Adverse Events Related to Off-Label Drugs Using Spontaneous Adverse Event Reporting Systems.
The purpose of this study was to investigate the adverse events (AEs) related to the use of off-label drugs. A cross-sectional study was carried out using available data pertaining to off-label drug were sourced from U.S. FDA spontaneous adverse drug reaction reporting database (FAERS) and Korea Adverse Event Reporting System database (KIDS-KD) for the years 2014 to 2018. The number and frequencies of AE cases were calculated. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the information component (IC), and the empirical Bayes geometric mean (EBGM) methods. The reported AEs associated with off-label drug use were more common among older patients compared with younger patients. Gastric nonspecific symptoms and therapeutic procedure (4.16-4.57%) and haemorrage term (4.16-5.29%) were the most common AE symptoms and antithrombotic agents and immunosuppressants were the drugs most commonly reported to cause AEs in FAERS. Secondary term events (43.45-48.62%) including inappropriate schedule of drug administration and medication error were the most common AEs, and immunosuppressants and antipsychotics were the most common AE-related drugs from KIDS-KD. The numbers of reported AEs in new drug categories such as other antineoplastic agents trended to increase from 2014 to 2018 in both datasets. The numbers of reported AEs with off-label drug increased annually. AEs associated with off-label drugs may have a significant impact on older patients. Healthcare experts should be concerned about prescriptions of off-label drugs, especially anticoagulants and newly developed drugs such as immunosuppressants and antineoplastic agents.


Health Benefits and Adverse Effects of a Gluten-Free Diet in Non-Celiac Disease Patients.
Gluten-related diseases such as celiac disease and gluten ataxia are rare conditions, affecting less than 1% of the population in the United States. Despite the rarity of these diseases, there have been significant increases in the adoption of a gluten-free lifestyle and the consumption of gluten-free foods in the United States over the last 3 decades. More than $15.5 billion were spent on retail sales of gluten-free foods in 2016. The gluten-free diet is driven by multiple factors, including social and traditional media coverage, aggressive consumer-directed marketing by manufacturers and retail outlets, and reports in the medical literature and mainstream press of the clinical benefits of gluten avoidance. Individuals may restrict gluten from their diets for a variety of reasons, such as improvement of gastrointestinal and nongastrointestinal symptoms, as well as a perception that gluten is potentially harmful and, thus, restriction represents a healthy lifestyle. Emerging evidence shows that gluten avoidance may be beneficial for some patients with gastrointestinal symptoms, such as those commonly encountered with irritable bowel syndrome. However, high-quality evidence supporting gluten avoidance for physical symptoms or diseases other than those specifically known to be caused by immune-mediated responses to gluten is neither robust nor convincing. In fact, gluten avoidance may be associated with adverse effects in patients without proven gluten-related diseases. This article provides insight regarding gluten avoidance patterns and effects on patients without gluten-related diseases, and highlights concerns surrounding gluten avoidance in the absence of a gluten-mediated immunologic disease.


[Clinico-echocardiographic studies of the state of the heart in vibration disease].
Established was the rate of interventricular septum asymmetrical hypertrophy and left auricle exstasia in vibration disease patients as a result of local vibration. The left ventricle myocardium contraction in major parameters (ventricular ejection, maximum ejection, ejection time and volume, the myocardium circular contraction rate and anterior-posterior contraction, systolic ejection rate) were not affected to a significant degree. The left ventricular systolic function was tending to decrease in vibration disease cases combined with IHD and AH. Desirability of using EchoCG in combination with load testing was proposed for the differential diagnosis of metabolic coronary lesions of the myocardium in vibration disease patients.


[Search for phosphopeptides in the feces of axenic rats fed radioactive ovine casein].
Radioactive ovine casein was obtained by injecting 100 microCi of 14C-Ser into the jugular vein of an ewe. The milk collected 17 and 24 h after this injection contained 12 p. 100 of the radioactivity injected in protein form. The seryl residues were specificially labelled. This casein was used as the only protein source fed to axenic rats; 0.30 p. 100 of the tracer ingested was found in the feces of those rats. Since phosphoserine represented 25 p. 100 of the total casein seryl residues, the phosphopeptides may not be selectively unabsorbable.


Ursolic Acid's Alluring Journey: One Triterpenoid vs. Cancer Hallmarks.
Cancer is a multifactorial disease characterized by various hallmarks, including uncontrolled cell growth, evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis, among others. Traditional cancer therapies often target specific hallmarks, leading to limited efficacy and the development of resistance. Thus, there is a growing need for alternative strategies that can address multiple hallmarks concomitantly. Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid, has recently emerged as a promising candidate for multitargeted cancer therapy. This review aims to summarize the current knowledge on the anticancer properties of UA, focusing on its ability to modulate various cancer hallmarks. The literature reveals that UA exhibits potent anticancer effects through diverse mechanisms, including the inhibition of cell proliferation, induction of apoptosis, suppression of angiogenesis, inhibition of metastasis, and modulation of the tumor microenvironment. Additionally, UA has demonstrated promising activity against different cancer types (e.g., breast, lung, prostate, colon, and liver) by targeting various cancer hallmarks. This review discusses the molecular targets and signaling pathways involved in the anticancer effects of UA. Notably, UA has been found to modulate key signaling pathways, such as PI3K/Akt, MAPK/ERK, NF-κB, and Wnt/β-catenin, which play crucial roles in cancer development and progression. Moreover, the ability of UA to destroy cancer cells through various mechanisms (e.g., apoptosis, autophagy, inhibiting cell growth, dysregulating cancer cell metabolism, etc.) contributes to its multitargeted effects on cancer hallmarks. Despite promising anticancer effects, this review acknowledges hurdles related to UA's low bioavailability, emphasizing the need for enhanced therapeutic strategies.


PKC-zeta is required for angiotensin II-induced activation of ERK and synthesis of C-FOS in MCF-7 cells.
We examined the signalling pathways responsible for the Ang II induction of growth in MCF-7 human breast cancer cells. Ang II in MCF-7 cells induced: (a) the translocation from the cytosol to membrane and nucleus of atypical protein kinase C-zeta (PKC-zeta) but not of PKC-alpha, -delta, - epsilon and -eta; (b) the expression of c-fos mRNA and protein; (c) the phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). All these effects were due to the activation of the Ang II type I receptor (AT1) since they were blocked by the AT1 antagonist losartan. The Ang II-stimulated ERK1/2 phosphorylation was blocked by (a) high doses of staurosporine, inhibitor of PKC-zeta, and by a synthetic myristoylated peptide with sequences based on the endogenous PKC-zeta pseudosubstrate region (zeta-PS); (b) PD098059, a mitogen-activated protein kinase kinase inhibitor (MAPKK/MEK); and, moreover, (c) the inhibitors of phosphoinositide 3-kinases (PI3K), LY294002 and wortmannin, thus indicating that PI3K may act upstream of ERK1/2. The Ang II-evoked c-fos induction was blocked only by high doses of staurosporine and by zeta-PS whilst PD098059, LY294002 and wortmannin were ineffective, thus indicating that c-fos induction is not due to ERK1/2 activity. When the epidermal growth factor-receptor (EGFR) tyrosine kinase activity was inhibited by the use of its inhibitor AG1478, Ang II was still able to induce ERK1/2 phosphorylation and c-fos expression, therefore proving that the transactivation of EGFR was not required for these Ang II effects in MCF-7 cells. The previously reported proliferation of MCF-7 cells induced by Ang II was blocked by PD098059 and by wortmannin in a dose-dependent manner, thereby indicating that in MCF-7 cells the PI3K and ERK pathways mediate the mitogenic signalling of AT1. Our results suggest that in MCF-7 cells Ang II activates multiple signalling pathways involving PKC-zeta, PI3K and MAPK; of these pathways only PKC-zeta appears responsible for the induction of c-fos.


Large Granular Lymphocyte Leukemia.
BACKGROUND: Clonal diseases of large granular lymphocyte (LGL) disorders can arise from a CD3+ T-cell lineage or from a CD3- NK-cell lineage. CD3+ LGL leukemia is the most frequent form of LGL leukemia and is a distinct entity by FAB and REAL classifications. METHODS: The clinical course, biological features, and recent data on pathogenesis of CD3+ LGL leukemia are reviewed. The spectrum of differential diagnosis is described. RESULTS: T-LGL leukemia affects elderly people. Approximately 60% of patients are symptomatic; recurrent infections secondary to chronic neutropenia, anemia, and rheumatoid arthritis are the main clinical features. The most common phenotype is CD3+, CD8+, CD57+. Clonality is detected by clonal rearrangement of the T-cell receptor gene. Clinical and molecular remission can be obtained with oral low-dose methotrexate. Serologic findings show frequent reactivity to the BA21 epitope of HTLV-I env p21e, suggesting that a cellular or retroviral protein with homology to BA21 may be important in pathogenesis. Clonal expansion may be facilitated by IL-12 and IL-15 lymphokines. Constitutive expression of Fas ligand by leukemic LGLs support the hypothesis that leukemic cells arise from antigen-activated cytotoxic T cells. Leukemic LGLs express a multidrug-resistance phenotype that could partly explain the chemoresistance observed in aggressive cases. CONCLUSIONS: CD3+ LGL leukemia is a distinct lymphoproliferative T-cell disorder with specific clinicobiological aspects. The clinical spectrum of LGL proliferations is wide and immunophenotypic, and genotypic studies are needed to establish the diagnosis.


Metabolism and kinetics in the regulation of animal drugs.
"Criteria and Procedures for Evaluating Assays for Carcinogenic Residues," popularly known as the "Sensitivity of the Method (SOM)" proposal for the regulation of animal drugs and feed additives, employs an initial analysis to determine whether a compound must meet the requirements as a suspect carcinogen or the requirements for general food safety (GFS). Metabolism and kinetics of drug depletion play an important role in the six-step procedure that is used for either set of regulatory criteria. The only significant difference that exists between the two sets of criteria is the degree of testing required. However, the difference will usually not be manifest until positive findings of carcinogenicity in the chronic studies in laboratory animals trigger a further evaluation of the metabolism of the drug or feed additive. For both SOM and GFS, metabolic information will be used to determine the appropriateness of the test species as well as to help select a compound for residue analysis. Residue depletion kinetics in the food animals also play an integral role in the selection of species-strains for toxicity testing selection as well as in the selection of the compound for residue analysis in food. Furthermore, depletion kinetics are used to set a safe withdrawal period. The development of guidelines is discussed.


Induction of Staphylococcus epidermidis biofilm formation via proteolytic processing of the accumulation-associated protein by staphylococcal and host proteases.
Because of its biofilm forming potential Staphylococcus epidermidis has evolved as a leading cause of device-related infections. The polysaccharide intercellular adhesin (PIA) is significantly involved in biofilm accumulation. However, infections because of PIA-negative strains are not uncommon, suggesting the existence of PIA-independent biofilm accumulation mechanisms. Here we found that biofilm formation in the clinically significant S. epidermidis 5179 depended on the expression of a truncated 140 kDa isoform of the 220 kDa accumulation-associated protein Aap. As expression of the truncated Aap isoform leads to biofilm formation in aap-negative S. epidermidis 1585, this domain mediates intercellular adhesion in a polysaccharide-independent manner. In contrast, expression of full-length Aap did not lead to a biofilm-positive phenotype. Obviously, to gain adhesive function, full-length Aap has to be proteolytically processed through staphylococcal proteases as demonstrated by inhibition of biofilm formation by alpha(2)-macroglobulin. Importantly, also exogenously added granulocyte proteases activated Aap, thereby inducing biofilm formation in S. epidermidis 5179 and four additional, independent clinical S. epidermidis strains. It is therefore reasonable to assume that in vivo effector mechanisms of the innate immunity can directly induce protein-dependent S. epidermidis cell aggregation and biofilm formation, thereby enabling the pathogen to evade clearance by phagocytes.


Evaluation of orthodontists' perception of treatment need and the peer assessment rating (PAR) index.
This paper examines the relationship between orthodontists' subjective assessment of treatment need and objective measurements obtained during standardized intra- and extraoral examinations. Logistic regression modeling was used to develop predictive models of treatment need. Data were obtained from 1155 eighth-grade students by four orthodontists who used standardized examination forms to assess demographics, trauma, skeletal relationships, morphologic malocclusion traits, and mandibular function. At the conclusion of the examination, the orthodontist rated the subjective treatment need as none, elective, recommended, soon, or immediate. For some analyses, the categories were collapsed to represent no need and need. The peer assessment rating (PAR) index (American validated version) was computed from the clinical exam findings and scoring of dental models; PAR scores were used to document malocclusion severity and treatment difficulty. Spearman rank correlation coefficients quantified the relationship between PAR scores and need categories. Logistic regression analysis modeled treatment need using components of the PAR index as well as other variables. The components of these models, as well as sensitivity and specificity, were compared with malocclusion severity/treatment difficulty scores obtained from malocclusion assessments using the PAR index. The five subjective treatment need categories and the PAR index scores were significantly correlated (rho = 0.62, p<0.001). Significant differences were detected between the need and no need groups for all PAR components (p<0.001). PAR index scores and predicted probabilities from logistic regression models performed equally well for classification purposes (no need, need). The data suggest that the PAR index is highly correlated with orthodontists' subjective assessment of treatment need when that assessment is made in the absence of financial considerations and patient desires.


NK Cell Subpopulations and Receptor Expression in Recovering SARS-CoV-2 Infection.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic of coronavirus disease (COVID-19). Whereas in most cases COVID-19 is asymptomatic or pauci-symptomatic, extremely severe clinical forms are observed. In this case, complex immune dysregulations and an excessive inflammatory response are reported and are the main cause of morbidity and mortality. Natural killer cells are key players in the control of viral infection, and their activity is regulated by a tight balance between activating and inhibitory receptors; an alteration of NK activity was suggested to be associated with the development of severe forms of COVID-19. In this study, we analyzed peripheral NK cell subpopulations and the expression of activating and inhibitory receptors in 30 patients suffering from neurological conditions who recovered from mild, moderate, or severe SARS-CoV-2 infection, comparing the results to those of 10 SARS-CoV-2-uninfected patients. Results showed that an expansion of NK subset with lower cytolytic activity and an augmented expression of the 2DL1 inhibitory receptor, particularly when in association with the C2 ligand (KIR2DL1-C2), characterized the immunological scenario of severe COVID-19 infection. An increase of NK expressing the ILT2 inhibitory receptor was instead seen in patients recovering from mild or moderate infection compared to controls. Results herein suggest that the KIR2DL1-C2 NK inhibitory complex is a risk factor toward the development of severe form of COVID-19. Our results confirm that a complex alteration of NK activity is present in COVID-19 infection and offer a molecular explanation for this observation.


Centrin is necessary for the formation of the motile apparatus in spermatids of Marsilea.
During spermiogenesis in the water fern, Marsilea vestita, basal bodies are synthesized de novo in cells that lack preexisting centrioles, in a particle known as a blepharoplast. We have focused on basal body assembly in this organism, asking what components are required for blepharoplast formation. Spermiogenesis is a rapid process that is activated by placing dry microspores into water. Dry microspores contain large quantities of stored protein and stored mRNA, and inhibitors reveal that certain proteins are translated from stored transcripts at specific times during development. Centrin translation accompanies blepharoplast appearance, while beta-tubulin translation occurs later, during axonemal formation. In asking whether centrin is an essential component of the blepharoplast, we used antisense, sense, and double-stranded RNA probes made from the Marsilea centrin cDNA, MvCen1, to block centrin translation. We employed a novel method to introduce these RNAs directly into the cells. Antisense and sense both arrest spermiogenesis when blepharoplasts should appear, and dsRNA made from the same cDNA is an effective inhibitor at concentrations at least 10 times lower than either of the single-stranded RNA used in these experiments. Blepharoplasts are undetectable and basal bodies fail to form. Antisense, sense, and dsRNA probes made from Marsilea beta-tubulin permitted normal development until axonemes form. In controls, antisense, sense, and dsRNA, made from a segment of HIV, had no effect on spermiogenesis. Immunoblots suggest that translational blocks induced by centrin-based RNA are gene specific and concentration dependent, since neither beta-tubulin- nor HIV-derived RNAs affects centrin translation. The disruption of centrin translation affects microtubule distributions in spermatids, since centrin appears to control formation of the cytoskeleton and motile apparatus. These results show that centrin plays an essential role in the formation of a motile apparatus during spermiogenesis of M. vestita.


A retrospective review of 61 cases of adenomatoid odontogenic tumour seen in five tertiary health facilities in Nigeria.
Adenomatoid odontogenic tumor (AOT) is a benign lesion originating from the dental lamina or its remnants. It is a relatively uncommon neoplasm representing about 3% of all odontogenic tumors. The aim of this study was to examine the clinical and radiological characteristics of AOTs in five major tertiary centres in Nigeria. Archival hospital-based data stores of five tertiary health facilities in Nigeria were accessed. Case files and biopsy records were retrieved to obtain relevant information. Data was collected according to a proforma for standardization and entered into and analysed using SPSS for Windows (version 20.0; SPSS Inc. Chicago, IL). 61 (4.5%) cases of AOT were documented. The age range was 8-46 years with a mean age of 20.4±9.9 years. Male: Female ratio was 1:1.3. The anterior maxilla had 34 (55.8%) cases and the anterior mandible had 20 (32.8%) cases. 40 (65.6%) follicular cases, 20 (32.8%) extra-follicular cases and 1(1.6%) extra-osseous case were found. 31 cases (61.1%) were associated with impacted teeth and the upper canine was involved in 19 (57.6%) cases. This study showed AOT to be more common in the maxilla, more in females, most often associated with impacted canines, however, the suggestion of AOT being a "Two third tumour" was not observed in this study.


MALDI-MS Imaging Analysis of Noninflammatory Type III Rotaxane Dendrimers.
Rotaxane dendrimers with hyperbranched macromolecular interlocked structures and size modulation capacity demonstrate drug binding and release ability upon external stimuli. Mass spectrometry imaging (MSI) can offer the high-throughput screening of endogenous/exogenous compounds. Herein, we reported a novel method to display the in situ spatial distribution of label-free monodispersed type III rotaxane dendrimers (RDs) G1 (first generation, size ∼1.5 nm) and G2 (second generation, size ∼5 nm) that were explored as potential drug vehicles in spleen tissue by using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-MSI). Experimental results indicated that the trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB) matrix exhibited the best performance for monodispersed type III RDs G1 and G2. The optimized method was successfully applied to map the in vivo spatial distribution of type III RDs G1 and G2 in the spleen from intraperitoneally injected mice. The MALDI-MSI images revealed that RDs G1 and G2 were relatively stable in the spleen within 24 h after administration. It was found that the identified type III RDs G1 and G2 penetrated through the tunica serosa and were predominantly localized in red pulp regions of spleens. They were also mapped in a marginal zone of spleens simultaneously. There was almost no toxicity of type III RDs G1 and G2 to mice spleens from the H&E results. Furthermore, the type III RDs did not induce the expression of inflammatory cytokines from peripheral blood mononuclear cells (PBMCs) or THP-1 monocytes. The MSI analysis not only demonstrated its ability to image select rotaxane dendrimers in a rapid and efficient manner but also provided tremendous assistance on the applications of the further treatment of cancerous tissue as safe drug carriers. Furthermore, the new strategy demonstrated in this study could be applied on other label-free mechanically interlocked molecules, molecular machines, and macromolecules, which opened a new path to evaluate the toxicological and pharmacokinetic characteristics of these novel materials at the suborgan level.


Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans.
The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD.


#patientstoo - Professional sexual misconduct by healthcare professionals towards patients: a representative study.
Sexual border violations are a severe problem in the healthcare system. Studies using non-probability samples indicate a high prevalence of professional sexual misconduct (PSM) towards patients. However, valid prevalence rates are lacking. We did a cross-sectional, observational study in Germany from February to April 2020. By different sampling steps, a probability sample of the German population above the age of 14 was generated. The final sample consisted 2503 persons (50.2% female, mean age: 49.5 years). Participants were asked about sexual contacts with and sexual harassment by healthcare professionals. Using descriptive statistics, prevalence rates of PSM were estimated. PSM was reported by 56 (4.5%) female and 17 (1.4%) male participants. In detail, 28 (2.2%) female and 10 (0.8%) male participants reported sexual contacts with healthcare professionals. One third of these sexual contacts took place before the age of 18 and one third against the will of the patients. 40 (3.2%) female and 8 (0.6%) male participants reported unnecessary physical examinations, 31 (2.5%) female and 7 (0.6%) male participants reported sexual harassment. The majority of perpetrators were male. Our data provide an important first insight into the prevalence of PSM by healthcare professionals towards patients in a representative sample. Results suggest a high prevalence of PSM in the general population of Germany. Preventive measures to increase awareness of PSM and concepts for protection of patients are needed.


Chromatographic methods development, validation and degradation characterization of the antithyroid drug Carbimazole.
The current paper reports the development and validation of stability-indicating HPLC and HPTLC methods for the separation and quantification of main impurity and degradation product of Carbimazole. The structures of the degradation products formed under stress degradation conditions, including hydrolytic and oxidative, photolytic and thermal conditions, were characterized and confirmed by MS and IR analyses. Based on the characterization data, the obtained degradation product from hydrolytic conditions was found to be methimazole-impurity A of Carbimazole as reported by the British Pharmacopeia and the European Pharmacopeia. A stability-indicating HPLC method was carried out using a Zorbax Eclipse Plus CN column (150 × 4.6 mm i.d, 5 μm particle size) and a mobile phase composed of acetonitrile-0.05 m KH2 PO4 (20: 80, v/v) in isocratic elution, at a flow rate of 1 mL/min. The method was proved to be sensitive for the determination down to 0.5% of Carbimazole impurity A. Additionally, a stability-indicating chromatographic HPTLC method was achieved using cyclohexane-ethanol (9:1, v/v) as a developing system on HPTLC plates F254 with UV detection at 225 nm. The proposed HPLC and HPTLC methods were successfully applied to Carbimazole® tablets with mean percentage recoveries of 100.12 and 99.73%, respectively.


Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer.
Ovarian cancer is a highly malignant gynecological cancer influenced by the immune microenvironment, metabolic reprogramming, and cellular senescence. This review provides a comprehensive overview of these characteristics. Metabolic reprogramming affects immune cell function and tumor growth signals. Cellular senescence in immune and tumor cells impacts anti-tumor responses and therapy resistance. Targeting immune cell metabolism and inducing tumor cell senescence offer potential therapeutic strategies. However, challenges remain in identifying specific targets and biomarkers. Understanding the interplay of these characteristics can lead to innovative therapeutic approaches. Further research is needed to elucidate mechanisms, validate strategies, and improve patient outcomes in ovarian cancer.


Ultrafast all-optical integrator based on a fiber Bragg grating: proposal and design.
We demonstrate a simple technique for the implementation of an all-optical integrator based on a uniform-period fiber Bragg grating (FBG) in reflection that is designed to present a decreasing exponential impulse response. The proposed FBG integrator is readily feasible and can perform close to ideal integration of few-picosecond and subpicosecond pulses.


Dengue: a new challenge for neurology.
Dengue infection is a leading cause of illness and death in tropical and subtropical regions of the world. Forty percent of the world's population currently lives in these areas. The clinical picture resulting from dengue infection can range from relatively minor to catastrophic hemorrhagic fever. Recently, reports have increased of neurological manifestations. Neuropathogenesis seems to be related to direct nervous system viral invasion, autoimmune reaction, metabolic and hemorrhagic disturbance. Neurological manifestations include encephalitis, encephalopathy, meningitis, Guillain-Barré syndrome, myelitis, acute disseminated encephalomyelitis, polyneuropathy, mononeuropathy, and cerebromeningeal hemorrhage. The development of neurological symptoms in patients with positive Immunoglobulin M (IgM) dengue serology suggests a means of diagnosing the neurological complications associated with dengue. Viral antigens, specific IgM antibodies, and the intrathecal synthesis of dengue antibodies have been successfully detected in cerebrospinal fluid. However, despite diagnostic advancements, the treatment of neurological dengue is problematic. The launch of a dengue vaccine is expected to be beneficial.


Mapping the subcortical connectome using in vivo diffusion MRI: Feasibility and reliability.
Tractography combined with regions of interest (ROIs) has been used to non-invasively study the structural connectivity of the cortex as well as to assess the reliability of these connections. However, the subcortical connectome (subcortex to subcortex) has not been comprehensively examined, in part due to the difficulty of performing tractography in this complex and compact region. In this study, we performed an in vivo investigation using tractography to assess the feasibility and reliability of mapping known connections between structures of the subcortex using the test-retest dataset from the Human Connectome Project (HCP). We further validated our observations using a separate unrelated subjects dataset from the HCP. Quantitative assessment was performed by computing tract densities and spatial overlap of identified connections between subcortical ROIs. Further, known connections between structures of the basal ganglia and thalamus were identified and visually inspected, comparing tractography reconstructed trajectories with descriptions from tract-tracing studies. Our observations demonstrate both the feasibility and reliability of using a data-driven tractography-based approach to map the subcortical connectome in vivo.


Ethyl-2-cyanoacrylate as a sealant after partial cecum resection in rattus norvegicus albinus.
To evaluate the use of ethyl-2-cyanoacrylate in the treatment of an injury caused in a partially excluded segment of the mouse gut: the cecum. We used 45 male Wistar rats, divided into three equal groups; in all there was performed a partial resection of the cecum. The groups were designated as Group 1: the lesion was treated with application of ethyl-2-cyanoacrylate, Group 2: suture and application of ethyl-2-cyanoacrylate, Group 3: purse-string suture. The animals were monitored postoperatively and half of each group was necropsied 14 days after the procedure, the remaining on the 28th. They were subjected to macroscopic evaluation, had cecal samples collected for histological examination and the findings were submitted to statistical analysis. Weight gain after the experiment was different among groups (p=0.028). The presence of microabscesses was higher at 28 days postoperatively in group 2 when compared to group 3 (p=0.003). The collagen deposition on the 28th postoperative day was greater in group 1 (p=0.036) and intensity of inflammation at the 14th postoperative day was greater in group 1 (p=0.045). In the other parameters there was no statistical difference. The use of ethyl-2-cyanoacrylate was effective in the treatment of cecal stump exclusion of rats as for macroscopic and microscopic findings and postoperative outcome.


Cigarette smoking and reproductive function.
To perform a systematic review of the literature on the relationship between cigarette smoking and reproductive function. Whenever possible, this review is focused on the most recently published studies (mainly the past 2 years). Nevertheless, in many instances older literature was too relevant not to be taken into account. Tobacco compounds exert a deleterious effect on the process of ovarian follicle maturation. This effect is expressed by worse in-vitro fertilization parameters in cycles performed on women with smoking habits. Also, uterine receptiveness is significantly altered by the smoking habit. In men, cigarette smoking reduces sperm production, increases oxidative stress, and DNA damage. Spermatozoa from smokers have reduced fertilizing capacity, and embryos display lower implantation rates. Even in-utero exposition to tobacco constituents leads to reduced sperm count in adult life. A strong body of evidence indicates that the negative effect of cigarette smoking on fertility comprises fairly every system involved in the reproductive process. Couples in reproductive age should be strongly discouraged to smoke.


A help or a hindrance? The impact of job training on the employment status of disadvantaged women.
The objective of this study is to evaluate whether welfare-sponsored, government-funded job training helps participants improve their employment status. The negligible effects found in prior studies may be due to design limitations or inherent flaws in job training programs and therefore do not necessarily contradict human capital theory. The present study uses longitudinal and representative data, dynamic modeling techniques, an appropriate counterfactual, and important contextual variables to assess the likelihood of obtaining employment for job training participants and nonparticipants. It also describes the types of jobs women obtain by examining wages, industry, occupation, and labor union membership. Whereas some of the results support prior research, the focus is on the unique contributions of this study, which include a differential training effect for full- and part-time workers and a detailed analysis of macro-structural variables, which are rarely included in studies of labor supply.


Colonic transcriptional profiling in resistance and susceptibility to trichuriasis: phenotyping a chronic colitis and lessons for iatrogenic helminthosis.
Helminth therapy is advocated to restore and maintain control of inflammatory responses, particularly chronic colitis. However, helminths can induce chronic colitis in susceptible individuals. Susceptibility has an immunogenetic basis: defining this is essential if nematode therapy is to be successfully and safely targeted in inflammatory bowel disease (IBD). To validate a preclinical mouse model we phenotyped the response to Trichuris muris in mice. We determined colonic transcriptional activity in naïve and infected mice and linked differential gene expression to mechanistic pathways. T. muris-infected resistant (BALB/c) and susceptible (AKR) mice were studied to a chronic colitic timepoint (day 35). Colonic genome-wide expression was performed by microarray. Significant transcriptional changes were analyzed by cluster and gene ontology filtering and KEGG pathway mapping. Day 35 infected AKR displayed chronic diarrhea, weight loss, and transmural colonic inflammation; BALB/c remained asymptomatic, cleared the infection, and demonstrated normal histology. Compared to BALB/c mice, infected AKR upregulated gene expression clusters were overrepresented by immune response, chemotaxis, and apoptosis pathways. Cellular/tissue homeostasis and tight junction pathways dominated downregulated AKR expression clusters. Infected AKR T-helper cell development/polarization markers demonstrated predominant T(H) 1/T(H) 17 transcriptional activity. Colitic AKR data mirrored established murine models and human colitis. T. muris infection in the mouse shows striking phenotypic and transcriptional similarities to widely used models of IBD and human IBD. This preclinical mouse model presents a platform to examine biological commonalities among chronic colitides. However, these data urge caution in untargeted therapeutic helminth use until risk/benefit in susceptible individuals is more fully understood.


Degradative enzymes in osteoarthritis.
A central feature of the osteoarthritic disease process involves erosive destruction of the articular cartilage extracellular matrix (ECM) on the surfaces of diarthrotic joints. The resultant loss of joint function makes studies on mechanisms underlying ECM degradation critical for treatment of the disease and prevention of disability. Candidate pathways to account for the loss of cartilage involve expression of a combination of proteases that degrade the major cartilage matrix macromolecules, aggrecan and type II collagen. The specific types of enzymatic activities associated with the progressive removal of ECM and severity of joint disease include the matrix metalloproteinases, collagenase, gelatinase and aggrecanase(s). The degradative enzymes originate in synovial cells, cartilage cells, the chondrocytes, distributed within the ECM and leukocytes that actively invade the joint space. Specific enzymes arising from each of these tissues exhibit selective ECM degrading properties; the different categories of these tissue-derived enzymes will be discussed in this chapter. A perspective on the efficacy of existing agents and the potential for development of novel therapeutic agents is also included. While the degradative enzymes serve as a focal point for therapeutic intervention, a fundamental understanding of the mechanisms underlying degradative enzyme expression in osteoarthritis remains an important goal for prevention of disease.


Underutilization of prescribed drugs use among first generation elderly immigrants in the Netherlands.
In developed countries, health care utilization among immigrant groups differs where the dominant interpretation is unjustified overutilization due to lack of acculturation. We investigated utilization of prescribed drugs in native Dutch and various groups of immigrant elderly. Cross-sectional study using data from the survey "Social Position, Health and Well-being of Elderly Immigrants" (the Netherlands, 2003). Ethnicity-matched interviewers conducted the survey among first generation immigrants aged 55 years and older. Outcome measure is self-reported use of prescribed drugs. Utilization is explained by need, and by enabling and predisposing factors, in particular acculturation; analysis is conducted by multiple logistic regression. The study population consisted of immigrants from Turkey (n = 307), Morocco (n = 284), Surinam (n = 308) and the Netherlands Antilles (n = 300), and a native Dutch reference group (n = 304). Prevalence of diabetes mellitus (DM), COPD and musculoskeletal disorders was relatively high among immigrant elderly. Drug utilization in especially Turkish and Moroccan elderly with DM and COPD was relatively low. Drugs use for non-mental chronic diseases was explained by more chronic conditions (OR 2.64), higher age (OR 1.03), and modern attitudes on male-female roles (OR 0.74) and religiosity (OR 0.89). Ethnicity specific effects remained only among Turkish elderly (OR 0.42). Drugs use for mental health problems was explained by more chronic conditions (OR 1.43), better mental health (OR 0.95) and modern attitudes on family values (OR 0.59). Ethnicity specific effects remained only among Moroccan (OR 0.19) and Antillean elderly (OR 0.31). Explanation of underutilization of drugs among diseased with diabetes and musculoskeletal disorders are found in number of chronic diseases (OR 0.74 and OR 0.78) and regarding diabetes also in language proficiency (OR 0.66) and modern attitudes on male-female roles (OR 1.69). Need and predisposing factors (acculturation) are the strongest determinants for drugs utilization among elderly immigrants. Significant drugs underutilization exists among migrants with diabetes and musculoskeletal disorders.


New broad-spectrum cephalosporins with anti-pseudomonal activity. II. Synthesis and antibacterial activity of 7 beta-[2-acylamino-2-(4-hydroxyphenyl)acetamido]-3-[ (1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acids.
The influence of the chirality of the 7-acyl side chain and of various N-acyl moieties (A-CO-) on the in vitro activity of 7 beta-[2-acylamino-2-(4-hydroxyphenyl)acetamido ]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acids (6) was investigated. A cephalosporin having a 7-acyl side chain of S-configuration (6r) was only weakly active against Staphylococcus aureus and Klebsiella pneumoniae and was inactive against the other species tested. Among the various N-acyl moieties in the cephalosporins having a 7-acyl side chain of the R-configuration, the 4-hydroxypyridine-3-carbonyl moiety, unsubstituted or substituted with 5-bromo and/or 6-alkyl groups and the 4-hydroxy-1,5-naphthyridine-3-carbonyl moiety, unsubstituted or substituted with a 6-methyl and a 6-methoxy group gave the most active compounds. N-Ethylation of the 4-hydroxy-1,5-naphthyridine-3-carbonyl derivative and the 4-hydroxypyridine-3-carbonyl derivative (6p, 6q) resulted in a decrease of the in vitro activity.


Evaluation of the Effect of Fixed Anterior Biteplane Treatment on Temporomandibular Joint in Patients with Deep Bite.
To investigate the effects of fixed anterior biteplane treatment on temporomandibular joint in deep bite patients. The sample comprised 17 Class II patients with deep bite and decreased lower anterior facial height. The average patient age was 9.9±0.9 years. Transcranial temporomandibular joint radiographs were obtained from the subjects before (T0) and after fixed anterior biteplane treatment (T1). Anterior joint space, posterior joint space, superior joint space, anteroposterior thickness of the condylar head, vertical height of the articular fossa, and the articular fossa slope were measured on temporomandibular joint radiographs to evaluate the position of the mandibular condyles in the glenoid fossa. The average treatment duration was 8.5±2.1 months. Slope of the articular fossa, vertical height of the articular fossa, anteroposterior thickness of the condyle, posterior joint space, superior joint space, and anterior joint space showed no statistically significant difference between T0 and T1 (p>0.05). Fixed anterior biteplane appliance treatment did not change the condyle fossa relationship in Class II deep bite patients at the time of appliance removal.


A flexible spatial scan statistic with a restricted likelihood ratio for detecting disease clusters.
Spatial scan statistics are widely used tools for detection of disease clusters. Especially, the circular spatial scan statistic proposed by Kulldorff (1997) has been utilized in a wide variety of epidemiological studies and disease surveillance. However, as it cannot detect noncircular, irregularly shaped clusters, many authors have proposed different spatial scan statistics, including the elliptic version of Kulldorff's scan statistic. The flexible spatial scan statistic proposed by Tango and Takahashi (2005) has also been used for detecting irregularly shaped clusters. However, this method sets a feasible limitation of a maximum of 30 nearest neighbors for searching candidate clusters because of heavy computational load. In this paper, we show a flexible spatial scan statistic implemented with a restricted likelihood ratio proposed by Tango (2008) to (1) eliminate the limitation of 30 nearest neighbors and (2) to have surprisingly much less computational time than the original flexible spatial scan statistic. As a side effect, it is shown to be able to detect clusters with any shape reasonably well as the relative risk of the cluster becomes large via Monte Carlo simulation. We illustrate the proposed spatial scan statistic with data on mortality from cerebrovascular disease in the Tokyo Metropolitan area, Japan.


Effects of an educational program and a standardized insulin order form on glycemic outcomes in non-critically ill hospitalized patients.
The optimal approach to managing hyperglycemia in noncritically ill hospital patients is unclear. To investigate the effects of targeted quality improvement interventions on insulin prescribing and glycemic control. A cohort study comparing an intervention group (IG) to a concurrent control group (CCG) and an historic control group (HCG). University of Michigan Hospital. Hyperglycemic, noncritically ill hospital patients treated with insulin. Physician and nurse education and a standardized insulin order form based on the principles of physiologic insulin use. Glycemic control and insulin prescribing patterns. Patients in the IG were more likely to be treated with a combination of scheduled basal and nutritional insulin than in the other groups. In the final adjusted regression model, patients in the IG were more likely to be in the target glucose range (odds ratio [OR], 1.72; P = 0.01) and less likely to be severely hyperglycemic (OR, 0.65; P < 0.01) when compared to those in the CCG. Patients in the IG were also less likely to experience hypoglycemia than those in the CCG (P = 0.06) or the HCG (P = 0.01). Over 80% of all patient-days for all groups contained glucose readings outside of the target range. Standardized interventions encouraging the physiologic use of subcutaneous insulin can lead to significant improvements in glycemic control and patient safety in hospitalized patients. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. Additional research is needed to determine the best strategy for safely achieving metabolic control in these patients.


Calcaneus metastasis: a rare presentation of poorly differentiated thyroid cancer.
A 60-year-old woman presented to our clinic with an acute onset 3 months history of right ankle pain. The patient had a history of poorly differentiated thyroid cancer, which was treated with total thyroidectomy, left lateral neck dissection levels II-V and central neck dissection levels VI-VII followed by postoperative I-131 radioactive iodine (131I) ablation therapy 3.7 GBq 6 months ago. The post-131I WBS showed residual iodine-avid thyroid tissue with no other iodine-avid disease or metastasis. SPECT/CT of the neck and chest showed nonavid bilateral pulmonary nodules, discrete nodal masses in mediastinum and nonavid bone lesions. FDG-PET CT scan showed FDG-avid mediastinal lymph nodes (LN), innumerable non-FDG-avid subcentimetric pulmonary nodules and few FDG-avid lytic lesions in the skeleton. X-ray and MRI of the right ankle showed a well-marginated lytic lesion in the posterior body of calcaneus and 5 × 6 cm soft tissue mass lesion, respectively. The histopathology of the calcaneus mass confirmed a positive immunostaining for thyroid origin which includes thyroglobulin and TTF-1 with PAX-8. Endobronchial mediastinal and bronchial LN biopsy confirmed thyroid cancer metastasis. Gene mutation showed HRAS and GNA13 with a high tumor mutational burden. We describe a rare case of poorly differentiated thyroid cancer in a patient who presented with right ankle pain; we confirmed the cause to be a calcaneus metastasis from the thyroid cancer, with calcaneus being an extremely rare site for bone metastases. Gene mutations points toward treatment with immune checkpoint inhibitors. Poorly differentiated thyroid carcinoma (PDTC) usually metastasizes to lung and bone but can rarely occur in the calcaneus. Patients with distant metastases have significantly worse long-term prognosis. Radiotherapy is effective in reducing the metastatic pains as well as reducing the size of the metastasis. PAX-8 staining can be used to differentiate thyroid carcinomas from lung adenocarcinomas. The importance of searching for gene mutations to decide the treatment of PDTC.


Dissolution of concentrated surfactant solutions: from microscopy imaging to rheological measurements through numerical simulations.
Concentrated aqueous solutions of surfactants, often referred to as pastes, experience complex phase and rheology changes upon dissolution in water, which is a typical step in the production of liquid detergents. During the dilution process, depending on water content, surfactant molecules can arrange in different morphologies, such as lamellar or cubic and hexagonal structures. These phases are characterized by different physico-chemical properties, such as viscosity or diffusivity, which lead to non-simple transport mechanisms during the dissolution process. In this work, we investigate the dissolution of concentrated Sodium Lauryl Ether Sulfate (SLES) pastes in water under quiescent conditions by coupling different experimental techniques. A thorough rheological characterization of the system showed non-monotonic changes of several orders of magnitude in its viscosity and viscoelastic moduli as a function of water content. Time-lapse microscopy allowed us to image the dynamic evolution of the phase changes as water penetrated in a disk-shaped sample (with the same geometry used in rheological tests). Numerical simulation, based on a simple diffusion-based multi-parameter model is shown to describe satisfactorily SLES dissolution data.


The Sunnybrook Stroke Study: a prospective study of depressive symptoms and functional outcome.
To assess the prevalence of depressive symptoms, their clinical correlates, and the effects of depressive symptoms on stroke recovery, a relatively unselected, well-diagnosed cohort of consecutive stroke survivors was followed prospectively. Consecutive admissions to a regional stroke center who met World Health Organization and National Institute of Neurological Disorders and Stroke criteria for stroke were eligible. Subarachnoid hemorrhage and brain stem strokes were excluded. Patients underwent CT, single-photon emission CT, and standardized neurological and cognitive examinations at entry. At 3 months and 1 year after stroke, depressive symptoms were assessed with the Montgomery Asberg Depression Rating Scale (MADRS) and the Zung Self-Rating Depression Scale (SDS). Functional outcome was measured with the Functional Independence Measure, and handicap was assessed by the Oxford Handicap Scale. We assessed 436 patients at entry (mean +/- SD age, 74.9 +/- 11.6 years). There were 150 patients available for assessment at 3 months and 136 at 1 year. Marked depressive symptoms were noted in 22% (SDS) to 27% (MADRS) at 3 months and 21% (SDS) to 22% (MADRS) at 1 year. Patents with marked depressive symptoms had more neurological impairment (P<.008), were more likely to be female (P<.05), and were more likely to have previous histories of depression (P<.03). There was no relationship between depressive symptoms and age, lesion volume, or side of lesion. Depressive symptoms were correlated with functional outcome (r = -.31, P<.0001) and handicap (r = .41, P<.0001) at 3 months and 1 year (r= -.28, P<.001; r = .35, P<.0001). Depressive symptoms and functional outcome are correlated. In view of the prevalence of depressive symptoms in this population, diagnosis and treatment of depression are important in optimizing recovery.


Molecular analysis of Xenopus laevis SPARC (Secreted Protein, Acidic, Rich in Cysteine). A highly conserved acidic calcium-binding extracellular-matrix protein.
SPARC (Secreted Protein, Acidic, Rich in Cysteine) is expressed as a 1.6 kb mRNA in Xenopus laevis. On the basis of cDNA sequence analysis, Xenopus SPARC has a core Mr of 32643, with one potential N-glycosylation site. Western analysis of SPARC isolated from Xenopus long bone indicates that the mature protein has an Mr of 43,000. At the amino acid level, Xenopus SPARC has 78-79% sequence similarity to mouse, bovine and human SPARC. The least-conserved region is found within the N-terminal glutamic acid-rich domain, with the C-terminal Ca(2+)-binding domain being the most conserved. Adult Xenopus tissues show the same pattern of tissue-specific distribution of SPARC mRNAs as adult mouse.


ADIPOQ rs266729 G/C gene polymorphism and plasmatic adipocytokines connect metabolic syndrome to colorectal cancer.
Background: ADIPOQ gene, which encode for Adiponectin (APN), is sited on chromosome 3q27 and linked to a susceptibility locus for metabolic syndrome (MetS). The ADIPOQ rs266729 G/C gene polymorphism is significantly associated with low APN levels and linked to susceptibility to develop cancer. In addition, decreased APN serum levels are linked with tumor development and progression and inversely associated with markers of inflammation. Here, we investigate the influence of APN rs266729 G/C polymorphism on adipocytokine circulating levels and their association with MetS in colorectal cancer patients (CRC). Methods: Blood samples from 105 CRC patients (50 women and 55 men) with and without MetS were genotyped for APN rs266729 G/C polymorphism by TETRA ARMS PCR. ELISA assay was used to measure plasma levels of APN and inflammatory TNF-α cytokine. Biochemical and anthropometric parameters of MetS were also analyzed. Results: We found that CRC patients (N=75) with genotype rs266729G/C or carriers of G allele were associated with a significantly increased risk of MetS development (OR =2.9) compared to those with CC genotype (N=30). Also, CG/GG genotypes were associated with significantly lower plasma APN levels and higher TNF-α levels in comparison to CC genotype (P=0.034) and APN levels were decreased in relation to BMI increases (P=0.001). Conclusions: Our findings show that APN rs266729 G/C polymorphism is associated with lower APN levels in CRC patients, indicating that decreased circulating levels of APN may be a determinant risk factor for CRC in MetS patients.


Enrolling people of color to evaluate a practice intervention: lessons from the shared decision-making for atrial fibrillation (SDM4AFib) trial.
Trial recruitment of Black, indigenous, and people of color (BIPOC) is key for interventions that interact with socioeconomic factors and cultural norms, preferences, and values. We report on our experience enrolling BIPOC participants into a multicenter trial of a shared decision-making intervention about anticoagulation to prevent strokes, in patients with atrial fibrillation (AF). We enrolled patients with AF and their clinicians in 5 healthcare systems (three academic medical centers, an urban/suburban community medical center, and a safety-net inner-city medical center) located in three states (Minnesota, Alabama, and Mississippi) in the United States. Clinical encounters were randomized to usual care with or without a shared decision-making tool about anticoagulation. We analyzed BIPOC patient enrollment by site, categorized reasons for non-enrollment, and examined how enrollment of BIPOC patients was promoted across sites. Of 2247 patients assessed, 922 were enrolled of which 147 (16%) were BIPOC patients. Eligible Black participants were significantly less likely (p < .001) to enroll (102, 11%) than trial-eligible White participants (185, 15%). The enrollment rate of BIPOC patients varied by site. The inclusion and prioritization of clinical practices that care for more BIPOC patients contributed to a higher enrollment rate into the trial. Specific efforts to reach BIPOC clinic attendees and prioritize their enrollment had lower yield. Best practices to optimize the enrollment of BIPOC participants into trials that examined complex and culturally sensitive interventions remain to be developed. This study suggests a high yield from enrolling BIPOC patients from practices that prioritize their care. ClinicalTrials.gov (NCT02905032).


Association Between Formative Assessment and Academic Performance for Undergraduate Medical Students in a Chinese Clinical Skills Training Course.
BACKGROUND Previous research suggests that formative assessment (FA) enhances learning outcomes, but few studies have evaluated its impact on clinical skills training in China. We conducted this study in a clinical skills integral curriculum to further explore the educational value of FA. MATERIAL AND METHODS Sixty undergraduates from the Second Clinical Medical School of the Southern Medical University in 2016 were selected as the experimental group (consecutive FA), and 50 undergraduates in 2015 were selected as the control term (only final summative assessment, SA). Undergraduates in the FA group completed the after-class questionnaire at each lesson. Teachers, teaching content, assessment objectives, and topics are the same in both groups. RESULTS The results of single-factor covariance (ANCOVA) analysis and Cochran-Mantel-Haenszel (CMH) analysis demonstrated that students of the FA group obtained better performance and higher success rates in summative examination than in the SA group. The students with relatively poor grades benefited more from FA, while the performance of students with higher grades was similar between the FA group and SA group. According to the results of questionnaire for students, the satisfaction of students with the course increased gradually, from 84.4% to 93.0%. CONCLUSIONS Proper use of FA is associated with better learning outcomes for students, especially for those with poorer grades. Our results, together with previous research, indicated that the use of FA may be of great benefit to students' academic performance and satisfaction with the clinical skills training curriculum.


Independent Control of Elastomer Properties through Stereocontrolled Synthesis.
In most synthetic elastomers, changing the physical properties by monomer choice also results in a change to the crystallinity of the material, which manifests through alteration of its mechanical performance. Using organocatalyzed stereospecific additions of thiols to activated alkynes, high-molar-mass elastomers were isolated via step-growth polymerization. The resulting controllable double-bond stereochemistry defines the crystallinity and the concomitant mechanical properties as well as enabling the synthesis of materials that retain their excellent mechanical properties through changing monomer composition. Using this approach to elastomer synthesis, further end group modification and toughening through vulcanization strategies are also possible. The organocatalytic control of stereochemistry opens the realm to a new and easily scalable class of elastomers that will have unique chemical handles for functionalization and post synthetic processing.


Ultrastructural studies on myofibrillogenesis and neogenesis of skeletal muscles after prolonged traction in rabbits.
Little is known about the morphological response of muscle after long term traction. The purpose of this study was to investigate the morphological changes of skeletal muscle during limb lengthening. After application of mini-extraskeletal fixator, the hindlimb of New Zealand white rabbit was osteotomized and then slowly lengthened at the rate of 1 mm/day up to a 20 mm gain in length. The muscles of hindlimbs were perfused and dissected. Morphological studies were performed at electron microscopic level. Transmission electron microscopy revealed foci of microtrauma at the myotendinous junction. The distance between the muscle fibers and tendon parenchyma increased, with numerous primitive mesenchyme-like cells interposed within this gap. The cytoplasmic space of these cells was devoid of myofibril formation at the ends of stretched fibers. Within the satellite near the myotendinous junction myofilament production was observed in various gradations of maturation. It is concluded that myofibrillogenesis with traction neogenesis of skeletal muscle during limb lengthening does exist and occurs mainly near the myotendinous junction. The myotendinous junction in mature skeletal muscle actively participated in the process of limb lengthening.


The Proposal of a BDS Syllabus Framework to Suit Choice Based Credit System (CBCS).
Higher education takes a new dimension universally in the form of choice based Credit System (CBCS). In India, the University Grants Commission (UGC) has made CBCS mandatory in all fields except for Health Profession. Not much attempts were made in designing a BDS syllabus to suit CBCS. Aim of the study was to propose a model dental syllabus to fit into choice based credit system. A model BDS syllabus Prototype for CBCS was designed based on the UGC guidelines for terms as well as calculations for CBCS. Engineering curriculum models from IIT and Anna University were also referred to. Semester based BDS syllabus was designed without changing the norms of Dental Council of India (DCI). All the must know areas of the subjects were considered as "core" areas and the desirable and nice to know areas are left for "electives" by the students. By this method, none of the subject was left out at the same time students are provided with electives to learn deeper on their topics of choice. The existing BDS syllabus can be effectively modified by incorporating few changes based on the UGC regulations for Choice based credit system. The proposed framework gives an insight on the nature of modifications that are needed. By adopting this, BDS Course regulations can also follow CBCS without neglecting or reducing the weightage of any subject.


Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin.
Although oxytocin commonly is used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly among women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene. To identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements. Term, nulliparous women requiring oxytocin doses of ≤4 mU/min (low-dose-requiring, n = 83) or ≥20 mU/min (high-dose-requiring, n = 104) for labor augmentation or induction provided consent to a postpartum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage >30×) with MiSeq (Illumina) was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. The Fisher exact or χ2 tests were used for categorical variables, and Student t tests or Wilcoxon rank sum tests were used for continuous variables. A P value < .05 was considered statistically significant. The high-dose-requiring women had greater rates of obesity and diabetes and were more likely to have undergone labor induction and required prostaglandins. High-dose-requiring women were more likely to undergo cesarean delivery for first-stage arrest and less likely to undergo cesarean delivery for nonreassuring fetal status. Targeted sequencing of the oxytocin receptor gene in the total cohort (n = 187) revealed 30 distinct coding variants: 17 nonsynonymous, 11 synonymous, and 2 small structural variants. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine nonsynonymous variants were unique to the high-dose-requiring group. These included 3 known variants (R151C, G221S, and W228C) and 6 novel variants (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173R were predicted by Scale-Invariant Feature Transform algorithm to damage oxytocin receptor function. There was no statistically significant association between the numbers of synonymous and nonsynonymous substitutions in the patient groups. Obesity, diabetes, and labor induction were associated with the requirement for high doses of oxytocin. We did not identify significant differences in the prevalence of oxytocin receptor variants between low-dose-requiring and high-dose-requiring women, but novel oxytocin receptor variants were enriched in the high-dose-requiring women. We also found 3 oxytocin receptor variants (2 novel, 1 known) that were predicted to damage oxytocin receptor function and would likely increase an individual's risk for requiring a high oxytocin dose. Further investigation of oxytocin receptor variants and their effects on protein function will inform precision medicine in pregnant women.


Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through activation of mitochondrial ATP-sensitive potassium channels and a nitrate-like effect.
The anti-anginal drug nicorandil has been shown to inhibit apoptosis by activating mitochondrial ATP-sensitive potassium (K(ATP)) channels. The possible contribution of the nitrate moiety of this drug to its anti-apoptotic effect has now been investigated in neonatal rat ventricular myocytes subjected to oxidative stress. Exposure of cultured myocytes to 100 micromol/l hydrogen peroxide (H(2)O(2)) increased the number of nuclei stained by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique as well as induced internucleosomal DNA fragmentation, loss of mitochondrial membrane potential, cytochrome c release into the cytosol, and activation of caspases-3 and -9, all of which are characteristics of apoptosis. Pretreatment of cells with nicorandil (100 micromol/l) inhibited these effects of H(2)O(2). Both the mitochondrial K(ATP) channel antagonist 5-hydroxydecanoate (5-HD) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, attenuated the anti-apoptotic effect of nicorandil in concentration-dependent manners. Coapplication of ODQ (10 micromol/l) and 5-HD (500 micromol/l) completely abolished nicorandil-induced cytoprotection. The effect of nicorandil was also reduced by an inhibitor of cGMP-dependent protein kinase (KT5823, 1 micromol/l). The nitric oxide donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP, 50 micromol/l) mimicked the protective effect of nicorandil in a manner sensitive to ODQ but not to 5-HD. A cell-permeable cGMP analog, 8-bromo-cGMP, also reduced H(2)O(2)-induced apoptosis. The inhibition of the H(2)O(2)-induced activation of caspase-3, but not that of caspase-9, by nicorandil in the presence of 5-HD or by SNAP was reversed by the addition of dithiothreitol to the enzyme assay. Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through a nitric oxide/cGMP-dependent mechanism as well as by activating mitochondrial K(ATP) channels.


[Confocal microscopy of the cornea. Communication 2. Morphological changes in keratoconus].
The paper presents the results of studying morphological changes in keratoconus by life-time confocal microscopy. A total of 50 patients (100 eyes) with grades 1-to-4 keratoconus were examined. The most pronounced changes were found in the corneal areas involved in an ectatic process. Four grades of epitheliopathy were conventionally identified in relation to the desquamation of superficial epitheliocytes, the change of their shape, impaired adhesion with the underlying layers, and transparency disorders. The indirect signs of altered Bowman's membrane were revealed. In early keratocons, the stroma showed hyperreflectivity of anterior layers, higher activated keratocytes, their changed shape and spatial orientation. The emergence of microstrium in the posterior stromal layers with their gradual spread to the midstroma and anterior stroma, abnormal transparency, and scarring were typical of the progress of the disease. There were processes of homogenization and fibrotization of stromal structure and fewer keratocytes. There might be changes in Descemet's membrane (undulating folds) and posterior epithelium (polymegatism, polymorphism, enlarged intercellular spaces, and cell apoptosis). Thus, confocal microscopy reveals certain regularities of a pathological process in keratoconus at different stages of the disease.


Cross-Validation of the Implementation Leadership Scale (ILS) in Child Welfare Service Organizations.
The Implementation Leadership Scale (ILS) is a brief, pragmatic, and efficient measure that can be used for research or organizational development to assess leader behaviors and actions that actively support effective implementation of evidence-based practices (EBPs). The ILS was originally validated with mental health clinicians. This study validates the ILS factor structure with providers in community-based organizations (CBOs) providing child welfare services. Participants were 214 service providers working in 12 CBOs that provide child welfare services. All participants completed the ILS, reporting on their immediate supervisor. Confirmatory factor analyses were conducted to examine the factor structure of the ILS. Internal consistency reliability and measurement invariance were also examined. Confirmatory factor analyses showed acceptable fit to the hypothesized first- and second-order factor structure. Internal consistency reliability was strong and there was partial measurement invariance for the first-order factor structure when comparing child welfare and mental health samples. The results support the use of the ILS to assess leadership for implementation of EBPs in child welfare organizations.


Pose Estimation for Augmented Reality: A Hands-On Survey.
Augmented reality (AR) allows to seamlessly insert virtual objects in an image sequence. In order to accomplish this goal, it is important that synthetic elements are rendered and aligned in the scene in an accurate and visually acceptable way. The solution of this problem can be related to a pose estimation or, equivalently, a camera localization process. This paper aims at presenting a brief but almost self-contented introduction to the most important approaches dedicated to vision-based camera localization along with a survey of several extension proposed in the recent years. For most of the presented approaches, we also provide links to code of short examples. This should allow readers to easily bridge the gap between theoretical aspects and practical implementations.


Association of endothelial nitric oxide synthase gene variants in pre-eclampsia: an updated systematic review and meta-analysis.
Three common endothelial nitric oxide synthase (eNOS) gene variants are existed such as; G-894T, T-786C, and variable number tandem repeats in intron-4 (VNTR intron-4) which has been proposed to be linked with PE. However, there is still debate regarding the findings. To address this, a review was conducted to assess the potential association of eNOS gene variants at these positions with the risk of PE. PubMed, Scopus, Science Direct, Hinari, and African Journal Online databases and Google Scholar search engines were utilized to search studies published in English-language until 30 January 2023. The Joanna Briggs Institute Meta-Analysis instrument was used for data extraction process and the Newcastle-Ottawa Scale was used to appraise the quality of the included studies. Meta-regression analysis was conducted using Stata 14 statistical software. The pooled odds ratios (ORs) of fixed and random effect models were utilized to evaluate the association of eNOS gene polymorphism with the risk of PE at 95% CI. Publication bias was assessed using Egger's test and a funnel plot. The study included 47 observational studies involving 13,795 pregnant women (6216 cases and 7579 controls). Pregnant women carrying TT and CC genotypes of eNOS gene at 894 and 786 positions were found to have a greater probability of developing PE as compared to GG and TT genotypes (OR = 1.54 vs. 1.43 and CI: 1.12 - 2.14 vs.1.02 - 2.00 at 95% CI), respectively. However, a significant association was not observed between aa genotype of eNOS gene in VNTR intron-4 region and risk of PE as compared to bb genotype (OR =1.26, 95% CI: 0.83 - 1.89). The allelic model of eNOS gene at all positions showed nonsignificant association with the risk of PE. The women having eNOS gene variants at 894 and 786 positions showed a significant association with the risk of PE. Yet, the women having eNOS gene variant at intron-4 region showed nonsignificant association with the risk of PE. Thus, this study suggests that eNOS gene variants may play a role in the development of PE, but large-scale studies are required to inaugurate concrete evidence on the roles of eNOS gene variants in PE pathogenesis.


Behavioural and neurochemical evaluation of Perment an herbal formulation in chronic unpredictable mild stress induced depressive model.
Perment, a polyherbal Ayurvedic formulation that contains equal parts of Clitoria ternatea Linn., Withania somnifera Dun., Asparagus racemosus Linn., Bacopa monniera Linn., is used clinically as mood elevators. The aim of the present study was to explore the behavioural effects and to understand possible mode of action of Perment in stress induced depressive model. Chronic unpredictable mild stress (CUMS) was used to induce depression in rats. Open field exploratory behaviour, elevated plus maze, social interaction and behavioural despair tests were used to assess behaviour. Using standard protocols plasma noradrenaline, serotonin, corticosterone and brain/adrenal corticosterone levels were measured to support the behavioural effects of Perment. Exposure to CUMS for 21 days caused anxiety and depression in rats, as indicated by significant decrease in locomotor activity in the open field exploratory behaviour test and increased immobility period in the behavioural despair test. Perment predominantly exhibited antidepressant action than anxiolytic activity. Further Perment increased the plasma noradrenaline and serotonin levels in stressed rats. No significant alteration in the brain corticosterone level in stressed rats was observed with Perment treatment. However the adrenal corticosterone level is decreased with Perment. It can be concluded that the Perment formulation exhibited synergistic activity, has a significant antidepressant and anxiolytic activity, which may be mediated through adrenergic and serotonergic system activation. Currently the formulation is clinically used as anxiolytic but the present results suggest that the formulation can also be indicated in patients affected with depression.


Hemoglobin A1c levels in children and adolescents with diabetes mellitus.
Hemoglobin A1c (HbA1c) was measured as an indicator of glucose control in 180 children and adolescents with diabetes mellitus who received two daily injections of insulin as part of a highly structured treatment program. A total of 426 HbA1c determinations was made in the group of 180 patients. HbA1c values were elevated in most patients despite the aggressive treatment. The HbA1c level was very elevated at diagnosis, fell to near normal after 60-90 days of insulin therapy, increased gradually, and reached a plateau after approximately 4 yr duration (at about twice the level in normal subjects) (mean +/- SEM, 10.0 +/- 0.2% and 5.34 +/- 0.07%, respectively). Mean insulin dose (U/kg/24 h) paralleled both HbA1c and duration of diabetes. The relationship between endogenous insulin secretion and glucose control was examined in those patients with diabetes for longer than 5 yr. Patients were separated into three groups based on HbA1c levels: those with HbA1c less than 9% (N = 22), between 9 and 11% (N = 26), and greater than 11% (N = 28). Serum C-peptide and glucose concentrations were measured 2 h after a standard breakfast in those patients in the "low" and "high" HbA1c groups (mean HbA1c values 8.2% and 12.7%, respectively). C-peptide was detectable in all patients and the mean C-peptide levels did not differ significantly in the two groups, although postprandial glucose concentrations were significantly lower in the "low" HbA1c group (means +/- SEM, 96 +/- 11 and 211 +/- 21 mg/dl, respectively; P less than 0.001).


Prevalence and risk factors for depressive symptoms in patients with neovascular age-related macular degeneration who present for anti-VEGF therapy.
To examine the prevalence and risk factors for depressive symptoms in patients with neovascular age-related macular degeneration (nAMD) presenting for anti-vascular endothelial growth factor (anti-VEGF) therapy. In a clinic-based cohort of 547 patients with nAMD who presented for treatment, the Centre of Epidemiological Studies Depression 10-point scale (CES-D-10) and Mental Health Index (MHI) component of the 36-item Short Form Survey were administered to assess for the presence of depressive symptoms. Logistic regression analyses were used to calculate odds ratios and 95% confidence intervals for factors associated with an increased likelihood of depressive symptoms. The prevalence of depressive symptoms was 42.04% and 31.78% as per the CES-D-10 and MHI scales, respectively. Poor self-rated health (SRH) is associated with increased odds of depressive symptoms [multivariable-adjusted OR: 3.00 (95% CI 1.90-4.73) for CES-D-10; OR: 2.67 (95% CI 1.67-4.28) for MHI]. Impaired activities of daily living (ADLs) [multivariable-adjusted OR: 2.62 (95% CI 1.56-4.38) for CES-D-10; OR: 3.59 (95% CI 2.10-6.15) for MHI] and a visual function score within the two lowest quartiles were also associated with increased odds of depressive symptoms using both scales. A high prevalence of depressive symptoms was observed among nAMD patients presenting for treatment. Poorer SRH, ADL impairment and reduced visual function were associated with increased odds of depressive symptoms.


Social interactions, feeding patterns, and feed efficiency of same- and mixed-parity groups of lactating cows.
Social dynamics in group-housed animals can have important impacts on their welfare, feed efficiency, and production potential. Our objectives were to: 1) evaluate the effects of parity and social grouping on competition behavior, feeding patterns, and feed efficiency, and 2) investigate cow-level relationships between competition and feeding behavior, production, and feed efficiency. Fifty-nine Holstein cows (144.5 ± 21.8 starting DIM, mean ± SD) were housed in a freestall pen with 30 Roughage Intake Control (RIC) bins. We evaluated the effects of parity [primiparous (PR, n = 29) vs. multiparous (MU, n = 30)] and group composition at the feed bunk [same-parity (SM, n = 39) vs. mixed-parity (MX, n = 20, 50% of each parity)] with a 2 × 2 factorial design (SM-MU: n = 20; SM-PR: n = 19; MX-MU: n = 10; MX-PR: n = 10) on competition behavior, feeding patterns, and feed efficiency. Within the pen, groups of 9 to 10 cows were considered subgroups and assigned to treatments defined by sets of 5 assigned bins (2:1 stocking density). Feed bunk competition and feeding patterns were recorded via continuous video in the first hour after morning feed delivery and 24-h RIC data, respectively. Residual feed intake (RFI) was calculated as the difference between predicted and observed dry matter intake (DMI) after accounting for known energy sinks. Linear models were used to evaluate the effects and interactions of parity and group composition on competition, feeding behavior, and feed efficiency. Within-cow correlations were performed between competition, feeding behavior, and RFI. Cows in MX, compared with SM, were involved in more competitive interactions [mean (95% CI): competitive contacts: 11.5 (8.1,16.3) vs. 7.2 (5.5,9.3) events; displacements: 4.0 (3.0,5.3) vs. 2.1 (1.7,2.7) events, and replacements: 3.5 (2.6,4.7) vs. 1.9 (1.5,2.5) events]. Cows in MX vs. those in SM had more bunk visits/meal [ 4.3 (3.9, 4.8) vs. 3.7 (3.4, 3.9) visits/meal] and longer meals (31.2 vs. 27.4 ± 0.9 min/meal) and tended to have higher RFI (0.41 ± 0.3 vs. -0.21 ± 0.2) and were therefore less feed efficient. Multiparous vs. PR cows had greater DMI per day (29.3 ± 0.6 vs. 25.5 ± 0.4 kg/d) and per meal [4.2 (4.0, 4.4) vs. 3.4 (3.2, 3.6) kg/meal], faster eating rates [0.14 (0.13, 0.15) vs. 0.12 (0.11, 0.13) kg/min], and fewer bunk visits/d [26.6 (24.0, 29.4) vs. 32.8 (29.7, 35.9)]. Regardless of grouping or parity, cows with shorter latencies to first visit the bunk after feed delivery were involved in more competition and tended to be less feed efficient. Overall, individual cow- and group-level relationships among competition, feeding behavior, and feed efficiency play an important role in feed bunk social dynamics. At a competitive 2:1 stocking density, mixed-parity groups for lactating cows may have potentially negative animal welfare and feed efficiency implications that should be considered when selecting grouping strategies on the farm.


[The interesting case -- case no. 68. Metastasis of a small-cell bronchial carcinoma to the parotid gland].
We present a case of a metastasis to the parotid gland from a small cell carcinoma of lung. The patient noted swelling in right parotid region without pain and saw an otorhinolaryngologist. There was no facial nerve palsy. He was admitted to our hospital. The total parotidectomy with facial nerve preserving was performed. The pathological findings indicated small cell carcinoma. After receipt of this report, we examined the lungs. An abnormal shadow could be found in the chest X-rays. CT revealed a lung tumor on a left site which was determined to be small cell carcinoma by transbronchial lung biopsy. Metastasis to the parotid glands from any distant primary site is quite unusual. In most cases of secundary parotid involvement of malignant tumors primary tumors originated from the head and neck region. Primary tumors in the neighborhood are the skin of the head and neck and the mucosa of the upper airway and digestive tract. Distant metastases to the parotid gland have been reported to arise from bronchial carcinoma, renal carcinoma, colonic carcinoma, prostat and breast. The distinction between primary salivary glands tumors and metastases of other primary tumors is difficult often. Histologic and immunhistological methods can be helpful.


Prognostic significance of mean platelet volume on admission in an unselected cohort of patients with non ST-segment elevation acute coronary syndrome.
Mean platelet volume (MPV) has been proposed as a marker of platelet reactivity and cardiovascular risk. Its prognostic significance has not been thoroughly investigated in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). We included 1,041 consecutive patients with NSTE-ACS. Patients were divided in quartiles according to the MPV value on admission (fl) i.e. Q1<7.5; Q2=7.5-8.0; Q3=8.1-8.8; Q4≥8.9. The primary study endpoint was the composite of cardiovascular death and re-myocardial infarction (MI) at one year. Secondary study endpoints were individual cardiovascular death and re-MI. Patients in Q4 were older, had a higher prevalence of previous MI, peripheral artery disease and advanced Killip class compared to patients in Q1-Q3. Elevated MPV levels (Q4) was independently associated with gender, smoking status, platelet count and creatinine level. Overall, 210 patients (20.2%) reached the primary endpoint, 124 (12.1%) died from cardiovascular causes and 125 (12.0%) suffered from re-MI. On multivariable analysis patients in Q4 were at higher risk of primary endpoint (HR=1.41; 95%CI 1.06-1.89; p=0.02) whilst the association with cardiovascular death and re-MI was attenuated. MPV as continuous variable was independently associated with both primary endpoint (HR=1.19; 95%CI 1.06-1.33; p=0.003) and cardiovascular death (HR=1.23; 95%CI 1.06-1.42, p=0.006). The incorporation of MPV into a comprehensive model of risk significantly increased the likelihood ratio chi-square for prediction of both the composite endpoint (p=0.004) and cardiovascular death (p=0.009). Therefore, MPV may be useful to improve risk stratification in NSTE-ACS patients and should be included in future prospective studies evaluating the role of platelet function in promoting cardiovascular events.


No gradient exists between lumbar and ventricular cerebrospinal fluid beta-endorphin.
In 8 patients, beta-lipotropin (beta-LPH), beta-endorphin (beta-EP), ACTH, protein and chloride concentrations were measured in cerebrospinal fluid (CSF) samples obtained simultaneously from the lumbar space and lateral ventricle. Albumin and IgG levels were significantly higher in lumbar than in ventricular CSF samples while no craniocaudal gradient was observed for neuropeptide concentrations. The importance of molecular weight in determining such a regional distribution is supported also by the similar lumbar and ventricular levels of chlorides. These data would validate the CSF approach through lumbar puncture as a tool for exploring neuropeptides in the central nervous system.


Factors influencing early withdrawal from a drug and alcohol treatment program and client perceptions of successful recovery and employment: a qualitative study.
Substance use disorders are a major contributor to the economic and healthcare burden in Australia. Therapeutic communities (TCs) are utilised treatment methods globally, though low program completion rates continue to represent a major obstacle in effective and sustainable drug and alcohol treatment. The aim of this study was to explore reasons for early withdrawal from TC programs and perceptions of successful recovery. This study also aimed to explore how employment and volunteering related to early exit and perceptions of successful recovery. Semi-structured qualitative interviews were conducted with 13 ex-residents from a long-term TC program at a community-based rehab organisation in regional Australia. Thematic analysis revealed a complex interplay of factors contributing to early TC withdrawal, and perceptions of successful recovery from a lived experience perspective and how this was shaped by employment and volunteering. Eleven themes were identified. Three relating to reasons for joining the program, which connected with ultimate withdrawal from the program: Pre-program existing relationships, pre-program employment situation and needing a 'circuit breaker' in their life. Three relating to reasons for early withdrawal: TC program characteristics, relationships during the program and planning future employment. Five relating to perceptions of successful recovery: Improved understanding of their addiction, reduced substance use, improved physical and psychological health, relationship success and employment success. Reasons for leaving treatment early are multi-faceted and revolve around relationships, planning future employment and program characteristics. The influence that each plays on their decision to leave early is varied and determined by the value they assign it. Perceived success extends far beyond achieving and maintaining abstinence to encompass improved relationships, psychological and physical wellbeing, understanding of addiction and employment, studying or volunteering. Self-worth and feeling able to contribute to society through employment, study and volunteering were perceived to be essential elements of successful recovery. Clinicians, policy makers and program developers should use the extended definition of successful recovery from the ex-clients perspective when determining the clinical and economic effectiveness of TC programs.


[Cerebellar hemorrhage complicating a supratentorial craniotomy. A case report and review of the literature].
Postoperative cerebellar hemorrhage after a supratentorial craniotomy represents a rare event. We report a case of a patient with a meningioma of the jugum who developed suddenly after surgery a neurological deterioration due to a cerebellar hemorrhage detected on the CT scan. An occipital craniectomy and an external ventricular drainage were performed in emergency. A complete neurological recovery was observed after surgery. Nineteen similar other cases are found in the literature. Pre- and postoperative high blood pressure, lowered intracranial pressure and mispositioning of the head during surgery could be at the origin of the hemorrhage. Size of the hemorrhage, time between diagnosis and treatment represent two prognostic factors. All patients, who present a neurological deterioration in postoperative course, must have CT scan including posterior fossa.


LOXL as a target to increase the elastin content in adult skin: a dill extract induces the LOXL gene expression.
The lysyl oxidases lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) are responsible for elastin cross-linking. It was shown recently that LOXL is essential for the elastic fibres homeostasis and for their maintenance at adult age. We first determined whether or not elastin, LOX and LOXL are less expressed during adulthood. The LOX and LOXL mRNA level, quantified by real-time reverse transcriptase-polymerase chain reaction decreased in adult skin fibroblasts compared with fibroblasts from children. In contrast, the elastin mRNA level remains stable at all ages. The goal of this study was to induce elastogenesis at the adult age. Therefore, both enzymes, and in particular LOXL, of which expression is the most affected by age, could be targeted to induce elastogenesis in adult skin. We screened a library of about 1000 active ingredients to find activators capable to stimulate specifically the LOXL gene expression in adult dermal fibroblasts. The positive effect of selected active ingredients was confirmed on fibroblasts grown on monolayers and on dermal and skin equivalent cultures. One extract, obtained from dill (LYS'LASTINE V, Engelhard, Lyon, France), stimulates the LOXL gene expression in dermal equivalents (+64% increase in the LOXL mRNA level when compared with control). At the same time, the elastin detection is increased in dermal equivalents and under the dermal-epidermal junction of skin equivalents, without increase of the elastin mRNA. In conclusion, LOXL can be considered as a new target to reinduce elastogenesis. Its stimulation by a dill extract is correlated with increased elastin detection, suggesting an increase in elastogenesis efficiency.


Potential of selective estrogen receptor modulators as treatments and preventives of breast cancer.
Estrogen plays vital roles in human health and diseases. Estrogen mediates its actions almost entirely by binding to estrogen receptors (ER), alpha and beta which further function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by series of experiments in the laboratory which laid the foundation of its clinical use. Unfortunately, use of tamoxifen is associated with de-novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to precisely understand the mechanism of SERM action which may further help in designing new and improved SERMs. Recent clinical studies reveal that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which not only can be used for therapeutic and preventive purposes of breast cancers but also for various other diseases and disorders. Major efforts are therefore directed to make new SERMs with a better therapeutic profile and fewer side effects.


Adverse Childhood Experiences and Food Insecurity in Adulthood: Evidence From the National Longitudinal Study of Adolescent to Adult Health.
Adverse childhood experiences (ACEs) are associated with food insecurity in childhood and adolescence. A growing body of research also finds ACEs are associated with deleterious health outcomes in adulthood. However, research has not investigated whether ACEs have consequences for food insecurity among young adults. The present study examines the association between individual and cumulative ACE exposure and food insecurity among young adults. Furthermore, we assess whether income, physical disability, depressive symptoms, and substance use reduces the magnitude of this association. Data are from the National Longitudinal Study of Adolescent to Adult Health (N = 12,288). Multivariate logistic regression was used to analyze the association between ACEs and food insecurity. The Karlson-Holm-Breen method was used to test for confounding effects. An accumulation of ACEs is associated with a higher odds of experiencing food insecurity. After adjusting for baseline control variables, being exposed to four or more ACEs was associated with a 3.4-fold increase in the odds of food insecurity in young adulthood relative to being exposed to no ACEs. Depressive symptoms, income, and drug use were found to partially reduce the magnitude of this association. ACEs carry consequences for well-being and serve as an antecedent to food insecurity in young adulthood. Developing interventions such as expanding access to nutrition assistance programs for ACE-exposed populations may yield benefits for alleviating food insecurity and promoting greater health equity.


[Analysis of monosaccharides of bacterial glycocalix of Bacillus-Lactobacillus-Streptococcus group by gas-chromatography].
The glycocalix of some bacteria of the Bacillus--Lactobacillus--Streptococcus (Bacillus subtilis 3, B. subtilis 668, B. licheniformis 31, Lactobacillus plantarum 11/16, Enterococcus faecium K-50) group were isolated and composition of neutral monosaccharides was investigated. Such sugars as rhamnose, ribose, fucose, arabinose, xylose, mannose, galactose, and glucose were found in the investigated representatives of genus Bacillus--Lactobacillus--Streptococcus. Presence of significant quantity of glucose and galactose did not depend on cultivation conditions. This fact testifies to its conservatism and a possibility to use it as phylogenetic marker.


Comparative transcriptome analysis of E. coli & Staphylococcus aureus infected goat mammary epithelial cells reveals genes associated with infection.
Mastitis, an inflammatory disease of the mammary gland, imposes a significant financial burden on the dairy sector. However, the specific molecular mechanisms underlying their interactions with goat mammary epithelial cells (GMECs) remain poorly understood. This study aimed to investigate the transcriptomic response of GMECs during infection with E. coli and S. aureus, providing insights into the host-pathogen interactions. Differential expression of gene (DEGs) analysis was done to find genes and pathways dysregulated in the wake of infection. E. coli infection triggered a robust upregulation of immune response genes, including pro-inflammatory chemokines and cytokines as well as genes involved in tissue repair and remodeling. Conversely, S. aureus infection showed a more complex pattern, involving the activation of immune-related gene as well as those involved in autophagy, apoptosis and tissue remodeling. Furthermore, several key pathways, such as Toll-like receptor signaling and cytokine-cytokine receptor interaction, were differentially modulated in response to each pathogen. Understanding the specific responses of GMECs to these pathogens will provide a foundation for understanding the complex dynamics of infection and host response, offering potential avenues for the development of novel strategies to prevent and treat bacterial infections in both animals and humans.


Macroalgal Polysaccharides in Biomimetic Nanodelivery Systems.
Imitating nature in the design of bio-inspired drug delivery systems resulted in several success stories. However, the practical application of biomimicry is still largely unrealized owing to the fact that we tend to copy the shape more often than the whole biology. Interesting chemistry of polysaccharides provides endless possibilities for drug complex formation and creation of delivery systems with diverse morphological and surface properties. However, the type of biological response, which may be induced by these systems, remains largely unexploited. Considering the most current research for the given topic, in this review, we will try to present the integrative approaches for the design of biomimetic DDS's with improved therapeutic or theranostic effects based on different algal polysaccharides that exert multiple biological functions. Algal polysaccharides may provide building blocks for bioinspired drug delivery systems capable of supporting the mechanical properties of nanomedicines and mimicking various biological processes by molecular interactions at the nanoscale. Numerous research studies demonstrate the efficacy and safety of multifunctional nanoparticles integrating several functions in one delivery system, composed of alginate, carrageenan, ulvan, fucoidan and their derivatives, intended to be used as bioartificial microenvironment or for diagnosis and therapy of different diseases. Nanodimensional structure of polysaccharide DDS's shows substantial influence on the bioactive motifs potential availability for interaction with a variety of biomolecules and cells. Evaluation of the nano dimensional structure-activity relationship is crucial for unlocking the full potential of the future application of polysaccharide bio-mimicking DDS in modern diagnostic and therapeutic procedures.