Advances in the management of congenital and infantile cataract.
Congenital and infantile cataracts produce deprivation amblyopia and can thus cause lifelong visual impairment. Successful management is dependent on early diagnosis and referral for surgery when indicated. Accurate optical rehabilitation and postoperative supervision are essential.The timing of surgery and its relationship to the duration of deprivation is important. Unilateral congenital cataract surgery within 6 weeks of birth produces the best outcomes. The equivalent 'latent' period for bilateral visual deprivation may be longer at around 10 weeks. Visual deprivation has a significant impact on the development of fixation stability. Major form deprivation, even after early surgery, leads to nystagmus. This is mostly manifest latent nystagmus (MLN). The latent period for fixation stability may be as short as 3 weeks. Preoperative congenital nystagmus (CN) can convert to more benign MLN after surgery. Infantile IOL implantation is becoming increasingly accepted. A satisfactory long-term refractive result requires that allowance be made for childhood axial growth and myopic shift. In a series of 25 infants (33 eyes) implanted before 12 months of age, the mean myopic shift at 12 months was 4.83 D. This increased to 5.3 D in infants implanted before 10 weeks. The initial desired refractive outcome following IOL implantation is thus hypermetropia, with the degree dependent on the age of the child. Glaucoma or ocular hypertension is a common complication following paediatric cataract surgery. Microphthalmia and surgery in early infancy are risk factors. Tonometry results may be influenced by the increased corneal thickness seen in aphakic and pseudophakic children. The long-term prognosis of eyes with aphakic glaucoma is not necessarily poor but intraocular pressure control may require three or more medications. Surgical intervention appears to be necessary in over a quarter of eyes. Posterior capsule opacification (PCO) is common in infants undergoing primary lens implantation. Primary capsulotomy and anterior vitrectomy reduce the risk of PCO. In the absence of anterior vitrectomy, primary posterior capsulotomy does not prevent visual axis opacification. Further developments will continue to be driven by clinical research. The prevention of capsule opacification and cellular proliferation may in future be achieved by the use of devices to specifically target epithelial cells at surgery.


A health recreation program for u-healthcare clients: effects on mental health.
In this study, a health recreation program was implemented with elderly patients (60 years of age or older) who were receiving ubiquitous healthcare (u-healthcare) services. Furthermore, we examined the effects of health recreation on perceived stress, anxiety, and depression, by comparing survey results before and after the recreation program was conducted. Thus, the aim of this study was to develop an offline service with the ability to promote the impact of the u-healthcare service on mental healthcare. A health recreation program, consisting of a variety of weekly games, songs, and minilectures about mental health over a 10-week period, was offered at a senior citizens center in K-Gu, Seoul, Korea. This program targeted 18 elderly people currently receiving u-healthcare services. Data on the impact of the program on the mental health of the elderly were collected through surveys administered before and after the recreation program, and the results were compared with those of a control group. The control group consisted of 18 elderly people who were receiving u-healthcare services from the same district. The perceived stress and anxiety of the experimental group decreased significantly compared with those of the control group. However, the program did not result in a significant reduction in depression. This offline health recreation program offered to elderly u-healthcare service clients contributed to the promotion of their mental health. Further studies will be required to better incorporate the offline mental healthcare program into their daily lives within the u-healthcare service.


Pediatric multisystem inflammatory syndrome associated with COVID-19: urgent attention required.
To identify epidemiological and clinical characteristics of multisystemic inflammatory syndrome associated with coronavirus infection as one of the severe forms of COVID-19 involvement in children and adolescents. review was based on articles published in 2020 in the PubMed, Medline, Scopus, SciELO and Cochrane databases. Multisystemic inflammatory syndrome is a serious clinical disorder that affects children and adolescents and is associated with the detection of previous exposure to SARS-CoV-2. It is characterized by the installation of a shock picture, with a significant increase in inflammatory markers such as presentations of Kawasaki Disease or shock syndrome related to Kawasaki Disease, or even toxic shock syndrome, with the clinical picture being characterized by fever of difficult control, rash, conjunctivitis, peripheral edema, generalized pain in the extremities and gastrointestinal symptoms. Although the vast majority of children with COVID-19 have mild symptoms, it is necessary to consider that some have a hyperinflammatory response. It is essential that health professionals receive information that can assist in the recognition of this clinical condition, differentiating it from other diagnoses, so that early and appropriate treatment is instituted.


[Ninety cases of postoperative complications in elderly patients after surgical removal of meningiomas].
To identify the causes and risk factors of postoperative complications in elderly patients receiving meningioma removal. A total of 320 elderly patients received meningioma removal at our hospital between 1998 to 2007. Among them, 90 patients, aged 65 to 82 years old, developed postoperative complications. The diagnoses were confirmed by pathological findings. The average diameter of tumors was 5 cm. The average operative duration was 4.8 hours. Local or systemic complications occurring in this group of patients included new-onset neurological deficit (n = 37), prolonged coma (n = 16), central nervous system infection (n = 14), postoperative hematoma (n = 10), cerebral infarction (n = 7), CSF leakage (n = 12), pulmonary infection (n = 18), deep vein thrombosis or pulmonary embolism (n = 15), gastrointestinal bleeding (n = 3) and myocardial infarction (n = 2). Twelve patients died within 30 days after operation. Postoperative complications prolonged hospitalization and increased medical costs. Large size of tumors, difficulties in resection and preexisting conditions are primary causes of a high rate of operative morbidity in elderly patients receiving meningioma removal.


Asymmetric optical second-harmonic generation from chiral G-shaped gold nanostructures.
We present a new electromagnetic phenomenon-the asymmetric second-harmonic generation from planar chiral structures. The effect consists in distinguishing the handedness of a chiral material by rotating the sample in an experiment involving solely linearly polarized light. This phenomenon originates in the surface plasmon resonance of chiral gold nanostructures, where homodyne interference of anisotropic and chiral electric and/or magnetic multipoles appears to play an important role.


Enhancement of anti-TNFα monoclonal antibody production in CHO cells through the use of UCOE and DHFR elements in vector construction and the optimization of cell culture media.
Recently, there has been a high demand for anti-tumor necrosis factor-α monoclonal antibodies (mAbTNFα) in the treatment of rheumatoid arthritis and other autoimmune diseases. Thus, efficient strategies and stable high-producing cell lines need to be established to increase antibody production. In this study, we describe an efficient approach to establish a mAbTNFα high-producing clone through the optimization of expression vectors and cell culture media. The ubiquitous chromatin opening element (UCOE) and dihydrofolate reductase (DHFR)-based vectors encoding mAbTNFα were introduced into the CHO-DG44 cells using lipofection. Clones were obtained by selecting transfected cells with G418, amplifying them by treatment with methotrexate, and isolating them by limiting dilution. Different media formulated with commercial feeds and media were also screened to develop an improved medium. The antibody produced by the selected clone was purified, characterized, and compared to standard adalimumab. Using our established protocol, a cell clone obtained from stable mAbTNFα-expressing cell pools showed a 3.8-fold higher antibody titer compared to stable cell pools. Furthermore, the highest antibody yield of selected clones cultured in fed-batch mode using improved medium was 2450 ± 30 µg/mL, which was 13.2-fold higher than that of stable cell pool cultivated in batch mode using a basal medium. The purified antibody had primary chemical and biological characteristics similar to those of adalimumab. Therefore, the use of UCOE and DHFR vectors in combination with the optimization of cell culture media may help in establishing stable and high-producing CHO cell lines for therapeutic antibody production.


Therapy for child sexual abuse:women talk about helpful and unhelpful therapy experiences.
Women with histories of childhood sexual abuse (CSA) were asked to describe what was helpful and unhelpful to them in therapy. From 191 completed postal questionnaires, a subsample of 20 participants was interviewed. This paper focuses on three specific areas of therapy raised by interviewees: (1) Establishing a therapeutic relationship; (2) talking about experiences and effects of CSA; and (3) dealing with errors in therapy. Findings suggest that to avoid making serious therapy errors, therapists (1) need special skills to be aware of the dynamics and effects of CSA and of abuse-focused therapy and to deal with abuse-related material, and (2) need to develop an equal and open therapy relationship that includes ongoing consultation with clients about their experiences of therapy. doi:10.1300/J070v15n04_03.


Osteoblastlike cells in a serum-free methylcellulose medium form colonies: effects of insulin and insulinlike growth factor I.
Osteoblastlike (OB) cells obtained from a heterogeneous primary cell population by enzymatic cell digestion of calvaria of newborn rats are grown in a serum-free viscous alpha-MEM/F-12 medium containing 0.8% methylcellulose. In contrast to cell monolayers in conventional tissue cultures OB cells proliferate into colonies of rounded-up cells to form morulalike spherical cell clusters containing up to 100 cells. These colonies, with different cell numbers, are clearly not fibroblastlike since fibroblasts from the same rats always grow as a cell monolayer. Alkaline phosphatase activity and cAMP responsivness to PTH are expressed more markedly (70% and 250% respectively) by OB cells in the described culture system than in conventional tissue cultures. Rounded-up OB cells sediment and colonies stick to the dish; proliferation of OB cells is favored and starts 3-4 days after inoculation. Increasing concentrations of insulinlike growth factor (IGF) I (0.4-35 nM) and insulin (20-660 nM), as well as increasing initial cell density, enhances mitogenic activity of these cells in a dose-dependent way. On a molar ratio IGF I (physiological concentrations) is 10 times as potent as insulin (pharmacological concentrations) with respect to proliferation. If less than 10(5) cells/ml are inoculated, there exists an apparent relationship between initial cell density and major onset of replication, indicating the presence and accumulation of local growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)


Brain Functional Connectivity in de novo Parkinson's Disease Patients Based on Clinical EEG.
In Parkinson's disease (PD), cortical-subcortical interplay plays a relevant role in affecting clinical performance. Functional MRI sequences described changes in functional connectivity at different stages of disease. Scarce are, instead, the investigations examining brain connectivity in patients with PD at early stages of disease. For this aim, here we analyzed the differences in functional connectivity between de novo, never treated, PD patients and healthy controls. The analyses were based upon custom-written scripts on the Matlab platform, combined with high-level functions of Fieldtrip, Brainstorm, and Brain Connectivity toolboxes. First, we proceeded to the spectral analysis of the EEG data in the five frequency bands (δ-θ-α-β-γ). Second, we calculated functional connectivity matrices based on both coherency (COH) and imaginary part of coherency (iCOH), in the δ-θ-α-β-γ frequency bands. Then, four network measures (density, transitivity, global efficiency, and assortativity) were computed in identified connectivity matrices. Finally, we compared the spectral density, functional connectivity matrices, and network measured between healthy controls and de novo PD patients through two-samples T-test. A total of 21 de novo PD patients and 20 healthy subjects were studied. No differences were observed in spectral analysis between the two groups, with the exception of the γ band where a significant increase in power density was found in PD patients. A reduced connectivity in the main EEG frequency bands (α-β frequency bands) was observed in PD patients compared to controls, while a hyperconnectivity was found in PD patients in γ band. Among the network measures, a reduced assortativity coefficient was found in de novo PD patients in α frequency band. Our results show the occurrence of early EEG functional connectivity alterations from the initial stages of PD. From this point of view, connectivity analysis may ease a better understanding of the complexity of PD physiopathology.


Duodenal switch provides superior weight loss in the super-obese (BMI > or =50 kg/m2) compared with gastric bypass.
Although weight loss following Roux-en-Y gastric bypass is acceptable in patients with preoperative body mass index (BMI) between 35 and 50 kg/m, results from several series demonstrate that failure rates approach 40% when BMI is > or =50 kg/m. Here we report the first large single institution series directly comparing weight-loss outcomes in super-obese patients following biliopancreatic diversion with duodenal switch (DS) and Roux-en-Y Gastric Bypass (RYGB). All super-obese patients (BMI > or =50 kg/m) undergoing standardized laparoscopic and open DS and RYGB between August 2002 and October 2005 were identified from a prospective database. Two-sample t tests were used to compare weight loss, decrease in BMI, and percentage of excess body weight loss (% EBWL) after surgery. chi analysis was used to determine the rate of successful weight loss, defined as achieving at least 50% loss of excess body weight. A total of 350 super-obese patients underwent DS (n = 198) or RYGB (n = 152) with equal 30-day mortality (DS,1 of 198; RYGB, 0 of 152; P = not significant). The % EBWL at follow-up was greater for DS than RY (12 months, 64.1% vs. 55.9%; 18 months, 71. 9% vs. 62.8%; 24 months, 71.6% vs. 60.1%; 36 months, 68.9% vs. 54.9%; P < 0.05). Total weight loss and decrease in BMI were also statistically greater for the DS (data not shown). Importantly, the likelihood of successful weight loss (EBWL >50%) was significantly greater in patients following DS (12 months, 83.9% vs. 70.4%; 18 months, 90.3% vs. 75.9%; 36 months, 84.2% vs. 59.3%; P < 0.05). Direct comparison of DS to RYGB demonstrates superior weight loss outcomes for DS.


Oral health curricula in physician assistant programs: a survey of physician assistant program directors.
a review of the medical literature indicates that physician assistants (PAs) are not educationally prepared for oral health issues. The purpose of this study was to evaluate the status of oral health curricula and the knowledge and skills taught within PA curricula. a survey examining oral health curricula in PA education was distributed electronically to the directors of all 142 accredited PA programs in the United States. The survey focused on aspects of oral health that programs currently teach and aspects that merit future inclusion. The survey data were analyzed using SPSS version 17. eighty-three of the 142 PA program directors (58.4%) responded to the survey. Over 74% believed that dental disease prevention should be addressed in PA education, yet only 21% of programs actually did so. Most respondents (94.7%) also agreed that PAs should routinely assess and screen for early signs of dental disease and counsel patients on preventing dental problems. Currently, over half of PA programs teach examination of children's teeth for cavities (55.6%), dedicating on average 3.6 hours toward oral health education. Most respondents (more than 90%) expressed a desire to implement an oral health module in their programs. On average, program directors felt that 5.3 hours should be dedicated to oral health. many PA program directors believe that PA programs are responsible for educating students about oral health; however, most PA program directors report a lack of oral health education within their curricula.


Are there differences in the health outcomes of mothers in Europe and East-Asia? A cross-cultural health survey.
The aim of the current study was to investigate differences in quality of life outcomes and depression of mothers in East-Asia and Central Europe. 170 women in Japan and 226 women in Austria with children between 3 and 5 answered the same cross-culturally validated questionnaires. The Quality of Life Questionnaire from the WHO (WHOQOL-Bref), the Patient Health Questionnaire (PHQ-2), the Sense of Coherence Scale (SOC-13), a Social Support Scale (MSPSS), and questions on gender orientation were used. In all dimensions of QOL (physical, psychological, social, and environmental) Japanese women had lower QOL scores compared to Austrian mothers (P < 001). Seven percent of women in both countries experienced major depression. In both countries sense of coherence, experienced stress level, satisfaction with income, social support, and gender roles had an influence on QOL and depressive symptoms. Mothers in Japan consider life events less comprehensible, manageable, and meaningful and experience less support. Consequently, creating an environment where fathers could be more involved in child rearing and mothers have more opportunities to choose between life styles and working and social environments would improve QOL not only in Japanese mothers but also in other countries all over the world.


Accelerated idioventricular rhythm during ajmaline test: a case report.
We present an unusual transient pro-arrhythmic effect of ajmaline in a patient with resuscitated cardiac arrest and a left ventricular apical aneurysm. We discuss the clinical presentation and the possible physio-pathological explanation for this new pro-arrhythmic effect linked to administration of intravenous ajmaline.


[Growth and development aspects of international adoption].
With the increase in the number of children being adopted by Israeli families from abroad, the medical system has to face heretofore unfamiliar medical and developmental challenges. Many of the biological mothers of these children were substance abusers and suffered from a variety of illnesses and nutritional deficiencies during their pregnancy. Their infants and young children were placed in orphanages at a very young age. The ensuing emotional and environmental deprivation in many cases impacted negatively on their neurological, physical and emotional development. Whereas our previous survey dealt with the purely medical aspects of international adoption, the current review deals with the growth and developmental issues involved in raising these children.


Pharmacogenomics in breast cancer: current trends and future directions.
Pharmacogenomics is the study of genetic variations between individuals to predict the risk of toxic side effects and the probability that a patient will respond to single- or multidrug chemotherapy. Breast cancer remains one of the most common cancers among women worldwide and is second only to lung cancer in cancer-related death. A better understanding of the mechanisms of initiation and progression of breast cancer is needed for early diagnosis and development of better therapeutic methodologies. Differences in cancer patients' responses to chemotherapy have often been attributed to pathogenesis and severity of the disease, drug interactions, patient's age, gender, nutritional status, organ functions and tumor biology. It is now well recognized that genetic variations in drug target genes, disease pathway genes and drug metabolizing enzymes can have greater influence on drug efficacy and toxicity. In addition, germline variants can be used to study breast cancer susceptibility, as well as the variable response to both drug and radiation therapy used in the treatment of breast cancer. This review discusses clinically relevant individual gene variations that influence breast cancer susceptibility and cancer therapy, as well as the microarray-based expression profiling studies that have great potential in cancer pharmacogenomics in terms of tumor classification, drug and biomarker discovery and drug efficacy testing.


Challenges and Achievements in Prevention and Treatment of Smallpox.
Declaration of smallpox eradication by the WHO in 1980 led to discontinuation of the worldwide vaccination campaign. The increasing percentage of unvaccinated individuals, the existence of its causative infectious agent variola virus (VARV), and the recent synthetic achievements increase the threat of intentional or accidental release and reemergence of smallpox. Control of smallpox would require an emergency vaccination campaign, as no other protective measure has been approved to achieve eradication and ensure worldwide protection. Experimental data in surrogate animal models support the assumption, based on anecdotal, uncontrolled historical data, that vaccination up to 4 days postexposure confers effective protection. The long incubation period, and the uncertainty of the exposure status in the surrounding population, call for the development and evaluation of safe and effective methods enabling extension of the therapeutic window, and to reduce the disease manifestations and vaccine adverse reactions. To achieve these goals, we need to evaluate the efficacy of novel and already licensed vaccines as a sole treatment, or in conjunction with immune modulators and antiviral drugs. In this review, we address the available data, recent achievements, and open questions.


Tricellular junctions: how to build junctions at the TRICkiest points of epithelial cells.
Tricellular contacts are the places where three cells meet. In vertebrate epithelial cells, specialized structures called tricellular tight junctions (tTJs) and tricellular adherens junctions (tAJs) have been identified. tTJs are important for the maintenance of barrier function, and disruption of tTJ proteins contributes to familial deafness. tAJs have recently been attracting the attention of mechanobiologists because these sites are hot spots of epithelial tension. Although the molecular components, regulation, and function of tTJs and tAJs, as well as of invertebrate tricellular junctions, are beginning to be characterized, many questions remain. Here we broadly cover what is known about tricellular junctions, propose a new model for tension transmission at tAJs, and discuss key open questions.


Optical assessment of particle size and composition in the Santa Barbara Channel, California.
The suspended particle assemblage in complex coastal waters is a mixture of living phytoplankton, other autochthonous matter, and materials of terrestrial origin. The characterization of suspended particles is important for understanding regional primary productivity and rates of carbon sequestration, the fate of anthropogenic materials released to the coastal environment, as well as its effects on bulk optical properties, which influence the passive optical remote sensing of the coastal ocean. Here, the extensive bio-optical Plumes and Blooms data set is used to characterize the surface particle assemblage in the Santa Barbara Channel, California, a highly productive, upwelling-dominated, coastal site affected by episodic sediment inputs. Available variables sensitive to characteristics of the particle assemblage include particle beam attenuation and backscattering coefficients, High Performance Liquid Chromatography (HPLC) pigment concentration observations, chlorophyll and particulate organic carbon concentration, particulate and phytoplankton absorption coefficients, and Laser In-situ Scattering and Transmissometry (LISST) 100-X particle sizer observations. Comparisons among these particle assemblage proxy variables indicate good agreement and internal consistency among the data set. Correlations among chlorophyll concentration, particulate organic carbon concentration (POC), HPLC pigments, and proxies sensitive to the entire particle assemblage such as backscattering and LISST data strongly indicate that in spite of its coastal character, variability in the particle assemblage in the Santa Barbara Channel is dominated by its marine biogenic component. Relatively high estimates of the bulk real index of refraction and its positive correlation with chlorophyll and lithogenic silica concentration tentatively indicate that there is minerogenic particle influence in the Santa Barbara Channel that tends to covary with the phytoplankton blooms. Limitations of each particle assemblage proxy and remote-sensing applications are discussed.


Decision-making in ileocecal Crohn's disease management: surgery versus pharmacotherapy.
Ileocecal Crohn's disease (CD) can be treated medically as well as surgically. Both treatment modalities have been improved markedly in the last two decades, making CD more manageable. However, multidisciplinary research, addressing issues such as timing of surgery or medical treatment versus surgery, is scarce. Particularly in limited ileocecal CD, ileocolic resection might be a good alternative to long-term medical therapy. This review discusses the evidence on medical and surgical treatment options for ileocecal CD. It provides an aid in decision-making by discussing a treatment algorithm that can be used until further evidence on treatment is available.


[Sick sinus syndrome discovered after induction of general anesthesia in a patient with normal preoperative Holter ECG].
We reported a case of 50-year-old male who was found to have SSS after induction of general anesthesia though his preoperative cardiac function studies including Holter ECG were normal. He was scheduled to have anterior transposition of ulnar nerve for idiopathic ulnar nerve palsy. He had suffered from lung edema during the same operation about 10 months previously at another hospital and the cause had been unknown. We monitored direct radial artery pressure continuously before induction of general anesthesia. About 5 minutes after the induction, ECG showed bradycardia of less than 40.min-1 and systolic blood pressure decreased to 40 mmHg. Intravenous injection of atropine increased heart rate to 60.min-1 only transiently. We began continuous infusion of isoproterenol. It was effective and no bradycardia and hypotension occurred afterwards throughout the operation. About 2 months later, he showed severe dizziness and Holter ECG revealed sinus arrest for 5 seconds. Therefore, a permanent pacemaker was implanted.


Synaptic multiprotein complexes associated with 5-HT(2C) receptors: a proteomic approach.
Membrane-bound receptors such as tyrosine kinases and ionotropic receptors are associated with large protein networks structured by protein-protein interactions involving multidomain proteins. Although these networks have emerged as a general mechanism of cellular signalling, much less is known about the protein complexes associated with G-protein-coupled receptors (GPCRs). Using a proteomic approach based on peptide affinity chromatography followed by mass spectrometry and immunoblotting, we have identified 15 proteins that interact with the C- terminal tail of the 5-hydroxytryptamine 2C (5-HT(2C)) receptor, a GPCR. These proteins include several synaptic multidomain proteins containing one or several PDZ domains (PSD95 and the proteins of the tripartite complex Veli3-CASK-Mint1), proteins of the actin/spectrin cytoskeleton and signalling proteins. Coimmunoprecipitation experiments showed that 5-HT(2C) receptors interact with PSD95 and the Veli3-CASK-Mint1 complex in vivo. Electron microscopy also indicated a synaptic enrichment of Veli3 and 5-HT(2C) receptors and their colocalization in microvilli of choroidal cells. These results indicate that the 5-HT(2C) receptor is associated with protein networks that are important for its synaptic localization and its coupling to the signalling machinery.


Systematic Dissection of Sequence Elements Controlling σ70 Promoters Using a Genomically Encoded Multiplexed Reporter Assay in Escherichia coli.
Promoters are the key drivers of gene expression and are largely responsible for the regulation of cellular responses to time and environment. In Escherichia coli, decades of studies have revealed most, if not all, of the sequence elements necessary to encode promoter function. Despite our knowledge of these motifs, it is still not possible to predict the strength and regulation of a promoter from primary sequence alone. Here we develop a novel multiplexed assay to study promoter function in E. coli by building a site-specific genomic recombination-mediated cassette exchange system that allows for the facile construction and testing of large libraries of genetic designs integrated into precise genomic locations. We build and test a library of 10898 σ70 promoter variants consisting of all combinations of a set of eight -35 elements, eight -10 elements, three UP elements, eight spacers, and eight backgrounds. We find that the -35 and -10 sequence elements can explain approximately 74% of the variance in promoter strength within our data set using a simple log-linear statistical model. Simple neural network models explain >95% of the variance in our data set by capturing nonlinear interactions with the spacer, background, and UP elements.


Optimal use of arterial grafts during current coronary artery bypass surgery.
Multiple arterial grafting, including the use of the bilateral internal thoracic arteries (ITAs), has strong benefits on patient clinical outcomes after coronary artery bypass grafting (CABG) but is far from commonly accepted at present. We reviewed the previous randomized and leading observational studies and assembled an up-to-date profile on multiple arterial grafting. Many of the previous trials successfully showed the beneficial effects of arterial grafting after CABG. Although many of these were retrospective studies, the data presented, mostly from world-famous surgeons, show that multiple arterial grafting does have advantages with regard to the long-term patient outcome without increasing rates of early mortality or morbidity. However, it is true that some surgeons experience a certain amount of stress when using multiple arterial conduits. Multiple arterial reconstruction has a strong advantage for patients undergoing CABG and is now a standard worldwide strategy. Surgeons nowadays need to make efforts to master arterial conduit techniques properly to provide state-of-the-art CABG to patients.


Facile Synthesis of Cu/NiCu Electrocatalysts Integrating Alloy, Core-Shell, and One-Dimensional Structures for Efficient Methanol Oxidation Reaction.
The design and development of low-cost Pt-free, high-active, and durable noble-metal-free electrocatalysts for methanol electrooxidation is highly desirable but remains a challenge. Herein, unique Cu/NiCu nanowires (NWs) integrating alloy, core-shell, and one-dimensional structures are prepared by a facile one-pot strategy. It is found that the Ni-Cu surface alloying structure can effectively change the charge distribution of the atomic configuration, the core-shell structure can be optimized with the usage of Ni and Cu, and the one-dimensional structure can effectively enhance the charge transfer between the electrode surface and the active sites, making the prepared NWs promising electrocatalysts. Detailed catalytic investigations showed that the obtained Cu/NiCu NWs exhibit an enhanced electrocatalytic performance for methanol oxidation reaction (MOR). The optimized Cu/NiCu NWs in this work show a mass current density of 867.1 mA mgmetal-1 at 1.55 V (vs. RHE) for MOR, which is far higher than those of Ni-based previously reported electrocatalysts. This work opens up a new pathway for the design and engineering of noble-metal-free alloy electrocatalysts with enhanced activity and durability.


Camphor-related self-inflicted keratoconjunctivitis complicating delusions of parasitosis.
To report a case of camphor-related self-inflicted keratoconjunctivitis secondary to delusions of parasitosis. A 61-year-old man with delusions of parasitosis suffered from camphor-related self-inflicted ocular trauma that manifested with corneal epithelial defects and secondary anterior chamber reaction. Two episodes of exacerbation of the ocular conditions related to the use of camphor occurred. The left eye had secondary infection with Sternotrophomonas maltophilia and Staphylococcus aureus in the second episode of exacerbation. The right eye recovered well with the treatment of topical lubricants and corticosteroids and had best-corrected visual acuity (BCVA) of 20/25. The infection of the left eye led to corneal perforation, necessitating penetrating keratoplasty; BCVA was hand motions because of a mature cataract. Olanzapine therapy for 1 month to decrease the delusions of parasitosis and 24-hour watch to prevent the use of camphor led to the resolution of self-inflicted keratoconjunctivitis in the patient. Delusions of parasitosis may lead to vision-threatening self-inflicted ocular trauma. This may be the first case report of pure camphor-related self-inflicted toxic keratoconjunctivitis.


Photoconductivity Enhancement in Atomically Thin Molybdenum Disulfide through Local Doping from Confined Water.
Two-dimensional transition metal dichalcogenide (TMDC) materials have shown great potential for usage in opto-electronic devices, especially down to the regime of a few layers to a single layer. However, at these limits, the material properties can be strongly influenced by the interfaces. By using photoconductive atomic force microscopy, we show a local enhancement of photoconductivity at the nanoscale in bilayer molybdenum disulfide on mica, where water is confined between the TMDC and the substrate. We have found that the structural phase of the water influences the doping level and thus the tunneling barrier at the nanojunction. This leads to an increase in photocurrent and enhanced photopower generation.


Therapy-related Acute Myeloid Leukemia after the Long-term Administration of Low-dose Etoposide for Chronic-type Adult T-cell Leukemia-lymphoma: A Case Report and Literature Review.
A 61-year-old woman with chronic-type adult T-cell leukemia-lymphoma (ATL) had been taking low-dose oral etoposide for progressive lymphocytosis. After taking this for 3.5 years, she was diagnosed with therapy-related acute myeloid leukemia (t-AML), with a chromosomal translocation of t (6:11) (q27; q23). She thus received remission induction therapy, consolidation therapy, and allogeneic hematopoietic stem cell transplantation. Although both t-AML and ATL were in remissive states, she died of a therapy-related infection within 1 year. We reviewed 12 reported cases of AML complicating ATL to better characterize this unusual disease. We should therefore include t-AML in the differential diagnosis when administering low-dose etoposide for ATL over a long period of time.


Efficacy and safety of trifluridine/tipiracil plus ramucirumab in comparison with trifluridine/tipiracil monotherapy for patients with advanced gastric cancer-single institutional experience.
Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile in previous phase II trial. However, little is known about its efficacy and safety in clinical practice in comparison with trifluridine/tipiracil monotherapy. We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients. Forty-one patients receiving trifluridine/tipiracil plus RAM and 60 patients receiving trifluridine/tipiracil monotherapy were analyzed. The objective response rate (ORR) and the disease control rate (DCR) were 13.5% and 64.9% in the trifluridine/tipiracil plus RAM group, and 3.8% and 42.3% in the trifluridine/tipiracil monotherapy group, respectively (ORR; P = 0.122, DCR; P = 0.052). The median progression-free survival (PFS) and the median overall survival (OS) were 3.0 months and 7.2 months in the trifluridine/tipiracil plus RAM group, and 1.8 months and 3.8 months in the trifluridine/tipiracil monotherapy group, respectively (HR for PFS = 0.66; P = 0.059, HR for OS = 0.50; P = 0.007). Multivariate analysis showed significantly longer PFS (HR = 0.52; P = 0.011) and OS (HR = 0.51; P = 0.031) in the trifluridine/tipiracil plus RAM group compared to the trifluridine/tipiracil monotherapy group. No unexpected adverse events were observed in both groups. Trifluridine/tipiracil plus RAM might show favorable anti-tumor activity with an acceptable toxicity profile in comparison with trifluridine/tipiracil monotherapy, suggesting one treatment option for AGC patients in salvage line. The combination needs further evaluation in ongoing randomized trials.


A new group of aromatic prenyltransferases in fungi, catalyzing a 2,7-dihydroxynaphthalene 3-dimethylallyl-transferase reaction.
Five fungal genomes from the Ascomycota (sac fungi) were found to contain a gene with sequence similarity to a recently discovered small group of bacterial prenyltransferases that catalyze the C-prenylation of aromatic substrates in secondary metabolism. The genes from Aspergillus terreus NIH2624, Botryotinia fuckeliana B05.10 and Sclerotinia sclerotiorum 1980 were expressed in Escherichia coli, and the resulting His(8)-tagged proteins were purified and investigated biochemically. Their substrate specificity was found to be different from that of any other prenyltransferase investigated previously. Using 2,7-dihydroxynaphthalene (2,7-DHN) and dimethylallyl diphosphate as substrates, they catalyzed a regiospecific Friedel-Crafts alkylation of 2,7-DHN at position 3. Using the enzyme of A. terreus, the K(m) values for 2,7-DHN and dimethylallyl diphosphate were determined as 324 +/- 25 microM and 325 +/- 35 microM, respectively, and k(cat) as 0.026 +/- 0.001 s(-1). A significantly lower level of prenylation activity was found using dihydrophenazine-1-carboxylic acid as aromatic substrate, and only traces of products were detected with aspulvinone E, flaviolin, or 4-hydroxybenzoic acid. No product was formed with l-tryptophan, l-tyrosine, or 4-hydroxyphenylpyruvate. The genes for these fungal prenyltransferases are not located within recognizable secondary metabolic gene clusters. Their physiological function is yet unknown.


Protection of the Queuosine Biosynthesis Enzyme QueF from Irreversible Oxidation by a Conserved Intramolecular Disulfide.
QueF enzymes catalyze the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of the nitrile group of 7-cyano-7-deazaguanine (preQ₀) to 7-aminomethyl-7-deazaguanine (preQ₁) in the biosynthetic pathway to the tRNA modified nucleoside queuosine. The QueF-catalyzed reaction includes formation of a covalent thioimide intermediate with a conserved active site cysteine that is prone to oxidation in vivo. Here, we report the crystal structure of a mutant of Bacillus subtilis QueF, which reveals an unanticipated intramolecular disulfide formed between the catalytic Cys55 and a conserved Cys99 located near the active site. This structure is more symmetric than the substrate-bound structure and exhibits major rearrangement of the loops responsible for substrate binding. Mutation of Cys99 to Ala/Ser does not compromise enzyme activity, indicating that the disulfide does not play a catalytic role. Peroxide-induced inactivation of the wild-type enzyme is reversible with thioredoxin, while such inactivation of the Cys99Ala/Ser mutants is irreversible, consistent with protection of Cys55 from irreversible oxidation by disulfide formation with Cys99. Conservation of the cysteine pair, and the reported in vivo interaction of QueF with the thioredoxin-like hydroperoxide reductase AhpC in Escherichia coli suggest that regulation by the thioredoxin disulfide-thiol exchange system may constitute a general mechanism for protection of QueF from oxidative stress in vivo.


High-Resolution Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of PTP1B Inhibitors from Vietnamese Plants.
Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator in insulin signal transduction by deactivating the insulin receptor. Thus, PTP1B inhibition has emerged as a potential therapeutic strategy for curing insulin resistance. In this study, 40 extracts from 18 different plant species were investigated for PTP1B inhibitory activity in vitro. The most promising one, the EtOAc extract of Ficus racemosa, was investigated by high-resolution PTP1B inhibition profiling combined with HPLC-HRMS-SPE-NMR analysis. This led to the identification of isoderrone (1), derrone (2), alpinumisoflavone (3) and mucusisoflavone B (4) as PTP1B inhibitors. IC50 of these compounds were 22.7 ± 1.7, 12.6 ± 1.6, 21.2 ± 3.8 and 2.5 ± 0.2 µM, respectively. Kinetics analysis revealed that these compounds inhibited PTP1B non-competitively with Ki values of 21.3 ± 2.8, 7.9 ± 1.9, 14.3 ± 2.0, and 3.0 ± 0.5 µM, respectively. These findings support the important role of F. racemosa as a novel source of new drugs and/or as a herbal remedy for treatment of type 2 diabetes.


Acute Liver Failure From Sickle Cell Hepatopathy Treated With Exchange Transfusion.
Sickle cell disease (SCD) is a qualitative hemoglobinopathy that can cause widespread sickling and vaso-occlusive events in all organ systems. Sickle cell hepatopathy is an umbrella term for various acute and chronic pathologies of the liver as a result of sickling in SCD patients. We present below the case of a 49-year-old woman who had an acute liver failure in the setting of a hepatic crisis with recovery after exchange transfusion. Hepatic involvement in SCD may be life-threatening. Understanding the etiology and severity of hepatic involvement by sickling is necessary for appropriate treatment.


Adaptive designs for confirmatory clinical trials with subgroup selection.
Growing interest in stratified medicine is leading to increasing importance of subgroup analyses in confirmatory clinical trials. Conventionally, confirmatory clinical trials either focus on a subgroup identified in advance or assess subgroup effects once the trial is completed. The focus of this article is methodology for adaptive clinical trials that both identify whether a treatment is particularly effective in a predefined subgroup, potentially enabling alteration of recruitment, and assess the effectiveness in the subgroup and/or whole population. Methods for such adaptive trials are described and compared, and the logistical and regulatory issues associated with such approaches are discussed.


Characterization of two Drosophila POU domain genes, related to oct-1 and oct-2, and the regulation of their expression patterns.
We have characterized two genes from Drosophila melanogaster that encode proteins with POU domains showing a high degree of identity with the human Oct-1 and Oct-2 transcription factors. These POU domain genes, pdm-1 and pdm-2, are expressed at high levels during early embryogenesis and at lower levels throughout the rest of development. Both genes are expressed as two stripes in the presumptive abdominal region during the blastoderm stage, followed by thirteen stripes in the germ band extended stage. This pattern of expression is altered in mutants for a gap gene (hunchback) and a pair-rule gene (fushi tarazu). In later stage embryos, both pdm-1 and pdm-2 are expressed in selected neuroblasts in the ventral nervous system, with higher levels in the three thoracic segments and lower levels in the abdominal segments. The low level of expression in the abdominal segments is maintained by the genes within the bithorax complex (BX-C). We have also identified the cells in the dorsal and lateral clusters of the peripheral nervous system that express pdm-1 and pdm-2, and show that some of these cells derive from lineages that require BX-C functions. Together, these results suggest that previously characterized members of the embryonic regulatory hierarchy specify the patterns of the POU domain gene expression, which, in turn, function during neurogenesis and perhaps in earlier stages.


Polynomial spline estimation and inference of proportional hazards regression models with flexible relative risk form.
The Cox proportional hazards model usually assumes an exponential form for the dependence of the hazard function on covariate variables. However, in practice this assumption may be violated and other relative risk forms may be more appropriate. In this article, we consider the proportional hazards model with an unknown relative risk form. Issues in model interpretation are addressed. We propose a method to estimate the relative risk form and the regression parameters simultaneously by first approximating the logarithm of the relative risk form by a spline, and then employing the maximum partial likelihood estimation. An iterative alternating optimization procedure is developed for efficient implementation. Statistical inference of the regression coefficients and of the relative risk form based on parametric asymptotic theory is discussed. The proposed methods are illustrated using simulation and an application to the Veteran's Administration lung cancer data.


Potential Application of Cephalosporins Carried in Organic or Inorganic Nanosystems against Gram-Negative Pathogens.
Cephalosporins are β-lactam antibiotics, classified into five generations and extensively used in clinical practice against infections caused by Gram-negative pathogens, including Enterobacteriaceae and P. aeruginosa. Commercially, conventional pharmaceutical forms require high doses to ensure clinical efficacy. Additionally, β-lactam resistance mechanisms, such as the production of enzymes (called extended-spectrum β-lactamases) and the low plasma half-life of these antibiotics, have been challenging in clinical therapy based on the use of cephalosporins. In this context, its incorporation into nanoparticles, whether organic or inorganic, is an alternative to temporally and spatially control the drug release and improve its pharmacokinetic and pharmacodynamic limitations. Considering this, the present review unites the cephalosporins encapsulated into organic and inorganic nanoparticles against resistant and nonresistant enterobacteria. We divide cephalosporin generation into subtopics in which we discuss all molecules approved by regulatory agencies. In addition, changes in the side chains at positions R1 and R2 of the central structure of cephalosporins for all semisynthetic derivatives developed were discussed and presented, as the changes in these groups are related to modifications in pharmacological and pharmacokinetic properties, respectively. Ultimately, we exhibit the advances and differences in the release profile and in vitro activity of cephalosporins incorporated in different nanoparticles.


Clinical characteristics of polypoidal choroidal vasculopathy in Chinese patients.
To describe the clinical characteristics of polypoidal choroidal vasculopathy (PCV) in a large number of Chinese patients. This study enrolled 204 consecutive patients (246 eyes) in our department who were diagnosed as having polypoidal choroidal vasculopathy PCV. Patients underwent ophthalmologic examinations including best-corrected visual acuity (BCVA) testing, ophthalmoscopy, fundus photography, fluorescein angiography, indocyanine green angiography, and optic coherence tomography. Mean patient age was 66.1 years and 60.3% were men. Of the cases, 79.4% were unilateral and 51.2% of BCVA was less than 35 letters. In 171 eyes (69.5%), polypoidal lesions were located in the macula area. Among them, polypoidal lesions were located in the foveal area in 29 eyes (11.8%), in the parafoveal area in 50 eyes (20.3%), and in the extrafoveal area in 88 eyes (35.8%), in both the foveal and parafoveal area in three eyes (1.2%), and in both the parafoveal and extrafoveal area in one eye (0.4%). In 37 eyes (15.0%), PCV lesions were under the temporal retinal vascular arcade; in 11 eyes (4.5%), PCV lesions were found peripapillary. PCV lesion formation was single in 88 eyes (35.8%), cluster in 145 eyes (59.0%), string in two eyes (0.8%), and branch in two eyes (0.8%). In nine eyes (3.6%), the formation of PCV lesions showed both single and cluster shape in the same eye. There were 54.5% with drusen, 44.7% with serous PED, 20.7% with hemorrhagic PED, and 39.0% with neuroretinal detachment. The majority of Chinese PCV patients were male, unilateral, and showed macular polyps. Drusen, serous PED, hemorrhagic PED, and neuroretinal detachment on OCT were commonly seen.


Pain Management With Bilateral Continuous Thoracic Paravertebral Block in a Patient With Fontan-Associated Hepatocellular Carcinoma Undergoing Hepatectomy.
We report a case of perioperative management of a single-ventricle patient with Fontan-associated liver disease undergoing hepatectomy. A 12-year-old boy with Fontan circulation was scheduled for partial hepatectomy to remove a liver mass in segment 6. He received stent implantation to relieve conduit stenosis 6 months before the operation. The operation was performed under general anesthesia and with a bilateral thoracic paravertebral block (PVB). A continuous paravertebral infusion of levobupivacaine was administered via right and left catheters postoperatively. He was hemodynamically stable throughout the perioperative period, extubated soon after surgery, and had an uncomplicated postoperative course. An analgesic regimen including thoracic PVB resulted in a rapid recovery without opioid-related side effects and early reinitiation of anticoagulation therapy. Our case illustrates the effective application of thoracic PVB in congenital heart disease patients for non-cardiac-related surgery.


Balance of powers: Social Security and the mentally disabled, 1980-1985.
Concern about costs in the early 1980s led both Congress and the newly installed Reagan administration to initiate an intensive review of eligibility for disability benefits under the Social Security system. Within a year it became apparent that a high percentage of mentally disabled were being declared ineligible. Much of the problem derived from the use of outdated criteria to determine mental disability. After a protracted struggle, the executive branch yielded to pressure from various advocacy groups, as well as the judiciary and legislative branches, and began to revise the criteria on the basis of contemporary psychiatric and rehabilitation standards.


[Experimental study on anti-angiogenesis in mice with Lewis lung carcinoma by low-dose of cyclophosphamide combined with ginsenoside Rg3].
To evaluate the anti-angiogenetic effect of the combination of low-dose cyclophosphamide(CTX) and ginsenoside Rg3 in mice with Lewis lung carcinoma, and to observe the anti-tumor effect, toxicity, adverse reaction of the treatment and survival time of the tumor bearing mice. Holland C57/ BL6 Lewis lung carcinoma mice were taken as the model and randomly divided into 5 groups, i.e. the low-dose CTX (LDCTX) group, the maximum tolerable dose CTX (MTDCTX) group, the ginsenoside Rg3 (Rg3) group, the low-dose CTX combined with ginsenoside Rg3 group (LDCTX + Rg3), and the model group. Tumor volume, weight of mice, peripheral white blood cell counts and survival time of mice were observed, tumor microvascular density (MVD) and vascular endothelial growth factor (VEGF) gene expression were determined during the therapeutic course. In the LDCTX group, tumor grew comparatively slow, no significant decrease in body weight or peripheral white blood cells, and survival time was prolonged. In the LDCTX + Rg3 group, the tumor inhibitory effect was more persistent and steady without any increase of toxicity or adverse reaction. Besides, the survival time of mice was prolonged (P < 0.01). MVD was lower in the LDCTX group than that in the MTDCTX group (P< 0. 05). Compared with the model group, MVD and VEGF expression were lower in the LDCTX and the Rg3 group, and the lowering action was more significant when the two drugs were used in combination (P < 0.05). The combination of low-dose CTX and Rg3 has obvious synergetic action of anti-angiogenesis, it shows significant and persistent tumor inhibitory effect, with less toxic and adverse reaction, and could induce longer survival time than treatment of CTX or Rg3 alone.


Individual variation and the challenge hypothesis.
In this paper I discuss how the challenge hypothesis (Wingfield et al., 1990) influenced the development of ideas about animal personality, and describe particularly promising areas for future study at the intersection of these two topics. I argue that the challenge hypothesis influenced the study of animal personality in at least three specific ways. First, the challenge hypothesis drew attention to the ways in which the environment experienced by an organism - including the social environment - can influence biological processes internal to the organism, e.g. changes to physiology, gene expression, neuroendocrine state and epigenetic modifications. That is, the challenge hypothesis illustrated the bidirectional, dynamic relationship between hormones and (social) environments, thereby helping us to understand how behavioral variation among individuals can emerge over time. Because the paper was inspired by data collected on free living animals in natural populations, it drew behavioral ecologists' attention to this phenomenon. Second, the challenge hypothesis highlighted what became a paradigmatic example of a hormonal mechanism for a behavioral spillover, i.e. testosterone's pleiotropic effects on both territorial aggression and parental care causes aggression to "spillover" to influence parenting behavior, thereby limiting behavioral plasticity. Third, the challenge hypothesis contributed to what is now a cottage industry examining individual differences in hormone titres and their relationship with behavioral variation. I argue that one particularly promising future research direction in this area is to consider the active role of behavior and behavioral types in eliciting social interactions, including territorial challenges.


Optimizing the embryo transfer technique.
The technique of embryo transfer is very crucial and great attention and time should be given to this step. In order to optimize the embryo transfer technique, several precautions should be taken. The first and most important is to avoid the initiation of uterine contractility. This can be achieved by the use of soft catheters, gentle manipulation and by avoiding touching the fundus. Secondly, proper evaluation of the uterine cavity and utero-cervical angulation is very important, and can be achieved by performing dummy embryo transfer and by ultrasound evaluation of the utero-cervical angulation and uterine cavity length. Another important step is the removal of cervical mucus so that it does not stick to the catheter and inadvertently remove the embryo during catheter withdrawal. Finally, one has to be absolutely sure that the embryo transfer catheter has passed the internal cervical os and that the embryos are delivered gently inside the uterine cavity.


Acute myeloid leukemia or myelodysplastic syndrome with chromosome 17 abnormalities and long-term outcomes with or without hematopoietic stem cell transplantation.
Chromosome 17 abnormalities, especially disorders of the 17p region and including TP53 gene mutations, result in very low rates of cure for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) treated with conventional chemotherapy or allogeneic hematopoietic cell transplant (allo-HCT). Our retrospective study analyzed outcomes in patients with chromosome 17 (ch17) abnormalities who received conventional chemotherapy followed by allo-HCT versus those who did not receive a transplant. We analyzed whether poor outcomes extend to patients with all types of ch17 abnormalities and the impact of concomitant TP53 gene mutations assessed by next-generation sequencing (NGS) on prognosis. We retrospectively analyzed diagnostic and outcome data on 98 patients treated at our institution from 2012 to 2018 with AML or MDS who possessed ch17 abnormalities by cytogenetic analysis. The presence of TP53 mutations was analyzed by NGS. Primary endpoint of our study was overall survival (OS). 61 patients with AML and 37 with MDS were included. Complete remission (CR) with first line treatment was similar between induction chemotherapy or hypomethylating agents (HMA), 22.9 % versus 21.6 % (p = 0.33). Median OS for all patients (with or without transplant) was 10 months. Patients with abnormal ch17 in conjunction with any TP53 mutation(s) exhibited worse OS compared to patients without a TP53 mutation (10 versus 23 months, p = 0.02). 30 patients (19 AML, 11 MDS) underwent HCT, with a median OS of 11 months. For AML patients who underwent allo-HCT, 18 were in CR (13 with cytogenetic remission) and 1 had persistent disease at transplant. In the MDS cohort, 3 patients were in CR (2 with cytogenetic remission) and 8 had stable disease. Post allo-HCT survival of AML and MDS cohorts did not differ (p = 0.6), although cytogenetic CR at time of HCT trended towards improved OS (17 versus 8 months; p = 0.6). AML/MDS patients with ch17 abnormalities have poor outcomes with or without HCT. Our results show that patients with ch17 abnormalities and TP53 mutations have a significantly poorer survival compared to patients who have ch17 abnormalities but no TP53 mutations. Drugs targeting abnormalities of the p53 pathway, improvement in depth of response prior to HCT, and novel maintenance strategies are needed for improved outcomes in these patients.


Laparoscopic colectomy in the obese, morbidly obese, and super morbidly obese: when does weight matter?
Previous studies have demonstrated that obese patients (BMI >30) undergoing laparoscopic colectomy have longer operative times and increased complications when compared to non-obese cohorts. However, there is little data that specifically evaluates the outcomes of obese patients based on the degree of their obesity. The aim of this study was to evaluate the impact of increasing severity of obesity on patients undergoing laparoscopic colectomy. A retrospective review was performed of all patients undergoing laparoscopic colectomy between 1996 and 2013. Patients were classified according to their BMI as obese (BMI 30.0-39.9), morbidly obese (BMI 40.0-49.9), and super obese (BMI >50). Main outcome measures included conversion rate, operative time, estimated blood loss, post-operative complications, and length of stay. There were 923 patients who met inclusion criteria. Overall, 604 (65.4%), 257 (27.9%), and 62 (6.7%) were classified as obese (O), morbidly obese (MO), and super obese (SO), respectively. Clinicopathologic characteristics were similar among the three groups. The SO group had significantly higher conversion rates (17.7 vs. 7 vs. 4.8%; P = 0.031), longer average hospital stays (7.1 days vs. 4.9 vs. 3.4; P = 0.001), higher morbidity (40.3 vs. 16.3 vs. 12.4%; P = 0.001), and longer operative times (206 min vs. 184 vs. 163; P = 0.04) compared to the MO and O groups, respectively. The anastomotic leak rate in the SO (4.8%; P = 0.027) and MO males (4.1%; P = 0.033) was significantly higher than MO females (2.2%) and all obese patients (1.8%). Increasing severity of obesity is associated with worse perioperative outcomes following laparoscopic colectomy.


Probiotics: Isolated bacteria strain or mixtures of different strains? Two different approaches in the use of probiotics as therapeutics.
Probiotics are cultures of beneficial bacteria from the healthy gut microflora that improve the balance of the intestinal milieu by modifying the intestinal microflora and suppressing enhanced inflammatory responses. Probiotics are currently the subject of intense and widespread research as functional foods since they are known to induce health benefits, may be used as pharmaceutical preparations, and have achieved a "generally recognized as safe" (GRAS) status. Lactobacillus strains can also be genetically engineered for use in oral immunotherapeutic applications, such as vaccination and delivery of immunoregulatory substances. In the present review we evaluate the two different approaches to the therapeutic use of probiotics. We also focus on recent findings in the field of molecular biology and genetics of the intestinal immune response related to the microflora and intestinal ecology, in order to understand the mechanisms of action of probiotics and their present indications in gastrointestinal diseases. Finally, with a view to future perspectives we provide some examples of probiotics that are being assessed and have great potential in improving the health of animals and man.


Generalization of the Minkwitz theorem to nonumbilical lines of symmetrical surfaces.
The linear relation between the increase of peripheral astigmatism and the increase of power along an umbilical line was described by Minkwitz and is known as the Minkwitz theorem. However, in many cases, modern progressive addition lenses do not show an umbilical principal line. Therefore, we propose to extend the Minkwitz theorem to nonumbilical lines and higher order terms than the linear term of the increase in the peripheral astigmatism. We were able to derive a "generalized Minkwitz theorem," which holds true for a prescribed astigmatism at the principal line. The derived generalized Minkwitz theorem also indicates that the increase of the astigmatism perpendicular to the principal line depends not only on the power increase, as described by the Minkwitz theorem, but also on the astigmatism increase along the principal line. The Minkwitz theorem itself is a special case of this generalization.


Vascular pharmacology of a novel cannabinoid-like compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the rat.
A putative novel cannabinoid receptor mediates vasorelaxation to anandamide and abnormal-cannabidiol and is blocked by O-1918 and by high concentrations of rimonabant. This study investigates VSN16, a novel water-soluble agonist, as a vasorelaxant potentially acting at non-CB1, non-CB2 cannabinoid receptors in the vasculature. VSN16 and some analogues were synthesized and assayed for vasodilator activity in the rat third generation mesenteric artery using wire myography. Also carried out with VSN16 were haemodynamic studies in conscious rats and binding studies to CB1 receptors of rat cerebellum. VSN16 relaxed mesenteric arteries in an endothelium-dependent manner. The vasorelaxation was antagonized by high concentrations of the classical cannabinoid antagonists, rimonabant and AM 251, as well as by O-1918, an antagonist at the abnormal-cannabidiol receptor but not at CB1 or CB2 receptors. It did not affect [3H]CP55,940 binding to CB1 receptors in rat cerebellum. The vasorelaxation was not pertussis toxin-sensitive but was reduced by inhibition of nitric oxide synthesis, Ca(2+)-sensitive K+ channels (KCa) and TRPV1 receptors. In conscious rats VSN16 transiently increased blood pressure and caused a longer-lasting increase in mesenteric vascular conductance. Structure-activity studies on vasorelaxation showed a stringent interaction with the target receptor. VSN16 is an agonist at a novel cannabinoid receptor of the vasculature. It acts on the endothelium to release nitric oxide and activate KCa and TRPV1. As it is water-soluble it might be useful in bringing about peripheral cannabinoid-like effects without accompanying central or severe cardiovascular responses.


25-hydroxyvitamin D concentrations during fetal life and bone health in children aged 6 years: a population-based prospective cohort study.
25-hydroxyvitamin D (25[OH]D) concentrations during fetal life might have long-lasting effects on skeletal development, but results from previous studies are inconsistent. We investigated the associations of maternal and fetal 25(OH)D concentrations with childhood bone health. In a prospective multiethnic population-based cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), pregnant women living in the study area with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible for participation in the study at our research centre in the Erasmus MC-Sophia Children's Hospital. We measured maternal 25(OH)D concentrations during mid-pregnancy (at a median of 20·4 weeks gestation [IQR 19·9-21·1]) and fetal 25(OH)D concentrations at birth (at a median of 40·1 weeks gestation [39·3-41·0]). We measured total-body bone mineral density, bone mineral content (BMC), area-adjusted BMC, and bone area using dual-energy X-ray absorptiometry (DXA) in offspring at 6 years of age. We examined associations using multivariable linear regression models, adjusted for several sociodemographic and lifestyle variables, and for child's height. We enrolled 9901 mother-and-child pairs and obtained both mid-pregnancy maternal 25(OH)D concentrations and offspring DXA scans at age 6 years in 4815 pairs. Severe maternal 25(OH)D deficiency (<25 nmol/L) during mid-pregnancy was associated with higher offspring BMC (4·71 g, 95% CI 1·09 to 8·33; p=0·011) and larger bone area (7·54 cm2, 2·99 to 12·11; p=0·001) at age 6 years, compared with maternal 25(OH)D sufficiency (≥50 nmol/L) during mid-pregnancy. However, in a subgroup of children with available data on 25(OH)D concentrations at 6 years (n=3034), such associations for BMC (4·67 g, -0·05 to 9·39; p=0·052) and bone area (5·25 cm2, -0·41 to 10·91; p=0·069) were no longer significant after adjustment for the child's own 25(OH)D concentrations. No associations were seen between maternal 25(OH)D concentrations in mid-pregnancy and offspring bone mineral density (1·07 mg/cm2, -1·84 to 3·99; p=0·47) or area-adjusted BMC (-1·58 g, -4·72 to 1·61; p=0·32), and the association with skeletal parameters at 6 years did not differ by maternal BMI, maternal calcium intake, child sex, or weight status. Similar associations were seen with fetal 25(OH)D concentrations at birth. We found inverse associations between 25(OH)D concentrations during fetal life with BMC and bone area in childhood, but these associations were no longer significant after adjustment for childhood 25(OH)D status. Our data suggest that 25(OH)D concentrations during childhood might be more relevant for bone outcomes than than 25(OH)D concentrations during fetal life. Erasmus University Medical Center, Organization for Health Research and Development (ZonMw), Organization for Scientific Research (NWO), the Ministry of Health, Welfare and Sport.


Commonly used medications and endometrial cancer survival: a population-based cohort study.
Increasing incidence and new indications for existing drugs make it important to identify new adjuvant therapies for endometrial cancer (EC). This is a prospective cohort study of 3058 newly diagnosed EC cases from 1998 to 2010, identified through record linkages between the UK Clinical Practice Research Datalink, the National Cancer Research Datalink and death registrations from the Office of National Statistics. Using Cox regression models, unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for EC-specific survival. Over a mean 6.1 (range 1-16) years of follow-up, there were 394 EC-specific deaths. There was no evidence of a significant association between post-diagnostic use of statins (adjusted HR 0.83, 95% CI 0.64, 1.08), β-blockers (adjusted HR 0.86, 95% CI 0.65, 1.13) or low-dose aspirin (adjusted HR 0.91, 95% CI 0.69, 1.20) and EC survival before or after adjustment for confounders. There were also no evidence of a dose-response association between these drug groups and EC survival. In this large UK population-based study, no significant associations were observed for post-diagnostic use of statins, β-blockers or low-dose aspirin and EC survival.


History of the recurrent laryngeal nerve: from Galen to Lahey.
During the second century A.D., Galen described a nerve that came from the brain on each side of the neck, went down toward the heart, and then reversed course and ascended to the larynx and caused the vocal cords to open. He called these "reversivi" (or recurrent nerves) and stated that he was the first to discover "these wonderful things." Demonstrating before the elders of Rome, he showed that cutting the recurrent laryngeal nerve in the neck caused a live pig to stop squealing-an extraordinary feat. Because of Galen's fame and influence, this nerve retained great importance in dissections by later anatomists and surgeons before and throughout the Renaissance. This paper documents many of these anatomical findings and highlights the importance of a careful, delicate, recurrent laryngeal nerve dissection during thyroidectomy, as popularized by Dr. Frank Lahey in 1938.


Insights into eastern health care: some transcultural nursing perspectives.
This paper describes the author's formal introduction to Eastern holistic health care while attending a conference in India. The author discusses reasons for the Western interest in Eastern health care concepts and practices, and examines the ancient holistic system of Ayurveda medicine. Leininger's (1991) three modes of action from her theory of Culture Care are examined to suggest nursing care decisions and actions that could assist nurses to provide culturally congruent care to individuals who prefer Ayurveda to traditional Western health care practices. Similarities and differences between Western and Ayurvedic approaches to health care are discussed.


Trichoderma Histone Deacetylase HDA-2 Modulates Multiple Responses in Arabidopsis.
Trichoderma spp. are a rich source of secondary metabolites and volatile organic compounds (VOCs), which may induce plant defenses and modulate plant growth. In filamentous fungi, chromatin modifications regulate secondary metabolism. In this study we investigated how the absence of histone deacetylase HDA-2 in the Trichoderma atroviride strain Δhda-2 impacts its effect on a host, Arabidopsis (Arabidopsis thaliana). The production of VOCs and their impact on plant growth and development were assessed as well. The Δhda-2 strain was impaired in its ability to colonize Arabidopsis roots, thus affecting the promotion of plant growth and modulation of plant defenses against foliar pathogens Botrytis cinerea and Pseudomonas syringae, which normally result from interaction with T. atroviride Furthermore, Δhda-2 VOCs were incapable of triggering plant defenses to counterattack foliar pathogens. The Δhda-2 overproduced the VOC 6-pentyl-2H-pyran-2-one (6-PP), which resulted in enhanced root branching and differentially regulated phytohormone-related genes. Analysis of ten VOCs (including 6-PP) revealed that three of them positively regulated plant growth, whereas six had the opposite effect. Assessment of secondary metabolites, detoxification, and communication with plant-related genes showed a dual role for HDA-2 in T. atroviride gene expression regulation during its interaction with plants. Chromatin immunoprecipitation of acetylated histone H3 on the promoters of plant-responsive genes in Δhda-2 showed, in the presence of Arabidopsis, low levels of epl-1 and abc-2 compared with that in the wild type; whereas ctf-1 presented high constitutive levels, supporting a dual role of HDA-2 in gene regulation. This work highlights the importance of HDA-2 as a global regulator in Trichoderma to modulate multiple responses in Arabidopsis.


The current role of staging laparoscopy for adenocarcinoma of the pancreas: a review.
In the absence of metastatic disease patients with localized or locally advanced pancreatic cancer can benefit from surgical resection or chemoradiation. Despite the advances of imaging technology, however, noninvasive staging modalities are still inaccurate in identifying small volume metastatic disease leading potentially to inappropriate treatment and avoidable morbidity in a subgroup of patients. Staging laparoscopy may identify those patients with unsuspected metastatic disease on preoperative imaging and prevent unnecessary laparotomy or chemoradiation. A controversy exists, however, as to whether the procedure should be used routinely or selectively in pancreatic cancer patients with no evidence of metastasis on noninvasive staging. This review aims to assess the current role of staging laparoscopy by examining its diagnostic accuracy and ability to prevent unnecessary treatment as well as its morbidity, oncologic effect and cost-effectiveness. The available literature will be evaluated critically, its limitations identified and exisiting controversies addressed.


Google Maps offers a new way to evaluate claudication.
Accurate determination of walking capacity is important for the clinical diagnosis and management plan for patients with peripheral arterial disease. The current "gold standard" of measurement is walking distance on a treadmill. However, treadmill testing is not always reflective of the patient's natural walking conditions, and it may not be fully accessible in every vascular clinic. The objective of this study was to determine whether Google Maps, the readily available GPS-based mapping tool, offers an accurate and accessible method of evaluating walking distances in vascular claudication patients. Patients presenting to the outpatient vascular surgery clinic between November 2013 and April 2014 at the Ottawa Hospital with vasculogenic calf, buttock, and thigh claudication symptoms were identified and prospectively enrolled in our study. Onset of claudication symptoms and maximal walking distance (MWD) were evaluated using four tools: history; Walking Impairment Questionnaire (WIQ), a validated claudication survey; Google Maps distance calculator (patients were asked to report their daily walking routes on the Google Maps-based tool runningmap.com, and walking distances were calculated accordingly); and treadmill testing for onset of symptoms and MWD, recorded in a double-blinded fashion. Fifteen patients were recruited for the study. Determination of walking distances using Google Maps proved to be more accurate than by both clinical history and WIQ, correlating highly with the gold standard of treadmill testing for both claudication onset (r = .805; P < .001) and MWD (r = .928; P < .0001). In addition, distances were generally under-reported on history and WIQ. The Google Maps tool was also efficient, with reporting times averaging below 4 minutes. For vascular claudicants with no other walking limitations, Google Maps is a promising new tool that combines the objective strengths of the treadmill test and incorporates real-world walking environments. It offers an accurate, efficient, inexpensive, and readily accessible way to assess walking distances in patients with peripheral vascular disease.


Biomechanical comparison of tension band suture fixation and tension band wiring in olecranon fractures.
Traditional tension band wire fixation (TBWF) of olecranon fractures is associated with high revision rates due to implant-related complications. The purpose of the study was to compare the strength of fixation in olecranon fractures between TBWF and an all-suture based technique. A transverse fracture was created in 20 paired fresh-frozen human cadaveric elbows. Fractures were randomly (alternating right-left) assigned for fixation with either tension band suture fixation (TBSF) or TBWF. The elbow was fixed in 90° of flexion and underwent cycling loading by pulling the triceps tendon to 300 N for 200 cycles. Fracture displacement was optically recorded using digital image correlation (DIC). Finally, load-to-failure was assessed by a monotonic pull to 1000 N and failure mechanism was recorded. Two specimens in the TBSF group were excluded from the cycling loading analysis due to technical difficulties with the DIC. After cyclic loading, median (min-max) fracture displacement was 0.28 mm (0.10-0.44) in the TBSF group and 0.18 mm (0.00-1.48) in the TBWF group (p = 0.315). No difference was found between the two groups in the repeated measures analysis of variance (p = 0.329). In the load-to-failure test, 6/10 specimens failed in the TBSF group (median load-to-failure 791 N) vs. 8/10 in the TBWF group (median load-to-failure 747 N). The TBSF constructs failed due to fracture of the dorsal cortex, suture breakage or triceps failure. The TBWF constructs failed due to breakage of the wire. There was no difference in fixation strength between the TBWF and TBSF constructs. Our findings suggest TBSF to be a feasible alternative to TBWF and we hypothesize that a non-metallic implant may have fewer implant-related complications. Basic science study.


Predictive and prognostic factors in the complex treatment of patients with colorectal cancer.
Colon cancer is the second most prevalent lethal cancer. The main cause for high mortality rate is that the prognosis for progressed metastatic colon cancer is most unfavorable. Recent data suggest that disease outcome can be further improved by the addition of targeted biological agents to the first- or second-line treatment. As a result of molecularly targeted anti-EGFR therapies (cetuximab and panitumumab) complementing chemotherapy, liver metastases can reduce in size and become operable in certain patients, which can contribute to the complete recovery of the patient. The main problem, however, is the fact that a positive response only occurs in one third of the patients, even in the case of chemotherapy combined protocol, and the side effects are considerable. For the application of individually tailored treatments, it is an urgent need to develop a system of biomarkers that can predict the effect of treatment and provide information about the optimal selection of both chemotherapy and biological treatment. It should be clarified what the most important requirements of a good and reliable biomarker are. As currently there is no precise predictive molecular diagnostics at our disposal, oncologists have to make one of two choices: they treat a large number of patients with anti-EGFR agents which has negative effects on the quality of life and also reduces the patient's chances of getting appropriate treatment or, if the oncologists refuse to take risks, they omit the use of anti-EGFR treatment in which case those patients for whom this would have been the appropriate treatment are also denied the chance of short-term survival or recovery. Clinical data (response rate, time to progression (TTP) and overall survival (OS)) of 130 colorectal cancer patients have been retrospectively analyzed. Patients have received different chemotherapy protocols in combination with anti-VEGF antibody or with anti-EGFR antibody therapies. EGFR expression was evaluated with immunohistochemistry, KRAS, BRAF and PIK3CA mutations were evaluated by direct sequencing and high resolution melting analysis in the archived formalin-fixed, paraffin-embedded tissue samples. The study found similar efficacy of first-line therapeutic protocols. Protocols combining chemotherapy with biological therapies achieved better overall survival but this difference was not significant (OS: 35.9 versus 36.7 months). The frequency of KRAS mutations was 44% (n=100). None of the KRAS mutant tumors responded to the anti-EGFR monotherapy. TTP in the case of cetuximab monotherapy was twice longer (208 months) than in the KRAS mutant tumors (104 months). One BRAF mutant tumor was also identified (4%) This tumor was also resistant to cetuximab monotherapy. The KRAS and BRAF mutations excluded each other. Except one case, the KRAS status was identical in both the primary tumor and the metastasis. In contrast, PIK3CA mutations were heterogeneous in different tumor samples. In 5 out of 6 cases the mutation status of PIK3CA was different in the primary tumor and the metastasis. New biological therapies provide an additional clinical benefit only for a subset of patients. We need biomarkers to identify these patients. KRAS and most probably BRAF testing can double the efficacy of the anti-EGFR therapies, but we need additional molecular diagnostic tests. PIK3CA is an important candidate but we might need to take biopsy directly from the metastasis or we have to evaluate the circulating tumor cells to judge the molecular status of distant metastasis.


[Unstable or hyperkinetic children. A comparative study of the concepts].
In this literature, the authors analyze and compare the concepts of instability and hyperkinesia. One historic chapter shows that we are dealing with two parallel bibliographies that don't cross-check. It's a question of two different ways of naming and describing the same children. A differential semiological analysis in relation to three conceptual pairs, chosen because of their key positions (agitation-excitation, motor weakness-dyspraxia, personality problems-psychopathy) shows that it's sometimes impossible to clearly separate instability-hyperkinesia from these other concepts, insofar as they have been blown out of proportion and deformed. Nosographic categories overlap and cross-penetrate each other, which greatly limits their interest. Finally, it seems as if instability, a vast idea originally, had been progressively dismembered to the advantage of other categories, then disappeared from french literature entirely only to be replaced by hyperkinesia. This hyperkinesia can be taken literally as a personality disorder like any other, and also covers whatever is left of "instability". But the very concept of hyperkinesia, as was the case with instability, is blurred. The idea of MBD, and currently TDA, has historically been placed as a return to a huge category encompassing disorders that instability had progressively been differentiated from, and might be an attempt to anchor this nosology more firmly in medical speech. But the amalgam of social, physiological and psychological data resolves nothing and the problem remains intact.


Grief after second-trimester termination for fetal anomaly: a qualitative study.
We aimed to qualitatively evaluate factors that contribute to and alleviate grief associated with termination of a pregnancy for a fetal anomaly and how that grief changes over time. We conducted a longitudinal qualitative study of decision satisfaction, grief and coping among women undergoing termination (dilation and evacuation or induction termination) for fetal anomalies and other complications. We conducted three post-procedure interviews at 1-3 weeks, 3 months and 1 year. We used a generative thematic approach to analyze themes related to grief using NVivo software program. Of the 19 women in the overall study, 13 women's interviews were eligible for analysis of the grief experience. Eleven women completed all three interviews, and two completed only the first interview. Themes that contributed to grief include self-blame for the diagnosis, guilt around the termination decision, social isolation related to discomfort with abortion and grief triggered by reminders of pregnancy. Social support and time are mechanisms that serve to alleviate grief. Pregnancy termination in this context is experienced as a significant loss similar to other types of pregnancy loss and is also associated with real and perceived stigma. Women choosing termination for fetal anomalies may benefit from tailored counseling that includes dispelling misconceptions about cause of the anomaly. In addition, efforts to decrease abortion stigma and increase social support may improve women's experiences and lessen their grief response. The nature and course of grief after second-trimester termination for fetal anomaly are, as of yet, poorly understood. With improved understanding of how women grieve over time, clinicians can better recognize the significance of their patients' suffering and offer tools to direct their grief toward positive coping.


Joule-heated graphene-wrapped sponge enables fast clean-up of viscous crude-oil spill.
The clean-up of viscous crude-oil spills is a global challenge. Hydrophobic and oleophilic oil sorbents have been demonstrated as promising candidates for oil-spill remediation. However, the sorption speeds of these oil sorbents for viscous crude oil are rather limited. Herein we report a Joule-heated graphene-wrapped sponge (GWS) to clean-up viscous crude oil at a high sorption speed. The Joule heat of the GWS reduced in situ the viscosity of the crude oil, which prominently increased the oil-diffusion coefficient in the pores of the GWS and thus speeded up the oil-sorption rate. The oil-sorption time was reduced by 94.6% compared with that of non-heated GWS. Besides, the oil-recovery speed was increased because of the viscosity decrease of crude oil. This in situ Joule self-heated sorbent design will promote the practical application of hydrophobic and oleophilic oil sorbents in the clean-up of viscous crude-oil spills.


Cellular repair in the parkinsonian nonhuman primate brain.
Parkinson disease (PD) is a neurodegenerative disorder that provides a useful model for testing cell replacement strategies to rejuvenate the affected dopaminergic neural systems, which have been destroyed by aging and the disease. We first showed that grafts of fetal dopaminergic neurons can reverse parkinsonian motor deficits induced by the toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), validating the feasibility of cellular repair in a primate nervous system. Subsequent clinical trials in Parkinson patients showed encouraging results, including long-term improvement of neurological signs and reduction of medications in some patients. However, many experienced little therapeutic benefit, and some recipients experienced dyskinesias, suggesting a lack of regulated control of the grafts. We have since attempted to improve cell replacements by placing grafts in their correct anatomical location in the substantia nigra and using strategies such as co-grafting fetal striatal tissue or growth factors into the physiologic striatal targets. Moreover, the use of fetal cells depends on a variable supply of donor material, making it difficult to standardize cell quality and quantity. Therefore, we have also explored possibilities of using human neural stem cells (hNSCs) to ameliorate parkinsonism in nonhuman primates with encouraging results. hNSCs implanted into the striatum showed a remarkable migratory ability and were found in the substantia nigra, where a small number appeared to differentiate into dopamine neurons. The majority became growth factor-producing glia that could provide beneficial effects on host dopamine neurons. Studies to determine the optimum stage of differentiation from embryonic stem cells and to derive useful cells from somatic cell sources are in progress.


Immune response elicited by two rBCG strains devoid of genes involved in c-di-GMP metabolism affect protection versus challenge with M. tuberculosis strains of different virulence.
Pellicles, a type of biofilm, have gathered a renewed interest in the field of tuberculosis as a structure that mimics some characteristics occurring during M. tuberculosis infection, such as antibiotic recalcitrance and chronicity of infection, and as a source of antigens for humoral response in infected guinea pigs. In other bacteria, it has been well documented that the second messenger c-di-GMP modulates the transition from planktonic cells to biofilm formation. In this work, we used the live vaccine Mycobacterium bovis BCG to determine whether deletion of genes involved in c-di-GMP metabolism would affect interaction with macrophages, capacity to induce immune response in a murine cell line and mice, and how the protein profile was modified when grown as surface pellicles. We found that deletion of the BCG1419c (Delta c-di-GMP phosphodiesterase, ΔPDE) gene, or deletion of the BCG1416c (Delta c-di-GMP diguanylate cyclase, ΔDGC) gene, altered production of TNF-α, IL-6, and IL-1β, in murine macrophages, and resulted in attenuation in intra-macrophage replication. Moreover, in addition to the improved immunogenicity of the BCGΔBCG1419c mutant already reported, deletion of the BCG1416c gene leads to increased T CD4+ and T CD8+ activation. This correlated with protection versus lethality in mice infected with the highly virulent M. tuberculosis 5186 afforded by vaccination with all the tested BCG strains, and controlled the growth of the mildly virulent M. tuberculosis H37Rv in lungs by vaccination with BCGΔBCG1419c during chronic late infection from 4 to 6 months after challenge. Furthermore, when grown as surface pellicles, a condition used to manufacture BCG vaccine, in comparison to BCG wild type, both rBCGs changed expression of antigenic proteins such as DnaK, HbhA, PstS2, 35KDa antigen, GroEL2, as well as AcpM, a protein involved in synthesis of mycolic acids, molecules relevant to modulate inflammatory responses.


The addition of biphasic calcium phosphate to porous chitosan scaffolds enhances bone tissue development in vitro.
Uniform distribution of cells and their extracellular matrix is essential for the in vivo success of bone tissue engineering constructs produced in vitro. In this study, the effects of biphasic calcium phosphate (BCP) granules embedded into chitosan scaffolds on the distribution, morphology, and phenotypic expression of osteoblastic cells were investigated. Mesenchymal stem cells (MSCs) and preosteoblasts were cultured on chitosan scaffolds with and without BCP under osteoblastic differentiation/maturation conditions for periods up to 4 weeks. The addition of 25 wt % BCP to chitosan created a uniform layer of calcium phosphate (CaP) precipitation similar to bone mineral on the scaffold surfaces as determined by scanning electron microscopy and X-ray spectroscopy. Scaffolds with this CaP layer yielded more uniform and complete cell and ECM distribution than chitosan scaffolds without BCP. The suggestion of chemotaxis in the appearance of this response was confirmed by successive experiments in a Boyden chamber. The CaP layer also altered morphology of cells initially attached to the scaffold surfaces, leading to higher expression of marker proteins of osteoblastic phenotype including alkaline phosphatase and osteocalcin. The use of chitosan/BCP scaffolds for culture of MSCs and preosteoblasts enhances bone tissue development in vitro.


Embolic events in infective endocarditis: a review and report of 4 cases.
Infective endocarditis (IE) remains a dangerous disease in terms of morbidity and mortality. Valve damage with or without congestive heart failure, paravalvular extension, embolization of vegetation, damage due to immunological involvement and septic shock are the main complications of IE. Embolic events are frequent and life-threatening complications of IE. In previous series, the reported figures of embolic complication vary from 10 to 50%. We describe four cases of patients with IE and peripheral embolization. In this paper, we will briefly discuss the role of echocardiography, infective microorganisms and clinical aspects in the prediction of an embolic event. Therapeutic strategies are discussed.


Three-dimensional CT study on normal anatomical features of atlanto-axial joints.
It has long been a research hotspot to diagnose atlanto-axial disorder by observing the shape and motions of atlanto-axial joints. The basis for correlative studies is to ascertain the normal anatomic features of atlanto-axial joints. In our study, 33 normal subjects were examined for atlanto-axial joints, by three-dimensional CT (3D-CT) in functional positions (neutral, left and right rotary position). The contraposition between superior and inferior articular facets of lateral atlanto-axial joints (AFLAJ), including its shape and type, the width of rotational facets displacement (RFD), head's rotational angle (HRA) and rotational angle at C(1-2) (RAC(1-2)) were observed and measured on 3D-CT images. In neutral position, a complete contraposition of AFLAJ was found in 25 subjects as well as a basic contraposition in 8. In rotary position, the width of RFD was between 6.16 and 8.68 mm, the angle of HRA was between 30.2 degrees and 45.8 degrees , and RAC(1-2) between 26.7 degrees and 38.9 degrees . There is no significant difference in RFD, HRA or RAC(1-2) (P > 0.05) in between levorotatory and dextrogyrate orientation, and there is a positive correlation between RFD and RAC(1-2) (r = 0.5078, P < 0.05). Our study results show that the contraposition of AFLAJ can be clearly displayed by 3D-CT, and complete or basic contraposition in neutral position and symmetry RFD, HRA and RAC(1-2) in rotary position, are the normal anatomic features of atlanto-axial joints.


[Experiences with laparoscopic lymphocele drainage].
Lymphoceles are among the most frequent surgical complications of pelvic surgery. In ten patients with large lymphoceles in the pelvis after successful kidney transplantation or radical suprapubic prostatectomy we performed laparoscopic drainage of the lymphocele. Laparoscopic windowing of lymphoceles is a safe, minimally invasive form of treatment and a successful alternative to open surgical marsupialization, percutaneous puncture or external drainage of the lymphocele.


BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors.
The anilino-quinazoline derivative BIBW-2992, which is being developed by Boehringer Ingelheim Corp for the potential treatment of solid tumors, is an oral dual receptor tyrosine kinase inhibitor of human EGF receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)/neu. EGFR and HER-2/neu activate numerous signaling pathways leading to cancer cell proliferation, survival and migration. In vitro, BIBW-2992 effectively and selectively inhibited EGFR and HER-2/neu and inhibited EGFR and HER-2/neu total tyrosine phosphorylation and tumor cell proliferation in vivo. Importantly, BIBW-2992 was active against tumors overexpressing EGFR with the secondary Thr790Met point mutation, which confers resistance to the first-generation EGFR inhibitors gefitinib and erlotinib. In phase I/II trials, BIBW-2992 was effective in patients with solid tumors, including those with NSCLC tumors activating mutations in the EGFR tyrosine kinase domain. BIBW-2992 was generally well tolerated with the main adverse effects being gastrointestinal or cutaneous disorders. At the time of publication, BIBW-2992 was undergoing phase II trials for NSCLC, breast and prostate cancers, head and neck carcinoma, as well as glioma. BIBW-2992 was granted Fast-Track status by the FDA for NSCLC and was investigated in phase III trials for this indication.


Proactive Control: Neural Oscillatory Correlates of Conflict Anticipation and Response Slowing.
Proactive control allows us to anticipate environmental changes and adjust behavioral strategy. In the laboratory, investigators have used a number of different behavioral paradigms, including the stop-signal task (SST), to examine the neural processes of proactive control. Previous functional MRI studies of the SST have demonstrated regional responses to conflict anticipation-the likelihood of a stop signal or P(stop) as estimated by a Bayesian model-and reaction time (RT) slowing and how these responses are interrelated. Here, in an electrophysiological study, we investigated the time-frequency domain substrates of proactive control. The results showed that conflict anticipation as indexed by P(stop) was positively correlated with the power in low-theta band (3-5 Hz) in the fixation (trial onset)-locked interval, and go-RT was negatively correlated with the power in delta-theta band (2-8 Hz) in the go-locked interval. Stimulus prediction error was positively correlated with the power in the low-beta band (12-22 Hz) in the stop-locked interval. Further, the power of the P(stop) and go-RT clusters was negatively correlated, providing a mechanism relating conflict anticipation to RT slowing in the SST. Source reconstruction with beamformer localized these time-frequency activities close to brain regions as revealed by functional MRI in earlier work. These are the novel results to show oscillatory electrophysiological substrates in support of trial-by-trial behavioral adjustment for proactive control.