The importance of sensory nerve endings as sites of drug action.
The role that sensory nerve endings can play in drug action and the strategy used for its experimental analysis and proof is first exemplified by three effects of nicotine which are seen when the lowest effective doses of the drug are given intravenously in the cat: (1) a vasopressor effect due to arterial chemoreceptor stimulation; (2) a triad of bradycardia, hypotension and apnea, and (3) a depressant effect upon somatic motor activity, both of which are traced to vagal afferent endings in the pulmonary circulation. While receptors in the lung are responsible at least for the initial phase of the reflex responses listed in (2) and (3), sensory endings in heart, aorta, and carotid sinus region may be recruited into action as the drug reaches them. Several of these reflex effects can also be elicited by other sensory stimulant agents such as phenyldiguanide, 5-hydroxytryptamine, and veratrum alkaloids. In the second part, a general outline is given of what may be classified as 'Afferent Pharmacology', dealing with drug action upon sensory receptors and with the resulting remote drug effects. The action upon sensory receptors can either be a direct one ('primary' drug effect) consisting of stimulation, sensitization, desensitization, depression or combinations thereof, or an indirect ('secondary') effect brought about by a variety of drug-induced changes in the tissues surrounding the receptors. Depending on the nature of the primary or secondary action, the remote drug effect can be either an initiation, modification or impairment of those reflexes which have their origin in the sensory endings acted upon. Indeed, the grossly observable pharmacological actions of 'afferent drugs' are generally those relating to the reflex response. To avoid blurring of the boundaries of afferent pharmacology, drugs acting on central synapses of reflex pathways, or on the elaborate efferent control system of afferent input, are not included. A discussion follows of the topics of investigation, the influence of experimental conditions and anesthesia, various approaches and methods, the physiological and pharmacological importance of inquiry in this area, and some of the therapeutic aspects. Finally, brief mention is made of certain features and problems which appear to be characteristic of afferent pharmacology.


Bionic Scarfskin-Inspired Hierarchy Configuration toward Tunable Microwave-Absorbing Performance.
Maintaining the dynamical microwave synchronization between a target and its background is the key to electromagnetical invisibility in real environment. Herein, we introduce an archetypical paradigm for ultraelastic films of graphene-functionalized ionic gel with tunable microwave-absorbing behaviors. Inspired by the local structural changes during the wing-spreading process of vespertilionids, the experimental and finite element simulations have revealed that proper shape changing of 3D wrinkled structure containing ridge walls with moderate impedance is the effective way to minimize reflected wave and promote energy attenuation. An optimal RL value of -43.6 dB and valid regulatory amplitude of 41.5 dB, covering a microwave-absorbing to shielding state, could be reached with only 0.2% weight fraction of the active ingredient RGO filler. The significant regulatory performance is attributed to the competitive effect between intrinsic dielectric attenuation of silicon nitride modified reduced graphene oxide (RGO-SiN), multiscattering of a 3D wrinkled structure, and evolution of the oriented RGO-SiN.


Comparison of treatment effect between phase 2 and phase 3 trials in patients with inflammatory bowel disease.
The accumulation of multiple randomized controlled trials in the field of inflammatory bowel diseases provides an opportunity to compare treatment effects between phase 2 and 3 trials. We aimed to determine whether treatment effects observed in phase 3 investigating biologics and small molecule drugs differed from those in their preceding phase 2 trial. We first performed a review of phase 2 and phase 3 trials enrolling ulcerative colitis (UC) or Crohn's disease (CD) patients. We compared the percent overall success for key endpoints between phases (several phase 3 could be matched to a single phase 2 trial). Then, we compared the percent overall success in the matched phase 2 and 3 trials (ratio 1:1), and performed sensitivity analysis. We identified 14 phase 2 (8 CD; 6 UC) and 24 phase 3 (13 CD; 11 UC) trials. In CD, the different analyses suggest that the percentage of overall success of clinical remission and clinical response was significantly higher in phase 2 than in phase 3 trials. In UC, the analyses suggest collectively that the percent of treatment effect seemed similar for clinical remission, clinical response and histologic outcomes between phases but with a lower percentage of overall success in phase 2 than in phase 3 trials for endoscopic endpoints. In UC, we observed a similar percentage of treatment effect for clinical and histologic outcomes between phase 2 and 3 trials but not for endoscopic outcomes. Whereas in CD, we showed a failure to reproduce similar results between phases. These results may help sponsors in the design of future drug development programs.


Role of the complex upstream region of the GDH2 gene in nitrogen regulation of the NAD-linked glutamate dehydrogenase in Saccharomyces cerevisiae.
We analyzed the upstream region of the GDH2 gene, which encodes the NAD-linked glutamate dehydrogenase in Saccharomyces cerevisiae, for elements important for the regulation of the gene by the nitrogen source. The levels of this enzyme are high in cells grown with glutamate as the sole source of nitrogen and low in cells grown with glutamine or ammonium. We found that this regulation occurs at the level of transcription and that a total of six sites are required to cause a CYC1-lacZ fusion to the GDH2 gene to be regulated in the same manner as the NAD-linked glutamate dehydrogenase. Two sites behaved as upstream activation sites (UASs). The remaining four sites were found to block the effects of the two UASs in such a way that the GDH2-CYC1-lacZ fusion was not expressed unless the cells containing it were grown under conditions favorable for the activity of both UASs. This complex regulatory system appears to account for the fact that GDH2 expression is exquisitely sensitive to glutamine, whereas the expression of GLN1, coding for glutamine synthetase, is not nearly as sensitive.


Dual role of oxidative stress-JNK activation in autophagy and apoptosis induced by nickel oxide nanoparticles in human cancer cells.
Nickel oxide nanoparticles (NiO-NPs) are an important group of nanoparticles with increasing applications in many aspects of industry. At present, there is evidence demonstrating the cytotoxic characteristics of NiO-NPs, while the involvement of autophagy in the cytotoxicity of NiO-NPs has not been reported. In this study, we aimed to study the role of autophagy in the cytotoxicity of NiO-NPs and the underlying regulatory mechanisms. First, we provided evidence that NiO-NPs induce autophagy in human cancer cells. Second, we found that the enhanced autophagic flux by NiO-NPs via the generation of intracellular reactive oxygen species (ROS) from mitochondria and the subsequent activation of the JNK pathway. Third, we demonstrated that the activation of JNK is a main force in mediating NiO-NPs-induced apoptosis. Finally, we demonstrated that the autophagic response plays an important protective role against the cytotoxic effect of NiO-NPs. Therefore, this study identifies the dual role of oxidative stress-JNK activation in the biological effects of NiO-NPs via promoting autophagy and mediating apoptosis. Understanding the protective role of autophagy and the underlying mechanism is important for the potential application of NiO-NPs in the biomedical industry.


[Early results of laparoscopic surgical procedures in Crohn's disease].
During the last years laparoscopic surgical procedures are used more frequently in benign bowel diseases like Crohn's disease. We are reporting early results of laparoscopic procedures in Crohn's disease at our hospital. From 1994 to 2003 54 patients (20 male and 34 female) underwent laparoscopic colonic and small bowel surgery in Crohn's disease. The mean age was 32 years (range: 16 to 55 years). Complications occurred in 6 patients (11.1 %). 3 patients needed a laparotomy. One computed tomography puncture was performed due to a hematoma. The remaining patients are treated successfully non-operatively. No patient died during the perioperative period. The mean operating time was 152 minutes (range 35 to 360 minutes) and the mean postoperative stay in hospital was 10 days (range 6-35 days). 0.2 blood cell concentrates were needed per operation (range 0 to 6), on average. The patients needed no analgesics after the 5 (th) day (range 1 to 13 days), got liquid diet on the 2 (nd) (range 0 to 6 days) and solid diet on the 3 (rd) day after surgery (range 1 to 14 days). Laparoscopic surgery in Crohńs disease is safe when performed by an experienced surgeon. The laparoscopic procedure results in a better cosmetic result, while the longer operating time is the mean disadvantage. There are low complication rates during the early postoperative period.


Perioperative myocardial infarction during cardiac surgery. Diagnosis, ECG and enzyme testing.
The detection of perioperative myocardial infarction is complicated by the variety of electrocardiographic changes normally seen concomitantly with cardiac surgery. Unequivocal electrocardiographic diagnoses based on new Q wave development and evolution of ST and T segments are virtually always confirmed by inappropriately high postoperative enzyme test results. For those patients exhibiting nondiagnostic but suggestive electrocardiographic changes, enzyme testing provides a valuable adjunct in determining whether infarction has indeed taken place. Enzyme testing, similarly, in and of itself, cannot provide the dichotomous situation between those patients experiencing infarction and those who are not. SGOT and LDH appear the most reliable indicators of infarction. CPK is quite volatile with sporadic occurrences of high enzyme elevations without obvious clinical or electrocardiographic explanation. The Ck isoenzymes provide a highly specific test for myocardial damage. However, their sensitivity is sufficiently great that a relatively minor cardiac manipulation may result in uninterpretable results.


A long-term study on the use of evening primrose oil (Efamol) in atopic children.
The effect of essential fatty acids on atopic eczema is controversial. Some workers have reported that patients with atopic eczema improved following oral treatment with evening primrose oil (an oil with a high concentration of gamma-linolenic acid), but others have disputed this. This study was designed to look at the effect of evening primrose oil as a long-term oral supplementation for children with atopic eczema. Treated children dramatically improved their clinical condition after 4 weeks of therapy, and this improvement was maintained during the whole period of treatment (20 weeks). At the same time, modifications in plasma, neutrophil and lymphocyte fatty acid composition were detected.


[Effects of lactone I from Atractylodes macrocephala Koidz on cytokines and proteolysis-inducing factors in cachectic cancer patients].
To observe the effect of lactone I from Atractylodes macrocephala Koidz (LAMK I) on the cytokines and proteolysis-inducing factors (PIF) in cachectic cancer patients. Sixty-four cachectic cancer patients were randomized into two groups, namely LAMK I group and FOE (fish oil-enriched nutritional supplementation) treatment group. The appetite, body weight changes, mid-arm muscle circumference (MAMC), and KPS scores were recorded 3 and 7 weeks after the treatment. Immunohistochemistry was used to analyze the changes in the cytokines interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha and Western blotting employed to examine the changes of PIF after the treatment. The patients' appetite and MAMC in LAMKI group was better than those of patients in FOE group, and the serum IL-1 and TNF-alpha levels and urine PIF level were significantly lower than those of FOE group. Body weight and serum IL-6 level were not significantly different between the two groups. Lactone I from Atractylodes macrocephala Koidz can be beneficial for treating cancer cachexia.


Photo-induced DNA damage and photocytotoxicity of retinyl palmitate and its photodecomposition products.
Retinyl palmitate (RP) is an ester of retinol (vitamin A) and the predominant form of retinol found endogenously in the skin. We have previously reported that photoirradiation of RP with UVA light resulted in the formation of anhydroretinol (AR), 5,6-epoxyretinyl palmitate (5,6-epoxy-RP) and other photodecomposition products. While AR was formed through an ionic photodissociation mechanism, 5,6-epoxy-RP was formed through a light-mediated, free radical-initiated chain reaction. In the current study, the phototoxicity of RP, AR and 5,6-epoxy-RP in human skin Jurkat T-cells with and without light irradiation was determined using a fluorescein diacetate assay. Under similar conditions, the Comet assay was used to assess damage to cellular DNA. Nuclear DNA was not significantly damaged when the cells were irradiated by UVA plus visible light in the absence of a retinoid; however, when the cells were illuminated with UVA plus visible light in the presence of either RP, 5,6-epoxy-RP or AR (50, 100, 150 and 200 microM), DNA fragmentation was observed. Cell death was observed for retinoid concentrations of 100 microM or higher. When treated with 150 microM of RP, 5,6-epoxy-RP or AR, cell death was 52, 33 and 52%, respectively. These results suggest that RP and its two photodecomposition products, AR and 5,6-epoxy-RP, induce DNA damage and cytotoxicity when irradiated with UVA plus visible light. We also determined that photoirradiation of RP, AR and 5,6-epoxy-RP causes single strand breaks in supercoiled phi chi 174 plasmid DNA. Using a constant dose of UVA light (50 J/cm2), the level of DNA cleavage was highest in the presence of AR, followed by 5,6-epoxy-RP, then RP. The induced DNA strand cleavage was inhibited by NaN3. These results suggest that photoirradiation of RP, 5,6-epoxy-RP and AR with UVA light generates free radicals that initiate DNA strand cleavage.


A Rare Case of Dense Spontaneous Echo Contrast within Inferior Vena Cava.
A 33-year-old gentleman was examined because of fatigue and progressive right heart failure. A striking finding in his echocardiogram was intense and slow-moving dense echo contrast in the inferior vena cava (IVC). Cardiac catheterization revealed constrictive pericarditis, and pericardiectomy was performed. Postoperatively spontaneous echo contrast in IVC have resolved. This case helps explain the origin of spontaneous IVC contrast.


Interpolative background subtraction.
A method for background subtraction is presented. The data are digitized scintigraphic images, stored in 64 X 64 frames. Within this array a rectangular area surrounding the target is defined. All data points outside of this area are set equal to zero. From each data point within the area, the computer subtracts a background value equal to the average of the two intersecting linear interpolations between the values at the edges of the rectangular area having the ordinate and abscissa values of the point of interest. The rationale for this approach is discussed and its application in myocardial perfusion studies is illustrated.


Osteoblast Biocompatibility and Antibacterial Effects Using 2-Methacryloyloxyethyl Phosphocholine-Grafted Stainless-Steel Composite for Implant Applications.
Poor osteogenesis and bacterial infections lead to an implant failure, so the enhanced osteogenic and antimicrobial activity of the implantable device is of great importance in orthopedic applications. In this study, 2-methacryloyloxyethyl phosphocholine (MPC) was grafted onto 316L stainless steel (SS) using a facile photo-induced radical graft polymerization method via a benzophenone (BP) photo initiator. Atomic force microscopy (AFM) was employed to determine the nanoscale morphological changes on the surface. The grafted BP-MPC layer was estimated to be tens of nanometers thick. The SS-BP-MPC composite was more hydrophilic and smoother than the untreated and BP-treated SS samples. Staphylococcus aureus (S. aureus) bacteria binding onto the SS-BP-MPC composite film surface was significantly reduced compared with the pristine SS and SS-BP samples. Mouse pre-osteoblast (MC3T3-E1) cells showed good adhesion on the MPC-modified samples and better proliferation and metabolic activity (73% higher) than the pristine SS sample. Biological studies revealed that grafting MPC onto the SS substrate enhanced the antibacterial efficiency and also retained osteoblast biocompatibility. This proposed procedure is promising for use with other implant materials.


Epidemiological Profile of Hospitalized Patients with Cystic Fibrosis in Brazil Due to Severe Acute Respiratory Infection during the COVID-19 Pandemic and a Systematic Review of Worldwide COVID-19 in Those with Cystic Fibrosis.
Since the onset of the coronavirus disease, COVID-19 pandemic, concern arose for those who might be at higher risk of a worse COVID-19 prognosis, such as those with cystic fibrosis (CF). In this context, we evaluated the features of hospitalized patients with CF due to severe acute respiratory infection (SARI) in Brazil and we also performed a systematic review including all the studies published from the beginning of the first case of COVID-19 (17 November 2019) to the date of this search (23 May 2022) which included, concomitantly, patients with CF and COVID-19 in the worldwide population. In our Brazilian data, we evaluated the period from December 2019 to March 2022, and we included 33 demographical and clinical patients' features. We classified the patients into groups: (G1) SARI due to another viral infection than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (23; 5.4%), (G2) SARI due to an unknown etiological agent (286; 67.1%), and (G3) SARI due to SARS-CoV-2 infection (117; 27.5%). The individuals in G3 tended to be older, especially over 50 years old, and presented a higher prevalence of dyspnea, peripheral capillary oxygen saturation (SpO2) <95%, and cardiopathy. The highest prevalence for intensive care unit (ICU) treatment (52; 44.4%) and invasive mechanical ventilation (29; 24.8%) was for patients in G3. Almost half of the patients in G3 died (51; 43.6%); in contrast, none in G1 died. However, we observed 43 (15.0%) deaths in G2. In addition, 12 (4.2%) and one (0.9%) death not associated with SARI occurred, respectively, in the G2 and G3. The patients who died due to SARS-CoV-2 infection had a higher frequency of SpO2 <95% (46; 90.2%), ICU treatment (34; 66.7%), and invasive mechanical ventilation (27; 52.9%) when compared to those who recovered. The systematic review comprised a total of 31 papers published as observational studies. These studies comprised 661,386 patients in total, including children, adults, and elderly age groups. However, only 19,150 (2.9%) patients were diagnosed with CF and, from these patients, 2523 (0.4%) were diagnosed with both CF and COVID-19. It was observed that the most common outcome was the need for hospitalization (n = 322 patients with CF), and the need for oxygen support (n = 139 patients with CF). One hundred patients with CF needed intensive care units, fifty patients needed non-invasive mechanical ventilation support, and only three patients were described as receiving invasive mechanical ventilation support. Deaths were described in 38 patients with CF. Importantly, lung-transplanted patients with CF represented an increased risk of death in one publication; in accordance, another study described that lung transplantation and moderate to severe lung disease were independent risk factors for severe outcomes after SARS-CoV-2 infection. In contrast with the literature, in conclusion, Brazilian patients in G3 presented a severe phenotype, even though most of the other studies did not observe worse outcomes in patients with CF and COVID-19.


Examining the association between educational attainment and life expectancy in MENA region: A panel data analysis.
The purpose of this study is to investigate the association between educational attainment and life expectancy in 18 countries in MENA region. We used World Bank database for a panel of 18 MENA countries during the years 1995 to 2009. We used Life Expectancy at Birth, as the key health care output measure. Additionally, we used six health care input independent variables. All variables were transformed into natural logarithms. We estimated the production function using Cobb-Douglas function. Results indicate that 1% increase in educational attainment of males 25 to 34 years old, males 25 years and older, females 25 to 34 years old, females 25 years and older, and females aged 15 to 44 years old will increase life expectancy by 0.14%, 0.07%, 0.04%, 0.03%, and 0.04%, respectively, while everything else remains constant. Our results suggest that for MENA region countries investing in education to broaden access would improve health outcomes and life expectancy. Boosting educational attainment for both male and female population may close the life expectancy gaps between the MENA region and other developed countries, and males and females within the same country. Education attainment has the potential to be a social remedy for better health outcomes in MENA countries.


Palliative Care Doula: an innovative model.
Walking the journey of serious illness is very difficult and stressful for patients and families. A universal principle of palliative care is caring for the patient/ family unit. This article introduces a model for the Palliative Care Doula for experienced and advanced practice palliative care nurses to support patients and families during the traumatic and vulnerable period of end-of-life care.


The role of adaptive T cell immunity in atherosclerosis.
There is now solid evidence that T cell adaptive immunity is involved in atherogenesis. While initial studies have focused on the pathogenic arm of the immune response, more recent work clearly suggests an important role for several subsets of regulatory T cells in the protection against lesion development. Here, we review the current knowledge on the role of both pathogenic and regulatory adaptive T cell immunity in atherosclerosis, generated mainly from the study of mouse models of the disease.


Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage.
TGR5 (G protein-coupled bile acid receptor 1, M-Bar) is a G protein-coupled cell surface receptor responsive to bile acids (BA) and different steroid hormones. TGR5 mRNA is detected almost ubiquitious in human and rodent tissues with a very high expression in gallbladder, liver and intestine. In liver, TGR5 is found in sinusoidal endothelial cells, Kupffer cells and cholangiocytes. Activation of TGR5 triggers an elevation of intracellular cyclic AMP and further downstream signalling. Key Messages: TGR5 exerts anti-inflammatory effects, protects cholangiocytes from BA-induced toxicity, promotes cholangiocyte secretion and proliferation and reduces portal perfusion pressure. Furthermore, TGR5 mediates gallbladder filling. TGR5 knockout mice have a smaller BA pool size with altered composition and develop more severe liver injury after BA feeding, common bile duct ligation or injection of lipopolysaccharide. The absence of TGR5 also reduces the proliferative and regenerative capacity after partial hepatectomy or liver damage. Stimulation of TGR5 signalling can improve steatohepatitis, portal hypertension and hepatic inflammation in rodent models of liver damage. However, TGR5 activation also promotes the proliferation of cystic and malignant-transformed cholangiocytes. TGR5 plays an important role in the protection of the liver from BA toxicity under cholestatic conditions. Stimulation of the receptor prevents excessive liver damage in rodent models of cholestasis, steatohepatitis, liver fibrosis and inflammation and also promotes liver regeneration. However, the activation of TGR5-dependent signalling may also trigger proliferation and apoptosis resistance of cystic cholangiocytes and malignantly transformed cholangiocytes, thus promoting cyst growth in polycystic liver disease or progression of cholangiocarcinoma. Depending on the type of liver disease stimulation as well as inhibition of TGR5, signalling may present a useful therapeutic approach.


Progress in research on the role of exosomal miRNAs in the diagnosis and treatment of cardiovascular diseases.
Cardiovascular diseases are the most common diseases threatening the health of the elderly, and the incidence and mortality rates associated with cardiovascular diseases remain high and are increasing gradually. Studies on the treatment and prevention of cardiovascular diseases are underway. Currently, several research groups are studying the role of exosomes and biomolecules incorporated by exosomes in the prevention, diagnosis, and treatment of clinical diseases, including cardiovascular diseases. Now, based on the results of published studies, this review discusses the characteristics, separation, extraction, and identification of exosomes, specifically the role of exosomal miRNAs in atherosclerosis, myocardial injury and infarction, heart failure, aortic dissection, myocardial fibrosis, ischemic reperfusion, atrial fibrillation, and other diseases. We believe that the observations noted in this article will aid in the prevention, diagnosis, and treatment of cardiovascular diseases.


WHSC1L1 drives cell cycle progression through transcriptional regulation of CDC6 and CDK2 in squamous cell carcinoma of the head and neck.
Wolf-Hisrchhorn Syndrome Candidate 1-Like 1 (WHSC1L1) is a protein lysine methyltransferase that is recurrently amplified (8p11.23) in patients with squamous cell carcinoma of the head and neck (SCCHN). In this study, we investigated the oncogenic role of WHSC1L1 in SCCHN. Using immunohistochemistry on tissue microarrays of patients with locoregionally advanced SCCHN, we found that WHSC1L1 is significantly overexpressed in patients with SCCHN, and is associated with poor grade and heavy smoking history. Knockdown of WHSC1L1 expression resulted in significant growth suppression and reduction of H3K36 dimethylation (H3K36me2) in SCCHN cells. Chromatin immunoprecipitation analysis showed that WHSC1L1 and H3K36me2 are enriched in the gene bodies of the cell cycle-related genes CDC6 and CDK2, implying that WHSC1L1 directly regulates the transcription of these genes. According to the importance of CDC6 and CDK2 for G1 to S transition, WHSC1L1 knockdown induced strong G0/G1 arrest which was rescued by introduction of wild-type WHSC1L1 but not by that of enzyme-inactive WHSC1L1. Our results imply that WHSC1L1 and its product H3K36me2 are essential for the transition from G1 to S phase in SCCHN cells and that WHSC1L1 could serve as a rational target for anticancer drug development for patients with head and neck cancer.


[Relationships between insulin resistant and hypertension and traditional Chinese medicine intervention].
Recently many researches have demonstrated that insulin resistant (IR), as an important pathologic process, is increasingly involved with a series of diseases such as central obesity and diabetes. Hypertension is highly associated with IR. The relationships between IR and glucose or lipid metabolism disorders are well established. However, association of IR with hypertension is less covered. Current researches on insulin resistance and pathogenesis of hypertension are reviewed in this paper, which holds that traditional Chinese medicine treatment on IR in patients with hypertension has a good prospect.


Comment on "The diatomic dication CuZn2+ in the gas phase" [J. Chem. Phys. 135, 034306 (2011)].
In this Comment, the density functional theory (DFT) calculations carried out by Diez et al. [J. Chem. Phys. 135, 034306 (2011)] are revised within the framework of the coupled-cluster single double triple method. These more sophisticated calculations allow us to show that the (2)Σ(+) electronic ground state of CuZn(2+), characterized as the metastable ground state by DFT calculations, is a repulsive state instead. The (2)Δ and (2)Π metastable states of CuZn(2+), on the other hand, should be responsible for the formation mechanism of the dication through the near-resonant electron transfer CuZn(+) + Ar(+) → CuZn(2+) + Ar reaction.


Mouse Models of C9orf72 Hexanucleotide Repeat Expansion in Amyotrophic Lateral Sclerosis/ Frontotemporal Dementia.
The presence of hexanucleotide repeat expansion (HRE) in the first intron of the human C9orf72 gene is the most common genetic cause underlying both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies aimed at elucidating the pathogenic mechanisms associated of C9orf72 FTD and ALS (C9FTD/ALS) have focused on the hypothesis of RNA and protein toxic gain-of-function models, including formation of nuclear RNA foci containing GGGGCC (G4C2) HRE, inclusions containing dipeptide repeat proteins through a non-canonical repeat associated non-ATG (RAN) translation mechanism, and on loss-of-function of the C9orf72 protein. Immense effort to elucidate these mechanisms has been put forth and toxic gain-of-function models have especially gained attention. Various mouse models that recapitulate distinct disease-related pathological, functional, and behavioral phenotypes have been generated and characterized. Although these models express the C9orf72 HRE mutation, there are numerous differences among them, including the transgenesis approach to introduce G4C2-repeat DNA, genomic coverage of C9orf72 features in the transgene, G4C2-repeat length after genomic stabilization, spatiotemporal expression profiles of RNA foci and RAN protein aggregates, neuropathological features, and neurodegeneration-related clinical symptoms. This review aims to (1) provide an overview of the key characteristics; (2) provide insights into potential pathological factors contributing to neurotoxicity and clinical phenotypes through systematic comparison of these models.


Isolation of mutants of Acinetobacter calcoaceticus deficient in wax ester synthesis and complementation of one mutation with a gene encoding a fatty acyl coenzyme A reductase.
Acinetobacter calcoaceticus BD413 accumulates wax esters and triacylglycerol under conditions of mineral nutrient limitation. Nitrosoguanidine-induced mutants of strain BD413 were isolated that failed to accumulate wax esters under nitrogen-limited growth conditions. One of the mutants, Wow15 (without wax), accumulated wax when grown in the presence of cis-11-hexadecenal and hexadecanol but not hexadecane or hexadecanoic acid. This suggested that the mutation may have inactivated a gene encoding either an acyl-acyl carrier protein or acyl-coenzyme A (CoA) reductase. The Wow15 mutant was complemented with a cosmid genomic library prepared from wild-type A. calcoaceticus BD413. The complementary region was localized to a single gene (acr1) encoding a protein of 32,468 Da that is 44% identical over a region of 264 amino acids to a product of unknown function encoded by an open reading frame associated with mycolic acid synthesis in Mycobacterium tuberculosis H37Ra. Extracts of Escherichia coli cells expressing the acr1 gene catalyzed the reduction of acyl-CoA to the corresponding fatty aldehyde, indicating that the gene encodes a novel fatty acyl-CoA reductase.


[A mechanism for modulation of N-methyl-D-aspartate receptor channels by free ferrous ions in cultured rat cortical neurons].
Rat cortical neurons cultured in DMEM/F-12 in the absence of fetal calf serum were harvested on days 3, 6 and 9 in vitro (DIV), followed by homogenization and subsequent SDS-PAGE for immunoblotting using an antibody against MAP-2 or GFAP. Expression of MAP-2 was not markedly changed during cultivation for 3 to 9 DIV, while GFAP was profoundly expressed after 6 DIV in a manner dependent on the duration of culturing. Cortical neurons cultured for 3 DIV were pre-incubated with fluo-3 AM and then subjected to fluorescence image analysis using a confocal microscope. The exposure to NMDA markedly increased the number of neurons with high fluorescence intensity in the absence of MgCl2, without prominently affecting that in the presence of MgCl2. The addition of FeCI2, but not hemoglobin and transferrin, markedly reduced the increase in a concentration-dependent manner in the presence of NMDA. This inhibition by FeCl2 was not affected by the addition of dithiothreitol or 2-mercaptoethanol. These results suggest that free ferrous ions may selectively prevent Ca2+ influx across NMDA receptor channels in a manner different from that done by the redox site on the channels in cultured rat cortical neurons.


Epidemiologic and clinical characteristics of heart transplant recipients during the 2019 coronavirus outbreak in Wuhan, China: A descriptive survey report.
The epidemiologic and clinical characteristics of heart transplant (HTx) recipients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic remains unclear. We studied the characteristics of HTx recipients from December 20, 2019, to February 25, 2020, in an effort to understand their risk and outcomes. All accessible HTx recipients were included in this single-center retrospective study. We collected information on the recipients using a web-based questionnaire as well as the hospital database. We followed 87 HTx recipients (72.4% were men, and the average age was 51 years). A total of 79 recipients resided in Hubei, and 57 recipients had a Wuhan-related history of travel or contact. Most took precautionary measures while in contact with suspicious crowds, and 96.6% of the families and communities undertook prevention and quarantine procedures. Four upper airway infections were reported, and 3 of them tested negative for SARS-CoV-2 (the fourth recovered and was not tested). All cases were mild and successfully recovered after proper treatment. Laboratory results of 47 HTx cases within the last 2 months were extracted. Of these, 21.3% of recipients had pre-existing lymphopenia, and 87.2% of recipients had a therapeutic concentration of tacrolimus (5-12 ng/ml). Liver and kidney insufficiency was seen in 5 and 6 recipients, respectively. HTx recipients who practiced appropriate prevention measures had a low rate of infection with SARS-CoV-2 and transition to the associated disease COVID-19. These early data will require confirmation as the pandemic establishes around the world.


Implantation energy- and size-dependent light output of enhanced-efficiency micro-LED arrays fabricated by ion implantation.
A new process is presented for fabricating enhanced-efficiency micro-pixelated vertical-structured light-emitting diode (µVLED) arrays based on ion-implantation technology. High-resistivity selective regions are locally introduced in the n-GaN layer by ion implantation and then used as effective and non-destructive electrical isolation for realizing µVLED arrays with ultra-small pixel diameters. The implantation energy-dependent and size-dependent opto-electrical characteristics of fluorine (F-) implanted µVLED arrays are investigated systematically. The results show that the optimally designed F- ion implantation not only can achieve smaller reverse leakage current but also can realize ion-induced thermal relaxation effectively and is more suited for fabricating high-resolution µVLED arrays with higher optical output power. For the F--implanted µVLED array with pixel diameters of 10 µm, a measured output power density reaches a value of 82.1 W cm-2 at a high injection current density of 220 A cm-2, before power saturation. Further, the output power densities and external quantum efficiencies of F--implanted µVLED arrays with pixel diameters less than 10µm show strong dependences on pixel size due to the presence of defects-related SRH process. So, the high-efficiency µVLED arrays with ultra-small pixel sizes could be fabricated by an appropriately designed ion implantation combined with control of defect densities to meet the industrial requirement of microdisplay applications.


Variables predicting distant metastases in thyroid cancer.
Distant metastases from thyroid cancer are uncommon and have a variable prognosis. We present a series of patients with distant metastases to determine which patients are at risk of developing distant disease and to examine the significant prognostic variables. Retrospective chart review of 30 patients with distant metastases compared with 633 controls from the Mount Sinai Thyroid Cancer Database and literature review. The prevalence of distant metastases was 4.5%, and median follow-up of survivors was 12.7 years. Histologic type was Hurthle cell carcinoma in 3, follicular in 3, papillary in 19, and 5 patients had focal anaplasia either in the primary site or regional metastases. Predictors for distant metastases, locoregional control, and survival were analyzed. Cumulative survival for patients with distant metastases was 49.5% at 10 years and 12.9% at 20 years. Site of metastases was lung in 26, bone in 11 and brain in 1 patient, with 8 patients having multiple sites. The median time to diagnosis of distant metastases was 3 months. Variables that predicted for development of distant disease were male sex, age, size, extrathyroidal extension, regional metastases, and elevated thyroglobulin. Survival in patients without distant disease was significantly better than those with distant metastases (P < .001). Variables that predicted poor outcome in patients with distant metastases on analysis were age greater than 45 years (P = .003) and histologic type of thyroid cancer (P = .009). Although patients with thyroid cancer and distant metastases may live prolonged periods with disease, it does significantly impact on patient survival. Age remains an important variable in both predicting for development of distant metastases and also influences long-term survival in patients with existing distant metastases.


Hypothalamic-pituitary-adrenal axis function and exposure to stress factors and cannabis use in recent-onset psychosis.
Objectives: Previous studies suggest that childhood trauma, stressful life events, and cannabis use are associated with psychosis. We aimed to explore whether these environmental factors have an effect on hypothalamic-pituitary-adrenal (HPA) axis indices in recent-onset psychosis.Methods: We studied 56 recent-onset psychosis outpatients and 47 healthy controls. Childhood trauma was assessed with the Childhood Trauma Questionnaire. Stressful life events were assessed with the Holmes-Rahe Social Readjustment Scale. Cannabis use was assessed by semistructured interviews. Several HPA axis measures were analysed in saliva: cortisol awakening response (CAR), diurnal cortisol slope, and dexamethasone suppression test ratio (DSTR) after 0.25 mg of dexamethasone. Multiple linear regression analyses were conducted to explore the contribution of environmental factors to each HPA axis measure while adjusting for covariates (diagnosis, age, gender, smoking, body mass index and treatments).Results: There were no significant differences in HPA axis measures between diagnostic groups. Cannabis use was associated with a more flattened diurnal cortisol slope (standardized β = 0.21, p = 0.038), independent of recent-onset psychosis diagnosis. No associations were found between environmental factors and other HPA axis measures (CAR, DSTR).Conclusions: Our study provides evidence for the effect of cannabis exposure in cortisol secretion patterns in both healthy controls and recent-onset psychosis patients.


Self-care behavior prevention of COVID-19 in the general population based on Pender Health Promotion Model: A cross-sectional study.
Coronavirus with its sudden and widespread outbreak has obviously imposed devastating consequences in various aspects of human life. The purpose of this study was to determine the predictive value of Pender's Health Promotion Model (HPM) structures in self-care preventive behavior against coronavirus disease 2019 (COVID-19) among the general population of Ardabil, Iran. The present retrospective descriptive-correlational study was conducted on citizens of Ardabil aged 18 years and over in 2021. After dividing the city of Ardabil into four parts, 50 people from each area of the city and a total of 200 people were selected through the available sampling method through social media. Data collection tools included a demographic profile, perceived self-efficacy scale, perceived emotional questionnaire, perceived social support questionnaire, perceived benefits and barriers questionnaire, researcher-made COVID-19 self-care questionnaire, and commitment to action questionnaire based on Pender's HPM structures in an online manner. Data were analyzed by Amos 22 software and using structural equation modeling. According to the results, direct path analysis to COVID-19 self-care behavior indicated that the variables of perceived self-efficacy (β = 0.18, p < 0.01), interpersonal effects (β = 0.19, p < 0.01), positive emotion (β = 0.15, p < 0.05) and perceived benefits (β = 0.20, p < 0.01) are able to significantly predict self-care behaviors. Moreover, the bootstrapping test results in the indirect path analysis demonstrated that the variables of perceived self-efficacy (95% confidence interval [CI], 0.012, 0.066), perceived social support (95% CI, 0.002, 0.026), and perceived barriers (95% CI, -0.019, -0.002) and benefits (95% CI, 0.001, 0. 015) through the mediator variable of commitment to action are able to significantly predict COVID-19 self-care behavior. Based on the findings of the present study, it can be claimed that the proposed model of COVID-19 self-care behavior has an acceptable fitness in the general population. This model can be used in developing educational programs and intervention techniques to modify people's attitudes and behaviors.


Physiological elongation of ligamentous complex surrounding the hindfoot joints: in vitro biomechanical study.
Ligaments surrounding the hindfoot joints play an important role in hindfoot stability. This in vitro study investigated anatomical and biomechanical characteristics of nine major ligamentous structures, including length and orientation at neutral position and physiological elongation with the foot in five different positions relative to the neutral position. The results showed that ligament elongation depended on the ligament length, orientation in neutral position, and movement of bones to which they were attached.


Health status after Ilizarov reconstruction of post-traumatic lower-limb deformity.
Previous studies of the Ilizarov procedure have concentrated on musculoskeletal assessments rather than the opinions of patients. In a prospective trial of 25 consecutive patients, we evaluated the effect of Ilizarov reconstruction of post-traumatic deformity on general health status using the SF36 and Nottingham Health Profile (NHP). The patients had very low preoperative scores, which remained low during treatment and correction, but increased postoperatively. The mean overall SF36 score improved from 36 +/- 3 to 58 +/- 7 (p = 0.031) and the NHP score from 39 +/- 11 to 67 +/- 10 (p = 0.002). The improvements in scores were not limited to the physical components and were equal or better than the improvements reported for other orthopaedic procedures, including total joint arthroplasty. Ilizarov-type reconstruction of deformity of the lower limb not only restores bony configuration, but also produces a large improvement in the general health status of patients.


FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression.
During somite development, a fibroblast growth factor (FGF) signal secreted from the myotome induces formation of a scleraxis (Scx)-expressing tendon progenitor population in the sclerotome, at the juncture between the future lineages of muscle and cartilage. While overexpression studies show that the entire sclerotome is competent to express Scx in response to FGF signaling, the normal Scx expression domain includes only the anterior and posterior dorsal sclerotome. To understand the molecular basis for this restriction, we examined the expression of a set of genes involved in FGF signaling and found that several members of the Fgf8 synexpression group are co-expressed with Scx in the dorsal sclerotome. Of particular interest were the Ets transcription factors Pea3 and Erm, which function as transcriptional effectors of FGF signaling. We show here that transcriptional activation by Pea3 and Erm in response to FGF signaling is both necessary and sufficient for Scx expression in the somite, and propose that the domain of the somitic tendon progenitors is regulated both by the restricted expression of Pea3 and Erm, and by the precise spatial relationship between these Ets transcription factors and the FGF signal originating in the myotome.


A cuproptosis-related genes signature associated with prognosis and immune cell infiltration in osteosarcoma.
Osteosarcoma (OS) is one of the most prevalent primary bone tumors at all ages of human development. The objective of our study was to develop a model of Cuproptosis-Related Genes (CRGs) for predicting prognosis in OS patients. All datasets of OS patients were obtained from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database and Gene Expression Omnibus (GEO) database. We obtained the gene set (81 CRGs) related to cuproptosis by accessing the database and previous literature. All the CRGs were analyzed by univariate COX regression, least absolute shrinkage and selection operator (LASSO) COX regression analysis to screen for CRGs associated with prognosis in OS patients. Then these CRGs were used to construct a prognostic signature, which was further verified by independent cohort (GSE21257) and clinical correlation analysis. Afterward, to identify underlying mechanisms, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for the high-risk group by using the GSEA method. The association between the prognostic signature and 28 types of immune infiltrating cells in the tumor microenvironment was assessed. Ultimately, Lipoic Acid Synthetase (LIAS) (HR=0.632, P=0.004), Lipoyltransferase 1 (LIPT1) (HR=0.524, P=0.011), BCL2 Like 1 (BCL2L1/BCL-XL) (HR=0.593, P=0.022), and Pyruvate Dehydrogenase Kinase 1 (PDK1) (HR=0.662, P=0.025) were identified. Subsequently, they were used to calculate the risk score and build a prognostic model. In the training cohort, risk score (HR=1.878, P=0.003) could be considered as an independent prognostic factor, and OS patients with high-risk scores showed lower survival rates. Biological pathways related to substance metabolism and transport were enriched. There were significant differences in immune infiltrating cells in the tumor microenvironment. All in all, The CRGs signature is related to the tumor immune microenvironment and could be used as a credible predictor of the prognostic status in OS patients.


Time Trends of Persistent Organic Pollutants in Benthic and Pelagic Indicator Fishes from Puget Sound, Washington, USA.
We modeled temporal trends in polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and dichlorodiphenyltrichloroethane and its metabolites (DDTs) in two indicator fish species representing benthic and pelagic habitats in Puget Sound, Washington, USA. English sole (Parophrys vetulus, benthic) index sites and larger-scale Pacific herring (Clupea pallasii, pelagic) foraging areas represented a wide range of possible contamination conditions, with sampling locations situated adjacent to watersheds exhibiting high, medium and low development. Consistency in analytical data throughout the study was maintained by either calculating method-bias-correction factors on paired samples as methods evolved or by analyzing older archived samples by current methods. PCBs declined moderately in two herring stocks from a low-development basin (2.3 and 4.0% annual rate of decline) and showed no change in the highly developed and moderately developed basins during a 16- to 21-year period. PCBs increased in English sole from four of ten sites (2.9-7.1%), and the remaining six exhibited no significant change. PBDEs and DDTs declined significantly in all herring stocks (4.2-8.1%), although analytical challenges warrant caution in interpreting DDT results. PBDEs declined in English sole from two high-development and one low-development site (3.7-7.2%) and remained unchanged in the remaining seven. DDTs increased in English sole from one high-development site (Tacoma City Waterway) and declined in two high-development and one low development site. As with herring, analytical challenges warrant caution in interpreting the English sole DDT results. It is likely that source controls and mitigation efforts have contributed to the declines in PBDEs and DDTs overall, whereas PCBs appear to have persisted, especially in the pelagic food web, despite bans in PCB production and use.


Increase in renal vascular resistance after intake of cyclosporin A and tacrolimus and reversal by nitroglycerin spray: a study in patients with stable renal allograft function.
Acute effects of drug administration on renal arterial resistance index (RI) are still discussed controversially. In our study we investigated the immediate effects of cyclosporin A (CyA) and tacrolimus (FK-506) on renal arterial resistance indices in patients with stable graft function after renal transplantation. Additionally we studied the effects of nitroglycerin spray on resistance indices. RI was measured by color Doppler sonography at baseline, at 1 and 2 hours after intake of medication and 30 minutes after administration of nitroglycerin spray which followed the 2-hour measurement. 34 renal transplant recipients were examined. 16 patients received CyA, 18 patients received FK-506. Whole blood levels of calcineurin inhibitors were taken at each time point. Arterial blood pressure and heart rate were measured to assess possible systemic hemodynamic effects. Mean RI values increased significantly in both groups 1 hour after calcineurin inhibitor intake and remained still significantly elevated after 2 hours. There was no significant increase of mean arterial blood pressure nor was there any correlation between whole blood levels of calcineurin inhibitors and mean RI. 30 minutes after administration of nitroglycerin spray, mean RI values decreased significantly to a level even below baseline. Mean arterial blood pressure also decreased after administration of nitroglycerin. Renal RI values are markedly influenced by a recent intake of calcineurin inhibitors and vasoactive substances such as nitrates. This demonstrates the necessity of keeping standardized conditions when using RI as a tool in followup investigations after renal transplantation.


Structural effects of nucleobase variations at key active site residue Ade38 in the hairpin ribozyme.
The hairpin ribozyme requires functional groups from Ade38 to achieve efficient bond cleavage or ligation. To identify molecular features that contribute to catalysis, structures of position 38 base variants 2,6-diaminopurine (DAP), 2-aminopurine (AP), cytosine (Cyt), and guanine (Gua) were determined between 2.2 and 2.8 A resolution. For each variant, two substrate modifications were compared: (1) a 2'-O-methyl-substituent at Ade-1 was used in lieu of the nucleophile to mimic the precatalytic state, and (2) a 3'-deoxy-2',5'-phosphodiester linkage between Ade-1 and Gua+1 was used to mimic a reaction-intermediate conformation. While the global fold of each variant remained intact, the results revealed the importance of Ade38 N1 and N6 groups. Absence of N6 resulting from AP38 coincided with failure to localize the precatalytic scissile phosphate. Cyt38 severely impaired catalysis in a prior study, and its structures here indicated an anti base conformation that sequesters the imino moiety from the scissile bond. Gua38 was shown to be even more deleterious to activity. Although the precatalytic structure was nominally affected, the reaction-intermediate conformation indicated a severe electrostatic clash between the Gua38 keto oxygen and the pro-Rp oxygen of the scissile bond. Overall, position 38 modifications solved in the presence of 2'-OMe Ade-1 deviated from in-line geometry, whereas variants with a 2',5' linkage exhibited S-turn destabilization, as well as base conformational changes from syn to anti. These findings demonstrate the importance of the Ade38 Watson-Crick face in attaining a reaction-intermediate state and the sensitivity of the RNA fold to restructuring when electrostatic and shape features fail to complement.


Hemangiopericytoma of the parotid gland with a review of the literature.
Hemangiopericytoma, a rare vascular tumor characterized by pericytes, has been confused with benign lesions. The tumor cannot be identified clinically and requires histopathologic examination. Although the five year survival rate is good, the 10 year survival rate is poor for tumors in the head and neck region. Aggressive treatment with wide surgical margins appears warranted. Surgery in combination with radiotherapy has improved the poor prognosis. A case of hemangiopericytoma of the parotid gland, the eighth known in the surgical literature, is presented which illustrates the difficulty in the diagnosis and treatment of this lesion.


Minimizing Aryloxy Elimination in Rh(I) -Catalyzed Asymmetric Hydrogenation of β-Aryloxyacrylic Acids using a Mixed-Ligand Strategy.
The first example of efficient asymmetric hydrogenation of challenging β-aryloxyacrylic acids was realized using a Rh(I) -complex based on the heterocombination of a readily available chiral monodentate secondary phosphine oxide (SPO) and an achiral monodentate phosphine ligand as the catalyst. Excellent enantioselectivities (92->99 % ee) were achieved for a wide variety of chiral β-aryloxypropionic acids with minor aryloxy elimination in most cases. The resultant products were readily transformed into biologically active compounds through simple synthetic manipulations.


Writing peer-reviewed articles with diverse teams: considerations for novice scholars conducting community-engaged research.
Given the growth of interdisciplinary and community-engaged health promotion research, it has become increasingly common to conduct studies in diverse teams. While there is literature to guide collaborative research proposal development, data collection and analysis, little has been written about writing peer-reviewed publications collaboratively in teams. This gap is particularly important for junior researchers who lead articles involving diverse and community-engaged co-authors. The purpose of this article is to present a series of considerations to guide novice researchers in writing for peer-reviewed publication with diverse teams. The following considerations are addressed: justifying the value of peer-reviewed publication with non-academic partners; establishing co-author roles that respect expertise and interest; clarifying the message and audience; using the article outline as a form of engagement; knowledge translation within and beyond the academy; and multiple strategies for generating and reviewing drafts. Community-engaged research often involves collaboration with communities that have long suffered a history of colonial and extractive research practices. Authentic engagement of these partners can be supported through research practices, including manuscript development, that are transparent and that honour the voices of all team members. Ensuring meaningful participation and diverse perspectives is key to transforming research relationships and sharing new insights into seemingly intractable health problems.


Domain structure of calpain: mapping the binding site for calpastatin.
The peptide EKLGERDDTIPPEYRELLEKKTGV was synthesized to mimic the central consensus sequence of calpastatin, the specific, endogenous inhibitor of the calpains (EC 126.96.36.199). The peptide competitively inhibits hydrolysis of casein by either micro- or milli-calpain but does not affect the activity of other proteases. This inhibitory peptide was preferentially cross-linked to milli-calpain in the presence of calcium using the heterobifunctional cross-linking reagent m-maleimidobenzoyl-N-hydroxysuccinimide ester. Cross-linking of the peptide was blocked by calpastatin. The site of cross-linking for the peptide within milli-calpain was localized using random chemical cleavage of the enzyme-peptide complex at cysteine residues. Calpain fragments were identified as amino-terminal fragments through reactivity with a peptide-specific antiserum or as non-amino-terminal fragments through incorporation of 14C from 14CN. Analysis of the control and cross-linked fragments, from experiments using both milli-calpain and micro-calpain, maps the chemical cross-linking site to cysteine-497 and localizes the binding site for the calpastatin-like peptide to this highly conserved region of domain III of calpains catalytic subunit.


The association between a Fatty Acid Binding Protein 1 (FABP1) gene polymorphism and serum lipid abnormalities in the MASHAD cohort study.
Dyslipidemia is a known risk factor for cardiovascular disease and is partially determined by genetic variations in the genes involved in lipoprotein metabolism. Therefore, we aimed to assess the association between a polymorphism of the Fatty Acid Binding Protein1 (rs2241883) gene locus and dyslipidemia in an Iranian cohort. This is a case-control study 2737 individuals were recruited (2203 subjects with dyslipidemia and 534 controls). Dyslipidemia was defined as total cholesterol≥200 mg/dl, or TG≥150 mg/dl, or LDL-C≥130 mg/dl, or HDL-C<40 mg/dl in males and <50 mg/dl in females. Serum lipid profile was determined using a Alcyon Abbott biochemical auto analyzer, USA. Genotyping was made through double amplification refractory mutation system polymerase chain reaction (ARMs PCR). The frequency of TT, CT, CC genotypes of rs2241883 polymorphism of FABP1 gene were 65.5, 33.4, 5.1 in subjects with dyslipidemia and 56.9%, 40.4%, 2.6% in subjects without dyslipidemia, respectively. Using a dominant genetic model, subjects carrying C allele (CC&CT genotypes) had a 22% lower risk of dyslipidemia (OR: 0.78, CI 95%: 0.62-0.98 P, 0.03). Individuals with CT vs. TT genotypes had a significantly lower risk of a high serum TC and LDL level. Further analysis showed that there was a positive association between FABP1 genotype (CT) and isolated HTG as well as combined dyslipidemia. The change of a polar amino acid (threonine) in position T94A to a hydrophobic amino acid (alanine) can cause transformation protein. A CC genotype of the rs2241883 polymorphism of the FABP1 gene appears to confer a higher risk of dyslipidemia in our representative cohort of Iranian individuals.


Self-Managed Medication Abortion: Implications for Clinical Practice.
Medication abortion represents more than 50 percent of abortions in the United States (US). Since its approval in the US in 2000, the Food and Drug Administration (FDA) has progressively relaxed the prescribing requirements such that currently, no office visit, in-person dispensing, or ultrasound is required. Obtaining medication for abortion online without medical supervision or evaluation is also possible. This article reviews the complications of medication abortion by examining major studies and delineates the risks specific to self-managed abortion to inform clinicians in caring for women. Medication abortion has become the most common abortion method in the United States. This document provides a detailed history of the relaxation requirements on medication abortion and reviews the major studies on medication abortion complications including a discussion of their limitations. Finally, the paper delineates the ease of access to medication abortion without a health care provider and the risks associated with self-managed abortion. This paper is intended to provide information for clinicians who likely will be encountering increasing number of patients with such complications.


Major adverse cardiovascular events and mortality with opioids versus NSAIDs initiation in patients with rheumatoid arthritis.
Assess major adverse cardiovascular event (MACE) risk with opioids compared with non-steroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA) METHODS: We conducted a new-user active comparator cohort study among patients with RA within FORWARD, The National Databank for Rheumatic Diseases, with ≥1 year participation between 1998 and 2021. Each opioid initiator was matched to two NSAID initiators by propensity scores (PSs). Patients were followed until the occurrence of the composite endpoint of MACE (myocardial infarction, stroke, heart failure, cardiovascular disease (CVD) death, venous thromboembolism (VTE)) and all-cause mortality. The risk of outcomes was estimated using Cox proportional hazards with adjustment for PS weights and imbalanced covariables. Among 6866 opioid initiators and 13 689 NSAID initiators, 212 vs 253 MACE (20.6/1000 person-years (PY) vs 18.9/1000 PY) and 144 vs 150 deaths (13.5/1000 PY vs 10.8/1000 PY) occurred, respectively. The risk of MACE with opioids was similar to NSAIDs (HR=1.02, 95% CI 0.85 to 1.22), whereas all-cause mortality with opioids was 33% higher than NSAIDs (HR=1.33, 95% CI 1.06 to 1.67) in PS-weighted models. Among the individual outcomes of MACE, VTE risk tended to be higher in opioid initiators than NSAID initiators (HR=1.41, 95% CI 0.84 to 2.35). Strong opioids had a higher risk for all-cause mortality and VTE than weak opioids compared with NSAIDs suggesting a dose-dependent association. Opioids had similar MACE risk compared with NSAIDs in patients with RA with increased all-cause mortality and likely VTE, which suggests that opioids are not safer than NSAIDs, as clinicians have perceived.


Multislice CT angiography in the selection of patients with ruptured intracranial aneurysms suitable for clipping or coiling.
We sought to establish whether CT angiography (CTA) can be applied to the planning and performance of clipping or coiling in ruptured intracranial aneurysms without recourse to intraarterial digital subtraction angiography (IA-DSA). Over the period April 2003 to January 2006 in all patients presenting with a subarachnoid haemorrhage CTA was performed primarily. If CTA demonstrated an aneurysm, coiling or clipping was undertaken. IA-DSA was limited to patients with negative or inconclusive CTA findings. We compared CTA images with findings at surgery or coiling in patients with positive CTA findings and in patients with negative and inconclusive findings in whom IA-DSA had been performed. In this study, 224 consecutive patients (mean age 52.7 years, 135 women) were included. In 133 patients (59%) CTA demonstrated an aneurysm, and CTA was followed directly by neurosurgical (n = 55) or endovascular treatment (n = 78). In 31 patients (14%) CTA findings were categorized as inconclusive, and in 60 (27%) CTA findings were negative. One patient received surgical treatment on the basis of false-positive CTA findings. In 17 patients in whom CTA findings were inconclusive, IA-DSA provided further diagnostic information required for correct patient selection for any therapy. Five ruptured aneurysms in patients with a nonperimesencephalic SAH were negative on CTA, and four of these were also false-negative on IA-DSA. On a patient basis the positive predictive value, negative predictive value, sensitivity, specificity and accuracy of CTA for symptomatic aneurysms were 99%, 90%, 96%, 98% and 96%, respectively. CTA should be used as the first diagnostic modality in the selection of patients for surgical or endovascular treatment of ruptured intracranial aneurysms. If CTA renders inconclusive results, IA-DSA should be performed. With negative CTA results the complementary value of IA-DSA is marginal. IA-DSA is not needed in patients with negative CTA and classic perimesencephalic SAH. Repeat IA-DSA or CTA should still be performed in patients with a nonperimesencephalic SAH.


Novel axial dynamic mechanical analysis setup for thermo-analytical study and curing kinetics optimization of thermoset adhesives.
Thermo-analytical studies of thermoset adhesives, either during research and development or in quality assurance activities, involve the application of various analytical equipment for adhesive characterization, from initial mixing to final product decomposition. Gelation is usually measured with rheometers or dynamic mechanical analyzers (DMAs); curing, post-curing, and curing kinetics are often studied using differential scanning calorimetry (DSC). Glass transition temperature (Tg) is measured via DSC or DMA, and finally, thermal decomposition measurements are done using thermal gravimetric analysis. Here, we present a new curing kinetics optimization module (C-KOM), an extension to an axial DMA, and a protocol for its usage, which combines elements from all of the above thermo-analytical techniques into one tool. As a case study, we apply C-KOM to investigate the effect of the curing temperature on the physical properties of an epoxy adhesive including gelation and end of cure points as well as its Tg. The data collected via C-KOM were used to extract the adhesive's curing reaction rates and its activation energy. Our research allowed us to compare and evaluate previously suggested curing procedures and assess their validity. As a final step, the thermal decomposition temperature of the epoxy adhesive was also identified via C-KOM. The newly suggested C-KOM setup provides a fast path toward characterization and optimization of the curing processes of thermoset materials in a way that was not available before.


[Anthropology of the father role].
The anthropological basic characteristics of the "father role" are presented by means of biological and early cultural aspects. The "father role" in its origin arose from mothercentered groups. For them only the "social fatherhood" was of any importance. The female primary groups accepted that man as being "the father" who could provide maximum protection for mother and children. It was not until the post ice-age extinction of many wild animals and the transition to owning of domestic animals--the capital of the shepherds--that patriarchy did develop. Now the "biological fatherhood" as a means of controlling female fertility changed to be the focal point within euroasian cultures.


Emergency Preparedness and Modish Practices among Primary Healthcare Delivery Systems Facilitated through Public-private Partnership Models in a South Indian Metropolitan City: A Descriptive Cross-sectional Study.
Access to health care is supposed to be a basic human right but the present scenario of the healthcare sector in India displays a large disparity in the healthcare services provided by the public and private sectors with wide variations in the infrastructure and services delivered by both sectors. Hence, public-private partnership (PPP) in healthcare delivery is an urgent and essential component that needs attention to ameliorate this gap. The aim of this study was to assess the current practices in healthcare services provided through PPPs in Bengaluru city. A cross-sectional questionnaire survey was conducted among primary healthcare centers (PHC) run under PPP in Bengaluru city, Karnataka, India. The pretested self-designed structured questionnaire consisted of 18 items regarding the current practices of PPP at the primary healthcare level. Descriptive statistics were used to describe the data. A total of 15 PPPs at the primary healthcare level were identified and included in the study. All of the participants provided basic healthcare services, some participants (33%) provided specialized services, and some (27%) mobile healthcare services. The overall impression of the medical officers in charge interviewed was that PPPs are better than individual endeavors by both public and private sectors. They also believed that it was important to have policies and guidelines in place to monitors aspects like the functioning of the setup, risk sharing, etc. The results indicated that all the participants were at the primary healthcare level and mostly involved in preventive practices. It is also important to look at venturing into services that provide curative services as well. Oral health, however, did not prominently feature at any point and is another area that requires attention. Mukherji I, Eshwar S, Srivastava BK, et al. Emergency Preparedness and Modish Practices among Primary Healthcare Delivery Systems Facilitated through Public-private Partnership Models in a South Indian Metropolitan City: A Descriptive Cross-sectional Study. Int J Clin Pediatr Dent 2022;15(2):153-158.


The role of biofilms in persistent infections and factors involved in ica-independent biofilm development and gene regulation in Staphylococcus aureus.
Staphylococcus aureus biofilms represent a unique micro-environment that directly contribute to the bacterial fitness within hospital settings. The accumulation of this structure on implanted medical devices has frequently caused the development of persistent and chronic S. aureus-associated infections, which represent an important social and economic burden worldwide. ica-independent biofilms are composed of an assortment of bacterial products and modulated by a multifaceted and overlapping regulatory network; therefore, biofilm composition can vary among S. aureus strains. In the microniches formed by biofilms-produced by a number of bacterial species and composed by different structural components-drug refractory cell subpopulations with distinct physiological characteristics can emerge and result in therapeutic failures in patients with recalcitrant bacterial infections. In this review, we highlight the importance of biofilms in the development of persistence and chronicity in some S. aureus diseases, the main molecules associated with ica-independent biofilm development and the regulatory mechanisms that modulate ica-independent biofilm production, accumulation, and dispersion.


The influence of behavioral factors on the daily variation of blood pressure.
Blood pressure (BP) changes continually throughout the day and night in response to changes in activity and in the environment. Behavioral influences include posture, physical and mental activity, and emotional state. The absolute magnitude of these influences may show consistent differences according to demographic factors such as gender and environment (eg, at work or at home). Occupational stress appears to have a greater effect on the BP in men than in women, while domestic stress (eg, the number of children) influences BP more in women. Ambulatory BP recordings should be interpreted according to the behavioral setting in which they are made.


Elevating mothers' voices: recommendations for improved patient-centered postpartum.
The weeks and months after birth are vital not only for infant health but also for the health and well-being of women and families as a whole. The first 12 weeks postpartum, also known as the 4th trimester, is part of a continuum of pregnancy to recovery and family adjustment. In the United States, this transitional period has been a neglected area for women's health, especially considering the inherent biological, physical, and social changes experienced by millions of women each year. The Patient-Centered Outcomes Research Institute supported the 4th Trimester Project to partner with new mothers, health care providers, and health advocates to better describe and understand unmet maternal postpartum health needs. Through woman-centered engagement, the patient-researcher-clinician-advocate team co-developed priority areas for research, policy, communication, and health care service delivery.


[Acid fog: hygiene and health observations correlated with an aspect of atmospheric pollution].
In the last years the interest about acid depositions has been shifted to heterogeneous phase reactions and, particularly, to occult precipitations (fog, mist, ecc.). It is very improbable that some kind of human health hazards could derive from acid rain exposure. Instead, the human exposure to acid fog could represent a possible respiratory vehicle for the assumption of acid pollutants as well as of many other pollutants. This last assertion can be supported by the following considerations: 1) Fog may represent an important chemical reactor that can modify the nature of pollutant material in the atmosphere (acidification and other events). 2) Fog is formed near the ground where pollution sources are located so that pollution is the heaviest. The fog water droplets coalesce around preexisting aerosol which is most highly concentrated near the ground (cities and industrial areas). Since fog water droplets contain muc less water than rain drops, they do not dilute the acidity as much as rain. 3) Finally, fog is partially inhalable. In certain areas of the world, wet deposition by fog can be important to the human health, even if the acqueous concentrations of fog droplets, the acidity per volume of air and the acid deposition rate are all important factors to consider. Particularly the pH of fog does not tell the whole story, but it represents a sufficient information about the severity of the atmospheric situation that can be correlated to seriousness of human risk.


Soft haptic sensation increases the expectation in the social context but not in the non-social context.
Previous studies have proposed that holding soft objects can increase expectations to be included in a Cyberball task. The present study investigated whether effects of holding soft objects on expectations are restricted to social contexts or can appear in non-social contexts. Sixty-six participants performed a social or non-social ball task, both modified versions of the Cyberball task. In the social ball task, participants were told that they would play a ball-tossing game with computer-generated players. In the non-social ball task, participants were told that they would take part in a judgement task. During the task, participants held either soft or hard cushions, and their electroencephalographic signals were recorded to evaluate the contingent negative variation (CNV), which is considered to reflect expectation and anticipation of an imperative stimulus. The results showed that participants who performed the social ball task exhibited larger late CNV when they held the soft cushion compared to when they held the hard cushion, whereas participants who performed the non-social ball task exhibited no such difference. The results indicate that holding soft objects increases expectations to be included only in social contexts.


Silicon carbide X-ray beam position monitors for synchrotron applications.
In this work, the performance of thin silicon carbide membranes as material for radiation hard X-ray beam position monitors (XBPMs) is investigated. Thermal and electrical behavior of XBPMs made from thin silicon carbide membranes and single-crystal diamond is compared using finite-element simulations. Fabricated silicon carbide devices are also compared with a 12 µm commercial polycrystalline diamond XBPM at the Swiss Light Source at the Paul Scherrer Institute. Results show that silicon carbide devices can reach equivalent transparencies while showing improved linearity, dynamics and signal-to-noise ratio compared with commercial polycrystalline diamond XBPMs. Given the obtained results and availability of electronic-grade epitaxies on up to 6 inch wafers, it is expected that silicon carbide can substitute for diamond in most beam monitoring applications, whereas diamond, owing to its lower absorption, could remain the material of choice in cases of extreme X-ray power densities, such as pink and white beams.


Ultrastructural organization of obliquely striated muscle fibers in Ascaris lumbricoides.
The somatic musculature of the nematode, Ascaris, is currently thought to consist of smooth muscle fibers, which contain intracellular supporting fibrils arranged in a regular pattern. Electron microscopic examination shows that the muscle fibers are, in fact, comparable to the striated muscles of vertebrates in that they contain interdigitating arrays of thick and thin myofilaments which form H, A, and I bands. In the A bands each thick filament is surrounded by about 10 to 12 thin filaments. The earlier confusion about the classification of this muscle probably arose from the fact that in one longitudinal plane the myofilaments are markedly staggered and, as a result, the striations in that plane of section are not transverse but oblique, forming an angle of only about 6 degrees with the filament axis. The apparent direction of the striations changes with the plane of the section and may vary all the way from radial to longitudinal. A three-dimensional model is proposed which accounts for the appearance of this muscle in various planes. Z lines as such are absent but are replaced by smaller, less orderly, counterpart "Z bundles" to which thin filaments attach. These bundles are closely associated with fibrillar dense bodies and with deep infoldings of the plasma membrane. The invaginations of the plasma membrane together with intracellular, flattened, membranous cisternae form dyads and triads. It is suggested that these complexes, which also occur at the cell surface, may constitute strategically located, low-impedance patches through which local currents are channeled selectively.


The influence of imatinib mesylate (STI571) used alone or in combination with purine nucleoside analogues on the normal and chronic myelogenous leukaemia progenitor cells in vitro.
Imatinib mesylate (STI571, Glivec), a signal transduction inhibitor used as a single agent demonstrates significant activity in patients with chronic myelogenous leukaemia (CML). Nevertheless, the interaction between STI571 and other antileukaemic drugs such as hydroxyurea, interferon alpha or cytarabine have also been investigated in order to further improve its effectiveness. In this study we have tried to answer the question if the combination of STI571 with purine nucleoside analogues (PNAs)- cladribine (2-CdA) and fludarabine (F-ara-A) intensifies the antiproliferative effect on granulocyte-macrophage progenitor cells (CFU-GM) from patients with CML as well as from normal persons. Our studies were based on the method of semisolid CFU-GM cultures in vitro. We added STI571 or PNAs singly to the culture, each of the drugs at three concentrations, as well as in combinations of the concentrations used. We showed that STI571 (0.5, 1.0 and 2.0 microM) used alone inhibited the colony growth of CML CFU-GM, as compared to CFU-GM derived from normal donors (p = 0.03; p = 0.0004; p = 0.0001). We also observed that STI571 used together with 2-CdA (5,10 and 20 microM) or F-ara-A (0.2, 0.4 and 0.8 microM) at all the combinations significantly inhibited the colony growth of CML CFU-GM, as compared either to the control or to STI571 used alone (p < 0.05). In addition, the differences between CML and normal CFU-GM colony growth inhibition after the use of the combination of the highest concentrations of STI571 either with 2-CdA or F-ara-A were statistically significant (p = 0.03 and p = 0.01, respectively). In conclusion, STI571 used together with both the PNAs had an additive effect on CML CFU-GM cells. However, further experimental and clinical studies concerning the usefulness of these combinations in the treatment of CML patients seem warranted.


Characterization of TauC3 antibody and demonstration of its potential to block tau propagation.
The spread of neurofibrillary tangle (NFT) pathology through the human brain is a hallmark of Alzheimer's disease (AD), which is thought to be caused by the propagation of "seeding" competent soluble misfolded tau. "TauC3", a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW) protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.


Hepatic iron concentration does not influence response to therapy with interferon plus ribavirin in chronic HCV infection.
In patients with chronic hepatitis C, prior studies have suggested that increased hepatic iron concentration (HIC) is predictive of a poor response to interferon (IFN) monotherapy. The aim of this study was to assess the importance of HIC on the virologic response to therapy with IFN alone or when combined with ribavirin. Records of 91 patients were reviewed for inclusion in this study. Fifty-one received IFN alone, and 40 received IFN plus ribavirin. HIC and serum iron studies, alanine aminotransferase (ALT) values, hepatitis C virus (HCV) genotype, and HCV RNA were determined prior to therapy. Sustained response was defined as the absence of HCV RNA 6 months after the end of therapy. In the IFN monotherapy group, mean HIC was higher for nonresponders (803 + 89 microg/g, range 130-2808 microg/g) compared with sustained responders (241 + 54 micro g/g, range 187-295 microg/g) (p < 0.01). In contrast, in the combination therapy group, the mean HIC was similar for both groups (533 + 86 microg/g, range 79-1338 microg/g in the nonresponders, and 662 + 95 microg/g, range 94-2031 microg/g, in the sustained responders). No difference between transferrin saturation and serum ferritin level was observed in sustained responder or nonresponder patients treated with IFN plus ribavirin. IFN monotherapy nonresponder patients tended to have a higher HIC. With IFN plus ribavirin, the sustained virologic response rate was not affected by the HIC.


Beryllium and boron decoration forms planar tetracoordinate carbon strips at the edge of graphene nanoribbons.
Graphene has been viewed as one of the most promising materials in many fields. Recently, it has been found that by using Cu-decoration at the edge of zigzag graphene nanoribbons (ZGNR), a novel kind of planar tetracoordinate carbon (ptC) strip can be formed. In this paper, we investigate the edge-decoration of armchair graphene nanoribbons (AGNR) by various atom types and find that two new kinds of ptC strip can be effectively formed by using Be or B decoration. For the Be-decorated AGNR, the edge Be atoms take the form of a "zigzag-like" chain, and all the edge C atoms have a ptC nature. However, for the B-decorated AGNR, the edge B atoms form an infinite yet "fractured" chain consisting of separate B(4)-subunits, which results in only 50% of the edge C atoms being ptCs, in contrast with Be-decorated AGNR and Cu-decorated ZGNR. The high thermal stability of both types of ptC-based AGNR is indicated by isomeric sampling and molecular dynamics simulations.


Health impact assessment of auto rickshaw and cab drivers due to exposure to vehicular pollution in Delhi: an integrated approach.
Vehicular emission is an important contributor to air pollution in the urban environment and impacts the health of commuters as well as drivers. The in-vehicle concentration of pollutants is known to be higher than the ambient environment and varies with the mode of transport. Thus, this study attempts to assess the health impacts of air pollution exposure on auto rickshaws and cab drivers. The study was conducted in Delhi using a triangular approach involving a health perception survey, lung function test and in-vehicle monitoring of particulate matter (PM1, PM2.5, PM10) concentration to assess the health impacts of air pollution on auto rickshaw and cab drivers. A total of 150 respondents (75 from each occupation) were surveyed, and spirometry was performed for 40 respondents (20 from each occupation). Binary logistic regression showed auto rickshaw drivers were exposed to significantly higher in-vehicle PM concentrations in summers and winters and, thus, had a significantly higher risk of developing respiratory, ophthalmic and dermatological health symptoms (p< 0.05 and relative risk >1). Pulmonary function test showed obstructive lung impairment was reported only among auto rickshaw drivers (6%) and restrictive lung impairment was also more prevalent among auto rickshaw drivers (48%) than cab drivers (33%), suggesting a greater vulnerability of auto rickshaw drivers to respiratory health issues. Lung function impairment was associated with age (p= 0.002). The health and well-being of individuals is a matter of global concern, also highlighted in sustainable development goal no. 3. However, it was observed that neither auto rickshaw drivers nor cab drivers used formal/standard protective measures mainly due to unawareness or unaffordability. The study suggests increasing awareness and formulating guidelines to highlight the use of proper protective measures by these vulnerable groups and specific policy measures to protect outdoor workers like auto rickshaw drivers.


Intracorporeal Esophagojejunostomy during Reduced-port Totally Robotic Gastrectomy for Proximal Gastric Cancer: a Novel Application of the Single-Site® Plus 2-port System.
Intracorporeal esophagojejunostomy during reduced-port gastrectomy for proximal gastric cancer is a technically challenging technique. No study has yet reported a robotic technique for anastomosis. Therefore, to address this gap, we describe our reduced-port technique and the short-term outcomes of intracorporeal esophagojejunostomy. We conducted a retrospective review of patients who underwent a totally robotic reduced-port total or proximal gastrectomy between August 2016 and March 2020. We used an infra-umbilical Single-Site® port with two additional ports on both sides of the abdomen. To transect the esophagus, a 45-mm endolinear stapler was inserted via the right abdominal port. The common channel of the esophagojejunostomy was created between the apertures in the esophagus and proximal jejunum using a 45-mm linear stapler. The entry hole was closed with a 45-mm linear stapler or robot-sewn continuous suture. All anastomoses were performed without the aid of an assistant or placement of stay sutures. Among the 40 patients, there were no conversions to open, laparoscopic, or conventional 5-port robotic surgery. The median operation time and blood loss were 254 min and 50 mL, respectively. The median number of retrieved lymph nodes was 40.5. The median time to first flatus, soft diet intake, and length of hospital stay were 3, 5, and 7 days, respectively. Three (7.5%) major complications, including two anastomosis-related complications and a case of small bowel obstruction, were treated with an endoscopic procedure and re-operation, respectively. No mortality occurred during the study period. Intracorporeal esophagojejunostomy during reduced-port gastrectomy can be safely performed and is feasible with acceptable surgical outcomes.


Hemoglobin and mean platelet volume predicts diffuse T1-MRI white matter volume decrease in sickle cell disease patients.
Sickle cell disease (SCD) is a life-threatening genetic condition. Patients suffer from chronic systemic and cerebral vascular disease that leads to early and cumulative neurological damage. Few studies have quantified the effects of this disease on brain morphometry and even fewer efforts have been devoted to older patients despite the progressive nature of the disease. This study quantifies global and regional brain volumes in adolescent and young adult patients with SCD and racially matched controls with the aim of distinguishing between age related changes associated with normal brain maturation and damage from sickle cell disease. T1 weighted images were acquired on 33 clinically asymptomatic SCD patients (age = 21.3 ± 7.8; F = 18, M = 15) and 32 racially matched control subjects (age = 24.4 ± 7.5; F = 22, M = 10). Exclusion criteria included pregnancy, previous overt stroke, acute chest, or pain crisis hospitalization within one month. All brain volume comparisons were corrected for age and sex. Globally, grey matter volume was not different but white matter volume was 8.1% lower (p = 0.0056) in the right hemisphere and 6.8% (p = 0.0068) in the left hemisphere in SCD patients compared with controls. Multivariate analysis retained hemoglobin (β = 0.33; p = 0.0036), sex (β = 0.35; p = 0.0017) and mean platelet volume (β = 0.27; p = 0.016) as significant factors in the final prediction model for white matter volume for a combined r2 of 0.37 (p < 0.0001). Lower white matter volume was confined to phylogenetically younger brain regions in the anterior and middle cerebral artery distributions. Our findings suggest that there are diffuse white matter abnormalities in SCD patients, especially in the frontal, parietal and temporal lobes, that are associated with low hemoglobin levels and mean platelet volume. The pattern of brain loss suggests chronic microvascular insufficiency and tissue hypoxia as the causal mechanism. However, longitudinal studies of global and regional brain morphometry can help us give further insights on the pathophysiology of SCD in the brain.


A quantitative determination of free radicals and strand breaks in pure and radiosensitized DNA.
The yields of free radicals and of single strand breaks were studied quantitatively after gamma-irradiation at 77 K of solid calf thymus DNA without and with incorporated misonidazole. At 77 K the rate of formation of the free radicals (the nature of which had been previously elucidated in oriented DNA samples) was found to be 1.7 x 10 (-12) and 2.4 x 10 (-12) per rad per dalton for DNA without and with misonidazole, respectively. The corresponding yield of single strand breaks in samples thawed and dissolved before alkaline sucrose gradient ultracentrifugation was found to be 1.2 x 10(-13) per rad per dalton, not significantly (within 30%) different for DNA without and with misonidazole. The significant quantitative difference between induction of free radicals and single strand breaks shows that there is no simple relation between the appearance of the two types of lesions.


Identification of novel cystinuria mutations and polymorphisms in SLC3A1 and SLC7A9 genes: absence of SLC7A10 gene mutations in cystinuric patients.
Cystinuria represents 3% of nephrolithiasis in humans with an overall prevalence of 1 in 7,000 neonates. Two genes have been reported to account for the genetic basis of cystinuria, the SLC3A1 and the SLC7A9. Recently, the possible involvement of the SLC7A10 gene in the genetic basis of the disorder was also reported. In the present study, we found a total of 15 mutations in 20 Greek cystinuric patients. Eight mutations are novel, 4 in the SLC3A1: F266S, T351I, R456C, and N516D, and 4 in the SLC7A9: 479-1G>C, Y232C, D233E, and 1399+1G>T. Furthermore, 2 polymorphisms were identified in the SLC3A1 gene and 16 polymorphic variants were also found in the SLC7A9 gene of which the 235+18C>A, 604+10G>A, and 604+24T>C are novel. Finally, no mutation was found in the SLC7A10 gene in all patients. Only, the novel 634+8C>G and the previously reported 913-11C+T polymorphisms were identified in the SLC7A10 gene. In conclusion, a spectrum of SLC3A1 and SLC7A9 mutations are responsible for the genetic basis of cystinuria in Greek patients.


Sexual Competitiveness of Anastrepha ludens (Diptera: Tephritidae) Males Exposed to Citrus aurantium and Citrus paradisi Essential Oils.
Males of the Mediterranean fruit fly (Ceratitis capitata (Wiedemann)) display increased mating competitiveness following exposure to the odor of certain host and nonhost plants, and this phenomenon has been used in the sterile insect technique to boost the mating success of released, sterile males. Here, we aimed to establish whether males of the Mexican fruit fly (Anastrepha ludens (Loew)) gain a mating advantage when exposed to the aroma of two preferred hosts, grapefruit (Citrus paradisi Macfadyen) and bitter orange (Citrus aurantium L.). Under seminatural conditions, we observed that, in trials using wildish males (from a young laboratory colony started with wild flies) exclusively, exposure to the aroma of bitter orange had no effect on male mating success but exposure to the odor grapefruit oil increased male mating success significantly. In a separate test involving both exposed and nonexposed wildish and mass-reared, sterile males, although wildish males were clearly more competitive than sterile males, exposure to grapefruit oil had no detectable effect on either male type. Exposure to oils had no effect on copulation duration in any of the experiments. We discuss the possibility that the positive effect of grapefruit essential oils on wildish male competitiveness may have been linked to exposure of females to grapefruit as a larval food, which may have imprinted them with grapefruit odors during pupal eclosion and biased their response as adults to odors of their maternal host.


The pharmacokinetics of chloroquine in healthy and Plasmodium chabaudi-infected mice: implications for chronotherapy.
The schizogony of malarial parasite is a typical cyclic phenomenon where the different stages of parasite development appear at regular time intervals. Each of the stages is specifically sensitive to different antimalarial drugs. Knowledge of the details of the cycle, drug susceptibility and the pharmacokinetics of drugs, could allow the improvement of drug action by the chronotherapeutic approach: treatment at the time of appearance of the drug sensitive stage with a drug that displays rapid pharmacokinetics. Since murine malarias serve as preferable models for in vivo drug testing, the pharmacokinetics of subcutaneously (sc) administered chloroquine (CQ) were tested in the whole blood of healthy mice and in animals slightly (1.5-3.5% parasitemia) or heavily infected (21-25% parasitemia) with Plasmodium chabaudi chabaudi. The half-time of absorption was around 5 min and almost independent of parasitemia. The apparent half-time of drug concentration decay was around 40 min in healthy animals, about 90 min at low parasitemia and about 410 min in heavy infection, indicating that the concentration of CQ is a typical spike, that is prolonged by asymptomatic disease, and considerably more by the active accumulation of CQ in infected cells. The latter is confirmed by the 3-fold higher peak blood [CQ] at the trophozoite stage and < 1.5-fold increase during schizogony. In conjunction with our previous experiments which showed that a single sc injection of 5 mg/kg CQ is sufficient to eliminate the drug susceptible mid-term trophozoite stage, the present results seem to justify to propose the chronotherapeutic approach for the treatment of malaria.


A Dynamic Cycle of Familial Mental Illness.
In this paper, we present A Dynamic Cycle of Familial Mental Illness; an innovative framework, which considers family members' experiences and responses to mental illness. There is an acknowledged discourse noting parental experiences of mental illness alongside a growing body of knowledge acknowledging children's needs while living with parental mental illness. However, there is a paucity of literature that makes reference to the concept of familial mental illness and the cyclic interface of parental and child distress and symptoms. The model is supported by published research studies from several differing disciplines to demonstrate the relationship between parent and child experiences and to synthesise the published short- and longer-term possible impact of familial mental illness. An extensive search of the literature using recognised search engines, keywords and phrases has been undertaken, to generate an appropriate literature base for this work. This literature demonstrates how a child's possible emotional distancing as a response to parental mental illness could increase parental distress. A Dynamic Cycle of Familial Mental Illness adopts the underpinning philosophy of a Stress Vulnerability Model of Mental Illness, which assumes that predisposing factors and increased stress for a parent may have possible links to exacerbation of parental mental distress and symptomology. We advocate for further research of familial mental illness, and argue for a family approach to mental health assessment and treatment in mainstream health and social care sectors.