Purification and characterization of endoglucanase Ss from Clostridium thermocellum.
The extracellular cellulolytic enzymes of the thermophilic anaerobe Clostridium thermocellum occur as a protein complex or aggregate known as the cellulosome. By using a combination of ion-exchange, adsorption and hydrophobic-interaction chromatography, it was possible to isolate from extracellular broth a specific endoglucanase of interest without the use of denaturants. The endoglucanase was identified as the cellulosomal subunit Ss by the use of specific antibodies. The enzyme has an Mr of 83,000, an isoelectric point of 3.55, optimum pH of 6.6 and optimum temperature of 70 degrees C. It hydrolyses CM-cellulose and, at a higher rate, the cellodextrins, cellotetraose and cellopentaose, but does not hydrolyse a crystalline cellulose such as Avicel. Cellobiose and cellotriose are also immune to attack. It differs from endoglucanases previously isolated by others and a 76,000-Mr endoglucanase recently isolated in this laboratory.


Calcium signaling induces acquisition of dendritic cell characteristics in chronic myelogenous leukemia myeloid progenitor cells.
Effective host T lymphocyte sensitization to malignant cells depends on successful antigen presentation. In this study, we examined the capacity of malignant myeloid progenitor cells of patients in the chronic phase of chronic myelogenous leukemia (CML) to acquire characteristics of activated dendritic cells (DCs) after intracellular calcium mobilization, thereby bypassing a need for third-party antigen-presenting cells. Treatment of purified CD33(+) CML cells from 15 patients with calcium ionophore (CI) consistently resulted in de novo expression of the costimulatory molecules CD80 (B7.1) and CD86 (B7.2), CD40 and the DC-specific activation marker CD83, as well as marked up-regulation of MHC class I and II molecules and the adhesion molecule CD54. Most of these changes occurred within 24 hr of treatment. Morphologically, CI-treated CML cells developed long dendritic projections similar to those seen in mature DCs. Functionally, CI-treated CML cells provided stimulation of allogeneic T lymphocytes 10- to 20-fold that of untreated CML cells or untreated monocytes. Fluorescent in situ hybridization of CI-activated CML cells confirmed their leukemic origin by displaying the typical bcr/abl fusion signal. No difference in bcr/abl translocation percentages between untreated and CI-treated CML nuclei was observed. These observations indicate that calcium mobilization may constitute a valuable approach for rapidly and reliably generating CML-derived DCs for immunotherapy of CML.


HIV infection and risk behaviours among young gay and bisexual men in Vancouver.
Young gay and bisexual men may perceive that the consequences of HIV infection have dramatically improved with the availability of highly active antiretroviral therapy. We therefore sought to identify trends in HIV infection rates and associated risk behaviours among young gay and bisexual men in Vancouver. Prospective cohort study involving gay and bisexual men aged 18-30 years who had not previously tested HIV positive. Subjects were recruited through physicians, clinics and community outreach in Vancouver. Annually participants were tested for HIV antibodies and asked to complete a self-administered questionnaire pertaining to sociodemographic characteristics, sexual behaviours and substance use. Prevalence of HIV infection and risk behaviours were determined for eligible participants who completed a baseline questionnaire and HIV testing as of May 1998. The primary outcome was the proportion of men who reported having protected sex during the year before enrollment and who reported any episode of unprotected sex by the time of the first follow-up visit. A total of 681 men completed a baseline questionnaire and HIV testing as of May 1998. The median duration between baseline and the first follow-up visit was 14 months. The median age was 25 years. Most of the subjects were white and of high socioeconomic status. The majority (549 [80.6%]) reported having sex only with men; 81 (11.9%) reported bisexual activity. Of the 503 men who had one or more regular male partners, 245 (48.7%) reported at least one episode of unprotected anal sex in the year before enrollment; the corresponding number among the 537 who had one or more casual male partners was 140 (26.1%). The prevalence and incidence of HIV seropositivity were 1.8% (95% confidence interval [CI] 0.8%-2.8%) and 1.7 per 100 person-years [95% CI 0.7-2.7], respectively. Fifty-two (26.5%) of the 196 and 55 (29.7%) of the 185 men with regular partners who reported having practiced protected insertive and receptive anal sex in the year before the baseline visit reported engaging in these activities without a condom at the follow-up visit; the corresponding numbers among the 232 and 242 men with causal partners who had practiced protected insertive and receptive anal sex before the baseline visit were 43 (15.5%) and 26 (9.4%) respectively at follow-up. The incidence of HIV infection is unacceptably high among this cohort of young gay and bisexual men. Preliminary results suggest a disturbing trend toward increasing levels of unprotected anal intercourse.


Computerised cognitive remediation to enhance mobility in older adults: a single-blind, single-centre, randomised trial.
Decline in executive functions and related cognitive processes is associated with mobility decline, and these functions might be amenable to cognitive remediation. This study aimed to examine whether a computerised cognitive remediation programme would improve walking in adults aged 70 years and older. This single-blind, randomised trial at one academic centre in the USA evaluated the efficacy of an 8-week computerised programme (also known as brain games) of progressive intensity and complexity to improve walking in older adults at high-risk for mobility disability. Inclusion criteria included being 70 years or older; ambulatory; and at high-risk for mobility disability, defined using a cutscore of nine or less (frail range) on the Short Physical Performance Battery and a walking speed of 100 cm/s or less. Individuals with dementia, acute or terminal medical illnesses, recent or planned surgery affecting mobility, mobility limitations solely due to musculoskeletal limitation or pain that prevented them from completing mobility tests, and those who were nursing home residents were excluded. Participants were block randomised (1:1; block size 12 and no stratification) to the intervention group or the control group (low complexity computer games and health education classes). Primary outcomes were change in walking speed at normal pace and walking while talking conditions assessed from baseline to 8 weeks post-intervention by investigators who were masked to group assignment. Groups were compared using the intention-to-treat principle with linear mixed models adjusted for confounders. This trial was registered with ClinicalTrails.gov, NCT02567227. Between March 1, 2016, and March 12, 2020, 383 patients were enrolled and randomly assigned to the intervention or control group. After randomisation, 11 (3%) patients were diagnosed with dementia. 372 (97%; 271 [73%] women) were included in the intention-to-treat analysis. The mean age of participants was 77·0 years [SD 5·6]). 183 (49·2%) participants were Black and 62 (16·7%) were Hispanic. 314 (93%) of the target 338 completers had finished the intervention when the trial was terminated due to the COVID-19 pandemic. Although there were significant within-group improvements in both groups after the 8-week intervention, there was no significant difference in normal walking speed (-1·03 cm/s [SD 1·30]; 95% CI -3·60 to 1·54) and walking while talking conditions (0·59 cm/s [SD 1·61]; 95% CI -2·59 to 3·76) between the intervention and control groups. Similarly, within-group, but no between-group, differences were seen on executive function tests and physical function. There were no severe adverse events related to interventions. Computerised cognitive remediation improved walking in adults aged 70 years and older at high-risk for mobility disability, but improvements were not significantly greater compared with an active control. Although our findings corroborate the within-group improvements on cognition and mobility reported in previous pilot clinical trials, future studies are required to determine the optimal dose, frequency, intensity, and content of computerised cognitive remediation programmes. National Institute on Aging.


Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain.
Neuroinflammation and dysfunctional glial glutamate transporters (GTs) in the spinal dorsal horn are implicated in the genesis of neuropathic pain. The authors determined whether adenosine monophosphate-activated protein kinase (AMPK) in the spinal dorsal horn regulates these processes in rodents with neuropathic pain. Hind paw withdrawal responses to radiant heat and mechanical stimuli were used to assess nociceptive behaviors. Spinal markers related to neuroinflammation and glial GTs were determined by Western blotting. AMPK activities were manipulated pharmacologically and genetically. Regulation of glial GTs was determined by measuring protein expression and activities of glial GTs. AMPK activities were reduced in the spinal dorsal horn of rats (n = 5) with thermal hyperalgesia induced by nerve injury, which were accompanied with the activation of astrocytes, increased production of interleukin-1β and activities of glycogen synthase kinase 3β, and suppressed protein expression of glial glutamate transporter-1. Thermal hyperalgesia was reversed by spinal activation of AMPK in neuropathic rats (n = 10) and induced by inhibiting spinal AMPK in naive rats (n = 7 to 8). Spinal AMPKα knockdown (n = 6) and AMPKα1 conditional knockout (n = 6) induced thermal hyperalgesia and mechanical allodynia. These genetic alterations mimicked the changes of molecular markers induced by nerve injury. Pharmacological activation of AMPK enhanced glial GT activity in mice with neuropathic pain (n = 8) and attenuated glial glutamate transporter-1 internalization induced by interleukin-1β (n = 4). These findings suggest that enhancing spinal AMPK activities could be an effective approach for the treatment of neuropathic pain.


SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx.
The primate lentivirus auxiliary protein Vpx counteracts an unknown restriction factor that renders human dendritic and myeloid cells largely refractory to HIV-1 infection. Here we identify SAMHD1 as this restriction factor. SAMHD1 is a protein involved in Aicardi-Goutières syndrome, a genetic encephalopathy with symptoms mimicking congenital viral infection, that has been proposed to act as a negative regulator of the interferon response. We show that Vpx induces proteasomal degradation of SAMHD1. Silencing of SAMHD1 in non-permissive cell lines alleviates HIV-1 restriction and is associated with a significant accumulation of viral DNA in infected cells. Concurrently, overexpression of SAMHD1 in sensitive cells inhibits HIV-1 infection. The putative phosphohydrolase activity of SAMHD1 is probably required for HIV-1 restriction. Vpx-mediated relief of restriction is abolished in SAMHD1-negative cells. Finally, silencing of SAMHD1 markedly increases the susceptibility of monocytic-derived dendritic cells to infection. Our results demonstrate that SAMHD1 is an antiretroviral protein expressed in cells of the myeloid lineage that inhibits an early step of the viral life cycle.


Topological Data Analysis of Electroencephalogram Signals for Pediatric Obstructive Sleep Apnea.
Topological data analysis (TDA) is an emerging technique for biological signal processing. TDA leverages the invariant topological features of signals in a metric space for robust analysis of signals even in the presence of noise. In this paper, we leverage TDA on brain connectivity networks derived from electroencephalogram (EEG) signals to identify statistical differences between pediatric patients with obstructive sleep apnea (OSA) and pediatric patients without OSA. We leverage a large corpus of data, and show that TDA enables us to see a statistical difference between the brain dynamics of the two groups.Clinical relevance- This establishes the potential of topological data analysis as a tool to identify obstructive sleep apnea without requiring a full polysomnogram study, and provides an initial investigation towards easier and more scalable obstructive sleep apnea diagnosis.


Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer's disease: the OmegAD study.
Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA. Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured. F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid. The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.


Theory meets experiment for elucidating the structure and stability of non-covalent complexes: water-amine interaction as a proof of concept.
Several gas-phase spectroscopic investigations have focused on a better understanding of the nature of weak, non-covalent interactions in model systems. However, their characterization and interpretation are still far from being satisfactory. A promising route to fill this gap is offered by strategies in which high-resolution rotational spectroscopy is deeply integrated with state-of-the-art quantum-chemical methodology to accurately determine intermolecular parameters and interaction energies, with the latter interpreted by means of powerful energy decomposition analyses (EDAs). As a proof of concept of this approach, we have selected the adducts formed by n-propylamine (PA) and iso-propylamine (IPA) with water. Among the stable structures computationally predicted, four (out of five) isomers of the PA-water complex and two isomers (trans and gauche) of the IPA-water adduct have been characterized with supersonic jet Fourier transform microwave spectroscopy. Starting from the experimental rotational constants for different isotopic species, computation of the corresponding vibrational corrections allowed a semi-experimental determination of the intermolecular parameters. Different EDAs point out that in all cases a strong O-HN hydrogen bond is the primary interaction. Accurate computations indicate that the length and ramification of the alkyl chain do not significantly affect the water-amine interactions, which - on the contrary - modify the stability order of PA conformers with respect to the isolated systems.


Clinical predictors of epidemic outcome in meningococcal infection in Jos, Nigeria.
The clinical predictors of outcome in children admitted into the Emergency Paediatric Unit at the Jos University Teaching Hospital with meningococcal infection during an out-break of the disease (between February-April 1996) were studied. Eighty seven children were admitted with meningococcal infection during the period. There were 60 males and 27 females (M:F = 2.2:1), aged between five weeks and 16 years (mean 7.7 +/- 4.9 years). Overall mortality was 26.4 per cent. Eighty five per cent of the patients who presented in shock died, compared with nine per cent who presented without shock (p < 0.000001). Similarly, 65% of the patients who presented in coma died, compared with 12.5% who did not present in coma (p < 0.000001). Other factors associated with a poor outcome included age one year and below, petechial/purpuric rash on presentation and meningococcaemia. Complications were documented in 27 (31.0%) of the patients, consisting mainly of deafness, extensive vasculitis/ulceration of extremities, gangrene of legs hemiparesis and cranial nerve palsies.


Bmp2, Bmp4 and Bmp7 are co-required in the mouse AER for normal digit patterning but not limb outgrowth.
Outgrowth and patterning of the vertebrate limb requires a functional apical ectodermal ridge (AER). The AER is a thickening of ectodermal tissue located at the distal end of the limb bud. Loss of this structure, either through genetic or physical manipulations results in truncation of the limb. A number of genes, including Bmps, are expressed in the AER. Previously, it was shown that removal of the BMP receptor Bmpr1a specifically from the AER resulted in complete loss of hindlimbs suggesting that Bmp signaling in the AER is required for limb outgrowth. In this report, we genetically removed the three known AER-expressed Bmp ligands, Bmp2, Bmp4 and Bmp7 from the AER of the limb bud using floxed conditional alleles and the Msx2-cre allele. Surprisingly, only defects in digit patterning and not limb outgrowth were observed. In triple mutants, the anterior and posterior AER was present but loss of the central region of the AER was observed. These data suggest that Bmp ligands expressed in the AER are not required for limb outgrowth but instead play an essential role in maintaining the AER and patterning vertebrate digits.


Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-alpha-selective agonist.
To investigate the involvement of retinoic acid receptor (RAR)-alpha in allograft rejection, we investigated the effect of a novel selective agonist to the receptor, ER-38925, in a mouse cardiac allograft model. Prophylactic treatment with ER-38925 inhibited the acute rejection of the mouse cardiac allograft (BALB/c --> C3H/HeN) at 0.3 and 3 mg/kg, and its effect was enhanced in combination with tacrolimus. In this model, ER-38925 remarkably inhibited cytotoxic T lymphocyte induction and alloantigen-stimulated production of cytokines, i.e. IL-2, IL-12 and IFN-gamma. In the chronic rejection model, combined treatment with tacrolimus and ER-38925 reduced the grade and incidence of arteriosclerosis in the cardiac allografts significantly more potently than tacrolimus monotherapy. ER-38925 inhibited the proliferation of rat aortic smooth muscle cells stimulated in vitro, presumably through the induction of a cyclin-dependent kinase inhibitor, p27(kip-1). Those results provide a rationale for using RAR-alpha agonists as immunosuppressants in human organ transplantation.


White blood cell differential: a call for standards.
The technology available to count and classify white blood cells has rapidly evolved from 1974 to the present. Two previous conferences, the College of American Pathologists Aspen Conference (1977) and Blood Cells in Paris (1980) have considered the technical and medical questions raised by these new technologies. The National Committee for Clinical Laboratory Standards (NCCLS) met in November 1984 to continue this debate and to provide a forum for manufacturers, laboratory directors, and government regulatory agencies to establish standards for the performance of the white blood cell differential. The development and clinical evaluation of the current commercially available white cell differential counters is reviewed as background for this meeting.


Exciton-to-Dopant Energy Transfer Dynamics in Mn2+ Doped CsPbBr3 Nanowires Synthesized by Diffusion Doping.
Mn2+ doped perovskite nanocrystals have garnered significant attention in optoelectronic applications. However, the synthesis of Mn2+ doped perovskite nanowires (NWs) poses challenges, and the dynamics of energy transfer from the exciton to Mn2+ remains unexplored, which is crucial for optimizing Mn2+ luminescence efficiency. Herein, we present a method to synthesize Mn2+ doped CsPbBr3 NWs with a photoluminescence quantum yield of 52% by diffusing Mn2+ into seed CsPbBr3 NWs grown via a hot injection method. We control the solution and lattice chemical potentials of Pb2+ and Mn2+ to enable Mn2+ to diffuse into the CsPbBr3 NWs while minimizing Ostwald ripening. Variable temperature photoluminescence spectroscopy reveals that the energy transfer from the exciton to Mn2+ in Mn2+ doped CsPbBr3 NWs is temperature dependent. A dynamic competition is observed between energy transfer and backward energy transfer, resulting in stronger Mn2+ photoluminescence at 80 K. This work provides a specific synthesis pathway for Mn2+ doped CsPbBr3 NWs and sheds light on their exciton-to-Mn2+ energy transfer dynamics.


Is BRAFV600E mutation a marker for central nodal metastasis in small papillary thyroid carcinoma?
Utilizing BRAF(V600E) mutation as a marker may reduce unnecessary prophylactic central neck dissection (pCND) in clinically nodal negative (cN0) neck for small (≤2 cm) classical papillary thyroid carcinoma (PTC). We aimed to assess whether BRAF is a significant independent predictor of occult central nodal metastasis (CNM) and its contribution to the overall prediction after adjusting for other significant preoperative clinical factors in small PTC. Primary tumor tissue (paraffin-embedded) from 845 patients with small classical cN0 PTC who underwent pCND was tested for BRAF mutation. Clinicopathologic factors were compared between those with and without BRAF. BRAF was evaluated to see if it was an independent factor for CNM. Prediction scores were generated using logistic regression models and their predictability was measured by the area under the ROC curve (AUC). The prevalence of BRAF was 628/845 (74.3%) while the rate of CNM was 285/845 (33.7%). Male sex (odds ratio (OR): 2.68, 95% CI: 1.71-4.20), large tumor size (OR: 2.68, 95% CI: 1.80-4.00), multifocality (OR: 1.49, 95% CI: 1.07-2.09), lymphovascular permeation (OR: 10.40, 95% CI: 5.18-20.88), and BRAF (OR: 1.65, 95% CI: 1.10-2.46) were significant independent predictors of CNM, while coexisting Hashimoto's thyroiditis (OR: 0.56, 95% CI: 0.40-0.80) was an independent protective factor. The AUC for prediction score based on tumor size and male sex was similar to that of prediction score based on tumor size, male sex, and BRAF status (0.68 vs 0.69, P=0.60). Although BRAF was an independent predictor of CNM, knowing its status did not substantially improve the overall prediction. A simpler prediction score based on male sex and tumor size might be sufficient.


Short-term plasticity based network model of place cells dynamics.
Rodent hippocampus exhibits strikingly different regimes of population activity in different behavioral states. During locomotion, hippocampal activity oscillates at theta frequency (5-12 Hz) and cells fire at specific locations in the environment, the place fields. As the animal runs through a place field, spikes are emitted at progressively earlier phases of the theta cycles. During immobility, hippocampus exhibits sharp irregular bursts of activity, with occasional rapid orderly activation of place cells expressing a possible trajectory of the animal. The mechanisms underlying this rich repertoire of dynamics are still unclear. We developed a novel recurrent network model that accounts for the observed phenomena. We assume that the network stores a map of the environment in its recurrent connections, which are endowed with short-term synaptic depression. We show that the network dynamics exhibits two different regimes that are similar to the experimentally observed population activity states in the hippocampus. The operating regime can be solely controlled by external inputs. Our results suggest that short-term synaptic plasticity is a potential mechanism contributing to shape the population activity in hippocampus.


Hematopoietic stem cell transplantation with unrelated cord blood or haploidentical donor grafts in adult patients with secondary acute myeloid leukemia, a comparative study from Eurocord and the ALWP EBMT.
Survival of patients with secondary acute myeloid leukemia (sAML) is poor. Cord blood transplantation (UCBT) and non-T-cell-depleted stem cell transplantation from haploidentical donors (HAPLO) are both strategies that have shown encouraging results in patients who do not have an human leukocyte antigen (HLA)-matched sibling or unrelated donor. We retrospectively analyzed outcomes of 409 adults with sAML receiving either UCBT (n = 163) or HAPLO (n = 246) in EBMT centers. Myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD) was the antecedent diagnosis in 79% of UCBT and 85% of HAPLO recipients. In multivariate analysis, UCBT was associated with higher risk of grade II-IV acute GVHD (HR 1.9, p = 0.009) and lower GHVD-free-relapse-free-survival (GRFS) (HR 1.57, p = 0.007) compared to HAPLO. Chronic-GVHD, RI, NRM, LFS, and OS were not statistically different between the two. Early disease stage at transplant was independently associated with lower RI and NRM and higher OS and LFS. These results indicate that HAPLO is associated with better GRFS and lower aGvHD compared to UCBT in patients with sAML and that UCBT can be a valid alternative for sAML patients who lack a matched sibling, a proper haploidentical or an unrelated donor.


Accumulation, internalization and therapeutic efficacy of neuropilin-1-targeted liposomes.
Advancements in liposomal drug delivery have produced long circulating and very stable drug formulations. These formulations minimize systemic exposure; however, unfortunately, therapeutic efficacy has remained limited due to the slow diffusion of liposomal particles within the tumor and limited release or uptake of the encapsulated drug. Here, the carboxyl-terminated CRPPR peptide, with affinity for the receptor neuropilin-1 (NRP), which is expressed on both endothelial and cancer cells, was conjugated to liposomes to enhance the tumor accumulation. Using a pH sensitive probe, liposomes were optimized for specific NRP binding and subsequent cellular internalization using in vitro cellular assays. Liposomes conjugated with the carboxyl-terminated CRPPR peptide (termed C-LPP liposomes) bound to the NRP-positive primary prostatic carcinoma cell line (PPC-1) but did not bind to the NRP-negative PC-3 cell line, and binding was observed with liposomal peptide concentrations as low as 0.16mol%. Binding of the C-LPP liposomes was receptor-limited, with saturation observed at high liposome concentrations. The identical peptide sequence bearing an amide terminus did not bind specifically, accumulating only with a high (2.5mol%) peptide concentration and adhering equally to NRP positive and negative cell lines. The binding of C-LPP liposomes conjugated with 0.63mol% of the peptide was 83-fold greater than liposomes conjugated with the amide version of the peptide. Cellular internalization was also enhanced with C-LPP liposomes, with 80% internalized following 3h incubation. Additionally, fluorescence in the blood pool (~40% of the injected dose) was similar for liposomes conjugated with 0.63mol% of carboxyl-terminated peptide and non-targeted liposomes at 24h after injection, indicating stable circulation. Prior to doxorubicin treatment, in vivo tumor accumulation and vascular targeting were increased for peptide-conjugated liposomes compared to non-targeted liposomes based on confocal imaging of a fluorescent cargo, and the availability of the vascular receptor was confirmed with ultrasound molecular imaging. Finally, over a 4-week course of therapy, tumor knockdown resulting from doxorubicin-loaded, C-LPP liposomes was similar to non-targeted liposomes in syngeneic tumor-bearing FVB mice and C-LPP liposomes reduced doxorubicin accumulation in the skin and heart and eliminated skin toxicity. Taken together, our results demonstrate that a carboxyl-terminated RXXR peptide sequence, conjugated to liposomes at a concentration of 0.63mol%, retains long circulation but enhances binding and internalization, and reduces toxicity.


HPLC determination of caffeine and paraxanthine in urine: An assay for cytochrome P450 1A2 activity.
Cytochrome P450 enzymes are a family of heme-containing proteins located throughout the body with roles in metabolism of endogenous and exogenous compounds. Among exogenous compounds, clinically relevant pharmaceutical agents are nearly all metabolized by P450 enzymes. However, the activity of the different cytochrome P450 enzymes varies among individuals and, therefore, so does drug efficacy as well as susceptibility to side effects and toxicity. Thus, assessing P450 activity is of great interest in drug development and clinical pharmacology. This study investigates the phenotyping of a single P450 activity by analyzing urine samples using isocratic reverse-phase HPLC. Specifically, the activity of human P450 1A2, which converts caffeine into paraxanthine, can be investigated by measuring the change in caffeine and paraxanthine concentrations in urine over time following a single dose of caffeine. There is an observable relationship between caffeine intake and paraxanthine formation that varies among individuals. This laboratory exercise provides a means for simple assessment of P450 1A2 metabolic activity using an HPLC method without additional extraction or purification steps and introduces students to the complexities of individualized medicine as well as the basic biochemical techniques of sample preparation and quantitative HPLC. Furthermore, students may design and test their own hypothesis using these methods.


'A landmark in psychiatric progress'? The role of evidence in the rise and fall of insulin coma therapy.
This paper examines the evidence behind the use and decline of insulin coma therapy as a treatment for schizophrenia and how this was viewed by the psychiatric profession. The paper demonstrates that, from the time of its introduction, there was considerable debate regarding the evidence for insulin treatment, and scepticism about its purported benefits. The randomized trials conducted in the 1950s were the result, rather than the origins, of this debate. Although insulin treatment was subsequently abandoned, it was still regarded as a historic moment in the modernization of psychiatry. Then, as now, evidence does not speak for itself, and insulin continued to be incorporated into the story of psychiatric progress even after it was shown to be ineffective.


Daprodustat: A potential game-changer in renal anemia therapy-A perspective.
The United States FDA has approved daprodustat (DPD) as the first oral treatment option for anemia due to chronic kidney disease (CKD) in dialysis patients. Clinical trials have demonstrated DPD's efficacy and safety, showing non-inferiority to darbepoetin and suggesting reduced IV iron usage. DPD also holds potential for treating chronic kidney disease anemia in non-dialysis patients and may have benefits for patients with coexisting renal anemia and heart failure, pending further research and trials.


Non-Catalytic Domains of DNA Polymerase λ: Influence on Enzyme Activity and Its Regulation.
DNA polymerase λ (Polλ) belongs to the same structural X-family as DNA polymerase β, the main polymerase of base excision repair. The role of Polλ in this process remains not fully understood. A significant difference between the two DNA polymerases is the presence of an extended non-catalytic N-terminal region in the Polλ structure. The influence of this region on the interaction of Polλ with DNA and multifunctional proteins, poly(ADP-ribose)polymerase 1 (PARP1) and replication protein A (RPA), was studied in detail for the first time. The data obtained suggest that non-catalytic Polλ domains play a suppressor role both in relation to the polymerase activity of the enzyme and in interaction with DNA and PARP1.


An epidemiological study of natural in utero infection with bovine leukemia virus.
The purpose of this study was to examine rates of natural in utero infection with bovine leukemia virus for association with breed, sex, dam age, dam parity and time of maternal seroconversion. Analyses conducted for breed and sex, dam age and parity and time of maternal seroconversion were the FUNCAT procedure for categorical data, Wilcoxon Rank Sums test and Fisher's exact test, respectively. A total of 223 calves born between July 1979, and September 1980, to cows infected with bovine leukemia virus in the University of Florida Dairy Research Unit herd were tested for detectable bovine leukemia virus antibodies prior to the consumption of colostrum. Sera were tested for antibodies by agar-gel immunodiffusion and radioimmunoprecipitation using the glycoprotein-51 antigen. In a group of 125 calves in which in utero infection could be confirmed through serological follow-up (group A), eight calves (6.4%) had precolostral bovine leukemia virus antibodies. For all 223 calves (group B), 18 (8.1%) had detectable bovine leukemia virus antibodies. For calves in group A, no associations were detected between precolostral bovine leukemia virus antibodies and breed (p = 0.66), dam age (p = 0.86), dam parity (p = 0.83), or time of maternal seroconversion to bovine leukemia virus (p = 0.50). However, precolostral bovine leukemia virus antibodies were found in 17.4% of the males and 3.6% of the females in group A (p = 0.11) and in 12.4% of the males and 3.6% of the females in group B (p = 0.04).


[Advances in the diagnosis and treatment of narcolepsy-cataplexy syndrome].
Narcolepsy is a disabling sleep disorder that is characterised by excessive daytime sleepiness and abnormal manifestations in REM (rapid eye movement) sleep that include, among other symptoms, cataplexy (the sudden loss of muscle tone triggered by strong emotions). Studies on the prevalence of narcolepsy-cataplexy in Europe and the United States have yielded a figure of 0.013-0.067% in the general population. Although its prevalence is low, it is probably under-diagnosed for a number of different reasons, the most important perhaps being the difficulties involved in its diagnosis. Because its diagnosis is essentially clinical, complementary tests can often be very helpful. Today, it is one of the most extensively studied sleep disorders at the molecular level. Human narcolepsy is associated with diminished hypocretin/orexin concentrations, unlike the case of canine narcolepsy, where mutations in the Hcrt receptor have been found. The treatment of narcolepsy must be tailored to meet the needs of each patient after an individual analysis of his or her symptoms. Daytime sleepiness can be controlled by drugs that stimulate the central nervous system, the most common being methylphenidate and modafinil. Cataplexy is usually treated with tricyclic antidepressants and selective serotonin reuptake inhibitors. The appearance of new drugs like sodium oxybate sheds a ray of light on the dark horizon of patients with narcolepsy-cataplexy syndrome. Early identification of excessive daytime sleepiness by primary care physicians and specialists is essential for a better management and follow-up of these patients.


Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.
Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. ClinicalTrials.gov Identifier: NCT02462590.


Three-dimensional mapping of the attenuation coefficient in optical coherence tomography to enhance breast tissue microarchitecture contrast.
Effective intraoperative tumor margin assessment is needed to reduce re-excision rates in breast-conserving surgery (BCS). Mapping the attenuation coefficient in optical coherence tomography (OCT) throughout a sample to create an image (attenuation imaging) is one promising approach. For the first time, three-dimensional OCT attenuation imaging of human breast tissue microarchitecture using a wide-field (up to ~45 × 45 × 3.5 mm) imaging system is demonstrated. Representative results from three mastectomy and one BCS specimen (from 31 specimens) are presented with co-registered postoperative histology. Attenuation imaging is shown to provide substantially improved contrast over OCT, delineating nuanced features within tumors (including necrosis and variations in tumor cell density and growth patterns) and benign features (such as sclerosing adenosis). Additionally, quantitative micro-elastography (QME) images presented alongside OCT and attenuation images show that these techniques provide complementary contrast, suggesting that multimodal imaging could increase tissue identification accuracy and potentially improve tumor margin assessment.


Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome.
Metabolic syndrome (MS) is becoming the leading risk factor for hepatocellular carcinoma (HCC). HCC development related to MS may occur in advanced or non-advanced liver fibrosis, suggesting specific molecular pathways. Among these pathways, basal inflammatory state and adipokines production are involved. The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4). In this study, we demonstrate the specific overexpression of FABP4 in human HCC samples from patients with MS compared to other risk factors for chronic liver disease with FABP4 expression restricted to peritumoral endothelial cells. In vitro, glucose, insulin, VEGFA and hypoxia upregulated endothelial FABP4, which was reversed by metformin through mTOR pathway inhibition. FABP4 exerts oncogenic effects on hepatoma cell lines by upregulating the angiogenesis gene signature and pathways involved in the cell cycle, leading to increased cell proliferation and migration, and downregulating HIF1 pathway; effects were reversed in the presence of a specific FABP4 inhibitor (BMS309403). We showed the role of microvesicles as FABP4 vectors between endothelial and tumor cells. In vivo, BMS309403 significantly reduces tumor growth in heterotopic and orthotopic xenografted mice model. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in HCC related to MS, and highlights new anti-neoplastic mechanism of metformin.


ABH and Lewis histo-blood group antigens in cancer.
Antigens of the ABH and Lewis histo-blood group family can be found on many normal cells, mainly of epithelial type. In carcinomas, altered expression of the various carbohydrate epitopes of this family occur, and are often strongly associated with either a good or bad prognosis. A review of the available data on these tumor-associated markers, their biosynthesis and their prognostic value is proposed here. For a long time it has been unclear whether their presence could affect the behavior of carcinoma cells. Recent data, however, indicate that they play biological roles in the course of tumor progression. The presence of sialyl-Le(a) or sialyl-Le(x), which are ligands for selectins, promotes the metastatic process by facilitating interaction with the endothelium of distant organs. The loss of A and B antigens increases cellular motility, while the presence of H epitopes increases resistance to apoptosis by mechanisms that remain to be defined. The Le(y) antigen has procoagulant and angiogenic activities. All these observations are used to present a model that may account for the described associations between the presence or loss of these markers and the outcome of disease. Finally, their potential clinical applications as tumor-associated markers or as targets of immunotherapy are reviewed.


Application of dose kernel calculation using a simplified Monte Carlo method to treatment plan for scanned proton beams.
Full Monte Carlo (FMC) calculation of dose distribution has been recognized to have superior accuracy, compared with the pencil beam algorithm (PBA). However, since the FMC methods require long calculation time, it is difficult to apply them to routine treatment planning at present. In order to improve the situation, a simplified Monte Carlo (SMC) method has been introduced to the dose kernel calculation applicable to dose optimization procedure for the proton pencil beam scanning. We have evaluated accuracy of the SMC calculation by comparing a result of the dose kernel calculation using the SMC method with that using the FMC method in an inhomogeneous phantom. The dose distribution obtained by the SMC method was in good agreement with that obtained by the FMC method. To assess the usefulness of SMC calculation in clinical situations, we have compared results of the dose calculation using the SMC with those using the PBA method for three clinical cases of tumor treatment. The dose distributions calculated with the PBA dose kernels appear to be homogeneous in the planning target volumes (PTVs). In practice, the dose distributions calculated with the SMC dose kernels with the spot weights optimized with the PBA method show largely inhomogeneous dose distributions in the PTVs, while those with the spot weights optimized with the SMC method have moderately homogeneous distributions in the PTVs. Calculation using the SMC method is faster than that using the GEANT4 by three orders of magnitude. In addition, the graphic processing unit (GPU) boosts the calculation speed by 13 times for the treatment planning using the SMC method. Thence, the SMC method will be applicable to routine clinical treatment planning for reproduction of the complex dose distribution more accurately than the PBA method in a reasonably short time by use of the GPU-based calculation engine.


Characterization of the Natural Soundscape of Zebrafish and Comparison with the Captive Noise Conditions.
Zebrafish is a well-established model organism in hearing research. Although the acoustic environment is known to shape the structure and sensitivity of auditory systems, there is no information on the natural soundscape of this species. Moreover, zebrafish are typically reared in large-scale housing systems (HS), although their acoustic properties and potential effects on hearing remain unknown. We characterized the soundscape of both zebrafish natural habitats and laboratory captive conditions, and discussed possible impact on auditory sensitivity. Sound recordings were conducted in five distinct zebrafish habitats (Southwest India), from quieter stagnant environments with diverse biological/abiotic sounds to louder watercourses characterized by current and moving substrate sounds. Sound pressure level (SPL) varied between 98 and 126 dB re 1 μPa. Sound spectra presented most energy below 3000 Hz and quieter noise windows were found in the noisiest habitats matching the species best hearing range. Contrastingly, recordings from three zebrafish HS revealed higher SPL (122-143 dB) and most energy below 1000 Hz with more spectral peaks, which might cause significant auditory masking. This study establishes an important ground for future research on the adaptation of zebrafish auditory system to the natural soundscapes, and highlights the importance of controlling noise conditions in captivity.


Reconstructive eyelid surgery.
A review will be presented of some available eyelid reconstructive methods--such as the inverse triangles; and the H and rotation flap method for the correction of lid defects, e.g. after lidtumor removal. Emphasis will be put on the choice of method, handling, reconstruction and suturing of skinflaps and lid edges.


An excitatory amino acid(s) in the ventrolateral medulla is (are) required for breathing to occur in the anesthetized cat.
The purpose of the present study was to identify sites(s) in the ventrolateral medulla where excitatory amino acids are involved in respiratory control. For this purpose, the respiratory effects produced by bilateral microinjection of excitatory amino acid antagonist drugs were examined while tidal volume (Vt), respiratory rate (f), arterial blood pressure and heart rate were monitored in chloralose-anesthetized cats. Microinjection of kynurenic acid (12.5 nmol) into a site approximately 3 mm rostral to obex, 4 mm lateral to midline and 1.5 mm below the ventral surface produced a decrease in Vt (-20 +/- 2 ml), an increase in f (+20 +/- 3 breaths/min) and a decrease in respiratory minute volume (-108 +/- 19 ml/min) (n = 8). These changes progressed to apnea in each animal tested. No significant changes in blood pressure or heart rate were observed. To determine the excitatory amino acid receptor subtype(s) involved, antagonists of n-methyl-D-aspartate (NMDA) (3-[(RS)-carboxypiperazin-4-yl]-propyl-1-phosphoric acid (CPP] and non-NMDA [6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] receptors were microinjected bilaterally into this site. In the case of CPP, three doses were studied (0.25 nmol, n = 4; 0.75 nmol, n = 3; 2.25 nmol, n = 2). All three doses produced similar decreases in Vt (-12 +/- 1, P less than .05; -10 +/- 1, P less than .05; and -16 +/- 5 ml, respectively) and increases in f (+14 +/- 2, P less than .05; +10 +/- 3, P less than .05; and +12 +/- 3 breaths/min, respectively). None of these animals exhibited apnea.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of corn processing method and dietary inclusion of corn wet distillers grains with solubles on odor and gas production in cattle manure.
The growing ethanol industry in the Southern Great Plains has recently increased the use of wet distillers grains with solubles (WDGS) in beef cattle finishing diets. Two experiments were conducted to evaluate odorous compound production in urine and feces of feedlot steers fed diets with different concentrations of WDGS and different grain processing methods. In both experiments, a Latin square design was used. In Exp. 1, a 2× 2 factorial arrangement of treatments was used and the factors consisted of corn processing method [steam-flaked corn (SFC) or dry-rolled corn (DRC)] and inclusion of corn-based WDGS (0 or 30% on a DM basis). Thus, the 4 treatment combinations consisted of: 1) SFC-based diet with 0% WDGS (SFC-0); 2) SFC-based diet with 30% WDGS (SFC-30); 3) DRC-based diet with 0% WDGS (DRC-0); and 4) DRC-based diet with 30% WDGS (DRC-30). In Exp. 2, all diets were based on SFC and the 4 treatments consisted of: 1) 0% WDGS (SFC-0); 2) 15% WDGS (SFC-15); 3) 30% WDGS (SFC-30); and 4) 45% WDGS (SFC-45). In both experiments, diets were balanced for degradable intake protein and ether extract by the addition of cottonseed meal and fat. Fecal slurries were prepared from a 5-d composite of urine and feces collected from each treatment. The slurries were analyzed using a gas chromatograph for VFA, phenol, p-cresol, indole, skatole, hydrogen, methane (CH(4),) and total gas production. In Exp. 1, the DRC fecal slurries had greater initial total VFA concentration compared with the SFC-based slurries and accumulated a greater concentration of total gas throughout the incubation; however, the SFC-based manure resulted in more CH(4) production. In Exp. 2, total VFA concentrations did not differ across all fecal slurries initially and on d 28; however, throughout the incubation, slurries with 0 and 15% WDGS had the greatest total VFA concentration. Overall, the presence of starch in the feces was likely the determining factor for the accumulation of odorous compounds in the fecal slurries initially, which was especially evident in diets including DRC, and once methanogenic microorganisms were established they likely converted VFA to CH(4).


The Netherlands Twin Register biobank: a resource for genetic epidemiological studies.
In 2004 the Netherlands Twin Register (NTR) started a large scale biological sample collection in twin families to create a resource for genetic studies on health, lifestyle and personality. Between January 2004 and July 2008, adult participants from NTR research projects were invited into the study. During a home visit between 7:00 and 10:00 am, fasting blood and morning urine samples were collected. Fertile women were bled on day 2-4 of the menstrual cycle, or in their pill-free week. Biological samples were collected for DNA isolation, gene expression studies, creation of cell lines and for biomarker assessment. At the time of blood sampling, additional phenotypic information concerning health, medication use, body composition and smoking was collected. Of the participants contacted, 69% participated. Blood and urine samples were collected in 9,530 participants (63% female, average age 44.4 (SD 15.5) years) from 3,477 families. Lipid profile, glucose, insulin, HbA1c, haematology, CRP, fibrinogen, liver enzymes and creatinine have been assessed. Longitudinal survey data on health, personality and lifestyle are currently available for 90% of all participants. Genome-wide SNP data are available for 3,524 participants, with additional genotyping ongoing. The NTR biobank, combined with the extensive phenotypic information available within the NTR, provides a valuable resource for the study of genetic determinants of individual differences in mental and physical health. It offers opportunities for DNA-based and gene expression studies as well as for future metabolomic and proteomic projects.


Economic burden of elderly patients with acute myeloid leukemia treated in routine clinical care in the United States.
This retrospective claims database study examined healthcare utilization (HCU) and costs associated with acute myeloid leukemia (AML) in 237 elderly patients who received chemotherapy or a stem cell transplant (SCT) following AML diagnosis. Patients with secondary AML were excluded. Over the entire follow-up period, 92.0% of patients had ≥1 inpatient admission; 85.7% had ≥1 AML-related admission, and 42.6% had ≥1 non-AML-related admission. During inpatient admissions, 39.2% of patients had ≥1 intensive care unit (ICU) admission, with 20.7% having ≥1 AML-related ICU admission, and 27.8% having ≥1 non-AML-related ICU admission. Total mean per-patient per-month (PPPM) costs over the follow-up period were $25,243 (SD: $21,909), with costs from Year 1 ($27,756 [SD: $22,121]) more than double those in Year 2 ($12,953 [SD: $26,334]) following AML diagnosis. The majority of total costs were medical ($24,512 PPPM [SD: $21,704]), which included inpatient admissions ($6548 PPPM [SD: $10,777]), other outpatient visits ($5021 PPPM [SD: $7997]), supportive care ($3640 PPPM [SD: $5589], and chemotherapy administration ($2029 PPPM [SD: $2345]). Healthcare costs of treated elderly AML patients are substantial, particularly in the first year following diagnosis. Further research is needed to understand factors contributing to high costs in various settings of care for elderly AML patients.


Effects of unique biomedical education programs for engineers: REDEEM and ESTEEM projects.
Current engineering applications in the medical arena are extremely progressive. However, it is rather difficult for medical doctors and engineers to discuss issues because they do not always understand one another's jargon or ways of thinking. Ideally, medical engineers should become acquainted with medicine, and engineers should be able to understand how medical doctors think. Tohoku University in Japan has managed a number of unique reeducation programs for working engineers. Recurrent Education for the Development of Engineering Enhanced Medicine has been offered as a basic learning course since 2004, and Education through Synergetic Training for Engineering Enhanced Medicine has been offered as an advanced learning course since 2006. These programs, which were developed especially for engineers, consist of interactive, modular, and disease-based lectures (case studies) and substantial laboratory work. As a result of taking these courses, all students obtained better objective outcomes, on tests, and subjective outcomes, through student satisfaction. In this article, we report on our unique biomedical education programs for engineers and their effects on working engineers.


Comparison of adult corn rootworm (Coleoptera: Chrysomelidae) sampling methods.
Studies were conducted in Kansas corn and soybean fields during 1997 to compare various sampling methods, traps, and trap components for capturing three species of adult corn rootworms: western (Diabrotica virgifera virgifera Leconte), southern (D. undecimpunctata howardi Barber), and northern (D. barberi Smith & Lawrence). Lure constituents affected the species of beetle attracted to the trap. Traps with a lure containing 4-methoxycinnamaldehyde attracted more western corn rootworms, those with a lure containing eugenol were more attractive to northern corn rootworms, and those containing trans-cinnamaldehyde were most attractive to southern corn rootworms. Multigard sticky traps caught more beetles than did Pherocon AM sticky traps. In corn, a newly designed lure trap caught more beetles than did sticky traps on most occasions. Also, lure-baited sticky traps caught more beetles than did nonbaited sticky traps. Varying the color of the lure trap bottom did not affect the number caught. In soybeans, the new lure traps captured more beetles than did the nonbaited Multigard or Pherocon AM sticky traps. Results of this study suggest the new lure trap may provide a more accurate assessment of corn rootworm populations than traditional monitoring techniques and may be more esthetically pleasing to growers and consultants.


Activity increases in empathy-related brain regions when children contribute to peers' sadness and happiness.
Responding empathically when causing peers' emotions is critical to children's interpersonal functioning, yet there are surprising gaps in the literature. Previous research has focused on empathy when witnessing others' emotions instead of causing others' emotions, on negative emotions instead of positive emotions, and on behavioral correlates instead of neural correlates. In this study, children (N = 38; Mage = 9.28 years; 50% female) completed a functional magnetic resonance imaging block design task in which they played a rigged game where they won and lost coins for themselves or peers and viewed their peers' happiness and sadness. We used a region of interest approach to test whether activity in brain regions associated with positive and negative empathy in adults showed significantly greater activity in each condition (i.e., when children won and lost tokens for themselves and peers) compared with a fixation baseline. We predicted that experiencing self-conscious emotions, such as pride and guilt, would heighten the experience of empathy. Activity in the amygdala, which is associated with visceral arousal, and in the anterior insula and dorsal anterior cingulate cortex, which are associated with integrated arousal, increased significantly when winning and losing for oneself and peers and observing their resulting happy and sad facial expressions. Activity did not differ when playing for oneself versus peers, indicating that self-conscious emotions do not heighten empathy and instead support similar neural processes underlying firsthand and secondhand (empathic) emotions. These findings support that empathy during middle childhood involves the same brain regions as empathy during adulthood and that children experience firsthand and secondhand positive and negative emotions in similar ways.


Characteristics of Corneal Astigmatism of Anterior and Posterior Surface in a Normal Control Group and Patients With Keratoconus.
To evaluate and compare power and axis orientation of anterior and posterior astigmatism in eyes with keratoconus with healthy eyes. In this retrospective cohort study, we examined 861 eyes of 494 patients diagnosed with keratoconus at the Department of Ophthalmology, University Hospital Frankfurt, and 256 eyes of 256 healthy individuals. Using a Scheimpflug device (Pentacam HR), we measured the magnitude and axis orientation of anterior and posterior corneal astigmatism, corneal thickness, and conus location. The results were compared between different stages of the disease according to the Amsler-Krumeich classification and the control group. Magnitude of corneal astigmatism was 3.47 ± 2.10 diopters (D) on the anterior surface and 0.69 ± 0.40 D on the posterior surface in eyes across all keratoconus stages. We found a significant increase of anterior and posterior corneal astigmatism with progression of disease (P < 0.01, 1-way analysis of variance) and a significant correlation between anterior and posterior corneal astigmatism (r = 0.77, P < 0.01). In contrast to eyes of healthy individuals, in which posterior corneal axis alignment is vertical in most cases independent of anterior alignment, we found in eyes with keratoconus a match between anterior and posterior alignment when alignment was vertical in 97% of eyes, 46% when oblique and 61% when horizontal (Cohen kappa coefficient κ = 0.55, P < 0.01). With progression of disease, alignment of anterior and posterior corneal astigmatism became increasingly vertical. In eyes with keratoconus, posterior axis alignment of corneal astigmatism is in line with alignment of the anterior surface in the majority of cases. Posterior astigmatism axis alignment could potentially be used in algorithms to support diagnosis and staging of keratoconus.


Argon laser curing of fluoride-releasing pit and fissure sealant: in vitro caries development.
The purpose of this study was to compare the effect of argon laser polymerization of a visible-light-cured, fluoride-releasing pit and fissure sealant on caries development in vitro. A total of twelve caries-free premolar and molar teeth was selected, and underwent a fluoride-free prophylaxis and soft tissue debridement. Cavity preparations were placed in buccal and lingual surfaces. Lingual cavity preparations were filled with the fluoride-releasing sealant (UltraSealXTplus, Ultradent) and visible light cured per the manufacturer's recommendation. Buccal preparations were filled with the fluoride-releasing sealant and argon laser cured (231 mW, 12 J/cm2 for 10 seconds). Following sealant placement, the teeth were sectioned into buccal and lingual halves. An acid-resistant varnish was placed leaving a 1 mm rim of exposed surface enamel adjacent to the sealant. The specimens were then thermocycled in synthetic saliva (500 cycles, 5 to 50 degrees C). In vitro caries lesions were formed (2.2 mM Ca, 2.2 mM PO4, 50 mM acetic acid, 5 ppm fluoride, pH 3.95). Longitudinal sections (five sections per tooth half) were obtained and evaluated by polarized light microscopy for mean outer surface lesion depths and frequency of wall lesions. Mean primary surface (outer) lesion depth was significantly decreased (ANOVA, DMR, P < .05) for the fluoride-releasing sealant with argon laser polymerization (152 +/- 16 um) when compared with visible light curing (211 +/- 23 um). Likewise, wall lesion frequency was substantially reduced for the argon laser polymerized sealants (17 percent) when compared with that for the visible light polymerized sealants (24 percent, ANOVA, DMR, P < .05). Argon laser polymerization of a fluoride-releasing pit and fissure sealant improved caries resistance markedly in the surface enamel adjacent to the sealant material. Argon laser curing enhanced the caries protective ability of the sealant along the enamel-resin cavosurface, as noted by a decrease in wall lesion frequency. Argon laser polymerization provides further caries protection against a cariogenic challenge over that afforded by fluoride-releasing sealants. Caries development around a sealant material may be hampered by the combination of fluoride release from the sealant and argon laser polymerization.


Leveraging Generative AI and Large Language Models: A Comprehensive Roadmap for Healthcare Integration.
Generative artificial intelligence (AI) and large language models (LLMs), exemplified by ChatGPT, are promising for revolutionizing data and information management in healthcare and medicine. However, there is scant literature guiding their integration for non-AI professionals. This study conducts a scoping literature review to address the critical need for guidance on integrating generative AI and LLMs into healthcare and medical practices. It elucidates the distinct mechanisms underpinning these technologies, such as Reinforcement Learning from Human Feedback (RLFH), including few-shot learning and chain-of-thought reasoning, which differentiates them from traditional, rule-based AI systems. It requires an inclusive, collaborative co-design process that engages all pertinent stakeholders, including clinicians and consumers, to achieve these benefits. Although global research is examining both opportunities and challenges, including ethical and legal dimensions, LLMs offer promising advancements in healthcare by enhancing data management, information retrieval, and decision-making processes. Continued innovation in data acquisition, model fine-tuning, prompt strategy development, evaluation, and system implementation is imperative for realizing the full potential of these technologies. Organizations should proactively engage with these technologies to improve healthcare quality, safety, and efficiency, adhering to ethical and legal guidelines for responsible application.


Iodized oil pleural effusion in a patient previously treated with transarterial chemoembolization for hepatocellular carcinoma.
Transarterial chemoembolization (TACE) is a nonsurgical therapeutic option for the control of hepatocellular carcinoma (HCC) in patients with cirrhosis. Although less invasive than surgical approaches, this procedure can have severe side effects, with both local and extrahepatic complications, mostly related to treatment-induced ischemic damage. Here, we describe the case of a cirrhotic female patient affected by multinodular HCC, who presented with sudden onset dyspnea and chest pain. After a thorough follow-up, her condition was found to be due to iodinized oil pleural effusion following diaphragm rupture by a fistula. This had developed from a sterile abscess formed on the site of a previously performed TACE. We discuss the differential diagnosis and the management of this case, which, to our knowledge, has never been described as a late side effect of TACE.


Prior renovascular hypertension does not predispose to atherosclerosis in mice.
Hypertension is a major risk factor for development of atherosclerotic cardiovascular disease (ASCVD). Although lowering blood pressure with antihypertensive drugs reduces the increased risk of ASCVD, residual increased risk still remains, suggesting that hypertension may cause chronic changes that promote atherosclerosis. Thus, we tested the hypothesis that hypertension increases the susceptibility to atherosclerosis in mice even after a period of re-established normotension. We used the 2-kidney, 1-clip (2K1C) technique to induce angiotensin-driven renovascular hypertension, and overexpression of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene to cause severe hypercholesterolemia and atherosclerosis. First, we performed 2K1C (n = 8) or sham surgery (n = 9) in PCSK9 transgenic mice before they were fed a high fat diet for 14 weeks. As expected, 2K1C did not affect cholesterol levels, but induced cardiac hypertrophy and significantly increased the atherosclerotic lesion area compared to sham mice (1.8 fold, p < 0.01). Next, we performed 2K1C (n = 13) or sham surgery (n = 14) in wild-type mice but removed the clipped/sham-operated kidney after 10 weeks to eliminate hypertension, and subsequently induced hypercholesterolemia by way of adeno-associated virus-mediated hepatic gene transfer of PCSK9 combined with high-fat diet. After 14 weeks of hypercholesterolemia, atherosclerotic lesion areas were not significantly different in mice with or without prior 2K1C hypertension (0.95 fold, p = 0.35). Renovascular hypertension in mice does not induce pro-atherogenic changes that persist beyond the hypertensive phase. These results indicate that hypertension only promotes atherogenesis when coinciding temporally with hypercholesterolemia.


The role of calcium antagonists in patients with chronic renal failure.
The objective of antihypertensive treatment in patients with chronic renal failure, many of whom have elevated blood pressure levels, is to reduce cardiovascular events and to slow down the progression of kidney function impairment. Calcium antagonists have been shown to be effective and safe antihypertensive drugs in patients from different age groups, including children. On the basis of numerous studies, one may conclude that the main benefit of antihypertensive therapy is because of the blood pressure lowering effect per se and that calcium antagonists do not differ from other antihypertensive drugs in the ability to prevent cardiovascular complications of hypertension. In particular, calcium antagonists are not inferior to other groups of antihypertensive agents in the prevention of coronary artery disease. There is, however, now evidence from controlled clinical trials that drugs interfering with the renin-angiotensin system are more beneficial than other antihypertensive agents in patients with chronic renal failure. Thus, several studies have demonstrated that ACE-inhibitors and, in patients with type-2 diabetic nephropathy, AT 1-antagonists are superior to other classes of antihypertensive drugs, including calcium antagonists, in delaying the progression of renal insufficiency. Therefore, in hypertensive patients with chronic renal failure antihypertensive treatment should be initiated with a drug that inhibits the renin-angiotensin system.


[Detection of malnutrition risk in hospitalized elderly patients].
OBJECTIVE AND SCOPE: To validate a protocol for the detection of malnutrition risk in a population of elderly patients admitted to a general hospital for non-surgical reasons. The study involved 95 patients (34 of them male) over the age of 65 who were assessed on the third and fifth day after admission by means of a simple screening protocol (PC in its Spanish acronym) that considered recent changes in weight, serum albumin, lymphocyte concentration, food intake and diagnosis on admission, together with a more complex diagnostic protocol (PD in its Spanish acronym) including anthropometric, biochemical and immunological parameters. The PC was applied by personnel not expert in nutrition, while the PD was carried out by persons trained in nutritional assessment. The results of the PC and PD were compared, with statistical significance being considered at levels of p < 0.05. According to the PD, 75 patients (78.9%) suffered protein-energy malnutrition (39 slight, 31 moderate, 5 severe). The score obtained in the PC had a significant relationship with the severity of the malnutrition diagnosed using PD (p < 0.001). Furthermore, the absence or presence of nutritional risk assessed using the PC had a significant correlation with the diagnosis of malnutrition and its degree according to the PD (p < 0.01), thus indicating the validity of the PC as a method for screening of malnutrition. 1. In our population of geriatric patients admitted for reasons other than surgery, there was a high prevalence of protein-energy malnutrition. 2. The risk of malnutrition in an elderly population in hospital settings is appropriately assessed by means of a simple screening test effected by non-specialized personnel. 3. The score obtained in the PC is linked with the presence of malnutrition and with its severity. 4. The use of simple screening techniques in populations with a high prevalence of malnutrition may contribute to the detection and correction of this problem.


Effects of historical inequity and institutional power on cannabis research: Moving toward equity and inclusion.
Given historical inequities in cannabis laws and policies, there is an obligation on the part of researchers and policy makers to actively work toward improving equity in cannabis research at a time when the field is rapidly expanding. We wish to propose a way forward for cannabis research that acknowledges this history of discrimination and misuse of institutional power and embraces equity and inclusion. This article provides a brief perspective on historical drug policy, recent legalization trends that have disproportionately benefitted some groups over others, and the repercussions of those trends for the cannabis research enterprise. In addition, it proposes five key actions in both policy and research domains that are necessary to move the field of cannabis research, and perhaps biomedical research in substance use more broadly, forward in a productive and inclusionary way. Specifically, recommendations focus on equity-focused legislation and policy, supporting the entry and retention of scientists of color into the field, engaging in more ethical research practices, and practicing intentionally inclusive recruitment of participants will help to move the field of cannabis research forward. These efforts will ensure that scientific gains are shared equitably moving forward.


Calculation of x-ray spectra emerging from an x-ray tube. Part II. X-ray production and filtration in x-ray targets.
A new approach to the calculation of the x-ray spectrum emerging from an x-ray tube is proposed. Theoretical results for the bremsstrahlung cross section appearing in the literature are summarized. Four different treatments of electron penetration, based on the work presented in Part I, are then used to generate bremsstrahlung spectra. These spectra are compared to experimental data at 50, 80 and 100 kVp tube potentials. The most sophisticated treatment of electron penetration was required to obtain good agreement. With this treatment both the National Institute of Standards and Technology bremsstrahlung cross sections, based on accurate partial wave calculations, and the Bethe-Heitler cross section [H. A. Bethe and W. Heitler, Proc R. Soc. London, Ser. A. 146, 83-112 (1934)] corrected by a modified Elwert factor [G. Elwert, Ann. Phys. (Leipzig) 426, 178-208 (1939)], provided good agreement to measured data. An approximate treatment of the characteristic spectrum is suggested. The dependencies of the bremsstrahlung and characteristic outputs of an x-ray tube on tube potential are compared to experimentally derived data for 70-140 kVp potentials. Agreement is to within a few percent of the total output over the entire range. The spectral predictions of the semiempirical models of Birch and Marshall [R. Birch and M. Marshall, Phys. Med. Biol. 24, 505-513 (1979)] (IPEM Report 78) and of Tucker et al. [D. M. Tucker, G. T. Barnes, and D. P. Chakraborty, Med. Phys. 18, 211-218 (1991).] are also assessed. The predictions of Tucker et al. are very close to the model developed here. The predictions of IPEM Report 78 are similar, but consistently harder for the range of tube potentials examined (50-100 kV). Unlike the semiempirical models, the model proposed here requires the introduction of no empirical and unphysical parameters in the differential bremsstrahlung cross section, bar an overall normalization factor which is close to unity.


Float trajectories in simple kinematic flows.
A simple kinematic model has been used to compute Lagrangian trajectories. Although it is certainly too simple to model geophysical flows, it has provided insights into the behavior of Lagrangian tracers. In particular, the existence of trapping regions has been shown to greatly increase the dispersion rate of tracers and to lead to net tracer displacements when the Eulerian mean flow is zero. In general, the spectrum of spatial scales present in the trajectories is wider than the Eulerian spectrum and is biased towards shorter wavelengths; the disparity between the 100-km Eulerian scale and the much shorter length scales experienced by the tracers is demonstrated. The estimation of the Eulerian parameters of the field from Lagranian observations must be done with a great deal of care, particularly if the eddy flow velocities are comparable to or exceed the mean flow. With a limited number of tracers it is extremely difficult to estimate, with any degree of confidence, the properties of either the mean Eulerian flow or the eddy field. Clearly, more effort must be spent to better understand the behavior of tracers in more realistic flows, to devise data analysis techniques, and to relate the Eulerian and Lagrangian spectra.


[Comparison of matrix metalloproteinase-9 between Wistar rat and spontaneously hypertensive rat in pulmonary injury model].
To compare the expression of matrix metalloproteinase-9 (MMP9) and observe the change of cigarette smoke-induced pulmonary injury in Wistar and spontaneously hypertensive (SH) rats. A total of 10 male Wistar rats and 10 male SH rats were randomly divided into four groups of Wistar control, Wistar cigarette smoking, SH control and SH cigarette smoking (n=5 each). The control groups were fed routinely while the cigarette smoking groups were placed into a homemade organic glass box and exposed to cigarette smoking for twice daily 6 days a week. After 8-week treatment, general condition, lung function and pathological changes of lung tissues were detected. The expressions of nuclear factor (NF)-κB, IκB-α and MMP9 were determined by Western blot. And real-time polymerase chain reaction (RT-PCR) was employed to detect the mRNA levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Immunohistochemistry was used to detect the expression of MMP9 in lung tissue. Both cigarette smoking groups were marantic along with intermittent cough and polypnea. Resistance index (RI) in Wistar control, Wistar cigarette smoking, SH control and SH cigarette smoking groups was (0.23±0.04), (0.33±0.05), (0.33±0.02) and (0.46±0.08) cmH2O·s·ml(-1) respectively. RI increased in Wistar cigarette smoking group versus Wistar control group. And SH cigarette smoking group was significantly higher than SH control and Wistar cigarette smoking groups (P<0.05). Hematoxylin & eosin staining demonstrated that the lesion of chronic bronchitic inflammation and emphysema existed in two cigarette smoking groups while it was more severe in SH rats than Wistar rats. The mean alveolar number (MAN) was significantly reduced in two cigarette smoking groups compared with that in control groups (P<0.05, respectively). And mean lining interval (MLI), damage index (DI), bronchial smooth muscle index and collagen index significantly increased in Wistar cigarette smoking group compared with Wistar control group, SH cigarette smoking group significantly increased than that in SH control and Wistar cigarette smoking groups (P<0.05, respectively). On Western blot, the protein level of NF-κB in Wistar control, Wistar cigarette smoking, SH control and SH cigarette smoking groups was (0.322±0.014), (0.558±0.044), (0.373±0.029) and (1.156±0.197) respectively. The protein level of MMP9 in these groups was (0.255±0.070), (0.456±0.089), (0.594±0.184) and (0.847±0.138) respectively. The protein levels of NF-κB and MMP9 increased obviously in Wistar cigarette smoking group versus Wistar control group and those in SH cigarette smoking group were significantly higher than SH control and Wistar cigarette smoking groups (P<0.05). Additionally, IκB-α expression in SH cigarette smoking group was markedly decreased in comparison to that in SH control group and Wistar cigarette smoking group (P<0.05). The mRNA level of TNF-α increased obviously in two cigarette smoking groups in comparison to those in controls (P<0.05) and the mRNA level of IL-6 significantly increased in the SH cigarette smoking group compared with SH control group and Wistar cigarette smoking group (P<0.05). As for immunohistochemistry, the MMP9 positive cells were prominently distributed in the lungs of cigarette smoking groups versus the stained cells in the control group. And SH cigarette smoking group was significantly higher than Wistar cigarette smoking group (P<0.05). Both Wistar and SH rats induced by cigarette smoking may have an onset of lung injury symptom analogous to chronic obstructive pulmonary disease and SH rat are more severe.


Conductive properties of the rabbit outer medullary collecting duct: outer stripe.
Segments of the outer medullary collecting duct were dissected from the outer stripe of the rabbit kidney (OMCDo) and perfused in vitro. The conductive properties of the tubule epithelium and individual cell membranes were determined by means of cable analysis and intracellular voltage-recording microelectrodes. The transepithelial voltage (VT) and resistance (RT) averaged -10.7 +/- 2.5 mV, lumen negative, and 28.5 +/- 2.9 k omega X cm (n = 27), respectively. Two cell types could be defined by their electrophysiological properties. One cell type (n = 7) had a mean basolateral membrane voltage (Vbl) of -30.1 +/- 2.4 mV, a fractional resistance of the apical membrane (fRa = Ra/Ra + Rbl) near unity (0.99 +/- 0.01), and a predominantly Cl(-)-selective basolateral cell membrane. The second cell type (n = 27) had a mean Vbl of -63.7 +/- 2.7 mV, a fRa of 0.81 +/- 0.02, and a predominantly K+-selective basolateral cell membrane. The present study focused on defining the conductive properties of this latter cell type. Amiloride (10(-5) M) and BaCl2 (2 mM) were used as probes of apical cell membrane Na+ and K+ conductive pathways, respectively. Amiloride increased fRa from 0.80 +/- 0.02 to 0.98 +/- 0.01 (n = 12), whereas BaCl2 increased fRa from 0.77 +/- 0.03 to 0.82 +/- 0.03 (n = 9). The conductive properties of the basolateral cell membrane were assessed by ion substitutions of the bath solution. A 10-fold increase in the bath [K+] depolarized Vbl by 34.9 +/- 1.9 mV (n = 16) in less than 1 s, indicating that this membrane was predominantly K+ selective.(ABSTRACT TRUNCATED AT 250 WORDS)


Temporal enhancer profiling of parallel lineages identifies AHR and GLIS1 as regulators of mesenchymal multipotency.
Temporal data on gene expression and context-specific open chromatin states can improve identification of key transcription factors (TFs) and the gene regulatory networks (GRNs) controlling cellular differentiation. However, their integration remains challenging. Here, we delineate a general approach for data-driven and unbiased identification of key TFs and dynamic GRNs, called EPIC-DREM. We generated time-series transcriptomic and epigenomic profiles during differentiation of mouse multipotent bone marrow stromal cell line (ST2) toward adipocytes and osteoblasts. Using our novel approach we constructed time-resolved GRNs for both lineages and identifed the shared TFs involved in both differentiation processes. To take an alternative approach to prioritize the identified shared regulators, we mapped dynamic super-enhancers in both lineages and associated them to target genes with correlated expression profiles. The combination of the two approaches identified aryl hydrocarbon receptor (AHR) and Glis family zinc finger 1 (GLIS1) as mesenchymal key TFs controlled by dynamic cell type-specific super-enhancers that become repressed in both lineages. AHR and GLIS1 control differentiation-induced genes and their overexpression can inhibit the lineage commitment of the multipotent bone marrow-derived ST2 cells.


Male Circumcision and STI Acquisition in Britain: Evidence from a National Probability Sample Survey.
It is well-established that male circumcision reduces acquisition of HIV, herpes simplex virus 2, chancroid, and syphilis. However, the effect on the acquisition of non-ulcerative sexually transmitted infections (STIs) remains unclear. We examined the relationship between circumcision and biological measures of three STIs: human papillomavirus (HPV), Chlamydia trachomatis and Mycoplasma genitalium. A probability sample survey of 15,162 men and women aged 16-74 years (including 4,060 men aged 16-44 years) was carried out in Britain between 2010 and 2012. Participants completed a computer-assisted personal interview, including a computer-assisted self-interview, which asked about experience of STI diagnoses, and circumcision. Additionally, 1,850 urine samples from sexually-experienced men aged 16-44 years were collected and tested for STIs. Multivariable logistic regression was used to calculate adjusted odds ratios (AOR) to quantify associations between circumcision and i) self-reporting any STI diagnosis and ii) presence of STIs in urine, in men aged 16-44 years, adjusting for key socio-demographic and sexual behavioural factors. The prevalence of circumcision in sexually-experienced men aged 16-44 years was 17.4% (95%CI 16.0-19.0). There was no association between circumcision and reporting any previous STI diagnoses, and specifically previous chlamydia or genital warts. However, circumcised men were less likely to have any HPV type (AOR 0.26, 95% confidence interval (CI) 0.13-0.50) including high-risk HPV types (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and/or 68) (AOR 0.14, 95% CI 0.05-0.40) detected in urine. Circumcised men had reduced odds of HPV detection in urine. These findings have implications for improving the precision of models of STI transmission in populations with different circumcision prevalence and in designing interventions to reduce STI acquisition.


Asymmetries in the representation of space in the human auditory cortex depend on the global stimulus context.
Studies on humans and other mammals have provided evidence for a two-channel or three-channel representation of horizontal space in the auditory system, with one channel maximally responsive to each of the left hemispace, the right hemispace and, possibly, the midline. Mammalian studies have suggested that the contralateral channel is larger in both cortices, but human studies have found this contralateral preference in only one of the cortices. However, human studies are in conflict as to whether the contralateral preference is in the left or the right auditory cortex, and there are a number of methodological differences that this conflict could be attributed to. A key difference between studies is the duration of the silent interval preceding each stimulus and any perception of sound-source movement that the absence of a silent interval creates. We presented auditory noises that alternated between -90° (left) and +90° (right) and recorded neural responses (event-related potentials) using electroencephalography. We randomly varied the duration of the silent interval preceding each stimulus to create a condition with an immediate (local) stimulus context similar to that used in a study reporting contralateral preference in the left auditory cortex, a condition with a local context similar to that in a study reporting contralateral preference in the right auditory cortex, and an intermediate condition. Surprisingly, we found that both auditory cortices exhibited a similarly strong contralateral preference under all conditions, with responses 27% greater, on average, to the contralateral than the ipsilateral space. This suggests that both the cortices can exhibit a contralateral preference, but whether these preferences manifest depends on the global, rather than the local, stimulus context.


Periocular necrotizing fasciitis: a review of five cases.
The purpose of the study is to display a spectrum of clinical presentations of periocular necrotizing fasciitis caused by group A streptococci and to discuss recent trends and treatment of this disease. A case series of five patients (four female and one male) was seen between July 1990 and January 1995 in four university centers. All had clinical evidence of periocular necrotizing fasciitis and grew group A streptococci on wound cultures or had serologic evidence of streptococcal infection. Details of patient presentation, treatment, and outcome are examined. The five patients showed a spectrum of clinical severity from a necrotizing infection confined to the eyelid to a potentially fatal, severe shock-like syndrome characterized by sepsis and multiorgan system failure. A history of trauma often was absent. Patients were treated successfully by a combination of appropriate antibiotics and surgical debridement. Group A streptococci can cause severe necrotizing infections of the eyelids. Early recognition and prompt treatment can be essential to these patients' survival.


AgNORs in hyperplasia, papilloma and oral squamous cell carcinoma.
Ten inflammatory fibrous hyperplasias, ten papillomas, and nineteen oral squamous cell carcinomas were analyzed by the AgNOR technique to determine if different disturbances of oral epithelia presented different AgNOR counts. The papilloma group showed higher mean AgNOR counts (3.15 +/- 0.58) than the hyperplasia group (1.98 +/- 0.24) and smaller than the well-differentiated oral squamous cell carcinoma group (6.56 +/- 1.25) and poorly differentiated oral squamous cell carcinoma group (7.07 +/- 1.60). The differences among the groups of lesions were statistically significant (P < 0.05) except between the well differentiated oral squamous cell carcinoma group and the poorly differentiated oral squamous cell carcinoma group. Our findings suggest that the cellular proliferation ratio in papillomas is greater than hyperplasias and smaller than carcinomas.


Zafirlukast improves asthma symptoms and quality of life in patients with moderate reversible airflow obstruction.
Previous trials demonstrated the effectiveness of the leukotriene receptor antagonist zafirlukast in patients with mild-to-moderate asthma. We sought to assess the efficacy and safety of zafirlukast and its effect on patients' quality of life (QOL) during a 13-week, double-blind, placebo-controlled, multicenter trial in adults and adolescents with moderate reversible airflow obstruction. Patients (age range, 12 to 68 years) with total daytime asthma symptoms scores of 10 or greater over 7 consecutive days (maximum, 21/wk), FEV1 45% or greater but less than or equal to 80% of predicted value (>/=6 hours after beta2 -agonist), and reversible airway disease were randomized to 20 mg zafirlukast twice daily (nZ = 231) or placebo twice daily (nP = 223). Efficacy was assessed from changes in daytime and nocturnal symptoms, beta2 -agonist use, nasal congestion score, and pulmonary function. QOL was evaluated with a disease-specific Asthma Quality of Life Questionnaire. Safety was determined from adverse event information and clinical laboratory test results. Zafirlukast was significantly (P <.001) more effective than placebo, with reductions from baseline in the daytime asthma symptoms score (-23%), nighttime awakenings with asthma (-19%), and beta2 -agonist use (-24%) and improvements from baseline in morning (+25 L/min) and evening (+18 L/min) peak expiratory flow rates. Compared with placebo, zafirlukast significantly (P </=.018) improved scores for QOL domains (activity limitations, symptoms, emotional function, and exposure to environmental stimuli) and overall QOL, with a significantly greater proportion of zafirlukast-treated patients demonstrating clinically meaningful improvements (>/=0.5-unit change from baseline; P </=.037). The safety profile of zafirlukast was clinically indistinguishable from that of placebo. Zafirlukast is effective and well tolerated and improves QOL in the long-term treatment of patients with moderate reversible airflow obstruction.


Allelic variants of XRCC1 and XRCC3 repair genes and susceptibility of oral cancer in Brazilian patients.
The capacity for DNA repair is essential in maintaining cellular functions and homeostasis; however, this capacity can be altered based on DNA sequence variations in DNA repair genes, which may contribute to the onset of cancer. Many single-nucleotide polymorphisms (SNPs) in repair genes have been found to be associated with oral cancer. The aim of this study was to investigate the relationship between the presence of allelic variants Arg194Trp (rs:1799782) and Arg399Gln (rs: 25487) of XRCC1 gene and Thr241Met (rs: 861539) of XRCC3 gene and susceptibility to oral cancer. We also attempted to correlate the frequencies obtained for each of the SNPs to histopathological parameters. A case-control study was conducted with genomic DNA from 150 patients with oral squamous cell carcinomas and 150 controls. SNPs were genotyped by RFLP-PCR. The presence of the polymorphic variants of the XRCC1 gene within codon 194 (OR 0.82, 95% CI: 0.44-1.51) and codon 399 (OR 0.94, 95% CI: 0.59-1.50) and within the XRCC3 gene (OR 0.72; 95% CI: 0.45-1.16) were not associated with an increased risk of oral cancer. A combinational analysis of SNPs in both genes indicated no association. The presence of the allelic variants of these two genes had no statistically significant effect on tumor differentiation, lymph node invasion or tumor size. These results suggest that allelic variants of XRCC1 and XRCC3 are not suitable markers for susceptibility to carcinomas of the oral cavity and are also not related to the later stages of such tumors.


Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-β and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.


A systematic review on idiopathic intracranial hypertension comorbid with polycystic ovarian syndrome and its consequences.
A few publications have examined the frequency and medical implications of individuals with idiopathic intracranial hypertension (IIH) and polycystic ovarian syndrome (PCOS), but the findings have been inconclusive. IIH and PCOS both mainly affect obese women of reproductive age and have an impact on women's health at various levels. The aim of this systematic review was to compare the prevalence and association between comorbid IIH and PCOS, and their effect on such aspects as metabolism, abnormalities in hormone levels, and reproduction. The criterion for inclusion was a research study of patients suffering from both syndromes. We excluded review articles, case reports, and papers with an inappropriate study design, patient population or outcomes. Electronic databases PubMed, Scopus, Web of Science and gray literature were searched to retrieve studies published from inception to June 10, 2023. The risk of bias assessment was conducted utilizing Covidence software and by discussion between co-authors. After applying our inclusion/exclusion criteria, we consolidated the initial pool to a final selection of 9 articles, and 2185 patients with comorbidity of these two conditions. The prevalence of PCOS among patients with IIH was observed, with incidence rates ranging from 15.5% to 57%, which is up to 8 times greater, than the 4-10% prevalence of PCOS in the general population. These data may be valuable in clinical practice for both neurologists and gynecologists. PCOS associated with obesity facilitates concurrence of IIH. The diagnosis of concurrence of IIH and PCOS may have significant clinical implications for patients due to the accompanying hormonal disorders, obesity-related consequences, and fertility issues. Other No systematic review was found. We have registered the study in PROSPERO (International prospective register of systematic reviews), and the registration number is CRD42023437485.


Review on Pediatric Malignant Focal Liver Lesions with Imaging Evaluation: Part I.
Malignant focal liver lesions (FLLs) are commonly reported in adults but rarely seen in the pediatric population. Due to the rarity, the understanding of these diseases is still very limited. In children, most malignant FLLs are congenital. It is very important to choose appropriate imaging examination concerning various factors. This paper will outline common pediatric malignant FLLs, including hepatoblastoma, hepatocellular carcinoma, and cholangiocarcinoma and discuss them against the background of the latest knowledge on comparable/similar tumors in adults. Medical imaging features are of vital importance for the non-invasive diagnosis and follow-up of treatment of FLLs in pediatric patients. The use of CEUS in pediatric patients for characterizing those FLLs that remain indeterminate on conventional B mode ultrasounds may be an effective option in the future and has great potential to be integrated into imaging algorithms without the risk of exposure to ionizing radiation.