Epitope mapping of imidazolium cations in ionic liquid-protein interactions unveils the balance between hydrophobicity and electrostatics towards protein destabilisation.
We investigated imidazolium-based ionic liquid (IL) interactions with human serum albumin (HSA) to discern the level of cation interactions towards protein stability. STD-NMR spectroscopy was used to observe the imidazolium IL protons involved in direct binding and to identify the interactions responsible for changes in Tm as accessed by differential scanning calorimetry (DSC). Cations influence protein stability less than anions but still significantly. It was found that longer alkyl side chains of imidazolium-based ILs (more hydrophobic) are associated with a higher destabilisation effect on HSA than short-alkyl groups (less hydrophobic). The reason for such destabilisation lies on the increased surface contact area of the cation with the protein, particularly on the hydrophobic contacts promoted by the terminus of the alkyl chain. The relevance of the hydrophobic contacts is clearly demonstrated by the introduction of a polar moiety in the alkyl chain: a methoxy or alcohol group. Such structural modification reduces the degree of hydrophobic contacts with HSA explaining the lesser extent of protein destabilisation when compared to longer alkyl side chain groups: above [C2mim](+). Competition STD-NMR experiments using [C2mim](+), [C4mim](+) and [C2OHmim](+) also validate the importance of the hydrophobic interactions. The combined effect of cation and anion interactions was explored using (35)Cl NMR. Such experiments show that the nature of the cation has no influence on the anion-protein contacts, still the nature of the anion modulates the cation-protein interaction. Herein we propose that more destabilising anions are likely to be a result of a partial contribution from the cation as a direct consequence of the different levels of interaction (cation-anion pair and cation-protein).


High Volumetric and Gravimetric Capacity Electrodeposited Mesostructured Sb2 O3 Sodium Ion Battery Anodes.
Sodium ion batteries (SIBs) are considered promising alternatives to lithium ion batteries for grid-scale and other energy storage applications because of the broad geographical distribution and low cost of sodium relative to lithium. Here, fabrication and characterization of high gravimetric and volumetric capacity 3D Ni-supported Sb2 O3 anodes for SIBs are presented. The electrodes are prepared by colloidal templating and pulsed electrodeposition followed by heat treatment. The colloidal template is optimized to provide large pore interconnects in the 3D scaffold to enable a high active materials loading and accommodate a large volume expansion during cycling. An electrodeposited loading of 1.1 g cm-3 is chosen to enable a combined high gravimetric and volumetric capacity. At this loading, the electrodes exhibit a specific capacity of ≈445 mA h g-1 and a volumetric capacity of ≈488 mA h cm-3 with a capacity retention of 89% after 200 cycles at 200 mA g-1 . The stable cycling performance can be attributed to the 3D metal scaffold, which supports active materials undergoing large volume changes, and an initial heat treatment appears to improve the adhesion of the Sb2 O3 to the metal scaffold.


Yttrium-90 ibritumomab tiuxetan followed by rituximab maintenance as treatment for patients with diffuse large B-cell lymphoma are not candidates for autologous stem cell transplant.
Not all patients with diffuse large B-cell lymphoma (DLBCL) are candidates for aggressive regimens. (90)Y ibritumomab tiuxetan ((90)Y-IT), an anti-CD20 radionuclide-conjugated antibody, has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile. This phase II trial investigated the overall response rate (ORR), event-free survival (EFS), overall survival (OS) and toxicity of treatment with (90)Y-IT (0.4 or 0.3 mCi (90)Y/kg based on platelets) followed by rituximab maintenance therapy in patients with DLBCL not candidates for transplant. 25 patients were enrolled. At best response 8 patients obtained a complete response (CR) and 1 a partial response (ORR 36%). Median EFS was 2.5 months and OS 8.1 months. No patient who obtained CR later relapsed systemically. Two patients were free of disease at the 61- and 100-month follow-ups; 65% had grade 3/4 thrombocytopenia, but no significant bleeding was observed. Grade 3 nonhematologic toxicity occurred in 36%. Patients who had progressed through a rituximab-containing regimen responded poorly. The ORR of 36% with (90)Y-IT as salvage therapy for DLBCL while inferior to more aggressive regimens is significant with acceptable toxicity. For a subset of patients not candidates for salvage with autologous transplant, this treatment strategy can produce a durable, long-lasting remission.


Ellagic acid prevents cognitive and hippocampal long-term potentiation deficits and brain inflammation in rat with traumatic brain injury.
Traumatic brain injury (TBI) remains one of the main clinical problems globally and is a common cause of death among youth. Cognitive defects such as thinking, memory and behavior or mental health disorders are considered as the most frequent effects of severe and moderate TBI. It has been reported that ellagic acid (EA), a natural polyphenol, exhibits protective effects against oxidative damage. This study was performed to examine the EA preventive effects on cognitive impairments, long-term potentiation (LTP) deficits in hippocampus and brain inflammation induced by diffuse TBI in rat. Subchronic oral administration of 100 mg/kg EA, 7 consecutive days before induction of trauma (once daily) was used to elucidate the EA effects on passive avoidance memory and hippocampal LTP following TBI. To illustrate the possible mechanisms related to the preventive effects of EA on brain function following TBI, brain content of IL-1β, IL-6 and blood-brain barrier (BBB) permeability were determined. EA pretreatment significantly (P<0.001) prevented TBI-induced memory and hippocampal LTP impairments in rat. Furthermore TBI induced elevation in brain content of IL-1β, IL-6 and BBB permeability were decreased significantly (P<0.001) due to EA pre-treatment. Our findings suggest that EA can prevent cognitive and LTP deficits and also prevent brain inflammation following TBI.


[Effect of platelet lysate on chondrogenic differentiation of human umbilical cord derived mesenchymal stem cells in vitro].
To study the effect of platelet lysate (PL) on chondrogenic differentiation of human umbilical cord derived mesenchymal stem cells (hUCMSCs) in vitro. Umbilical cords were voluntarily donated by healthy mothers. The hUCMSCs were isolated by collagenase digestion and cultured in vitro. The surface markers of the cells were detected by flow cytometer. According to different components of inductive medium, the cultured hUCMSCs were divided into 3 groups: group A [H-DMEM medium, 10% fetal bovine serum (FBS), and 10%PL]; group B [H-DMEM medium, 10%FBS, 10 ng/mL transforming growth factor beta1 (TGF-beta1), 1 x 10(-7) mol/L dexamethasone, 50 microg/mL Vitamin C, and 1% insulin-transferrin-selenium (ITS)]; and group C (H-DMEM medium, 10%FBS, 10 ng/mL TGF-beta1, 1 x 10(-7) mol/L dexamethasone, 50 microg/mL vitamin C, 1%ITS, and 10%PL). The hUCMSCs were induced in the mediums for 2 weeks. Toluidine blue staining was used to detect the secretion of chondrocyte matrix. Immunofluorescence method was used to identify the existence of collagen type II. The expressions of Aggrecan and collagen type II were detected by semiquantitative RT-PCR. Flow cytometer results showed that the hUCMSCs did not express the surface markers of hematopoietic cell CD34, CD45, and human leukocyte antigen DR, but expressed the surface markers of adhesion molecule and mesenchymal stem cells CD44, CD105, and CD146. Toluidine blue staining and immunofluorescence showed positive results in group C, weak positive results in group B, and negative results in group A. Semiquantitative RT-PCR showed the expressions of Aggrecan and collagen type II at mRNA level in groups B and C, but no expression in group A. The mRNA expressions of Aggrecan and collagen type II were higher in group C than in group B (P < 0.05). Only 10%PL can not induce differentiation of hUCMSCs into chondrocytes, but it can be a supplement to the induced mediums. PL can improve hUCMSCs differentiating into chondrocytes obviously in vitro. This study provides new available conditions for constructing tissue engineered cartilage.


COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.
Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.


A molecular dynamics study on pH response of protein adsorbed on peptide-modified polyvinyl alcohol hydrogel.
The interactions between proteins and functional biomaterials under different physical and environmental conditions need to be understood when designing biomedical devices. Herein, we present a molecular dynamics simulation study of the fragment antigen-binding (Fab) of trastuzumab (a monoclonal antibody) and its complex with a peptide-modified polyvinyl alcohol (PVA) hydrogel at different pH values. Consistent with experiments, PVA when modified by charged ligands does shrink as a direct response to a drop in the pH. The protein maintains a stable conformation when adsorbed on the hydrogel matrix with a varied pH, showing no signs of denaturation in all simulated systems, suggesting that peptide-grafted PVA is a good biocompatible material. Under neutral conditions, the hydrogel alone stabilizes the interactions between the protein and the peptide ligands. Strikingly under acidic conditions the protein-ligand interactions are disrupted by a collective protonation of ligands. A sharp decrease in the interaction energies, accompanied by the sudden increase of the protein-ligand distance, indicates a rapid pH response in the protein-hydrogel complex. This will be important in protein delivery and purification. The effect of pH on the interactions and the dynamics of the protein and the sudden pH response of the hydrogel at the atomic level present a new functional perspective in developing new hydrogels with desirable properties.


Binding of IGF I and IGF I-stimulated phosphorylation in canine renal basolateral membranes.
To characterize the interaction of the renal proximal tubular cell with insulin like growth factor I (IGF I), we measured binding of 125I-IGF I to proximal tubular basolateral membranes from dog kidney and induced IGF I-stimulated phosphorylation of basolateral membranes. Specific binding of 125I-IGF I to basolateral membranes was observed that was half-maximal at between 10(-9) and 10(-8) M IGF I. 125I-IGF I was affinity cross-linked to a 135,000 Mr protein in basolateral membranes that was distinct from the alpha-subunit of the insulin receptor and from the IGF II receptor. IGF I-stimulated phosphorylation of a 92,000 Mr protein was effected in detergent-solubilized membranes incubated with 100 microM [gamma-32P]ATP. The 32P-labeled protein was distinct from the beta-subunit of the insulin receptor, the 32P phosphorylation of which was stimulated by insulin. We conclude that specific receptors for IGF I are present in the basolateral membrane of the renal proximal tubular cell. Physiological actions of IGF I at this nephron site may occur through the binding of this peptide circulating in plasma, to specific basolateral membrane receptors, followed by IGF I stimulated phosphorylation.


Cost of youth tobacco-control policies in seven European countries.
Tobacco-control policies have been suggested to reduce smoking among adolescents. However, there is limited evidence on the real-world costs of implementation in different settings. In this study, we aimed at estimating the costs of school smoking bans, school prevention programmes and non-school bans (smoking bans in non-educational public settings, bans on sales to minors and bans on point-of-sale advertising), implemented in Finland, Ireland, the Netherlands, Belgium, Germany, Italy and Portugal, for 2016. We retrospectively collected costs related to the inspection, monitoring and sanctioning activities related to bans and educational activities related to smoking prevention programmes. We used an 'ingredients-based' approach, identifying each resource used, quantity and unit value for one full year, under the state perspective. Costs were measured at national, regional, local and school-level and were informed by data on how these activities were performed in reality. Purchasing power parities adjusted-costs varied between €0.02 and €0.74 (average €0.24) per person (pp) for bans implemented outside schools. Mean costs of school smoking bans ranged from €3.31 to €34.76 (average €20.60), and mean costs of school educational programmes from €0.75 to €4.65 (average €2.92). It is feasible to estimate costs of health policies as implemented in different settings. Costs of the tobacco control policies evaluated here depend mainly on the number of person-hours allocated to their implementation, and on the scale of intervention. Non-school bans presented the lowest costs, and the implementation of all policies cost up to €36 pp for 1 year.


[Nutritional profile of the Xukuru-Kariri indigenous people in the state of Minas Gerais in accordance with different anthropometric and body composition indicators].
The scope of this study was to evaluate the nutritional profile of indigenous Xukuru-Kariri villagers in the state of Minas Gerais between seven and seventy-eight years of age in accordance with the different anthropometric and body composition indicator. The measurements were: weight, height, waist circumference (WC) and body fat percentage (BF%). The sensitivity and specificity of anthropometric indices were calculated with a confidence interval of 95% and positive predictive value (PPV) and negative predictive value (NPV). A total of 58 individuals was evaluated, of which 56.9% (n =33) were male and 43.1% (n =25) were female. Specificity was greater than sensitivity in all indices. It was seen that 29% of individuals were classified as having excess body fat as assessed by BMI and hand-to-hand bioimpedance and 50% of subjects had high body fat in relation to BMI and WC. Studies need to be conducted with different ethnic groups in order to construct indicators for specific nutritional guidance of indigenous health services.


Voice rehabilitation of Broca's aphasia following total laryngectomy.
Total laryngectomy, as a consequence of carcinoma of the larynx, results in loss of speech function. Cerebrovascular stroke is the leading cause of reduced speech production ability, and thereby communication difficulties. The case is presented of a 60-year-old male patient who suffered stroke five years after a total laryngectomy. Speech rehabilitation was hampered due to the depressive state of the patient. Although contraindicated, the secondary voice prosthesis was implanted. Only at that moment the patient showed willingness and motivation for speech rehabilitation. The aim of this presentation is to demonstrate that not all neurological disorders are contraindicated for implantation of voice prostheses.


The Determinants of Leptin Levels in Diabetic and Nondiabetic Saudi Males.
Objective. This study aimed to identify the main determinants of serum leptin levels. Methods. A sample of 113 Saudi adult males (55 diabetic and 58 nondiabetic) was selected according to the inclusion and exclusion criteria identified below. Blood samples were taken from participants after fasting for 12 hours. For diabetic patients, the insulin dose was given 12 hours before. In general, the study instrument consisted of blood biochemical tests. Metabolic parameters, glycosylated hemoglobin (HbA1c), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, and triglyceride (TG), and adipokines, leptin, adiponectin, visfatin, and resistin, were measured. Multivariate model was utilized to identify the relationship between leptin levels and the independent variables. Results. When adjusted for resistin in the diabetic group, the results demonstrated a significant relationship between visfatin, LDL and TG, and leptin levels (p < 0.05). However, when controlled for resistin, the effect of LDL and TG disappeared while that of visfatin stayed in the model. For the nondiabetic group, the results indicated a significant relationship between insulin, BMI, and leptin levels when adjusted for resistin (p < 0.05). However, the effect of insulin disappeared when the model was controlled for resistin. The study results found no relationship between leptin and adiponectin levels in either the diabetic or nondiabetic group and whether adjusted or controlled for resistin. Conclusion. This study provided better understanding of the metabolism of leptin and unveiled the major determinants of leptin levels in diabetic and nondiabetic males. In conclusion, these results show that the association between leptin and metabolic parameters decreases with the progress of disease.


A highly fatal tremorgenic mycotoxicosis of cattle caused by Aspergillus clavatus.
During February 1975, a tremorgenic neurotoxicosis decimated a herd of cattle in the northern Transvaal. This hitherto unidentified disease was characterized by hypersensitivity, incoordination, a peculiar stiff-legged gait of the hind legs, severe generalized tumors of the sketetal muscles, progressive paresis, paralysis and constipation. The most notable gross pathological lesions were degenerative and necrotic changes in certain skeletal muscles, haemorrhages on the serosal surfaces, especially on the dorsal aspect of the rumen, and gastro-intestinal stasis. Microscopical examination of the central nervous system revealed cytopathological changes consisting of degeneration and necrosis of the large motor cells in the ventral horns of the spinal cord and bigger neurones in numerous nuclei of the medulla oblongata, midbrain and thalamus. By feeding the suspect ration and its component parts to cattle and sheep, it was possible to identify mouldy sorghum beer residue as the toxic component in the ration. A. clavatus, the dominant fungus on the toxic residue, was readily isolated in pure culture. The entire syndrome was then reproduced in a yearling Friesland steer dosed with pure cultures of the A. clavatus isolate grown on autoclaved non-toxic sorghum beer residue. The toxic principle is not known, but it does not appear to be patulin, tryptoquivalone, tryptoquivaline, or any other known tremorgen.


Extracorporeal Membrane Oxygenation in Predominantly Leuco- and Thrombocytopenic Haematologic/Oncologic Patients with Acute Respiratory Distress Syndrome - a Single-Centre Experience.
The acute respiratory distress syndrome (ARDS) is a frequent condition following pneumonia in immunocompromised cancer patients. Extracorporeal membrane oxygenation (ECMO) may serve as a rescue therapy in refractory ARDS but has still not been studied in predominantly leuco- and thrombocytopenic cancer patients. In this monocentric, retrospective, observational study, we assessed all cancer patients treated with ECMO for ARDS between 2013 and 2017. 25 patients, 11 of whom underwent haematopoietic stem cell transplantation (SCT), were analysed. The main reason for ARDS was pneumonia in 72%. All patients were under invasive ventilation at ECMO. All but 9/3 patients suffered from leuco-/thrombocytopenia due to anti-cancer treatment or underlying disease. Overall, 17 patients (68%) died on ECMO, whereas 5 patients survived to hospital discharge (20%). All patients after recent allogeneic (allo-)SCT have died. 4 patients experienced severe bleeding events. Discouraging survival rates in patients treated after allo-SCT do not support the use of ECMO for ARDS in this patient subgroup. On the contrary, cancer patients in at least stable disease otherwise eligible for full-code intensive care unit management, even those with severe thrombocytopenia, may be potential candidates for ECMO in case of severe ARDS failing conventional measures.


Has pharmacogenetics brought us closer to 'personalized medicine' for initial drug treatment of hypertension?
To describe recent advances in antihypertensive pharmacogenetics and discuss challenges related to translating this knowledge into 'personalized medicine' for the initial drug treatment of hypertension. Recent studies included both prospective and retrospective analyses ranging from small clinical investigations of 42 participants to large, multicenter, randomized, outcome-based clinical trials of nearly 40 000 individuals. Treatment with drugs from five classes of antihypertensives was evaluated in these studies. The duration of treatment ranged from week-long follow up for blood pressure response to a decade-long follow up for clinical outcomes. In total, associations with 12 different candidate genes were assessed. These studies present the now familiar mixture of significant and nonsignificant pharmacogenetic findings that are sometimes consistent with, sometimes inconsistent with, previous findings in antihypertensive pharmacogenetics. Recent research in antihypertensive pharmacogenetics has added to the existing evidence base, and novel genes and variants as well as new methodologies are cause for continued optimism. However, translation of genomic science to clinical settings has not kept pace with growing interest in personalized medicine for hypertension. New research paradigms may be needed to translate pharmacogenetics into clinical tools. Clinical application will also require a trained clinical workforce, validated genetic tests, and payers willing to fund pretreatment testing.


The consumer's perspective and the professional literature: what do persons with spinal cord injury want?
Different motives and purposes drive research. New knowledge advances any discipline, and use of the information obtained from careful scientific study as the basis for clinical practice promotes patient care. It is important to consider the preferences of persons with spinal cord injury (SCI) and use this as the framework in formulating research questions and clinical applications of discoveries made in the laboratory. A literature review of articles related to the interests and concerns of persons with SCI was conducted through the National Library of Medicine resource. Patient interest in finding a "cure" for SCI was not directly ascertained by any of the studies reviewed. Mobility remains the area of greatest interest, and decreased mobility has been rated as the most difficult consequence to deal with after the injury. This review indicates a congruence of the interests of both patients and researchers. However, the methodology most often used to ascertain the preferences of persons with SCI may need to be supplemented with different approaches. In addition, these preferences and the factors that influence them should be longitudinally assessed.


Intestinal parasitic infections in hosted Saharawi children.
Literatures on intestinal parasitic infections in Saharawi children were scarce and distributed in non parasitological journals. This was the first article that specifically highlighted on the prevalence of these infections in 270 Saharawi children aged from 6 to 12 years hosted in Spain. Six different intestinal parasites were identified in this study and 78, 46, 40, 24, 13 and 5 were positive for Giardia lamblia (29%), Entamoeba coli (17%), Blastocystis hominis (15%), Endolimax nana (9%), Hymenolepis nana (5%) and Enterobius vermicularis (2%), respectively. Mixed intestinal parasitic infections were seen in 12 (4.4%) studied children. Six (2.2%) double infections for G. lamblia and B. hominis were seen in these children while in four (1.5%) had G. lamblia and H. nana. Triple intestinal parasitic infections of G. lamblia, B. hominis and H. nana were observed in two (0.7%) of the children studied. In the other hand, about 14.8% of the studied children had a mild anaemia and 15.5 and 16.6% had iron deficiency and eosinophilia, respectively.


Mapping retinal projections from double nasal and double temporal compound eyes to dually innervated tectum in Xenopus.
Right double nasal (NN) and left double temporal (TT) compound eyes were formed in the same animal by the fusion of two similar halves at early embryonic stages in Xenopus. After metamorphosis either the right or left optic nerve was sectioned to induce optic fiber regeneration from one of the two eyes to both tecta. Retinal projections from each eye to the monocularly and dually innervated tecta were later investigated by visuotectal mapping and by [3H]proline autoradiography. Visuotectal and autoradiographic maps from NN and TT eyes showed the restoration of typical compound eye projections where each of the hemiretinal projections extended across the entire contralateral (monocularly innervated) tectum. In contrast, the tectum ipsilateral to the optic nerve section was dually innervated by fibers from the TT and NN eyes. The rostral and caudal poles of the tectum were innervated by fibers from the TT and NN eyes respectively, whereas the middle third received partially overlapping projections from both eyes. Thus the full expansion of the hemiretinal projection across the dually innervated tectum was prevented by fiber-fiber interactions between optic fibers from the TT and NN eyes. It is concluded that tectal polarity cues determine the proper orientation, and fiber-fiber interaction the extent and orderliness of the retinotectal map. The formation of the latter two features of the retinotectal map does not require the existence of independent tectal positional markers.


Long-term quality of life and functional outcomes after management of spinal epidural abscess.
In recent years, the incidence of spinal epidural abscesses (SEA) has tripled in number and non-operative management has risen in popularity. While there has been a shift towards reserving surgical intervention for patients with focal neurologic deficits, a third of patients will still fail medical management and require surgical intervention. Failure to understand long-term quality of life and functional outcomes hinders effective decision making and prognostication. To describe patterns and associated factors impacting long-term quality of life following treatment of spinal epidural abscess. Multi-center cohort study at two urban academic tertiary referral centers and two community centers. Adult patients treated for a spinal epidural abscess. EuroQoL 5-Dimension 5L (EQ5D), Neuro-Quality of Life Lower Extremity - Mobility (Short Form; NeuroQoL-LE), Patient-Reported Outcomes Measurement Information System Physical Function (short form 4a; PROMIS PF), and PROMIS Global Mental Health score (PROMIS Mental). Eligible patients were enrolled and administered questionnaires. Multivariable analysis assessed the influence of ambulatory status on HRQL, adjusting for covariates including age, biologic sex, Charlson comorbidity index, intravenous drug use, management approach, and ASIA grade on presentation. Sixty-one patients were enrolled (mean age 60.5 years, 46% male). Thirty-four patients (58%) underwent operative management. Mean (SD) results for HRQL measures were: EQ5D 0.51 (0.37), EQ5D visual analogue scale 60.34 (25.11), NeuroQoL Lower extremity 41.47 (10.64), PROMIS physical function 39.49 (10.07), and PROMIS global mental health 44.23 (10.36). Adjusted analysis demonstrated ambulatory status at presentation, and at one year, to be important drivers of HRQL, irrespective of other factors including IVDU and ASIA grade. Patients with independent ambulatory function at one year had mean EQ5D utility of 0.65 (95% CI 0.55, 0.75), whereas those requiring assistive devices saw a 49% decrease with mean EQ5D utility of 0.32 (0.14, 0.51). Ambulatory status was associated with global and physical function but did not impact overall health self-assessment or mental health scores. We found that ambulatory status was the most important factor associated with long-term HRQL regardless of other factors such as ASIA grade or IVDU. Given prior literature demonstrating the protective effect of operative intervention on ambulatory function, this highlights ambulatory dysfunction as a potential indication for surgery and a marker of poor long-term prognosis, even in the absence of focal neurologic deficits. Our work also highlights the importance of optimized long-term rehabilitation strategies aimed to preserve ambulatory function in this high-risk population.


Salivary trace elements in relation to dental caries in a group of multi-ethnic schoolchildren in Shah Alam, Malaysia.
To assess the salivary levels of Copper (Cu), Zinc (Zn), Manganese (Mn) and Iron (Fe) obtained from children of different ethnic backgrounds in Shah Alam, Malaysia and investigate the possible relationships with caries. One hundred and twenty primary school children were included. They were divided into caries and caries-free groups. Unstimulated whole saliva was collected from each participant using spitting method. The salivary elements were measured using an Atomic Absorption Spectrophotometer. Descriptive statistics, bivariate and Pearson's correlation analysis were performed. Salivary Cu and Zn levels were significantly higher in children with dental caries compared to those caries-free (p < 0.05). Moreover, these elements had a positive correlation with dental caries (Cu: r=0.698, p<0.001; Zn: r=0.181, p<0.05). No significant variations in Mn and Fe were observed between caries and caries-free group (p>0.05). Additionally, there were significant differences in salivary Zn and Fe among different age groups (p<0.05) and highly significant differences in salivary Cu, Mn and Fe among different ethnic groups (p<0.001). However, all elements exhibited no significant differences between males and females. The salivary Cu and Zn levels showed significant differences between caries and caries-free groups. The findings also revealed significant variations in the levels of salivary Cu, Mn and Fe among different ethnic groups and salivary Zn and Fe among different age groups.


Clinical and psychobiological characteristics of simultaneous panic disorder and major depression.
Simultaneous major depression and panic disorder appears to be a common occurrence in psychiatric patients. Patients with this condition present with more severe symptoms than patients with major depression only, respond less well to conventional antidepressants, and in general exhibit greater psychopathology over the course of their illness. Evidence suggesting a possible "dual diathesis," depression and panic, in these patients is reviewed from epidemiological, clinical, and biological perspectives. The importance of taking into account the combined symptoms in treatment planning and physiopathological studies is discussed.


Patent vitellointestinal duct.
During the 3rd week of intrauterine life there is a communication between the intraembryonic gut and the yolk sac. As the development proceeds this communication narrows into a tube known as the vitellointestinal duct (VID). With the establishment of placental nutrition this duct usually becomes obliterated by the end of the 7th week of intrauterine life. In about 2% of humans this duct persists and gives rise to a group of anomalies of which Meckel's diverticulum is the commonest and complete patency of the duct is the rarest.1 We report a case of a 4-month-old infant who presented with umbilical polyp, discharge from the umbilicus, significant dehydration and failure to thrive because of complete patency of the VID.


Heterogeneity in Malignant Pleural Mesothelioma.
Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses reveal a high heterogeneity (i) between patients; (ii) within different areas of a given tumor in terms of different clonal compositions; and (iii) during treatment over time. The aim of the present review is to highlight this diversity and its therapeutic implications.


Autonomic nervous system activity in acute schizophrenia: II. relationships to short-term prognosis and clinical state.
Autonomic nervous system (ANS) activity in acute schizophrenic patients was assessed to examine predictive relationships to clinical course. Unmedicated patients were rated on global psychopathology and tested on skin conductance, heart rate, and skin temperature during rest, a series of tones, and reaction time and mental arithmetic tasks three weeks after admission and again about three months later. On the admission tests, a pattern of ANS activity found in schizophrenics in general (high resting "arousal," slow habituation, and attenuated ANS reactivity, particularly to demanding stimuli and situations) was found in patients who were to remain clinically ill but not in patients whose recovery was more complete, especially in males. Thus, ANS activity is predictive of short-term outcome in acute schizophrenia. Minimal ANS changes accompanied clinical improvement, which suggests a "'trait" interpretation, but "state" effects cannot be completely ruled out.


Ultrasound evaluation of plantar fasciitis.
To investigate the sonographic features of plantar fasciitis (PF). High-resolution ultrasound was used to measure the thickness and echogenicity of the proximal plantar fascia and associated heel pad thickness for 102 consecutive patients with PF (unilateral: 81, bilateral: 21) and 33 control subjects. The mean thickness of the plantar fascia was greater on the symptomatic side for patients with bilateral and unilateral PF than on the asymptomatic side for patients with unilateral PF, and also control subjects (5.47+/-1.09, 5.61+/-1.19, 3.83+/-0.72, 3.19+/-0.43 mm, respectively, p<0.001). A substantial difference in thickness between the asymptomatic side of patients with unilateral PF and control subjects was also noted (p=0.001). The heel pad thickness was not show different between control subjects and patients with PF. The incidence of hypoechoic fascia was 68.3% (84/123). Other findings among the patients from our test group included intratendinous calcification (two cases), the presence of perifascial fluid (one case), atrophic heel pads (one case), and the partial rupture of plantar fascia (one case). Increased thickness and hypoechoic plantar fascia are consistent sonographic findings in patients exhibiting PF. These objective measurements can provide sufficient information for the physician to confirm an initial diagnosis of PF and assess individual treatment regimens.


Prognostic value of neurofilament light in blood in patients with polyneuropathy: A systematic review.
Neurofilament light protein (NfL) is a part of the neuronal skeleton, primarily expressed in axons and is released when nerves are damage. NfL has been found to be a potential diagnostic biomarker in different types of polyneuropathies. However, whether NfL levels can be used as a predictor for the risk of disease progression is currently less understood. We searched MEDLINE (PubMed), Embase, Cochrane Library, and Web of Science Searches and included longitudinal studies with a baseline and follow-up examination of adult patients with polyneuropathy and NfL measured in blood. Twenty studies investigating NfL as a predictor of disease progression were identified, examining eight polyneuropathy subtypes. The results from studies in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) patients were divergent, with two out of five studies finding a statistically significant association between NfL levels and clinical outcome. Meta-analysis of the three Guillian-Barré Syndrome (GBS) studies found higher odds for the inability to run after one year in patients with high levels of NfL (OR 2.18, 95% CI 1.04-4.56). Results from studies examining other subacute or chronic polyneuropathies like Charcot-Marie-Tooth (CMT) varied in study design and results. Our findings suggest NfL can be used as a predictor of disease progression, particularly in polyneuropathies as CIDP and GBS. However, NfL may not serve as a reliable and cost-effective biomarker for slowly progressive polyneuropathies like CMT. Future standardized studies considering NfL as a prognostic blood biomarker in patients with different types of polyneuropathies are warranted.


Intergenerational effects of maternal post-traumatic stress disorder on offspring epigenetic patterns and cortisol levels.
Aim: To investigate the association between maternal post-traumatic stress disorder (PTSD) during pregnancy and offspring DNA methylation and cortisol levels. Materials & methods: Blood genome-wide DNA methylation and cortisol was measured in the youngest child of 117 women who experienced sexual violence/torture during the Kosovo war. Results: Seventy-two percent of women had PTSD symptoms during pregnancy. Their children had higher cortisol levels and differential methylation at candidate genes (NR3C1, HTR3A and BNDF). No methylation differences reached epigenome-wide corrected significance levels. Conclusion: Identifying the biological processes whereby the negative effects of trauma are passed across generations and defining groups at high risk is a key step to breaking the intergenerational transmission of the effects of mental disorders.


Effect of microplastics on soil greenhouse gas emissions in agroecosystems: Does it depend upon microplastic shape and soil type?
Microplastics have emerged as a significant pollutant in terrestrial ecosystems, with their accumulation in agricultural fields influencing soil greenhouse gas emissions. Nevertheless, the specific impact of microplastics, particularly in relation to their varying shapes, and how this effect manifests across diverse soil types, remains largely unexplored. In this study, a 56-day incubation experiment was conducted to assess the influence of microplastic shapes (fibers, films, and spheres) on CO2 and N2O emissions in three types of soils (Chernozems, Luvisols, and Ferralsols), while also investigating potential associations with the compositional and functional characteristics of soil bacterial communities. When compared to the control group, the introduction of microplastic fibers resulted in an increase of 21.7 % in cumulative CO2 emissions and a 31.4 % rise in cumulative N2O emissions in Ferralsols. This increase was closely linked to the proliferation of the Actinobacteria and Bacilli classes and the orders of Catenulisporales, Bacillales, Streptomycetales, Micrococcales, and Burkholderiales within the bacterial communities of Ferralsols, alongside an observed elevation in N-acetyl-glucosaminidase enzyme activity. The inclusion of microplastic fibers did not result in significant alterations in greenhouse gas emissions within Chernozems and Luvisols. This is likely attributed to the inherent buffering capacity of these soils, which helps stabilize substrate and nutrient availability for microbial communities. These findings highlight that the response of greenhouse gas emissions to microplastic additions is contingent upon the shape of the microplastics and the specific soil types.


Correlations between tear cytokines, chemokines, and soluble receptors and clinical severity of dry eye disease.
To determine cytokine and chemokine concentrations in the tears of patients with dry eye disease (DED) and analyze the possible relationships with the clinical severity of DED. Patients were examined using the Ocular Surface Disease Index, corneal and conjunctival staining, tear breakup time, and impression cytology. They were divided into four groups according to the Dry Eye Workshop severity classification. Tears were collected from 133 patients with DED and 70 healthy controls. Concentrations of cytokines, chemokines, and soluble receptors in collected tear samples were analyzed using current technology with a Human Cytokine/Chemokine kit, a Human Cytokine/Chemokine Panel, and a Human Soluble Cytokine Receptor Panel. The levels of cytokines interleukin (IL)-1β (P < 0.05), IL-6 (P < 0.001), IL-16 (P < 0.001), IL-33 (P < 0.05), G-CSF (P < 0.001), and transforming growth factor (TGF)-α (P < 0.05) were significantly higher in patients with DED, whereas those of cytokines IL-4 (P < 0.001), IL-12 (p40) (P < 0.001), IL-17A (P < 0.05), and interferon-γ (P < 0.001) were significantly lower. The levels of Fractalkine (chemokine [C-X3-C motif] ligand 1; CX3CL1), MCP-1 (chemokine [C-C motif] ligand 2; CCL2), MIP-1δ (chemokine [C-C motif] ligand 15; CCL15), and ENA-78 (chemokine [C-X-C motif] ligand 5; CXCL5) (P < 0.001, respectively) and soluble receptors, sIL-1RI (P < 0.05), soluble glycoprotein (sgp) 130 (P < 0.05), sIL-6R (P < 0.001), soluble epidermal growth factor receptor (P < 0.05), and soluble tumor necrosis factor receptor 2 (P < 0.001), were higher in patients with DED. There were significant correlations between these molecules and the clinical severity of DED. Fifteen molecules were elevated in the tears of patients with DED; four molecules were decreased. Although the levels of sIL-6R, sIL-6R, and sgp130 may be potential indicators of the homeostatic process, an increase in the levels of IL-6 and IL-1 β are the earliest observable changes in patients with DED. Further study on the biomarkers in the pathogenesis of DED and treatment target modalities would be needed.


Risk Factors for Podoconiosis: Kamwenge District, Western Uganda, September 2015.
AbstractPodoconiosis, a noninfectious elephantiasis, is a disabling neglected tropical disease. In August 2015, an elephantiasis case-cluster was reported in Kamwenge District, western Uganda. We investigated to identify the disease's nature and risk factors. We defined a suspected podoconiosis case as onset in a Kamwenge resident of bilateral asymmetrical lower limb swelling lasting ≥ 1 month, plus ≥ 1 of the following associated symptoms: skin itching, burning sensation, plantar edema, lymph ooze, prominent skin markings, rigid toes, or mossy papillomata. A probable case was a suspected case with negative microfilaria antigen immunochromatographic card test (ruling out filarial elephantiasis). We conducted active case-finding. In a case-control investigation, we tested the hypothesis that the disease was caused by prolonged foot skin exposure to irritant soils, using 40 probable case-persons and 80 asymptomatic village control-persons, individually matched by age and sex. We collected soil samples to characterize irritants. We identified 52 suspected (including 40 probable) cases with onset from 1980 to 2015. Prevalence rates increased with age; annual incidence (by reported onset of disease) was stable over time at 2.9/100,000. We found that 93% (37/40) of cases and 68% (54/80) of controls never wore shoes at work (Mantel-Haenszel odds ratio [ORMH] = 7.7; 95% [confidence interval] CI = 2.0-30); 80% (32/40) of cases and 49% (39/80) of controls never wore shoes at home (ORMH = 5.2; 95% CI = 1.8-15); and 70% (27/39) of cases and 44% (35/79) of controls washed feet at day end (versus immediately after work) (OR = 11; 95% CI = 2.1-56). Soil samples were characterized as rich black-red volcanic clays. In conclusion, this reported elephantiasis is podoconiosis associated with prolonged foot exposure to volcanic soil. We recommended foot hygiene and universal use of protective shoes.


Point process modelling of the Afghan War Diary.
Modern conflicts are characterized by an ever increasing use of information and sensing technology, resulting in vast amounts of high resolution data. Modelling and prediction of conflict, however, remain challenging tasks due to the heterogeneous and dynamic nature of the data typically available. Here we propose the use of dynamic spatiotemporal modelling tools for the identification of complex underlying processes in conflict, such as diffusion, relocation, heterogeneous escalation, and volatility. Using ideas from statistics, signal processing, and ecology, we provide a predictive framework able to assimilate data and give confidence estimates on the predictions. We demonstrate our methods on the WikiLeaks Afghan War Diary. Our results show that the approach allows deeper insights into conflict dynamics and allows a strikingly statistically accurate forward prediction of armed opposition group activity in 2010, based solely on data from previous years.


Volatile compounds from anal glands of the wolverine, Gulo gulo.
Dichloromethane extracts of wolverine (Gulo gulo, Mustelinae, Mustelidae) anal gland secretion were examined by gas chromatography-mass spectrometry. The secretion composition was complex and variable for the six samples examined: 123 compounds were detected in total, with the number per animal ranging from 45 to 71 compounds. Only six compounds were common to all extracts: 3-methylbutanoic acid, 2-methylbutanoic acid, phenylacetic acid, alpha-tocopherol, cholesterol, and a compound tentatively identified as 2-methyldecanoic acid. The highly odoriferous thietanes and dithiolanes found in anal gland secretions of some members of the Mustelinae [ferrets, mink, stoats, and weasels (Mustela spp.) and zorillas (Ictonyx spp.)] were not observed. The composition of the wolverine's anal gland secretion is similar to that of two other members of the Mustelinae, the pine and beech marten (Martes spp.).


Diagnosing Horner's syndrome.
The diagnosis of Horner's syndrome is divided into two stages: (1) the recognition of the sympathetic deficit, and (2) the localization of the lesion. The second step is of vital importance in the management of the patient with Horner's syndrome. If the lesion is preganglionic, the risk of malignancy is high; the patient should have cervical spine and chest roentgenograms (PA, lateral and apical lordotic) and perhaps a referral to a surgeon. If the lesion is postganglionic, it is most likely a benign vascular headache syndrome and the patient should go to a neurologist.


Regiospecific Hetero-Assembly of DNA-Functionalized Plasmonic Upconversion Superstructures.
We report a novel strategy for regiospecific hetero-assembly of DNA-modified gold nanoparticles (DNA-AuNPs) onto upconversion nanoparticles (UCNPs) into hybrid lab-on-a-particle systems. The DNA-AuNPs have been assembled onto the hexagonal plate-like UCNPs with well-regulated stoichiometry and controlled organization onto the different facets of UCNP, forming various addressable superstructures. The fine-tuning of stoichiometry and organization is realized by biorecognition specificity of DNA toward specific crystal facets of UCNPs. Such a hetero-assembled DNA-AuNP/UCNP system maintains both plasmonic resonance of AuNPs and fluorescent properties of UCNPs, allowing targeted dual-modality imaging of cancer cells using an aptamer.


Changes in solvation during DNA binding and cleavage are critical to altered specificity of the EcoRI endonuclease.
Restriction endonucleases such as EcoRI bind and cleave DNA with great specificity and represent a paradigm for protein-DNA interactions and molecular recognition. Using osmotic pressure to induce water release, we demonstrate the participation of bound waters in the sequence discrimination of substrate DNA by EcoRI. Changes in solvation can play a critical role in directing sequence-specific DNA binding by EcoRI and are also crucial in assisting site discrimination during catalysis. By measuring the volume change for complex formation, we show that at the cognate sequence (GAATTC) EcoRI binding releases about 70 fewer water molecules than binding at an alternate DNA sequence (TAATTC), which differs by a single base pair. EcoRI complexation with nonspecific DNA releases substantially less water than either of these specific complexes. In cognate substrates (GAATTC) kcat decreases as osmotic pressure is increased, indicating the binding of about 30 water molecules accompanies the cleavage reaction. For the alternate substrate (TAATTC), release of about 40 water molecules accompanies the reaction, indicated by a dramatic acceleration of the rate when osmotic pressure is raised. These large differences in solvation effects demonstrate that water molecules can be key players in the molecular recognition process during both association and catalytic phases of the EcoRI reaction, acting to change the specificity of the enzyme. For both the protein-DNA complex and the transition state, there may be substantial conformational differences between cognate and alternate sites, accompanied by significant alterations in hydration and solvent accessibility.


A Collection of Transgenic Medaka Strains for Efficient Site-Directed Transgenesis Mediated by phiC31 Integrase.
Genetic analysis is facilitated by the efficient production of transgenic strains expressing a DNA of interest as a single copy at a designated chromosomal location. However, technical progress toward this goal in medaka fish (Oryzias latipes), a vertebrate model organism, has been slow. It is well known that phiC31 integrase enables efficient site-directed transgenesis by catalyzing the recombination of an attP DNA motif in a host genome with an attB motif in a targeting vector. This system was pioneered in medaka using the Sleeping Beauty transposon system, and the attP site was established at three chromosomal locations. However, this number appeared insufficient with regard to genetic linkage between the attP-landing site and a genetically modified locus of interest. Here, to establish a collection of transgenic strains of medaka, we introduced an attP motif into the medaka genome using the Ac/Ds maize transposon system and established 12 independent transgenic strains harboring a single copy of the attP motif in at least 11 of the 24 medaka chromosomes. We designed an attB-targeting vector that was integrated efficiently and precisely into the attP-landing site, and with which the DNA of interest was efficiently transmitted to germline cells. Extraneous sequences in the integrants derived from the bacterial backbone of the attB-targeting vector as well as a transgenic fluorescence marker present in the attP-landing site were removable through flippase-mediated recombination. Further, an advanced targeting vector with a heart-specific recombination marker served as a useful tool for easily screening phiC31 integrase-mediated recombinant G0 embryos, leading to the efficient establishment of transgenic strains. Thus, our resources advance genetic research in medaka.


Importance of estimated functional capacity as a predictor of all-cause mortality among patients referred for exercise thallium single-photon emission computed tomography: report of 3,400 patients from a single center.
We sought to determine the relative influence of estimated functional capacity and thallium-201 (Tl-201) single-photon emission computed tomographic (SPECT) findings on prediction of short-term all-cause and cardiac-related mortality. Decreased functional capacity and abnormal Tl-201 SPECT findings are predictive of increased cardiovascular risk and mortality. However, the relative importance of these variables as predictors of all-cause mortality is not well established. Analyses were based on 3,400 consecutive adults undergoing symptom-limited exercise Tl-201 SPECT testing at the Cleveland Clinic Foundation between September 1990 and December 1993; none had previous invasive procedures, heart failure or valve disease. Estimated functional capacity, classified by age and gender, and thallium perfusion defects, expressed as a stress extent thallium score on a 12-segment scale, were analyzed to determine their relative prognostic importance during 2 years of follow-up. Of 3,400 patients, 108 (3.2%) died during follow-up; 32 deaths were identified as cardiac related. On univariable analysis, estimated functional capacity was a strong predictor of death, with 62 (57%) deaths occurring in patients achieving < 6 metabolic equivalents (METs) (log-rank chi-square 86, p < 0.0001). On multivariable analysis, the strongest independent predictors of all-cause mortality were fair or poor functional capacity (adjusted relative risk [RR] 3.96, 95% confidence interval [CI] 2.36 to 6.64, chi-square 27, p < 0.0001) and age (adjusted RR for 10 years 2.25, 95% CI 1.80 to 2.80, chi-square 27, p < 0.0001). The presence of SPECT thallium perfusion defects was a less powerful predictor of death (for each two additional segments with defects, adjusted RR 1.21, 95% CI 1.03 to 1.43, chi-square 5, p = 0.02). Cardiac mortality was predicted by both fair or poor functional capacity (adjusted RR 4.37, 95% CI 1.59 to 12.00, chi-square 8, p = 0.004) and by stress extent thallium score (adjusted RR 1.62, 95% CI 1.25 to 2.11, chi-square 13, p = 0.0003). In this clinically low risk group, estimated functional capacity was a strong and overwhelmingly important independent predictor of all-cause mortality among patients undergoing exercise Tl-201 SPECT testing. The extent of myocardial perfusion defects was of comparable importance for the prediction of cardiac mortality.


Improving the quality of operative notes by implementing a new electronic template for upper limb surgery at the Royal Derby Hospital.
The RCS has published clear and succinct guidelines dictating the necessity for the documentation of legible and timely surgical operative notes and exactly what should be included. A baseline study within the upper limb unit at our trust showed a 71.1% adherence with the RCS guidelines with an average delay of typing of notes after dictation was 11.6 days. This quality improvement project designed and developed a bespoke electronic surgical notes template built within an existing database driven software within the Trust. After implementation of the templates we found no delays in full operative notes being typed and a 100% adherence with the RCS guidelines. This project significantly improved the quality and timely production of electronic surgical notes within a sustainable electronic software solution.


Somatic mosaicism for Duchenne dystrophy: evidence for genetic normalization mitigating muscle symptoms.
We describe a young adult male presenting with cardiac failure necessitating cardiac transplantation 7 months after presentation. Skeletal muscle biopsy showed mosaic immunostaining for dystrophin. DNA studies showed somatic mosaicism for a nonsense mutation in the dystrophin gene (Arg2905X). The frequency of normal versus mutant genes were determined in blood/DNA (50:50), muscle/DNA (80:20) and muscle/mRNA (90:10). These data are consistent with genetic normalization processes that may biochemically rescue skeletal muscle in male somatic mosaic patients mitigating muscle symptoms (gradual loss of dystrophin-negative skeletal muscle tissue replaced by dystrophin-positive stem cells). To our knowledge, this is only the second reported case of a clinically ascertained patient showing somatic mosaicism for Duchenne muscular dystrophy (DMD). We hypothesize that many somatic mosaic males for DMD exist, yet they are not detected clinically due to genetic normalization. Somatic mosaicism for DMD should be considered in acute heart failure with dilated cardiomyopathy, as genetic normalization in heart is unlikely to occur.


Trabecular microbypass stent combined with phacoemulsification in patients with open-angle glaucoma, 1-year outcome in a Taiwanese population.
The purpose of this study was to evaluate the safety and efficacy of one trabecular microbypass stent (first generation iStent) combined with phacoemulsification cataract surgery (phaco) in eyes with open-angle glaucoma (OAG) in a Taiwanese population. One trabecular microbypass stent was implanted after phacoemulsification cataract surgery by one surgeon. Intraocular pressure (IOP), medications, corrected distance visual acuity, complications, and adverse events were evaluated. This case series included 28 eyes of 25 patients with OAG (19 primary open-angle glaucoma [POAG] and 9 normal tension glaucoma [NTG]). None had previous trabeculectomy or laser trabeculoplasty. At 1 year, the mean IOP decreased from 19.34 ± 3.92 mmHg to 15.84 ± 3.05 mmHg, and the mean number of glaucoma medications decreased from 1.82 ± 1.12 to 0.79 ± 1.17 (both P < 0.001). Longer survival was observed in the NTG eyes (NTG: 11.67 ± 1.00 months, POAG: 9.53 ± 3.78 months, P = 0.031). iStent reposition was performed in one eye, and four eyes received laser treatment for stent occlusion. None had secondary glaucoma surgery. Combined phacoemulsification and iStent implantations are a safe and effective way in reducing IOP and medication burden in patients with OAG, especially NTG.


A review of the effects of breastfeeding on respiratory infections, atopy, and childhood asthma.
The etiology of childhood asthma is not fully understood. Early exposure to certain respiratory infections may be protective for atopy and/or asthma whereas some infections have been suggested to exert the opposite effects. Wheezing lower respiratory illness (LRI) in the first year of life and atopy are independently associated with increased risk for current asthma in childhood and their effects are mediated via different causal pathways. These risk factors are multiplicative when they operate concommitantly within individual children. Exclusive breastfeeding protects against asthma via effects on both these pathways, as well as through other as yet undefined mechanisms. Furthermore, exclusive breastfeeding may protect against asthma and may reduce the incidence of lower respiratory illness, especially respiratory syncytial virus (RSV). We have previously demonstrated a protective effect of exclusive breastfeeding on asthmatic traits in children. The aim of this review was to clarify this protective association from intermediate associations with respiratory infections, atopy, or through other facets of breastfeeding. The bioactivity of breast milk and subsequent pathways that may act upon the development of asthma in children are explored.


One-year results of photodynamic therapy combined with intravitreal ranibizumab for exudative age-related macular degeneration.
Purpose. To evaluate the effects of photodynamic therapy (PDT) combined with intravitreal injection of ranibizumab (IVR) for exudative age-related macular degeneration (AMD). Methods. Retrospective case series. Thirty eight eyes of 38 patients with exudative AMD underwent combined therapy consisting first of IVR, followed by PDT within a week and the second IVR at 1 month. All patients were followed up for more than 12 months. The best corrected visual acuity (BCVA) and central macular thickness (CMT) were examined. Results. The mean number of IVR and PDT sessions were 2.9 ± 1.3 and 1.1 ± 0.3, respectively. The mean BCVA and CMT were significantly improved to 0.38 logMAR units (P < 0.01) and 240 μm (P < 0.01) at 12 months, respectively. Thirty-six of 38 eyes (94.8%) improved or maintained BCVA at 12 months. Conclusion. PDT combined with IVR for exudative AMD was effective at improving visual acuity and CMT with a low recurrence rate for 12 months.


Medicinal chemistry aspects of uracil containing dUTPase inhibitors targeting colorectal cancer.
Deoxyuridine-5'-triphosphate nucleotidohydrolase (dUTPase), a vital enzyme in pyrimidine metabolism, is a prime target for treating colorectal cancer. Uracil shares structural traits with DNA/RNA bases, prompting exploration by medicinal chemists for pharmacological modifications. Some existing drugs, including thymidylate synthase (TS) and dUTPase inhibitors, incorporate uracil moieties. These derivatives hinder crucial cell proliferation pathways encompassing TS, dUTPases, dihydropyrimidine dehydrogenase, and uracil-DNA glycosylase. This review compiles uracil derivatives that have served as dUTPase inhibitors across various organisms, forming a library for targeting human dUTPase. Insights into their structural requisites for human applications and comparative analyses of binding pockets are provided for analyzing the compounds against human dUTPase.


Self-adjuvanting therapeutic peptide-based vaccine induce CD8+ cytotoxic T lymphocyte responses in a murine human papillomavirus tumor model.
Vaccine candidates for the treatment of human papillomavirus (HPV)-associated cancers are aimed to activate T-cells and induce development of cytotoxic anti-tumor specific responses. Peptide epitopes derived from HPV-16 E7 oncogenic protein have been identified as promising antigens for vaccine development. However, peptide-based antigens alone elicit poor cytotoxic T lymphocyte (CTL) responses and need to be formulated with an adjuvant (immunostimulant) to achieve the desired immune responses. We have reported the ability of polyacrylate 4-arm star-polymer (S4) conjugated with HPV-16 E744-57 (8Qmin) epitope to reduce and eradicate TC-1 tumor in the mouse model. Herein, we have studied the mechanism of induction of immune responses by this polymer-peptide conjugate and found prompt uptake of conjugate by antigen presenting cells, stimulating stronger CD8(+) rather than CD4(+) or NK cell responses.


Serum transforming growth factor β1 during diabetes development in non-obese diabetic mice and humans.
Recent data show that regulatory cells with transforming growth factor (TGF)-β1-dependent activity are able to restore self-tolerance in overtly diabetic non-obese diabetic (NOD) mice. Thus, TGF-β1 seems to have a relevant role in protection from autoimmune diabetes. Our aim was to investigate the possible significance of serum TGF-β1 measurement in the natural history of diabetes in NOD mice, as well as in children positive for at least one islet-related antibody. Serum TGF-β1 (both total and active) was measured by enzyme-linked immunosorbent assay at monthly intervals in 26 NOD mice during the spontaneous development of diabetes and, on a yearly basis, in nine siblings of patients with type 1 diabetes (T1D) with a follow-up of 4 years. Diabetes appeared between the 12th week of age and the end of the study period (36 weeks) in 17 mice. TGF-β1 serum level variations occurred in the prediabetic period in both NOD mice and humans and diabetes diagnosis followed a continuing reduction of active TGF-β1 (aTGF-β1) serum levels. In mice, aTGF-β1 serum levels measured at 4 weeks of age correlated positively with severity of insulitis, and negatively with percentage of insulin-positive cells. Our findings suggest that in NOD mice serum TGF-β1 levels during the natural history of the diabetes reflect the course of islet inflammation. The measurement of aTGF-β1 in islet-related antibody-positive subjects may provide insights into the natural history of prediabetic phase of T1D.


Triplane rhytidectomy. Combining the best of all worlds.
To combine certain aspects of the sub-superficial musculoaponeurotic system (sub-SMAS) and subperiosteal rhytidectomies to maximize the advantages while minimizing the disadvantages of each. The subperiosteal rhytidectomy is used to reposition the ptotic malar fat pad concomitantly with the elevation of the corner of the mouth by means of shifting upward the origin of the zygomatic major muscle. The sub-SMAS rhytidectomy is used to maximize elevation of the jowl. Ambulatory surgical facility. Preauricular and temporal dissection is subcutaneous to the malar eminence above and angle of mandible below. A subperiosteal dissection of the middle part of the face is then accomplished through a sublabial approach combined with an incision over the malar eminence. An incision is made through the SMAS from the malar eminence to the mandibular angle and sub-SMAS dissection is accomplished under the jowl. The subperiosteal dissection is suspended to the temporal fascia and the SMAS dissection is imbricated with 2 suspension suture lines. Follow-up in patients who are 1-year postoperative demonstrates a continued youthful elevation and flattening of the melolabial fold and complete correction of the jowl. No facial nerve injury or hematomas were observed.


Biochar, Bentonite and Zeolite Supplemented Feeding of Layer Chickens Alters Intestinal Microbiota and Reduces Campylobacter Load.
A range of feed supplements, including antibiotics, have been commonly used in poultry production to improve health and productivity. Alternative methods are needed to suppress pathogen loads and maintain productivity. As an alternative to antibiotics use, we investigated the ability of biochar, bentonite and zeolite as separate 4% feed additives, to selectively remove pathogens without reducing microbial richness and diversity in the gut. Neither biochar, bentonite nor zeolite made any significant alterations to the overall richness and diversity of intestinal bacterial community. However, reduction of some bacterial species, including some potential pathogens was detected. The microbiota of bentonite fed animals were lacking all members of the order Campylobacterales. Specifically, the following operational taxonomic units (OTUs) were absent: an OTU 100% identical to Campylobacter jejuni; an OTU 99% identical to Helicobacter pullorum; multiple Gallibacterium anatis (>97%) related OTUs; Bacteroides dorei (99%) and Clostridium aldenense (95%) related OTUs. Biochar and zeolite treatments had similar but milder effects compared to bentonite. Zeolite amended feed was also associated with significant reduction in the phylum Proteobacteria. All three additives showed potential for the control of major poultry zoonotic pathogens.


Some models for epidemics of vector-transmitted diseases.
Vector-transmitted diseases such as dengue fever and chikungunya have been spreading rapidly in many parts of the world. The Zika virus has been known since 1947 and invaded South America in 2013. It can be transmitted not only by (mosquito) vectors but also directly through sexual contact. Zika has developed into a serious global health problem because, while most cases are asymptomatic or very light, babies born to Zika - infected mothers may develop microcephaly and other very serious birth defects. We formulate and analyze two epidemic models for vector-transmitted diseases, one appropriate for dengue and chikungunya fever outbreaks and one that includes direct transmission appropriate for Zika virus outbreaks. This is especially important because the Zika virus is the first example of a disease that can be spread both indirectly through a vector and directly (through sexual contact). In both cases, we obtain expressions for the basic reproduction number and show how to use the initial exponential growth rate to estimate the basic reproduction number. However, for the model that includes direct transmission some additional data would be needed to identify the fraction of cases transmitted directly. Data for the 2015 Zika virus outbreak in Barranquilla, Colombia has been used to fit parameters to the model developed here and to estimate the basic reproduction number.


Revisiting the Taxonomy of the Genus Arcobacter: Getting Order From the Chaos.
Since the description of the genus Arcobacter in 1991, a total of 27 species have been described, although some species have shown 16S rRNA similarities below 95%, which is the cut-off that usually separates species that belong to different genera. The objective of the present study was to reassess the taxonomy of the genus Arcobacter using information derived from the core genome (286 genes), a Multilocus Sequence Analysis (MLSA) with 13 housekeeping genes, as well as different genomic indexes like Average Nucleotide Identity (ANI), in silico DNA-DNA hybridization (isDDH), Average Amino-acid Identity (AAI), Percentage of Conserved Proteins (POCPs), and Relative Synonymous Codon Usage (RSCU). The study included a total of 39 strains that represent all the 27 species included in the genus Arcobacter together with 13 strains that are potentially new species, and the analysis of 57 genomes. The different phylogenetic analyses showed that the Arcobacter species grouped into four clusters. In addition, A. lekithochrous and the candidatus species 'A. aquaticus' appeared, as did A. nitrofigilis, the type species of the genus, in separate branches. Furthermore, the genomic indices ANI and isDDH not only confirmed that all the species were well-defined, but also the coherence of the clusters. The AAI and POCP values showed intra-cluster ranges above the respective cut-off values of 60% and 50% described for species belonging to the same genus. Phenotypic analysis showed that certain test combinations could allow the differentiation of the four clusters and the three orphan species established by the phylogenetic and genomic analyses. The origin of the strains showed that each of the clusters embraced species recovered from a common or related environment. The results obtained enable the division of the current genus Arcobacter in at least seven different genera, for which the names Arcobacter, Aliiarcobacter gen. nov., Pseudoarcobacter gen. nov., Haloarcobacter gen. nov., Malacobacter gen. nov., Poseidonibacter gen. nov., and Candidate 'Arcomarinus' gen. nov. are proposed.


High anticonvulsant potency of gamma-aminobutyric acid (GABA)mimetic drugs in gerbils with genetically determined epilepsy.
Seven GABAmimetic drugs, namely cetyl gamma-aminobutyric acid (cetyl GABA), 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol, progabide, aminooxyacetic acid, alpha-acetylenic GABA, (-)-nipecotic acid ethyl ester and (+/-)-cis-4-hydroxynipecotic acid methyl ester, were tested for their potency to block "major" (generalized clonic-tonic) seizures in gerbils, induced by blowing at the animals with compressed air. Valproic acid was included as a reference standard. All drugs proved able to protect gerbils from induced seizures. Most effective were 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol (ED50, 1.3 mg/kg i.p.), aminooxyacetic acid (0.9), cetyl GABA (4.5) and gamma-acetylenic GABA (2.1). A comparison with anticonvulsant ED50 values of common antiepileptics in the gerbil showed that these four GABAmimetics were clearly more potent than phenobarbital, phenytoin, carbamazepine, ethosuximide and valproic acid and were only surpassed in potency by diazepam. Furthermore, most GABAmimetics proved strikingly more active in the gerbil compared with the classical electroshock and pentylenetetrazol seizure models in mice. After administration of gamma-acetylenic GABA, GABA increases in the brain of only about 40% were found sufficient to reach almost complete seizure protection in gerbils. The present data are compatible with the possibility that the GABA system is critically involved in the seizure-prone state in the gerbil.


Cyclosporin A affects extracellular matrix synthesis and degradation by mouse MC3T3-E1 osteoblasts in vitro.
Immunosuppressant therapy is thought to be a major contributor to post-transplant bone disease. Histological data and serum parameters suggest that Cyclosporin A (CsA) treatment causes osteopenia as a result of an altered bone turnover, but the pathogenic mechanisms of this process remain unclear. We investigate if CsA affects cell turnover and extracellular matrix (ECM) synthesis and degradation in MC3T3-E1 osteoblasts, as a surrogate model for in vivo events. Cells were exposed to increasing doses of CsA (0, 0.5, 1 and 5 microg/ml). Proliferation was evaluated by bromodeoxyuridine (BrdU) incorporation, viability by Trypan Blue exclusion and apoptosis by ELISA. Type I collagen was measured by ELISA and reverse transcription-polymerase chain reaction (RT-PCR), matrix metalloproteinases (MMP) by zymography and RT-PCR, and tissue inhibitors of MMP (TIMP) by reverse zymography. CsA exposure for 48 h decreased osteoblast number in a dose-dependent manner in the absence of apoptosis or cytotoxicity. CsA at a dose of 5 microg/ml for 72 h caused decreased collagen type I mRNA expression and protein accumulation. While MMP-2 remained unaffected, MMP-9 activity increased. TIMP-1 activity was unaffected, while a dose-dependent increase of TIMP-2 was observed. These data suggest that CsA alters ECM synthesis and degradation in MC3T3-E1 osteoblasts by decreasing type I collagen production and increasing MMP-9 activity. The combination of increased MMP-9 with unchanged TIMP-1 activity could reduce the osteoid matrix available for mineralization. In addition, decreased proliferation could further reduce the number of cells synthesizing new osteoid matrix and thus contribute to the process of bone loss.


Weaning strategies for the withdrawal of non-invasive respiratory support applying continuous positive airway pressure in preterm infants: a systematic review and meta-analysis.
The optimal method to wean preterm infants from non-invasive respiratory support (NIVRS) with nasal continuous positive airway pressure (CPAP) or high-flow nasal cannula is still unclear, and methods used vary considerably between neonatal units. Perform a systematic review and meta-analysis to determine the most effective strategy for weaning preterm infants born before 37 weeks' gestation from NIVRS. EMBASE, MEDLINE, CINAHL, Google and Cochrane Central Register of Controlled Trials were searched for randomised controlled trials comparing different weaning strategies of NIVRS in infants born before 37 weeks' gestation. Fifteen trials (1.547 infants) were included. With gradual pressure wean, the relative risk of successful weaning at the first attempt was 1.30 (95% CI 0.93 to 1.83), as compared with sudden discontinuation. Infants were weaned at a later postmenstrual age (PMA) (median difference (MD) 0.93 weeks (95% CI 0.19 to 1.67)). A stepdown strategy to nasal cannula resulted in an almost 3-week reduction in the PMA at successful weaning (MD -2.70 (95% CI -3.87 to -1.52)) but was associated with a significantly longer duration of oxygen supplementation (MD 7.80 days (95% CI 5.31 to 10.28)). A strategy using interval training had no clinical benefits. None of the strategies had any effect on the risk of chronic lung disease or the duration of hospital stay. A strategy of gradual weaning of airway pressure might increase the chances of successful weaning. Stepdown strategy from CPAP to nasal cannula is a useful alternative resulting in an earlier weaning, but the focus should remain on continued weaning in order to avoid prolonged oxygen supplementation. Interval training should probably not be used.


Thermo-chemotherapy Induced miR-218 upregulation inhibits the invasion of gastric cancer via targeting Gli2 and E-cadherin.
Thermo-chemotherapy has been proven to reduce the invasion capability of cancer cells. However, the molecular mechanism underlying this anti-invasion effect is still unclear. In this study, the role of thermo-chemotherapy in the inhibition of tumor invasion was studied. The results demonstrated that expression of miR-218 was downregulated in gastric cancer tissues, which had a positive correlation with tumor invasion and metastasis. In vitro thermo-chemotherapy increased miR-218 expression in SGC7901 cells and inhibited both proliferation and invasion of cancer cells. Gli2 was identified as a downstream target of miR-218, and its expression was negatively regulated by miR-218. The thermo-chemotherapy induced miR-218 upregulation was also accompanied by increasing of E-cadherin expression. In conclusion, the present study indicates that thermo-chemotherapy can effectively decrease the invasion capability of cancer cells and increase cell-cell adhesion. miR-218 and its downstream target Gli2, as well as E-cadherin, participate in the anti-invasion process.


[Anatomo-pathologic findings in 25 autopsy cases of AIDS].
Pathologic findings in 25 autopsies of AIDS. The common and severe changes of the central nervous system, lungs, adrenals, heart, kidneys and gonads are reviewed in a series of autopsies of AIDS. In the brain, HIV infection induces directly inflammatory infiltrates including the typical multinucleated giant cells described by Sharer. In addition, primary lymphomas are seen as well as reactive and inflammatory lesions that are caused by opportunistic infections, such as those of poliomavirus, Cytomegalovirus and Toxoplasma gondii. In the lung, interstitial inflammation prevails, which may be related to direct HIV infection and include rare multinucleated giant cells like the ones described by Sharer. Opportunistic infections are often associated, and are commonly sustained by Cytomegalovirus and Pneumocystis carinii. A peculiar findings is the evolution from septal inflammation to fine fibrosis and hyaline degeneration, either focal or diffuse. We believe that the severe respiratory insufficiency that is commonly seen in the advanced stages of AIDS could be related to the interstitial damage. In the adrenal gland, the most common change is Cytomegalovirus infection affecting both the cortex and the medulla, and inducing massive necrosis in the cortex with little or no reaction. Again, adrenal involvement should be related to adrenal functional insufficiency, which may be over-looked clinically because of the preponderant lesions of other sites. In the heart, myocarditis is often discrete, and may be complicated by perivascular fibrosis and rare foci of myocytolysis; in some cases primary lymphomas may also develop. In the kidney, several histological lesions are found, including glomerular damage with segmental necrosis, cortical areas of hyporeactive necrosis, and mild interstitial inflammation. In the gonads, the changes are partly induced by drug abuse, and consist of atrophy with secondary hypoplasia of the germ cells and interstitial fibrosis. In conclusion, the most important abnormalities consist of opportunistic infections, hyporeactive necrosis, fibrotic evolution of the inflammatory infiltrates and neoplasias (Kaposi's sarcoma and lymphomas). In this work, the changes of the lymphoid organs are only mentioned, for they have been widely reviewed elsewhere.


Biogeographic, climatic and spatial drivers differentially affect α-, β- and γ-diversities on oceanic archipelagos.
Island biogeographic studies traditionally treat single islands as units of analysis. This ignores the fact that most islands are spatially nested within archipelagos. Here, we took a fundamentally different approach and focused on entire archipelagos using species richness of vascular plants on 23 archipelagos worldwide and their 174 constituent islands. We assessed differential effects of biogeographic factors (area, isolation, age, elevation), current and past climate (temperature, precipitation, seasonality, climate change velocity) and intra-archipelagic spatial structure (archipelago area, number of islands, area range, connectivity, environmental volume, inter-island distance) on plant diversity. Species diversity of each archipelago (γ) was additively partitioned into α, β, nestedness and replacement β-components to investigate the relative importance of environmental and spatial drivers. Multiple regressions revealed strong effects of biogeography and climate on α and γ, whereas spatial factors, particularly number of islands, inter-island distance and area range, were key to explain β. Structural equation models additionally suggested that γ is predominantly determined by indirect abiotic effects via its components, particularly β. This highlights that β and the spatial arrangement of islands are essential to understand insular ecology and evolution. Our methodological framework can be applied more widely to other taxa and archipelago-like systems, allowing new insights into biodiversity origin and maintenance.


PNH is a debilitating, fatal but treatable disease: same disease, different clinical presentations.
Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic persistent hemolysis, multi-organ damage and eventually multiple organ failure. PNH develops as a result of increased sensitivity to complement due to an acquired deficiency of certain glycosylphosphatidylinositol (GPI)-linked proteins. The clinical presentation of PNH varies greatly from one patient to another. We present three cases of PNH with different clinical presentations to illustrate the debilitating nature of the disease, possible fatal outcomes, and the need to timely diagnosis and targeted therapy. These cases also underline the need for increased awareness of PNH among relevant healthcare specialties. PNH should be considered as a differential diagnosis in patients with unexplained abdominal pain, dyspnea, renal failure, thrombosis and non-immune hemolytic anemia.


[Collagen metabolism indices, and plasma concentrations of lipids, cyclic 3',5'-AMP, and certain hormones in 40-59-year-old men].
Concentrations of protein-bound hydroxyprolin, free hydroxyproline, cholesterol, alpha-cholesterol, triglycerides, testosterone, estradiol, insuline and 3',5'-cAMP were estimated in blood plasma of 40-59 years old men. The persons thus examined were divided into three groups depending on the content of protein-bound hydroxyproline. Only in blood plasma of persons with low concentration of the protein-bound hydroxyproline a direct correlation was found between cAMP and testosterone, cAMP and alpha-cholesterol, between cAMP and the ratio of the cholesterol from atherogenous lipoproteins to the cholesterol from alpha-lipoproteins, as well as reciprocal correlation--between cAMP and insulin. The increase of protein-bound hydroxyproline concentration and the decrease of cAMP content in blood plasma might be related to proliferation of smooth muscle cells in the vessel wall, dependent, first, on alteration in the ratio of lipoproteins of various density in blood plasma and, second, on alteration in the hormone concentration in blood and tissues.


A multi-component, community-based strategy to facilitate COVID-19 vaccine uptake among Latinx populations: From theory to practice.
COVID-19 vaccine coverage in the Latinx community depends on delivery systems that overcome barriers such as institutional distrust, misinformation, and access to care. We hypothesized that a community-centered vaccination strategy that included mobilization, vaccination, and "activation" components could successfully reach an underserved Latinx population, utilizing its social networks to boost vaccination coverage. Our community-academic-public health partnership, "Unidos en Salud," utilized a theory-informed approach to design our "Motivate, Vaccinate, and Activate" COVID-19 vaccination strategy. Our strategy's design was guided by the PRECEDE Model and sought to address and overcome predisposing, enabling, and reinforcing barriers to COVID-19 vaccination faced by Latinx individuals in San Francisco. We evaluated our prototype outdoor, "neighborhood" vaccination program located in a central commercial and transport hub in the Mission District in San Francisco, using the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework during a 16-week period from February 1, 2021 to May 19, 2021. Programmatic data, city-wide COVID-19 surveillance data, and a survey conducted between May 2, 2021 and May 19, 2021 among 997 vaccinated clients ≥16 years old were used in the evaluation. There were 20,792 COVID-19 vaccinations administered at the neighborhood site during the 16-week evaluation period. Vaccine recipients had a median age of 43 (IQR 32-56) years, 53.9% were male and 70.5% were Latinx, 14.1% white, 7.7% Asian, 2.4% Black, and 5.3% other. Latinx vaccinated clients were substantially more likely than non-Latinx clients to have an annual household income of less than $50,000 a year (76.1% vs. 33.5%), be a first-generation immigrant (60.2% vs. 30.1%), not have health insurance (47.3% vs. 16.0%), and not have access to primary care provider (62.4% vs. 36.2%). The most frequently reported reasons for choosing vaccination at the site were its neighborhood location (28.6%), easy and convenient scheduling (26.9%) and recommendation by someone they trusted (18.1%); approximately 99% reported having an overall positive experience, regardless of ethnicity. Notably, 58.3% of clients reported that they were able to get vaccinated earlier because of the neighborhood vaccination site, 98.4% of clients completed both vaccine doses, and 90.7% said that they were more likely to recommend COVID-19 vaccination to family and friends after their experience; these findings did not substantially differ according to ethnicity. There were 40.3% of vaccinated clients who said they still knew at least one unvaccinated person (64.6% knew ≥3). Among clients who received both vaccine doses (n = 729), 91.0% said that after their vaccination experience, they had personally reached out to at least one unvaccinated person they knew (61.6% reached out to ≥3) to recommend getting vaccinated; 83.0% of clients reported that one or more friends, and/or family members got vaccinated as a result of their outreach, including 18.9% who reported 6 or more persons got vaccinated as a result of their influence. A multi-component, "Motivate, Vaccinate, and Activate" community-based strategy addressing barriers to COVID-19 vaccination for the Latinx population reached the intended population, and vaccinated individuals served as ambassadors to recruit other friends and family members to get vaccinated.


[Demonstration and organizational structure of the DNA of human papillomaviruses in laryngeal and hypopharyngeal carcinomas].
Thirty biopsy specimens from various histological types of human carcinomas of the larynx and hypopharynx were analysed for the presence of human papillomavirus (HPV) DNA: DNA from the individual specimens were tested for the presence of homologous sequences to HPV genotypes 1, 2, 4, 8, 9, 10, 11, 13, 16 and 18. One squamous cell carcinoma of the hypopharynx (postcricoideal area) contained multiple copies of DNA hybridizing under stringent conditions with HPV 16 DNA. The latter DNA has been found to be frequently associated with human genital cancer. HPV 16 DNA was found mostly episomally as oligomeric circles of 7.9 kbp size, and as larger rear-ranged circular molecules. Integration of the viral DNA in the host cell DNA seems quite likely. Integration and rearrangement of viral DNA into cellular DNA may play a role in the induction and maintenance of the transformed state. The presence of sequences reacting under semistringent conditions with HPV DNA was observed in two additional biopsy specimens of this study. This could suggest that additional laryngeal cancers are associated with papilloma virus infections.


Pilot study of postoperative reirradiation, chemotherapy, and amifostine after surgical salvage for recurrent head-and-neck cancer.
Salvage surgery alone after radiotherapy (RT) failure for locally advanced head-and-neck cancer is frequently unsuccessful because of subsequent recurrence. We designed a prospective protocol to determine the feasibility, toxicity, and preliminary efficacy of a regimen of postoperative reirradiation, chemotherapy and the radioprotector amifostine after salvage head-and-neck surgery. Eligible patients had biopsy-proven locally advanced, but resectable, recurrence without distant metastases >6 months after previous RT. After adequate healing from surgery, patients underwent RT to 54-66 Gy within 5-5.5 weeks to the resection bed (lifetime RT dose, 100-130 Gy). The fractionation was 1.5 Gy b.i.d. within 2 weeks, followed by a 1-week break, followed by 1.5 Gy b.i.d. to a total of 54-66 Gy. Chemotherapy consisted of cisplatin 25 mg/m(2)/d three times and 5-fluorouracil 500 mg/m(2)/d continuous infusion for 4 days, for two cycles (Weeks 1 and 5). Amifostine (500 mg i.v.) was administered daily, 30 min before either the morning or the afternoon RT. Between 1998 and 2001, 16 patients were enrolled and studied. Two patients had gross residual disease after surgery; all other patients underwent complete surgical resection but had high-risk features (rT3-T4 and/or N+ disease). Three patients (19%) had serious acute toxicity events (nonneutropenic infections) that were reversible. The median follow-up was 35 months. The actuarial locoregional control rate was 81% at 3 years. Three patients developed isolated distant metastases and one developed a fatal second primary cancer (hepatoma). The 2- and 3-year actuarial event-free survival rate was 81% and 50%, respectively. The 2- and 3-year actuarial overall survival rate was 81% and 63%, respectively. Both patients who had gross residual disease after surgery had early recurrence; if these patients were excluded from analysis, the 3-year actuarial survival and event-free survival rate was 67% and 59%, respectively. Of the 16 patients, 6 (38%) developed Grade 3+ late toxicity, including one fatal stroke and two life-threatening major vessel necrosis and/or bleeding events. This regimen of postoperative reirradiation/chemotherapy plus amifostine is feasible and was well tolerated acutely, with encouraging oncologic efficacy. However, the incidence and severity of late effects was significant and suggests that modifications are necessary for future studies in this patient population.


Cathepsin protease expression in infiltrative soft tissue sarcomas: cathepsin-K correlates with infiltrative tumor growth and clinical outcomes.
Cathepsin proteases, activated in the lysosomes, are upregulated in many cancers. Intraoperative detection systems of microscopic residual tumor using cathepsin-mediated release of fluorescent nanoparticles may guide surgical excisions to improve local control. We sought to define the genetic and proteomic expression of cathepsins and their clinicopathological correlates in myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS)-soft tissue sarcomas with high rates of positive resection margins and local recurrence-and to establish a cellular justification for cathepsin-dependent systems to identify residual cancer in the resection bed. Real-time quantitative polymerase chain reaction analysis of 58 fresh-frozen tumor specimens revealed that 56 (97%) had elevated mRNA expression of ≥1 cathepsin, including cathepsin-B (79%), cathepsin-K (59%), cathepsin-L (71%), and -S (71%). Immunohistochemical analysis of these fresh-frozen specimens revealed that 98% of tumors were positive for one or more of cathepsin-B (85%), cathepsin-K (50%), cathepsin-L (63%), and -S (10%). Strong cathepsin-K expression was associated with greater risks of local recurrence (hazard ratio, 3.78; p = 0.044) and disease-specific mortality (hazard ratio, 3.70; p = 0.025). Immunohistochemical analysis of 33 formalin-fixed paraffin-embedded block samples revealed that 97% were positive for cathepsin-B (88%), cathepsin-K (76%), cathepsin-L (52%), or -S (52%) at the tumor periphery; cathepsin-K positivity correlated with a radiographic tail-like sign (p = 0.004) and microscopic infiltrative growth (p = 0.020). We conclude that cathepsins are broadly overexpressed in myxofibrosarcoma and UPS, and cathepsin-K may be an immunohistochemical marker of local infiltration and poorer prognosis that could be used to guide precision surgery.


Porphyria cutanea tarda in human immunodeficiency virus-seropositive men: case report and literature review.
Porphyria cutanea tarda (PCT) is a disorder of heme synthesis characterized by (a) a diminished activity of uroporphyrinogen decarboxylase biochemically and (b) cutaneous lesions secondary to a delayed type of photosensitivity clinically. A human immunodeficiency virus (HIV)-infected patient with PCT is reported and the world literature is reviewed. To date, 17 HIV-seropositive men with PCT have been described. The initial appearance of PCT occurred before or concurrent with the diagnosis of HIV infection in 71% of these individuals (12 men). The median age at onset of PCT was 36 years (range of 20 to 69 years); the median age for the detection of HIV infection was 35 years (range of less than 20 to 71 years). All of these patients had elevated levels of urine porphyrins and blisters on their dorsal hands. Abnormal liver function tests, erosions, hyperpigmentation, hypertrichosis, and skin fragility were also present in some of the men. Polycythemia, serologic evidence of increased iron stores, scarring, milia, and sclerodermoid changes were rarely observed. Successful therapeutic approaches for PCT in men with HIV infection included (a) elimination of PCT-precipitating agents, (b) avoidance of sun exposure, and (c) periodic phlebotomy. Multiple hypotheses for an etiologic role of the HIV and/or an HIV-associated infection, directly or indirectly, in the pathogenesis of PCT in HIV-seropositive men have been suggested.


Plaque histological characteristics in individuals with sudden coronary death.
Coronary artery disease (CAD) remains the leading cause of death in the Western world in individuals >20 years of age. CAD is the most common substrate underlying sudden cardiac death (SCD) in the Western world, being responsible for 50-75% of SCDs. In individuals dying suddenly with coronary thrombosis, plaque rupture occurs in 65%, plaque erosion in 30% and calcified nodule in 5%. We evaluated the extent of calcification in radiographs of hearts from patients dying of SCD and showed that calcification is absent in nearly 50% of erosion cases whereas only 10% of plaque rupture show no calcification. Conversely, stable plaques with >75% cross-sectional area luminal narrowing show the severest calcification (moderate to severe) in nearly 50% of cases. Identifying individuals who are susceptible to atherosclerosis may help reduce the incidence of SCD. The identification of coronary calcifications by noninvasive tools, however, only captures a fraction of complicating coronary lesions.


The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative.
To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival. C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were randomly assigned to four groups: no treatment, artemether treated, ET(A) receptor antagonist (HJP-272) treated, or HJP-272 and artemether treated. The uninfected control mice were treated with HJP-272 and artemether. We analyzed survival, cerebral hemorrhage, weight change, blood glucose levels and parasitemia. Our studies demonstrated decreased brain hemorrhage in PbA-infected (ECM) mice treated when HJP-272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one novel ET(A) receptor antagonist synthesized by our group, is used in conjunction with artemether, an anti-malarial agent. In addition, despite adversely affecting parasitemia and weight in non-artemether treated infected mice, HJP-272, seemed to confer some survival benefit when used as adjunctive therapy, though this did not reach significance. Previous studies demonstrate that the endothelin pathway is associated with vasculopathy, neuronal injury and inflammation in ECM. As demonstrated here, components of the ET-1 pathway may be important targets for adjunctive therapy in ECM, and may help in preventing hemorrhage and in improving survival when used as adjunctive therapy during malaria infection. The data presented suggest that our novel agent, HJP-272, may ameliorate alterations in the vasculature which can potentially lead to inflammation, neurological dysfunction, and subsequent death in mice with ECM.