Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals.
Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99–1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.


Ataxia telangiectasia-mutated protein can regulate p53 and neuronal death independent of Chk2 in response to DNA damage.
DNA damage is a key initiator of neuronal death. We have previously shown that the tumor suppressor p53, in conjunction with cyclin-dependent kinases (CDKs), regulates the mitochondrial pathway of death in neurons exposed to genotoxic agents. However, the mechanisms by which p53 is regulated is unclear. Presently, we show that p53 is phosphorylated on Ser-15 following DNA damage and this occurs independently of the CDK pathway. Instead, we show that p53 phosphorylation, stability, as well as neuronal death is regulated, in part, by the ataxia telangiectasia-mutated (ATM) protein. Previous reports have suggested that ATM regulation of p53 occurs through Chk2. However, in our present paradigms, we show that ATM functions separately from Chk2 to regulate p53 stability and neuronal death. Chk2 deficiency does not affect p53 stability or neuronal death induced by Topoisomerase I or II inhibition. Taken together, our results provide a model by which DNA damage can activate an ATM-dependent, Chk2-independent pathway of p53-mediated neuronal death.


An insidious internal hernia 30 years after jejunoileal bypass: a case report.
Jejunoileal bypass (JIB) was an early bariatric procedure that involved bypassing most of the small bowel resulting in malabsorption and weight loss. Due to serious complications associated with the procedure, JIB was largely discontinued by the mid-1980s. We report the case of a 77-year-old woman with a history of JIB 31 years earlier. In 2022, she was hospitalized for acute abdominal pain. A computed tomography (CT) scan revealed a suspicion of internal hernia (IH) with a typical swirl sign. Due to the quick relief of symptoms an emergency surgery was not considered at the time. Nevertheless, a subsequent operation revealed a large mesenteric defect, adhesions and 100 cm of effective small bowel left. Although the procedure is no longer performed, some patients with JIB are still alive and develop late complications. To our knowledge, this is the first case report describing an IH in a patient who has undergone JIB.


Hyperbaric Oxygen as Radiation Sensitizer for Locally Advanced Squamous Cell Carcinoma of the Oropharynx: A Phase 1 Dose-Escalation Study.
To explore, in a dose-escalation study, the feasibility of hyperbaric oxygen (HBO) treatments immediately before intensity modulated radiation therapy in conjunction with cisplatinum chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). Eligible patients presented with SCCHN (stage III-IV [M0]), life expectancy >6 months, and Karnofsky performance status ≥70. Enrollees received intensity modulated radiation therapy, 70 Gy in 35 fractions over 7 weeks with weekly cisplatinum. Patients received HBO-100% oxygen, 2.4 atmospheres absolute (ATA) for 30 minutes-twice per week initially. Subsequent patients were escalated to 3 and then 5 times per week. Intensity modulated radiation therapy began within 15 minutes after HBO. Patients were followed for 2 years after RT with quality-of-life questionnaires (Performance Status Scale-Head and Neck Cancer and the Functional Assessment of Cancer Therapy-Head and Neck Cancer) and for 5+ years for local recurrence, distant metastases, disease-specific survival, and overall survival. Twelve subjects enrolled from 3 centers. Two withdrew during radiation therapy and 1 within 14 weeks after radiation therapy. The remaining 9 had primary oropharyngeal disease and were stage IVA (7) or IVB (2). No dose-limiting toxicities were observed with daily HBO. Two patients (22%) required pressure equalization tubes. The average time between HBO and radiation therapy was 8.5 minutes, with 2 of 231 administrations delivered beyond 15 minutes (0.5%). Per-protocol analysis showed a clinical complete response in 7 and a pathologic complete response without tumor in salvage neck dissections in 2. With minimum follow-up of 61 months, per-protocol 5-year overall survival was 100%, local recurrence 0%, and distant metastases 11%. Patient-reported outcomes for quality of life (Functional Assessment of Cancer Therapy-Head and Neck Cancer) were comparable to published results for chemoradiotherapy without HBO. While acknowledging the study's small size and early attrition of 3 patients, our in-depth review of the acquired data indicates the feasibility of combining HBO with chemoradiation.


Multifaceted remediation program: experience of a residency program to rescue residents who failed the American Board of Anesthesiology basic examination.
Passing the American Board of Anesthesiology (ABA) basic examination is required to progress through anesthesiology training in USA. Failing the test may be related to medical knowledge gaps, presence of negative psychosocial factors, and/or individual approaches to learning. This article describes the experience of development and implementation of a multifaceted remediation program (MRP) in residents who failed the ABA basic test. This is a retrospective analysis of four cases of residents who failed the ABA basic test between 2016 and 2017. The MRP is described. Pedagogical diagnosis, objectives, teaching strategies and assessment, and their constructive alignment are presented. Information regarding test performance is also presented. This study involves accredited anesthesiology residency program in USA. Outcomes: Four subjects (11% of program residents) failed the ABA basic test. Superficial approach to learning was observed in 100% of cases. The total possible number of participants was 4. The actual number of participants was 4, and the response rate was 100%. Four residents fell under 10th percentile on the first attempt, and 100% passed the test on the second attempt. There was 38% improvement in the number of failed keywords between the two attempts. Implementation of the MRP developed at our institution is successful to remediate anesthesiology residents who fail the ABA basic examination. We learned that the deep analysis of learning approaches, psychosocial factors, and medical knowledge gaps can be used to develop a remediation program based on the constructive alignment between objectives, curriculum, and assessment.


Characterizing protein glycosylation sites through higher-energy C-trap dissociation.
Assigning glycosylation sites of glycoproteins and their microheterogeneity is still a very challenging analytical task despite the rapid advancements in mass spectrometry. It is shown here that glycopeptide ions can be fragmented efficiently using the higher-energy C-trap dissociation (HCD) feature of a linear ion trap orbitrap hybrid mass spectrometer (LTQ Orbitrap). An attractive aspect of this dissociation option is the generation of distinct Y1 ions (peptide+GlcNAc), thus allowing unequivocal assignment of N-glycosylation sites of glycoproteins. The combination of the very informative collision-induced dissociation spectra acquired in the linear ion trap with the distinct features of HCD offers very useful information aiding in the characterization of the glycosylation sites of glycoproteins. The HCD activation energy needed to obtain optimum Y1 ions was studied in terms of glycan structure and charge state, and size and structure of the peptide backbone. The latter appeared to be primarily dictating the needed HCD energy. The distinct Y1 ion formation in HCD facilitated an easy assignment of such an ion and its subsequent isolation and dissociation through multiple-stage tandem mass spectrometry. The resulting MS(3) spectrum of the Y1 ion facilitates database searching and de novo sequencing thus prompting the subsequent identification of the peptide backbone and associated glycosylation sites. Moreover, fragment ions formed by HCD are detected in the Orbitrap, thus overcoming the 1/3 cut-off limitation that is commonly associated with ion trap mass spectrometers. As a result, in addition to the Y1 ion, the common glycan oxonium ions are also detected. The high mass accuracy offered by the LTQ Orbitrap mass spectrometer is also an attractive feature that allows a confident assignment of protein glycosylation sites and the microheterogeneity of such sites.


Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.
Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high-dose therapy. Thalidomide, a glutamic acid derivative with anti-angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of MM patients. From October 1999 to January 2001, 65 patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty-six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after >= 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty-one (93.8%) patients were in stage III, median b2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200mg every other week to a maximum of 800 mg/day. The median administered dose of thalidomide was 400 mg/day. WHO grade > II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed > or = 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed > or = 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow-up, 15/28 patients are alive and progression-free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre-treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 165 pg/mL vs 227.11 70 pg/mL, p=0.04). These data confirm that thalidomide is active in patients with advanced relapsed/refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.


Public Health Effects of Restricting Retail Tobacco Product Displays and Ads.
To estimate the public health impact from restricting US retail point-of-sale (POS) tobacco product displays and advertising. Based on existing research, this paper estimates the effects on initiation and cessation rates from restricting POS tobacco product displays and ads in the US and uses the SimSmoke simulation model to project related smoking declines and health benefits. New comprehensive POS restrictions are projected to reduce smoking prevalence by approximately 16% [range=3%-31%] relative to the status quo by 2065, preventing about 630,000 smoking-attributable deaths [range=108,000-1,225,000], 215,000 low birth weight births [range=33,000-421,000], 140,000 preterm births [range=22,000-271,000], and 1900 infant deaths from SIDSs [range=300-3800]. Federal, state, or local action to restrict POS tobacco product displays and ads would contribute to a substantial reduction in smoking-attributed death and disease.


An AraC/XylS Family Transcriptional Regulator Modulates the Oxidative Stress Response of Francisella tularensis.
Francisella tularensis is a Gram-negative bacterium that causes a fatal human disease known as tularemia. The Centers for Disease Control and Prevention have classified F. tularensis as a category A tier 1 select agent. The virulence mechanisms of Francisella are not entirely understood. Francisella possesses very few transcription regulators, and most of these regulate the expression of genes involved in intracellular survival and virulence. The F. tularensis genome sequence analysis reveals an AraC (FTL_0689) transcriptional regulator homologous to the AraC/XylS family of transcriptional regulators. In Gram-negative bacteria, AraC activates genes required for l-arabinose utilization and catabolism. The role of the FTL_0689 regulator in F. tularensis is not known. In this study, we characterized the role of FTL_0689 in the gene regulation of F. tularensis and investigated its contribution to intracellular survival and virulence. The results demonstrate that FTL_0689 in Francisella is not required for l-arabinose utilization. Instead, FTL_0689 specifically regulates the expression of the oxidative and global stress response, virulence, metabolism, and other key pathways genes required by Francisella when exposed to oxidative stress. The FTL_0689 mutant is attenuated for intramacrophage growth and virulence in mice. Based on the deletion mutant phenotype, FTL_0689 was termed osrR (oxidative stress response regulator). Altogether, this study elucidates the role of the osrR transcriptional regulator in tularemia pathogenesis. IMPORTANCE The virulence mechanisms of category A select agent Francisella tularensis, the causative agent of a fatal human disease known as tularemia, remain largely undefined. The present study investigated the role of a transcriptional regulator and its overall contribution to the oxidative stress resistance of F. tularensis. The results provide an insight into a novel gene regulatory mechanism, especially when Francisella is exposed to oxidative stress conditions. Understanding such Francisella- specific regulatory mechanisms will help identify potential targets for developing effective therapies and vaccines to prevent tularemia.


Kinetics of release of serotonin from isolated secretory granules. I. Amperometric detection of serotonin from electroporated granules.
We developed a method for measuring the efflux of 5-hydroxytryptamine (5-HT, serotonin) from isolated intact granules of the mast cell of the beige mouse. This method combines electroporation of the vesicle membrane with amperometric detection of 5-HT. A single secretory granule is placed between two platinum electrodes (distance approximately 100 microm) and positioned adjacent (<1 microm) to a carbon fiber microelectrode. A short (approximately 30 micros) high-intensity voltage pulse (electric field of approximately 5 kV/cm) is delivered to the electrodes to trigger the mechanical breakdown of the granule membrane, which activates the release of 5-HT. We observed concurrent swelling of the granule matrix with the oxidation of 5-HT at the carbon fiber electrode (overpotential + 650 mV). Similar to the release of secretory products during exocytosis, the oxidation current exhibits a spike-like time course with a noninstantaneous rising phase (time between onset of current and maximum flux, t(max)) with approximately 25% of the molecules released during this period. When the current reaches its maximum, the granule matrix attains its maximum swollen state. We found that the rising phase depends on the initial cross-sectional area of the granule (t(max) approximately 21r2) and reflects the time required for membrane rupture. The average t(1/2)spike of the amperometric spikes was found to be approximately 150 ms, which is 3-7 times faster than the t(1/2) measured during cellular exocytosis.


Cell death and proliferation and its relation to collagen degradation in uterine involution of rat.
Collagen concentration, procollagenase localization, and their association with cell proliferation and apoptosis during postpartum involution, were investigated biochemically and histochemically in postpartum day 1, 3, 5, and 7 rat uterine tissues. In control animals, uterine wet weight, soluble protein, and collagen decreased rapidly during days 1 to 3 postpartum, and the DNA concentration in the uterine horn rapidly decreased, as noted by others. Simultaneously, both apoptosis and cell proliferation were observed in these tissues. These processes were highest in smooth muscle cells on day 3 postpartum. Procollagenase was found in the cell cytoplasm through days 1 to 3 postpartum, was highest on the third day postpartum, and appeared to gradually diminish by day 5 postpartum. Disorganization of collagen fibers was observed, under polarized microscopy by a strong birefringence of collagen fibers of the circular smooth muscle cell layers. However, this disorganization of the uterine collagen diminished progressively from day 3 to day 7. Treatment with estradiol or a combination of estradiol and progesterone suppressed cellular turnover and attenuated the changes in DNA, total amino acids, and collagen on day 3 postpartum. In this study, cellular turnover and biochemical and morphological changes appeared to be closely associated. Gonadal steroid hormones appear to influence these changes and retard uterine involution. This study suggests that a dynamic turnover of the cellular population takes place during uterine involution. It is possible that other factors, in addition to steroid hormones, contribute to uterine involution. It is to be postulated that these factors either are themselves decreased or, alternatively, may increase the inhibition of other unknown factors by an indirect mechanism.


Exposure of free-ranging maned wolves (Chrysocyon brachyurus) to infectious and parasitic disease agents in the Noël Kempff Mercado National Park, Bolivia.
Maned wolves (Chrysocyon brachyurus) are neotropic mammals, listed as a CITES Appendix II species, with a distribution south of the Amazon forest from Bolivia, through northern Argentina and Paraguay and into eastern Brazil and northern Uruguay. Primary threats to the survival of free-ranging maned wolves include habitat loss, road kills, and shooting by farmers. An additional threat to the conservation of maned wolves is the risk of morbidity and mortality due to infectious and parasitic diseases. Captive maned wolves are susceptible to, and die from, common infectious diseases of domestic dogs (Canis familiaris) including canine distemper virus (CDV), canine parvovirus (CPV), rabies virus, and canine adenovirus (CAV). Results from this study show that free-ranging maned wolves in a remote area of Bolivia have been exposed to multiple infectious and parasitic agents of domestic carnivores, including CAV, CDV, CPV, canine coronavirus, rabies virus, Leptospira interrogans spp., Toxoplasma gondii, and Dirofilaria immitis, and may be at increased risk for disease due to these agents.


Instant ODFs - Development of an intermediate, nanoparticle-based product platform for individualized medication.
The individualization of solid dosage forms to realize a flexible therapy for all patient groups is a topic which increasingly gains importance in pharmaceutical research. The goal of this study was to develop a nanoparticulate, instant orodispersible film (iODF) powder which can easily be reconstituted in water to cast ODFs containing an individualized concentration of an active pharmaceutical ingredient (API). It was shown that the processing of the film casing mass to iODF powders by spray drying provides the same advantageous film properties, particles sizes redispersed from the ODF and dissolution profiles as compared to the common production route. Due to the realization of nanoparticle loads up to 50wt.% in the iODF powders, high API loads (11.8mgcm-2) are achieved in final ODFs. The powders are well storable at different temperatures for at least three months and do not change their crystalline state during storage. Furthermore, dissolution of a defined amount of API from ODFs was found to be the fastest with the highest drug loads in the films.


Organic vs. psychogenic factors in visual dysfunction.
A 17-year-old black male first complained of a relatively acute visual loss in both eyes just weeks before his 15th birthday. Extensive evaluations provided no definite organic cause for the acuity drop from 20/25 in June 1983 to 20/200 in November 1983. A psychogenic etiology was suspected but never confirmed. To date, optical devices provide the only means in attaining maximum visual efficiency.


[Activation of total and ribosomal RNA transcription under adapting doses of ionizing radiation inducing displacement of chromosome loci in human G0-lymphocyte].
As we demonstrated earlier, the adapting X-ray doses (3 and 10 cGy) induced movement of chromosome centromeric loci in G0-lymphocyte nuclei. In the present study we investigated the influence of X-rays with 3 and 10 cGy doses on the content of total, 18S and 45S rRNA in human G0-lymphocytes because it is known that the transcription products participate in nucleus organization. It was shown that 3 h after irradiation the content of both total and 18S RNA was significantly increased. The 3 cGy dose induced higher level of the rRNA than 10 cGy dose did in cells of some individuals. At the same time, the 45S RNA content was not changed significantly. This result may suggest that process of rRNA transcription and primary transcript (45S rRNA) processing have been completed during 3 h after irradiation. The data about an activation of rRNA synthesis were confirmed by cytological observation. Under 3 and 10 cGy doses both nuclei diameter and area of the Ag-stained granules were increased, depending on dose. These data also may be connected with an initiation of rRNA transcription because of correlation of Ag-painting with nucleolus activity. Thus, adapting X-ray doses induce displacement of chromosome loci in lymphocyte nuclei and activation of rRNA transcription. Further investigations are required for understanding of these phenomena interconnection.


Command hallucinations and criminality: a clinical quandary.
Clinical literature on the role of command hallucinations in producing antisocial behavior is sparse and fragmented. This article reviews exploratory models of auditory hallucinations and the prevalence of command hallucinations in clinical and forensic settings. In addition, clinical guidelines are offered for assessing the authenticity of command hallucinations and their relevance to criminal behavior within the context of forensic evaluations.


Characterization of disinfectant susceptibility profiles among clinical isolates of Acinetobacter baumannii in Ardabil, Iran.
Antimicrobial disinfectants have been extensively used to control hospital-acquired infections worldwide. Prolonged exposure to bacteria could promote resistance to antimicrobial disinfectants. This study evaluated the antimicrobial activity of four commonly used disinfectants; triclosan, chlorhexidine digluconate, benzalkonium chloride, and formaldehyde against Acinetobacter baumannii clinical isolates. This study also determined the prevalence and association of efflux pumps encoding genes qacE, qacED1, emrA, and aceI with tolerance to disinfectants. A total of 100 A. baumannii isolates were included in the current study. The antimicrobial disinfectants' minimum inhibitory concentration (MIC) was determined using an agar dilution method. Genes involved in resistance to disinfectants were investigated by PCR method. The benzalkonium chloride MICs ranged between 32 and 128 μg mL-1, chlorhexidine digluconate 8-64 μg mL-1, triclosan 1-32 μg mL-1, and formaldehyde 128 μg mL-1. Overall, the highest MIC90 value was identified for formaldehyde (128 μg mL-1), followed by benzalkonium chloride and chlorhexidine digluconate (64 μg mL-1, each one) and triclosan (4 μg mL-1). In the present study, the qacE, qacED1, emrA, and aceI genes were found in 91%, 55%, 100%, and 88% of isolates, respectively. The qacG gene was not identified in our A. baumannii isolates. The qacED1 gene was associated with higher MICs for all disinfectants tested (P < 0.05), while the qacE and aceI genes were associated with higher MICs for benzalkonium chloride and chlorhexidine. This study indicated that triclosan is the most effective disinfectant against A. baumannii isolates.


CE: Original Research: Creating an Evidence-Based Progression for Clinical Advancement Programs.
: Background: The Institute of Medicine (IOM) and the Quality and Safety Education for Nurses (QSEN) project have identified six nursing competencies and supported their integration into undergraduate and graduate nursing curricula nationwide. But integration of those competencies into clinical practice has been limited, and evidence for the progression of competency proficiency within clinical advancement programs is scant. Using an evidence-based approach and building on the competencies identified by the IOM and QSEN, a team of experts at an academic health system developed eight competency domains and 186 related knowledge, skills, and attitudes (KSAs) for professional nursing practice. The aim of our study was to validate the eight identified competencies and 186 related KSAs and determine their developmental progression within a clinical advancement program. Using the Delphi technique, nursing leadership validated the newly identified competency domains and KSAs as essential to practice. Clinical experts from 13 Magnet-designated hospitals with clinical advancement programs then participated in Delphi rounds aimed at reaching consensus on the developmental progression of the 186 KSAs through four levels of clinical advancement. Two Delphi rounds resulted in consensus by the expert participants. All eight competency domains were determined to be essential at all four levels of clinical practice. At the novice level of practice, the experts identified a greater number of KSAs in the domains of safety and patient- and family-centered care. At more advanced practice levels, the experts identified a greater number of KSAs in the domains of professionalism, teamwork, technology and informatics, and continuous quality improvement. Incorporating the eight competency domains and the 186 KSAs into a framework for clinical advancement programs will likely result in more clearly defined role expectations; enhance accountability; and elevate and promote nursing practice, thereby improving clinical outcomes and quality of care. With their emphasis on quality and safety, the eight competency domains also offer a framework for enhancing position descriptions, performance evaluations, clinical recognition, initial and ongoing competency assessment programs, and orientation and residency programs.


Mitogen-induced blastogenesis of peripheral blood and efferent lymph lymphocytes from sheep.
Peripheral blood lymphocytes and efferent lymph lymphocytes (ELL) from 20 healthy adult sheep were studied for their blastogenic responses to the phytolectins concanavalin A, phytohemagglutinin, and pokeweed mitogen. Peripheral blood lymphocytes generally incorporated significantly (P less than 0.00001) more [3H]thymidine than did ELL. The lower response in ELL, especially in concanavalin A- and pokeweed mitogen-stimulated cultures, may be due to an insufficiency of accessory cells that may be required for optimal proliferation.


Polymeric nanofibers: targeted gastro-retentive drug delivery systems.
Conventional oral dosage forms exhibit poor/low bioavailability due to incomplete release of drug and short residence time at the absorption site. Gastro-retentive drug delivery system (GRDDS) is particularly used to improve bioavailability of the drugs, which have narrow absorption window down in the levels of gastrointestinal tract and also to treat local disorders. The purpose of this review is to describe the utility of the nanofibers as gastro-retentive dosage form. From last few decades, formulation scientists have put extensive efforts to develop suitable gastro-retentive drug delivery system, which is appropriate for commercialization. Current approaches used for preparation of gastro-retentive drug delivery system offers limited functional features to control the floating behavior. Recently, an extensive research has been developed to improve the gastric residence time by using nanofibers, which ultimately leads to the increased bioavailability of the drug. Multiple functional features and unique properties of nanofibers improve its gastro retention. Nanofiber system provides stomach-specific drug release for longer duration; moreover, increased local action of the drug due to prolonged contact time with the gastric mucosa. Thus, the nanofiber system promises to be the potential approach for gastric retention drug delivery system.


Niche differentiation drives microbial community assembly and succession in full-scale activated sludge bioreactors.
Network models and community phylogenetic analyses are applied to assess the composition, structure, and ecological assembly mechanisms of microbial communities. Here we combine both approaches to investigate the temporal dynamics of network properties in individual samples of two activated sludge systems at different adaptation stages. At initial assembly stages, we observed microbial communities adapting to activated sludge, with an increase in network modularity and co-exclusion proportion, and a decrease in network clustering, here interpreted as a consequence of niche specialization. The selective pressure of deterministic factors at wastewater treatment plants produces this trend and maintains the structure of highly functional and specialized communities responding to seasonal environmental changes.


Use of plasmid-derived external quality control samples in pharmacogenetic testing.
Genetic variation in genes encoding for drug-metabolizing enzymes, drug targets and signaling pathways have proven to contribute significantly to differences in drug response. Pharmacogenetics is now expanding from clinical pharmacological research to its application in clinical practice. Genotyping of patients in a routine clinical setting requires robust and reliable genotyping methods. A survey of pharmacogenetic association studies for quality control samples published from 2005 to 2007 in the two most prominent pharmacogenetic journals, and development of plasmid-derived external controls. Surveying journals revealed that only a minority of papers report the use of quality controls, and no standard procedures are applied. We established 12 plasmid-derived external controls and applied these in pharmacogenetic testing. There still is a need for quality control materials, especially for application in pharmacogenetic testing. We hope that our initiative to create plasmid-derived controls will help to facilitate quality in the pharmacogenetic genotyping tests applied in research, as well as in routine patient care.


Significantly different proliferative potential of oral mucosal epithelial cells between six animal species.
There has been an upsurge in regenerative medicine in recent years. In particular, because oral mucosal epithelial cells can be obtained noninvasively, cultured epithelial cell sheets have been used in a number of ectopic transplantations. Additionally, the verification of the properties of experimental animals' cultured cells has accelerated the application of regenerative medicine. In the present study, the properties of oral mucosal epithelial cells were compared between six animal species. The human and pig epithelia were relatively thicker than the epithelia of the other species. The colony-forming efficiency of the rat was the highest, followed by those of the dog, human, rabbit, and pig, whereas the colonies of the mouse cells were all paraclone and uncountable in the colony-forming assay. We also found that the rabbit and pig cells proliferated poorly and were unable to form cell sheets without feeder layers. In contrast, even in the absence of feeder layers and cholera toxin, cultured dog and mouse cells formed contiguous sheets, when the cell seeding density was high. These results indicate that interspecies variation is considerable in oral mucosal epithelial cells and that specific experimental animal or human cells must be chosen according to the intended use.


The lathyrogenic effect of isonicotinic acid hydrazide (INAH) on the chick embryo and its reversal by pyridoxal.
When applied to the chorio-allantoic membrane of the chick embryo, isoniazid was shown to produce an increase in the fragility of the embryo and in the amount of collagen which was extractable from the bones with cold 1 M sodium chloride. The administration of pyridoxal reversed these phenomena almost completely. The effect of isoniazid differed from that of beta-aminopropionitrile in that the latter was of greater magnitude, and was not affected by pyridoxal; whereas beta-aminopropionitrile caused skeletal deformities, isoniazid even at 12 times the concentration produced no deformities. The aldehyde group of pyridoxal was shown to be necessary for its interaction with isoniazid.


NCI-RTOG translational program strategic guidelines for the early-stage development of radiosensitizers.
The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry's diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials-acute toxicity and maximum-tolerated dose-are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II "screening" trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation.


Parathyroid carcinoma: is there a role for adjuvant radiation therapy?
The authors proposed to determine risk factors associated with postoperative progression of parathyroid carcinoma within the neck (locoregional) and to assess the efficacy of postoperative adjuvant radiation therapy in preventing disease progression within the neck. A retrospective review of patients with pathologically confirmed parathyroid carcinoma who underwent surgical resection was performed. Risk factors identified on univariate analysis were applied in a proportional hazards analysis to identify significant independent predictors of locoregional disease progression and cause-specific survival after surgical resection. Fifty-seven patients were treated with surgery alone (no adjuvant radiation therapy [RT]) and were determined to have sufficient follow-up and pathologically confirmed features to be included in the current analysis. Four patients were treated with surgery and adjuvant RT. Four patients received RT to the neck and mediastinum for unresectable locoregional disease progression. Patients were followed for a median of 75.6 months (range, 8.4-358 months). Twenty-five patients (44%) developed locoregional disease progression at a median of 27.1 months after surgery (range, 6.2-138.3 months). The univariate analysis revealed that surgical margin status and the institution at which the initial surgery was performed were predictive of locoregional progression-free survival. The institution at which the initial surgery was performed was found to be an independent predictor of cause-specific survival. Of the four patients treated with surgery and adjuvant RT, all were alive and without disease at the time of last follow-up. All four patients who received RT for locoregional disease progression after initial surgery achieved locoregional disease control. Patients with parathyroid carcinoma are reported to have a significant risk of locoregional disease progression after surgery alone. The results of the current study demonstrated that the risk of postoperative disease progression can be predicted by surgical margin status and the institution at which the initial surgery is performed. Patients treated with surgery and postoperative RT may have a lower risk of locoregional disease progression and improved cause-specific survival. RT can be used to provide locoregional control of recurrent disease.


Cutaneous melanoma in childhood and adolescence: retrospective study of 32 patients.
This study was performed to analyse the behaviour, risk factors, prognosis and evolution of cutaneous melanoma in childhood and adolescence treated in a single institution. A retrospective study was performed between 1980 and 2000 of patients aged 18 years or younger followed at the Hospital do Cancer de Sao Paulo, Brazil. Data included demographic status, risk factors, clinical and histopathological characteristics of the primary and metastatic lesions, stage and follow-up. Seventeen female (53.1%) and 15 male (46.9%) patients were studied. Twelve patients (37.5%) were aged 12 years or younger. The trunk was the most common location (14 patients; 43.8%). Five patients (15.6%) had giant congenital melanocytic naevus, three (9.4%) had xeroderma pigmentosum and one (3%) had dysplastic melanocytic naevus. Nodular melanoma was the most frequent histological type and 43.8% had a thickness of more than 4 mm. Five of the 32 patients (15.6%) were lost to follow-up and 15 (46.9%) were alive at the last year's follow-up, 11 (34.4%) without disease and four (12.5%) with active disease. The 5-year overall survival was 64.34%. An overall survival of 11.71% was found in patients with visceral metastasis with or without cutaneous and/or lymph node involvement, whereas the corresponding value was 90.48% (P value=0.0002) in patients with only cutaneous and/or lymph node metastasis. Cutaneous melanomas are uncommon in the young and are seldom diagnosed in the early stages, perhaps due to a reluctance to accept this diagnosis in this age group. Prevention and early stage diagnosis depend upon the recognition that this disease is present in the young.


Filters for three-dimensional limited-angle tomography.
One approach to the three-dimensional, tomographic reconstruction of data from a planar dual-detector stationary positron camera necessitates frequency-space filtering of the image obtained from back-projection. It is therefore useful to have a closed-form expression for the appropriate filter, but the derivation is complicated by the fact that the camera measures only a limited angular range of projections. Nevertheless, suitable expressions can be obtained and are here derived for detectors of rectangular and circular cross-section.


The impact behaviour of silk cocoons.
Silk cocoons, constructed by silkmoths (Lepidoptera), are protective structural composites. Some cocoons appear to have evolved towards structural and material optimisation in order to sustain impact strikes from predators and hinder parasite ingress. This study investigates the protective properties of silk cocoons with different morphologies by evaluating their impact resistance and damage tolerance. Finite element analysis was used to analyse empirical observations of the quasi-static impact response of the silk cocoons, and to evaluate the separate benefits of the structures and materials through the deformation and damage mechanism. We use design principles from composite engineering in order to understand the structure-property-function relationship of silkworm cocoons. Understanding the highly evolved survival strategies of the organisms building natural cocoons will hopefully lead to inspiration that in turn could lead to improved composite design.


Visual function and quality of life among patients with glaucoma.
This study determines the relation between visual field impairment, visual functioning, and global quality of life in patients with glaucoma. Binocular visual field impairment was calculated from simultaneous Esterman visual field testing using the Humphrey automated perimeter. Visual acuity impairment, defined with the American Medical Association's Guides to the Evaluation of Permanent Impairment; visual functioning, measured with the VF-14 and the field test version of the National Eye Institute-Visual Functioning Questionnaire; and global quality of life, assessed with the Medical Outcomes Study 36-Item Short Form Health Survey, were determined in 147 consecutive patients with glaucoma. None of the Medical Outcomes Study 36-Item Short Form Health Survey domains demonstrated more than a weak correlation with visual field impairment. The VF-14 scores were moderately correlated (r = -0.58). Of the National Eye Institute-Visual Functioning Questionnaire scales, peripheral vision (r = -0.60), distance activities (r = -0.56), and vision-specific dependency (r = -0.56) were moderately correlated with visual field impairment; vision-specific social functioning, near activities, vision-specific role difficulties, general vision, vision-specific mental health, color vision, and driving were modestly correlated with visual field impairment (r value between -0.32 and -0.55); visual pain was weakly correlated with visual field impairment; and general health and vision-specific expectations were not notably correlated with visual field impairment. Statistically adjusting for visual acuity weakened the correlations. The Medical Outcomes Study 36-Item Short Form Health Survey indicated that our patients with glaucoma were comparable with previously studied patients without severe systemic medical problems. However, the Medical Outcomes Study 36-Item Short Form Health Survey scores did not correlate with visual field impairment in our study. Based on the moderate correlation between binocular visual field impairment with the VF-14 and the National Eye Institute-Visual Functioning Questionnaire, these questionnaires may be useful among patients with glaucoma.


Cryptosporidium source tracking in the Potomac River watershed.
To better characterize Cryptosporidium in the Potomac River watershed, a PCR-based genotyping tool was used to analyze 64 base flow and 28 storm flow samples from five sites in the watershed. These sites included two water treatment plant intakes, as well as three upstream sites, each associated with a different type of land use. The uses, including urban wastewater, agricultural (cattle) wastewater, and wildlife, posed different risks in terms of the potential contribution of Cryptosporidium oocysts to the source water. Cryptosporidium was detected in 27 base flow water samples and 23 storm flow water samples. The most frequently detected species was C. andersoni (detected in 41 samples), while 14 other species or genotypes, almost all wildlife associated, were occasionally detected. The two common human-pathogenic species, C. hominis and C. parvum, were not detected. Although C. andersoni was common at all four sites influenced by agriculture, it was largely absent at the urban wastewater site. There were very few positive samples as determined by Environmental Protection Agency method 1623 at any site; only 8 of 90 samples analyzed (9%) were positive for Cryptosporidium as determined by microscopy. The genotyping results suggest that many of the Cryptosporidium oocysts in the water treatment plant source waters were from old calves and adult cattle and might not pose a significant risk to human health.


[Parameters of mechanical ventilation].
Approximately 50% of children admitted to a pediatric intensive care unit require mechanical ventilation. The most important parameters to program in mechanical ventilation are the ventilation mode, (volume, pressure or dual), modality (controlled, assisted, support ventilation), and respiratory parameters. The main parameters are tidal volume and minute volume in volume modalities, peak pressure (in pressure modalities), respiratory frequency, positive end expiratory pressure, inspiratory time, inspiratory flow, inspiratory-to-expiratory ratio, time of pause, trigger sensitivity, support pressure, and expiratory trigger sensitivity. Moreover, to detect problems in the ventilator and changes in the patient, alarms for tidal and minute volume, peak pressure, respiratory frequency, FiO2, and apnea must be programmed.


Network of Networks: Preliminary Lessons from the Antwerp Port Authority on Crisis Management and Network Governance to Deal with the COVID-19 Pandemic.
In this article, the authors describe and illustrate what they call a "network of networks" perspective and map the development of a lead network for the Antwerp Port Authority that governed organizations and networks in the port community before and during the COVID-19 pandemic. They find that setting a collective focus and selective integration are crucial in the creation and reproduction of an effective system to adequately deal with a wicked problem like the COVID-19 pandemic. The findings on crisis management and network governance are used to engage practitioners and public policy planners to revisit the current design and governance of organizational networks within organizational fields that have been hit by the COVID-19 pandemic.


Effects of aerobic exercise in the management of erectile dysfunction: a meta analysis study on randomized controlled trials.
Penile erection is a hemodynamic process involving increased arterial inflow and restricted venous outflow, coordinated with corpus cavernosum and penile arterial smooth muscle relaxation. Any problem in this mechanism results in Erectile Dysfunction and its etiology is generally multifactorial. This study is aimed at determining the objective outcome of aerobic training in the management of Erectile Dysfunction of arterogenic origin using Meta analysis. Relevant publications were searched up to November 2010 in the MEDLINE (PubMed) database. The citation lists of randomized controlled trials on the effect of aerobic training and Erectile Dysfunction management using the International Index of Erectile Function (IIEF) as treatment outcome measure. Studies on different operative techniques on the effects of aerobic training for men with Erectile Dysfunction due to arterogenic Erecile Dysfunction were selected. Data on participants' characteristics, study quality, population, intervention, treatment outcome were collected and analyzed. There were 5 randomized controlled studies using the International Index of Erectile Function as measure of treatment outcome. A total of 385 subjects were involved in 5 studies; results indicated significant effect of aerobic training on Erecile Dysfunction (t=5.856, p= .000) at p< 0.05. Subjects with arterogenic Erectile Dysfunction might benefit from aerobic training. More randomized controlled studies in this area are warranted.


Hydrogen gas inhalation ameliorates cardiac remodelling and fibrosis by regulating NLRP3 inflammasome in myocardial infarction rats.
It is noteworthy that prolonged cardiac structural changes and excessive fibrosis caused by myocardial infarction (MI) seriously interfere with the treatment of heart failure in clinical practice. Currently, there are no effective and practical means of either prevention or treatment. Thus, novel therapeutic approaches are critical for the long-term quality of life of individuals with myocardial ischaemia. Herein, we aimed to explore the protective effect of H2 , a novel gas signal molecule with anti-oxidative stress and anti-inflammatory effects, on cardiac remodelling and fibrosis in MI rats, and to explore its possible mechanism. First, we successfully established MI model rats, which were then exposed to H2 inhalation with 2% concentration for 28 days (3 hours/day). The results showed that hydrogen gas can significantly improve cardiac function and reduce the area of cardiac fibrosis. In vitro experiments further proved that H2 can reduce the hypoxia-induced damage to cardiomyocytes and alleviate angiotensin II-induced migration and activation of cardiac fibroblasts. In conclusion, herein, we illustrated for the first time that inhalation of H2 ameliorates myocardial infarction-induced cardiac remodelling and fibrosis in MI rats and exert its protective effect mainly through inhibiting NLRP3-mediated pyroptosis.


Carbocatalysis with pristine graphite: on-surface nanochemistry assists solution-based catalysis.
Carbocatalysis holds a privileged position as a sustainable alternative to metal-based catalysis. While the focus in solution-based catalytic processes generally lies on how the heterogeneous catalyst affects the solution composition, more attention has recently been given to the analysis of the carbon material itself. Various outstanding surface characterisation techniques, efficient in assessing the catalyst on-surface composition, are now available. These include high-resolution imaging tools such as scanning tunneling microscopy (STM), capable of bringing new insights into the processes determining rate and selectivity effects induced by carbocatalysts. In this regard, the use of self-assembly on graphite as a strategy to direct the outcome of chemical reactions has already shown great potential. This promising approach gives the scientific community the exciting prospect of rationalising selectivity in carbocatalysis with pristine graphite by linking in-solution and on-surface composition.


Apomorphine: an underutilized therapy for Parkinson's disease.
Apomorphine was the first dopaminergic drug ever used to treat symptoms of Parkinson's disease. While powerful antiparkinsonian effects had been observed as early as 1951, the potential of treating fluctuating Parkinson's disease by subcutaneous administration of apomorphine has only recently become the subject of systematic study. A number of small scale clinical trials have unequivocally shown that intermittent subcutaneous apomorphine injections produce antiparkinsonian benefit close if not identical to that seen with levodopa and that apomorphine rescue injections can reliably revert off-periods even in patients with complex on-off motor swings. Continuous subcutaneous apomorphine infusions can reduce daily off-time by more than 50% in this group of patients, which appears to be a stronger effect than that generally seen with add-on therapy with oral dopamine agonists or COMT inhibitors. Extended follow-up studies of up to 8 years have demonstrated long-term persistence of apomorphine efficacy. In addition, there is convincing clinical evidence that monotherapy with continuous subcutaneous apomorphine infusions is associated with marked reductions of preexisting levodopa-induced dyskinesias. The main side effects of subcutaneous apomorphine treatment are related to cutaneous tolerability problems, whereas sedation and psychiatric complications play a lesser role. Given the marked degree of efficacy of subcutaneous apomorphine treatment in fluctuating Parkinson's disease, this approach seems to deserve more widespread clinical use.


Mental health during the COVID-19 pandemic in children and adolescents with ADHD: a systematic review of controlled longitudinal cohort studies.
Prior studies reported mixed effects of the COVID-19 pandemic on the mental health of children and adolescents with ADHD, but they were mainly cross-sectional and without controls. To clarify the impact, we searched Web of Science, EMBASE, Medline, and PsychINFO until 18/11/2023 and conducted a systematic review of controlled longitudinal cohort studies (Prospero: CRD42022308166). The Newcastle-Ottawa scale was used to assess quality. We identified 6 studies. Worsening of mental health symptoms was more evident in ADHD or control group according to symptom considered and context. However, those with ADHD had more persistent elevated symptoms and remained an at-risk population. Sleep problems deteriorated more significantly in those with ADHD. Lower pre-COVID emotion regulation skills and greater rumination were associated with worse mental health outcomes, and longer screen time with poorer sleep. Quality was rated as low in most studies, mainly due to self-report outcome measures and no information on attrition rates. Despite these limitations, results suggest a predominantly negative impact on youths with ADHD and may guide clinical practice and policy.


New technique of intracorneal ring segments suturing after migration.
To describe a new technique for suturing of the intracorneal ring segments to stabilize it in the proper location and to prevent recurrent displacement of the ring. Two patients with recurrent ring segment migration toward the incision were treated with this new surgical technique between 2010 and 2013. The first case had Intacs ring (Addition Technology, Fremont, CA) and migration occurred 2 months after implantation. The second case had Keraring segment (Mediphacos, Belo Horizonte, Brazil) and migration occurred 1 week postoperatively. The ring segments were fixated to the cornea with a 10-0 nylon suture through the channel. The suture was removed at 1 month postoperatively. Ring segments remained in the desired location with a follow-up period of at least 6 months after implantation. This newly described ring suturing technique is an effective procedure that can be used to treat ring segment migration in the channel.


Organogenesis: molecular mechanisms of tubulogenesis.
As organisms have evolved in size and complexity, tubular systems have developed to enable the efficient transport of substances into and out of tissues. These tubular systems are generated using strategies that are based on common elements of cell behaviour, including cell polarization, tube migration to target sites, cell-fate diversification and localization of specialized cells to different regions of the tube system. Using examples from both invertebrate and vertebrate systems, this review highlights progress in understanding these basic principles and briefly discusses the possible evolution of strategies to regulate the morphogenesis of tubular systems.


Ellagic acid-Fe nanoscale coordination polymer with higher longitudinal relaxivity for dual-modality T1-weighted magnetic resonance and photoacoustic tumor imaging.
Dual-modality contrast agents for T1-weighted magnetic resonance imaging (MRI) and photoacoustic imaging have attracted substantial attention as they combine the advantages of unlimited penetration depth and high sensitivity. However, most of the reported agents are Gd-based materials that exhibit nephrotoxicity, and few studies have focused on Fe-based materials owing to their lower relaxivity. This work describes the development of an ellagic acid (EA)-Fe nanoscale coordination polymer with high longitudinal relaxivity and strong near-infrared absorption for dual-modality T1-weighted MRI and photoacoustic imaging. The longitudinal relaxivity (r1) of the prepared EA-Fe@BSA nanoparticles was 2.54 mM-1 s-1, an increase of 185% compared with previously reported gallic acid-Fe nanoparticles. Furthermore, in vitro and in vivo experiments demonstrate that the EA-Fe@BSA NPs are an excellent T1-weighted MRI and photoacoustic dual-modality contrast agent with the advantages of convenient synthesis and low toxicity, exhibiting great potential for clinical use in tumor imaging.


[Isolation and characteristics of compound transposons Tn1000::Tn5].
Two types of compound transposons were derived. In the first case, transposon Tn5 is inserted into the gene responsible for Tn1000 transposase synthesis. In the other, Tn5 is inserted into the region near the left end of Tn1000, where no functionally significant genes were found. It is known that translocation of the compound transposons does not depend on their size and takes place with the efficiency close to that characteristic of the intact Tn1000. Insertion of Tn5 into the gene coding for Tn1000 transposase results in sharp decrease in the efficiency of Tn1000 translocations. This effect, however, may be eliminated by introduction into the cell of the intact Tn1000.


Somatosensory perception sensitivity in voluntary postural sway movements: Age, gender and sway effect magnitudes.
1) to develop a reliable device for assessing somatosensory perception sensitivity in voluntary postural sway movement, specifically a sway discrimination apparatus (SwayDA) for testing voluntary lateral sway discrimination sensitivity (VLSDS); 2) to explore the relationship between mobility performance and VLSDS in older adults, and 3) to determine the effects of age, gender and sway magnitude on VLSDS. First, eighteen healthy young adults (8 males, 10 females, age ranging from 22 to 70) were recruited for a test-retest reliability study. During the SwayDA test, the participants were asked to discriminate between four possible medial-lateral sway extents when moving away from neutral standing. For Objective 2, twenty-five older participants (9 males, 16 females, mean age 70.1) undertook both the SwayDA and the mobility tests. The mobility testing battery consisted of single task and cognitive dual task timed-up and-go tests, and the 5 times sit-to-stand test. Pearson's correlation was calculated between SwayDA scores and mobility performance. For Objective 3, 20 community-dwelling adults over 65 years old (10 males, 10 females, mean age 71.3) and 20 young volunteers (10 males, 10 females, mean age 23.6) were recruited to study the effects of age, gender and sway magnitude on VLSDS. To obtain a bias-free measure of VLSDS, the probability of correct response was considered as the true-positive judgment, while the probability of incorrect response was considered as false-positive judgment, and these were cumulated across the response values. A receiver operating characteristic (ROC) curve was then generated and the Area Under the ROC Curve (AUC) was used to measure VLSDS. There was no significant difference in AUC scores between Day 1 and Day 8 (p > 0.05). ICC(3,1) reliability indices were 0.750 for sway to the left and 0.879 for sway to the right. Pearson's correlation revealed a significant correlation between the SwayDA sores and timed-up-and-go (TUG), cognitive dual task TUG, 5 times sit-to-stand test (r = -0.456, -0.522, and - 0.416 respectively, all p < 0.05). Factorial ANOVA showed age and gender main effects (F = 8.144, p < 0.01, and F = 8.806, p < 0.01, respectively), suggesting older adults and females had worse VLSDS. In addition, a significant difference was found between the young and older participants in the inner range of VLSDS (t = -2.875, p < 0.017), indicating that the decline of somatosensory perception of postural sway in older people may be magnitude-specific, and greatest for small deviations from upright stance. The SwayDA has good to excellent test-retest reliability. The finding that VLSDS score was significantly correlated with mobility performance in older adults highlights the importance of somatosensory perception in postural control. More importantly, the significantly worse VLSDS in older people observed in the inner lateral movement range may represent a unique characteristic of neuromuscular degeneration associated with aging, which should be monitored and addressed in rehabilitation programs.


Occipitocervical fixation using occipital bone hooks and cervical lateral mass screws: analysis of 16 cases.
We present a series of 16 patients who underwent occipitocervical fixation with occipital bone hooks used as a substitute for occipital screws for the treatment of occipitocervical instability. In this technique; instrumentation was started following the decompression with insertion of screws into lateral masses. At the occipital level, two symmetrical burr holes were drilled and two occipital bone hooks were inserted into each burr hole with an inverted position with respect to each other. Afterwards, rod-plates were placed and locked on the hooks and screw heads. Bone grafting was also performed to achieve a solid fusion. There were no neurological or vascular complications associated with this technique. No infection-related complications or hematomas were observed. Cerebro-spinal fluid leaks (CSF) occurred when the burr holes were drilled in 4 patients; however, these ceased when the occipital bone hooks were inserted. There were no cases of postoperative CSF fistula or pseudo-meningocele formation. No instrumentation problem was noted in any of the cases during the follow-up period. Relatively long term (average 30.44 months) evaluation of the technique in terms of stability is satisfactory with no neurological, vascular or other major complications. However, further biomechanical studies are needed.


[Applicability of Children's Environment and Health Action Plan in Serbia].
The Children's Environment and Health Action Plan for Europe was adopted at the 4th Ministry Conference on Environment (the World Health Organization, 2004). It is focused on children health care against hazards originating from the human environment. In its conclusion, the need is expressed for the development of national plans in the field of Environmental and Children Health for European region by 2007. Mutual activities would be obligatory for each country and their realization should be the responsibility of Ministers of Health Care and Environmental Health. In our country, a draft version of this document was recently adopted, where the following priority regional goals are proposed: safe drinking water and adequate sanitation, injury prevention and adequate physical activity, clean indoor and outdoor air, the human environment without chemicals. Every segment has been explained in details through activities, expected results, indicators, sources of verification and the main participants in the project implementation. The end of the action plan period is proposed to be the year 2019. It is also followed by a defined set of indicators: exposure, activities and health status. The analyses of particular activities or data to be used have pointed to some drawbacks of this draft version, which can be overcome by respecting expert opinions.


[A neurophysiological study of chronic brain ischemia].
One hundred and eighty-six patients, aged 42-75 years, with chronic cerebrovascular insufficiency of the brain stem were studied using registration of spinal-bulbar and wink reflexes. The characteristics of neurophysiological methods were compared to MRI data. The results obtained suggest the presence of anticipating development of the neurophysiological changes comparing to the neuroimaging signs. The practical significance of this situation in view of cost-effectiveness of both methods is highlighted.


Age-dependent organotypic expression of microtubule-associated proteins (MAP1, MAP2, and MAP5) in rat brain.
Age-dependent changes in the distribution of microtubule-associated proteins (MAPs) were analyzed in young (3-months, N = 3) and old (24-months, N = 3) rat brain. In the young rats, MAP1 and MAP5 exhibited prominent immunostaining in the perikarya and dendrites whereas MAP2 was selectively localized in the dendrites. In the cerebellum, MAP2 was preferentially localized in finer and distal branches of Purkinje cell dendrites and in punctate deposits surrounding glomeruli. In general, aging resulted in obvious declines in MAP2- >> MAP1- and MAP5-immunoreactivities in the hippocampus and parietal cortex but no change in cerebellum. The results indicate that: (1) hippocampus is the most affected and cerebellum is the least affected region with regard to declines in MAPs-immunoreactivities in the aged rat brain; (2) dendrite-specific MAP2 is almost completely depleted from most dendrites in the hippocampus and cortex. In summary, loss of MAP2-immunoreactivity in the affected brain areas may be associated with age-related impairment of synaptic plasticity, cognition and memory functions.


Rhinosporidiosis of the lacrimal sac masquerading as chronic dacryocystitis: a rare presentation.
Rhinosporidiosis is a chronic infection of the mucous membrane caused by the Rhinosporiduim seeberi, which infects through transepithelial penetration. Although described worldwide, this entity is mostly found in the western hemisphere, afflicting young people, predominantly males, associated in many cases with recreational or professional contact with bath in ponds, rivers, or stagnant waters. The clinical features are varied depending on the affected membrane, in some cases mimicking other diseases postponing the correct diagnosis. Although nasal obstruction and epistaxis are the common clinical presentations in sinonasal rhinosporidiosis, patients with epiphora without a nasal mass often challenge the diagnosis. In the present case, we have documented a case of isolated lacrimal sac rhinosporidiosis masquerading as chronic dacryocystitis, which was successfully managed by endoscopic excision, accompanied by a literature review.


Phosphorylation of rabbit skeletal muscle myosin in situ.
Myosin light chain (P light chain) is phosphorylated by Ca2+ X calmodulin-dependent myosin light chain kinase. Based on studies with rat skeletal muscles, it has been shown that P light chain phosphorylation correlated to the extent of potentiation of isometric twitch tension. It is not clear whether this correlation exists in rabbit skeletal muscle, which has been the primary source of contractile proteins for biochemical studies. Therefore, phosphorylation of myosin P light chain in rabbit slow-twitch soleus and fast-twitch plantaris muscles in situ was examined. Electrical stimulation (5 Hz, 20 seconds) of plantaris muscle produced an increase in the phosphate content of P light chain from 0.17 to 0.45 mol phosphate/mol P light chain. This increase in phosphate content was accompanied by a 58% increase in maximal isometric twitch tension. Tetanic stimulation (100 Hz, 15 seconds) of rabbit soleus muscle resulted in only a small increase in P light chain phosphate content from 0.02 to 0.10 mol phosphate/mol P light chain, and posttetanic twitch tension did not increase significantly. The correlation between potentiated isometric twitch tension and P light chain phosphorylation in rabbit fast-twitch muscle is similar to that observed in rat skeletal muscle. These results were consistent with the hypothesis that phosphorylation of rabbit skeletal muscle myosin, which results in an increase in actin-activated ATPase activity, may be related to isometric twitch potentiation.


Managing anemia in lymphoma and multiple myeloma.
Anemia is common in cancer, and lymphoproliferative disease is no exception. Erythropoiesis-stimulating agents (ESA) have been used for renal anemia since 1986, and considerably later in cancer anemia. The first studies were published around 1993, but the use of ESA did not become common in cancer anemia until in the late 1990s. Cancer anemia is still under-treated. This review gives an overview of the use of ESA in hematologic malignancies. A background is given about this treatment in the cancer field generally. The pathophysiology of cancer anemia is described with special emphasis on the disturbances in iron metabolism. Functional iron deficiency has been shown to be both frequent and important as a hindrance for response to ESA treatment, and recent studies are reported in some detail, where the use of intravenous iron was shown to improve the response rate of ESA treatment.


Comparison of the human gastric microbiota in hypochlorhydric states arising as a result of Helicobacter pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use.
Several conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk. 95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq). Samples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase. Autoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.


Directed assembly of gold nanorods using aligned electrospun polymer nanofibers for highly efficient SERS substrates.
Nonspherical metal nanoparticles are very attractive plasmonic nanostructures owing to the facile tunability of the plasmonic properties and the presence of sharp corners and edges, which act as electromagnetic hot spots for surface enhanced Raman scattering (SERS). However, such anisotropic nanostructures exhibit strong polarization dependence in their plasmonic properties, exhibiting significantly higher SERS intensity in certain orientations. In this paper, we demonstrate a facile strategy to achieve directed assembly of aligned gold nanorods using highly aligned electrospun nanofibers. We believe that the interstices between the nanofibers act as micro-and nanochannels, resulting in hydrodynamic drag forces on the gold nanorods, thus inducing massive alignment of the same on the nanofibers. Apart from exhibiting nearly 50 times higher SERS intensity compared to a planar SERS substrate with randomly oriented nanorods, our results highlight the importance of the orientation of anisotropic nanostructures. Finite difference time domain (FDTD) simulations employed to understand the electromagnetic field distribution around an aligned nanorod array showed excellent agreement with the experimental observations.


Comparison of whole genome sequences of Streptococcus equi subsp. equi from an outbreak in Texas with isolates from within the region, Kentucky, USA, and other countries.
Strangles, caused by Streptococcus equi subspecies equi (S. equi) is an infectious disease of horses with worldwide distribution, but there are limited data available regarding strain variation using whole genome sequencing among and within outbreaks in the United States (US), and how US isolates compare with S. equi isolated globally. To address this knowledge-gap, we compared the whole genomes of 54 S. equi isolates from Texas and Kentucky and those of 230 publicly available sequences of S. equi isolates collected from other countries. Our results show that despite minimal variation among isolates within an outbreak some mutations do occur among individual outbreak isolates. Some S. equi strains from the US are closely related to S. equi isolates from other countries, likely reflecting international dissemination of isolates. Collectively, these data improve our understanding of phenotypic and genotypic variation of isolates within an outbreak, and the international distribution of S. equi. We also identify a novel variant of the S. equi M-protein, and observed cases of strangles that were caused by the modified-live vaccine but that were not recognized as vaccine-associated at the time of clinical sample submission.


Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells.
Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and beta-cell function in lipodystrophic HIV-infected patients. [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; > 34%, P < 0.001), hepatic insulin sensitivity (> 40%, P < 0.03), incremental glucose disposal (>50%, P < 0.001) and incremental exogenous glucose storage (>50%, P < 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P < 0.01), increased clamp free fatty acids (P < 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P < 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r = 0.69), incremental glucose disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all P < 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P = 0.05) in LIPO compared with the combined groups of NONLIPO and NAIVE, indicating an impaired adaptation of beta-cell function to insulin resistance in LIPO. Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and beta-cell function.


Effect of subcutaneously administered diclazuril on the output of Eimeria species oocysts by experimentally infected rabbits.
The effect of subcutaneously injected diclazuril on the output of Eimeria species oocysts was studied in experimentally infected rabbits. Diclazuril was administered either prophylactically at 0.5, 1 or 2 mg/kg bodyweight two days before each rabbit was inoculated with 20,000 oocysts of a mixed-species field isolate of Eimeria or therapeutically at 1, 2 or 4 mg/kg bodyweight five days after they were inoculated. The prophylactic treatments significantly reduced (P<0.05) the output of oocysts in faeces and the numbers in the rabbits' livers at all doses. The therapeutic treatment at 4 mg/kg also caused a significant reduction (P<0.05) in oocyst shedding, but the lower doses resulted in only a moderate reduction. The shedding of the pathogenic species Eimeria stiedae, Eimeria magna, Eimeria irresidua, Eimeria flavescens, Eimeria piriformis and Eimeria intestinalis was significantly reduced (P<0.05) in all the treated groups. The burden of oocysts in the livers of the therapeutic groups (4000 to 9000) were significantly lower (P<0.05) than in the inoculated but untreated control group (23,000), but higher than in the prophylactic groups (around 1000).


Should Physicians Be Able to Refuse to Care for Patients Insured by Medicare?
This commentary on a case considers whether and to what extent refusal to care for Medicare patients is a form of "turfing." Medicare is a federal program to provide insurance for people over age 65, those who have certain disabilities, and those with end-stage renal disease; eligibility criteria include contributions from wages and salaries during a patient's working career. Although all clinicians in the United States can care for Medicare patients, some opt out, resulting in harms to eligible patients and in oversubscription of remaining clinical practices. Opting out should be reconsidered, given that resident training is supported by Medicare funding. Although patients who receive services upon engaging with a health care practice might believe that they are under the care of a clinician, any harms of administrative nonadherence to practice guidelines accrue to the clinician.


The control of gene expression in melanocytes and melanomas.
Powerful evidence exists that deregulation of cell type-specific gene expression is a major feature of the genesis of several cancers, with many oncogenic proteins known to possess transcription regulation properties. As a consequence of this deregulation, melanomas may ectopically express HLA-DR and also fall to express enzymes required for melanin synthesis, resulting in amelanotic melanoma. Recent work has demonstrated that these phenomena may be accounted for by the expression of a transcription factor called Brn-2, now known to be involved with the development of neural crest-derived tissues. Brn-2 is normally expressed at high levels in melanoblasts and melanomas but only at low levels in normal melanocytes. Brn-2 may act by competing with another transcription factor, ml, necessary for normal melanocyte development.


Terahertz sources and detectors and their application to biological sensing.
Terahertz spectroscopy has long been used as an important measurement tool in fields such as radio astronomy, physical chemistry, atmospheric studies and plasma research. More recently terahertz technology has been used to develop an exciting new technique to investigate the properties of a wide range of biological materials. Although much research remains before a full understanding of the interaction between biomaterials and terahertz radiation is developed, these initial studies have created a compelling case for further scientific study. Also, the potential development of practical tools to detect and identify biological materials such as biological-warfare agents and food contaminants, or of medical diagnostic tools, is driving the need for improved terahertz technology. In particular, improved terahertz sources and detectors that can be used in practical spectroscopy systems are needed. This paper overviews some of the recent measurements of the terahertz spectra of biomaterials and the ongoing efforts to create an all-solid-state technology suitable not only for improved scientific experiments but also for military and commercial applications.


CD40 ligation prevents Trypanosoma cruzi infection through interleukin-12 upregulation.
Because of the critical role of the CD40-CD40 ligand (CD40L) pathway in the induction and effector phases of immune responses, we investigated the effects of CD40 ligation on the control of Trypanosoma cruzi infection. First, we observed that supernatants of murine spleen cells stimulated by CD40L-transfected 3T3 fibroblasts (3T3-CD40L transfectants) prevent the infection of mouse peritoneal macrophages (MPM) by T. cruzi. This phenomenon depends on de novo production of nitric oxide (NO) as it is prevented by the addition of N-nitro-L-arginine methyl ester, a NO synthase inhibitor. NO production requires interleukin (IL)-12-mediated gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis as demonstrated by inhibition experiments using neutralizing anti-IL-12, anti-IFN-gamma, and anti-TNF-alpha monoclonal antibodies (MAb). We found that an activating anti-CD40 MAb also directly stimulates IFN-gamma-activated MPM to produce NO and thereby to control T. cruzi infection. To determine the in vivo relevance of these in vitro findings, mice were injected with 3T3-CD40L transfectants or 3T3 control fibroblasts at the time of T. cruzi inoculation. We observed that in vivo CD40 ligation dramatically reduced both parasitemia and the mortality rate of T. cruzi-infected mice. A reduced parasitemia was still observed when the injection of 3T3-CD40L transfectants was delayed 8 days postinfection. It was abolished by injection of anti-IL-12 MAb. Taken together, these data establish that CD40 ligation facilitates the control of T. cruzi infection through a cascade involving IL-12, IFN-gamma, and NO.


Characterization of monoclonal antibodies against hantavirus nucleocapsid protein and their use for immunohistochemistry on rodent and human samples.
Monoclonal antibodies are important tools for various applications in hantavirus diagnostics. Recently, we generated Puumala virus (PUUV)-reactive monoclonal antibodies (mAbs) by immunisation of mice with chimeric polyomavirus-derived virus-like particles (VLPs) harbouring the 120-amino-acid-long amino-terminal region of the PUUV nucleocapsid (N) protein. Here, we describe the generation of two mAbs by co-immunisation of mice with hexahistidine-tagged full-length N proteins of Sin Nombre virus (SNV) and Andes virus (ANDV), their characterization by different immunoassays and comparison with the previously generated mAbs raised against a segment of PUUV N protein inserted into VLPs. All of the mAbs reacted strongly in ELISA and western blot tests with the antigens used for immunization and cross-reacted to varying extents with N proteins of other hantaviruses. All mAbs raised against a segment of the PUUV N protein presented on chimeric VLPs and both mAbs raised against the full-length AND/SNV N protein reacted with Vero cells infected with different hantaviruses. The reactivity of mAbs with native viral nucleocapsids was also confirmed by their reactivity in immunohistochemistry assays with kidney tissue specimens from experimentally SNV-infected rodents and human heart tissue specimens from hantavirus cardiopulmonary syndrome patients. Therefore, the described mAbs represent useful tools for the immunodetection of hantavirus infection.


Developing common learning: the new generation project undergraduate curriculum model.
This paper describes the curriculum model developed for an ambitious interprofessional education programme for health and social care professions implemented in two universities in the south of England (the New Generation Project). An outline of how the New Generation Project has interpreted the meaning of interprofessional learning is presented first. This is followed by an outline of the structure of the programme, describing both learning in common and interprofessional learning components. The pedagogies underpinning this curriculum initiative are presented and an integrated pedagogical model, facilitated collaborative interprofessional learning, is proposed. The New Generation Project curriculum is then discussed as an extension of an established typology of interprofessional education.


Lower vitamin-D production from solar ultraviolet-B irradiance may explain some differences in cancer survival rates.
Black Americans diagnosed with cancer generally have lower survival rates than white Americans, even after adjustment for stage of cancer at time of discovery and level of treatment received. The hypothesis developed in this work is that these lower cancer survival rates may be due to lower serum 25-hydroxyvitamin D [25(OH)DI for black Americans attributed to lower production rates of vitamin D from solar ultraviolet-B (UVB) irradiance due to darker skin. Black Americans generally have 50-75% as much serum 25(OH)D as white Americans, and vitamin D is now thought to reduce the risk of incidence and mortality for 18 types of cancer. To explore this hypothesis, data for mortality rates for various types of cancer for the period 1970-1994 for black Americans were used with indices for solar UVB levels for July, smoking, alcohol consumption, urban residence and poverty level, all averaged by state, in multiple linear regression analyses using the ecologic approach. Solar UVB was found significantly inversely correlated with mortality rates for breast, colon, esophageal, gastric and rectal cancers for black Americans, albeit with lower associations than for white Americans. Smoking and alcohol consumption were also significantly correlated with several cancers. Based on these results, it seems worthwhile to conduct observational, prevention and intervention studies to further test the hypothesis that vitamin D can reduce the risk of cancer incidence and death.


Oral anti-diabetic agents for women with established diabetes/impaired glucose tolerance or previous gestational diabetes planning pregnancy, or pregnant women with pre-existing diabetes.
While most guidance recommends the use of insulin in women whose pregnancies are affected by pre-existing diabetes, oral anti-diabetic agents may be more acceptable to women. The effects of these oral anti-diabetic agents on maternal and infant health outcomes need to be established in pregnant women with pre-existing diabetes or impaired glucose tolerance, as well as in women with previous gestational diabetes mellitus preconceptionally or during a subsequent pregnancy. This review is an update of a review that was first published in 2010. To investigate the effects of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who are planning a pregnancy, or pregnant women with pre-existing diabetes, on maternal and infant health. The use of oral anti-diabetic agents for the management of gestational diabetes in a current pregnancy is evaluated in a separate Cochrane Review. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2016) and reference lists of retrieved studies. Randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who were planning a pregnancy, or pregnant women with pre-existing diabetes. Cluster-RCTs were eligible for inclusion, but none were identified. Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included RCTs. Review authors checked the data for accuracy, and assessed the quality of the evidence using the GRADE approach. We identified six RCTs (707 women), eligible for inclusion in this updated review, however, three RCTs had mixed populations (that is, they included pregnant women with gestational diabetes) and did not report data separately for the relevant subset of women for this review. Therefore we have only included outcome data from three RCTs; data were available for 241 women and their infants. The three RCTs all compared an oral anti-diabetic agent (metformin) with insulin. The women in the RCTs that contributed data had type 2 diabetes diagnosed before or during their pregnancy. Overall, the RCTs were judged to be at varying risk of bias. We assessed the quality of the evidence for selected important outcomes using GRADE; the evidence was low- or very low-quality, due to downgrading because of design limitations (risk of bias) and imprecise effect estimates (for many outcomes only one or two RCTs contributed data).For our primary outcomes there was no clear difference between metformin and insulin groups for pre-eclampsia (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.33 to 1.20; RCTs = 2; participants = 227; very low-quality evidence) although in one RCT women receiving metformin were less likely to have pregnancy-induced hypertension (RR 0.58, 95% CI 0.37 to 0.91; RCTs = 1; participants = 206; low-quality evidence). Women receiving metformin were less likely to have a caesarean section compared with those receiving insulin (RR 0.73, 95% CI 0.61 to 0.88; RCTs = 3; participants = 241; low-quality evidence). In one RCT there was no clear difference between groups for large-for-gestational-age infants (RR 1.12, 95% CI 0.73 to 1.72; RCTs = 1; participants = 206; very low-quality evidence). There were no perinatal deaths in two RCTs (very low-quality evidence). Neonatal mortality or morbidity composite outcome and childhood/adulthood neurosensory disability were not reported.For other secondary outcomes we assessed using GRADE, there were no clear differences between metformin and insulin groups for induction of labour (RR 1.42, 95% CI 0.62 to 3.28; RCTs = 2; participants = 35; very low-quality evidence), though infant hypoglycaemia was reduced in the metformin group (RR 0.34, 95% CI 0.18 to 0.62; RCTs = 3; infants = 241; very low-quality evidence). Perineal trauma, maternal postnatal depression and postnatal weight retention, and childhood/adulthood adiposity and diabetes were not reported. There are insufficient RCT data to evaluate the use of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who are planning a pregnancy, or in pregnant women with pre-existing diabetes. Low to very low-quality evidence suggests possible reductions in pregnancy-induced hypertension, caesarean section birth and neonatal hypoglycaemia with metformin compared with insulin for women with type 2 diabetes diagnosed before or during their pregnancy, and no clear differences in pre-eclampsia, induction of labour and babies that are large-for-gestational age. Further high-quality RCTs that compare any combination of oral anti-diabetic agent, insulin and dietary and lifestyle advice for these women are needed. Future RCTs could be powered to evaluate effects on short- and long-term clinical outcomes; such RCTs could attempt to collect and report on the standard outcomes suggested in this review. We have identified three ongoing studies and four are awaiting classification. We will consider these when this review is updated.


Interfacial reactivity of ruthenium nanoparticles protected by ferrocenecarboxylates.
Stable ruthenium nanoparticles protected by ferrocenecarboxylates (RuFCA) were synthesized by thermolytic reduction of RuCl3 in 1,2-propanediol. The resulting particles exhibited an average core diameter of 1.22 ± 0.23 nm, as determined by TEM measurements. FTIR and (1)H NMR spectroscopic measurements showed that the ligands were bound onto the nanoparticle surface via Ru-O bonds in a bidentate configuration. XPS measurements exhibited a rather apparent positive shift of the Fe2p binding energy when the ligands were bound on the nanoparticle surface, which was ascribed to the formation of highly polarized Ru-O interfacial bonds that diminished the electron density of the iron centers. Consistent results were obtained in electrochemical measurements where the formal potential of the nanoparticle-bound ferrocenyl moieties was found to increase by ca. 120 mV. Interestingly, galvanic exchange reactions of the RuFCA nanoparticles with Pd(ii) followed by hydrothermal treatment at 200 °C led to (partial) decarboxylation of the ligands such that the ferrocenyl moieties were now directly bonded to the metal surface, as manifested in voltammetric measurements that suggested intervalence charge transfer between the nanoparticle-bound ferrocene groups.


Auditory perceptual abilities of formerly misarticulating children.
12 children who recently had satisfactorily completed therapy for 4+ phonemes, and normal controls, were given tasks of auditory perception consisting of (a) repeating 5-word recorded sentences (0, 1st- and 2nd-order approximations) at 0 and at 60% time compression, and (b) diotic and dichotic presentations at 40 db SL of the WIPI test split into 2 bandwidths (500-580 and 1950-2080 c/s). Results showed that the performance of the experimental Ss was significantly poorer than that of age-matched controls on time-compressed speech, but not on the binaural fusion task. The greatest diagnostic potential for time-compressed speech was at 60% compression. Results contrasted with previous data showing significantly poorer performance of severely misarticulating children on a binaural summation task (Flowers and Costello, J. Aud. Res., 1963, 3, 133-140). There is a need to monitor the auditory perceptual abilities of formerly misarticulating children with a battery of more than a single test.


Application of stochastic models in identification and apportionment of heavy metal pollution sources in the surface soils of a large-scale region.
As heavy metals occur naturally in soils at measurable concentrations and their natural background contents have significant spatial variations, identification and apportionment of heavy metal pollution sources across large-scale regions is a challenging task. Stochastic models, including the recently developed conditional inference tree (CIT) and the finite mixture distribution model (FMDM), were applied to identify the sources of heavy metals found in the surface soils of the Pearl River Delta, China, and to apportion the contributions from natural background and human activities. Regression trees were successfully developed for the concentrations of Cd, Cu, Zn, Pb, Cr, Ni, As, and Hg in 227 soil samples from a region of over 7.2 × 10(4) km(2) based on seven specific predictors relevant to the source and behavior of heavy metals: land use, soil type, soil organic carbon content, population density, gross domestic product per capita, and the lengths and classes of the roads surrounding the sampling sites. The CIT and FMDM results consistently indicate that Cd, Zn, Cu, Pb, and Cr in the surface soils of the PRD were contributed largely by anthropogenic sources, whereas As, Ni, and Hg in the surface soils mostly originated from the soil parent materials.


Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989).
Twenty-eight of 124 (23%) advanced germ cell tumor (GCT) patients who were treated on four successive platin-based induction regimens and who failed to achieve a durable complete response (CR) remain alive (median follow-up, 50 months). An analysis of prognostic factors for response and survival was conducted on the 94 patients who received salvage chemotherapy. Survival and/or response to salvage therapy were significantly enhanced for patients with a prior CR to induction chemotherapy, treatment with a cisplatin-based salvage regimen, a testis primary site, a normal serum human chorionic gonadotropin level, a normal serum lactate dehydrogenase level, one site of metastasis, and an Indiana Class of 6 or less. Patients with a prior incomplete response (IR) had a particularly poor prognosis (P = 0.00007) with only 4 of 52 (9%) patients alive (median follow-up, 37 months) compared with 15 of 42 (36%) patients with a prior best response of a CR (median follow-up, 35 months). The poor survival of patients who fail to achieve a durable CR to induction chemotherapy warrants the continued investigation of new salvage therapy. The identification of prognostic features may direct salvage therapy and aid in the interpretation of clinical trials of salvage regimens.