Inductively powered wireless pacing via a miniature pacemaker and remote stimulation control system.
Pacemakers have existed for decades as a means to restore cardiac electrical rhythms. However, lead-related complications have remained a clinical challenge. While market-released leadless devices have addressed some of the issues, their pacer-integrated batteries cause new health risks and functional limitations. Inductive power transfer enables wireless powering of bioelectronic devices; however, Specific Absorption Rate and size limitations reduce power efficiency for biomedical applications. We designed a remote-controlled system in which power requirements were significantly reduced via intermittent power transfer to control stimulation intervals. In parallel, the cardiac component was miniaturized to facilitate intravascular deployment into the anterior cardiac vein. Given size constraints, efficiency was optimal via a circular receiver coil wrapped into a half-cylinder with a meandering tail. The pacemaker was epicardially tested in a euthanized pig at 60 beats per minute, 2 V amplitude, and 1 ms pulse width, restoring mean arterial pressure from 0 to 37 mmHg. Power consumption was 1 mW at a range of > 3 cm with no misalignment and at 2 cm with 45° displacement misalignment, 45° x-axis angular misalignment, or 45° y-axis angular misalignment. Thus, we demonstrated a remote-controlled miniaturized pacing system with low power consumption, thereby providing a basis for the next generation of wireless implantable devices.


An integrated materials approach to ultrapermeable and ultraselective CO2 polymer membranes.
Advances in membrane technologies that combine greatly improved carbon dioxide (CO2) separation efficacy with low costs, facile fabrication, feasible upscaling, and mechanical robustness are needed to help mitigate global climate change. We introduce a hybrid-integrated membrane strategy wherein a high-permeability thin film is chemically functionalized with a patchy CO2-philic grafted chain surface layer. A high-solubility mechanism enriches the concentration of CO2 in the surface layer hydrated by water vapor naturally present in target gas streams, followed by fast CO2 transport through a highly permeable (but low-selectivity) polymer substrate. Analytical methods confirm the existence of an amine surface layer. Integrated multilayer membranes prepared in this way are not diffusion limited and retain much of their high CO2 permeability, and their CO2 selectivity is concurrently increased in some cases by more than ~150-fold.


Past, present and future of Barrett's oesophagus.
Barrett's oesophagus is a condition which predisposes towards development of oesophageal adenocarcinoma, a highly lethal tumour which has been increasing in incidence in the Western world over the past three decades. There have been tremendous advances in the field of Barrett's oesophagus, not only in diagnostic modalities, but also in therapeutic strategies available to treat this premalignant disease. In this review, we discuss the past, present and future of Barrett's oesophagus. We describe the historical and new evolving diagnostic criteria of Barrett's oesophagus, while also comparing and contrasting the British Society of Gastroenterology guidelines, American College of Gastroenterology guidelines and International Benign Barrett's and CAncer Taskforce (BOBCAT) for Barrett's oesophagus. Advances in endoscopic modalities such as confocal and volumetric laser endomicroscopy, and a non-endoscopic sampling device, the Cytosponge, are described which could aid in identification of Barrett's oesophagus. With regards to therapy we review the evidence for the utility of endoscopic mucosal resection and radiofrequency ablation when coupled with better characterization of dysplasia. These endoscopic advances have transformed the management of Barrett's oesophagus from a primarily surgical disease into an endoscopically managed condition.


The moderating effect of resting heart rate variability on the relationship between internet addiction tendency and brain morphology.
Previous neuroimaging studies have investigated brain morphology associated with internet addiction tendency (IAT) in healthy subjects. However, whether resting vagally-mediated heart rate variability (HRV) exerting influences on the association of IAT and brain morphology remains unclear. This study used voxel-based morphometry (VBM) and multiple regression analyses to assess the interaction effect of IAT and resting vagally-mediated HRV on regional grey matter volumes in 82 healthy subjects. To further illustrate the observed interaction effect, the moderated hierarchical regression analysis was performed. The results showed that resting vagally-mediated HRV moderated the relationship between IAT scores and grey matter volume (GMV) in the precuneus and cerebellum. Specifically, individuals with higher resting vagally-mediated HRV showed a significant positive relationship between IAT scores and GMV in the precuneus, whereas individuals with lower resting vagally-mediated HRV showed a significant negative relationship between IAT scores and GMV in the precuneus. In addition, IAT scores were negatively correlated with GMV in the cerebellum among individuals with lower resting vagally-mediated HRV, but not among individuals with higher resting vagally-mediated HRV. These findings have demonstrated a moderating role of resting vagally-mediated HRV on the association of IAT and brain morphology.


Providing a Routine Medical Necessity Letter to Improve Access to Care for Our Patients.
This column explains the value of developing routine medical necessity letters to help patients maximize the likelihood of securing insurance approval for medically necessary services for the treatment of mental and substance use disorders, including psychotherapeutic treatment. The structure proposed for such medical necessity letters is based on the terms of the Mental Health Parity and Addiction Equity Act and the landmark verdict in the federal class action known as Wit v. United Behavioral Health/Optum.


[Sudden death from coronary disease in younger women (author's transl)].
Eleven sudden deaths from coronary disease were studied in women aged 29--44 years. These cases occured between 1971 and 1976 in the Institute for Forensic Medicine, University of Cologne, BRD. Postmortal morphological examinations resulted excessive stenosed coronary arteries caused by arteriosclerosis in all cases, in eight combined with acute obstructing thrombus. Our study group is not representative of the incidence of fatal coronary disease in the community. The prevailing conclusions about influence of sex hormones from oral contraceptives upon the development of arteriosclerosis, hypercoagulability and thrombosis demonstrate contrary evaluation. Our reflections about aetiology and pathogenesis from the pathomorphological findings don't substantiate a proof correlation between coronary disease or coronary thrombosis and oral contraceptions. Many other factors are equal important. The opinion of increased incidence and risk for death from coronary disease in users of oral hormonal contraceptions is not evident for us.


[Reducing the risk of radiation-induced cardiotoxicity in patients with left breast tumor].
Breast cancer is one of the most common malignancies affecting women. Treatment with drugs and radiotherapy increases the incidence of late cardiovascular disease. It is therefore particularly important to protect the heart from radiation exposure. We prepared an irradiation plan for 45 patients with left breast cancer using deep breathing and normal breathing techniques. The plans were compared and analyzed. The irradiation plans were created in the Philips Pinnacle v. 16 planning system. At the same target volume coverage, the use of the deep breathing technique leads to a reduction of the dose burden to the heart and to the left descending coronary branch, thus reducing the incidence of late cardiovascular complications. The results obtained show that the use of the deep breathing technique during adjuvant radiotherapy of left-sided breast cancer patients has a beneficial effect on the radiation exposure of the heart. Our results are in good agreement with similar data from national centres. We were not only able to maintain planning target volume coverage, but also to achieve an improvement of 1%. There is a significant difference in dose to the heart and coronary artery. By using the deep breathing technique, we were able to reduce the average cardiac dose by almost half (deep breathing: 2.87 Gy, normal breathing: 5.4 Gy). The coronary exposure was reduced from 19.5 Gy to 10.98 Gy. The accuracy of treatment can be further improved by using a respiratory gating system with a surface-guided radiotherapy system. The successful use of deep breathing technique requires professionalism of the treatment staff and good patient cooperation. It is less equipment intensive than a respiration-guided system. The deep breathing technique is no longer considered state-of-the-art in the era of breath-holding, but the experience gained in our department is worth describing because of its relevance to oncocardiology. Orv Hetil. 2023; 164(11): 420-425.


Saprochaete Capitata Peritonitis in a Non-neutropenic Patient Without Underlying Malignancies: A Case Report.
Saprochaete capitata (S. capitata) is an opportunistic arthroconidial yeast-like fungus causing invasive infections in immunocompromised patients, mainly those with hematological malignancies and severe neutropenia. However, infections due to S. capitata are extremely rare in immunocompetent and non-neutropenic patients. Saprochaete spp. are microscopically characterized by arthroconidia with hyaline-septated hyphae. S. capitata is known to be intrinsically resistant to echinocandins and highly resistant to fluconazole. It is suggested to use amphotericin B or voriconazole (in monotherapy or in combination) as the gold standard treatment for S. capitatasystemic infections. We report a rare case of S. capitata peritonitis with fatal outcome in a non-neutropenic patient without underlying malignancies. This case report highlights the value of direct microscopic examination and stained smears in a prompt preliminary diagnosis of S. capitata invasive fungal infections. We also aim to emphasize the importance of early initiation of appropriate antifungal treatment in patients with S. capitata systemic infections, thus improving their therapeutic outcome.


Mucosal dominant pemphigus vulgaris with anti-desmoplakin autoantibodies.
Anti-desmoplakin (DP) antibodies are present in paraneoplastic pemphigus (PNP) as a component of a complex humoral autoimmune reaction characterized by antibodies against proteins of the plakin family, desmogleins, and an unidentified 170 kd protein. Anti-DP antibodies have also been rarely identified in other blistering diseases. The significance of anti-DP antibodies in the pathogenesis of bullous diseases is unclear. We studied 3 patients with severe and chronic mucosal dominant pemphigus vulgaris (PV). In addition to anti-desmoglein 3 antibodies, these patients had anti-DP autoantibodies, demonstrable by immunofluorescence (IF), immunoprecipitation (IP), and indirect immunoelectromicroscopy (IIEM). This finding suggested these patients may have had PNP and not PV. However, antibodies against periplakin, envoplakin, bullous pemphigoid antigen 1 (BPAG 1), plectin, and 170 kd PNP antigen could not be detected using IP and immunoblotting. Extensive and repeated investigations for an underlying neoplasm throughout the follow-up period were consistently negative for all patients. This study demonstrates that anti-DP antibodies without the presence of any other anti-plakin antibodies are not specific for PNP, and are present in some cases of PV. Cellular disadhesion induced by anti-desmoglein antibodies can trigger an epitope-spreading phenomenon with a secondary formation of autoantibodies against desmoplakins, intracellular desmosomal antigens. The role of anti-DP antibodies in the pathogenesis of these PV patients is still unclear. The presence of anti-DP antibodies will produce a false positive serologic interpretation for the diagnosis of PNP especially if one uses only indirect IF on murine bladder, the most commonly employed screening test to identify PNP. More specific immunologic tests are required in this subset of patients with PV.


Synthesis and biological activity of unsaturated carboacyclic purine nucleoside analogues.
Two new carboacyclic nucleoside analogues, 9-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]adenine (6) and 9-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]guanine (5), modeled on the unsaturated carbocyclic nucleoside analogue neplanocin A (2), have been synthesized and tested for antiviral activity against HSV-2 and, in the case of 6, for activity against influenza and in vitro inhibition of S-adenosylhomocysteine hydrolase. The synthesis was accomplished through the coupling of either adenine or the guanine precursor 2-amino-6-chloropurine (15) to the key intermediate 1-(benzyloxy)-2-[(benzyloxy)methyl]-4-chloro-2-butene (13). Debenzylation of the N-9 adenine adduct gave 6 directly, while the product of the debenzylation of the N-9 adduct of 15 when treated with sodium hydroxide gave the guanine analogue 5. The carboacyclic guanine analogue (5) exhibited significant antiviral activity against HSV-2 (VR = 1.5, MIC50 = 65.6 micrograms/mL), a level of activity that is superior to that of ara-A but inferior to that of acyclovir. The adenine analogue 6 was active against HSV-2 only at a very high dose; it was devoid of antiviral activity against influenza type A2, and it lacked inhibitory activity against S-adenosylhomocysteine hydrolase.


Popliteal Vein Valve Transplantation for Deep Venous Valvular Incompetence.
Interest in deep venous reconstruction for severe chronic venous insufficiency (CVI) is burgeoning. Vein valve transplantation for deep venous valvular incompetence, an indirect method for correcting deep venous valvular incompetence achieves its physiologic benefits by placing a normal functioning valve harvested from the upper extremity into the deep system. By contrast, other authors in this volume have presented alternative forms of deep venous valvular reconstruction where the valve mechanism itself is directly repaired or a local segment of vein containing a functioning valve from the same anatomic area, such as the saphenous or profunda, is transposed into the deep venous circuit. Several factors influence the role of deep venous valvular surgery and its frequency. For example, the incidence of deep venous involvement in patients with advanced stage II or frank ulceration (stage III) is variable and depends upon patient selection process.


Navigating your course in medical practice administration. What MGMA member research says about your career.
Plotting your career as a medical practice management professional can be a lot like charting the course of a small boat on open waters: The environment may be glassy-smooth, choppy and rife with undercurrents, or even as tumultuous as a hurricane. But you can learn from the experiences of others who've navigated the same seas. The MGMA Center for Research studied the career paths of medical practice administrators, focusing on the positions held during a career, the time spent in each and the reasons for changing jobs. The data and administrators' comments provide a compelling portrait of your profession.


The t(15;17) translocation in acute promyelocytic leukemia.
Acute promyelocytic leukemia is characterized by a specific t(15;17) chromosomal translocation and a particular sensitivity to retinoic acid. The translocation fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene resulting in the production of a PML-RAR alpha fusion protein. The hybrid molecule retains most of the functional domains of both native products, PML and RAR alpha, but it has novel features. Its cellular distribution is completely reorganized when compared to that of PML: the hybrid is found in multiple small nuclear substructures and upon retinoic acid treatment, it goes back to the normal PML localization, that is in typical well organized nuclear bodies. PML-RAR alpha also acquires novel transcriptional properties if compared to RAR alpha, it does so either by direct binding to target gene regulatory sequences or by protein interaction with cofactors. Expression of PML-RAR alpha in HL60 or U937 cell has been shown to block their maturation while it can force their differentiation at high doses of retinoic acid. Different mechanisms are proposed to explain how PML-RAR alpha blocks differentiation and how this may be reversed by retinoic acid. A likely hypothesis might be the delocalization of critical cofactors into the aberrant PML-RAR alpha substructures while the therapeutic effect of retinoic acid would be correlated to its capacity to restore a normal nuclear organization.


Margins for translational and rotational uncertainties: a probability-based approach.
To define margins for systematic rotations and translations, based on known statistical distributions of these deviations. The confidence interval-based expansion method for translations, known as the "rolling ball algorithm," was extended to include rotations. This new method, which we call the Rotational and Translational Confidence Limit (RTCL) method, is exact for a point with arbitrary rotations and translations or for a finite shape with rotations only. The method was compared with two existing expansion methods: a rolling ball algorithm without rotations, and a convolution (blurring) method which included rotations. On the basis of these methods, planning target volumes (PTVs, expanded clinical target volumes [CTVs]) were constructed for a number of shapes (a sphere, a sphere with an extension, and three prostate cases), and evaluated in several ways by means of a Monte Carlo method. The accuracy of each method was measured by determining the probability of finding the CTV completely inside the PTV (P(CTVinPTV)), using parameters that yield a 90% probability for a sphere-shaped CTV without rotations. Furthermore, with the expansion parameters adjusted to give an equal P(CTVinPTV) for all methods, PTV volumes were compared. With the expansion algorithm parameters chosen to yield P(CTVinPTV) = 90% for a sphere, an average P(CTVinPTV) of 84%, 57%, and 46% was obtained for the other shapes, using the RTCL method, coverage probability, and rolling ball, respectively. With the parameters adjusted to yield an equal P(CTVinPTV) for all methods, the PTV volume was on average 8% larger for the coverage probability method and 15% larger for the rolling ball algorithm compared to the RTCL method. The RTCL method provides an accurate way to include the effects of systematic rotations in the margin. Compared to other algorithms, the method is less sensitive to the shape of the CTV, and, given a fixed probability of finding the CTV inside the PTV, a smaller PTV volume can be obtained.


Increase of specificity of RNase from Bacillus amyloliquefaciens (barnase) by substitution of Glu for Ser57 using site-directed mutagenesis.
Bacterial ribonucleases from Bacillus amyloliquefaciens and Bacillus intermedius show the specificity towards the nature of a nucleoside at the O3' end of the phosphodiester bond to be split in the preference order G > A >> U > C in the cleavage reactions of polynucleotides. It follows from the X-ray data that the substrate guanosine base is bound at the active site of these RNases in the same manner as for high-specificity guanylic RNases. We supposed that the difference in specificity for the two types of RNases is due to the additional hydrogen bond between the protein and a purine base in the case of bacterial guanyl-preferring RNases in contrast to the high-specificity guanylic RNases. To examine this hypothesis we prepared the Ser57 --> Glu mutant of B. amyloliquefaciens, in which this hydrogen bond is eliminated. Kinetic studies demonstrate that the specificity of this mutant towards guanylic substrates is 35-times greater than that of the wild-type RNases from B. amyloliquefaciens and close to that of RNases T1.


Screening silica-confined single-atom catalysts for nonoxidative conversion of methane.
The development of a single-atom iron catalyst (Fe©SiO2) for the direct conversion of methane to olefins, aromatics, and hydrogen is a breakthrough in the field of nonoxidative conversion of methane (NCM). However, the optimization of the catalyst remains desirable for industrial applications. Herein, 25 transition metals, including Sc, Ti, V, Cr, Mn, Co, Ni, Cu, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Hf, Ta, W, Re, Os, Ir, Pt, and Au, are selected to replace the central Fe atom for screening out better single-atom catalysts for the NCM. Using the performance on the activation of methane, such as the adsorption energy of methane, the dissociation energy, and the barrier of methane as the screening descriptors, Mn©SiO2, Fe©SiO2, W©SiO2, and Re©SiO2 are first screened out. The remarkable performance of the four catalysts on methane activation is attributed to the unique geometric structure and the dz 2 orbitals of the central metal crossing over the Fermi level, which can benefit the interaction between methane and the catalysts. By considering the catalytic performance on the whole pathway of methane to ethylene, W©SiO2 is finally selected as the most active catalyst for the NCM, which has the lowest rate-determining barrier of 1.62 eV and the smallest free energy span (1.06 eV) of the overall catalytic cycle.


Primary liposarcoma of the heart.
The author reports a case of a 64-year-old man, who presented with a 4-week history of dyspnoea and dizziness suffering from a large mass in the pericardium. CT of the chest showed a lobulated mass in the pericardial sac located between the pulmonary veins and the ascending aorta reaching the superior vena cava. The tumour was completely resected and histopathological analysis revealed the tumour to be a well-differentiated lipoma-like and focal sclerosing liposarcoma, which was composed predominantly of adipocytes with hyperchromatic nuclei and eosinophilic-to-vacuolated cytoplasm disrupted by fibrous septa. Two years after initial tumour diagnosis the patient is still alive without signs of tumour recurrence.


Margins Matter: current radiation therapy practice and future directions.
Commentary is provided in the context of current practices for calculating radiation therapy margins and future directions that will impact on this.


TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth.
Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197-specific neonatal CD4+ cells, activation of newborn and infant Streptococcus pneumoniae polysaccharide-specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10-100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development.


The nucleotide exchange rates of rho and rac small GTP-binding proteins are enhanced to different extents by their regulatory protein Smg GDS.
Rho p21 and rac p21 small GTP-binding proteins are regulated by the same inhibitory and stimulatory GDP/GTP exchange proteins termed rho GDI and smg GDS, respectively. RhoA p21 and rac1 p21 bind with similar affinities to rho GDI and both proteins also bind with similar affinities to smg GDS. RhoA p21 and rac1 p21 have similar GDP/GTP exchange rates in the absence of rho GDI and smg GDS. The velocity of the GDP/GTP exchange reaction for rhoA p21 was enhanced much more by smg GDS than was the velocity of nucleotide exchange for rac1 p21. In the presence and absence of smg GDS, rho GDI reduced the velocities of these nucleotide exchange reactions of rhoA p21 and rac1 p21 to similar extents. These results suggest that rhoA p21 is activated first followed by rac1 p21 activation in response to extracellular signals.


Photosynthesis limitations of grapevine after treatment with the fungicide fludioxonil.
The aim of this work was to determine the major limitations to photosynthesis induced by the fungicide fludioxonil (fdx) on nontarget grapevines using cutting as a model. The fdx treatments (1.2, 6, and 30 mM) induced a net photosynthetic rate ( P n) decrease without changes in stomatal conductance, suggesting a nonstomatal limitation. Fdx effects on P n were related neither to photosynthetic capacity alteration in leaves nor to loss in PSII activity. The mechanism underlying photosynthesis reduction differed according to the concentration. Fdx at 6 mM led to an increase of light requirement for photosynthesis while 30 mM fdx induced an increase in the respiration rate in the light. P n decrease after 1.2 mM fdx could rather be related to wetness caused by the spraying than to fungicide toxicity. P n recovered 10 days after treatment, meaning that fdx had little deleterious effect on plant physiology or that grapevine has a great capacity to overcome this temporary stress.


Repeat uterine artery embolization: indications and technical findings.
To determine the indications and technical aspects of procedures in patients undergoing repeat uterine artery embolization (UAE). At a single center, 24 patients underwent repeat embolization for recurrent or persistent symptoms. The magnetic resonance (MR) imaging findings before repeat embolization were compared with those of earlier studies. The extent of tumor infarction after the first procedure was determined, and the status of existing or new tumors before the second procedure was assessed. The angiographic studies from the initial and repeat embolization studies were reviewed and summarized. These findings were assessed with the use of summary statistics. Twenty-four patients underwent repeat embolization 6-66 months after the initial embolization. The most common symptom at representation was pressure and/or bulk symptoms (n=15), followed by recurrent heavy bleeding (n=12) and pelvic pain or cramping (n=7). MR imaging studies before repeat embolization revealed incomplete infarction of tumors present before the first embolization in 22 of 24 patients. New tumors were identified in 12 patients, two of whom had new tumors only. During repeat embolization, nine patients (37%) required ovarian artery embolization to occlude ovarian supply to the uterus. Among 21 women with clinical follow-up after the second embolization, 19 (90%) had symptom control. Repeat embolization prompted by recurrent uterine leiomyomas usually occurs in the setting of regrowth of incompletely infarcted tumors. Although ovarian embolization was often needed, on the basis of this limited experience, symptoms appear to respond well to repeat embolization.


[The effect of halothane and enflurane as well as of propanidid and ketamin on the aortic baroreceptor discharge of decerebrated cats (author's transl)].
The effect of halothane, enflurane, propanidid and ketamine on the sensitivity of the aortic baroreceptors and its quantitative relationship with arterial pressure were studied in decerebrated cats. Receptor response curves (single baroreceptor fibres of the depressor nerve) were constructed by plotting the average discharge rate (spikes/sec) against the aortic mean pressure and the effect of the anaesthetics on them was analysed. The blood pressure was changed over wide ranges by inflating a balloon placed in the thoracic part of the descending aorta through a femoral artery. Receptor sensitivity increased with halothane and enflurane, yet it decreased with propanidid. It remained uneffected duringanesthesia with ketamine. Thus, different anesthetics act differently on the afferent impulse traffic of baroreceptors. The possible role of these effects on blood pressure control during anaesthesia is discussed.


Nucleotide sequence of cDNA encoding the mitochondrial precursor protein of the ATPase inhibitor from the giant panda (Ailuropoda melanoleuca).
Mitochondrial ATP synthase (F1Fo-ATPase) is regulated by an intrinsic ATPase inhibitor protein. In the present study, using RT-PCR combined with in silico cloning, we isolated and sequenced the cDNA encoding the inhibitor protein of the giant panda (Ailuropoda melanoleuca). The deduced protein sequence showed that the protein is composed of 106 amino acids and the estimated molecular weight of the ATPIF(1) protein is 12.32 kDa with an isoelectric point (pI) of 10.17. Alignment analysis revealed that the deduced protein sequence shares 66%, 78.3%, 66%, 72.6%, 77.4%, and 78.3% homology with that of Mus musculus, Pan troglodytes, Rattus norvegicus, Bos taurus, Macaca mulatta, and Homo sapiens, respectively. Topology prediction showed that there are three protein kinase C phosphorylation sites, one amidation site, three N-myristoylation sites, one casein kinase II phosphorylation site, and one tyrosine kinase phosphorylation site in the ATPase inhibitor. In particular, amino acids in the region between 39 and 72, which is the minimum sequence showing ATPase inhibitory activity, were highly conserved in the protein.


Egg Cannibalism and its Life History Consequences Vary with Life Stage, Sex, and Reproductive Status in Hippodamia convergens (Coleoptera: Coccinellidae).
Egg cannibalism is common in Coccinellidae, but its biological consequences have not been fully explored. We examined egg cannibalism by neonates, fourth instars, and adults of Hippodamia convergens Guerin-Meneville for effects on development, reproduction, and progeny fitness. We also tested female adults for ability to avoid cannibalizing their own eggs and first-instar larvae, and both sexes for changes in cannibalism propensity following mating, all in the presence of ad libitum food [larvae: eggs of Ephestia kuehniella Zeller (Lepidoptera: Pyralidae), adults: Schizaphis graminum (Rondani)]. Cannibalism by neonates reduced developmental time and increased male body size. Cannibalism in the fourth instar accelerated pupation and led to the production of eggs that hatched faster, regardless of which parent cannibalized. However, egg fertility was improved only by maternal cannibalism in the fourth instar. Females recognized their own egg clusters, sometimes added eggs to them, and preferentially cannibalized nonfilial clusters. Most gravid females cannibalized a first-instar larva within 30 min, whether filial or not. Adult egg cannibalism was similar for virgin males and females, but declined after mating in males, and increased in females, although it had no effect on fecundity or fertility. Daughters of cannibal pairs were heavier than those of other mating combinations, but offspring of noncannibal parents had the fastest development. Reproductive females appeared to use egg cannibalism to reduce risk for their own eggs, increasing the number cannibalized with the number laid. Thus, egg cannibalism in coccinellids varies with life stage, sex, and reproductive condition, independent of food availability, and benefits are life stage specific.


Wld(S) reduces paraquat-induced cytotoxicity via SIRT1 in non-neuronal cells by attenuating the depletion of NAD.
Wld(S) is a fusion protein with NAD synthesis activity, and has been reported to protect axonal and synaptic compartments of neurons from various mechanical, genetic and chemical insults. However, whether Wld(S) can protect non-neuronal cells against toxic chemicals is largely unknown. Here we found that Wld(S) significantly reduced the cytotoxicity of bipyridylium herbicides paraquat and diquat in mouse embryonic fibroblasts, but had no effect on the cytotoxicity induced by chromium (VI), hydrogen peroxide, etoposide, tunicamycin or brefeldin A. Wld(S) also slowed down the death of mice induced by intraperitoneal injection of paraquat. Further studies demonstrated that Wld(S) markedly attenuated mitochondrial injury including disruption of mitochondrial membrane potential, structural damage and decline of ATP induced by paraquat. Disruption of the NAD synthesis activity of Wld(S) by an H112A or F116S point mutation resulted in loss of its protective function against paraquat-induced cell death. Furthermore, Wld(S) delayed the decrease of intracellular NAD levels induced by paraquat. Similarly, treatment with NAD or its precursor nicotinamide mononucleotide attenuated paraquat-induced cytotoxicity and decline of ATP and NAD levels. In addition, we showed that SIRT1 was required for both exogenous NAD and Wld(S)-mediated cellular protection against paraquat. These findings suggest that NAD and SIRT1 mediate the protective function of Wld(S) against the cytotoxicity induced by paraquat, which provides new clues for the mechanisms underlying the protective function of Wld(S) in both neuronal and non-neuronal cells, and implies that attenuation of NAD depletion may be effective to alleviate paraquat poisoning.


Counter-terrorism and humanitarian action: UK INGO responses since 2015.
There has been growing awareness in recent years of the wide-ranging negative impacts that counter-terrorism measures and sanctions impose on humanitarian action. Drawing on semi-structured interviews with the staff of international non-governmental organisations (INGOs), this paper examines these impacts on INGOs based in the United Kingdom. This is a context where a particularly complex array of laws, policies, and regulatory regimes have emerged alongside an increasingly hostile political and media setting for INGOs, creating an environment characterised by uncertainty. The paper shows that counter-terrorism measures and sanctions are leading INGOs to adopt more conservative approaches to partnership in areas controlled by proscribed groups, undermining broader commitments to the localisation agenda. The analysis reveals that perceptions of risk within INGOs vary considerably, but that despite this, INGOs have developed strategies to reduce the impacts of counter-terrorism measures, which over time, have led to improved coordination, and in some instances, a willingness to push back against regulations.


Sequential changes in intrarenal hemodynamics during saline infusion in the dog.
Intrarenal blood flow and volume (indicator-dilution technique), kidney volume (mercury-in-rubber resistance gage), intr-renal venous pressure, filtration fraction, and sodium excretion were determined dequentially before and during a l-h infusion of isotonicsaline 80 ml/kg in anesthetized dogs. The cortical fraction of renal blood flow roseduring the first 20 min of infusion from an average of 70 to 77%, butreturned nearly to control levels during the last 20 min of infusion because ofa low rise in noncortical flow. During the first 20 min a 23% increase in cortical blood volume accounted for one-third of the 8.5% increase in kidney volume, whereasin the last 20 min cortical blood volume had fallen nearly to control values and kidneyvolume was increased by 17.2%. Intrarenal resistances calculated from intrarenalpressure and flow indicated persistent cortical prevenous dilatation, progressive cortical venous constriction, and only a slight late reduction in noncortical resistance. These data indicate that hemodynamics are shanging continuously during saline infusion and the natriuresis probably is multifactorial.


Fibroblast growth factor receptor (FGFR) gene: pathogenesis and treatment implications in urothelial carcinoma of the bladder.
Dysregulation of fibroblast growth factor receptors (FGFRs) has been implicated in several human malignancies, including urothelial carcinoma. In urothelial carcinoma, the oncogenic role of mutated FGFR is mediated by the RAS-mitogen-activated protein kinase pathway, resembling the effects observed with activated HRAS Activating somatic mutations of FGFR3 are clustered in three hotspots in exons 7, 10 and 15, and are almost always missense mutations leading to amino acid substitution in the external, transmembrane or intracellular regions of the receptor. A fusion of FGFR3 to transforming acid coiled-coil containing protein 3, FGFR3 amplification and alternative splicing leading to aberrant FGFR3 activation are less common molecular alterations. In April 2020, the Food and Drug Administration (FDA) approved the first targeted FGFR therapy, erdafitinib, in patients with locally advanced or metastatic bladder cancer who have progressed on platinum-based chemotherapy. Herein, we reviewed the normal structure and function of FGFR We also explored its role in the development of urothelial carcinoma and major developments in the FGFR-targeted therapy.


Lexical methods for managing variation in biomedical terminologies.
Access to biomedical terminologies is hampered by the high degree of variability inherent in natural language terms and in the terminologies themselves. The lexicon, lexical programs, databases, and indexes included with the 1994 release of the UMLS Knowledge Sources are designed to help users manage this variability. We describe these resources and illustrate their flexibility and usefulness in providing enhanced access to data in the UMLS Metathesaurus.


Tandem field and laboratory approaches to quantify attenuation mechanisms of pharmaceutical and pharmaceutical transformation products in a wastewater effluent-dominated stream.
Evolving complex mixtures of pharmaceuticals and transformation products in effluent-dominated streams pose potential impacts to aquatic species; thus, understanding the attenuation dynamics in the field and characterizing the prominent attenuation mechanisms of pharmaceuticals and their transformation products (TPs) is critical for hazard assessments. Herein, we determined the attenuation dynamics and the associated prominent mechanisms of pharmaceuticals and their corresponding TPs via a combined long-term field study and controlled laboratory experiments. For the field study, we quantified spatiotemporal exposure concentrations of five pharmaceuticals and six associated TPs in a small, temperate-region effluent-dominated stream during baseflow conditions where the wastewater plant was the main source of pharmaceuticals. We selected four sites (upstream, at, and two progressively downstream from effluent discharge) and collected water samples at 16 time points (64 samples in total, approximately twice monthly, depending on flows) for 1 year. Concurrently, we conducted photolysis, sorption, and biodegradation batch tests under controlled conditions to determine the major attenuation mechanisms. We observed 10-fold greater attenuation rates in the field compared to batch tests, demonstrating that connecting laboratory batch tests with field measurements to enhance predictive power is a critical need. Batch systems alone, often used for assessment, are useful for determining fate processes but poorly approximate in-stream attenuation kinetics. Sorption was the dominant attenuation process (t1/2<7.7 d) for 5 of 11 compounds in the batch tests, while the other compounds (n = 6) persisted in the batch tests and along the 5.1 km stream reach. In-stream parent-to-product transformation was minimal. Differential attenuation contributed to the evolving pharmaceutical mixture and created changing exposure conditions with concomitant implications for aquatic and terrestrial biota. Tandem field and laboratory characterization can better inform modeling efforts for transport and risk assessments.


Metabolic reprogramming in breast cancer results in distinct mitochondrial bioenergetics between luminal and basal subtypes.
Mitochondrial dysfunction is a key feature of cancer and is frequently associated with increased aggressiveness and metastatic potential. Recent evidence has brought to light a metabolic rewiring that takes place during the epithelial-to-mesenchymal transition (EMT), a process that drives the invasive capability of malignant tumors, and highlights a mechanistic link between mitochondrial dysfunction and EMT that has been only partially investigated. In this study, we characterized mitochondrial function and bioenergetic status of cultured human breast cancer cell lines, including luminal-like and basal-like subtypes. Through a combination of biochemical and functional studies, we demonstrated that basal-like cell lines exhibit impaired, but not completely inactive, mitochondrial function, and rely on a consequent metabolic switch to glycolysis to support their ATP demand. These altered metabolic activities are linked to modifications of key electron transport chain proteins and a significant increase in levels of reactive oxygen species compared to luminal cells. Furthermore, we observed that the stable knockdown of EMT markers caused functional changes in mitochondria that result in acquisition of a hybrid glycolysis/OXPHOS phenotype in cancer cells as a means to sustain their metabolic demand.


Lead-induced cell death of human neuroblastoma cells involves GSH deprivation.
Lead (Pb2+) is a toxic heavy metal that has adverse effects on the health of humans and other animals. The developing central nervous system is especially sensitive and vulnerable to Pb2+ toxicity. In this study, the effects of low levels of Pb2+ exposure on human SH-SY5Y neuroblastoma cell cultures were assessed. The cells were exposed to Pb2+ (0.01 microM-10 microM) for 48 hrs, and the level of cell proliferation was determined. Pb2+ significantly inhibited the proliferation of neuroblastoma cells in a concentration-dependent manner. A 50% inhibition (IC50) in cellular proliferation was observed with 5 microM Pb2+. A significant decrease in the levels of glutathione (GSH), a critical intracellular antioxidant, was observed at all the lead concentrations. There was also a multifold increase in the activity of caspase-3, a key executioner of apoptosis, and in the levels of prostaglandin E2 (PGE2). Our results suggest that the neurotoxic effects of Pb may be mediated by apoptosis and PGE2 release, which could be potentially detrimental to neuronal survival.


Spectral and thermodynamic properties of a strong-leg quantum spin ladder.
The strong-leg S=1/2 Heisenberg spin ladder system (C(7)H(10)N)(2)CuBr(4) is investigated using density matrix renormalization group calculations, inelastic neutron scattering, and bulk magnetothermodynamic measurements. Measurements showed qualitative differences compared to the strong-rung case. A long-lived two-triplon bound state is confirmed to persist across most of the Brillouin zone in a zero field. In applied fields, in the Tomonaga-Luttinger spin-liquid phase, elementary excitations are attractive, rather than repulsive. In the presence of weak interladder interactions, the strong-leg system is considerably more prone to three-dimensional ordering.


Study of spectral-domain optical coherence tomography in children: normal values and influence of age, sex, and refractive status.
To establish normal values for retinal nerve fiber layer (RNFL), macular thickness, and macular volume in children using spectral-domain optical coherence tomography (OCT). A descriptive cross-sectional study was performed in healthy children between 3 and 14 years of age. Each child underwent a comprehensive ophthalmic examination that included 3 OCT scans with Spectralis (Heidelberg Engineering, Heidelberg, Germany). All measurements were performed by the same operator, and one eye was randomly selected. The influence of age, sex, and refraction on OCT measurements was analyzed. The sample consisted of 162 Caucasian subjects, mean age 8.1 ± 3.03 years. The spherical equivalent was 0.03 ± 0.19 D (range ±4 D, astigmatism <1 D). The average values were 263.69 ± 4.54 µm for central macular thickness, 0.21 ± 0.01 mm3 for central macular volume, and 100.45 ± 1.98 µm for RNFL. A significant correlation between RNFL and spherical equivalent was found for the nasal (p = 0.001), inferior (p = 0.009), and inferior nasal (p = 0.005) sectors. No differences were found with regard to sex (p>0.05). However, central macular thickness and central macular volume were correlated with age (p = 0.027, p = 0.02). This study provides reference values for macular thickness, macular volume, and RNFL in healthy children.


Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia.
Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.


Imaging of Heritable Thoracic Aortic Disease.
Heritable Thoracic Aortic Disease (HTAD) is caused by mutation of a gene that confers a high risk for thoracic aortic aneurysms and dissections. Syndromic HTAD are associated with systemic manifestations and include Marfan, Loeys-Dietz, vascular Ehlers Danlos and Turner Syndromes. The purpose of this review is to summarize the pathophysiology, cardiovascular imaging features and management of HTAD. Imaging plays an important role in screening for aortic dilatation and monitoring progression. Echocardiogram, Computed tomography and Magnetic resonance imaging are the commonly used modalities. Based on consensus guidelines, prophylactic aortic replacement is indicated when a certain threshold diameter is reached.


Agreement Between Self-Report and Medical Record Prevalence of 16 Chronic Conditions in the Alaska EARTH Study.
The gold standard for health information is the health record. Hospitalization and outpatient diagnoses provide health systems with data on which to project health costs and plan programmatic changes. Although health record information may be reliable and perceived as accurate, it may not include population-specific information and may exclude care provided outside a specific health care facility. Sole reliance on medical record information may lead to underutilization of health care services and inadequate assessment of population health status. In this study, we analyzed agreement, without assuming a gold standard, between self-reported and recorded chronic conditions in an American Indian/Alaska Native cohort. Self-reported health history was collected from 3821 adult participants of the Alaska EARTH study during 2004-2006. Participant medical records were electronically accessed and reviewed. Self-reported chronic conditions were underreported in relation to the medical record and both information sources reported the absence more reliably than the presence of conditions (across conditions, median positive predictive value = 64%, median negative predictive value = 94%). Agreement was affected by age, gender, and education. Differences between participant- and provider-based prevalence of chronic conditions demonstrate why health care administrators and policy makers should not rely exclusively on medical record-based administrative data for a comprehensive evaluation of population health.


Osteoporosis in older persons: current pharmacotherapy and future directions.
Osteopororic fractures are highly prevalent in older persons having catastrophic consequences in their quality of life and increasing disability and mortality in this population. The mechanisms of osteoporosis in older persons are unique in terms of cellular changes and response to osteoporosis treatment. Therefore, specifically targeted treatments are required in this particular population. This paper provides an overview on the particular mechanisms of osteoporosis in older persons and the current and future therapeutic strategies to improve bone mass and prevent fractures in this population. Osteoporosis in older persons (especially in the old-old) has a unique pathophysiology that predisposes them to fractures thus having catastrophic consequences. Identification of patients at risk followed by therapies targeted to their cellular changes is pivotal to close the care gap observed in osteoporosis, predominantly in the older population. The treatment of osteoporosis has evolved from daily to yearly dosing thus facilitating compliance and effectiveness. It is expected that future biologically targeted treatments will have a similar separate dosing regime with better anti-fracture efficacy and lower incidence of side effects.


Health behavior and adherence to treatment for sleep breathing disorder in the patient with heart failure.
Heart failure can be complicated by a variety of comorbidities including sleep breathing disorder (SBD). Treatment for SBD in the heart failure patient can improve quality of life and decrease mortality. Few studies have sought to examine the reasons why patients with heart failure who screen positive for SBD do not follow through with diagnostic testing and recommendations for evidence based treatments. The purpose of this study was to describe and compare the characteristics of patients with heart failure who adhered to recommendations for evaluation and treatment of SBD with those who did not. Additionally, the study sought to examine reasons for nonadherence. A descriptive comparative design was used. Descriptive statistics were used to define and compare the study population in terms of demographic data, which included age, gender, ethnicity, New York Heart Association heart failure classification, and comorbidities. Additionally, patients were surveyed to determine reasons for nonadherence to recommended overnight sleep study evaluation and or treatment with positive airway pressure. Demographics with higher percentages of adherence to evaluation and treatment included younger individuals and male gender. Prevalent reasons for nonadherence for evaluation and treatment included negative perceptions of an overnight sleep study evaluation and advanced age. The community nurse educator can use the descriptive comparative findings in this study to tailor educational programs toward individuals with heart failure who have screened positive for SBD who are most at risk for nonadherence.


Biophysical characterization of layer-by-layer synthesis of aptamer-drug microparticles for enhanced cell targeting.
Targeted delivery of drug molecules to specific cells in mammalian systems demonstrates a great potential to enhance the efficacy of current pharmaceutical therapies. Conventional strategies for pharmaceutical delivery are often associated with poor therapeutic indices and high systemic cytotoxicity, and this result in poor disease suppression, low surviving rates, and potential contraindication of drug formulation. The emergence of aptamers has elicited new research interests into enhanced targeted drug delivery due to their unique characteristics as targeting elements. Aptamers can be engineered to bind to their cognate cellular targets with high affinity and specificity, and this is important to navigate active drug molecules and deliver sufficient dosage to targeted malignant cells. However, the targeting performance of aptamers can be impacted by several factors including endonuclease-mediated degradation, rapid renal filtration, biochemical complexation, and cell membrane electrostatic repulsion. This has subsequently led to the development of smart aptamer-immobilized biopolymer systems as delivery vehicles for controlled and sustained drug release to specific cells at effective therapeutic dosage and minimal systemic cytotoxicity. This article reports the synthesis and in vitro characterization of a novel multi-layer co-polymeric targeted drug delivery system based on drug-loaded PLGA-Aptamer-PEI (DPAP) formulation with a stage-wise delivery mechanism. A thrombin-specific DNA aptamer was used to develop the DPAP system while Bovine Serum Albumin (BSA) was used as a biopharmaceutical drug in the synthesis process by ultrasonication. Biophysical characterization of the DPAP system showed a spherical shaped particulate formulation with a unimodal particle size distribution of average size ∼0.685 µm and a zeta potential of +0.82 mV. The DPAP formulation showed a high encapsulation efficiency of 89.4 ± 3.6%, a loading capacity of 17.89 ± 0.72 mg BSA protein/100 mg PLGA polymeric particles, low cytotoxicity and a controlled drug release characteristics in 43 days. The results demonstrate a great promise in the development of DPAP formulation for enhanced in vivo cell targeting. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:249-261, 2018.


Congenital corneal anesthesia: problems in diagnosis.
Congenital corneal anesthesia (CCA) is a rare clinical entity that presents a whole gamut of problems before lending itself to a diagnosis by the clinician. Not recognizing the history of self-inflicted corneal injuries, not evaluating the corneal sensations in a child with recurrent corneal ulceration, misdiagnosis of such cases as viral keratitis, and not ruling out all the secondary causes of corneal anesthesia, as well as the other causes of self-inflicted injuries, are some of the pitfalls in the diagnosis of congenital corneal anesthesia. Four cases representative of different aspects of CCA are presented. The problems in the diagnosis of these cases are discussed. A clinical classification of congenital corneal anesthesia is suggested and the systemic anomalies associated with this disorder are enumerated.


Recurrence rate and survival implications of surgical margins in patients with acral melanoma. Is a wide margin necessary?
Appropriate size of resection margins in acral melanoma is not clearly established. To investigate whether narrow-margin excision is appropriate for thick acral melanoma. Three-hundred and six patients with acral melanoma were examined. Factors associated with recurrence and survival were analyzed according to surgical margin size (1 to 2 cm and > 2 cm). Out of 306 patients, 183 were women (59.8%). Median Breslow thickness was 6 mm; 224 cases (73.2%) were ulcerated, 154 patients (50.3%) had clinical stage III disease, while 137 were at stage II (44.8%) and 15 at stage IV (4.9%). All cases had negative margins, with a median of 31.5 mm. A Breslow thickness of 7 mm (p = 0.001) and clinical stage III (p = 0.031) were associated with recurrence; the factors associated with survival were Breslow index (p = 0.047), ulceration (p = 0.003), advanced clinical stage (p < 0.001), and use of adjuvant therapy (p = 0.003). A resection margin of 1 to 2 cm did not affect tumor recurrence or survival in patients with acral melanoma.


Examination of the Pharmacology of Oxytocin and Clinical Guidelines for Use in Labor.
The use of exogenous oxytocin to induce or augment labor has increased in recent years. This literature-informed review examines the action of this medication and the potential associated complications, with an evaluation of current professional practice guidelines. A brief history of the use of exogenous oxytocin for labor induction or augmentation is presented. In addition, risk management strategies for the prevention of oxytocin-related adverse outcomes and subsequent litigation are identified.


Tuberculosis diagnosed / managed at NGMC, Teaching Hospital, Kohalpur: a joint private-public effort.
Medical colleges both in public and private sector in Nepal have been supporting national TB control program (NTP) in its effort to control TB and its eventual elimination. Official collaboration between Nepalganj Medical College (NGMC), a private sector medical college and NTP was developed in 2000; a joint private-public initiative to contain TB. This study has been done with the objectives a) to review the TB cases diagnosed/managed at NGMC Teaching Hospital (TH), Kohalpur, in Financial Year 2063/2064 (Shrawan 63 Asad 64) and b) to assess the contribution of NGMC, TH, Kohalpur towards TB control. This is record based review of TB cases diagnosed, categorized, treated at NGMC TH, Kohalpur and referred to respective health facilities in Financial Year 2063/2064 (Shrawan 63 Asad 64). And case detection with respect to detected TB cases in Midwestern Region and entire country. Around 13% of detected TB cases for Mid Western Region and 1.5 % of detected TB cases at national level were diagnosed at NGMC, TH, Kohalpur. 35% of cases were of pediatric TB; lymph node TB, pleural effusion & abdominal TB were common form of extra pulmonary (EP) TB seen in children. 20.8%, 44.8% and 34.4% of cases in adults were of sputum smear (SS) + pulmonary TB (PTB), SS- PTB & EPTB respectively; pleural effusion, lymph node TB, Miliary & abdominal TB were common form of EPTB seen in adults. Contribution of NGMC, TH, Kohalpur towards case detection seems to be significant. The role of medical colleges in TB control can not be underestimated.


Diagnosis of chronic inflammatory demyelinating polyneuropathy.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic immune-mediated peripheral form of polyneuropathy. No reliable diagnostic biomarkers are available by which to make the diagnosis of CIDP. As a result, diagnosis of the condition can be challenging. Many patients are not recognized early in the disease course, and on the other end of the spectrum both establishing early and accurate diagnosis as well as avoiding misdiagnosis and overtreatment. Identification of the hallmark clinical, electrophysiological, and laboratory features of the disease are critical to facilitate rapid diagnosis, while an understanding of diagnostic pitfalls can help prevent misdiagnosis. Since the original description of CIDP in the 1970s, over 15 sets of diagnostic criteria have been proposed. The criteria published in 2021 by the European Academy of Neurology / Peripheral Nerve Society (EAN/PNS) were developed for use during routine clinical care and are available in the public domain. These criteria provide clinicians with an invaluable resource by which the data collected during the evaluation of the patient with possible CIDP can be interpreted. One point of importance that bridges diagnosis to treatment is objectification of the treatment response. Interpretation of how patients respond to treatment drives both long-term treatment paradigms and the diagnosis at which these treatments are aimed. Although no approach is perfect, utilization of strength impairment and disability outcomes in clinical practice can help unravel the difficulties in interpreting response to treatment. Just as improvement in these outcomes is considered diagnostically supportive, the absence of objective benefit argues against it and should prompt reconsideration of a CIDP diagnosis.


[Association of TNF-alpha and IL-13 genes polymorphisms with bronchial asthma].
OBJECTIVE To assess the association of polymorphisms of TNF-alpha gene (rs1799724, rs1800630, rs1799964 and rs769178) and IL-13 gene (rs2158177 and rs1295687) with susceptibility to asthma among ethnic Chinese in Qingdao region. METHODS For 400 asthma patients and 200 healthy subjects, above polymorphisms were detected with a SNaPshot method. RESULTS For rs2158177, the frequency of genotype of GG in the asthma group was significantly lower than the control group (2.8% vs. 5%, OR = 0.31, 95%CI: 0.12-0.82, P = 0.021). No significant difference was detected in the genotypic frequencies for the remaining 5 polymorphisms between the two groups (All P > 0.05). CONCLUSION The study has indicated that rs2158177 polymorphism of the IL-13 gene is associated with asthma in ethnic Han Chinese from Qingdao. No association has been found between polymorphisms of TNF-alpha gene with susceptibility to asthma.


Assessment of Tumor Cell Cannibalism as a Predictor of Oral Squamous Cell Carcinoma - A Histopathologic Correlation.
Cellular cannibalism is defined as the ability of a cell to engulf another cell of its own type or any other. It has been recognized in various malignancies and is linked well with the aggressiveness, degree of anaplasia, invasiveness and metastatic potential. Literature search fetched up very few studies related to the presence and significance of cannibalism with respect to Oral squamous cell carcinoma [OSCC]. The present study was aimed to detect tumor cell cannibalism in OSCC and to validate its role as a prognosticator of OSCC in relation to metastasis and degree of differentiation. 30 histopathologically proven cases, 15 cases each of metastatic OSCC (7 well differentiated OSCC and 8 moderately differentiated OSCC) and non-metastatic OSCC (8 well differentiated OSCC and 7 moderately differentiated OSCC) were included in the study. Quantitative assessment of tumor cell cannibalism was done. The data was analyzed using Mann Whitney test. Metastatic OSCC showed higher frequency of cannibalistic cells compared to non-metastatic OSCC. More number of cannibalistic cells were found in moderately differentiated OSCC than well differentiated OSCC in both groups. Moreover, Grade III cannibalism and complex cannibalism was also found to be associated with metastatic, moderately differentiated OSCC exclusively. It has been found that higher number of cannibalistic cells were associated with OSCC showing metastasis indicating their aggressive behavior. So, we recommend that quantitative assessment of tumor cell cannibalism should become a part of the routine histopathological examination of OSCC to screen its hostile behavior.


Low-temperature pseudomorphic transformation of ordered hierarchical macro-mesoporous SiO2/C nanocomposite to SiC via magnesiothermic reduction.
A magnesiothermic reduction synthesis approach is reported for direct conversion of SiO(2)/C composite nanostructures to corresponding SiC materials without losing their nanostructure morphologies. Crystalline SiC materials can be obtained by this approach at a temperature as low as 600 degrees C, only approximately half of that applied in the generally used carbothermal reduction and preceramic polymer pyrolysis methods. An ordered hierarchical macro-mesoporous SiC material was synthesized for the first time as a demonstration. This pseudomorphic transformation can be regarded as a general synthesis method for different kinds of SiC nanostructures, and it can also be readily extended to other metal carbide materials as well as TiC.


Exercise and Curcumin in Combination Improves Cognitive Function and Attenuates ER Stress in Diabetic Rats.
Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with chronic low-grade inflammation that is mainly associated with lifestyles. Exercise and healthy diet are known to be beneficial for adults with T2DM in terms of maintaining blood glucose control and overall health. We investigated whether a combination of exercise and curcumin supplementation ameliorates diabetes-related cognitive distress by regulating inflammatory response and endoplasmic reticulum (ER) stress. This study was performed using male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a spontaneous diabetes Type 2 model) and Long-Evans Tokushima Otsuka (LETO) rats (LETO controls) by providing them with exercise alone or exercise and curcumin in combination. OLETF rats were fed either a diet of chow (as OLETF controls) or a diet of chow containing curcumin (5 g/kg diet) for five weeks. OLETF rats exercised with curcumin supplementation exhibited weight loss and improved glucose homeostasis and lipid profiles as compared with OLETF controls or exercised OLETF rats. Next, we examined cognitive functions using a Morris water maze test. Exercise plus curcumin improved escape latency and memory retention compared to OLETF controls. Furthermore, OLETF rats exercised and fed curcumin had lower IL6, TNFα, and IL10 levels (indicators of inflammatory response) and lower levels of ER stress markers (BiP and CHOP) in the intestine than OLETF controls. These observations suggest exercise plus curcumin may offer a means of treating diabetes-related cognitive dysfunction.


Epidemiology of Sarcopenia and Factors Associated With It Among Community-Dwelling Older Adults in Taiwan.
Sarcopenia is a well-recognized geriatric syndrome. We sought to determine the prevalence of sarcopenia and factors associated with it among community-dwelling older adults in Taiwan. A cross-sectional study was conducted in Yuanshan Township, Yilan County, Taiwan. Data of 731 community-dwelling adults aged 65 and older were evaluated. Demographic characteristics, anthropometry, medical history, biochemistry results, and dual-energy X-ray absorptiometry results were collected for analysis. Males had a higher rate of sarcopenia than did females and had lower values for body weight, body mass index, waist circumference, percentage of body fat, and lean body mass. Poor nutritional status as determined by the Mini Nutritional Assessment correlated positively with markers for sarcopenia. Levels of vitamin D and folic acid correlated positively with some sarcopenia markers. Gender differences and nutritional factors may influence the development of sarcopenia. Vitamin D is positively correlated with relative appendicular skeletal muscle mass in males with sarcopenia, and folic acid was positively correlated with gait speed in females with sarcopenia.


Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in the regulation of placental cell fusion.
The placental transcription factor glial cell missing 1 (GCM1) and its target gene syncytin-1 are involved in cAMP-stimulated trophoblastic fusion for syncytiotrophoblast formation. GCM1 DNA-binding activity is inhibited by sumoylation, whereas GCM1 stability is decreased by deacetylation. cAMP enhances GCM1 desumoylation through the Epac1/Rap1/CaMKI signaling cascade and CaMKI is known to down-regulate class IIa HDAC activity. In this paper, we study whether the Epac1/Rap1/CaMKI signaling cascade regulates GCM1 activity and placental cell fusion through class IIa HDACs. Interaction and co-localization of GCM1 and HDAC5 were characterized by co-immunoprecipitation analysis and immunofluorescence microscopy (IFM). Regulation of GCM1 transcription activity and syncytin-1 expression by HDAC5 was studied by transient expression. Phospho-specific antibodies against HDAC5, RNA interference and IFM were used to examine the de-repression of GCM1 activity, syncytin-1 expression and cell-cell fusion by Epac1/Rap1/CaMKI signaling cascade in placental BeWo cells expressing constitutively active Epac1 and CaMKI. We demonstrate that both GCM1 and HDAC5 are expressed in the syncytiotrophoblast layer of full-term placenta and the nuclei of BeWo cells. The interaction between HDAC5 and GCM1 facilitates GCM1 deacetylation and suppresses its transcriptional activity. In contrast, Epac1 stimulates HDAC5 phosphorylation on Ser259 and Ser498 in a Rap1- and CaMKI-dependent manner leading to nuclear export of HDAC5 and thereby de-repression of GCM1 transcriptional activity. Importantly, HDAC5 suppresses syncytin-1 expression and cell-cell fusion in BeWo cells, which is counteracted by Epac1 and CaMKI. Our results reveal a new layer of regulation of GCM1 activity and placental cell fusion through the Epac1/Rap1/CaMKI signaling cascade by restraining HDAC5 from interacting with and mediating GCM1 deacetylation.


The impact of combining pain education strategies with physical therapy interventions for patients with chronic pain: A systematic review and meta-analysis of randomized controlled trials.
Study Design: Systematic Review with meta-analysis.Background: Rehabilitation providers have begun to incorporate pain education into their treatment protocols to influence the patient's experience and knowledge to improve their condition. The purpose of this systematic review is to determine if the addition of pain education strategies to physical therapy treatments is beneficial in reducing pain intensity and disability for those with chronic musculoskeletal pain.Methods: A systematic database search was conducted for randomized control trials that investigated the concurrent use of pain education and physical therapy. Standardized methods for article identification, inclusion, and quality appraisal was utilized. Where possible, studies were pooled for meta-analysis, with pain and disability as the primary outcomes.Results: Fourteen articles were included in this review, of which all fourteen were rated as high quality using the PEDro scale of quality assessment. Meta-analyses were conducted on pain and disability constructs at short term (< 12 weeks) and long-term (≥ 12 weeks) for the studies that allowed for quantitative pooling of effect sizes. Thirteen out of the fourteen included studies demonstrated a decrease in pain and disability with the use of combined interventions. There was a large effect on short-term pain (SMD 0.837), long-term pain (SMD 0.964), and long-term disability (SMD 1.374). A moderate effect on with short-term disability (SMD 0.791).Conclusion: The results of this systematic review support the conclusion that utilizing pain education strategies in conjunction with interventions provided by physical therapists demonstrates a moderate to large effect sizes on pain and disability constructs but lack pooled statistical significance.


Characterization of CTX-M-140, a Variant of CTX-M-14 Extended-Spectrum β-Lactamase with Decreased Cephalosporin Hydrolytic Activity, from Cephalosporin-Resistant Proteus mirabilis.
CTX-M-140, a novel CTX-M-type extended-spectrum β-lactamase (ESBL), was identified in cephalosporin-resistant clinical isolates of Proteus mirabilis CTX-M-140 contained an alanine-to-threonine substitution at position 109 compared to its putative progenitor, CTX-M-14. When it was expressed in an Escherichia coli isogenic background, CTX-M-140 conferred 4- to 32-fold lower MICs of cephalosporins than those with CTX-M-14, indicating that the phenotype was attributable to this single substitution. For four mutants of CTX-M-14 that were constructed by site-directed mutagenesis (A109E, A109D, A109K, and A109R mutants), MICs of cephalosporins were similar to those for the E. coli host strain, which suggested that the alanine at position 109 was essential for cephalosporin hydrolysis. The kinetic properties of native CTX-M-14 and CTX-M-140 were consistent with the MICs for the E. coli clones. Compared with that of CTX-M-14, a lower hydrolytic activity against cephalosporins was observed for CTX-M-140. blaCTX-M-140 is located on the chromosome as determined by I-CeuI pulsed-field gel electrophoresis (I-CeuI-PFGE) and Southern hybridization. The genetic environment surrounding blaCTX-M-140 is identical to the sequence found in different plasmids with blaCTX-M-9-group genes among the Enterobacteriaceae Genome sequencing and analysis showed that P. mirabilis strains with blaCTX-M-140 have a genome size of ∼4 Mbp, with a GC content of 38.7% and 23 putative antibiotic resistance genes. Our results indicate that alanine at position 109 is critical for the hydrolytic activity of CTX-M-14 against oxyimino-cephalosporins.


An implication for bone posterity: dietary calcium intake in medical personnel in southern West Virginia.
Osteoporosis in the postmenopausal and elderly years is caused by a multitude of factors, which include calcium intake, and is felt largely to be a preventable situation. Low dietary calcium intakes (505 mgs. daily) are common in middle-aged females in southern West Virginia. Further information about the demographic factors in the elderly population from all socioeconomic groups needs to be explored to effect changes in dietary lifestyles.


Synthesis, structure, spectroscopic characterization, and protein binding affinity of new water-soluble hetero- and homometallic tetranuclear [Cu(II)2Zn(II)2] and [Cu(II)4] clusters.
Two new water-soluble hetero- and homometallic tetranuclear clusters, Na4[Cu2Zn2(ccdp)2(μ-OH)2]·CH3OH·6H2O (1) and K3[Cu4(ccdp)2(μ-OH)(μ-OH2)]·14H2O (2), have been synthesized in methanol-water at room temperature by exploiting the flexibility, chelating ability, and bridging potential of a carboxylate-rich dinucleating ligand, N,N'-bis(2-carboxybenzomethyl)-N,N'-bis(carboxymethyl)-1,3 diaminopropan-2-ol (H5ccdp). Complex 1 is obtained through the self-assembly of two monoanionic [CuZn(ccdp)](-)fragments, which are, in turn, exclusively bridged by two μ-OH(-)groups. Similarly, complex 2 is formed through the self-assembly of two monoanionic [Cu2(ccdp)](-) species exclusively bridged by one μ-OH(-) and one μ-OH2 groups. Complexes 1 and 2 are fully characterized in the solid state as well as in solution using various analytical techniques including a single-crystal X-ray diffraction study. The X-ray crystal structure of 1 reveals that two Cu(II) centers are in a distorted square-pyramidal geometry, whereas two Zn(II) centers are in a distorted trigonal-bipyramidal geometry. The solid-state structure of 2 contains two dinuclear [Cu2(ccdp)](-) units having one Cu(II) center in a distorted square-pyramidal geometry and another Cu(II) center in a distorted trigonal-bipyramidal geometry within each dinuclear unit. In the powder state, the high-field EPR spectrum of complex 1 indicates that two Cu(II) ions are not spin-coupled, whereas that of complex 2 exhibits at least one noninteracting Cu(II) center coordinated to a nitrogen atom of the ligand. Both complexes are investigated for their binding affinity with the protein bovine serum albumin (BSA) in an aqueous medium at pH ~7.2 using fluorescence spectroscopy. Synchronous fluorescence spectra clearly reveal that complexes 1 and 2 bind to the active sites in the protein, indicating that the effect is more pronounced toward tyrosine than tryptophan. Density functional theory calculations have been carried to find the Fukui functions at the metal sites in complexes 1 and 2 to predict the possible metal centers involved in the binding process with BSA protein.


Percutaneous drainage access: a simplified coaxial technique.
We describe an access technique that we have used in 150 nephrostomy and biliary drainage procedures and for access to some abscesses and viscera. The system provides safe coaxial access with a 22-gauge removable hub needle, which then acts as a guide wire and is replaced by an 18-gauge cannula. A major advantage is that only one guide wire is used (0.038-inch) for the entire drainage procedure. No significant complications have occurred to date with this method.


[Dehydroepiandrosterone and brain functioning].
The adrenal glands synthesize dehydroepiandrosterone (DHEA) and its sulphate form (DHEAS) more intensively than they do other steroid hormones. Researchers are interested in these hormones for several reasons. Firstly, for some years they have been trying to find the reason for DHEA and DHEAS to be synthesized and present in the organism in such high concentrations. Secondly, their attention have been attracted by age-dependent regression of DHEA, which is strictly determined. Thirdly, despite longstanding efforts of scientists, the physiological role and spectrum of the biological activity of DHEA is still unclear. Evidence of that DHEA and DHEAS can be synthesized in situ in the brain tissue, received in rat experiments, urged researchers to clarify the role of these neurosteroids in the CNS. The presented review covers ways of neurosteroid synthesis, possible mechanisms of the regulation of these processes, and their dynamics under the condition of stress. The authors analyze experimental and clinical observations undertaken with a goal to clarify a possible role of DHEA in the manifestation of various brain functions. Special attention is payed to ambiguous results of modern studies, dedicated to replacement therapy of various disorders of CNS functioning (Alzheimer's disease, depression, age-specific memory impairment, sleep disturbance etc.) with DHEAS.


Assessment of the effect of vacuum-formed retainers and Hawley retainers on periodontal health: A systematic review and meta-analysis.
Recently, increasing attention has been paid to the periodontal health of orthodontic patients in the maintenance stage in clinical practice. The focus of this meta-analysis was to compare the effects of vacuum-formed retainers (VFR) and Hawley retainers (HR) on periodontal health, in order to provide a reference for clinical selection. From the establishment of the database until November 2020, a large number of databases were searched to find relevant randomized control trials, including the Cochrane Library databases, Embase, PubMed, Medline via Ovi, Web of Science, Scopus, Grey Literature in Europe, Google Scholar and CNKI. Related literature was manually searched and included in the analysis. Two researchers screened the literature according to relevant criteria. The size of the effect was determined using RevMan5.3 software, and the mean difference and 95% confidence intervals (CI) were used to estimate the results using a random effects model. This meta-analysis included six randomized controlled trials involving 304 patients. The results of the meta-analysis showed that there was no statistical difference in sulcus probing depth status between the VFR group and the HR group, including at 1, 3, and 6 months. Compared with the VFR group, the HR group showed a lower gingival index at 1 month (mean difference = 0.12, 95%CI: 0.06 to 0.19) and 3 months (mean difference = 0.11, 95%CI: 0.06 to 0.17), while there was no statistically significant difference at 6 months (mean difference = 0.10, 95%CI: -0.07 to 0.27). The plaque index of the HR group also showed a good state at 1 month (mean difference = 0.06, 95%CI: 0.01 to 0.12), 3 months (mean difference = 0.12, 95%CI: 0.08 to 0.16), and 6 months (mean difference = 0.19, 95%CI: 0.09 to 0.29). Subgroup analysis of PLI showed that when all teeth were measured, PLI status was lower in the HR group at 6 months (mean difference = 0.32, 95%CI: 0.18 to 0.46). PLI status was also low for the other teeth group (mean difference = 0.15, 95%CI: 0.08 to 0.22). Our meta-analysis showed that patients using the Hawley retainer had better periodontal health compared with those using vacuum-formed retainers. However, more research is needed to look at the periodontal health of patients using these two retainers.


Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.
Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Approximately 9% of patients with VCP mutations had an amyotrophic lateral sclerosis (ALS) phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large interfamilial and intrafamilial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared with other molecular subtypes.


Benzoin Resin: An Overview on Its Production Process, Phytochemistry, Traditional Use and Quality Control.
Benzoin is a pathologic exudation produced by plants of the family Styrax. It is secreted by traumatic resin ducts after injury, which are derived from parenchymal cells in secondary xylem by schizolysigeny. Some 63 chemical constituents have been isolated and identified from this resin, including balsamic acid esters, lignans and terpenoids. It has a long history of applications, including as incense along with olibanum, a flavor enhancer in the food industry, materials in the daily chemistry industry as well as therapeutic uses. Up to now, high-performance liquid chromatography (HPLC) and gas chromatography mass spectrometry (GC-MS) have been widely used in qualitative and quantitative analysis of benzoin. Other technologies, including near-infrared reflectance spectroscopy (NIR), proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) and Fourier-transform infrared spectroscopy (FT-IR), have also been used to distinguish different resins. Herein, this paper provides a comprehensive overview of the production process, phytochemistry, traditional uses and quality control of benzoin and looks to the future for promoting its further research and applications.


Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals.
Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rbeta2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls. Fifty-four individuals (12 chronic LB, 14 subacute LB, 14 asymptomatic individuals and 14 healthy controls) were included in the study and provided a blood sample. Mononuclear cells were separated from the blood and stimulated with antigens. The IL-12Rbeta2 and FoxP3 mRNA expression was analysed with real-time reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of IL-12Rbeta2 on CD3(+), CD4(+), CD8(+) and CD56(+) cells was assessed by flow cytometry. Furthermore, the secretion of interferon (IFN)-gamma, IL-4, IL-5, IL-10, IL-12p70 and IL-13 was analysed by enzyme-linked immunospot (ELISPOT) and/or enzyme-linked immunosorbent assay (ELISA). Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rbeta2 on CD8(+) cells and also a lower number of Borrelia-specific IFN-gamma-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.


Evaluation of Peripheral Blood Circulation Disorder in Scleroderma Patients Using an Optical Sensor with a Pressurization Mechanism.
Blood circulation function of peripheral blood vessels in skin dermis was evaluated employing an optical sensor with a pressurization mechanism using the blood outflow and reflow characteristics. The device contains a light source and an optical sensor. When applied to the skin surface, it first exerts the primary pressure (higher than the systolic blood pressure), causing an outflow of blood from the dermal peripheral blood vessels. After two heartbeats, the pressure is lowered (secondary pressure) and blood reflows into the peripheral blood vessels. Hemoglobin concentration, which changes during blood outflow and reflow, is derived from the received light intensity using the Beer-Lambert law. This method was evaluated in 26 healthy female volunteers and 26 female scleroderma patients. In order to evaluate the blood circulation function of the peripheral blood vessels of scleroderma patients, pressurization sequence which consists of primary pressure followed by secondary pressure was adopted. Blood reflow during the first heartbeat period after applying the secondary pressure of 40mmHg was (mean±SD) 0.059±0.05%mm for scleroderma patients and 0.173±0.104%mm for healthy volunteers. Blood reflow was significantly lower in scleroderma patients than in healthy volunteers (p<0.05). This result indicates that the information necessary for assessing blood circulation disorder of peripheral blood vessels in scleroderma patients is objectively obtained by the proposed method.


Urinary adenosine triphosphate and nitric oxide levels in patients with underactive bladder: a preliminary study.
Various in vitro and in vivo animal studies have shown that adenosine triphosphate (ATP) has a stimulatory role and nitric oxide (NO) has an inhibitory role in modulating bladder contractility. However, it is not known what happens to the urinary levels of ATP and NO in humans with underactive bladder (UAB). In this prospective case-control study, we compared ATP and NO levels in twenty six male patients of UAB with a bladder contractility index (BCI) of < 100 and 18 healthy male volunteers without any lower urinary tract symptoms (LUTS). The mean urinary ATP levels were significantly lower in cases compared to controls (546.1 ± 37.3 pg/µl vs. 610.7 ± 24.9 pg/µl, p value < 0.001) and the mean NO levels were significantly higher in cases compared to controls (1233.4 ± 91.2 pg/µl vs. 1126.3 ± 91.3.4 pg/µl, p value < 0.001). The mean NO/ATP ratio in cases was significantly higher than that of controls (2.26 ± 0.2 vs. 1.84 ± 0.18, p value < 0.000). Using receiver operating curve (ROC) analysis, we noted the area under the curve (AUC) for NO/ATP ratio to be 0.91 in the diagnosis of cases. A cut-off value of 2.06 for NO/ATP ratio had sensitivity, specificity and diagnostic accuracy of 88.5%, 88.9% and 88.6%, respectively, in diagnosing patients with UAB. Patients with UAB have significantly higher levels of urinary NO and decreased levels of urinary ATP. Urinary NO/ATP levels can be considered as a noninvasive alternate test for diagnosing bladder underactivity.


Peoples' understanding, acceptance, and perceived challenges of vaccination against COVID-19: A cross-sectional study in Bangladesh.
In order to eliminate COVID-19, many countries provided vaccinations. However, success depends on peoples' knowledge levels and rates of acceptance. But, previous research on this topic is currently lacking in Bangladesh. This cross-sectional study aimed at to investigate Bangladeshi peoples' knowledge, acceptance, and perception of challenges regarding COVID-19 vaccines. Quantitative data were collected using an online survey (n = 1975) and face-to-face interviews (n = 2200) with a pre-tested structured questionnaire. In addition, seven open-ended interviews were conducted with health experts regarding challenges of vaccination. Binary logistic regression analyses were conducted to assess the association between explanatory and dependent variables. Effect size was estimated to understand the magnitude of relationship between two variables. Of 4175 respondents, 92.6% knew about COVID-19 vaccines, while only 37.4% believed vaccines to be effective in controlling COVID-19. Nearly 46% of respondents believed that COVID-19 vaccines have side-effects, and 16.4% of respondents believed that side-effects could be life-threatening. Only 60.5% of respondents indicated that they would receive the COVID-19 vaccine. Out of 1650 respondents (39.5%) who did not intend to receive the vaccine, 948 (57.4%) believed that they would be naturally protected. Regressions results indicated that men had higher rates of knowledge regarding the vaccine. In addition, rural respondents demonstrated lower knowledge regarding the vaccine. Furthermore, education had a significant association with knowledge of COVID-19 vaccines. Respondents with university education had more knowledge regarding the vaccine (Odds ratio, OR = 29.99; 95% confidence interval, CI 11.40-78.90, effect size 1.88; p = 0.01) and correct dosage (OR 27.34; 95% CI 15.25-49.00, effect size 1.83; p = 0.01). However, women (OR 1.16; 95% CI 0.96-1.40, effect size 0.08) and rural (OR 1.24; 95% CI 1.07-1.44, effect size 0.12; p = 0.01) respondents were more enthusiastic regarding receiving the COVID-19 vaccine. Higher educated respondents showed higher probability of receiving the vaccine. Those who believed in the effectiveness of the COVID-19 vaccine were 11.57 times more interested (OR 11.57; 95% CI 8.92-15.01, effect size 1.35; p = 0.01) in receiving the vaccine. Open-ended interviews identified several challenges toward successful COVID-19 vaccination. Mass awareness creation, uninterrupted supply, equitable distribution, and sectoral coordination were suggested to achieve at least 70% immunization across the country.


Iodide supplementation: 200 micrograms daily or 1,500 micrograms weekly?
25 euthyroid volunteers were divided into two groups. Each participant of group A received 200 micrograms iodine in the form of diiodotyrosine per day for a period of eight weeks, i.e. 7 x 200 micrograms iodine/week. Each participant of group B received 1,500 micrograms iodide once a week for a period of eight weeks. In addition to the basal excretion of iodine with the collected urine, the excretion values in group A amounted to 67% of the applied dose in the eighth week. In group B, the excretion values amounted to 65% of the applied dose in the eighth week. Hence, no significant difference between both groups was found.


Minimally invasive approach to the adrenal gland in obese patients with Cushing's syndrome.
Introduction: The combination of Cushing's syndrome and obesity, one of the most common manifestations of the syndrome itself, may be associated with the worsening of post-operative outcomes in case of laparoscopic adrenalectomy. This study focused on the laparoscopic treatment of Cushing's syndrome with the purpose to identify any relevant difference between morbidly obese, mildly obese and non-obese patients.Material and methods: Patients were retrospectively divided into three groups according to their Body Mass Index (BMI). Demographic characteristics, operative and post-operative data were collected. Data about different hemostatic devices were also collected and compared. Differences were analyzed with the Fisher's exact test for categorical variables, and the Mann-Whitney test for continuous variables.Results: No differences were found in operative time (101.5 ± 50.9 min; p = .919), conversion rate (2.6%; p = .655) or length of stay (4.3 ± 2.9 days; p = .886). Complication rate was 3% (p = .32), without any mortality. 95% of patients showed a complete resolution of hypercotisolyism-related symptoms, and a mean BMI reduction of 5 ± 3.2 kg/m2 (follow up = 6.3 ± 4.2 years). Conclusions: Laparoscopic adrenalectomy is safe and feasible in obese patients affected with Cushing's disease and it can lead to the resolution of the related symptoms.


Remission and pancreas isograft survival in recent onset diabetic NOD mice after treatment with low-dose anti-CD3 monoclonal antibodies.
Diabetes in NOD mice is an autoimmune disease similar to Type I diabetes in humans. Prior to hypoglycemia, changes in the islet infiltrate led to autoreactive T cell activation and destruction of the insulin-producing beta cells. If T cell activation can be inhibited before beta cell destruction is complete, islet cell rescue and regeneration can occur. Female NOD mice > 100 days old with blood glucose levels > 20 mM/l for less than 7 days were selected as 'recent onset' mice. Untreated, all of these animals would die of diabetes in < 40 days. Mice treated with anti-CD4 (GK1.5) achieved 14.3% permanent remission, while those treated with anti-CD8 (53.6.7) showed 33.3% permanent remission. Mice treated with anti-CD3 (145-2C1) also achieved 33.3% permanent remission, but 14% of these died of first dose syndrome. In mice treated with a low dose of anti-CD3 (10 microg KT3), which did not induce first dose syndrome, 50% remained in remission for > 100 days. This dose of mAb reduced insulitis but did not deplete splenic CD3 cells. When mice in remission were challenged with a vascularized pancreas isograft at 50 days, 9/22 remained normal and 13/22 had recurrent disease in both transplanted and native pancreas. Of the long-surviving isografts 7/9 were in KT3 treated recipients. Histology showed activated T cell infiltration in the native and transplanted pancreases of mice with transient remission. Benign insulitis with macrophages, B cells, CD4 > CD8 T cells and low levels of IL-2R, IL-2, IFN-gamma and IL-4 was seen in islets from the native pancreas and in long surviving pancreas isografts in mice that remained in remission. Thus, using low dose KT3, it was possible to halt the development of diabetes in 50% of animals treated soon after diagnosis, despite significant islet cell destruction at this stage. Of the KT3 treated mice in permanent remission, 70% had re-established tolerance to autoantigen and did not destroy vascularized pancreas isografts.


A voice of their own: women moving into their fifties.
This purpose of this qualitative study was to illuminate the developmental journey experienced by women moving into their fifties. A purposive sample of 23 women was asked to document any changes they perceived in themselves as they moved from their forties into their fifties. Themes identified included stepping out of the mold, letting go, walking in balance, moving in new directions, redefining relationships, and experiencing a freedom "to be". Understanding the patterns of meaning experienced by healthy women at midlife can provide clinicians with a blueprint for enabling women to become all they can be during late midlife and thereafter.


Biosynthesis of Glutamate, Aspartate, Asparagine, L-Alanine, and D-Alanine.
Glutamate, aspartate, asparagine, L-alanine, and D-alanine are derived from intermediates of central metabolism, mostly the citric acid cycle, in one or two steps. While the pathways are short, the importance and complexity of the functions of these amino acids befit their proximity to central metabolism. Inorganic nitrogen (ammonia) is assimilated into glutamate, which is the major intracellular nitrogen donor. Glutamate is a precursor for arginine, glutamine, proline, and the polyamines. Glutamate degradation is also important for survival in acidic environments, and changes in glutamate concentration accompany changes in osmolarity. Aspartate is a precursor for asparagine, isoleucine, methionine, lysine, threonine, pyrimidines, NAD, and pantothenate; a nitrogen donor for arginine and purine synthesis; and an important metabolic effector controlling the interconversion of C3 and C4 intermediates and the activity of the DcuS-DcuR two-component system. Finally, L- and D-alanine are components of the peptide of peptidoglycan, and L-alanine is an effector of the leucine responsive regulatory protein and an inhibitor of glutamine synthetase (GS). This review summarizes the genes and enzymes of glutamate, aspartate, asparagine, L-alanine, and D-alanine synthesis and the regulators and environmental factors that control the expression of these genes. Glutamate dehydrogenase (GDH) deficient strains of E. coli, K. aerogenes, and S. enterica serovar Typhimurium grow normally in glucose containing (energy-rich) minimal medium but are at a competitive disadvantage in energy limited medium. Glutamate, aspartate, asparagine, L-alanine, and D-alanine have multiple transport systems.


The problem with the species problem.
When Charles Darwin convinced the scientific community that species evolve, the long-held essentialist view of each species as fixed was rejected and a clear conceptual understanding of the term was lost. For the next century, a real species problem existed that became culturally entrenched within the scientific community. Although largely solved decades ago, the species problem remains entrenched today due to a suite of factors. Most of the factors that help maintain its perceived intractability have been revealed and logically dismissed; yet this is not widely known so those factors continue to be influential. It is time to recognize this false foundation and relegate the species problem to history.