Effects of three nasal topical steroids in the intraocular pressure compartment.
The purpose of this study was to evaluate whether the use of fluticasone propionate, mometasone furoate, or beclomethasone dipropionate for the treatment of rhinitis produced, as a side effect, an increase in the intraocular pressure; only one printed article proclaims that the increase of secondary intraocular pressure is due to the use of local nasal steroids. We conducted a comparative, double-blind, experimental, prospective, longitudinal study in which 360 patients were divided at random into 4 groups; 90 of them were given a placebo (control group) and the other 270 were divided into 3 other groups of 90 patients each and given a different local nasal steroid for each group. Measurement parameters All patients had their intraocular pressure measured by Goldman's tonometry at 3 weeks, 6 weeks, 3 months, 6 months, and 1 year after using the placebo or local nasal steroid. Variations were found in the intraocular pressure of patients who used local steroid, with discreet elevations in the beclomethasone dipropionate and mometasone furoate groups; however, variations were always within normal limits. Fluticasone propionate, mometasone furoate, and beclomethasone dipropionate cause variations in the intraocular pressure, but the variations are within normal limits.


Trends of Incidence and Survival Rates of Mucosa-associated Lymphoid Tissue Lymphoma in the Korean Population: Analysis of the Korea Central Cancer Registry Database.
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma) is an extranodal lymphoma that occurs at various sites in the body. There is a limited understanding of the incidence and survival rates of MALT-lymphoma. To investigate the nation-wide incidence and survival rates of MALT-lymphoma in Korea during 1999-2017, the data on MALT-lymphoma were retrieved from the Korea Central Cancer Registry. During the time period of 1999-2017, 11,128 patients were diagnosed with MALT-lymphoma. The age and sex of the patients and the Surveillance, Epidemiology, and End Results (SEER) summary stage of the tumor were analyzed, and the relative survival rates (RSRs) were calculated. The age-standardized incidence rates of MALT-lymphoma in 2017 among males and females were 1.53 and 1.61 per 100,000 individuals, respectively, whereas those in 1999 among males and females were 0.21 and 0.20, respectively in Korea. The RSRs were more than 97% at 10 years post-diagnosis between 1993 and 2017. The 5-year RSRs were 87.4%, 94.8%, 97.8%, and 98.6% during 1996-2000, 2001-2005, 2006-2010, and 2013-2017, respectively. Based on SEER summary staging, the 5-year RSRs during 2013-2017 were 100.3%, 90.8%, 91.3%, and 97.9% for patients with localized, regional, distant, and unknown stages of MALT-lymphoma, respectively. Although the incidence of MALT-lymphoma is low in Korea, it has been increasing in recent years. The prognosis of MALT-lymphoma is good even at advanced stages. These findings provide useful insights to clinicians about MALT-lymphoma and inform patients about the survival rate.


Can medroxyprogesterone acetate alter Toll-like receptor expression in a mouse model of intrauterine inflammation?
Activation of the innate immune receptors, Toll-like receptors 2 and 4, are critical for a host inflammatory response to both Gram-positive and Gram-negative organisms. These receptors can initiate and modulate the inflammatory response. Differential regulation of Toll-like receptors may be one of the mechanisms by which intrauterine inflammation signals parturition. Likewise, progestational agents may have the ability to modify this effect. These studies were performed to elucidate the effect of intrauterine inflammation and medroxyprogesterone acetate on Toll-like receptor expression in the uterus, cervix, and placenta in a mouse model of intrauterine inflammation. On day 15 of gestation, CD-1 mice were randomized to pretreatment with medroxyprogesterone acetate or vehicle before intrauterine infusion with lipopolysaccharide or sterile saline solution. Six hours after intrauterine infusion, uterine, cervical, and placental tissues were harvested. RNA and protein were extracted. Quantitative polymerase chain reaction was performed for Toll-like receptor 2 and 4 messenger RNA. Western blot analysis was performed with Toll-like receptor 4-specific antibodies. Intrauterine inflammation up-regulated Toll-like receptor 2 and 4 messenger RNA in uterus, cervix, and placenta. Pretreatment with medroxyprogesterone acetate decreased the lipopolysaccharide-induced up-regulation of Toll-like receptor 2 and 4 messenger RNA in the cervix and placenta. Medroxyprogesterone acetate treatment, in the presence of lipopolysaccharide, was unable to prevent the lipopolysaccharide-induced increase in Toll-like receptor 4 messenger RNA and protein in the uterus. Medroxyprogesterone acetate treatment alone in pregnant mice significantly increased Toll-like receptor 4 messenger RNA expression in the uterus. Intrauterine inflammation has a differential effect on Toll-like receptor 2 and 4 expression. The observed up-regulation of Toll-like receptor 2 in the uterus in response to intrauterine lipopolysaccharide may be a mechanism to augment the inflammatory response and may serve to promote parturition in the setting of inflammation. Consequently, the ability of medroxyprogesterone acetate to suppress lipopolysaccharide-induced up-regulation of Toll-like receptor 2 messenger RNA may be one of the mechanisms by which progestins are able to decrease preterm birth.


Long-Term Clinical Results of MR-Guided Stereotactic Body Radiotherapy of Liver Metastases.
(1) Background: Magnetic-resonance (MR)-guided stereotactic body radiotherapy (SBRT) allows for ablative, non-invasive treatment of liver metastases. However, long-term clinical outcome data are missing. (2) Methods: Patients received MR-guided SBRT with a MRIdian Linac between January 2019 and October 2021 and were part of an ongoing prospective observational registry. Local hepatic control (LHC), distant hepatic control (DHC), progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Toxicity was documented according to CTCAE (v.5.0). (3) Results: Forty patients were treated for a total of 54 liver metastases (56% with online plan adaptation). Median prescribed dose was 50 Gy in five fractions equal to a biologically effective dose (BED) (alpha/beta = 10 Gy) of 100 Gy. At 1 and 2 years, LHC was 98% and 75%, DHC was 34% and 15%, PFS was 21% and 5% and OS was 83% and 57%. Two-year LHC was higher in case of BED > 100 Gy (100% vs. 57%; log-rank p = 0.04). Acute grade 1 and 2 toxicity (mostly nausea) occurred in 26% and 7% of the patients, with no grade ≥ 3 event. (4) Conclusions: To our knowledge, this is the largest cohort of MR-guided liver SBRT. Long-term local control was promising and underscores the aim of achieving >100 Gy BED. Nonetheless, distant tumor control remains challenging.


Clinical and pathological evolution of alpha chain disease to immunoblastic lymphoma and response to COMP chemotherapy.
A small adolescent with alpha heavy chain disease presenting as malabsorption and evolving to immunoblastic lymphoma is reported. The pathological evolution is documented by serial endoscopy and small intestinal biopsy. Clinical and pathological remission was obtained by the use of COMP combination chemotherapy.


Iodide Recognition and Sensing in Water by a Halogen-Bonding Ruthenium(II)-Based Rotaxane.
The synthesis and anion-recognition properties of the first halogen-bonding rotaxane host to sense anions in water is described. The rotaxane features a halogen-bonding axle component, which is stoppered with water-solubilizing permethylated β-cyclodextrin motifs, and a luminescent tris(bipyridine)ruthenium(II)-based macrocycle component. (1) H NMR anion-binding titrations in D2 O reveal the halogen-bonding rotaxane to bind iodide with high affinity and with selectively over the smaller halide anions and sulfate. The binding affinity trend was explained through molecular dynamics simulations and free-energy calculations. Photo-physical investigations demonstrate the ability of the interlocked halogen-bonding host to sense iodide in water, through enhancement of the macrocycle component's Ru(II) metal-ligand charge transfer (MLCT) emission.


Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1+ immune cells in Epstein-Barr virus-associated gastric cancer: the prognostic implications.
Cancer cells use PD-L1 to evade antitumor immunity through interaction with programmed cell death protein 1 (PD-1) on T cells. Recent whole-genome sequence studies revealed frequent gene amplification of PD-L1 in Epstein-Barr virus-associated gastric cancer (EBVaGC). To investigate the significance of PD-L1 in cancer cells and their microenvironment in EBVaGC, we studied PD-L1 expression by analysis of the public database and immunohistochemistry with fluorescent in situ hybridization (FISH) of the PD-L1 gene. Analysis of the database from The Cancer Genome Atlas also disclosed high expression of PD-L1 in EBVaGC compared with other molecular subtypes of GC. Expression of PD-L1 was frequently detected in cancer cells of EBVaGC (33/96; 34%), with infiltration of PD-L1+ immune cells in its stroma (43/96; 45%). Both expression of PD-L1 in cancer cells and PD-L1+ immune cell infiltration in EBVaGC were significantly correlated with diffuse histology according to Lauren's classification and tumor invasion (pT1b or more). As a prognostic indicator, PD-L1 expression in cancer cells correlated with poor outcomes in both overall survival and disease-specific survival (P=0.0498, 0.007). PD-L1-positive cancers had dense infiltration of PD-L1+ immune cells as well as CD8+ and PD-1+ cells in EBVaGC. FISH analysis of representative samples of the tumor demonstrated gene amplification of PD-L1 in 11% of cases. PD-L1-amplified cells corresponded to PD-L1-positive cells showing high-intensity immunohistochemical staining among cancer cells showing weak or moderate intensities. Taken together, PD-L1 expression in cancer cells and their microenvironment may contribute to the progression of EBVaGC, and gene amplification occurs as clonal evolution during progression. This specific subtype of GC infected with EBV is potentially a good candidate for immunotherapy targeting of the PD-L1/PD-1 axis.


The Jack Rabbit chlorine release experiments: implications of dense gas removal from a depression and downwind concentrations.
The Jack Rabbit (JR) field experiment, involving releases of one or two tons of pressurized liquefied chlorine and ammonia into a depression, took place in 2010 at Dugway Proving Ground, Utah, USA. The releases, of duration about 30 s from a short pipe at a height of 2m, were directed towards the ground. The dense two phase cloud was initially confined in a depression of 2 m depth and 50 m diameter. With wind speeds<about 1.5 m s(-1), the cloud stayed in the depression for 30-60 min, during which it was slowly detrained and moved downwind. At wind speeds>about 1.5 m s(-1), the initial cloud was not well-confined in the depression and moved downwind. Formulas suggested by Briggs et al. in 1990 in this journal satisfactorily predict the time durations of confinement. Sensitivity runs with the SLAB dense gas model show that the effect of a long confinement on maximum downwind concentrations is strongest near the depression. The model-predicted and observed maximum 20 s chlorine concentrations agree within a factor of two most of the time, as long as the release times based on Briggs' theory are used.


Application of Standardised Yoga Protocols as the Basis of Physiotherapy Recommendation in Treatment of Sleep Apneas: Moving Beyond Pranayamas.
Yoga is an ancient Indian practice of mental and physical exercises (syn: asanas), postures (syn: mudras), movements and breathing techniques which sustain healthy living of the body and the mind. It incorporates various exercises of breathing, oropharyngeal structures and facial expressions, the physiology and effect of which are comparable to international physiotherapy recommendations in treatment of obstructive sleep apnea (OSA) i.e. to preserve upper airway patency by maintaining airway dilator muscle tone. Preliminary results show that yoga can be an effective and constructive alternative to physiotherapy for sleep apnea and snoring patients. To compare the physiotherapy recommendations in snoring patients with various yoga exercises postures. To determine the efficacy of yoga in treatment of sleep apnea. To formulate a standardized yoga protocol for universal usage in sleep apnea. We studied the available literature on physiotherapy recommendations for OSA and yoga asanas involving the nasal, oropharynx and facial structures and perceived a noteworthy similarity in physiological basis of both. A set of these yogasanas were put together and patients presenting with snoring and diagnosed with mild to moderate sleep apnea were presented and encouraged to perform the standardized set of yoga exercises for a period of 3 months. A total of 23 patients were recommended yoga protocols as initial form of treatment in snoring and mild to moderate sleep apnea. Clinical and statistically significant improvement gauzed by recommended score chart was discerned in majority of subjects. The results were comparable to the efficacy of existing physiotherapy regimen published in international literature. The benefits of yoga in sleep disorders go beyond the scope of measured outcomes. Standardizing the protocols for yoga in treatment for snoring and sleep apnea is the need of the hour. Further studies on efficacy of yoga need to be performed to understand its full realm of potential.


The taenia solium glucose transporters TGTP1 and TGTP2 are not immunologically recognized by cysticercotic humans and swine.
Cysticercosis caused by the metacestode of the tapeworm Taenia solium causes economic losses in pork meat production, as well as being a human health hazard in some parts of the world. In order to determine if the glucose transporters TGTPI and TGTP2 are recognized by antibodies in the sera from cysticercotic humans and pigs, western blot assays were carried out using membrane fractions of insect cells expressing the two T. solium glucose transporters. Results demonstrated a complete lack of recognition of both TGTPs. These results are unexpected, because at least one transporter is present on the apical surface of the cysticercus tegument.


Selection criteria related to long-term survival following liver transplantation for colorectal liver metastasis.
Patients with nonresectable colorectal cancer receiving palliative chemotherapy have a 5-year overall survival rate of about 10%. Liver transplant provided a Kaplan-Meier-estimated 5-year overall survival of up to 83%. The objective of the study was to evaluate the ability of different scoring systems to predict long-term overall survival after liver transplant. Patients with colorectal cancer with nonresectable liver-only metastases determined by computed tomography (CT)/magnetic resonance imaging/positron emission tomography (PET)-CT scans from 2 prospective studies (SECA-I and -II) were included. All included patients had previously received chemotherapy. PET-CT was performed within 90 days of the liver transplant. Overall survival, disease-free survival, and survival after relapse based on the Fong Clinical Risk Score, total PET liver uptake (metabolic tumor volume), and Oslo Score were compared. At median follow-up of 85 months for live patients, Kaplan-Meier overall survival rates at 5 years were 100%, 78%, and 67% in patients with Fong Clinical Risk Score 0 to 2, metabolic tumor volume-low group, and Oslo Score 0 to 2, respectively. Median overall survival was 101, 68, and 65 months in patients with Fong Clinical Risk Score 0 to 2, metabolic tumor volume-low, and Oslo Score 0 to 2. These selection criteria may be used to obtain 5-year overall survival rates comparable to other indications for liver transplant.


Strain and sex differences in serum alpha-fetoprotein levels in Mus musculus.
Normal levels of circulating serum alpha-fetoprotein (AFP) in different inbred strains of mice, as determined by radioimmunoassay, are reported. These strains show different and characteristic values for the mean serum AFP concentration, suggesting genetic control of the serum level of this protein. Furthermore, within each strain a difference in serum levels of the protein is observed between sexes; males have a significantly higher serum AFP concentration.


mtDNA makes a U-turn for the mitochondrial nucleoid.
Mitochondria contain mtDNA derived from the ancestral endosymbiont genome. Important subunits of the oxidative phosphorylation system, which supplies cells with the energy currency ATP, are encoded by mtDNA. A naked mtDNA molecule is longer than a typical mitochondrion and is therefore compacted in vivo to form a nucleoprotein complex, denoted the mitochondrial nucleoid. Mitochondrial transcription factor A (TFAM) is the main factor packaging mtDNA into nucleoids and is also essential for mtDNA transcription initiation. The crystal structure of TFAM shows that it bends mtDNA in a sharp U-turn, which likely provides the structural basis for its dual functions. Super-resolution imaging studies have revealed that the nucleoid has an average diameter of ∼100nm and frequently contains a single copy of mtDNA. In this review the structure of the mitochondrial nucleoid and its possible regulatory roles in mtDNA expression will be discussed.


Brain prolyl endopeptidase expression in aging, APP transgenic mice and Alzheimer's disease.
Prolyl endopeptidase (PEP) is believed to inactivate neuropeptides that are present in the extracellular space. However, the intracellular localization of PEP suggests additional, yet unidentified physiological functions for this enzyme. Here we studied the expression, enzymatic activity and subcellular localization of PEP in adult and aged mouse brain as well as in brains of age-matched APP transgenic Tg2576 mice and in brains of Alzheimer's disease patients. In mouse brain PEP was exclusively expressed by neurons and displayed region- and age-specific differences in expression levels, with the highest PEP activity being present in cerebellum and a significant increase in hippocampal but not cortical or cerebellar PEP activity in aged mouse brain. In brains of young APP transgenic Tg2576 mice, hippocampal PEP activity was increased compared to wild-type littermates in the pre-plaque phase but not in aged mice with beta-amyloid plaque pathology. This "accelerated aging" with regard to hippocampal PEP expression in young APP transgenic mice might be one factor contributing to the observed cognitive deficits in these mice in the pre-plaque phase and could also explain in part the cognition-enhancing effects of PEP inhibitors in several experimental paradigms.


Location and functional analysis of the Aspergillus nidulans Aurora kinase confirm mitotic functions and suggest non-mitotic roles.
Filamentous fungi have devastating negative impacts as pathogens and agents of food spoilage but also have critical ecological importance and are utilized for industrial applications. The characteristic multinucleate nature of filamentous fungi is facilitated by limiting if, when and where septation, the fungal equivalent of cytokinesis, occurs. In the model filamentous fungus Aspergillus nidulans septation does not occur immediately after mitosis and is an incomplete process resulting in the formation of a septal pore whose permeability is cell cycle regulated. How mitotic regulators, such as the Aurora kinase, contribute to the often unique biology of filamentous fungi is not well understood. The Aurora B kinase has not previously been investigated in any detail during hyphal growth. Here we demonstrate for the first time that Aurora displays cell cycle dependent locations to the region of forming septa, the septal pore and mature septa as well as the mitotic apparatus. To functionally analyze Aurora, we generated a temperature sensitive allele revealing essential mitotic and spindle assembly checkpoint functions consistent with its location to the kinetochore region and spindle midzone. Our analysis also reveals that cellular and kinetochore Aurora levels increase during a mitotic spindle assembly checkpoint arrest and we propose that this could be important for checkpoint inactivation when spindle formation is prevented. We demonstrate that Aurora accumulation at mature septa following mitotic entry does not require mitotic progression but is dependent upon a timing mechanism. Surprisingly we also find that Aurora inactivation leads to cellular swelling and lysis indicating an unexpected function for Aurora in fungal cell growth. Thus in addition to its conserved mitotic functions our data suggest that Aurora has the capacity to be an important regulator of septal biology and cell growth in filamentous fungi.


In vivo transfer of cholesteryl esters from high density lipoproteins to very low density lipoproteins in man.
The fate of cholesteryl esters in high density lipoprotein (HDL) was studied to determine whether the transfer of esterified cholesterol from HDL to other plasma lipoproteins occurred to a significant extent in man. HDL cholesteryl ester, labelled in vitro with [3H] cholesterol, was injected into human subjects. Labelling of cholesteryl esters in very low density (VLDL) occurred rapidly and by 3 h, the esterified cholesterol in VLDL reached peak specific radioactivity. The removal rate of cholesteryl esters from HDL appeared to be exponential and of the order of 0.2/h; calculation of the apparent flux was about 150 mg/h which approximates reported values for total cholesterol esterification in human plasma in vivo. The rapid rate of labelling of VLDL from HDL suggests that the transfer of HDL cholesteryl esters to VLDL may represent a significant pathway for the disposal of HDL cholesterol.


Efficacy of portable X-ray in identifying retained suture needles in ophthalmologic cases.
To evaluate the role and efficacy of portable X-ray in reliably identifying retained suture needles in ophthalmologic surgical cases. Ophthalmologic 10-0 nylon suture needles were placed into 10 of 20 porcine eyes positioned within the orbit of a human skull. Portable, plain film radiographs were taken of all eyes with a C-arm fluoroscopy machine. The films were reviewed by six ophthalmologists and six radiologists who were blinded to the presence or absence of needles, as well as the number of needles used in the protocol. The sensitivity and specificity of identifying retained suture needles by plain film radiographs were then analysed based on the results of the physicians' interpretations of the films. The overall sensitivity and specificity for physicians reviewing radiographs with suspected intraoperative suture needles were 54 and 77%, respectively. When looking separately at radiologists reviewing the films, the sensitivity was 57% and the specificity was 87%. Ophthalmologists reviewing the films identified retained needles less reliably with a sensitivity of 51% and a specificity of 67%. Significant controversy exists regarding the reliability and utility of plain film radiography in identifying intraocular foreign bodies. This study demonstrates that the use of plain film radiographs to rule-out the presence of an intraocular surgical needle is neither a sensitive nor specific imaging modality.


Public perception of laser-assisted blepharoplasty versus blade-assisted blepharoplasty.
To evaluate perceptions of blade- versus laser-based blepharoplasty before and after being provided educational information. This interventional pre-post study included 145 randomly selected participants (Maisonneuve-Rosemont Hospital, Montreal, Canada, August 2020) who were asked about their perceptions surrounding blepharoplasty. Participants then received information about the techniques before answering final questions. Participants perceived no difference in outcomes for blade (37%) versus laser (40%) blepharoplasty precounselling. This increased to laser blepharoplasty postintervention (56%, p < 0.001) despite being told that there was no difference in outcomes. The higher the level of education among participants, the more likely they were to correctly believe that both techniques had similar outcomes (p = 0.049). Most participants would choose laser blepharoplasty initially (64%), and this percentage increased postintervention (81%, p < 0.001). The preintervention perception of blade blepharoplasty recovery time (20.1 ± 32.6 days) was longer than that for laser blepharoplasty (13.5 ± 32.0 days, p = 0.01) and increased for both techniques postintervention (p < 0.001). Perceived pain was lower for laser blepharoplasty. Postintervention, participants responded that additional costs of ($975 ± $1,091) would justify laser over blade blepharoplasty. Elucidating patient perceptions and preferences for blade- versus laser-based blepharoplasty provides surgeons with perspective on how to tailor preoperative counselling. Before and after the intervention, participants had a bias toward choosing laser blepharoplasty. The intervention seems to falsely convince people that laser blepharoplasty leads to better outcomes. Because the doctor's advice can greatly impact patients' decisions, physicians have to be careful not to give false expectations when counselling patients. Inaccurate recall of key educational takeaways suggests that information should be vulgarized and delivered actively to patients.


Bovine gallbladder mucin binds bilirubin in vitro.
Gallbladder mucin glycoprotein and bilirubin are frequently identified at the center of human cholesterol gallstones, suggesting that mucin-bilirubin complexes might function as nucleating agents for cholesterol gallstones. This study was undertaken to determine if bovine gallbladder mucin was capable of binding bilirubin in vitro. Chromatography of dialyzed bovine gallbladder bile on Sepharose 4B revealed that bile pigment (OD420) eluted in a high-molecular weight fraction also containing mucin, as well as in an included (low-molecular weight) fraction. When bilirubin (98.8% as IX alpha by high-pressure liquid chromatography) and purified bovine gallbladder mucin were ultracentrifuged in a sucrose density gradient, the presence of bilirubin-mucin complexes was observed. Alteration of the polymeric structure of mucin with mercaptoethanol caused loss of its ability to bind bilirubin, suggesting that the native polymeric configuration is required. These results indicate that mucin can bind bilirubin in vitro, and might explain their occurrence in the nucleus of human cholesterol stones.


Targeted treatment of invasive fungal infections accelerates healing of foot wounds in patients with Type 2 diabetes.
To test the hypothesis that fluconazole plus standard care is superior to the standard care for diabetic foot wounds infected with deep-seated fungal infections. We carried out a randomized, controlled, open-label, parallel-arm study in 75 patients with both fungal and bacterial infections in deep tissues of diabetic foot wounds. Thirty-seven patients (control group) were given standard care (surgical debridement + culture-specific antibiotics + offloading + glycaemic control) and 38 patients (treatment group) were given fluconazole 150 mg daily plus standard care. Wound surface area was measured every 2 weeks until the endpoints (complete epithelialization or skin grafting) were met. By week 4, the mean wound surface area reduced to 27.3 from 111.5 cm(2) in the treatment group, as opposed to 67.1 from 87.3 cm(2) in the control group. Subsequently, the mean wound surface areas were remarkably smaller in the treatment group compared with the control group, and statistically significant differences (P ≤ 0.05) in mean wound surface area were observed between the treatment group and the control group at week 6. However, no statistically significant (P ≤ 0.47) difference in complete healing was observed between the treatment group and the control group, 20 vs. 24. The mean wound healing time for the treatment group was 7.3 weeks, whereas for the control group it was 11.3 weeks (P ≤ 0.022). Similarly, the probability of wound healing in the treatment group was 50 vs. 20% in the control group at week 10. Fluconazole plus standard care was superior to standard care alone in accelerating wound reduction among patients with diabetes with deep-seated fungal infections in diabetic foot wounds. Those in the treatment group who did heal, healed more quickly (P ≤ 0.022), but overall healing was not different.


High rates of incident and prevalent anal human papillomavirus infection among young men who have sex with men.
There are few published estimates of anal human papillomavirus (HPV) infection rates among young men who have sex with men (YMSM). We estimated incidence and prevalence of type-specific anal HPV infection using clinician-collected anal swabs for HPV DNA testing obtained during a 1-year prospective study of 94 YMSM (mean age, 21 years) in Seattle. Seventy percent of YMSM had any HPV infection detected during the study, and HPV-16 and/or -18 were detected in 37%. The incidence rate for any new HPV infection was 38.5 per 1000 person-months and 15.3 per 1000 person-months for HPV-16/18; 19% had persistent HPV-16/18 infection. No participant tested positive for all 4 HPV types in the quadrivalent vaccine. The number of lifetime male receptive anal sex partners was significantly associated with HPV infection. The prevalence of HPV-16/18 was 6% among YMSM with a history of 1 receptive anal sex partner and 31% among YMSM with ≥ 2 partners. Although the high prevalence of HPV among YMSM highlights the desirability of vaccinating all boys as a strategy to avert the morbidity of HPV infection, most YMSM appear to remain naive to either HPV-16 or -18 well into their sexual lives and would benefit from HPV immunization.


Efficient search for informational cores in complex systems: Application to brain networks.
An important step in understanding the nature of the brain is to identify "cores" in the brain network, where brain areas strongly interact with each other. Cores can be considered as essential sub-networks for brain functions. In the last few decades, an information-theoretic approach to identifying cores has been developed. In this approach, interactions between parts are measured by an information loss function, which quantifies how much information would be lost if interactions between parts were removed. Then, a core called a "complex" is defined as a subsystem wherein the amount of information loss is locally maximal. Although identifying complexes can be a novel and useful approach, its application is practically impossible because computation time grows exponentially with system size. Here we propose a fast and exact algorithm for finding complexes, called Hierarchical Partitioning for Complex search (HPC). HPC hierarchically partitions systems to narrow down candidates for complexes. The computation time of HPC is polynomial, enabling us to find complexes in large systems (up to several hundred) in a practical amount of time. We prove that HPC is exact when an information loss function satisfies a mathematical property, monotonicity. We show that mutual information is one such information loss function. We also show that a broad class of submodular functions can be considered as such information loss functions, indicating the expandability of our framework to the class. We applied HPC to electrocorticogram recordings from a monkey and demonstrated that HPC revealed temporally stable and characteristic complexes.


Descriptive Analysis of Patient Readmissions Within 60 Days Due to Medication-Related Events.
Hospital readmissions have become a marker for quality health care. Readmissions secondary to failures of the medication use process are poorly documented and underrecognized. To identify the incidence of readmissions related to the medication use process and identify associated patient- and therapy-related risk factors. A prospective observational cohort study including patients discharged from an acute care medicine unit and readmitted within 60 days. The primary outcome was percentage of readmissions related to drug-related problems (DRPs) as defined by Pharmaceutical Care Network Europe (PCNE). Secondary outcomes included classification of problems using PCNE criteria, type and extent of pharmacist involvement in patient care, and identification of variables associated with a readmission related to a DRP. One hundred patients provided informed consent and were included for analysis. A DRP associated with readmission was identified in 64 patients. Sixty-one percent were classified as a potential problem with effect or lack of effect of pharmacotherapy. Patients who had a pharmacy consult were less likely to have a DRP (27% vs 47%; P = .04), and patients who missed follow-up appointments were more than 3 times as likely to have a DRP (20% vs 4%; P = .03). Presence of a pharmacy consult (odds ratio [OR], 0.38; 95% CI, 0.15-0.99; P = .05) and missed follow-up appointments (OR, 5.63; 95% CI, 1.52-20.86; P = .01) remained significant in a multivariate regression model. DRPs were frequent in patients who were readmitted within 60 days. Clinical pharmacist involvement in care and support for appropriate patient follow-up may reduce unnecessary admissions.


Muscle LIM Protein: Master regulator of cardiac and skeletal muscle functions.
Muscle LIM Protein (MLP) has emerged as a key regulator of striated muscle physiology and pathophysiology. Mutations in cysteine and glycine-rich protein 3 (CSRP3), the gene encoding MLP, are causative of human cardiomyopathies, whereas altered expression patterns are observed in human failing heart and skeletal myopathies. In vitro and in vivo evidences reveal a complex and diverse functional role of MLP in striated muscle, which is determined by its multiple interacting partners and subcellular distribution. Experimental evidence suggests that MLP is implicated in both myogenic differentiation and myocyte cytoarchitecture, although the full spectrum of its intracellular roles still unfolds.


Heightened Immune Response to Presumed Loxosceles reclusa Envenomation.
Loxoscelism is a systemic inflammatory reaction in response to a brown recluse spider bite (BRSB). In this case we describe a patient with a heightened inflammatory response to a presumed BRSB, with Coomb's positive hemolysis, cytoplasmic antineutrophil cytoplasmic antibody (cANCA) vasculitis, and features of hemophagocytic lymphohistiocytosis (HLH). A 24-y-old female presented with sudden pain and swelling to her lower back, nausea, fever, and tachycardia after a presumed BRSB. Hemolysis began on hospital day 3 (15.9 g·dL-1) with a nadir on hospital day 5 (6.3 g·dL-1). She had an lactate dehydrogenase of 1415 U·L-1, ferritin of 15534 ng·mL-1, persistent fever, and signs of bone marrow suppression despite hemolysis, with thrombocytopenia (100,000 μL-1) and an inadequate reticulocyte response (1.7%) suggestive of HLH. The patient's blood was Coomb's and cANCA/antiproteinase 3 positive. She had signs of toxin-induced vasculitis, with respiratory failure requiring bilevel positive airway pressure, radiographs with bilateral pulmonary infiltrates, and a desquamating rash. She received 6 U of packed red blood cells, furosemide for pleural and pericardial effusions, antibiotics, and symptomatic treatment during the acute phase of her illness. Hemolysis improved without glucocorticoids by hospital day 6. The patient demonstrated a dysregulated immunologic and complement-mediated response to the presumed BRSB. The triad of Coomb's positive hemolysis, cANCA vasculitis, and HLH-like reaction associated with a presumed BRSB is described for the first time in the literature and brings up questions for future research regarding the role of immune modulators and complement inhibitors in the treatment of severe loxoscelism as well as the genetic factors that predispose certain individuals to such reactions.


Prostate-specific targeting of the aqueous root extract of Croton membranaceus in experimental animals.
Croton membranaceus Müll.Arg. (Euphorbiaceae) is used for benign prostate hyperplasia (BPH) treatment. The study aimed at investigating organs that the aqueous root extracts of C. membranaceus (CMARE) target, which is absent in literature. Twenty-four male Sprague-Dawley rats (100-140 g) were randomly divided into 4 groups. Group 1, the control group received distilled water. Groups 2, 3 and 4 received 30, 150 and 300 mg kg(-1) b.wt CMARE respectively (oral gavage). Rats fed 90 days the standard chow diet ad libitum. Upon sacrifice, major organs were histologically examined and serum prostate-specific antigen (PSA) biochemically determined. Only the prostate was abnormal. Histologically, H&E staining revealed thickness and infoldings of the epithelial cells shrinking with increasing dose. The 30 mg kg(-1) group showed low columnar or flattened epithelium cells, whereas the columnar epithelium infoldings of the 150 mg kg(-1) b.wt and 300 mg kg(-1) b.wt groups were virtually nonexistent. The acini of the control, 30 mg kg(-1) b.wt group and the 150 mg kg(-1) b.wt groups showed clear pinkish secretion. However, secretion of the high-dose group appeared light pink in colour and the stroma cells appeared much darker than all the treated and control group. C. membranaceus targets the prostate with significant PSA reduction (P < 0.01).


Non-cardiogenic pulmonary edema during basiliximab induction in three adolescent renal transplant patients.
Introduction of the anti-CD-25 mAb basiliximab into renal transplant protocols has reduced the incidence of acute rejection. However, its side-effect profile is still unfolding. We report three adolescents who developed severe non-cardiogenic PE within 2 days of renal transplantation. Pretransplant cardiorespiratory evaluation was normal in all cases. Transplant immunosuppression consisted of basiliximab induction, corticosteroids, and tacrolimus. Patients received standard fluid management during and after the transplant surgery. Patients 1 and 2 were 17- and 21-yr-old females. Pretransplant Hct values were 35 and 25% respectively. Each received 5-L normal saline during surgery. EBL was 200 and 500 mL in patients 1 and 2, respectively. There was immediate post-operative diuresis. Both developed non-cardiogenic PE by POD no. 2. BIPAP and PRVC were administered respectively. In both cases PE resolved within 1 wk. Patient 3 was a 19-yr-old male with pretransplant Hct of 43% who received a cadaveric renal transplant after 23.5-h cold-ischemia; 3.5 L normal saline was given during surgery. EBL was 100 mL. Non-cardiogenic PE ensued on POD no. 2 warranting assisted ventilation. The patient died following a sudden cardiopulmonary arrest on POD no. 3. Potential mechanisms for the development of PE include cytokine release from basiliximab with increased capillary permeability, volume overload and ischemic-reperfusion injury. Improved awareness of this potential complication, prudent fluid management, and efforts to minimize graft-ischemia are recommended to prevent further cases.


An oral carcinogenicity and toxicity study of senna (Tinnevelly senna fruits) in the rat.
Senna (Tinnevelly senna fruits), a known laxative derived from plants, was administered by gavage to Sprague-Dawley (Crl:CD (SD) BR) rats once daily at dose levels of 0, 25, 100 and 300 mg/kg/day for up to 104 consecutive weeks. Based upon clinical signs related to the laxation effect of senna, the highest dose (300 mg/kg/day) was considered to be a maximum tolerated dose. Sixty animals per sex were assigned to the control and dose groups. Assessments included clinical chemistry, hematology, full histology (control and high-dose groups; in addition, low and mid dose: intestinal tract, adrenals, liver, kidneys, brain and gross lesions) and toxicokinetics. The primary treatment-related clinical observation was mucoid feces seen at 300 mg/kg/day. When compared to controls, animals administered 300 mg/kg/day had slightly reduced body weights, increased water consumption and notable changes in electrolytes in serum (increases in potassium and chloride) and urine (decreases in sodium, potassium and chloride). The changes in electrolytes are most likely physiologic adaptations to the laxative effect of senna. At necropsy, dark discoloration of the kidneys was observed in animals in all treated groups. Histological changes were seen in the kidneys of animals from all treated groups and included slight to moderate tubular basophilia and tubular pigment deposits. In addition, for all treated groups, minimal to slight hyperplasia was evident in the colon and cecum. These histological changes, together with the changes seen in the evaluation of clinical chemistry and urine parameters, have been shown to be reversible in a previous 13-week rat study of senna. No treatment-related neoplastic changes were observed in any of the examined organs. Based upon these data, it is concluded that senna is not carcinogenic even after daily administration for 2 years at dosages of up to 300 mg/kg/day in Sprague-Dawley rats.


The effects of enforced running on the gastrocnemius muscle in aging mice: an ultrastructural study.
C57BL/6J mice (6, 19 and 27 months old) were trained in an electrically driven treadmill for a total period of 10 weeks. The training program started with 5 min. run per day and reached a maximum of 30 min. per day. Light and electron microscopy examinations of the gastrocnemius muscle showed that in young animals endurance training did not evoke any appreciable changes. In contrast, both test animals and their controls in the old group revealed clear signs of muscle cell atrophy which for the most part was accompanied by focal loss of myofilaments, mitochondrial changes and an increase in the amount of endomyseal collagen fibrils. In the old-trained group, the most obvious abnormality comprised of multiplication of both the T-tubules and of the tubules of the sarcoplasmic reticulum. Consequently, most of these animals showed the formation of tubular aggregates in their gastrocnemius muscle. Hence, it appears that endurance training in old animals tends to enhance the regressive changes that accompany the aging process of mammalian skeletal muscle.


Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR).
The tumor necrosis factor (TNF) superfamily (TNFSF) includes about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Receptors of the tumor necrosis factor (TNF) superfamily (TNFSFRs) are pharmacological targets for treatment of inflammatory and autoimmune diseases. Currently, drugs targeting TNFSFR signaling are biological drugs (monoclonal antibodies, decoy receptors) aimed at binding and sequestering TNFSFR ligands. The glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR) signaling is involved in a series of inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. Our study aimed at repurposing FDA approved small molecules as protein-protein disruptors at the GITR ligand (GITRL) trimer, in order to inhibit the binding of GITRL to its receptor (GITR). A structure based molecular modeling approach was carried out to identify, through high throughput virtual screening, GITRL monomer-monomer disruptors. We used a database of ~8,000 FDA approved drugs, and after virtual screening, we focused on two hit compounds, minocycline and oxytetracycline. These two compounds were tested for their capability to modulate IL-17, IL-21 and RORγT expression in T lymphocytes, isolated from wild-type and GITR knock-out (GITR-/-) mice. Minocycline showed immunomodulatory effects specific to GITR activation and could represent a novel pharmacological tool to treat inflammatory diseases.


Monitoring presynaptic calcium dynamics in projection fibers by in vivo loading of a novel calcium indicator.
Fluorometric calcium measurements have revealed presynaptic residual calcium (Ca(res)) to be an important regulator of synaptic strength. However, in the mammalian brain, it has not been possible to monitor Ca(res) in fibers that project from one brain region to another. Here, we label neuronal projections by injecting dextran-conjugated calcium indicators into brain nuclei in vivo. Currently available dextran conjugates distort Ca(res) due to their high affinity for calcium. Therefore, we synthesized a low-affinity indicator, fluo-4 dextran, that can more accurately measure the amplitude and time course of Ca(res). We then demonstrate the utility of fluo-4 dextran by measuring Ca(res) at climbing fiber presynaptic terminals. This method promises to facilitate the study of many synapses in the mammalian CNS, both in brain slices and in vivo.


Role of benzyl alcohol in the prevention of heat-induced aggregation and inactivation of hen egg white lysozyme.
The aim of the study was to investigate the stability of a model protein, lysozyme, in the presence of the commonly used preservative benzyl alcohol. Techniques including lytic assay, size exclusion chromatography, circular dichroism, differential scanning calorimetry, native polyacrylamide gel electrophoresis and dynamic light scattering were used to study the overall stability of lysozyme in the presence of benzyl alcohol. The stability of lysozyme against thermal stress was higher in the presence of benzyl alcohol. In the presence of 0.5%, 0.9% and 2% v/v benzyl alcohol, the enzyme showed 33%, 42% and 75% residual activity, respectively, when exposed to 75 degrees C for 2 h, as compared to the 22% activity of control sample. A gradual increase in the size of aggregates was observed for the control sample relative to the samples containing benzyl alcohol, as a result of loss of monomer concentration. The effect was found to be concentration-dependent with 2% benzyl alcohol showing maximum prevention of heat-induced unfolding and aggregation. This effect is remarkable since the thermal transition temperature of the enzyme decreases in the presence of benzyl alcohol. Benzyl alcohol favours the thermal denaturation of lysozyme but stabilizes the lysozyme against the heat-induced aggregation.


Expression of single chain antibodies (ScFvs) for c-myc oncoprotein in recombinant Escherichia coli membranes by using the ice-nucleation protein of Pseudomonas syringae.
The ice nucleation protein (INP) is a glycosyl phosphatidylinositol anchored outer membrane protein found in certain Gram-negative bacteria. In this study, the INP from Pseudomonas syringae was applied as a fusion partner with the single chain antibody fragment (ScFv) against the human oncoprotein c-myc. Two new plasmids pNinaZ-myc and pNinaZScFv-BsaA1 were constructed and cloned into Escherichia coli JM109. The expression of the fusion protein was successfully demonstrated in the cloned cells. The fusion proteins had no effect on the viability of the host cells. Ice nucleation activity measurements and flow cytometry studies were followed to investigate the membrane expression of the fusion protein.


Transcription factors controlling osteoblastogenesis.
The recent development of molecular biology and mouse genetics and the analysis of the skeletal phenotype induced by genetic mutations in humans led to a better understanding of the role of transcription factors that govern bone formation. This review summarizes the role of transcription factors in osteoblastogenesis and provides an integrated perspective on how the activities of multiple classes of factors are coordinated for the complex process of developing the osteoblast phenotype. The roles of Runx2, the principal transcriptional regulator of osteoblast differentiation, Osterix, beta-Catenin and ATF which act downstream of Runx2, and other transcription factors that contribute to the control of osteoblastogenesis including the AP1, C/EBPs, PPARgamma and homeodomain, helix-loop-helix proteins are discussed. This review also updates the regulation of transcription factor expression by signaling factors and hormones that control osteoblastogenesis.


Green Synthesis of Sodium Alginate Capped -CuInS2 Quantum Dots with Improved Fluorescence Properties.
CuInS2 (CIS) quantum dots (QDs) are known to be ideal fluorophores based on their low toxicity and tunable emission. However, due to low quantum yield (QY) and photostability, the surface is usually passivated by a higher bandgap shell (e.g. ZnS). This always resulted in a blue-shifted emission position which is not usually favourable for biological imaging. To address this problem, we herein report the passivation of green synthesized near infra-red emitting glutathione (GSH) capped CuInS2 QDs using different concentration of sodium alginate (SA) at different temperatures. The as-synthesized QDs are small (~ 3.2 nm), highly crystalline and emitted in the near infra-red region. The optical results showed a 36% increase in photostability and a 2-fold increase in quantum yield at ratio 1:8 (SA: CIS) which is suitable for prolonged biological imaging applications. Transmission electron microscope and X-ray diffraction (XRD) analyses showed that the materials are highly crystalline without any change in shape and size after passivation with the biopolymer. Graphical Abstract.


Treatment of unilateral L5-S1 locked facet in a pediatric patient.
Traumatic unilateral lumbosacral facet dislocations are rare injuries. The majority of cases are treated with open reduction and instrumented spinal fusions. Only less commonly can they be managed conservatively. A 7-year-old unrestrained passenger was involved in a high-speed motor vehicle accident. X-ray/magnetic resonance/computed tomography imaging documented a unilateral L5-S1 facet dislocation and multiple lumbar/sacral fractures. The patient underwent open reduction and temporary L5-pelvic instrumentation without fusion; the instrumentation was removed 10 weeks later at which point follow-up imaging showed preserved lumbosacral stability. Open reduction with temporary instrumentation without fusion was successfully utilized to treat a unilateral L5-S1 facet dislocation in a 7-year-old child.


Echinococcus multilocoularis infection in India: First case report proved at autopsy.
The occurrence of Echinococcus multilocularis is reported in India for the first time. The patient was a young man, various clinical diagnoses were made and he finally died after an attempted membranotomy for suspected membranous obstruction in the inferior vena cava. Autopsy revealed classical E. multilocularis infection of the liver with direct spread of the inferior vena cava, the right atrium and through the diaphragm into the base of the left lung. It also had caused an outflow tract obstruction to the hepatic venous flow by direct physical pressure distorting the proximal intrahepatic portion of the inferior vena cava. In addition the patient had multi-valvular lesions of rheumatic origin and a terminal infective endocarditis due to staphyloccal infection.


Orthogonal analysis of functional gold nanoparticles for biomedical applications.
We report a comprehensive strategy based on implementation of orthogonal measurement techniques to provide critical and verifiable material characteristics for functionalized gold nanoparticles (AuNPs) used in biomedical applications. Samples were analyzed before and after ≈50 months of cold storage (≈4 °C). Biomedical applications require long-term storage at cold temperatures, which could have an impact on AuNP therapeutics. Thiolated polyethylene glycol (SH-PEG)-conjugated AuNPs with different terminal groups (methyl-, carboxylic-, and amine-) were chosen as a model system due to their high relevancy in biomedical applications. Electrospray-differential mobility analysis, asymmetric-flow field flow fractionation, transmission electron microscopy, scanning electron microscopy, atomic force microscopy, inductively coupled plasma mass spectrometry, and small-angle X-ray scattering were employed to provide both complementary and orthogonal information on (1) particle size and size distribution, (2) particle concentrations, (3) molecular conjugation properties (i.e., conformation and surface packing density), and (4) colloidal stability. Results show that SH-PEGs were conjugated on the surface of AuNPs to form a brush-like polymer corona. The surface packing density of SH-PEG was ≈0.42 nm(-2) for the methyl-PEG-SH AuNPs, ≈0.26 nm(-2) for the amine-SH-PEG AuNPs, and ≈0.18 nm(-2) for the carboxylic-PEG-SH AuNPs before cold storage, approximately 10 % of its theoretical maximum value. The conformation of surface-bound SH-PEGs was then estimated to be in an intermediate state between brush-like and random-coiled, based on the measured thicknesses in liquid and in dry states. By analyzing the change in particle size distribution and number concentration in suspension following cold storage, the long term colloidal stability of AuNPs was shown to be significantly improved via functionalization with SH-PEG, especially in the case of methyl-PEG-SH and carboxylic-PEG-SH (i.e., we estimate that >80 % of SH-PEG5K remained on the surface of AuNPs during storage). The work described here provides a generic strategy to track and analyze the material properties of functional AuNPs intended for biomedical applications, and highlights the importance of a multi-technique analysis. The effects of long term storage on the physical state of the particles, and on the stability of the ligand-AuNP conjugates, are employed to demonstrate the capacity of this approach to address critical issues relevant to clinical applications.


Perspectives of Rare Disease Experts on Newborn Genome Sequencing.
Newborn genome sequencing (NBSeq) can detect infants at risk for treatable disorders currently undetected by conventional newborn screening. Despite broad stakeholder support for NBSeq, the perspectives of rare disease experts regarding which diseases should be screened have not been ascertained. To query rare disease experts about their perspectives on NBSeq and which gene-disease pairs they consider appropriate to evaluate in apparently healthy newborns. This survey study, designed between November 2, 2021, and February 11, 2022, assessed experts' perspectives on 6 statements related to NBSeq. Experts were also asked to indicate whether they would recommend including each of 649 gene-disease pairs associated with potentially treatable conditions in NBSeq. The survey was administered between February 11 and September 23, 2022, to 386 experts, including all 144 directors of accredited medical and laboratory genetics training programs in the US. Expert perspectives on newborn screening using genome sequencing. The proportion of experts indicating agreement or disagreement with each survey statement and those who selected inclusion of each gene-disease pair were tabulated. Exploratory analyses of responses by gender and age were conducted using t and χ2 tests. Of 386 experts invited, 238 (61.7%) responded (mean [SD] age, 52.6 [12.8] years [range 27-93 years]; 126 [52.9%] women and 112 [47.1%] men). Among the experts who responded, 161 (87.9%) agreed that NBSeq for monogenic treatable disorders should be made available to all newborns; 107 (58.5%) agreed that NBSeq should include genes associated with treatable disorders, even if those conditions were low penetrance; 68 (37.2%) agreed that actionable adult-onset conditions should be sequenced in newborns to facilitate cascade testing in parents, and 51 (27.9%) agreed that NBSeq should include screening for conditions with no established therapies or management guidelines. The following 25 genes were recommended by 85% or more of the experts: OTC, G6PC, SLC37A4, CYP11B1, ARSB, F8, F9, SLC2A1, CYP17A1, RB1, IDS, GUSB, DMD, GLUD1, CYP11A1, GALNS, CPS1, PLPBP, ALDH7A1, SLC26A3, SLC25A15, SMPD1, GATM, SLC7A7, and NAGS. Including these, 42 gene-disease pairs were endorsed by at least 80% of experts, and 432 genes were endorsed by at least 50% of experts. In this survey study, rare disease experts broadly supported NBSeq for treatable conditions and demonstrated substantial concordance regarding the inclusion of a specific subset of genes in NBSeq.


Single-incision laparoscopic enucleation for pancreatic insulinoma with preoperative nasopancreatic stent placement: A case report.
Most insulinomas are benign and solitary, with a tumor diameter less than 2 cm; therefore, laparoscopic enucleation, which is a minimally invasive procedure that can preserve the pancreatic parenchyma, is considered an optimal procedure. The key to enucleation is to avoid injury to the main pancreatic duct (MPD). Herein, we present a case in which single-incision laparoscopic enucleation (SILE) was performed for insulinomas, with preoperative nasopancreatic stent (NPS) placement. A male patient in his fifties underwent SILE for insulinomas. To prevent injury to the MPD, an NPS was preoperatively placed. All surgical procedures were performed through a single mini-laparotomy site in the umbilicus. NPS placement facilitated identification of the MPD under laparoscopic ultrasonography. Enucleation was successfully completed without any injury to the MPD, and the NPS was removed immediately after confirming that there was no injury to the MPD by the NPS via pancreatography. The postoperative course was uneventful. This report serves to highlight the maximum safety and minimal invasiveness of SILE with the preoperative NPS placement. Preoperative NPS placement is useful for avoiding injury to the MPD during enucleation and has the merit of helping to recognize whether leakage occurs by intraoperative pancreatography via the NPS. Preoperative NPS placement helps to ensure the safe enucleation of pancreatic insulinomas even in single-incision laparoscopic surgery, with minimal invasiveness and better cosmetic outcomes.


Atomic Structure of the Francisella T6SS Central Spike Reveals a Unique α-Helical Lid and a Putative Cargo.
Francisella bacteria rely on a phylogenetically distinct type VI secretion system (T6SS) to escape host phagosomes and cause the fatal disease tularemia, but the structural and molecular mechanisms involved are unknown. Here we report the atomic structure of the Francisella T6SS central spike complex, obtained by cryo-electron microscopy. Our structural and functional studies demonstrate that, unlike the single-protein spike composition of other T6SS subtypes, Francisella T6SS's central spike is formed by two proteins, PdpA and VgrG, akin to T4-bacteriophage gp27 and gp5, respectively, and that PdpA has unique characteristics, including a putative cargo within its cavity and an N-terminal helical lid. Structure-guided mutagenesis demonstrates that the PdpA N-terminal lid and C-terminal spike are essential to Francisella T6SS function. PdpA is thus both an adaptor, connecting VgrG to the tube, and a likely carrier of secreted cargo. These findings are important to understanding Francisella pathogenicity and designing therapeutics to combat tularemia.


Enrichment of apolipoprotein A-IV and apolipoprotein D in the HDL proteome is associated with HDL functions in diabetic kidney disease without dialysis.
Diabetic kidney disease (DKD) is associated with lipid derangements that worsen kidney function and enhance cardiovascular (CVD) risk. The management of dyslipidemia, hypertension and other traditional risk factors does not completely prevent CVD complications, bringing up the participation of nontraditional risk factors such as advanced glycation end products (AGEs), carbamoylation and changes in the HDL proteome and functionality. The HDL composition, proteome, chemical modification and functionality were analyzed in nondialysis subjects with DKD categorized according to the estimated glomerular filtration rate (eGFR) and urinary albumin excretion rate (AER). Individuals with DKD were divided into eGFR> 60 mL/min/1.73 m2 plus AER stages A1 and A2 (n = 10) and eGFR< 60 plus A3 (n = 25) and matched by age with control subjects (eGFR> 60; n = 8). Targeted proteomic analyses quantified 28 proteins associated with HDL in all groups, although only 2 were more highly expressed in the eGFR< 60 + A3 group than in the controls: apolipoprotein D (apoD) and apoA-IV. HDL from the eGFR< 60 + A3 group presented higher levels of total AGEs (20%), pentosidine (6.3%) and carbamoylation (4.2 x) and a reduced ability to remove 14C-cholesterol from macrophages (33%) in comparison to HDL from controls. The antioxidant role of HDL (lag time for LDL oxidation) was similar among groups, but HDL from the eGFR< 60 + A3 group presented a greater ability to inhibit the secretion of IL-6 and TNF-alpha (95%) in LPS-elicited macrophages in comparison to the control group. The increase in apoD and apoA-IV could contribute to counteracting the HDL chemical modification by AGEs and carbamoylation, which contributes to HDL loss of function in well-established DKD.


Oxylipin profile in saliva from patients with cystic fibrosis reveals a balance between pro-resolving and pro-inflammatory molecules.
Oxylipins are signaling molecules originated by fatty acids that modulate vascular and bronchial tone, bronchial secretion, cytokine production and immune cell activity. The unbalanced production of pro-inflammatory and pro-resolving (i.e., anti-inflammatory) oxylipins has a relevant role in the pathogenesis of pulmonary inflammation like in cystic fibrosis (CF). We analyzed by LC-MRM/MS 65 oxylipins and 4 fatty acids in resting saliva from 69 patients with CF and 50 healthy subjects (controls). The salivary levels of 48/65 oxylipins were significantly different between CF patients and controls. Among these, EpETE, DHET, 6ketoPGE1 and HDHA were significantly higher in saliva from CF patients than in controls. All these molecules display anti-inflammatory effects, i.e., releasing of bronchial and vascular tone, modulation of cytokine release. While 20-hydroxyPGF2A, PGB2, EpDPE, 9 K-12-ELA, bicyclo-PGE2, oleic acid, LTC4, linoleic acid, 15oxoEDE, 20 hydroxyPGE2 and DHK-PGD2/PGE2 (mostly associated to pro-inflammatory effects) resulted significantly lower in CF patients than in controls. Our data suggest that the salivary oxylipins profile in CF patients is addressed toward a global anti-inflammatory effect. Although these findings need be confirmed on larger populations in prospective studies, they will contribute to better understand the pathogenesis of CF chronic inflammation and to drive targeted therapies based on the modulation of oxylipins synthesis and degradation.


Position of the American Dietetic Association: Addressing world hunger, malnutrition, and food insecurity.
It is the position of the American Dietetic Association (ADA) that access to adequate amounts of safe, nutritious, and culturally appropriate food at all times is a fundamental human right. Hunger continues to be a worldwide problem of staggering proportions. The Association supports programs and encourages practices that combat hunger and malnutrition, produce food security, promote self-sufficiency, and are environmentally and economically sustainable. The Association is aware that hunger exists in a world of plenty and that poverty, gender inequity, ethnocentrism, racism, and the lack of political will are key constraints to solving the problems of global hunger and malnutrition. Recognizing that simplistic approaches are inadequate, the ADA identifies sustainable development as the long-term strategy to ending world hunger and achieving food security. Sustainable development requires political, economic, and social changes that include empowering the disenfranchised, widening access to assets and other resources, narrowing the gap between rich and poor, and adjusting consumption patterns so as to foster good stewardship of nature. Additionally, because the health status of future generations is related to the well-being of their mothers, achieving food security will also require increased access for women to education, adequate health care and sanitation, and economic opportunities. This position paper reviews the complex issues of global food insecurity and discusses long-term solutions for achieving world food security. Achieving the end of world hunger has been and is now within our grasp. There is sufficient food to feed everyone, and solutions can be realized now that will benefit all of humanity. As noted in the paper, most people who examine the costs of ending versus not ending world hunger are bewildered by the question of why humanity did not solve the problem a long time ago. The Association supports programs and encourages practices that combat hunger and malnutrition, produce food security, promote self-sufficiency, respect local cultures, and are environmentally and economically sustainable. The ADA recognizes that decisions and actions that dietetics professionals make as practitioners and consumers can help reduce the extent of poverty and hunger both here and abroad. This paper provides information, resources, and strategies to assist dietetics professionals in improving the public's understanding of key issues, becoming advocates of the poor, and influencing the political will to end world hunger.


A historical analysis of vaccine mandates in the United States military and its application to the COVID-19 vaccine mandate.
The Department of Defense has implemented a mandate that all military personnel be vaccinated against COVID-19. This article reviews the historical precedent of vaccine mandates for United States military personnel dating back to the formation of the continental army, as well as previous controversies about vaccine mandates such as the first influenza vaccine mandate and the Anthrax Vaccine Immunization Program. The historical review discusses precedent for the current COVID-19 vaccine mandate and the reception of these vaccine mandates by military personnel. The review then discusses how these historical lessons can inform the present COVID-19 vaccine mandate.


Mechanical properties of normal versus cancerous breast cells.
A cell's mechanical properties are important in determining its adhesion, migration, and response to the mechanical properties of its microenvironment and may help explain behavioral differences between normal and cancerous cells. Using fluorescently labeled peroxisomes as microrheological probes, the interior mechanical properties of normal breast cells were compared to a metastatic breast cell line, MDA-MB-231. To estimate the mechanical properties of cell cytoplasms from the motions of their peroxisomes, it was necessary to reduce the contribution of active cytoskeletal motions to peroxisome motion. This was done by treating the cells with blebbistatin, to inhibit myosin II, or with sodium azide and 2-deoxy-D-glucose, to reduce intracellular ATP. Using either treatment, the peroxisomes exhibited normal diffusion or subdiffusion, and their mean squared displacements (MSDs) showed that the MDA-MB-231 cells were significantly softer than normal cells. For these two cell types, peroxisome MSDs in treated and untreated cells converged at high frequencies, indicating that cytoskeletal structure was not altered by the drug treatment. The MSDs from ATP-depleted cells were analyzed by the generalized Stokes-Einstein relation to estimate the interior viscoelastic modulus G* and its components, the elastic shear modulus G' and viscous shear modulus G", at angular frequencies between 0.126 and 628 rad/s. These moduli are the material coefficients that enter into stress-strain relations and relaxation times in quantitative mechanical models such as the poroelastic model of the interior regions of cancerous and non-cancerous cells.


[Immediate improvement in facial paralysis after surgical decompression (author's transl)].
17 cases of severe facial paralysis were studied before and after microsurgical decompression, by quantitative electromyography (electromyogram integrated in volts) at the site of the zyogmatic arch. -- In 76% of cases, no significant improvement was measured. -- An immediate, frank improvement occurred infrequently (12%), was short-lived and did not have any influence on the final result.


Controlled Inhibition of Apoptosis by Photoactivatable Caspase Inhibitors.
Caspases control regulated cell death (apoptosis), a process that is crucial in the development of multicellular organisms as well as in various diseases. In order to spatiotemporally study apoptosis, we here develop photoactivatable caspase inhibitors. These are based on cysteine-reactive acyloxymethyl ketone electrophiles connected to a peptide targeting caspases. Importantly, the aspartate crucial for recognition by caspases is caged with a photoprotecting group. Ester photocages were found to be labile, and it was critical to have a nitroindoline cage, which forms a stable amide bond with the aspartate side chain. The nitroindoline-protected inhibitors lead to an efficient turn-on of inhibitory activity after irradiation with light. They are applicable in live cells, where they prevent anti-FAS-induced apoptosis only upon irradiation. Overall, these reagents will allow a better understanding of the spatial and temporal dimensions of apoptosis in complex, dynamic systems.


Predictors of uptake of influenza vaccination--a survey of pregnant women in Western Australia.
Pregnant women are at increased risk of complications following influenza infection. Vaccination is the most effective preventive strategy. This survey aimed to determine the levels of uptake of influenza vaccine in pregnant women in Western Australia (WA), the proportion of women offered vaccination as part of antenatal care, and women's attitudes toward influenza vaccination in pregnancy. Computer assisted telephone interviews were conducted with 416 randomly selected women who were pregnant during the 2012 influenza vaccination season. Influenza vaccination coverage was 23%. Predictors of vaccination included believing that vaccination is safe for the infant, having been recommended vaccination by an antenatal care provider, and attending a general practitioner for most antenatal care. The majority (74%) of unvaccinated women reported that they would have the vaccine if their antenatal care provider recommended it. General practitioners lead the way in antenatal influenza vaccination in WA. Vaccination coverage can be improved if recommending and offering influenza vaccination becomes a routine part of antenatal care.


Advising patients with diabetes about fasting during Ramadhan.
Fasting for Ramadhan is one of the five Pillars of Islam and is very important to Muslims. Nurses can help patients with diabetes to fast successfully by means of a pre-fast assessment, careful medicine management and good patient education.


Epstein-Barr virus is absent in gastric superficial neoplastic lesions.
Epstein-Barr virus (EBV) has been associated with about 9% of all gastric carcinomas, but its role in gastric carcinogenesis remains unclear since there is lack of evidence of EBV presence in pre-neoplastic lesions of gastric mucosa. This study intends to determine the prevalence of EBV in gastric dysplasia and superficial neoplasia to clarify whether EBV infection is an early or late event in gastric cancer development. This retrospective study included a total of 242 gastric lesions from 199 consecutive patients who were referred for endoscopic resection. The histological classification of lesions includes 137 low- and high-grade dysplasia and 105 superficial carcinomas. EBV infection was investigated by EBER-ISH. Results showed that EBV was not detected in any epithelial cells of any case with dysplasia or superficial carcinomas, although we observed the presence of a small number of EBV-infected lymphocytes in 2.1% of all lesions. These results showed that EBV is not present in gastric dysplasia neither in superficial carcinomas suggesting that EBV carcinogenesis is a late event in well/moderately differentiated gastric carcinogenesis.


Detection of neovascularization in diabetic retinopathy.
Diabetic retinopathy has become an increasingly important cause of blindness. Nevertheless, vision loss can be prevented from early detection of diabetic retinopathy and monitor with regular examination. Common automatic detection of retinal abnormalities is for microaneurysms, hemorrhages, hard exudates, and cotton wool spot. However, there is a worse case of retinal abnormality, but not much research was done to detect it. It is neovascularization where new blood vessels grow due to extensive lack of oxygen in the retinal capillaries. This paper shows that various combination of techniques such as image normalization, compactness classifier, morphology-based operator, Gaussian filtering, and thresholding techniques were used in developing of neovascularization detection. A function matrix box was added in order to classify the neovascularization from natural blood vessel. A region-based neovascularization classification was attempted as a diagnostic accuracy. The developed method was tested on images from different database sources with varying quality and image resolution. It shows that specificity and sensitivity results were 89.4% and 63.9%, respectively. The proposed approach yield encouraging results for future development.


Folate functionalized chitosan nanoparticles as targeted delivery systems for improved anticancer efficiency of cytarabine in MCF-7 human breast cancer cell lines.
Anticancer drug cytarabine, has been widely used for treating haematological malignancies while it has minimal activity against solid tumours, which demands continuous infusion leading to high dose cytarabine toxicity. In this study, folate conjugated chitosan nanoparticles (FCCNP) were used for targeted delivery of cytarabine in breast adenocarcinoma cell lines by making use of the overexpressed folate receptors on the surface of MCF-7. Folate was conjugated to chitosan using carbodiimide. FCCNPs show spherical morphology with a size of<50 nm. Zeta potential of + 45.2 mV and PDI of 0.98 from DLS measurement confirms a stable monodisperse nanoformulation. Cytotoxicity was studied in folate receptor positive, MCF-7 and folate receptor negative, A-549 cell lines. Increased cellular uptake of the drug incorporated nanoparticles was confirmed in MCF-7 cells with fluorophore, squaraine 650 compared to A-549 cells. The relative fold of expression of genes involved in apoptosis such as bax, cyt c and cas 9 were upregulated. The present in vitro study confirms improved cytotoxicity of cytarabine folate conjugated chitosan nanoparticles in MCF-7 cells.


Effectiveness of hospital lipid-lowering protocol of intensive lipid-lowering therapy for patients with acute coronary syndrome.
The achievement of a target low-density lipoprotein cholesterol (LDL-C) level in clinical settings is often insufficient. A hospital lipid-lowering protocol (HLP) could be effective for providing the optimal lipid-lowering therapy. Herein we determined the effectiveness of a HLP for acute coronary syndrome (ACS) patients. We retrospectively analyzed 1,497 patients who underwent successful percutaneous coronary intervention for ACS at our hospital (November 2011 to May 2020). In December 2018, we introduced a HLP that included the prescription of the maximum tolerated dose of statin, ezetimibe, and eicosapentaenoic acid. We compared the lipid profile and clinical outcomes at 12 months between before (Control group: 1,219 patients) and after the HLP's introduction (HLP group: 278 patients). The primary outcome was the achievement rate of LDL-C < 1.8 mmol/L (70 mg/dL). The key secondary outcomes were the change value and ratio of LDL-C plus the major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, target vessel revascularization, and stent thrombosis. The achievement rate of LDL-C < 1.8 mmol/L was significantly higher in the HLP group than in the Control group (58% vs. 27%, p < 0.01). The HLP group's change ratio and LDL-C values were significantly lower than those of the Control group (-39.5 [-55.1, -13.2]% vs. -20.4 [-38.4, 0]%, p < 0.001; -41 [-69, -11] mg/dL vs. -21 [-38, 0] mg/dL, p < 0.001). MACE was similar between the groups (16.9 vs. 15.5%, p = 0.66). Implementing a HLP for ACS patients improved the achievement of target LDL-C at 12 months.


Proton and sodium pumps regulate the plasma membrane potential of different stages of Trypanosoma cruzi.
We studied the plasma membrane potential (DeltaPsi) in different stages of Trypanosoma cruzi using the potentiometric fluorescent dye bisoxonol. Our results clearly demonstrate that a proton pump plays a significant role in the regulation of DeltaPsi in all stages of T. cruzi as evidenced by depolarization of the DeltaPsi by H(+)-ATPase inhibitors dicyclohexylcarbo-diimide, N-ethylmaleimide, diethylstilbestrol, and bafilomycin A(1). The H(+)-ATPase appeared to be activated by acidic conditions in trypomastigotes as evidenced by hyperpolarization of the DeltaPsi upon addition of acid. In contrast to epimastigotes and amastigotes, the DeltaPsi of trypomastigotes was markedly sensitive to extracellular Na(+) and K(+) concentrations and evidence was provided for an outward directed Cl(minus sign) channel in this stage as well. Additionally, for the first time, the existence of an ouabain-sensitive functional sodium pump was demonstrated in T. cruzi based on the depolarization of the DeltaPsi in trypomastigotes by ouabain in the presence of Na(+). In the epimastigotes, ouabain had no effect on the DeltaPsi in a sodium rich buffer. However, ouabain induced an additional significant depolarization in these stages when their DeltaPsi was already partially depolarized by the H(+)-ATPase inhibitor dicyclohexylcarbo-diimide, supporting the presence of an ouabain-sensitive sodium pump whose activity is masked by the H(+)-ATPase. In the amastigotes no evidence for a functional sodium pump could be found. In support of an inwardly directed K(+) channel, the DeltaPsi was hyperpolarized by K(+) free buffer in trypomastigotes and epimastigotes and by Ba(2+) in epimastigotes and amastigotes. The presence of K(+) channels in amastigotes and a sodium pump in trypomastigotes, in addition to the H(+)-ATPase, could provide important new targets for trypanocidal drug development.


Equol-producing status affects exercise training-induced improvement in arterial compliance in postmenopausal women.
Central arterial compliance decreases drastically after menopause. Regular intake of soy isoflavone and aerobic exercise increase arterial compliance. The equol is a metabolite of isoflavone daidzein by gut microbiome. We determined whether the equol-producing status affects aerobic exercise-induced improvement in carotid arterial compliance. Forty-three postmenopausal women were assigned to two intervention groups: 1) exercise and isoflavone (Ex+Iso, n = 27 females) or 2) isoflavone interventions (Iso; n = 16 females). Participants of the Ex+Iso intervention group completed an 8-wk aerobic exercise training, and all participants were administered with oral isoflavone supplements during the interventions. The equol-producing status (equol producers or nonproducers) was determined from urine equol concentrations after a soy challenge. In the Ex+Iso intervention group, carotid arterial compliance increased in the equol producers (0.084 ± 0.030→0.117 ± 0.035 mm2/mmHg), but not in the nonproducers (0.089 ± 0.028→0.097 ± 0.026 mm2/mmHg) after the intervention (interaction effect; P < 0.05). The magnitude of increases in carotid arterial compliance was significantly greater in the equol producers than in the non-equol producers (P < 0.05). In the isoflavone intervention group, there were no changes in any parameters after the intervention irrespective of the equol status. These results suggest that equol-producing status is obligatory to aerobic exercise training-induced improvements in central arterial compliance in postmenopausal women.NEW & NOTEWORTHY Isoflavone intake and aerobic exercise increase central artery compliance. Equol, a metabolite of isoflavone daidzein by gut microbiome, has beneficial effects on vascular function. We demonstrated for the first time that the interaction of aerobic exercise and equol production status plays an essential role in improvements in central artery compliance in postmenopausal women. More specifically, the equol-producing status was obligatory to exercise training-induced improvements in central arterial compliance in postmenopausal women.


Aspirin metabolites 2,3‑DHBA and 2,5‑DHBA inhibit cancer cell growth: Implications in colorectal cancer prevention.
Although compelling evidence exists on the ability of aspirin to treat colorectal cancer (CRC), and numerous theories and targets have been proposed, a consensus has not been reached regarding its mechanism of action. In this regard, a relatively unexplored area is the role played by aspirin metabolites 2,3‑dihydroxybenzoic acid (2,3‑DHBA) and 2,5‑dihydroxybenzoic acid (2,5‑DHBA) in its chemopreventive actions. In a previous study, we demonstrated that 2,3‑DHBA and 2,5‑DHBA inhibited CDK1 enzyme activity in vitro. The aim of the present study was to understand the effect of these metabolites on the enzyme activity of all CDKs involved in cell cycle regulation (CDKs 1, 2, 4 and 6) as well as their effect on clonal formation in three different cancer cell lines. Additionally, in silico studies were performed to determine the potential sites of interactions of 2,3‑DHBA and 2,5‑DHBA with CDKs. We demonstrated that 2,3‑DHBA and 2,5‑DHBA inhibits CDK‑1 enzyme activity beginning at 500 µM, while CDK2 and CDK4 activity was inhibited only at higher concentrations (>750 µM). 2,3‑DHBA inhibited CDK6 enzyme activity from 250 µM, while 2,5‑DHBA inhibited its activity >750 µM. Colony formation assays showed that 2,5‑DHBA was highly effective in inhibiting clonal formation in HCT‑116 and HT‑29 CRC cell lines (250‑500 µM), and in the MDA‑MB‑231 breast cancer cell line (~100 µM). In contrast 2,3‑DHBA was effective only in MDA‑MB‑231 cells (~500 µM). Both aspirin and salicylic acid failed to inhibit all four CDKs and colony formation. Based on the present results, it is suggested that 2,3‑DHBA and 2,5‑DHBA may contribute to the chemopreventive properties of aspirin, possibly through the inhibition of CDKs. The present data and the proposed mechanisms should open new areas for future investigations.


[Isolation of acido-alcohol resistant bacilli from peripheral blood in a case of severe miliary tuberculosis].
The case of a 64 years old woman with a severe miliary tuberculous dissemination is presented. The singularity of this case arises from the fact that it could be demonstrated in blood the presence of acid-alcohol resistant bacilli by means of the Ziehl-Neelsen technic.


Socio-economic status and pregnancy outcome. An Australian study.
A prospective cohort of 8556 pregnant women attending the Mater Misericordiae Mothers' Hospital in Brisbane was examined to consider the impact of socio-economic status on pregnancy outcome. The indicators of socio-economic status selected were family income, maternal education and paternal occupational status. Pregnancy outcomes considered were preterm delivery, low birthweight, low birthweight for gestational age, and perinatal death. Subsidiary analyses were also undertaken for Apgar scores, time to establish respiration, need for mechanical respiration and admission to intensive care. Before adjustment, the main consistent association was between the occupational status of the father and three measures of perinatal morbidity. Initial adjustment for the mother's socio-demographic background and weight/height ratio reduced the strength and statistical significance of the above associations, while further adjustment for lifestyle variations between the three status groups further reduced the above associations to marginal statistical significance. The findings suggest that observed class differences in pregnancy outcome are attributable to the mother's personal characteristics (height/weight, parity) and her lifestyle.


[Is basal hypersecretion an indication of the presence of Zollinger-Ellison syndrome?].
Twenty patients with gastric basal hipersecretion over 15 mEq/hr and a suspicion on a Z-E syndrome or gastrinoma were studied by means of histamin gastric analisis, calcium test and measurement of lower esophageal sphincter pressures. In none of them a pancreatic tumour was found at operation, being their post-operative course normal up to a 60 months follow-up. The use of these everyday techniques is proposed for medical centers which have no facilities for gastrin radioimmunoassay techniques.


A new method of auriculoplasty for protruding ears.
The paper describes a new method of correction of prominent ears which is based on mathematical preoperative planning of ear-to-skull distance. The antihelix is shaped by two dermosubcutaneous perichondrial flaps; the conchal spring is eased by means of a wedge-shaped cartilage excision in the area of the isthmus of the cartilage or the auricle, while residual protrusion of the lobule is corrected by a Z-plasty. This method was used to correct 233 protruding ears in 129 patients and better aesthetic results were obtained than those reported for other modern methods of corrective auriculoplasty. The advantages of the method are that it is radical, less traumatic than many others and eliminates any possibility of subjective errors in the preoperative planning of the ear-to-skull distance.


Progress in understanding the role of lipids in membrane protein folding.
Detailed investigations of membrane protein folding present a number of serious technical challenges. Most studies addressing this subject have emphasized aspects of protein amino acid sequence and structure. While it is generally accepted that the interplay between proteins and lipids plays an important role in membrane protein folding, the role(s) played by membrane lipids in this process have only recently been explored in any detail. This review is intended to summarize recent studies in which particular lipids or membrane physical properties have been shown to play a role in the folding of intact, functionally competent integral membrane proteins. This article is part of a Special Issue entitled: Protein Folding in Membranes.


Photoredox-HAT Catalysis for Primary Amine α-C-H Alkylation: Mechanistic Insight with Transient Absorption Spectroscopy.
The synergistic use of (organo)photoredox catalysts with hydrogen-atom transfer (HAT) cocatalysts has emerged as a powerful strategy for innate C(sp3)-H bond functionalization, particularly for C-H bonds α- to nitrogen. Azide ion (N3-) was recently identified as an effective HAT catalyst for the challenging α-C-H alkylation of unprotected, primary alkylamines, in combination with dicyanoarene photocatalysts such as 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN). Here, time-resolved transient absorption spectroscopy over sub-picosecond to microsecond timescales provides kinetic and mechanistic details of the photoredox catalytic cycle in acetonitrile solution. Direct observation of the electron transfer from N3- to photoexcited 4CzIPN reveals the participation of the S1 excited electronic state of the organic photocatalyst as an electron acceptor, but the N3• radical product of this reaction is not observed. Instead, both time-resolved infrared and UV-visible spectroscopic measurements implicate rapid association of N3• with N3- (a favorable process in acetonitrile) to form the N6•- radical anion. Electronic structure calculations indicate that N3• is the active participant in the HAT reaction, suggesting a role for N6•- as a reservoir that regulates the concentration of N3•.


Hot and cold tumors: Immunological features and the therapeutic strategies.
The "hotness" or "coldness" of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients' clinical efficacy. The switch mechanism of "hotness" and "coldness" and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the "hotness" or "coldness" effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of "hot and cold tumors," and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to "hot and cold tumors" in details. Different therapeutic strategies for "cold and hot tumors" based on clinical efficacy were analyzed with drug targets and proteins for "cold and hot tumors." Furthermore, this review combines the therapeutic strategies of different "hot and cold tumors" with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision-making of cancer treatment.


Continuous-Flow Synthesis of Cycloparaphenylene Building Blocks on a Large Scale.
The synthesis of [n]cycloparaphenylenes ([n]CPPs) and similar nanohoops is usually based on combining building blocks to a macrocyclic precursor, which is then aromatized in the final step. Access to those building blocks in large amounts will simplify the synthesis and studies of CPPs as novel functional materials for applications. Herein, we report a continuous-flow synthesis of key CPP building blocks by using versatile synthesis techniques such as electrochemical oxidation, lithiations and Suzuki cross-couplings in self-built reactors on up-to kilogram scale.


Correlations among Diabetic Microvascular Complications: A Systematic Review and Meta-analysis.
Early detection of diabetic microvascular complications is of great significance for disease prognosis. This systematic review and meta-analysis aimed to investigate the correlation among diabetic microvascular complications which may indicate the importance of screening for other complications in the presence of one disorder. PubMed, Embase, and the Cochrane Library were searched and a total of 26 cross-sectional studies met our inclusion criteria. Diabetic retinopathy (DR) had a proven risk association with diabetic kidney disease (DKD) [odds ratio (OR): 4.64, 95% confidence interval (CI): 2.47-8.75, p < 0.01], while DKD also related to DR (OR: 2.37, 95% CI: 1.79-3.15, p < 0.01). In addition, DR was associated with diabetic neuropathy (DN) (OR: 2.22, 95% CI: 1.70-2.90, p < 0.01), and DN was related to DR (OR: 1.73, 95% CI: 1.19-2.51, p < 0.01). However, the risk correlation between DKD and DN was not definite. Therefore, regular screening for the other two microvascular complications in the case of one complication makes sense, especially for patients with DR. The secondary results presented some physical conditions and comorbidities which were correlated with these three complications and thus should be paid more attention.


Characterization of RhoC expression in benign and malignant breast disease: a potential new marker for small breast carcinomas with metastatic ability.
The most important factor in predicting outcome in patients with early breast cancer is the stage of the disease. There is no robust marker capable of identifying invasive carcinomas that despite their small size have a high metastatic potential, and that would benefit from more aggressive treatment. RhoC-GTPase is a member of the Ras-superfamily and is involved in cell polarity and motility. We hypothesized that RhoC expression would be a good marker to identify breast cancer patients with high risk of developing metastases, and that it would be a prognostic marker useful in the clinic. We developed a specific anti-RhoC antibody and studied archival breast tissues that comprise a broad spectrum of breast disease. One hundred eighty-two specimens from 164 patients were used. Immunohistochemistry was performed on formalin-fixed tissues. Staining intensity was graded 0 to 3+ (0 to 1+ was considered negative and 2 to 3+ was considered positive). RhoC was not expressed in any of the normal, fibrocystic changes, atypical hyperplasia, or ductal carcinoma in situ, but was expressed in 36 of 118 invasive carcinomas and strongly correlated with tumor stage (P = 0.01). RhoC had high specificity (88%) in detecting invasive carcinomas with metastatic potential. Of the invasive carcinomas smaller than 1 cm, RhoC was highly specific in detecting tumors that developed metastases. RhoC expression was associated with negative progesterone receptor and HER-2/neu overexpression. We characterized RhoC expression in human breast tissues. RhoC is specifically expressed in invasive breast carcinomas capable of metastasizing, and it may be clinically useful in patients with tumors smaller than 1 cm to guide treatment.


The sitting active and prone passive lag test: an inter-rater reliability study.
To determine inter-rater reliability in identifying a knee extension lag using the sitting active and prone passive lag test (SAPLT). 56 patients with a diagnosis of knee pain were randomly assigned and independently examined by two physical therapists at a time, to determine the presence of an active or a passive extension lag at the knee. An active lag was determined by the inability of the erectly seated subject to actively extend the involved knee in maximal dorsiflexion of the ankle to the same level as the normal knee held in maximal extension and ankle in maximal dorsiflexion, as seen by the levels of the toes. A passive lag was determined by placing the subject prone with the knees just past the edge of the table and determining the high position of the heel in a fully resting extension position compared to the heel on the normal side. For the sitting active lag test, the inter-rater reliability was 'good' (Kappa 0.792, SE of kappa 0.115, 95% confidence interval). For the prone passive lag test, the inter-rater reliability was 'good' (Kappa 0.636, SE of kappa 0.136, 95% confidence interval). The SAPLT may be incorporated as a simple yet effective test to determine the presence of a knee extension lag. It identifies the type of restraint, active, passive or both, and is suggestive of the most appropriate management.


Detection and management of depression and/or anxiety for people with epilepsy in primary health care settings in Zambia.
Among the 50 million people with epilepsy (PWE) worldwide ∼15 to 60% likely also suffer from depression and/or anxiety and 80% reside in low-income regions where human and technological resources for care are extremely limited. In Zambia, we carried out a retrospective chart review of 200 randomly selected files of PWE using a structured abstraction form to systematically collect socio-demographic data and clinical details on the detection and treatment of depression and/or anxiety. Only 2 PWE (1%) had depression diagnosed and none were given a diagnosis of an anxiety disorder. Complaints suggestive of underlying depressive and/or anxiety disorders were documented in 120 (60%), but no diagnoses were made and no referrals, investigations or treatment were offered. Further research is required to establish the prevalence of depression and anxiety among PWE in sub-Saharan Africa and efforts are needed to improve screening and treatment for common, treatable psychiatric comorbidities in PWE in resource limited settings.


Randomized Comparison of Exercise Intervention Versus Usual Care in Older Adult Patients with Frailty After Acute Myocardial Infarction.
Older adult patients with frailty are rarely involved in rehabilitation programs after myocardial infarction. Our aim was to investigate the benefits of exercise intervention in these patients. A total of 150 survivors after acute myocardial infarction, ≥70 years and with pre-frailty or frailty (Fried scale ≥1 points), were randomized to control (n = 77) or intervention (n = 73) groups. The intervention consisted of a 3-month exercise program, under physiotherapist supervision, followed by an independent home-based program. The main outcome was frailty (Fried scale) at 3 months and 1 year. Secondary endpoints were clinical events (mortality or any readmission) at 1 year. Mean age was 80 years (range = 70-96). In the intervention group, 44 (60%) out of 73 patients participated in the program and 23 (32%) completed it. Overall, there was a decrease in the Fried score in the intervention group at 3 months, with no effect at 1 year. However, in the intention-to-treat analysis, such change did not achieve statistical significance (P = 0.110). Only treatment comparisons made among the subgroups that participated in (P = 0.033) and completed (P = 0.018) the program achieved statistical significance. There were no differences in clinical events. Worse Fried score trajectory along follow-up increased mortality risk (hazard ratio [HR] = 2.38, 95% confidence interval [CI] 1.24-4.55, P = 0.009) CONCLUSIONS: Recruitment and retention for a physical program in older adult patients with frailty after myocardial infarction was challenging. Frailty status improved in the subgroup that participated in the program, although this benefit was attenuated after shifting to a home-based program. A better frailty trajectory might influence midterm prognosis. (ClinicalTrials.govNCT02715453).


Developmental changes in choline acetyltransferase and glutamate decarboxylase activity in various regions of the brain of the male, female, and neonatally androgenized female rat.
In attempt to discern effects of sex hormones on the development of neurotransmitter systems in the rat brain, choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD) have been measured at postnatal days 8, 12, 25, and 60 in five regions (amygdala, anterior hypothalamus, hippocampus, olfactory bulbs, and cerebral cortex) of the brains of normal male, normal female, and neonatally androgen-treated female rats. Essentially no association between sex or of neonatal "androgenization" on either enzymol were found. The data, however, provide new information on the relative rates of development of ChAT and GAD in five regions of the rat brain which supplement the limited information already available in the literature. ChAT activity was highest in amygdala and hypothalamus, but developed most rapidly in hippocampus and cerebral cortex. The relative activities and patterns of development of GAD activity were similar to those of ChAT.