit isoforms of AMPK and activities and/or phosphorylation of AMPK and acetyl-CoA carboxylase-beta (ACCbeta) was measured in skeletal muscle from obese type 2 diabetic and well-matched control subjects during euglycemic-hyperinsulinemic clamps. Protein expression of all AMPK subunit isoforms (alpha1, alpha2, beta1, beta2, gamma1, gamma2, and gamma3) in muscle of obese type 2 diabetic subjects was similar to that of control subjects. In addition, alpha1- and alpha2-associated activities of AMPK, phosphorylation of alpha-AMPK subunits at Thr172, and phosphorylation of ACCbeta at Ser221 showed no difference between the two groups and were not regulated by physiological concentrations of insulin. These data suggest that impaired insulin action on glycogen synthesis and lipid oxidation in skeletal muscle of obese type 2 diabetic subjects is unlikely to involve changes in AMPK expression and activity.


Effect of Atorvastatin (10 mg) and Ezetimibe (10 mg) Combination Compared to Atorvastatin (40 mg) Alone on Coronary Atherosclerosis.
It remains inconclusive whether the additional low-density lipoprotein cholesterol (LDL-C) lowering effects of ezetimibe added to statin on coronary atherosclerosis and clinical outcomes are similar to those of statin monotherapy in the setting of comparable LDL-C reduction. We aimed to determine whether there were distinguishable differences in their effects on coronary atherosclerosis with intermediate stenosis between the combination of moderate-intensity statin plus ezetimibe and high-intensity statin monotherapy. Forty-one patients with stable angina undergoing percutaneous coronary intervention were randomized to receive either atorvastatin 10 mg plus ezetimibe 10 mg (ATO10/EZE10) or atorvastatin 40 mg alone (ATO40). The intermediate lesions were evaluated using a near-infrared spectroscopy-intravascular ultrasonography at baseline and after 12 months in 37 patients. The primary endpoint was percent atheroma volume (PAV). Mean LDL-C levels were significantly reduced by 40% and 38% from baseline in the ATO10/EZE10 group (n = 18, from 107 mg/dL to 61 mg/dL) and ATO40 group (n = 19, from 101 mg/dL to 58 mg/dL), respectively, without between-group difference. The absolute change of PAV was -2.9% in the ATO10/EZE10 group and -3.2% in the ATO40 group. The mean difference (95% confidence interval) for the absolute change in PAV between the 2 groups was 0.5% (-2.4% to 2.8%), which did not exceed the pre-defined non-inferiority margin of 5%. There was no significant reduction in lipid core burden index in both groups. In conclusion, the combination of atorvastatin 10 mg and ezetimibe 10 mg showed comparable LDL-C lowering and regression of coronary atherosclerosis in the intermediate lesions, compared with atorvastatin 40 mg alone.


Explanations for social inequalities in preterm delivery in the prospective Lifeways cohort in the Republic of Ireland.
Social inequalities in pregnancy outcomes have been extensively described but studies that explain these inequalities comprehensively are lacking. This analysis evaluated the contribution of material, psychosocial, behavioural, nutritional and obstetrical factors in explaining social inequalities in preterm delivery. The data were based on a prospective cohort of 1109 Irish pregnant women. Preterm delivery was obtained from clinical hospital records. Socio-economic status was measured using educational level. The contribution of the above factors in explaining the association between educational level and preterm delivery was examined using Cox models. Educational level was found to be a significant predictive factor of preterm delivery; women with low educational level were more likely to have a preterm delivery [hazard ratio (HR) = 2.14, 95% confidence interval (95% CI): 1.04-4.38)] after adjustment for age and parity. Rented and crowded home, smoking, alcohol consumption and intake of saturated fatty acids displayed educational differences and were predictive of preterm delivery. Material factors (rented and crowded home) reduced the HR of preterm delivery for low compared with highest educated women by 33%. The additional independent contribution of behavioural factors (smoking and alcohol consumption) was 5% and of saturated fatty acids intake was 4%. All these factors combined reduced the HR of preterm delivery for low educated women by 42% (HR = 1.66, 95% CI: 0.76-3.63). This study underlines the importance of material, behavioural and nutritional factors in explaining social inequalities in preterm delivery. These findings have cross-sectoral public policy implications.


Role of host ciliate Paramecium bursaria mitochondria and trichocysts for symbiotic Chlorella variabilis attachment beneath the host cell cortex.
Symbiotic Chlorella variabilis is encased in the perialgal vacuole (PV) membrane of ciliate Paramecium bursaria. The PV membrane is stably anchored below the host cell cortex by adhesion to host mitochondria. Host trichocysts, which are defensive organelles against predators, are present in the mitochondria and PV membrane vicinity. The mechanism by which PV attaches beneath the host cell cortex remains unknown. When P. bursaria is centrifuged at high speed, the symbiotic algae are displaced from the host cell cortex and concentrate at the posterior end. When centrifugation is stopped, the dislocated algae reattach beneath the host cell cortex with fast cytoplasmic streaming. The densities of mitochondria and trichocysts before and after centrifugation were compared using indirect immunofluorescence microscopy with monoclonal antibodies. Almost all trichocysts were shed by high-speed centrifugation, but dislocated algae could reattach even in the absence of trichocysts. In contrast, host mitochondria were unaffected in localization and number, and the dislocated algae also reattached. These findings suggest trichocysts are unnecessary for algal relocalization and that mitochondria are colocalized with the algae. However, many mitochondria were also present in the cell's anterior region without symbiotic algae. Therefore, not all areas with mitochondria contained algae, but there was an algal localization bias within the host cell.


CEBPA-mediated upregulation of the lncRNA PLIN2 promotes the development of chronic myelogenous leukemia via the GSK3 and Wnt/β-catenin signaling pathways.
Accumulating evidence has shown that long noncoding RNAs (lncRNAs) are significant regulators of multiple cellular processes, including the development of chronic myelocytic leukemia (CML). However, the mechanism of how the lncRNA PLIN2 affects CML development remains unclear. In this study, we aimed to investigate the potential roles of CEBPA-mediated upregulation of PLIN2 in the process of CML development by regulating the GSK3 and Wnt/β-catenin signaling pathways. We found that both CEBPA and PLIN2 were expressed at significantly higher levels in CML. Simultaneously, we found that CEBPA upregulated the expression of PLIN2 and that there was a positive correlation between CEBPA and PLIN2 in CML patients. CEBPA promoted the progression of CML by upregulating PLIN2. We also found that PLIN2 increased the expression levels of AKT, p-AKT, GSK-3β, β-catenin and Axin2/Conductin as well as promoted the progression of CML via the GSK3 and Wnt/β-catenin signaling pathways in vitro. Furthermore, we found that CEBPA-mediated upregulation of PLIN2 expression promotes tumor growth via GSK3 and Wnt/β-catenin signaling in vivo. Therefore, our study provided a new theoretical basis for CML treatment through the CEBPA/PLIN2 axis.


Using rare gas permeation to probe methanol diffusion near the glass transition temperature.
The permeation of rare-gas atoms through deeply supercooled metastable liquid methanol films is used to probe the diffusivity. The technique allows for measurement of supercooled liquid mobility at temperatures near the glass transition. The temperature dependence of the diffusivity is well described by a Vogel-Fulcher-Tamman equation. These new measurements and the temperature dependent kinetic parameters obtained from their analysis provide clear evidence that methanol is a fragile liquid near the glass transition.


Cemented total hip replacement for primary osteoarthritis in patients aged 55 years or older: results of the 12 most common cemented implants followed for 25 years in the Finnish Arthroplasty Register.
We have analysed from the Finnish Arthroplasty Register the long-term survivorship of the 12 most commonly-used cemented implants between 1980 and 2005 in patients aged 55 years or older with osteoarthritis. Only two designs of femoral component, the Exeter Universal and the Müller Straight femoral component had a survivorship of over 95% at ten years with revision for aseptic loosening as the endpoint. At 15 years of the femoral and acetabular component combinations, only the Exeter Universal/Exeter All-poly implant had a survival rate of over 90% with revision for aseptic loosening as the endpoint. In the subgroup of patients aged between 55 and 64 years, survivorship overall was less than 90% at ten years. The variation in the long-term rates of survival of different cemented hip implants was considerable in patients aged 55 years or older. In those aged between 55 and 64 years, none of the cemented prostheses studied yielded excellent long-term survival rates (> or = 90% at 15 years).


Network-assisted target identification for haploinsufficiency and homozygous profiling screens.
Chemical genomic screens have recently emerged as a systematic approach to drug discovery on a genome-wide scale. Drug target identification and elucidation of the mechanism of action (MoA) of hits from these noisy high-throughput screens remain difficult. Here, we present GIT (Genetic Interaction Network-Assisted Target Identification), a network analysis method for drug target identification in haploinsufficiency profiling (HIP) and homozygous profiling (HOP) screens. With the drug-induced phenotypic fitness defect of the deletion of a gene, GIT also incorporates the fitness defects of the gene's neighbors in the genetic interaction network. On three genome-scale yeast chemical genomic screens, GIT substantially outperforms previous scoring methods on target identification on HIP and HOP assays, respectively. Finally, we showed that by combining HIP and HOP assays, GIT further boosts target identification and reveals potential drug's mechanism of action.


Management of autoimmune hemolytic anemia in children and adolescents: A single center experience.
To present and discuss the treatment of autoimmune hemolytic anemia (AIHA). The medical records of all patients (n=19) diagnosed in a tertiary hematology center between 1999 and 2010 were retrospectively reviewed. Median age at diagnosis of AIHA was 5 years (range: 4 months-17 years). In all, 13 patients had primary (idiopathic) AIHA, whereas 2 had primary Evans Syndrome (ES), 2 had autoimmune lymphoproliferative syndrome (ALPS)+ES, and 1 had Wiskott-Aldrich syndrome (WAS)+AIHA. Among the 13 primary idiopathic AIHA patients, 9 recovered following a 4-8-week course of prednisolone treatment without relapses, whereas 3 patients required a longer course of prednisolone. One AIHA patient that was very resistant to prednisolone recovered after cyclosporine A was added to the treatment. All patients with primary idiopathic AIHA were in remission for a median of 3 years (range: 4 months-10 years) at the time this manuscript was written. Among the patients with primary ES, 2 had relapses similar to the ALPS patients. Splenectomy was performed in 1 primary ES patient, who at the time this report was written was also in remission. One ALPS patient required the addition of mycophenolate mofetil due to prednisolone resistance. The WAS patient was treatment resistant and died due to septicemia. Primary AIHA in pediatric patients generally has an acute onset and good response to corticosteroids. Primary or secondary ES has a chronic or relapsing course, and treatment may require other immunosuppressive agents in addition to corticosteroids. Complications of splenectomy must not be underestimated in patients with underlying immunodeficiency. AIHA often causes considerable morbidity and mortality in WAS.


Evaluation of Antiarthritic Potential of Methanolic Extract of Gentiana kurroo Royle.
Rheumatoid arthritis is a systemic disorder which involves the activation of immune system against the self-tissues. The main targets of this disease are the joints. Being systemic the development of this disease involves different mechanisms and thus the exact cause of this disease remains unknown. Although different drugs have been developed, none has been found to be the cure for this disease. In the current study the rat carrageenin paw was used as a model for acute inflammation and mycobacterium induced adjuvant arthritic model was used for exploring the antiarthritic potential of methanolic extract of Gentiana kurroo. In this study the different extracts tested showed less inhibition of acute inflammation than methanolic extract. The methanolic extract was further used in different doses and the anti-inflammatory efficacy was found to be dose dependent. The results obtained were significant with the control and the standard groups. In the arthritic model the methanolic extract showed decrease in the paw volume of arthritic animals and also in the arthritic symptoms. Again the results obtained were found to be significantly dose dependent. From the results obtained it can be concluded that this extract may serve as a source of drug against the rheumatoid arthritis.


Comprehensive quality assessment approach for flow cytometric immunophenotyping of human lymphocytes.
Flow cytometric immunophenotypic (IPT) evaluation has become an important adjunct to clinical patient management and epidemiological studies. This has precipitated a need for stringent quality assessment (QA) procedures to ascertain data integrity. We evaluated a QA approach to monitor all elements of the immunophenotyping process, inclusive of blood collection and processing procedures as well as of staining reagent and instrument performance. Central to our approach was preparation each day, in parallel with clinical analytes, of lymphocytes from healthy donors, selected from a 15 donor panel. IPT parameters evaluated over a 19 month period included frequencies of CD3+, CD4+, CD8+, and CD20+ lymphocytes and the ratio of CD4+ to CD8+ lymphocytes. The sensitivity for analytical error detection was reflected by median coefficients of variation of these parameters within individual panel donors, which were 4.1%, 4.5%, 3.9%, 8.2%, and 10.1%, respectively. IPT parameter values were determined each day for two of the panel donors, then averaged and standardized to obtain a quality or Q variate, which was the basis of QA. Error detection sensitivity decreased 0.6-1.7% and the number of false rejections increased 1.2-3.3% when one panel donor rather than two was used daily for QA. This study also illuminated important aspects of what constitutes the norm for longitudinal IPT parameter variation in healthy individuals including: 1) a generally low degree of temporal parameter variation within individual donors, but 2) significant differences between donors with respect to variance estimates for CD3+ and CD8+ lymphocyte frequencies and CD4+/CD8+ lymphocyte ratios, and 3) an apparent seasonal pattern of variation in CD4+ T-cell frequencies.


Residential segregation and obesity among a national sample of Hispanic adults.
We explored the role of residential segregation in obesity among a national sample of Hispanics for the first time. Data on the 8785 Hispanic adults in the 2000 Behavioral Risk Factor Surveillance System were linked to 2000 census data on the segregation of 290 metropolitan statistical areas. Multilevel modeling revealed that after controlling for individual-level variables, the odds of being obese for Hispanics residing in high-segregated metropolitan statistical areas were 26.4 percent higher than for those residing in low-segregated metropolitan statistical areas. This segregation effect might be mediated by the obesogenic features (e.g. paucity of recreational facilities and abundance of fast-food outlets) of segregated Hispanic neighborhoods.


Photobiomodulation Attenuates Neurotoxic Polarization of Macrophages by Inhibiting the Notch1-HIF-1α/NF-κB Signalling Pathway in Mice With Spinal Cord Injury.
Spinal cord injury (SCI) is a catastrophic disease with a complex pathogenesis that includes inflammation, oxidative stress, and glial scar formation. Macrophages are the main mediators of the inflammatory response and are distributed in the epicentre of the SCI. Macrophages have neurotoxic and neuroprotective phenotypes (also known as classically and alternatively activated macrophages or M1 and M2 macrophages) that are associated with pro- or anti- inflammatory gene expression. Our previous study demonstrated that photobiomodulation (PBM) alters the polarization state of macrophages in the SCI region towards the M2 phenotype and promotes the recovery of motor function in rats with SCI. However, the mechanism by which PBM promotes SCI repair remains largely undefined. This study is based on the replacement of conventional percutaneous irradiation with implantable biofibre optic in vivo irradiation. The aim was to further investigate the effects of PBM on SCI in mice under new irradiation patterns and its potential mechanisms of action. PBM was administered to male mice with clamped SCI for four consecutive weeks and significantly promoted the recovery of motor function in mice. Analysis of the macrophage phenotypes in the epicentre of the SCI in mice showed that PBM mainly inhibited the neurotoxic activation of macrophages in the SCI area and reduced the secretion of inflammatory factors such as IL-1α and IL-6; PBM had no effect on M2 macrophages. Immediately afterwards, we constructed in vitro models of the inflammatory polarization of macrophages and PBM intervention. We found that PBM attenuated the neurotoxicity of M1 macrophages on VSC 4.1 motor neurons and dorsal root ganglion (DRG) neurons. The effects of PBM on neurotoxic macrophages and the possible mechanisms of action were analysed using RNA sequencing (RNA-seq), which confirmed that the main role of PBM was to modulate the inflammatory response and immune system processes. Analysis of the differentially expressed genes (DEGs) associated with the inflammatory response showed that PBM had the most significant regulatory effects on genes such as interleukin (IL)-1α, IL-6, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and had obvious inhibitory effects on inflammation-related Notch1 and hypoxia-inducible factor-1α (HIF-1α) pathway genes. RNA-seq analysis of the effect of PBM on gene expression in resting-state macrophages and M2 macrophages did not show significant differences (data not shown). In conclusion, PBM promoted better motor recovery after SCI in mice by inhibiting the neurotoxic polarization of macrophages and the release of inflammatory mediators by acting on the Notch1-HIF-1α/NF-κB Signalling Pathway.


Chitosan as a biomaterial for the prevention and treatment of dental caries: antibacterial effect, biomimetic mineralization, and drug delivery.
Dental caries is a chronic, progressive disease caused by plaque, influenced by multiple factors and can damage the hard tissues of the teeth. In severe cases, it can also lead to the onset and development of other oral diseases, seriously affecting patients' quality of life. The creation of effective biomaterials for the prevention and treatment of dental caries has become one of the relentless goals of many researchers, with a focus on inhibiting the production of cariogenic plaque and retaining beneficial bacteria, guiding and promoting the reconstruction of dental hard tissues, and delaying the progression of existing caries. Chitosan is a natural cationic polymer extracted from the shells of crustaceans and shellfish. Since its discovery, chitosan has shown to have various biological functions such as antibacterial, biomimetic mineralization, drug delivery, etc., making it one of the most promising biopolymers for new caries prevention and materials of prostheses. Therefore, this article provides an overview of the anti-caries applications of chitosan, which mainly covers the basic research on the application of chitosan in caries prevention and treatment since 2010, with a focus on categorizing and summarizing the following characteristics of chitosan as a caries prevention material, including its antibacterial effect, biomimetic mineralization effect and delivery ability of caries prevention drugs and vaccines. It also explores the limitations of current research on chitosan as a caries prevention biomaterial and the difficulties that need to be focused on and overcome in the future to provide theoretical reference for the clinical implementation of chitosan as a caries prevention biomaterial.


Reduced Swimming Performance Repeatedly Evolves on Loss of Migration in Landlocked Populations of Alewife.
Whole-organism performance tasks are accomplished by the integration of morphological traits and physiological functions. Understanding how evolutionary change in morphology and physiology influences whole-organism performance will yield insight into the factors that shape its own evolution. We demonstrate that nonmigratory populations of alewife (Alosa pseudoharengus) have evolved reduced swimming performance in parallel, compared with their migratory ancestor. In contrast to theoretically and empirically based predictions, poor swimming among nonmigratory populations is unrelated to the evolution of osmoregulation and occurs despite the fact that nonmigratory alewives have a more fusiform (torpedo-like) body shape than their ancestor. Our results suggest that elimination of long-distance migration from the life cycle has shaped performance more than changes in body shape and physiological regulatory capacity.


Impact of a Medication Therapy Management Clinic on Glycosylated Hemoglobin, Blood Pressure, and Resource Utilization.
Medication therapy management is widely promoted to improve care. However, few well-controlled studies have evaluated its impact. We evaluated whether enrollment in a comprehensive medication therapy management clinic (MTMC) was associated with improved 12-month outcomes. This institutional review board approved study was a retrospective controlled cohort study in an academic health center serving low-income, African American and Latino populations. Between 2001 and 2011 MTMC patients were matched to control patients by age, gender, and comorbidities. Outcomes were mean change in glycosylated hemoglobin (A1C), diastolic (DBP) and systolic blood pressure (SBP), and emergency department (ED) and hospital admissions at 6 and 12 months. A difference-in-difference analysis was conducted for each outcome of interest, adjusting for observed, unmatched confounders. Patients with diabetes and receiving MTMC had greater A1C improvements, compared with controls, of 0.54% (P = 0.0067) at 6 months and 0.63% (P = 0.0160) at 12 months. At 6 months, SBP and DBP decreased in MTMC patients by 6.5 mm Hg (P = 0.0108) and 3.8 mm Hg (P = 0.0136) more than controls, respectively. At 12 months, those receiving MTMC services had SBP and DBP decreases, respectively, of 8.2 mm Hg (P = 0.0018) and 1.7 mm Hg (P = 0.2691) compared with controls. ED and hospital visits were not statistically significantly different between groups. Conclusion and Relevance: This MTMC potentially improved outcomes for referred patients in whom target goals were difficult to achieve and can serve as a model for other similar medication management programs.


[Influenza viruses in man and animals. A literature review (author's transl)].
Influenza viruses in man and animals. A literature reviewA literature review on the influenza viruses is presented in this paper. A description of the disease in man and domestic animals, as well as general considerations on morphological, physicochemical and antigenic properties of these viruses is given. Emphasis is put on the role of the antigenic changes of these viruses with regard to the epidemiology of the disease, as well as on the possible origin of the pandemic and epidemic strains.


Epigenetics in osteoarthritis: Novel spotlight.
Osteoarthritis (OA) is the most common type of arthritis and no longer is considered as an absolute consequence of joint mechanical use (wear and tear); rather recent data demonstrate the pivotal role of inflammatory mediators in the development and progression of this disease. This multifactorial disease results from several environmental and inherited factors. Genetic cannot solely explain all the contribution share of inheritance and, this way, it is speculated that epigenetics can play a role, too. Moreover, environmental factors can induce local epigenetic changes. The epigenetic contribution to OA pathogenesis occurs at all of its levels, DNA methylation, histone modification, microRNA, and long noncoding RNA. In fact, during early phases of OA pathogenesis, environmental factors employ epigenetic mechanisms to provide a positive feedback for the OA-related pathogenic mechanisms and pathways with an ultimate outcome of a well-established clinical OA. These epigenetic changes stay during clinical disease and prevent the body natural healing and regenerative processes to work properly, resulting in an incurable disease condition. In this review article, we aimed to have an overview on the studies performed with regard to understanding the role of epigenetics in the etiopathogenesis of OA and highlighted the importance of such kind of regulatory mechanisms within this context.


Imaging of abdominal aortic aneurysms.
Given the high rate of morbidity and mortality associated with abdominal aortic aneurysms (AAAs), accurate diagnosis and preoperative evaluation are essential for improved patient outcomes. Ultrasonography is the standard method of screening and monitoring AAAs that have not ruptured. In the past, aortography was commonly used for preoperative planning in the repair of AAAs. More recently, computed tomography (CT) has largely replaced older, more invasive methods. Recent advances in CT imaging technology, such as helical CT and CT angiography, offer significant advantages over traditional CT. These methods allow for more rapid scans and can produce three-dimensional images of the AAA and important adjacent vascular structures. Use of endovascular stent grafts has increased recently and is less invasive for the repair of AAAs in selected cases. Aortography and CT angiography can precisely determine the size and surrounding anatomy of the AAA to identify appropriate candidates for the use of endovascular stent grafts. Helical CT and CT angiography represent an exciting future in the preoperative evaluation of AAAs. However, this technology is not the standard of care because of the lack of widespread availability, the cost associated with obtaining new equipment, and the lack of universal protocols necessary for acquisition and reconstruction of these images.


A Drosophila model of spinal muscular atrophy uncouples snRNP biogenesis functions of survival motor neuron from locomotion and viability defects.
The spinal muscular atrophy (SMA) protein, survival motor neuron (SMN), functions in the biogenesis of small nuclear ribonucleoproteins (snRNPs). SMN has also been implicated in tissue-specific functions; however, it remains unclear which of these is important for the etiology of SMA. Smn null mutants display larval lethality and show significant locomotion defects as well as reductions in minor-class spliceosomal snRNAs. Despite these reductions, we found no appreciable defects in the splicing of mRNAs containing minor-class introns. Transgenic expression of low levels of either wild-type or an SMA patient-derived form of SMN rescued the larval lethality and locomotor defects; however, snRNA levels were not restored. Thus, the snRNP biogenesis function of SMN is not a major contributor to the phenotype of Smn null mutants. These findings have major implications for SMA etiology because they show that SMN's role in snRNP biogenesis can be uncoupled from the organismal viability and locomotor defects.


Dexamethasone regulates IL-1 beta and TNF-alpha-induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells.
We have investigated both constitutive- and cytokine-induced secretion of interleukin-8 (IL-8) and its regulation by dexamethasone and 17 beta-estradiol in normal human bone marrow stromal (HBMS), osteoblast-like cells (hOB), and osteosarcoma MG-63 cells. Although HBMS cells secrete low levels of IL-8 constitutively, treatment with IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) induced IL-8 secretion. Their effects were synergistic but IL-8 production was not affected by 17 beta-estradiol. Human osteosarcoma MG-63 cells also secreted low levels of IL-8 constitutively; the production was induced by IL-1 beta and TNF-alpha and was also not affected by 17 beta-estradiol. The magnitude of the response to cytokine stimulation of IL-8 in MG-63 cells was much lower than that of HBMS and hOB cells, indicating differences in response in normal and osteoblastic osteosarcoma cells. Dexamethasone (10(-7) M) significantly inhibited IL-1 beta plus TNF-alpha stimulated IL-8 production in HBMS, MG-63, and hOB cells. The accumulated results demonstrate that IL-8 is secreted by HBMS, MG-63, and hOB cells, suggesting that IL-8 may play a role in the regulation of bone cell function. These data also emphasize the importance of glucocorticoids in controlling cytokine secretion in HBMS, hOB, and MG-63 cells.


Synthesis of Bioactive 3,4-Dihydro-2 H-naphtho[2,3- b][1,4]oxazine-5,10-dione and 2,3,4,5-Tetrahydro-1 H-naphtho[2,3- b]azepine-6,11-dione Derivatives via the Copper-Catalyzed Intramolecular Coupling Reaction.
A convenient synthesis of 3,4-dihydro-2 H-naphtho[2,3- b][1,4]oxazine-5,10-diones and 2,3,4,5-tetrahydro-1 H-naphtho[2,3- b]azepine-6,11-diones via the copper-catalyzed intramolecular C-O/C-C coupling reaction is described. This method showed a good tolerance for functional groups and was applied to the synthesis of natural product core structures. Some coupling products exhibited moderate activities against lung cancer A549 cells.


Gaps in the capacity of modern forage crops to adapt to the changing climate in northern Europe.
The within-species diversity in response to weather and the gaps in the response diversity in the modern set of forage crop cultivars were determined using an approach that assessed the adaptive capacity under global climate change. The annual dry matter (DM) yields were recorded in multi-location MTT (Maa- ja elintarviketalouden tutkimuskeskus) Agrifood Research Official Variety Trials in Finland for modern forage crop cultivars from 2000 to 2012, as a response to agroclimatic variables critical to yield based on the year-round weather data. The effect and interaction of cultivars and agroclimatic variables were analysed using mixed model. The relatively low adaptive capacity of timothy (Phleum pratense L.) and meadow fescue (Festuca pratensis Huds.) indicates that diversification of the breeding material is warranted, particularly for resistance to high temperatures during primary growth and to high temperature sum 7 days after the first cut. All red clover cultivars (Trifolium pratense L.) suffered from both low and high accumulation of warm winter temperatures. Except for the red clover cultivars, cold stress during winter and lack of warm winter temperatures consistently reduced the yields of all species and cultivars. All tall fescue (Festuca arundinacea Schreb.) cultivars suffered from low precipitation during the fall hardening period. Although the set of festulolium (Festulolium pabulare) cultivars was also sensitive to low precipitation during the fall, festulolium was a good example of enhanced capacity to adapt to climate change with high response diversity because the cultivar germplasm base was diversified. Foreign origin in a cultivar pool was apparently not sufficient or necessary to ensure added value for a diversity of responses to climate change. Similar analyses to those used in this study, applied as practical tools for breeders, farmers and public actors, are important to secure the adaptive capacity of crops worldwide under global climate change.


Metabolic Regulation of Innate Lymphoid Cell-Mediated Tissue Protection-Linking the Nutritional State to Barrier Immunity.
Innate lymphoid cells (ILC) are a recently described group of tissue-resident immune cells that play essential roles in maintaining and protecting the tissue barrier against invading pathogens. Extensive research has revealed that ILC-mediated immune responses are controlled by dietary components and metabolites. An additional role of ILC as important direct regulators of host metabolism and glucose tolerance is emerging. This suggests that ILC may act as key dietary sensors integrating nutritional and metabolic stress to facilitate both maintenance of barrier sites and a coordinated immune response protecting these tissues. In this respect, investigations have begun to determine how different ILC responses are metabolically fueled and the impact of nutrient availability on the regulation of ILC function. Here, we discuss the current literature concerning dietary and metabolic control of ILC. In particular, we address whether the dietary and metabolic control of ILC and their simultaneous influence on host metabolism may function as a coordinated program of barrier defense.


Altered expression of the D1.1 ganglioside in the cerebellum of the Weaver mouse.
Expression of the D1.1 ganglioside was studied immunohistochemically in developing cerebella from normal and weaver mutant mice. In the normal cerebellum at postnatal day 7 (P7), D1.1 expression was restricted to the external granule-cell layer (EGL). At later ages, D1.1 disappeared as the developing granule neurons ceased mitosis and began migrating toward the internal granule-cell layer. In the weaver cerebellum, D1.1 was expressed in the EGL in apparently normal fashion at P7, but failed to disappear at later ages. As late as P35, D1.1 immunoreactivity was observed throughout the weaver cerebellar cortex. The relative amounts of D1.1 ganglioside in weaver and normal cerebella were compared by thin layer chromatography of total gangliosides, followed by overlay of the chromatogram with anti-D1.1 and 125I-labelled second antibody. Autoradiograms showed that at P12 and P35 the weaver tissue contains six- to tenfold more D1.1 than normal tissue. These findings suggest that one result of the weaver mutation is prolonged expression of D1.1. We speculate that the D1.1 ganglioside might be involved in adhesive interactions that regulate the timing of granule-cell migration from the EGL. The prolonged expression of D1.1 could be responsible, in part, for the failure of granule-cell migration in the weaver cerebellum.


Matrine induces hepatocellular carcinoma apoptosis and represses EMT and stemness through microRNA-299-3p/PGAM1 axis.
This study explored the impacts of matrine on hepatocellular carcinoma (HCC) cell growth, metastasis, epithelial-mesenchymal transition (EMT), and stemness through regulating the microRNA (miR)-299-3p/phosphoglycerate mutase 1 (PGAM1) axis. The association between miR-299-3p expression with the prognosis of HCC patients was studied. miR-299-3p and PGAM1 sequences were transfected into matrine-treated HCC cells, and cell proliferation, invasion, apoptosis, and stemness were detected, as well as protein expression of EMT- and stemness-related makers. The targeting relationship between miR-299-3p and PGAM1 was identified. Matrine elevated miR-299-3p expression, repressed proliferation, invasion, and anti-apoptosis of HCC cells, and constrained EMT and stemness in vitro. PGAM1 was a target of miR-299-3p. Repression of PGAM1 rescued the effects of miR-299-3p downregulation on HCC cells. Matrine stimulates HCC cell apoptosis and represses the process of EMT and stemness through the miR-299-3p/PGAM1 axis.


[Chinese expert consensus on intracorporeal digestive reconstruction after robotic gastrectomy (2021 edition)].
The robotic surgical system applied to gastrectomy is regarded as a safe technique which has similar short- and long-term outcomes compared to laparoscopic and open gastrectomy. With the iteration of anastomotic staplers and improvement of anastomotic skills, coupled with the flexible robot's rotatable device making the manual intracorporal anastomosis easier, gastrointestinal reconstruction after robotic gastrectomy has also started to move toward the era of complete intracorporal anastomosis. In order to further standardize the indications and operating points, the Upper Gastrointestinal Surgery Group of Surgical Branch of Chinese Medical Doctor Association, the Gastrointestinal Surgery Group of Surgery Branch of Chinese Medical Association, the Digestive Tract Cancer Committee of Chinese Research Hospital Association, and Cancer Gastroenterology Society of Chinese Anticancer Association jointly organized domestic experts in general surgery field to formulate the Chinese expert consensus on intracorporal digestive reconstruction after robotic gastrectomy (2021 edition). The definition of intracorporeal digestive reconstruction after robotic gastrectomy is that all surgical steps of digestive reconstruction are done totally in the abdominal cavity by robotic system or all steps mentioned above except jejunojejunal extracorporeal anastomosis. The digestive reconstructions mainly include Billroth I anastomosis, Billroth II anastomosis, Billroth II+ Braun anastomosis, Roux-en-Y anastomosis, Uncut Roux-en-Y anastomosis after distal gastrectomy; double-tract anastomosis, esophagogastric anastomosis by stapler or hand-sewn technique (double flap gastroesophagostomy) after proximal gastrectomy; FEEA method, π-type anastomosis, overlap method and modified procedures, Uncut Roux-en-Y anastomosis, Parisi's double-loop reconstruction after total gastrectomy. Compared with extracorporeal digestive reconstruction, intracorporeal digestive reconstruction operated by robotic system can minimize the surgical incision, reduce the risk of abdominal exposure and accelerate postoperative recovery, etc. Previous studies have demonstrated promising results. We believe that the publication of the consensus will guide surgeons to break through the technical barriers of intracorporeal digestive reconstruction after robotic gastrectomy, which will be more and more widespread with the gradual maturity of domestic robotic systems by bringing less medical costs.


The ARF GAP ELMOD2 acts with different GTPases to regulate centrosomal microtubule nucleation and cytokinesis.
ELMOD2 is a ∼32 kDa protein first purified by its GTPase-activating protein (GAP) activity toward ARL2 and later shown to have uniquely broad specificity toward ARF family GTPases in in vitro assays. To begin the task of defining its functions in cells, we deleted ELMOD2 in immortalized mouse embryonic fibroblasts and discovered a number of cellular defects, which are reversed upon expression of ELMOD2-myc. We show that these defects, resulting from the loss of ELMOD2, are linked to two different pathways and two different GTPases: with ARL2 and TBCD to support microtubule nucleation from centrosomes and with ARF6 in cytokinesis. These data highlight key aspects of signaling by ARF family GAPs that contribute to previously underappreciated sources of complexity, including GAPs acting from multiple sites in cells, working with multiple GTPases, and contributing to the spatial and temporal control of regulatory GTPases by serving as both GAPs and effectors.


An atypical presentation of infiltrating ductal carcinoma.
A 64-year-old African-American female presented with nonbloody nipple discharge. Clinical and cytological examination of the discharge was normal. The mammography suggested pleomorphic calcification in the left breast. A stereotactic biopsy showed ductal carcinoma in situ and her estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2-neu receptor were negative. We removed the tumor tissue through lumpectomy and found that the mass was invasive ductal carcinoma. This case report highlights invasive ductal carcinoma, presenting with unilateral nipple discharge.


Subpallial origin of a population of projecting pioneer neurons during corticogenesis.
Pyramidal neurons of the mammalian cerebral cortex are generated in the ventricular zone of the pallium whereas the subpallium provides the cortex with inhibitory interneurons. The marginal zone contains a subpial stream of migratory interneurons and two different classes of transient neurons, the pioneer neurons provided with corticofugal axons, and the reelin-expressing Cajal-Retzius cells. We found in cultured slices that the medial ganglionic eminence provides the reelin-negative pioneer neurons of the marginal zone. Pioneer neurons sent long projection axons that went through the cortical plate and reached the subplate and the lateral border of the lateral ganglionic eminence. In the cultured slices, pioneer neurons were functionally mature: they displayed a voltage-gated sodium current, expressed functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and showed gamma-aminobutyric acid type A (GABAA) postsynaptic events that were modulated by presynaptic AMPA receptors. Pioneer neurons expressed the adhesion molecules L1 and TAG-1; the latter has been reported to control tangential migrations to the neocortex [Denaxa, M., Chan, C.-H., Schachner, M., Parnavelas, J. & Karagogeos, D. (2001) Development (Cambridge, U.K.) 128, 4635-4644], and we show here that the pioneer neurons of the marginal zone are the cellular substrate of such a function. Finally, we show that, in early corticogenesis, reelin controls both the tangential migration of cortical interneurons toward the cortical plate and the tangential migration of pioneer neurons toward the marginal zone.


Ex vivo biomechanical properties of the female urethra in a rat model of birth trauma.
Stress urinary incontinence (SUI) is the involuntary release of urine during sudden increases in abdominal pressures. SUI is common in women after vaginal delivery or pelvic trauma and may alter the biomechanical properties of the urethra. Thus we hypothesize that injury due to vaginal distension (VD) decreases urethral basal tone and passive stiffness. This study aimed to assess the biomechanical properties of the urethra after VD in the baseline state, where basal muscle tone and extracellular matrix (ECM) are present, and in the passive state, where inactive muscle and ECM are present. Female rat urethras were isolated in a rat model of acute SUI induced by simulated birth trauma. Our established ex vivo system was utilized, wherein we applied intraluminal static pressures ranging from 0 to 20 mmHg. Outer diameter was measured via a laser micrometer. Measurements were recorded via computer. Urethral thickness was assessed histologically. Stress-strain responses of the urethra were altered by VD. Quantification of biomechanical parameters indicated that VD decreased baseline stiffness. The passive peak incremental elastic modulus of the distal segment in VD urethras was less than for controls (1.84 +/- 0.67 vs. 1.19 +/- 0.70 x 10(6) dyne/cm(2), respectively; P = 0.016). An increase was noted in passive low-pressure compliance values in proximal VD urethras compared with controls (9.44 +/- 2.43 vs. 4.62 +/- 0.60 mmHg(-1), respectively; P = 0.04). Biomechanical analyses suggest that VD alters urethral basal tone, proximal urethral compliance, and distal stiffness. Lack of basal smooth muscle tone, in combination with these changes in the proximal and distal urethra, may contribute to SUI induced by VD.


Drug Overdose Deaths in the United States, 1999-2015.
Key findings Data from the National Vital Statistics System, Mortality ● The age-adjusted rate of drug overdose deaths in the United States in 2015 (16.3 per 100,000) was more than 2.5 times the rate in 1999 (6.1). ● Drug overdose death rates increased for all age groups, with the greatest percentage increase among adults aged 55-64 (from 4.2 per 100,000 in 1999 to 21.8 in 2015). In 2015, adults aged 45-54 had the highest rate (30.0). ● In 2015, the age-adjusted rate of drug overdose deaths among non-Hispanic white persons (21.1 per 100,000) was nearly 3.5 times the rate in 1999 (6.2). ● The four states with the highest age-adjusted drug overdose death rates in 2015 were West Virginia (41.5), New Hampshire (34.3), Kentucky (29.9), and Ohio (29.9). ● In 2015, the percentage of drug overdose deaths involving heroin (25%) was triple the percentage in 2010 (8%). Deaths from drug overdose have been identified as a significant public health burden in the United States in recent years (1-4). This report uses data from the National Vital Statistics System (NVSS) to highlight recent trends in drug overdose deaths, describing demographic and geographic patterns as well as the types of drugs involved.


Transbronchial lung biopsy via the fiberoptic bronchoscope in sarcoidosis.
In a prospective study at two medical centers, 42 consecutive patients with suspected sarcoidosis underwent transbronchial lung biopsy during fiberoptic bronchoscopy. Transbronchial biopsy revealed noncaseating granulomas in 24 of the 38 cases (63%) in which adequate tissue was obtained. Special stains and cultures for acid-fast bacilli and fungi were negative, and sarcoidosis was subsequently diagnosed in all 42 cases. Positive biopsies were obtained in 11 of 20 patients with radiographic stage I disease, in 11 of 15 with stage II disease, and in 2 of 3 with stage III disease. There was a higher probability of a positive biopsy in patients with high symptom scores for cough, wheezing, and dyspnea, and in those with a vital capacity of less than 80% of predicted. The only complication was one small pneumothorax, which spontaneously resolved. Transbronchial lung biopsy is an attractive initial procedure for obtaining histologic confirmation of sarcoidosis.


Multiple regulatory mechanisms control the expression of the RAS1 and RAS2 genes of Saccharomyces cerevisiae.
Expression of the RAS1 and RAS2 genes of Saccharomyces cerevisiae has been examined at the transcriptional and translational levels. When dextrose is the carbon source, the steady-state amount of RAS1 mRNA and the rate of RAS1 protein synthesis are reduced in parallel as cells approach the mid-exponential phase of growth. RAS1 mRNA levels and protein synthesis are very low at all stages of growth when ethanol rather than dextrose is provided as the sole carbon source. The rate of RAS2 protein synthesis is regulated differently. In cells cultured on dextrose, it is lowest in the early exponential phase, increases approximately 10-fold and remains nearly constant as cells approach stationary phase. By contrast, RAS2 mRNA is found at uniformly high levels at all phases of exponential growth, suggesting that the translational efficiency of RAS2 mRNA is repressed during the early exponential phase. This repression is not observed when ethanol is the sole carbon source. Nutrient starvation, resulting in G1 arrest and sporulation in diploids, leads to greatly decreased amounts of RAS2 mRNA, accomplished in part by selective repression of RAS2 transcripts with particular 5' ends. However, this reduction in RAS2 mRNA levels has little effect on the rate of RAS2 protein synthesis, suggesting that the translational efficiency of RAS2 mRNA is stimulated by nutrient starvation. The combination of transcriptional and translational controls which regulate yeast RAS gene expression seems to ensure that one or the other RAS proteins will be produced over a wide range of physiological states.


Resveratrol Alleviates 27-Hydroxycholesterol-Induced Senescence in Nerve Cells and Affects Zebrafish Locomotor Behavior via Activation of SIRT1-Mediated STAT3 Signaling.
The oxysterol 27-hydroxycholesterol (27HC) is the first identified endogenous selective estrogen receptor modulator (SERM), which like endogenous estrogen 17β-estradiol (E2) induces the proliferation of estrogen receptor- (ER-) positive breast cancer cells in vitro. However, 27HC differs from E2 in that it shows adverse effects in the nervous system. Our previous study confirmed that 27HC could induce neural senescence by activating phosphorylated signal transducer and activator of transcription, which E2 could not. The purpose of the present study is to investigate whether STAT3 acetylation was involved in 27HC-induced neural senescence. Microglia (BV2 cells) and rat pheochromocytoma cells (PC12 cells) were used in vitro to explore the effect of resveratrol (REV) on 27HC-induced neural senescence. Senescence-associated β-galactosidase (SA-β-Gal) staining was performed using an SA-β-Gal Staining Kit in cells and zebrafish larvae. Zebrafish were used in vivo to assess the effect of 27HC on locomotor behavior and aging. We found that 27HC could induce senescence in neural cells, and REV, which has been employed as a Sirtuin-1 (SIRT1) agonist, could attenuate 27HC-induced senescence by inhibiting STAT3 signaling via SIRT1. Moreover, in the zebrafish model, REV attenuated 27HC-induced locomotor behavior disorder and aging in the spinal cord of zebrafish larvae, which was also associated with the activation of SIRT1-mediated STAT3 signaling. Our findings unveiled a novel mechanism by which REV alleviates 27HC-induced senescence in neural cells and affects zebrafish locomotor behavior by activating SIRT1-mediated STAT3 signaling.


Randomized clinical trial with alpha 2b-interferon in 26 stage A untreated B-chronic lymphocytic leukemia patients.
In a previous study we obtained a 50% response rate with alpha 2b Interferon in the first stages of chronic lymphocytic leukaemia. We have performed a second study randomizing 34 stage A patients, who were receiving no other treatment (8 non-treated controls and 26 patients who had been treated with 3 modalities). We obtained 17 responses (67%) with one complete haematological response (4%), 9 incomplete (34%) and 7 minor (37%). No bone marrow changes were noted after this treatment but there was a decrease in the lymph nodes or the spleen seen on three occasions. In a new randomised study we have studied the effects of the small doses of Interferon associated with chemotherapy.


Serum response factor promotes axon regeneration following spinal cord transection injury.
Studies have shown that serum response factor is beneficial for axonal regeneration of peripheral nerves. However, its role after central nervous system injury remains unclear. In this study, we established a rat model of T9-T10 spinal cord transection injury. We found that the expression of serum response factor in injured spinal cord gray matter neurons gradually increased with time, reached its peak on the 7th day, and then gradually decreased. To investigate the role of serum response factor, we used lentivirus vectors to overexpress and silence serum response factor in spinal cord tissue. We found that overexpression of serum response factor promoted motor function recovery in rats with spinal cord injury. Qualitative observation of biotinylated dextran amine anterograde tracing showed that overexpression of serum response factor increased nerve fibers in the injured spinal cord. Additionally, transmission electron microscopy showed that axon and myelin sheath morphology was restored. Silencing serum response factor had the opposite effects of overexpression. These findings suggest that serum response factor plays a role in the recovery of motor function after spinal cord injury. The underlying mechanism may be related to the regulation of axonal regeneration.


Increasing pedigree contribution to dairy sire evaluation.
Methods to improve contributions of ancestor information to sire evaluations computed by the Modified Contemporary Comparison were studied. Pedigree index (one-half evaluation of sire plus one-fourth evaluation of maternal grandsire ) was used to indicate ancestor merit with adjustment for type of sampling program and birth date. For Holsteins, effect of sampling through artificial insemination was 35 kg for milk yield; effect of birth date (trend of daughter merit not accounted for by pedigree index or type of sampling) was 7.3 kg/yr for milk yield and .36 kg/yr for fat yield. Trends were larger for milk and fat yields of Ayrshires , Brown Swiss, Guernseys , and Jerseys except for fat yield of Ayrshires , which had no significant trend. Correlations of daughter merit with pedigree index and with present group average (average daughter merit of bulls with similar pedigree indexes for milk yield) were computed. For milk yield, correlations of daughter merit with pedigree index and with group average were nearly the same; however, for fat yield, pedigree index had a higher correlation with daughter merit than did group average. Accounting for residual trend resulted in further increase of correlation. Replacing one-fourth evaluation of maternal grandsire with one-half Cow Index of dam also improved correlations slightly. Evaluations can be modified so that pedigree index adjusted by birth date replaces group average in representing ancestor merit. Such evaluations better predict performance of future daughters than do evaluations with grouping by pedigree index for milk yield, particularly for evaluations for fat yield. Dam's Cow Index provides little additional information.


Renal Leiomyosarcoma: Unraveling the Mysteries of a Rare Malignancy.
Primary leiomyosarcoma is a rare malignant kidney tumor. The diagnosis of this disease is usually made on the basis of histological examination because it lacks specific clinical or radiological characteristics. Differentiation between leiomyosarcoma and sarcomatoid renal cell carcinoma can be challenging because spindle cell morphology is observed in both tumors. Therefore, caution should be exercised when making a diagnosis of primary renal leiomyosarcoma. Both renal sarcoma and sarcomatoid renal cell carcinoma have a worse prognosis, and nephrectomy is the treatment of choice in locally resectable tumors. An example of such a tumor is discussed in relation to its diagnostic challenges. We report a case of a 35-year-old female who presented with a left renal mass. A left radical nephrectomy was performed, and a firm, tan-white, lobulated tumor (14x8x7.5 cm) was present on gross examination. A histological diagnosis of high-grade leiomyosarcoma was made on the basis of histology, positivity for caldesmon and desmin, and negative cytokeratin immunostaining. Sarcomatoid renal cell carcinoma was ruled out based on morphological findings after extensive sampling of the tumor along with negativity for CK, CD-10, and carbonic anhydrase IX immunostaining.


Olanzapine treatment for tics in an adult woman with severe tourette syndrome.
Olanzapine had been reported to be effective in the control of tics in a few adult female patients who had a short follow-up period. The author reports the successful outcome of long-term olanzapine treatment in an adult woman with severe Tourette syndrome. A 33-year-old woman who had severe motor and vocal tics (Modified Rush Videotape Rating Scale: 17/20) showed an excellent response to olanzapine 10 mg/day within 2 months. Her tic symptoms were well controlled with gradual reduction of her dose of olanzapine to 2.5 mg/day during the following 8 years. She was symptom-free without medications in the past 2 years. In addition, she had a normal menstrual cycle and became pregnant during the period of olanzapine treatment. Olanzapine may be the drug of first choice for treating severe Tourette syndrome in pubescent female adolescents and young women who wish to have children.


Searching for new markers of endogenous steroid administration in athletes: "looking outside the metabolic box".
A simple means of detecting the abuse of steroids that also occur naturally is a problem facing doping control laboratories. Specific markers are required to allow the detection of the administration of these steroids. These markers are commonly measured using a set of data obtained from the screening of samples by gas chromatography-mass spectrometry (GC-MS). Doping control laboratories further need to confirm identified abuse using techniques such as gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). An interesting urinary species was found while following the pharmacokinetics and changes to the steroid profile from single and multiple oral doses of the International Olympic Committee/World Anti Doping Agency (IOC/WADA) prohibited substance, dehydroepiandrosterone (DHEA). The urine samples collected from the administration studies were subject to GC-MS and GC-C-IRMS steroid analysis following cleanup by solid phase extraction techniques. A useful urinary product of DHEA administration was detected in the urine samples from each of the administration studies and was identified by GC-MS experiments to be 3alpha,5-cyclo-5alpha-androstan-6beta-ol-17-one (3alpha,5-cyclo). This compound occurs naturally but the concentrations of 3alpha,5-cyclo were elevated following both the single DHEA administration (up to 385 ng/mL) and multiple DHEA administrations (up to 1240 ng/mL), in relation to those observed prior to these administrations (70 and 80 ng/mL, respectively). A reference distribution of urine samples collected from elite athletes (n = 632) enabled the natural concentration range of 3alpha,5-cyclo to be established (0-280 ng/mL), with a mean concentration of 22 ng/mL. Based on this an upper 3alpha,5-cyclo concentration limit of 140 ng/mL is proposed as a GC-MS screening marker of DHEA abuse in athletes. GC-C-IRMS analysis revealed significant 13C depletion of 3alpha,5-cyclo following DHEA administration. In the single administration study, the delta13C value of 3alpha,5-cyclo changed from -24.3 per thousand to a minimum value of -31.1 per thousand at 9 h post-administration, before returning to its original value after 48 h. The multiple administration study had a minimum delta13C 3alpha,5-cyclo of -33.9 per thousand during the administration phase in contrast to the initial value of -24.2 per thousand. Preliminary studies have shown 3alpha,5-cyclo to most likely be produced from DHEA sulfate found at high levels in urine. The complementary use of GC-MS and GC-C-IRMS to identify new markers of steroid abuse and the application of screening criteria incorporating such markers could also be adapted by doping control laboratories to detect metabolites of androstenedione, testosterone and dihydrotestosterone abuse.