Lithium and venlafaxine interaction: a case of serotonin syndrome.
Serotonin syndrome, which occurs as a result of enhanced serotonin concentration in the central nervous system, is a well-known adverse effect of serotonin-active medications. The concomitant use of antidepressant drugs associated with lithium as a co-adjuvant seems to increase the risk of this adverse reaction. We report a case of the serotonin syndrome during treatment with lithium and venlafaxine, an antidepressant with a dual selective re-uptake inhibition mechanism, and review the literature for similar cases. A 71-year-old woman developed serotonin syndrome while receiving treatment with moderate doses of lithium and venlafaxine for refractory depression. She had been taking higher doses of venlafaxine during the previous months with no significant secondary effects. Use of the Naranjo adverse drug reaction probability algorithm indicated a probable relationship between serotonin syndrome and treatment with lithium and venlafaxine.


[Sequence analysis of the CTL epitopes in transmembrane region of latent membrane protein 2 of Epstein-Barr virus derived from nasopharyngeal carcinoma cells].
Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC) cells expresses Epstein-Barr nuclear antigen 1 (EBNA1), latent membrane protein 1 (LMP1), and LMP2. LMP2 is an ideal target for immunotherapy because LMP2 mRNA is detected in 100% nasopharyngeal carcinoma cells and LMP2 protein shows stronger immunogenity than the rest 2 viral proteins. This study was to analyze the sequence of CTL epitopes in the transmembrane region of LMP2 to optimize LMP2-targeted immunotherapy. Genomic DNA was extracted from 20 biopsies of NPC and 3 biopsies of normal nasopharynx from Cantonese. The transmembrane region of LMP2 gene was amplified with hemi-nest polymerase chain reaction (PCR), and then sequenced directly. As compared with prototype B95.8 cells, the transmembrane region of LMP2 gene, derived from Cantonese NPC and normal nasopharynx tissues, had 14 base pair substitutions, resulting in 6 amino acid substitutions. Among these substitutions, 3 changed amino acids were located in 4 HLA-restricted CTL epitopes (SSC, TYG, CLG, and VMS). Among these polymorphisms, the VMS variation was first identified. The sequence changes of the LMP2 derived from NPC was the same as those of the LMP2 from normal nasopharynx, indicating that those variations were due to geographic-associated polymorphisms rather than NPC-associated mutations. Polymorphisms of LMP2 exist in EBV derived from Cantonese, resulting in 4 CTL epitope variations, which implicates that the effect of LMP2 polymorphisms should be considered when LMP2-targeted vaccine is designed for immunotherapy.


Genetic and transcriptional organization of the Bacillus subtilis spc-alpha region.
We used chromosomal walking methods to isolate a 10.8-kb region from the major ribosomal protein (r-protein) gene cluster of Bacillus subtilis (Bs). The gene order in this region, given by gene product, was r-proteins L16-L29-S17-L14-L24-L5-S14-S8-L6-L18-S5-L30-L15-SecY-adenylate kinase (Adk)-methionine aminopeptidase (Map)-initiation factor 1 (IF1)-L36-S13-S11-alpha subunit of RNA polymerase-L17. The region cloned, therefore, contains the homologues for the last three genes of the Escherichia coli (Ec) S10 operon, together with entire spc and alpha operons. This Bs organization differs from the corresponding region in Ec by the inclusion of the genes encoding Adk, Map and IF1 between the genes encoding SecY and L36. Plasmid integration experiments indicated that all 22 genes comprise a single large transcriptional unit controlled from a major promoter which lies upstream from the gene encoding r-protein L16. Promoter probe experiments located lesser activities internal to this large transcriptional unit, the secY and map promoters. The secY promoter region (psecY) contained two activities, each principally functioning in the stationary growth phase when high protein export is required. Thus, the Bs S10-spc-alpha region differs from its Ec counterpart in both genetic and transcriptional organization. Given this difference in transcriptional organization, the mechanisms coordinating expression of the translational apparatus are also likely to differ between Ec and Bs.


Clinical and Neonatal Outcomes of Children Born After ICSI With or Without Surgically Acquired Sperm: A Retrospective Cohort Study.
The purpose of this study was to explore the effects of different methods of obtaining sperm for intracytoplasmic sperm injection (ICSI) cycles on the live birth rate (LBR) and neonatal outcomes. This was a single-center retrospective cohort study conducted from January 2016 to December 2019. A total of 3557 ICSI cycles were included in the analysis, including 540 cycles in the surgically acquired sperm group and 3017 cycles in the ejaculated sperm group. The main outcome measure was the LBR. The clinical pregnancy rate in the surgically acquired sperm group was 69.4%, which was significantly higher than the 59.7% clinical pregnancy rate in the ejaculated sperm group (P=0.01). The LBR of the surgically acquired sperm group was significantly higher than that of the ejaculated sperm group (63.1% vs. 51.2%, P<0.01). Similarly, the singleton LBR was also higher in the surgically acquired sperm group than in the ejaculated sperm group (45.4% vs. 39.2%, P=0.04). Due to differences in the baseline characteristics of the two groups, multiple logistic regression analysis was performed. After multiple logistic regression analysis, the different methods of obtaining sperm were independent risk factors influencing the clinical pregnancy rate (adjusted odds ratio (AOR)=0.73, 95% confidence (CI)=0.56-0.95, P=0.02) and LBR (AOR=0.69, 95% CI=0.54-0.89, P=0.01). The preterm birth rate (AOR=1.42, 95% CI=0.62-3.25, P=0.41) and the incidence of low birth weight (AOR=1.03, 95% CI=0.45-2.34, P=0.95), small for gestational age (AOR=0.81, 95% CI=0.39-1.68, P=0.57), macrosomia (AOR=0.88, 95% CI=0.47-1.66, P=0.70) and large for gestational age (AOR=1.08, 95% CI=0.65-1.82, P=0.76) were not affected by the different methods. The clinical pregnancy rate and LBR of the surgically acquired sperm group were higher than those of the ejaculated sperm group. There was no significant difference between the neonatal outcomes of the two groups.


Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity.
Growth hormone secretagogues (GHSs) stimulate GH secretion and food intake. GHS receptor (GHS-R) mRNA has been identified mainly in the arcuate nucleus (Arc) and ventromedial nucleus of the hypothalamus and in the pituitary. Ghrelin, an endogenous ligand for GHS-R, has recently been purified from rat stomach. Although ghrelin is also expressed in the hypothalamus, the physiological significance of the ghrelin/GHS-R system is still unknown. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase (TH), thus selectively attenuating GHS-R protein expression in the Arc. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma insulin-like growth factor-I levels were reduced in female Tg rats. These results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity.


Fatigue in healthy and diseased individuals.
Although fatigue is experienced by everyone, its definition and classification remains under debate. A review of the previously published data on fatigue. Fatigue is influenced by age, gender, physical condition, type of food, latency to last meal, mental status, psychological conditions, personality type, life experience, and the health status of an individual. Fatigue may not only be a symptom but also a measurable and quantifiable dimension, also known as fatigability. Additionally, it may be classified as a condition occurring at rest or under exercise or stress, as physiologic reaction or pathologic condition, as spontaneous phenomenon or triggerable state, as resistant or irresistant to preconditioning, training, or attitude, as prominent or collateral experience, and as accessible or inaccessible to any type of treatment or intervention. Fatigue may be the sole symptom of a disease or one among others. It may be also classified as acute or chronic. Quantification of fatigability is achievable by fatigue scores, force measurement, electromyography, or other means. Fatigue and fatigability need to be delineated from conditions such as sleepiness, apathy, exhaustion, exercise intolerance, lack of vigor, weakness, inertia, or tiredness. Among neurological disorders, the prevalence of fatigue is particularly increased in multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, traumatic brain injury, stroke, and bleeding and also in neuromuscular disorders. Fatigue may be influenced by training, mental preconditioning, or drugs. Fatigue needs to be recognized as an important condition that is not only a symptom but may also be quantified and can be modified by various measures depending on the underlying cause.


Sequence-independent recognition of the amyloid structural motif by GFP protein family.
Cnidarian fluorescent protein (FP) derivatives such as GFP, mCherry, and mEOS2 have been widely used to monitor gene expression and protein localization through biological imaging because they are considered functionally inert. We demonstrate that FPs specifically bind amyloid fibrils formed from many natural peptides and proteins. FPs do not bind other nonamyloid fibrillar structures such as microtubules or actin filaments and do not bind to amorphous aggregates. FPs can also bind small aggregates formed during the lag phase and early elongation phase of fibril formation and can inhibit amyloid fibril formation in a dose-dependent manner. These findings suggest caution should be taken in interpreting FP-fusion protein localization data when amyloid structures may be present. Given the pathological significance of amyloid-related species in some diseases, detection and inhibition of amyloid fibril formation using FPs can provide insights on developing diagnostic tools.


Interactions between nitric oxide and angiotensin II on renal cortical and papillary blood flow.
This study examined the role of angiotensin II (Ang II) on the effects of nitric oxide (NO) synthesis blockade on renal cortical and papillary blood flow in innervated and denervated kidneys of volume-expanded Munich-Wistar rats with hormonal influences on the kidney that were held constant by intravenous infusion. Cortical (CBF) and papillary (PBF) blood flow were measured by laser-Doppler flowmetry. A low dose of N omega-nitro-L-arginine methyl ester (L-NAME, 3.7 nmol x kg[-1] x min[-1]) reduced CBF only in innervated kidneys, and this effect was abolished by subsequent administration of valsartan (an AT1 antagonist). L-NAME 3.7 nmol x kg(-1) x min(-1) improved PBF autoregulation by lowering PBF to the range of 100 to 140 mm Hg of perfusion pressure, and this effect was attenuated or abolished by valsartan in innervated and denervated kidneys, respectively. These results indicate that the cortical and medullary vasoconstriction induced by a low dose of L-NAME are caused by potentiation of the vasoconstrictor influence of renal sympathetic nerves and Ang II. A higher dose of L-NAME (37 nmol x kg[-1] x min[-1]) lowered CBF and PBF in both innervated and denervated kidneys. This effect of L-NAME on the cortical circulation was abolished by valsartan, but this AT1 antagonist had no effect on the medullary vasoconstriction produced by NO synthesis blockade. Therefore, a higher dose of L-NAME induces a renal cortical vasoconstriction through potentiation of the renin-angiotensin system, whereas the fall of PBF seen after L-NAME 37 nmol x kg(-1) x min(-1) seems to be caused primarily by NO suppression. This Ang II potentiation produced by L-NAME in the renal cortex seems to be mediated by AT1 receptors, because it was unaffected by PD123319 (an AT2 antagonist). The results of the present study indicate that NO is an important modulator of the vasoconstrictor influence of Ang II in the renal cortical circulation of the rat. However, although there are some interactions between NO and renal nerves and Ang II on the medullary circulation, the renal medullary vasoconstriction produced by L-NAME appears to be caused primarily by NO suppression, with little influence of the renal vasoconstrictor systems.


IgG4-related sclerosing mastitis: description of a new member of the IgG4-related sclerosing diseases.
Immunoglobulin G (IgG)4-related sclerosing disease is a recently described syndrome characterized by mass-forming lesions in various organs due to dense lymphoplasmacytic infiltrates and stromal sclerosis, elevated serum IgG4 titer, increased tissue IgG4 plasma cells, and favorable clinical outcome. We describe 4 patients with IgG4-related sclerosing mastitis, which represents a new member of this family of diseases. All patients were female with a mean age of 47.5 years, presenting with painless masses in 1 or both breasts. One patient had concurrent IgG4-related lymphadenopathy, and another had eyelid swelling of undetermined cause. The serum IgG4 titer was elevated in 1 tested patient, and circulating autoantibodies were found in 3 tested patients. All patients were well with no recurrence after excision or biopsy of the mass. Histologically, the breast masses featured dense lymphoplasmacytic infiltrates, prominent stromal sclerosis and loss of breast lobules. Phlebitis was present in 1 case. IgG4 cells ranged from 272 to 495 per high-power field, constituting 49% to 85% of all IgG cells. IgG4 cells were scarce in 9 of 9 cases of lymphocytic mastitis and 6 of 7 cases of granulomatous mastitis studied as controls. In summary, IgG4-related sclerosing mastitis appears to be a distinctive form of mastitis, sometimes accompanied by other components of IgG4-related sclerosing disease, and shows a favorable clinical outcome.


Preoperative assessment and intraoperative care planning.
We interviewed ten theatre nurses about their contribution to patient care. Their assessment strategy usually involved meeting patients on arrival in the department and did not include accessing the Trust's preoperative assessment document. In this paper we discuss the nursing assessment of surgical patients in the context of the nursing process as it was described in our research interviews.


Dynamic response of adhesion complexes: beyond the single-path picture.
We analyze the response of molecular adhesion complexes to increasing pulling forces (dynamic force spectroscopy) when dissociation can occur along either one of two alternative trajectories in the underlying multidimensional energy landscape. A great diversity of behaviors (e.g., nonmonotonicity) is found for the unbinding force and time as a function of the rate at which the pulling force is increased. In particular we identify a class of "harpoon" stickers that bind easily but resist strong pulling efficiently. Using existing data, we also demonstrate the consequent difficulty of unambiguously determining the features of the energy landscape from such single-molecule pulling experiments.


The design and implementation of early childhood intervention programs: informing efforts to address risk and promote resilience.
With the goal of narrowing disparities in children's school success, a growing number of innovative early childhood interventions have been launched. As these interventions begin to show evidence of enhancing children's development, it is important that we understand the design of these interventions and their implementation. This themed issue of the Journal of Prevention and Intervention in the Community includes four articles that each highlight a different early childhood intervention program, and a fifth article that provides a commentary on the main set of articles, from a community perspective. The first article focuses on children with autism spectrum disorders (ASD) and a program that sought to integrate children with ASD into public schools. The next two articles center on children from low-income families, with a focus on preschool classrooms. The last article discusses a program that aimed to foster young children's school readiness as well as families' readiness for children's transition to school.


["Osteobiol" and other bone graft materials used in Hungary].
In the first part of a series of publications in connection with different bone graft materials we review the literature by hungarian authors in the topic. In the last 10 years (2001-2011) 12 articles were published in the Fogorvosi Szemle and 11 articles in other Hungarian journals. 34 articles were published by Hungarian authors in foreign journals. These articles present results with autologous bone, bovine xenografts and synthetic bone graft materials. The literature concludes that beta-tricalcium phosphate and all previously mentioned materials present satisfactory results in bone augmentation procedures. Based on histological and histomorphometrical analysis in the case of large bony defects (large cysts, sinus elevation) the use of beta-tricalcium phosphate ensures better long term results in terms of "rebuilding" of the bone. We present a bone graft material new in Hungary: "Osteobiol", which differs from other bone graft materials in the sense it is a mixture of porcine bone and collagen. The authors summerize the material science of different bone graft materials including "Osteobiol".


Retinal laser irradiation diameter estimation.
Eyes of rhesus monkeys were exposed to argon and helium-neon laser radiation, and the resulting image diameters produced were estimated using microphotometer scans of pictures taken. Grids of known dimension were projected onto the retina, and photographs referenced to the optic disk were used to check the results. The eyes were then enucleated, and gross sections were used to measure accurately the optic disk. Relative measurements of image diameters were converted into the corresponding absolute values The use of grids projected onto the retina and referenced to the optic disk was found to be a good first approximation of the retinal image diameter. The focal length of the rhesus monkey eye was estimated from the retinal image diameter and external laser beam characteristics.


Design and synthesis of substrate and intermediate analogue inhibitors of S-ribosylhomocysteinase.
S-Ribosylhomocysteinase (LuxS) catalyzes the cleavage of the thioether linkage in S-ribosylhomocysteine (SRH) to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione, the precursor of autoinducer 2. Inhibitors of LuxS should interfere with bacterial interspecies communication and potentially provide a novel class of antibacterial agents. LuxS utilizes a divalent metal ion as a Lewis acid during catalysis. In this work, a series of structural analogues of the substrate SRH and a 2-ketone intermediate were designed and synthesized. Kinetic studies indicate that the compounds act as reversible, competitive inhibitors against LuxS, with the most potent inhibitors having K(I) values in the submicromolar range. These represent the most potent LuxS inhibitors that have been reported to date. Cocrystal structures of LuxS bound with two of the inhibitors largely confirmed the design principles, i.e., the importance of both the homocysteine and ribose moieties in high-affinity binding to the LuxS active site.


Risk of Fracture Among Older Adults With Primary Hyperparathyroidism Receiving Parathyroidectomy vs Nonoperative Management.
Primary hyperparathyroidism (PHPT) contributes to the development and progression of osteoporosis in older adults. The effectiveness of parathyroidectomy for reducing fracture risk in older adults is unknown. To compare the incidence of clinical fracture among older adults with PHPT treated with parathyroidectomy vs nonoperative management. This was a population-based, longitudinal cohort study of all Medicare beneficiaries with PHPT from 2006 to 2017. Multivariable, inverse probability weighted Cox proportional hazards and Fine-Gray competing risk regression models were constructed to determine the association of parathyroidectomy vs nonoperative management with incident fracture. Data analysis was conducted from February 17, 2021, to September 14, 2021. The primary outcome was clinical fracture at any anatomic site not associated with major trauma during the follow-up period. Among the 210 206 Medicare beneficiaries with PHPT (mean [SD] age, 75 [6.8] years; 165 637 [78.8%] women; 183 433 [87.3%] White individuals), 63 136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis, and 147 070 (70.0%) were managed nonoperatively. During a mean (SD) follow-up period of 58.5 (35.5) months, the unadjusted incidence of fracture was 10.2% in patients treated with parathyroidectomy. During a mean (SD) follow-up of 52.5 (33.8) months, the unadjusted incidence of fracture was 13.7% in patients observed nonoperatively. On multivariable analysis, parathyroidectomy was associated with lower adjusted rates of any fracture (hazard ratio [HR], 0.78; 95% CI, 0.76-0.80]) and hip fracture (HR, 0.76; 95% CI, 0.72-0.79). At 2, 5, and 10 years, parathyroidectomy was associated with adjusted absolute fracture risk reduction of 1.2% (95% CI, 1.0-1.4), 2.8% (95% CI, 2.5-3.1), and 5.1% (95% CI, 4.6-5.5), respectively, compared with nonoperative management. On subgroup analysis, there were no significant differences in the association of parathyroidectomy with fracture risk by age group, sex, frailty, history of osteoporosis, or meeting operative guidelines. Fine-Gray competing risk regression confirmed parathyroidectomy was associated with a lower probability of any fracture and hip fracture when accounting for the competing risk of death (HR, 0.84; 95% CI, 0.82-0.85; and HR, 0.83; 95% CI, 0.80-0.85, respectively). This longitudinal cohort study found that parathyroidectomy was associated with a lower risk of any fracture and hip fracture among older adults with PHPT, suggesting a clinically meaningful benefit of operative management in this population.


Progesterone and Estrogen Receptors in Neurofibromas of Patients with NF1.
Neurofibromatosis type 1 (NF1) or von Recklinghausen disease is a genetic disorder affecting the growth of cells in nervous system. One of the most remarkable characteristics of this disease is the development of benign tumors of the nervous system (neurofibromas).The purpose of this study was to test tissue samples taken from neurofibromas and plexiform neurofibromas of NF1 patients for the presence of estrogen and progesterone receptors. We used previously collected samples from patients registered in the database of the Centro Nacional de Neurofibromatose (CNNF-Brazil). Samples from twenty-five patients in the database presenting plexiform neurofibromas (N1 group) and 25 samples from the same database from patients presenting neurofibromas (N2 group) were tested.We observed positive staining for progesterone receptors in 13 of the neurofibroma samples and 19 of the plexiform neurofibroma samples. Among the neurofibroma samples, we observed one sample with positive estrogen receptor staining, but none of the plexiform neurofibroma samples showed positive staining. We suggest further studies to investigate in greater depth possible hormonal influences on the development and growth of neurofibromas and plexiform neurofibromas in NF1.


Thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus. Effect of age, gender and HLA type.
Type 1 diabetes is often associated with additional autoimmune phenomena. However, data reported on the frequency of thyroid autoimmunity differ vastly. Therefore, the prevalence of thyroid autoantibodies was evaluated at a large pediatric diabetes center in Southern Germany. 2,305 determinations (TPO and TG, ELISA) were performed in 495 patients with type 1 diabetes (234 boys, 261 girls; age at last measurement: 15.4 +/- 0.3 years, duration of diabetes 7. 5 +/- 0.2 years). The prevalence of elevated thyroid antibodies increased dramatically with age: from 3.7% in patients less than 5 years of age up to 25.3% in the age group 15-20 years (p < 0.0001). For children older than 10 years, girls were significantly more affected than boys (p < 0.0001). Thyroid autoimmunity tended to be more prevalent in the subgroup of patients with the HLA type DR3/DR4 compared to patients with other HLA types (p = 0.08). In children older than 10 years, basal TSH concentrations were significantly elevated in antibody-positive patients (p < 0.05). In conclusion, thyroid autoimmunity is prevalent in children and adolescents with type 1 diabetes. Adolescent girls and young women are especially affected. Yearly routine determinations of thyroid antibodies are therefore recommended.


Novel Treatment Strategies for Primary Biliary Cholangitis.
Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13-16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging. Moreover, recent pilot studies evaluating several biological agents targeting immunity such as different monoclonal antibodies and other drugs that modulate cholestasis are under investigation, although with limited results at present.


Development of an SPR-based binding assay for characterization of anti-CD20 antibodies to CD20 expressed on extracellular vesicles.
Characterization of anti-CD20 antibody binding to CD20 is critical to development of anti-CD20 therapeutics. While SPR is widely used to characterize binding of therapeutics to their targets, its application to the characterization of anti-CD20 therapeutics has been limited by the challenges of obtaining recombinant or native full-length CD20 suitable for ligand binding assays. Extracellular vesicles (EVs) are nanoparticles naturally released from cells that provide a favorable microenvironment for membrane proteins such as CD20 to maintain proper conformation and activity. Here, we report a novel SPR-based assay that enables elucidation of binding kinetics and affinity measurements for anti-CD20 antibody binding to EV-expressed CD20. Our SPR assay is label-free, easy to perform, and demonstrates specific interaction of rituximab and obinutuzumab to CD20 expressed on EVs. The SPR assay revealed that rituximab and obinutuzumab have different binding kinetics and mechanisms to CD20 although both bind to CD20 with high affinity. Our results are consistent with existing literature and verified the validity of this method. The detailed binding kinetics information may also contribute to a better understanding of the interaction between these two antibodies and CD20. Moreover, our method provides a platform with which to characterize other therapeutic antibodies binding to EV-expressed membrane proteins.


Postradiation sarcomas of bone.
Fifty-nine patients with osteogenic sarcomas arising in bones following exposure to x rays and 20 patients with postradiation malignant fibrous histiocytomas of bone arising as a direct consequence of irradiation were studied. These represent 5.5% of all osteogenic sarcomas and 4.9% of all malignant fibrous histiocytomas of bones. The sarcomas may affect any skeletal site, but most commonly they arose in bones of the pelvic and shoulder girdles or the distal end of the femur. Grounds for irradiation were either nonosseous conditions or preexistent skeletal lesions. Reasons for incidental osseous irradiation included Hodgkin's disease, carcinoma of cervix, breast or lung; bilateral retinoblastoma and others, and giant cell tumor predominated among the irradiated skeletal lesions. The mean and the median radiation doses were 6,040 cGy (rad) and 5,700 cGy (rad), respectively. The period of latency between irradiation and the appearance of the bone sarcoma ranged from 3.5 to 47 y with a mean of 16.5 and median of 14.5, respectively. The cumulative disease-free survival rate for malignant fibrous histiocytoma patients at 3 y was 58%. The cumulative disease-free survival rate at 5 y for patients with osteogenic sarcoma was 17%, with a median survival estimate of 1 y. Although all patients with malignant fibrous histiocytoma who received their radiation therapy for a preexistent bone lesion survived, only 27% of the patients whose bone was normal at the time of irradiation are alive and well at the 3-y mark.


Transition state of the sulfuryl transfer reaction of estrogen sulfotransferase.
Kinetic isotope effects have been measured for the estrogen sulfotransferase-catalyzed sulfuryl (SO3) transfer from p-nitrophenyl sulfate to the 5'-phosphoryl group of 3'-phosphoadenosine 5'-phosphate. 18(V/K)nonbridge = 1.0016 +/- 0.0005, 18(V/K)bridge = 1.0280 +/- 0.0006, and 15(V/K) = 1.0014 +/- 0.0004. (15(V/K) refers to the nitro group in p-nitrophenyl sulfate). The kinetic isotope effects indicate substantial S O bond fission in the transition state, with partial charge neutralization of the leaving group. The small kinetic isotope effect in the nonbridging sulfuryl oxygen atoms suggests no significant change in bond orders of these atoms occurs, consistent with modest nucleophilic involvement. A comparison of the data for enzymatic and uncatalyzed sulfuryl transfer reactions suggests that both proceed through very similar transition states.


Low-Cost Flexible Glass-Based pH Sensor via Cold Atmospheric Plasma Deposition.
Many commercially available pH sensors are fabricated with a glass membrane as the sensing component because of several advantages of glass-based electrodes such as versatility, high accuracy, and excellent stability in various conditions. However, because of their bulkiness and poor mechanical properties, conventional glass-based sensors are not ideal for wearable or flexible applications. Here, we report for the first time the fabrication of a flexible glass-based pH sensor suitable for biomedical and environmental applications where flexibility and stability of the sensor are critical for long-term and real-time monitoring. The sensor was fabricated via a simple and facile approach using the cold atmospheric plasma technique in which a pH sensitive silica coating was deposited from a siloxane precursor onto a carbon electrode. In order to increase the sensitivity and stability of the sensor, we employed a postprocessing step which involves annealing of the silica coated electrode at elevated temperatures. This process was optimized to ensure that the crucial properties such as porosity and hydration functionality were balanced to obtain the best and most reliable sensitivity of the sensor. Our sensitivity test results indicated that these sensors exhibit excellent and stable sensitivity with a slope of about 48 mV/pH (r2 = 0.998) and selectivity across a pH range of 4 to 10 in the presence of various cations. The optimized sensor has shown stable sensitivity for a long period of time (30 h of immersion) and in different bending conditions. We demonstrate in this investigation that this flexible cost-effective pH sensor can withstand the sterilization process resulting from ultraviolet radiation and shows repeatable sensitivity with less than ±5 mV potential drift from the sensitivity values of the standard optimized sensor.


Characterization of the RNA Transcription Profile of Bombyx mori Bidensovirus.
Bombyx mori bidensovirus (BmBDV) is a single-stranded DNA (ssDNA) virus from the genus Bidensovirus of the Bidnaviridae family, which, thus far, solely infects insects. It has a unique genome that contains bipartite DNA molecules (VD1 and VD2). In this study, we explored the detailed transcription mapping of the complete BmBDV genome (VD1 and VD2) by rapid amplification of cDNA ends (RACE), reverse transcription quantitative real-time PCR (RT-qPCR), and luciferase assays. For the first time, we report the transcription map of VD2. Our mapping of the transcriptional start sites reveals that the NS genes in VD1 have separate transcripts that are derived from overlapping promoters, P5 and P5.5. Thus, our study provides a strategy for alternative promoter usage in the expression of BmBDV genes.


Neutrophil-to-lymphocyte ratio and scoring system for predicting coronary artery lesions of Kawasaki disease.
Kawasaki disease (KD) causes coronary artery lesions (CAL) and is the leading cause of acquired heart disease in children. The aim of this study is to evaluate the risk factors and set-up a scoring system for predicting CAL of KD. We retrospectively reviewed a total of 478 patients diagnosed with KD. We compared age, gender, laboratory data, and treatment response in two groups and developed a scoring system for predicting CAL. During the study period, 365 of these patients had complete medical records of coronary surveys by echocardiography. Anemia, hypoalbuminemia, C reactive protein (CRP), alanine aminotransferase, neutrophil count, and neutrophil/lymphocyte ratio (NLR) showed significant differences with CAL formation. We determined the cut-off value using a receiver-operating-characteristic (ROC) curve, and following multivariate logistic regression analysis, four independent risk factors demonstrated a significant difference with CAL formation, including CRP > 103 mg/L, NLR > 3.5, male gender, and intravenous immunoglobulin (IVIG) resistance. We established a score system based on the above evaluation, for which a ROC curve was performed, and a total score of ≥ 2 points showed a sensitivity of 60.8% and a specificity of 70.6%, with an area under the ROC curve of 0.696. Identifying children at risk is important in order to prevent CAL from developing. Four independent risk factors that can predict CAL formation were CRP > 103 mg/L, NLR > 3.5, male gender, and IVIG resistance. This first report incorporated NLR into score systems to predict CAL reinforces previously well-known risk factors for the CAL formation among KD patients.


Muscle Ultrasound and Sarcopenia in Older Individuals: A Clinical Perspective.
A precise quantitative measurement of skeletal muscle mass is fundamental for diagnosing sarcopenia in older individuals. The current techniques of assessment, including dual-energy x-ray absorptiometry (DXA), bioimpedance analysis (BIA), and magnetic resonance imaging (MRI) are either difficult to perform in everyday clinical practice or biased by concurrent clinical confounders. B-mode muscle ultrasound can be helpful in assessing muscle mass and architecture, and thus possibly useful for diagnosing or screening sarcopenia. A literature search of published articles on muscle ultrasound and sarcopenia in older individuals as of July 31, 2016, was made on PubMed and Scopus. Manual search and cross-referencing from reviews and original articles was also performed. Most of the existing studies were carried out on healthy well-fit subjects, with a low prevalence of sarcopenia. The main parameters that can be assessed through muscle ultrasound are muscle thickness, cross-sectional area, echo intensity, and, for pennate muscles, fascicle length and pennation angle. In older subjects, all these parameters show some degree of alteration compared to young adults, particularly in lower limb muscles with antigravitary function, such as the quadriceps femoris and gastrocnemius medialis. Each of these parameters may be theoretically useful for detecting the loss of muscle mass and functionality in geriatric patients. They are also poorly influenced by the presence of acute and chronic diseases and fluid balance, unlike DXA and BIA, but a high degree of standardization in ultrasound protocols is necessary. Frontier applications of ultrasound in the assessment of sarcopenia may include contrast-enhanced and diaphragm ultrasound. The current literature does not allow to make conclusive recommendations about the use of muscle ultrasound in geriatric practice. However, this technique is very promising, and further studies should validate its applications in the context of sarcopenia assessment.


Immunologically activated chloride channels involved in degranulation of rat mucosal mast cells.
Crosslinking of type I Fc epsilon receptors (Fc epsilon RI) on the surface of basophils or mast cells initiates a cascade of processes leading to the secretion of inflammatory mediators. We report here a correlation between mediator secretion and the activation of Cl- channels in rat mucosal-type mast cells (line RBL-2H3). Stimulation of RBL cells by either IgE and antigen or by a monoclonal antibody specific for the Fc epsilon RI, resulted in the activation of Cl- ion channels as detected by the patch-clamp technique. Channel activation occurred slowly, within minutes after stimulation. The channel has a slope conductance of 32 pS at potentials between 0 and -100 mV, and an increasing open-state probability with increasing depolarization. Activation of apparently the same Cl- channels could be mimicked without stimulation by isolating inside-out membrane patches in tyrode solution. Parallel inhibition of both Cl- channel activity and mediator secretion, as monitored by serotonin release, was observed by two compounds, the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and the anti-allergic drug cromolyn. NPPB inhibited both the antigen-induced Cl- current and the serotonin release, where half-maximal inhibition occurred at similar doses, at 52 microM and 77 microM, respectively. The drug cromolyn, recently found to inhibit immunologically induced mediator secretion from RBL cells upon intracellular application, also blocks Cl- channels (IC50 = 15 microM) when applied to the cytoplasmic side of an inside-out membrane patch. The observed Cl- channel activation upon immunological stimulation and the parallel inhibition of channel current and of serotonin release suggests a functional role for this Cl- channel in mediator secretion from the mast cells studied.


Long-term alterations of cytokines and growth factors expression in irradiated tissues and relation with histological severity scoring.
Beside its efficacy in cancer treatment, radiotherapy induces degeneration of healthy tissues within the irradiated area. The aim of this study was to analyze the variations of proinflammatory (IL-1α, IL-2, IL-6, TNF-α, IFN-γ), profibrotic (TGF-β1), proangiogneic (VEGF) and stem cell mobilizing (GM-CSF) cytokines and growth factors in an animal model of radiation-induced tissue degeneration. 24 rats were irradiated unilaterally on the hindlimb at a monodose of 30 Gy. Six weeks (n=8), 6 months (n=8) and 1 year (n=8) after irradiation the mediators expression in skin and muscle were analyzed using Western blot and the Bio-Plex® protein array (BPA) technology. Additional histological severity for fibrosis, inflammation, vascularity and cellularity alterations scoring was defined from histology and immnunohistochemistry analyses. A significant increase of histological severity scoring was found in irradiated tissue. Skin tissues were more radio-sensitive than muscle. A high level of TGF-β1 expression was found throughout the study and a significant relation was evidenced between TGF-β1 expression and fibrosis scoring. Irradiated tissue showed a chronic inflammation (IL-2 and TNF-α significantly increased). Moreover a persistent expression of GM-CSF and VEGF was found in all irradiated tissues. The vascular score was related to TGF-β1 expression and the cellular alterations score was significantly related with the level of IL-2, VEGF and GM-CSF. The results achieved in the present study underline the complexity and multiplicity of radio-induced alterations of cytokine network. It offers many perspectives of development, for the comprehension of the mechanisms of late injuries or for the histological and molecular evaluation of the mode of action and the efficacy of rehabilitation techniques.


Time-resolved mechanism of extracellular gate opening and substrate binding in a glutamate transporter.
Glutamate transporters, also referred to as excitatory amino acid transporters (EAATs), are membrane proteins that regulate glutamatergic signal transmission by clearing excess glutamate after its release at synapses. A structure-based understanding of their molecular mechanisms of function has been elusive until the recent determination of the x-ray structure of an archaeal transporter, Glt(Ph). Glt(Ph) exists as a trimer, with each subunit containing a core region that mediates substrate translocation. In the present study a series of molecular dynamics simulations have been conducted and analyzed in light of new experimental data on substrate binding properties of EAATs. The simulations provide for the first time a full atomic description of the time-resolved events that drive the recognition and binding of substrate. The core region of each subunit exhibits an intrinsic tendency to open the helical hairpin HP2 loop, the extracellular gate, within tens of nanoseconds exposing conserved polar residues that serve as attractors for substrate binding. The NMDGT motif on the partially unwound part of the transmembrane helix TM7 and the residues Asp-390 and Asp-394 on TM8 are also distinguished by their important role in substrate binding and close interaction with mediating water molecules and/or sodium ions. The simulations reveal a Na+ binding site comprised in part of Leu-303 on TM7 and Asp-405 on TM8 and support a role for sodium ions in stabilizing substrate-bound conformers. The functional importance of Leu-303 or its counterpart Leu-391 in human EAAT1 (hEAAT1) is confirmed by site-directed mutagenesis and Na+ dependence assays conducted with hEAAT1 mutants L391C and L391A.


Catalytic reduction of dinitrogen to ammonia using molybdenum porphyrin complexes.
Porphyrin complexes are well-known in O2 and CO2 reduction, but their application to N2 reduction is less developed. Here, we show that oxo and nitrido complexes of molybdenum supported by tetramesitylporphyrin (TMP) are effective precatalysts for catalytic N2 reduction to ammonia, verified by 15N2 labeling studies and other control experiments. Spectroscopic and electrochemical studies illuminate some relevant thermodynamic parameters, including the N-H bond dissociation free energy of (TMP)MoNH (43 ± 2 kcal mol-1). We place these results in the context of other work on homogeneous N2 reduction catalysis.


Parole terms for a killer: directing caspase3/CAD induced DNA strand breaks to coordinate changes in gene expression.
In a series of discoveries over the preceding decade, a number of laboratories have unequivocally established that apoptotic proteins and pathways are well conserved cell fate determinants, which act independent of a cell death response. Within this context, the role for apoptotic proteins in the induction of cell differentiation has been widely documented. Despite these discoveries, little information has been forthcoming regarding a conserved mechanism by which apoptotic proteins achieve this non-death outcome. In the following discussion, we will explore the premise that the penultimate step in apoptosis, genome wide DNA damage/strand breaks act as a conserved genomic reprogramming event necessary for cell differentiation (Larsen et al. Proc Natl Acad Sci USA 2010; 107:4230-5). Moreover, we hypothesis that directed DNA damage, as mediated by known apoptotic proteins, may participate in numerous forms of regulated gene expression.


Biomedical soft robots: current status and perspective.
This paper reviews the current status of soft robots in biomedical field. Soft robots are made of materials that have comparable modulus of elasticity to that of biological systems. Several advantages of soft robots over rigid robots are safe human interaction, ease of adaptation with wearable electronics and simpler gripping. We review design factors of soft robots including modeling, controls, actuation, fabrication and application, as well as their limitations and future work. For modeling, we survey kinematic, multibody and numerical finite element methods. Finite element methods are better suited for the analysis of soft robots, since they can accurately model nonlinearities in geometry and materials. However, their real-time integration with controls is challenging. We categorize the controls of soft robots as model-based and model-free. Model-free controllers do not rely on an explicit analytical or numerical model of the soft robot to perform actuation. Actuation is the ability to exert a force using actuators such as shape memory alloys, fluid gels, elastomers and piezoelectrics. Nonlinear geometry and materials of soft robots restrict using conventional rigid body controls. The fabrication techniques used for soft robots differ significantly from that of rigid robots. We survey a wide range of techniques used for fabrication of soft robots from simple molding to more advanced additive manufacturing methods such as 3D printing. We discuss the applications and limitations of biomedical soft robots covering aspects such as functionality, ease of use and cost. The paper concludes with the future discoveries in the emerging field of soft robots.


Chronic pain, stress, and the dynamics of affective differentiation.
We describe a program of research examining how the relationship between positive and negative affect varies both between individuals and within individuals over time. This Dynamic Model of Affect (DMA) proposes that under conditions that promote maximal information processing, positive and negative affective systems function relatively independently. In contrast, under conditions characterized by uncertainty, including pain and stress, the affects become strongly inversely related. Included in our consideration are potential individual differences in the ability to sustain affective differentiation during pain and other stressors and the implications of this model for perceptions of social relations and for interventions to improve well-being among the chronically ill.


Rapid increase in deep supercooling of xylem parenchyma.
Malus pumila Mill. twigs were collected from September through December and stored at 5 degrees C until the low temperature exotherms of the xylem were determined by differential thermal analysis. During the differential thermal analysis, cooling was interrupted, and temperatures of 5 to -18 degrees C were held for 0.4 to 10 hours before cooling to -50 degrees C was resumed. Control twigs were cooled to -50 degrees C without interruption. Holding the twigs at 1.3 to -5 degrees C shifted the start of the low temperature exotherm from about -20 to -30 degrees C. Slightly higher (2.6 degrees C) and lower (-10 degrees C) temperatures were occasionally effective. The shift began within 20 to 30 minutes and increased progressively to 150 minutes. The acclimation was reversibly inhibited by N(2) atmosphere.


Sterilization in Thailand.
Sterilization in Thailand began in the 40ies but the slow progress was due to lack of government support. In 1970 the government declared the population policy that resulted in the development of the tubal resection and vasectomy programs in the governmental hospitals and private sectors. The current total number of sterilizations reaches 200,000 cases annually with female to male ratio of 4:1. Contributions by the government and the private sectors are 80% and 20% respectively. The university hospitals have been involved in programme planning and various studies on sterilization acceptance and development of appropriate technology and delivery system. Sterilization service has been directed to the rural areas where 80% of the Thais live. All efforts are directed towards an objective to reduce the population growth to 1.2 by the end of 1990.


Organization of chemotherapeutic preparations in advance: Do we save or waste money?
The development of oncology day-hospital activities contributes to increase quality of life of patients and consequently have changed their perception about waiting. The extemporaneous preparation of antineoplastic has become difficult to achieve given the increasing activity, and hospital pharmacists have taken up the challenge by the implementation of the antineoplastic preparation in anticipation. Because anticipation can lead to an important number of preparations to be discarded, we also develop a recycled process for other patients to limit these waste extra costs. We aim to demonstrate the positive balance of anticipated preparation in this 4-year study report.Data sources: This prospective study was conducted in a major European oncology day-hospital from January, 2012 to December, 2015. The data were extracted from our software WinSimbad™ and updated as needed. The number and cost-associated of preparation ungiven chemotherapy doses (recycled or discarded) were compared to the global drug budget of our hospital in order to not exceed 2%.Data summary: 303,100 antineoplastic have been prepared. Approximately 35% of them were anticipated with an average of 5,431±984 that were finally ungiven. Two-third was recycled and the cost of the ungiven preparations finally discarded represents 1.7±0.15% of the global drug budget. This study assesses the drug wastage and its associated cost of this concept through a prospective study and discusses the cost of ungiven antineoplastic preparations. With prior consideration of the need to define the acceptable rate of discarded ungiven preparation, the hospitals with an high oncology day-hospital activity should implement this approach.


[Development of internet addiction measurement scales and Korean internet addiction index].
To develop measurement scales of Internet addiction, and propose a Korean Internet Addiction Index (K-IAI) and classification criteria for Internet addiction from the threshold scores developed. The identification of the concept of "Internet addiction" was based on the literature review. To select the scales, an exploratory factor analysis was applied. A construct validation was tested by a confirmatory factor analysis (CFA) with a structured equation model (SEM). In testing the validity of the classification criteria, ANOVA and non-recursive models with SEM were applied. Out of 1,080 questionnaires distributed, 1,037 were returned,; a response rate of 96%. The Cronbach-alpha of all items was over 0.75. Using an exploratory factor analysis in the condition of a 6 factor constrain as the study model proposed, 23 of the initial 28 items were identified. In testing the discriminant and convergent validity of the selected 23 scales using CFA with SEM, the Internet addiction model explained about 93% of all variances of the data collected, and all the latent variables significantly explained the designated scales. A K-IAI was proposed using the T-scores of the sum of all factor averages. In the classification of users, the basic concept was a two-standard deviation approach of the K-IAI as the criteria of MMPI. The addiction group had a score > or =70 in the K-IAI, the pre-addiction group between > or =50 and <70, and the average user group <50. The Internet use times of the classified groups were statistically different in the ANOVA and multiple comparisons. The K-IAI is a reliable and valid instrument for measuring Internet addiction. Moreover, the taxonomy of the groups was also verified using various methods.


A comparison of multiple imputation and fully augmented weighted estimators for Cox regression with missing covariates.
Several approaches exist for handling missing covariates in the Cox proportional hazards model. The multiple imputation (MI) is relatively easy to implement with various software available and results in consistent estimates if the imputation model is correct. On the other hand, the fully augmented weighted estimators (FAWEs) recover a substantial proportion of the efficiency and have the doubly robust property. In this paper, we compare the FAWEs and the MI through a comprehensive simulation study. For the MI, we consider the multiple imputation by chained equation and focus on two imputation methods: Bayesian linear regression imputation and predictive mean matching. Simulation results show that the imputation methods can be rather sensitive to model misspecification and may have large bias when the censoring time depends on the missing covariates. In contrast, the FAWEs allow the censoring time to depend on the missing covariates and are remarkably robust as long as getting either the conditional expectations or the selection probability correct due to the doubly robust property. The comparison suggests that the FAWEs show the potential for being a competitive and attractive tool for tackling the analysis of survival data with missing covariates.


Increased perinatal intracranial pressure and prediction of early puberty in girls with myelomeningocele.
An increased risk of developing precocious puberty has been reported in children with myelomeningocele. In order to evaluate this further and to study factors associated with early or precocious puberty the medical records of all girls with myelomeningocele, born from 1970 onwards (n = 64), who were admitted to our unit were reviewed. Early/precocious puberty (E/PP) was defined as breast development or pubic hair corresponding to Tanner stage 2 before the age of 9.2 years. In 32 out of 62 cases data were sufficient for evaluation of the timing of puberty. Twenty girls had E/PP and 12 girls normal timing of puberty. In the girls who had reached the age of 9.2 years the incidence of E/PP was at least 52%. Girls with E/PP had a higher incidence of hydrocephalus, were treated with intraventricular shunts more often, and had significantly higher frequency of increased intracranial pressure during the perinatal period (p < 0.05, p < 0.01, and p < 0.001, respectively). The group of girls developing E/PP was also more severely disabled with respect to motor and urological function and had more shunt revisions. In conclusion, E/PP in girls with myelomeningocele is strongly associated with increased intracranial pressure particularly during the perinatal period.


The roles of sodium channels in nociception: Implications for mechanisms of pain.
Understanding the role of voltage-gated sodium channels in nociception may provide important insights into pain mechanisms. Voltage-gated sodium channels are critically important for electrogenesis and nerve impulse conduction, and a target for important clinically relevant analgesics such as lidocaine. Furthermore, within the last decade studies have shown that certain sodium channel isoforms are predominantly expressed in peripheral sensory neurons associated with pain sensation, and that the expression and functional properties of voltage-gated sodium channels in peripheral sensory neurons can be dynamically regulated following axonal injury or peripheral inflammation. These data suggest that specific voltage-gated sodium channels may play crucial roles in nociception. Experiments with transgenic mice lines have clearly implicated Na(v)1.7, Na(v)1.8 and Na(v)1.9 in inflammatory, and possibly neuropathic, pain. However the most convincing and perhaps most exciting results regarding the role of voltage-gated sodium channels have come out recently from studies on human inherited disorders of nociception. Point mutations in Na(v)1.7 have been identified in patients with two distinct autosomal dominant severe chronic pain syndromes. Electrophysiological experiments indicate that these pain-associated mutations cause small yet significant changes in the gating properties of voltage-gated sodium channels that are likely to contribute substantially to the development of chronic pain. Equally exciting, recent studies indicate that recessive mutations in Na(v)1.7 that eliminate functional current can result in an apparent complete, and possibly specific, indifference to pain in humans, suggesting that isoform specific blockers could be very effective in treating pain. In this review we will examine what is known about the roles of voltage-gated sodium channels in nociception.


The effect of cyclophosphamide with and without dexamethasone on cytochrome P450 3A4 and 2B6 in human hepatocytes.
The purpose of this study was to characterize the concentration-response effects of cyclophosphamide (CPA) with and without dexamethasone (DEX; 10 microM) on the expression of CYP3A4 and CYP2B6 in cultured human hepatocytes at concentrations representative of standard- and high-dose CPA therapy (25 to 750 microM). CPA produced concentration-dependent increases in CYP3A4 and CYP2B6 activity and immunoreactive protein that peaked at 250 and 125 microM, respectively, and declined thereafter. The inductive effect of CPA alone and in combination with DEX was greater in magnitude for CYP2B6 compared with CYP3A4. To further examine the inductive effect of CPA on CYP3A4, CPA (250 microM) and DEX (10 microM) alone and in combination were examined in 10 hepatocyte preparations. The combination of CPA and DEX yielded higher rates of 6beta-hydroxytestosterone formation than either agent alone. However, the effect was less than additive in human hepatocyte cultures with relatively high baseline CYP3A4 activity and additive or synergistic in human hepatocyte cultures with relatively low baseline CYP3A4 activity. Induction index was highly correlated with CYP3A4 baseline activity for both CPA (r(2) = 0.75) and CPA plus DEX (r(2) = 0.85). To investigate the potential mechanism for CPA-induced increases in CYP3A4 activity, the ability of CPA alone and in combination with DEX to activate pregnane X receptor (PXR) was explored using transient transfection assays. CPA produced a dose-dependent increase in PXR activation that was maximal at the highest CPA concentration studied (500 microM). The addition of DEX to CPA resulted in a minor increase in PXR activation compared with CPA alone. These results indicate that CPA alone and in combination with DEX differentially induces the expression of CYP3A4 and 2B in a concentration-dependent manner, which may be mediated partially through activation of PXR. The impact of these effects on the efficacy and toxicity of CPA therapy warrants further investigation.


Intentional injury--homicide as a public health problem.
This article is an epidemiological analysis of Baltimore homicides between 1986 and 1990. The main findings were that young African-American males between 15 and 34 years of age are at greatest risk of homicide victimization. Homicidal events primarily occurred with handguns, in drug-related circumstances, between acquaintances, and in the western police district area. Questions are raised concerning the expansion of the public health professional's role and the use of epidemiologic data for injury prevention programs. This article is the result of a grant from the Centers for Disease Control and Prevention, Division of Injury Control, to the state of Maryland, Department of Health and Mental Hygiene, and the Baltimore City Health Department.


In vitro evaluation of intravascular stent artifacts in three-dimensional MR angiography.
To evaluate the intraluminal signal characteristics of various stents and stent-grafts in contrast-enhanced three-dimensional MR angiography (3D MRA) in vitro. Fourteen stents made of different materials (steel, nitinol, tantalum, cobalt-based alloy, polyethylene) and six stent-grafts were implanted in plastic tubes simulating the common iliac artery. The tubes were filled with gadopentetate dimeglumine in water at a concentration of 25 mmol/L and positioned in a plastic container filled with water. For imaging, the container was placed in the center of the magnet, parallel, orthogonal, and diagonal to the z axis. A 3D gradient-echo sequence (T1-FFE) was acquired with the following parameters: repetition time 5.3 ms, echo time 1.6 ms, flip angle 50 degrees, slice thickness 1.5 mm, and acquisition matrix 256 with zero filling to 512. To evaluate the influence of the frequency-encoding gradient on the appearance of the artifacts, stents were examined with their axes oriented in all three directions both with the frequency-encoding gradient in the feet-head and right-left directions. The size and pattern of stent-related artifacts were evaluated semiquantitatively for each measurement. Five different components of artifacts could be distinguished: homogeneous signal reduction inside the stent, narrowing of the stent lumen, structures of various shapes inside the stents, signal reduction or signal increase at the ends of the stents, and shift of the intraluminal signal orthogonal to the longitudinal axis of the vessel. The size of the artifacts depended heavily on the material of the stent. The polyethylene stent showed no artifacts, the tantalum stent only minor artifacts. Nitinol stents were characterized by artifacts at both ends and signal reduction intraluminally. Stents made of steel demonstrated the strongest artifacts, characterized by almost complete signal loss intraluminally. The characteristics of the artifacts of all stents depended on the direction of the stent relative to the frequency-encoding gradient. Three-dimensional MRA follow-up after stent placement may be applicable for stent patency evaluation in all instances. However, grading of stenoses seems to be unrealistic in steel stents and in most nitinol stents.


Discovery of new rheumatoid arthritis biomarkers using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry ProteinChip approach.
To identify serum protein biomarkers specific for rheumatoid arthritis (RA), using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology. A total of 103 serum samples from patients and healthy controls were analyzed. Thirty-four of the patients had a diagnosis of RA, based on the American College of Rheumatology criteria. The inflammation control group comprised 20 patients with psoriatic arthritis (PsA), 9 with asthma, and 10 with Crohn's disease. The noninflammation control group comprised 14 patients with knee osteoarthritis and 16 healthy control subjects. Serum protein profiles were obtained by SELDI-TOF-MS and compared in order to identify new biomarkers specific for RA. Data were analyzed by a machine learning algorithm called decision tree boosting, according to different preprocessing steps. The most discriminative mass/charge (m/z) values serving as potential biomarkers for RA were identified on arrays for both patients with RA versus controls and patients with RA versus patients with PsA. From among several candidates, the following peaks were highlighted: m/z values of 2,924 (RA versus controls on H4 arrays), 10,832 and 11,632 (RA versus controls on CM10 arrays), 4,824 (RA versus PsA on H4 arrays), and 4,666 (RA versus PsA on CM10 arrays). Positive results of proteomic analysis were associated with positive results of the anti-cyclic citrullinated peptide test. Our observations suggested that the 10,832 peak could represent myeloid-related protein 8. SELDI-TOF-MS technology allows rapid analysis of many serum samples, and use of decision tree boosting analysis as the main statistical method allowed us to propose a pattern of protein peaks specific for RA.


Grafting of alumina on SBA-15: effect of surface roughness.
Alumina-grafted materials were prepared by postsynthesis alumination of mesoporous SBA-15 silica in an aqueous solution of aluminum chlorhydrol. Prepared samples were characterized by nitrogen adsorption, scanning electron microscopy, X-ray powder diffraction, and (27)Al magic-angle-spinning NMR. The successive grafting of alumina on SBA-15 leads to a gradual filling of the corona surrounding the mesopores. As a consequence smoothing of the mesopore surface takes place. The in-depth analysis of nitrogen adsorption data proves that the alpha s method affords real values of the structure parameters, while the Kruk, Jaroniec, and Sayari (KJS) procedure based on the BJH algorithm provides only effective data corresponding to cylindrical mesopores of smooth geometrical surface. The quantification of the roughness of the SBA-15 mesopore surface based on the comparison of data obtained from the alpha s plot and KJS method was carried out.


Bacillus subtilis genome vector-based complete manipulation and reconstruction of genomic DNA for mouse transgenesis.
The Bacillus subtilis genome (BGM) vector is a novel cloning system for large DNA fragments, in which the entire 4.2 Mb genome of B. subtilis functions as a vector. The BGM vector system has several attractive properties, such as a large cloning capacity of over 3 Mb, stable propagation of cloned DNA and various modification strategies using RecA-mediated homologous recombination. However, genetic modifications using the BGM vector system have not been fully established, and this system has not been applied to transgenesis. In this study, we developed important additions to the genetic modification methods of the BGM vector system. To explore the potential of the BGM vector, we focused on the fish-like odorant receptor (class I OR) gene family, which consists of 158 genes and forms a single gene cluster. Although a cis-acting locus control region is expected to regulate transcription, this has not yet been determined experimentally. Using two contiguous bacterial artificial chromosome clones containing several class I OR genes, we constructed two transgenes in the BGM vector by inserting a reporter gene cassette into one class I OR gene. Because they were oriented in opposite directions, we performed an inversion modification to align their orientation and then fused them to enlarge the genomic structure. DNA sequencing revealed that no mutations occurred during gene manipulations with the BGM vector. We further demonstrated that the modified, reconstructed genomic DNA fragments could be used to generate transgenic mice. Transgenic mice carrying the enlarged transgene recapitulated the expression and axonal projection patterns of the target class I OR gene in the main olfactory system. We offer a complete genetic modification method for the BGM vector system, including insertion, deletion, inversion and fusion, to engineer genomic DNA fragments without any trace of modifications. In addition, we demonstrate that this system can be used for mouse transgenesis. Thus, the BGM vector system can be an alternative platform for engineering large DNA fragments in addition to conventional systems such as bacterial and yeast artificial chromosomes. Using this system, we provide the first experimental evidence of a cis-acting element for a class I OR gene.


[Laparoscopic hysterectomy. A series of 318 consecutive cases].
To evaluate the place of laparoscopy in hysterectomy. A retrospective study. Département de Gynécologie Obstétrique et Reproduction Humaine. Polyclinique de l'Hôtel-Dieu-CHU de Clermont-Ferrand. A 318 cases continuous series of laparoscopic hysterectomies performed from 1989 to 1993. Results were presented and compared to the largest series of vaginal or abdominal hysterectomies reported in the literature. Conversion to a vaginal route or a laparotomy was required in 11.3% of the cases. Operative duration was longer with laparoscopy than with the other technique. But hospital stay was shorter. The complications were extremely rare after laparoscopic hysterectomy. Urological complications rate was high. Operative route remains a controversial question. Laparoscopy has become the routine procedure for hysterectomy in our department.


Local circuit amplification of spatial selectivity in the hippocampus.
Local circuit architecture facilitates the emergence of feature selectivity in the cerebral cortex1. In the hippocampus, it remains unknown whether local computations supported by specific connectivity motifs2 regulate the spatial receptive fields of pyramidal cells3. Here we developed an in vivo electroporation method for monosynaptic retrograde tracing4 and optogenetics manipulation at single-cell resolution to interrogate the dynamic interaction of place cells with their microcircuitry during navigation. We found a local circuit mechanism in CA1 whereby the spatial tuning of an individual place cell can propagate to a functionally recurrent subnetwork5 to which it belongs. The emergence of place fields in individual neurons led to the development of inverse selectivity in a subset of their presynaptic interneurons, and recruited functionally coupled place cells at that location. Thus, the spatial selectivity of single CA1 neurons is amplified through local circuit plasticity to enable effective multi-neuronal representations that can flexibly scale environmental features locally without degrading the feedforward input structure.


Correlates of mobile screen media use among children aged 0-8: a systematic review.
This study is a systematic review of the peer-reviewed literature to identify the correlates of mobile screen media use among children aged 8 years and less. Home or community-based studies were included in this review while child care or school-based studies were excluded. Children aged 8 years or less were the study population. Studies that included larger age groups without subgroup analysis specific to the 0-8 years category were excluded. Eight electronic databases were searched for peer-reviewed English language primary research articles published or in press between January 2009 and March 2017 that have studied correlates of mobile screen media use in this age group. Mobile screen media use was the primary outcome measure. Mobile screen media use refers to children's use of mobile screens, such as mobile phones, electronic tablets, handheld computers or personal digital assistants. Thirteen studies meeting the inclusion criteria were identified of which a total of 36 correlates were examined. Older children, children better skilled in using mobile screen media devices, those having greater access to such devices at home and whose parents had high mobile screen media use were more likely to have higher use of mobile screen media devices. No association existed with parent's age, sex and education. Limited research has been undertaken into young children's mobile screen media use and most of the variables have been studied too infrequently for robust conclusions to be reached. Future studies with objective assessment of mobile screen media use and frequent examination of the potential correlates across multiple studies and settings are recommended. This review is registered with PROSPERO International Prospective Register of Ongoing Systematic Reviews (registration number: CRD42015028028).


Risk Factors and Outcome for Massive Intra-Abdominal Bleeding Among Patients With Infected Necrotizing Pancreatitis.
The incidence of acute bleeding is reported to be 13.5% in patients with acute necrotizing pancreatitis. However, of all the bleeding events, intra-abdominal bleeding was less studied in the literature and its risk factors have not been well defined yet. The purpose of the present study was to investigate the risk factors for massive intra-abdominal bleeding among the patients with infected necrotizing pancreatitis and assessed the outcome of these patients. Both univariate and multivariate logistic regression models were applied for evaluating risk factors for intra-abdominal bleeding using 33 indices, including age, sex, etiology of acute pancreatitis (AP), APACHE II score, etc. Outcome assessments such as mortality, hospital and intensive care unit (ICU) durations, and cost were also compared between patients with or without intra-abdominal bleeding. Acute kidney injury (AKI) (odds ratio [OR]: 7.54, 95% confidence interval [CI]: 2.53-22.52, P < 0.001) and number of operation (OR: 8.84, 95% CI: 2.01-38.86, P = 0.004) were 2 predictors for massive intra-abdominal bleeding in the patients with infected necrotizing pancreatitis. In addition, AP patients with intra-abdominal bleeding also showed significantly higher mortality rate, prolonged hospital and ICU durations, more complications and invasive treatments, as well as increased cost. Our study revealed that AKI and multiple operations were 2 critical factors increasing the risk of intra-abdominal bleeding among patients with infected necrotizing pancreatitis. Additionally, massive intra-abdominal bleeding was also associated with poor prognosis.


The 24-hour posttransfusion survival, oxygen transport function, and residual hemolysis of human outdated-rejuvenated red cell concentrates after washing and storage at 4 degrees C for 24 to 72 hours.
Red cell concentrates with hematocrit values of 80 +/- 5 percent were stored at 4 degrees C either in citrate-phosphate-dextrose for 22 to 28 days or in citrate-phosphate-dextrose-adenine-one for 35 to 39 days. After storage, the red cells had reduced 2,3-diphosphoglycerate and adenosine triphosphate levels, and biochemical treatment with a solution called PIPA was used to restore these levels. The red cells were not preserved further, but instead were washed after rejuvenation with an unbuffered sodium chloride-glucose solution, pH 5.0, for in vivo studies, and with a buffered sodium chloride-glucose-phosphate solution, pH 6.8, for comparative in vitro studies. The red cells were stored in the wash solution at 4 degrees C for 72 hours after washing. Red cell recovery after washing was about 95 percent. Twenty-four-hour posttransfusion survival value was about 80 percent, and the index of therapeutic effectiveness was greater than 75 percent. These biochemically modified washed red cells exhibited higher than normal P50 values, even after 3 days of postwash storage at 4 degrees C. The units that were washed with the sodium chloride-glucose solution with a pH of 5.0 exhibited a greater degree of hemolysis after 3 days of postwash storage at 4 degrees C than did the units that were washed with the sodium chloride-glucose-phosphate solution with a pH of 6.8.(ABSTRACT TRUNCATED AT 250 WORDS)


Greek Coffee Quality Loss During Home Storage: Modeling the Effect of Temperature and Water Activity.
The aim of this study was to monitor and characterize Greek coffee staling during home storage (secondary shelf life, SSL) using sensory evaluation techniques. Storage temperature (T) and product water activity (aw ) are considered as the major factors affecting SSL. Water sorption isotherms fitted to Guggenheim Anderson-de Boer model were used to predict product stability; coffee samples were stable at aw < 0.52. Coffee samples equilibrated at aw = 0.15 (the fresh sample), 0.22, 0.33, and 0.52 were stored at T = 25 °C, 35 °C, and 45 °C under simulated home storage conditions. Samples were obtained at appropriate times for each T and aw condition and sensorially evaluated. Greek coffee brews were prepared and freshly served during sensory evaluation. The use of Weibull hazard analysis provided an effective approach to SSL determination as a function of T and aw . SSL values ranged from 20 (Τ = 45 °C, aw = 0.52) to 104 days (Τ = 25 °C, aw = 0.15). Quality loss based on coffee aroma changes (aroma quality, aroma intensity, aftertaste, off-flavor) was also studied (Si , sensory scoring using 9-point magnitude scale) and kinetically modeled. Quality loss rates (ki ) were calculated and used to predict SSL values. Based on the results of both Weibull hazard analysis and sensory scoring of individual aroma characteristics, it was concluded that the lowest SSL was calculated for aw = 0.52 at T = 35 °C to 45 °C. The temperature dependence of aftertaste, aroma quality loss, and off-flavor production was not statistically significant for 0.15 < aw < 0.33 (P > 0.05); the aroma intensity was the most sensitive parameter. PRACTICAL APPLICATIONS: Secondary shelf life (SSL) represents the time after pack opening during which a food maintains an acceptable quality level. During home/catering usage, coffee is not consumed immediately after pack opening. During consumption, quality degradation reactions proceed with higher rates due to variable storage conditions mainly related to atmosphere changes in the pack, leading to the entrance of oxygen/moisture and temperature. Therefore, SSL is important, and can be used as a tool for product management during consumption reducing food waste. There is a lack of studies dealing with SSL prediction of coffee, while no studies have been carried out on Greek coffee.


The influence of metal ions on malic enzyme activity and lipid synthesis in Aspergillus niger.
In the presence of copper significant induction of citric acid overflow was observed, while concomitantly lower levels of total lipids were detected in the cells. Its effect was more obvious in a medium with magnesium as sole divalent metal ions, while in a medium with magnesium and manganese the addition of copper had a less pronounced effect. Since the malic enzyme was recognised as a supplier of reducing power in the form of reduced nicotinamide adenine dinucleotide phosphate for lipid biosynthesis, its kinetic parameters with regard to different concentrations of metal ions were investigated. Some inhibition was found with Fe(2+) and Zn(2+), while Cu(2+) ions in a concentration of 0.1 mM completely abolished malic enzyme activity. The same metal ions proportionally reduced the levels of total lipids in Aspergillus niger cells. A strong competitive inhibition of the enzyme by Cu(2+) was observed. It seemed that copper competes with Mg(2+) and Mn(2+) for the same binding site on the protein.


Screening for behavioral and emotional problems in primary care pediatrics.
Case identification indexes based on the mother-completed Missouri Children's Behavior Checklist (MCBC) were compared with pediatrician identification of behavioral and emotional problems in 41 children seen for well-child examinations. Case identification indexes also were examined as a function of child gender and age and maternal education. The criterion was presence of DSM-III diagnoses determined through Child Assessment Schedule interviews of child or mother. The MCBC yielded better case identification indexes and improvements in both overidentification and underidentification rates. Pediatrician identification indexes were directly related to maternal education and MCBC identification indexes were inversely related to child age. The findings indicate the necessity for including child report, as well as mother report, in screening procedures that are incorporated into primary care pediatric practice.


Correct immunoglobulin alpha mRNA processing depends on specific sequence in the C alpha 3-alpha M intron.
The maturation of IgM-expressing B cells to IgM-secreting plasma cells is associated with both an increase in mu mRNA and the ratio of secreted to membrane forms of mu mRNA which differ at the 3' termini. In contrast, both in vitro and in vivo the secreted form of alpha mRNA is predominant at all stages in the development of a secretory IgA response. Previous studies demonstrated that preferential usage of the alpha s poly(A) site does not result from transcription termination and is independent of either the poly(A) sites or the 3' splice site associated with the exon encoding the membrane exon of IgA (alpha M). The present study demonstrates that a 349-bp region located 774 bp 3' to the alpha s poly(A) site is required for the preferential usage of the alpha s terminus. This region, which is the first isotype-specific cis-acting regulatory sequence not immediately adjacent to a secretory poly(A) site to be identified, contains regulatory elements that increase the efficiency of polyadenylation/cleavage. A ubiquitous, approximately 58-kDa RNA-binding protein interacts specifically with this regulatory region. These studies support the premise that cis-acting elements unique to each CH gene can impinge upon a common mechanism regulating Ig mRNA processing.


Angiopoietin-2 mRNA expression is increased in chronic lymphocytic leukemia patients with poor prognostic features.
Several studies have demonstrated the potential prognostic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Elevated expression of angiopoietin-2 (Ang-2), an angiogenic cytokine, was recently reported in CLL. However, data regarding prognostic significance of Ang-2 in CLL are limited. Therefore, we quantitated Ang-2 mRNA in purified mononuclear cells of 33 untreated CLL patients and compared the transcript levels to traditional as well as modern prognostic factors in patients with CLL (clinical stage, disease course, IgVH mutation status, CD38, and ZAP-70 expression). Elevated Ang-2 mRNA concentrations were detected in 12 cases; 21 patients had very low or undetectable levels of Ang-2 transcript. There was significant association between high Ang-2 mRNA levels and unmutated IgVH genes (n=27, P=0.010) and with CD38 expression (n=32, P=0.011), but not with ZAP-70 expression (n=32, P=0.784), Rai stage (n=33, P=0.305) or stable versus progressive clinical course (n=33, P=0.443). There was a trend towards shorter progression-free survival in patients with high Ang-2 expression; however, it did not reach statistical significance (P=0.090). Our pilot data show that Ang-2 mRNA is differentially expressed in patients with CLL and its increased expression appears to be associated with poor prognostic features. Further studies are needed to confirm the results in a larger patient cohort.


Direct evidence of interlevel exciton transitions mediated by single phonons in a semiconductor quantum dot using resonance fluorescence spectroscopy.
Using resonance fluorescence, we investigate how acoustic phonons mediate couplings between multiple electronic levels in a semiconductor quantum dot. We show the first direct evidence of population up-conversion in a single quantum dot, which we attribute to absorption of single acoustic phonons. Moreover, through a rate equation analysis, we find that below 20 K such single-phonon mediated couplings between the exciton ground state and the first excited state are primarily responsible for decoherence of the exciton quantum state.


Application value of thromboelastography in perioperative clinical blood transfusion and its effect on the outcome of patient.
Application value of thromboelastography (TEG) in perioperative clinical blood transfusion and its effect on the outcome of patient were investigated. Seventy-four patients, admitted to The Surgical Department of the First Hospital of Zibo from March 2015 to March 2018, were selected for this study. Among them, 34 patients took only the traditional coagulation function testing method as the blood transfusion guide during the perioperative period and they were regarded as the control group. The other 40 patients used TEG as the blood transfusion guide during the perioperative period, and they were regarded as the TEG group. The coagulation function indicators in 2 h before the operation and in 24 h after the operation, the transfusion amount and blood loss during the operation, the condition of the blood transfusion during the perioperative period, the occurrence rate of the postoperative rebleeding, the length of hospital stay and mortality of the patients in the two groups were compared. The coagulation function indicators of the patients in the two groups in 2 h before the operation and in 24 h after the operation showed that there was no significant difference between the two groups (P>0.050). However, APTT and Pt of the patients in the two groups both increased when compared with those before the treatment (P<0.050) and Hb, Hct, Plt and Fib all decreased (P<0.050). The suspended erythrocytes, Plt, fibrinogen and plasma in the TEG group were both significantly lower than those in the control group (P<0.001). Compared with the traditional coagulation function test, TEG was more accurate for estimating the coagulation function of patient and was more suitable for estimating the condition of blood transfusion of patient in the perioperative period; also, it could shorten the recovery period of patient and it is worthwhile to promote it in the clinic.


Acute effects of three different stretching protocols on the wingate test performance.
The purpose of this study was to examine the acute effects of different stretching exercises on the performance of the traditional Wingate test (WT). Fifteen male participants performed five WT; one for familiarization (FT), and the remaining four after no stretching (NS), static stretching (SS), dynamic stretching (DS), and proprioceptive neuromuscular facilitation (PNF). Stretches were targeted for the hamstrings, quadriceps, and calf muscles. Peak power (PP), mean power (MP), and the time to reach PP (TP) were calculated. The MP was significantly lower when comparing the DS (7.7 ± 0.9 W/kg) to the PNF (7.3 ± 0.9 W/kg) condition (p < 0.05). For PP, significant differences were observed between more comparisons, with PNF stretching providing the lowest result. A consistent increase of TP was observed after all stretching exercises when compared to NS. The results suggest the type of stretching, or no stretching, should be considered by those who seek higher performance and practice sports that use maximal anaerobic power.


Levels of immunoglobulin A1 in peri-implant fluid and saliva from patients with mucositis: a preliminary study.
There are no studies evaluating the possible use of immunoglobulin A1 (IgA1) as an early marker for peri-implant inflammation. The aim of this study was to evaluate the IgA1 levels in peri-implant sulcular fluid (PISF) and saliva of partially edentulous patients as an indicator of mucositis. Twenty-seven patients were examined to determine the peri-implant status based on probing depth and bleeding on probing. Saliva and PISF around dental implants were collected and the IgA1 levels were evaluated by Elisa assay. IgA1 in saliva and PISF of these patients were compared and their correlations with clinical parameters were evaluated. Differences in IgA1 levels in saliva (821.1 ± 290.6; 779.8 ± 401.5) and PISF (26.6 ± 20.7; 25.1 ± 20.5) of healthy and mucositis groups, respectively were not observed (p>0.05). Correlation between clinical parameters and IgA1 in saliva or PISF was not observed in healthy or mucositis groups (p=0.607; p=0.826, respectively). These results suggest that IgA1 cannot be used as an immunological marker of mucositis.


[Tonal audiometry in hearing evaluation with a microcomputer system].
The own experiences with the computer microsystem for hearing evaluation "Audiocomp" were presented. The air and bone conduction thresholds as well as the others suprathreshold testing were performed by computer. The reproducibility of results were better than in standard audiometry. The influence of the examined person is lowered making the testing more objective.


[Capillary length in the human heart during physiological growth and under pathological conditions].
Knowledge about the capillary length in mammalian and human heart is still scanty. Because it is very difficult to examine this parameter directly we used an indirect method. The distance between the arterioles can be used as an approximately measurement for the double capillary length. We tried to measure the distances between arterioles in about 30 postmortem injected hearts using India ink to produce a kind of reflected imitated tabby (tiger) heart pattern. In addition we measured the distances between arterioles with orcein staining in histological preparation of 130 human hearts including 24 hearts with congenital vitia. Our results indicate that from birth there is a determined continuous growth of capillary length with increasing heart weight during physiological development and under pathological conditions. The capillary length in hypertrophic hearts may be an additional functional impairment of the pathological hearts.


Strain-release rearrangement of N-vinyl-2-arylaziridines. Total synthesis of the anti-leukemia alkaloid (-)-deoxyharringtonine.
Deoxyharringtonine (1) is among the most potent of the anti-leukemia alkaloids isolated from the Cephalotaxus genus. A convergent total synthesis of (-)-1 is reported, involving novel synthetic methods and strategies that include (1) the strain-release rearrangement of N-aryl-2-vinylaziridines for [3]benzazepine synthesis, (2) a vinylogous amide acylation-cycloaddition cascade for spiro-pyrrolidine construction, and (3) efficient acylation of the cephalotaxine core by alpha-(beta-lactone)carboxylic acid derivatives to access the biologically active cephalotaxus esters. These innovations should allow rapid access not only to other Cephalotaxus alkaloids but also to non-natural analogues of potential therapeutic utility.


Reevaluation of the periodic acid-Schiff stain in acute leukemia with immunophenotypic analyses.
To determine the sensitivity and specificity of the periodic acid-Schiff (PAS) stain in the diagnosis of acute leukemia in light of the finer characterization of this disorder now available through immunophenotyping, we examined the blasts from 51 patients with newly diagnosed acute leukemia by morphological, cytochemical, and immunophenotypic analyses. The 51 patients represented every new case of acute leukemia subjected to cytochemical stains and flow cytometry between July 1987 and February 1989. By cell-surface marker analysis, 29 exhibited lymphocytic lineage, while 21 were myelocytic. One was mixed lineage. The PAS positivity, defined by the presence of blocks or coarse granules in 5% or more of the blasts, was found in 15 of 29 lymphoblastic leukemias and in four of the myeloblastic leukemias. However, PAS-positive lymphoblastic leukemias were negative with the other cytochemical stains: myeloperoxidase, Sudan black B, and alpha-naphthyl butyrate esterase. The PAS-positive myeloblastic leukemias were positive with at least one other stain. Three cases of myeloblastic leukemia exhibited greater than 10% PAS-positive blasts, with all three being acute monoblastic leukemia. Thus, the sensitivity and specificity of the PAS stain alone for lymphoblastic leukemia was 52% (15 true positives of 29) and 81% (four false positives), respectively. The sensitivity of a cytochemical-staining combination of PAS positivity and myeloperoxidase, Sudan black B, and alpha-naphthyl butyrate esterase negativity in defining cases of lymphoblastic leukemia remained at 52%; however, the specificity of this combination for lymphoblastic leukemia was 100% (no false positives). Thus, a positive PAS stain, in combination with negative myeloperoxidase, Sudan black B, and alpha-naphthyl butyrate esterase stains, continues to have a diagnostic role in the distinction between lymphoblastic and myeloblastic leukemia, and greater immunologic sophistication serves to support this position.


miR-150 enhances apoptotic and anti-tumor effects of paclitaxel in paclitaxel-resistant ovarian cancer cells by targeting Notch3.
Tumor recurrence by obtaining chemoresistance is a major obstacle to treating ovarian cancer. By TargetScan database and a luciferase reporter assay, we identified miR-150 directly targets Notch3, which is a key oncogene in ovarian cancer. We, therefore, investigated the role of miR-150 in ovarian cancer cells, and the usefulness of miR-150 as a therapeutic target in chemoresistant ovarian cancer, through examining miR-150 expression by qRT-PCR in ovarian cancer cell lines and tissues, and assessing the gain-of-function effect by WST, colony forming, TUNEL, wound healing and angiogenesis assays. Western blotting was performed to evaluate its downstream targets. The miR-150 expression was significantly downregulated in ovarian cancers. Treatment with pre-miR-150 significantly inhibited cancer cell proliferation, and induced apoptosis in PTX (paclitaxel) -resistant SKpac cells, which was not seen by PTX only treatment. On spheroid forming assay, an additional pre-miR-150 treatment with PTX decreased cancer stem cell activation in PTX-resistant SKpac cells. An experimental upregulation of miR-150 also decreased cancer cell migration and angiogenesis in SKpac cells. The Notch3 downstream proteins(NICD3 and HEY2), and cell cycle-related proteins (cyclinD3, pS6, and NF-kB), and apoptosis-related proteins (BCL-2 and BCL-W) were significantly downregulated by pre-miR-150 transfection. Taken together, miR-150 is related with PTX-resistance in ovarian cancer, and treatment with pre-miR-150 resensitizes cancer cells to PTX. Therefore, it may be a promising treatment strategy in chemoresistant and recurrent ovarian cancer.


Effect of fermentation and autoclaving on dietary fiber fractions and antinutritional factors of beans (Phaseolus vulgaris L.).
The effect of fermentation on antinutritional factors and also on total dietary fiber (TDF), insoluble (IDF) and soluble (SDF) dietary fiber fractions was studied in beans (Phaseolus vulgaris L.). The processes studied were two types of fermentation (lactic acid and natural), and a portion of the obtained flours were processed by autoclaving. The dietary fiber (DF) content and its components were determined using the enzymatic-gravimetric and enzymatic-chemical methods. The TDF content ranged from 24.5% dry matter (DM) in the raw to 25.2% DM in the processed beans. All the processing treatments significantly decreased the SDF content, and irrelevant changes were noticed in the IDF content of processed beans. Cellulose content of all samples was reduced by the processing treatments. Correspondingly, higher amounts of resistant starch was observed in the processed beans, except in the lactic acid fermented ones. However, the levels of pectic polysaccharides and Klason lignin were higher in the samples fermented by Lactobacillus plantarum. The action of microorganisms was determinant for the different degradation of the bean cell wall, disrupting the protein-carbohydrate integration, thus reducing the solubility of DF.


Effect of malondialdehyde on the determination of furosine in milk-based products.
For nutritional purposes the recombination of milk or milk proteins with polyunsaturated fatty acids had long been considered in newly designed products, such as functional foods. Four milk-resembling model systems were prepared having malondialdehyde content ups to 1 mM. Systems were heated between 110 and 150 degrees C for up to 30 min. The effect of the presence of bifunctional aldehydes on the determination of furosine as a heat-induced marker was investigated. Levels of 0.01 mM MAD in the reaction mixture could affect significantly the determination of furosine in a milk-based system. Impairment of lysyl residues through the analysis of furosine could be underestimated in the presence of malondialdehyde.


Checking the Hippo in Sarcomatoid Renal Cell Carcinoma with Immunotherapy.
Subset analysis of patients with sarcomatoid renal cell carcinoma (sRCC) included in the CheckMate 214 trial of ipilimumab-nivolumab versus sunitinib showed improved outcomes in sRCC with ipilimumab-nivolumab. The use of checkpoint inhibitor-based regimens in sRCC, for which therapeutic options were once limited, is further supported by additional clinical trials.See related article by Tannir et al., p. 78.


Multilocus association mapping using variable-length Markov chains.
I propose a new method for association-based gene mapping that makes powerful use of multilocus data, is computationally efficient, and is straightforward to apply over large genomic regions. The approach is based on the fitting of variable-length Markov chain models, which automatically adapt to the degree of linkage disequilibrium (LD) between markers to create a parsimonious model for the LD structure. Edges of the fitted graph are tested for association with trait status. This approach can be thought of as haplotype testing with sophisticated windowing that accounts for extent of LD to reduce degrees of freedom and number of tests while maximizing information. I present analyses of two published data sets that show that this approach can have better power than single-marker tests or sliding-window haplotypic tests.


Donovanosis affecting cervix, uterus, and adnexae.
Donovanosis (granuloma inguinale), a disease often related to sexual contact, has been a clinical problem in Papua New Guinea for more than 9 decades. It is a common cause of anogenital lesions in females in this country. Lesions on the cervix or vaginal vault, and extension of the disease process from the external genitalia to the uterus, tubes and ovaries, are thought to be rare. In this study an attempt was made to discover the frequency of involvement of cervix, uterus and adnexae, with or without external genital involvement, by retrospectively analyzing the histological and clinical records of patients with anogenital donovanosis for a period of 8 years (1975-1982). In 35 of 351 patients (10%), donovanosis involved the cervix. The clinical profile of these cases, certain unusual features in a few cases, and the pathological findings are discussed.


History of echocardiographic contrast agents.
Since its experimental introduction over 30 years ago, the use of cardiac ultrasound has expanded expeditiously, particularly in the last decade. The inception of managed care has fueled this expansion because ultrasound technology has the potential to enhance cost-effective diagnosis and medical care. Another important factor driving the growth of cardiac ultrasound has been the recent and rapid development of contrast echocardiography (CE). This diagnostic technique, involving the injection of a contrast agent to enhance ultrasound imaging, provides a safe, noninvasive means of directly assessing myocardial perfusion and a host of other aspects of cardiovascular health and integrity.