Case studies from the biomedical and health systems research activities of the Swiss Tropical Institute in Africa.
Neither high theoretical efficacy of disease control tools, nor diagnostic accuracy, nor good compliance, nor adequate coverage can lead on its own to the final goal of community effectiveness. There is a complex relationship between these factors. The different steps in the process leading to effective health care in the community are discussed on the basis of biomedical and health systems research activities of the Swiss Tropical Institute. Schistosomiasis and malaria control provide the background to problems related to the efficacy of tools. In particular, information on the trial of a malaria vaccine candidate (SPf66) is given. Approaches to the rapid, accurate and economical diagnosis of communities at risk are discussed with reference to Schistosoma haematobium and S. mansoni. Health service support projects in Tanzania and Chad are presented to exemplify problems linked to the compliance of users/providers and coverage. Finally, it is shown that community effectiveness depends on the highest possible success rate for each step. This requires the co-operative efforts of all those involved: the scientist, the manager, the community health worker and, last but not least, the community itself.


Anti-inflammatory activities of oleanolic acid on HMGB1 activated HUVECs.
As a late mediator of inflammation, high mobility group box 1 (HMGB1) protein up-regulates pro-inflammatory cytokines in several inflammatory diseases. Further, high plasma levels of HMGB1 correlate with poor prognosis and increased mortality in patients with severe inflammation. Oleanolic acid (OA), a triterpenoid known for its anti-inflammatory and anti-cancer properties, is commonly present in several medicinal plants but the effects of OA on HMGB1-mediated pro-inflammatory responses of human endothelial cells is not well-studied. In this study, we investigated this question by monitoring the effect of OA on lipopolysaccharide (LPS)-mediated release of HMGB1 and the HMGB1-mediated modulation of inflammatory responses in human umbilical vein endothelial cells (HUVECs). OA potently inhibited the release of HMGB1 by HUVECs as well as down-regulated HMGB1-dependent adhesion and migration of the monocytic cell line THP-1 to activated HUVECs. OA also down-regulated the cell surface expression of the receptor of HMGB1, thereby inhibiting HMGB1-dependent pro-inflammatory responses by inhibiting activation of nuclear factor-κB (NF-κB) and production of tumor necrosis factor-α (TNF-α) by HMGB1. Given these results, OA showed anti-inflammatory activities and could be a candidate as a therapeutic agent for various inflammatory diseases through the inhibition of the HMGB1 signaling pathway.


Alpha-tocopherol: roles in prevention and therapy of human disease.
Alpha-tocopherol, one of the eight isoforms of vitamin E, is the most potent fat-soluble antioxidant known in nature. For years, it was thought that alpha-tocopherol only functioned as a scavenger of lipid peroxyl radicals, specifically, oxidized low-density lipoprotein (oxLDL), thereby serving as a chief antioxidant for the prevention of atherosclerosis. In recent years, the many roles of alpha-tocopherol have been uncovered, and include not only antioxidant functions, but also pro-oxidant, cell signaling and gene regulatory functions. Decades of clinical and preclinical studies have broadened our understanding of the antioxidant vitamin E and its utility in a number of chronic, oxidative stress-induced pathologies. The results of these studies have shown promising, albeit mixed reviews on the efficacy of alpha-tocopherol in the prevention and treatment of heart disease, cancer and Alzheimer's disease. Future studies to uncover cellular and systemic mechanisms may help guide appropriate clinical treatment strategies using vitamin E across a diverse population of aging individuals.


Warfarin anticoagulation in the perioperative period: is it safe?
This study was undertaken to determine if warfarin anticoagulation could be safely continued during surgery and in the perioperative period. An animal model was followed by a prospective human study of all patients on heparin or warfarin at the time of surgery. Twenty-four rabbits underwent laparotomy, during which a controlled liver injury was created and repaired. Group 1 (Warf) was anticoagulated with warfarin to raise the mean international normalization ratio (INR) to 2.5-3.0. Group 2 (Hep) was anticoagulated with heparin to raise the activated partial thromboplastin time to 1.5-2.0 times control. The heparin was then stopped 6 hr prior to surgery and resumed 6 hr postoperatively without a bolus. Group 3 (control) was not anticoagulated and received saline infusion. For the human study, data were collected on 40 patients undergoing 50 operations from October 1996 to January 1998. The results of this study reveal that (1) bleeding was less in the group anticoagulated with warfarin throughout surgery in the animal model, (2) bleeding complications were less in the patients continued on warfarin through surgery than those on heparin (3) older patients may have an increased risk of bleeding, and (4) an INR of >3 at the time of surgery may increase the risk of bleeding.


Are we on the right track?
We applaud Musculoskeletal Physiotherapy Australia for the formulation of the new Pre-Manipulative guidelines. The new guidelines are a step forward from the previous protocol because they allow individual practitioners choice when making clinical decisions. The previous protocol proved to be legally challenging and further increased practitioners' fear of manipulating.


Second Order Blind Identification of Event Related Potentials Sources.
Event-related potentials (ERPs) recorded on the surface of the head are a mixture of signals from many sources in the brain due to volume conductions. As a result, the spatial resolution of the ERPs is quite low. Blind source separation can help to recover source signals from multichannel ERP records. In this study, we present a novel implementation of a method for decomposing multi-channel ERP into components, which is based on the modeling of second-order statistics of ERPs. We also report a new implementation of Bayesian Information Criteria (BIC), which is used to select the optimal number of hidden signals (components) in the original ERPs. We tested these methods using both synthetic datasets and real ERPs data arrays. Testing has shown that the ERP decomposition method can reconstruct the source signals from their mixture with acceptable accuracy even when these signals overlap significantly in time and the presence of noise. The use of BIC allows us to determine the correct number of source signals at the signal-to-noise ratio commonly observed in ERP studies. The proposed approach was compared with conventionally used methods for the analysis of ERPs. It turned out that the use of this new method makes it possible to observe such phenomena that are hidden by other signals in the original ERPs. The proposed method for decomposing a multichannel ERP into components can be useful for studying cognitive processes in laboratory settings, as well as in clinical studies.


Evidence for an endogenous factor interfering with 3H-diazepam binding to rat brain membranes.
An in vitro "receptor" binding assay has been used to search for an endogenous compound which possibly interacts with benzodiazepine receptors in brain. Such an endogenous 3H-diazepam binding inhibitory factor (DIF) has been found. This compound is unevenly distributed in brain and in various peripheral organs. The partially purified compound appears to have a low molecular weight (below 500) and is not inactivated by proteolytic enzymes.


Molecular profiling of stomatal meristemoids reveals new component of asymmetric cell division and commonalities among stem cell populations in Arabidopsis.
The balance between maintenance and differentiation of stem cells is a central question in developmental biology. Development of stomata in Arabidopsis thaliana begins with de novo asymmetric divisions producing meristemoids, proliferating precursor cells with stem cell-like properties. The transient and asynchronous nature of the meristemoid has made it difficult to study its molecular characteristics. Synthetic combination of stomatal differentiation mutants due to loss- or gain-of-function mutations in SPEECHLESS, MUTE, and SCREAM create seedlings with an epidermis overwhelmingly composed of pavement cells, meristemoids, or stomata, respectively. Through transcriptome analysis, we define and characterize the molecular signatures of meristemoids. The reporter localization studies of meristemoid-enriched proteins reveals pathways not previously associated with stomatal development. We identified a novel protein, POLAR, and demonstrate through time-lapse live imaging that it exhibits transient polar localization and segregates unevenly during meristemoid asymmetric divisions. The polar localization of POLAR requires BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE. Comparative bioinformatic analysis of the transcriptional profiles of a meristemoid with shoot and root apical meristems highlighted cytokinin signaling and the ERECTA family receptor-like kinases in the broad regulation of stem cell populations. Our work reveals molecular constituents of stomatal stem cells and illuminates a common theme among stem cell populations in plants.


Dietary use and conservation concern of edible wetland plants at Indo-Burma hotspot: a case study from Northeast India.
The wetlands of the North East India fall among the global hotspots of biodiversity. However, they have received very little attention with relation to their intrinsic values to human kind; therefore their conservation is hardly addressed. These wetlands are critical for the sustenance of the tribal communities. Field research was conducted during 2003 to 2006 in seven major wetlands of four districts of Manipur state, Northeast India (viz. Imphal-East, Imphal-West, Thoubal, and Bishnupur). A total of 224 wetland-plant-collectors were interviewed for the use and economics of species using semi-structured questionnaires and interview schedules. Imphal, Bishenpur and Thoubal markets were investigated in detail for influx and consumption pattern of these plants. The collectors were also inquired for medicinal use of wetland species. Nutritive values of 21 species were analyzed in laboratory. The vouchers were collected for all the species and deposited in the CSIR-NEIST (Formerly Regional Research Laboratory), Substation, Lamphelpat, Imphal, Manipur, India. We recorded 51 edible wetland species used by indigenous people for food and medicinal purposes. Thirty eight species had high medicinal values and used in the traditional system to treat over 22 diseases. At least 27 species were traded in three markets studied (i.e. Imphal, Thoubal and Bishenpur), involving an annual turnover of 113 tons of wetland edible plants and a gross revenue of Rs. 907, 770/- (US$1 = Rs. 45/-). The Imphal market alone supplies 60% of the total business. Eighty per cent of the above mentioned species are very often used by the community. The community has a general opinion that the availability of 45% species has depleted in recent times, 15 species need consideration for conservation while another 7 species deserved immediate protection measures. The nutrient analysis showed that these species contribute to the dietary balance of tribal communities. Considering the importance of wild wetland plants in local sustenance, it is suggested to protect their habitats, develop domestication protocols of selected species, and build programs for the long-term management of wetland areas by involving local people. Some medicinal plants may also be used to develop into modern medicines.


Outcomes of Idiopathic Full-Thickness Macular Hole Surgery: Comparing Two Different ILM Peeling Sizes.
This study aimed to show the impact of different extents of internal limiting membrane (ILM) peeling on visual and anatomical outcomes following idiopathic full-thickness macular hole (FTMH) surgery. In this single-center prospective study, patients with idiopathic FTMH underwent standard pars plana vitrectomy with two different extents of ILM peeling: 2-disc diameters (DD) or 4 DD. The main outcome measures were the closure rate of the holes based on optical coherence tomography (OCT) findings at three months after surgery. Forty eyes from 39 patients were enrolled in the study. After three months, anatomical closure was achieved in 78% and 76% eyes in 2 DD peel and 4 DD peel groups, respectively. From 29 eyes with macular hole index (MHI) ≤ 0.5, type 1 closure was achieved in 42% eyes receiving a 2 DD ILM peel, compared to 66% eyes receiving a 4 DD peel (p=0.041). In comparison, this significant difference was not seen in the subgroup of MHI > 0.5 (p=061). In the subgroup of subjects with baseline MHI ≤ 0.5, visual improvement was significantly more in eyes with 4 DD ILM peeling (p=0.034), which was not seen in the MHI > 0.5 subgroup (p=0.61). In patients with idiopathic full-thickness macular hole (MHI ≤ 0.5), a larger ILM peel of 4 DD appears to yield better anatomical outcomes than a more limited 2 DD peel.


Immune checkpoint inhibitor-associated adrenal insufficiency in Chinese cancer patients: a retrospective analysis.
Immune checkpoint inhibitors (ICIs) are of great success in cancer therapy. This study aimed to identify adrenal insufficiency (AI) associated with immune checkpoint inhibitor (ICI) treatment in cancer patients receiving steroid replacement therapy and report the clinical characteristics of ICI-associated AI and concurrent immune-associated adverse events (irAEs). Patients prescribed cortisone acetate between January 2020 and March 2022 were reviewed to identify AI associated with ICI treatment. Data collected included indication of ICI (cancer type), drug characteristics, and outcomes. A total of 101 patients were diagnosed with AI following treatment with ICIs. The median age was 64 years (range 22-83 years); 73.3% of the patients were male. Median time to develop primary AI and secondary AI after starting ICI therapy was 200.5 (35-280) days and 178 (16-562) days, respectively. Concurrent irAEs occurred in 67 (66.3%) patients and included 63 (62.4%) endocrine irAEs. Log-rank test showed that there was a trend toward higher likelihood of death at 120-day follow-up in patients initially receiving intravenous hydrocortisone compared with those receiving oral cortisone acetate after diagnosis of AI (p = 0.029). This retrospective study comprehensively documented the clinical characterization of ICI-associated AI. Those initially receiving intravenous hydrocortisone after diagnosis of AI were associated with higher likelihood of death. Physicians should be aware of the variability of ICI-associated irAEs early in the treatment, early diagnoses, and timely management should be made.


Diagnosis of meningeal involvement in childhood acute lymphoblastic leukemia: cytomorphology and TdT.
Between December, 1984, and May, 1986, 98 CSF samples were sent to a central laboratory by postal express. The samples could be kept in a medium for up to 24 hours after the lumbar puncture. The quality of the cells proved to be good. Excluded were 5 samples delayed in delivery and 13 samples contaminated with blood, defined as the macroscopical presence of blood. The microscopical presence of erythrocytes in the cytocentrifuge preparation can make interpretation of the results difficult. Especially when leukemic blasts are present in the blood, extreme caution is necessary. A total of 71 samples could be studied by cytomorphology as well as by TdT-IF. When cytomorphological leukemic blasts were present, this was confirmed by TdT-IF positivity in all cases. But in 6 of 71 samples, TdT-IF was positive without the presence of cytomorphological leukemic blasts. Follow-up of these patients will show whether the therapeutic regimen has to be changed.


Medical malpractice litigations involving aortic dissection.
Medical malpractice litigation arises when a discrepancy exists between a patient's expectation of acceptable medical care and the care the patient receives. Aortic dissection is a frequently misdiagnosed and often-fatal condition. The purpose of this study was to characterize trends of medical malpractice litigations arising from aortic dissection, investigate the etiology, and analyze predictive factors regarding the verdict. The Westlaw legal database was used to compile relevant litigations from 1994 to 2019 across the United States. Each litigation was screened individually for inclusion, and after inclusion, descriptive factors were compiled, including patient data, litigation data, verdict data, and clinical outcomes data. The Fisher exact test was used to evaluate the significance of association between parameters and verdict type. In total, 135 unique litigations met criteria for inclusion, with a defendant verdict in 57% (n = 77), plaintiff verdict in 20% (n = 27), and settlements in 23% (n = 31). Plaintiffs most commonly cited a failure to diagnose as their reason for litigation in 64% (n = 87). Patient mortality was associated with a lower average plaintiff award, $1,892,781 versus $5,944,983, and a lower average settlement, $1,230,923 versus $2,250,000, than their surviving counterparts. California, Illinois, and Pennsylvania had the most cases filed. An alleged failure to test, failure to refer, failure to consult, incidence of a stroke, and incidence of an autopsy diagnosis were significantly associated with defendant verdicts and a failure to diagnose was significantly associated with plaintiff verdicts (P < .05). Plaintiffs frequently cited a failure to timely diagnose, order diagnostic tests, and interpret diagnostic tests as reasons for litigations. Defendant verdicts were common, suggesting judicially acceptable standards of care are commonly satisfied.


Metabolism of fatty acid in yeast: characterisation of beta-oxidation and ultrastructural changes in the genus Sporidiobolus sp. cultivated on ricinoleic acid methyl ester.
Cell structure modifications and beta-oxidation induction were monitored in two strains of Sporidiobolus, Sp. Ruinenii and Sp. pararoseus after cultivation on ricinoleic acid methyl ester. Ultrastructural observations of the yeast before and after cultivation on fatty acid esters did not reveal major modifications in Sp. ruinenii. Unexpectedly, in Sp. pararoseus a proliferation of the mitochondrion was observed. After induction, Sp. ruinenii principally exhibited an increase in the activities of acyl-CoA oxidase (ACO), hydroxyacyl-CoA deshydrogenase (HAD), thiolase and catalase. In contrast, Sp. pararoseus lacked ACO and catalase activities, but an increase in acyl-CoA deshydrogenase (ACDH) and enoyl-CoA hydratase (ECH) activity was observed. These data suggest that in Sp. ruinenii, beta-oxidation is preferentially localized in the microbody, whereas in Sp. pararoseus it might be localized in the mitochondria.


Antiplasmodial flavanones and a stilbene from Carpha glomerata.
Bioassay-guided fractionation of an extract of Carpha glomerata (Cyperaceae) led to the isolation of seven compounds. Compounds 1 (carphorin A), 3 (carphorin C), 4 (carphorin D), and 5 (carphabene) are new compounds, and compound 2 (8-(3″-hydroxyisoamyl)-naringenin) was isolated for the first time as a natural product. All structures were elucidated based on analyses of their HR-ESIMS and 1D and 2D NMR data. Compounds 1, 2, and 6, which have prenyl or hydroxyprenyl side chains, exhibited antiplasmodial activities with IC50 values of 5.2 ± 0.6, 3.4 ± 0.4, and 6.7 ± 0.8 µM against the drug-resistant Dd2 strain of Plasmodium falciparum. In addition the prenylated stilbene 5 also showed good activity, with IC50 5.8 ± 0.7 µM.


Phosphatidylserine inside out: a possible underlying mechanism in the inflammation and coagulation abnormalities of COVID-19.
The rapid ability of SARS-CoV-2 to spread among humans, along with the clinical complications of coronavirus disease 2019-COVID-19, have represented a significant challenge to the health management systems worldwide. The acute inflammation and coagulation abnormalities appear as the main causes for thousands of deaths worldwide. The intense inflammatory response could be involved with the formation of thrombi. For instance, the presence of uncleaved large multimers of von Willebrand (vWF), due to low ADAMTS13 activity in plasma could be explained by the inhibitory action of pro-inflammatory molecules such as IL-1β and C reactive protein. In addition, the damage to endothelial cells after viral infection and/or activation of endothelium by pro-inflammatory cytokines, such as IL-1β, IL-6, IFN-γ, IL-8, and TNF-α induces platelets and monocyte aggregation in the vascular wall and expression of tissue factor (TF). The TF expression may culminate in the formation of thrombi, and activation of cascade by the extrinsic pathway by association with factor VII. In this scenario, the phosphatidylserine-PtdSer exposure on the outer leaflet of the cell membrane as consequence of viral infection emerges as another possible underlying mechanism to acute immune inflammatory response and activation of coagulation cascade. The PtdSer exposure may be an important mechanism related to ADAM17-mediated ACE2, TNF-α, EGFR and IL-6R shedding, and the activation of TF on the surface of infected endothelial cells. In this review, we address the underlying mechanisms involved in the pathophysiology of inflammation and coagulation abnormalities. Moreover, we introduce key biochemical and pathophysiological concepts that support the possible participation of PtdSer exposure on the outer side of the SARS-CoV-2 infected cells membrane, in the pathophysiology of COVID-19. Video Abstract.


Hierarchical curiosity loops and active sensing.
A curious agent acts so as to optimize its learning about itself and its environment, without external supervision. We present a model of hierarchical curiosity loops for such an autonomous active learning agent, whereby each loop selects the optimal action that maximizes the agent's learning of sensory-motor correlations. The model is based on rewarding the learner's prediction errors in an actor-critic reinforcement learning (RL) paradigm. Hierarchy is achieved by utilizing previously learned motor-sensory mapping, which enables the learning of other mappings, thus increasing the extent and diversity of knowledge and skills. We demonstrate the relevance of this architecture to active sensing using the well-studied vibrissae (whiskers) system, where rodents acquire sensory information by virtue of repeated whisker movements. We show that hierarchical curiosity loops starting from optimally learning the internal models of whisker motion and then extending to object localization result in free-air whisking and object palpation, respectively.


Biochemical and behavioral effects of steroids on GABAA receptor function in long- and short-sleep mice.
The in vitro and in vivo effects of alphaxalone, a steroid anesthetic, and two physiological steroids, tetrahydrodeoxycorticosterone (THDOC) and pregnenolone sulfate (PS), on GABAA receptor function were evaluated in long-sleep (LS) and short-sleep (SS) mice. In vitro, both alphaxalone and THDOC enhanced GABAergic inhibition as measured by [3H]FNZ binding and GABA-stimulated 36Cl- flux. However, with the exception of alphaxalone potentiation of [3H]FNZ binding, which was greater in SS brain regions, LS and SS mice did not differ in their degree of enhancement. Pregnenolone sulfate produced mixed agonistic and antagonistic effects on GABAergic function, dependent upon brain region, with few differences between the lines of mice. In vivo effects of these steroids on sleep time indicated that, like other anesthetic agents, THDOC and alphaxalone induced longer sleep times in LS mice. Antagonism by PS of ethanol-induced sleep time was observed in LS mice only; however, this effect was dependent upon the dose of ethanol used and on the vehicle used to prepare the steroid. Pentobarbital-induced sleep time was not reduced by PS treatment in either line of mouse. These results demonstrate that few differences in sensitivity of the GABAergic receptor to these steroids exist between LS and SS mice. Thus, unlike the differences between LS and SS mice in GABAergic mediation of responses to ethanol and benzodiazepines, there is little genetic variability in subtypes of GABAA receptors capable of modulation by steroids in these lines of mice.


Ethosomes and ultradeformable liposomes for transdermal delivery of clotrimazole: A comparative assessment.
THE OBJECTIVE OF WORK WAS TO FORMULATE, EVALUATE AND COMPARE THE TRANSDERMAL POTENTIAL OF NOVEL VESICULAR NANOCARRIERS: ethosomes and ultradeformable liposomes, containing clotrimazole (CLT), an anti-fungal bioactive. The ethosomal formulation (ET4) and ultradeformable liposomal (UL) formulation (TT3) showed highest entrapment 68.73 ± 1.4% and 55.51 ± 1.7%, optimal nanometric size range 132 ± 9.5 nm and 121 ± 9.7 nm, and smallest polydispersity index 0.027 ± 0.011 and 0.067 ± 0.009, respectively. The formulation ET4 provided enhanced transdermal flux 56.25 ± 5.49 μg/cm(2)/h and decreased the lag time of 0.9 h in comparison to TT3 formulation (50.16 ± 3.84 μg/cm(2)/h; 1.0 h). Skin interaction and FT-IR studies revealed greater penetration enhancing effect of ET4 than TT3 formulation. ET4 formulation also had the highest zone of inhibition (34.6 ± 0.57 mm), in contrast to TT3 formulation (29.6 ± 0.57 mm) and marketed cream formulation (19.0 ± 1.00 mm) against candidal species. Results suggested ethosomes to be the most proficient carrier system for dermal and transdermal delivery of clotrimazole.


[Introductive remarks on ICU team].
What makes a team efficient? Because the components which lead to its functioning as a whole have changed over recent years, the very concept of a team is to be analysed.


Stimulation of two vascular smooth muscle-derived cell lines by angiotensin II: differential second messenger responses leading to mitogenesis.
1. We show here that angiotensin II (AII) and endothelin-1 (ET-1) stimulate [3H]-thymidine incorporation in a smooth muscle cell line derived from aortae of spontaneously hypertensive rats (SHR), but not in cells derived from normotensive controls (WKY). We have used the differential response of the two cell lines to investigate the relationship between second messenger systems and the mitogenic response. 2. AII produced an increase in accumulation of inositol 1,4,5-triphosphate which was greater in the SHR-derived cell line than in the WKY cells. 3. AII gave an increase in cytosolic Ca2+ in each of the cell lines, with both a larger peak (15-30 s) and plateau response (2 min) in the SHR cells. ET-1 gave an enhanced response in the SHR-derived cells with respect to the peak but not the plateau of cytosolic Ca2+. 4. Phospholipase D activity was studied by monitoring the formation of [3P]-phosphatidylbutanol in 32Pi prelabelled cells. AII stimulation gave a larger phospholipase D response in the SHR-derived cells, while ET-1 gave a larger response in WKY-derived cells. 5. Stimulation of SHR-derived cells with 100 nM AII for 1 h, followed by 19 h in the absence of agonist, stimulated [3H]-thymidine incorporation over the next 4 h. When the 1 h stimulation with AII was in the presence of increasing concentrations of butanol, which diverts the product of the phospholipase D pathway, there was a loss of stimulated [3H]-thymidine incorporation which was significant at 10 mM butanol and at 30-50 mM reached a maximum loss of 40%. 6. Contrasting with this there was no apparent loss of ET-l-stimulated thymidine incorporation when butanol was present at concentrations up to 40 mM.7. These results suggest that phospholipase D is one of several pathways in the mitogenic response of SHR-derived vascular smooth muscle cells to All.


177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model.
A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with (177)Lu, the peptide-polymer conjugates were renamed (177)Lu-metabolically active copolymers ((177)Lu-MACs) with the corresponding designations: (177)Lu-MAC0, (177)Lu-MAC1 and (177)Lu-MAC2. In vivo evaluation of the (177)Lu-MACs was performed in an HPAC human pancreatic cancer xenograft mouse model. (177)Lu-MAC1 and (177)Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control ((177)Lu-MAC0) at 72h post-injection. With regard to spleen retention, (177)Lu-MAC1 and (177)Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72h time point. However, the tumor accumulation of the (177)Lu-MAC0 was two to three times greater than (177)Lu-MAC1 and (177)Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the (177)Lu-labeled HPMA copolymers. While further studies are needed to optimize the pharmacokinetics of the (177)Lu-MACs design, the ability of the MAL to significantly decrease non-target retention establishes the potential this avenue of research may have for the improvement of diagnostic and radiotherapeutic drug delivery systems.


Novel rhein-phospholipid complex targeting skin diseases: development, in vitro, ex vivo, and in vivo studies.
Rhein (RH), an anthraquinone derivative, has proven to be a promising molecule for treating several skin disorders thanks to its pleiotropic pharmacological activities like antimicrobial, antifungal, antioxidant, and anticancer. However, RH's low water and oil solubility and poor skin permeability halted its topical delivery. This is the first work to investigate the expediency of tailoring a rhein-phospholipid complex (RH-PLC) to improve RH challenging physicochemical and skin permeability properties. The phospholipid complex was prepared by employing different methods and different RH/PL molar ratios. RH-PLC was successfully developed at a stoichiometric ratio of 1:1 using a novel pH-dependent method where at a certain pH, it exhibits the highest complexation efficiency (95%). RH-PLC formation was confirmed using FTIR, DSC, and XRPD analysis. RH-PLC showed a significant increase in water and n-octanol solubility. RH-PLC was self-assembled upon dispersion into water forming nano-sized particles (196.6 ± 1.6 nm) with high negatively charged surface (- 29.7 ± 2.45 mV). RH-PLC exhibited a significant 3.3- and 2.46-fold increase in ex vivo and in vivo skin permeability when compared with RH suspension, respectively. Confocal microscopy study confirmed the ability of RH-PLC to penetrate deeply into rat skin. Besides, skin irritation test on healthy rats indicated compatibility and safety of RH-PLC. Conclusively, phospholipid complex might be a suitable approach to improve permeability of RH and other promising abandoned poor-permeable drugs. The proposed RH-PLC is expected to be a major progressive step toward the development of a topical RH formulation. Graphical abstract.


Spatial principal components of multichannel maps evoked by lateral visual half-field stimuli.
Multichannel records of responses to large and small hemiretinal stimuli were obtained from 6 healthy subjects. Scalp distribution maps were constructed for all conditions at all post-stimulus times and component latencies were objectively determined by computing a reference-independent measure of field power. This procedure identified 2 components (at 100 and 140 msec). The scalp distribution data at these latencies were entered into a spatial principal components analysis which further reduced the data set to three underlying spatial principal components. These components may be regarded as reflecting underlying processes and were related to experimental conditions. A component reflecting lateralized brain activity displayed a significant interaction between size and retinal location of the stimulus with large stimuli showing a more pronounced lateralization over the hemisphere contralateral to the stimulated hemiretina, and the scores on this component were low for upper hemiretinal stimuli. These findings are in agreement with intracranially recorded evoked potential data and theoretical dipole source computations, and confirm a model of cortical neuronal generator processes whose locations and orientations in the hemisphere ipsilateral to the hemiretina stimulated are influenced not only by retinal stimulus location but also by stimulus size.


Critical role of an eight-amino acid sequence of VP1 in neutralization of poliovirus type 3.
The three serotypes of poliovirus are members of the picornaviradae, a group of viruses which cause a variety of diseases of considerable importance in man and animals. We have previously used antigenic mutants resistant to neutralizing monoclonal antibodies to identify a single antigenic site for the neutralization of poliovirus type 3 (ref. 1). Evidence based on oligonucleotide mapping suggested that this site corresponded largely to one physicochemical region of the capsid protein viral polypeptide 1 (VP1). We now present conclusive evidence that most of the mutations conferring resistance to neutralization are confined to an eight-amino acid region of VP1, specified by a sequence of viral RNA 277-300 bases from the start of the region coding for VP1. These data strongly suggest that this small region constitutes a major antigenic site involved in virus neutralization and they provide the most detailed information currently available on the antigenic site of a human virus.


Roles of low-molecular-weight penicillin-binding proteins in Bacillus subtilis spore peptidoglycan synthesis and spore properties.
The peptidoglycan cortex of endospores of Bacillus species is required for maintenance of spore dehydration and dormancy, and the structure of the cortex may also allow it to function in attainment of spore core dehydration. A significant difference between spore and growing cell peptidoglycan structure is the low degree of peptide cross-linking in cortical peptidoglycan; regulation of the degree of this cross-linking is exerted by D,D-carboxypeptidases. We report here the construction of mutant B. subtilis strains lacking all combinations of two and three of the four apparent D, D-carboxypeptidases encoded within the genome and the analysis of spore phenotypic properties and peptidoglycan structure for these strains. The data indicate that while the dacA and dacC products have no significant role in spore peptidoglycan formation, the dacB and dacF products both function in regulating the degree of cross-linking of spore peptidoglycan. The spore peptidoglycan of a dacB dacF double mutant was very highly cross-linked, and this structural modification resulted in a failure to achieve normal spore core dehydration and a decrease in spore heat resistance. A model for the specific roles of DacB and DacF in spore peptidoglycan synthesis is proposed.


Inhibition of GABA release from slices prepared from several brain regions of rats at various times following a convulsion.
1 A method is described for the measurement of the K+-evoked release of endogenous gamma-aminobutyric acid (GABA) from slices of rat cortex, hippocampus and striatum. 2 In tissue prepared 30 min following an electroconvulsive shock, K+-evoked GABA release (above basal release) was inhibited by 45% in cortex, 50% in hippocampus and 75% in striatum. A similar inhibition of release was observed with slices prepared from rats in which a convulsion had been induced by flurothyl. There was no change in spontaneous (basal) release following either procedure. 3 An inhibition of K+-evoked endogenous GABA release was also seen in tissue prepared 4 min postictally but not 2 h after the seizure. 4 No difference was observed in the release of [3H]-GABA from preloaded cortical slices prepared from rats given a single electroconvulsive shock. 5 It is proposed that a convulsion results in an inhibition of GABA release and that this inhibition may in turn inhibit GABA synthesis as described in the preceding paper. 6 It is also proposed that changes in the endogenous releasable pool of GABA may not be detected by preloading slices with [3H]-GABA.


Otorrhea bacterial profile, epidemiology before widespread use of the third-generation pneumococcal conjugate vaccine in French children, a prospective study from 2015 to 2023.
The aim of this study was to describe the bacterial profile of middle ear fluid from spontaneous perforation of the tympanic membrane (SPTM) prior to widespread utilization of third- generation pneumococcal conjugate vaccines (PCVs). From October 2015 to January 2023, children with SPTM were prospectively enrolled by pediatricians. Among the 852 children with SPTM, 73.2% were less than 3 years old; more frequently than older children, they were and suffering from complex acute otitis media (AOM) (27.9%) and conjunctivitis (13.1%). In children under 3 years of age, NT Haemophilus influenzae (49.7%) was the main otopathogen isolated, particularly in those with complex AOM (57.1%). In children over 3 years of age, Group A Streptococcus accounted for 57%. In pneumococcal cases (25.1%), serotype 3 was the main serotype isolated (16.2%), followed by 23B (15.2%). Our data from 2015 to 2023 represent a robust baseline preceding the widespread utilization of next-generation PCVs.


Combined assessment of clinical and patient factors on doctors' decisions to prescribe antibiotics.
Antibiotic overprescription is a worldwide problem. Decisions regarding antibiotic prescription for respiratory tract infections (RTIs) are influenced by medical and non-medical factors. In family medicine practices in Białystok, Poland, family medicine residents directly observed consultations with patients with RTI symptoms. The observing residents completed a questionnaire including patient data, clinical symptoms, diagnosis, any prescribed antibiotic, and assessment of ten patient pressure factors. Of 1546 consultations of patients with RTIs, 54.26 % resulted in antibiotic prescription. Antibiotic prescription was strongly associated with rales (OR 26.90, 95 % CI 9.00-80.40), tonsillar exudates (OR 13.03, 95 % CI 7.10-23.80), and wheezing (OR 14.72, 95 % CI 7.70-28.10). The likelihood of antibiotic prescription was increased by a >7-day disease duration (OR 3.94, 95 % CI 2.80-5.50), purulent nasal discharge (OR 3.87, 95 % CI 2.40-6.10), starting self-medication with antibiotics (OR 4.11, 95 % CI 2.30-7.30), and direct request for antibiotics (OR 1.87, 95 % CI 1.30-2.80). Direct request not to prescribe antibiotics decreased the likelihood of receiving antibiotics (OR 0.34, 95 % CI 0.27-0.55). While clinical signs and symptoms principally impact prescribing decisions, patient factors also contribute. The most influential patient pressure factors were starting self-medication with antibiotics, and directly requesting antibiotic prescription or no antibiotic prescription. Interventions aiming to improve clinical sign and symptom interpretation and to help doctors resist direct patient pressure could be beneficial for reducing unnecessary antibiotic prescribing.


Stereospecific assignment of H5' and H5″ in a (5'R)-/(5'S)-deuterium- labeled DNA decamer for(3) J (HH) determination and unambiguous NOE assignments.
The stereoselective deuterium labeling at the 5' methylene protons of the ribose ring recently developed by Kawashima et al. [1995, Tetrahedron Lett., 36, 6699-6700] enabled the assignment of pro-R and pro-S protons at the 5' position. The deuterium-labeled nucleotides, [(5'S)-(2)H]- and [(5'R)-(2)H]-diastereomers, in an approximate ratio of 2:1, were incorporated in the decamer 5'-d(GCATTAATGC)-3'. Thus, both pro-R and pro-S methylene proton signals without geminal coupling appeared in the NOESY and DQF-COSY spectra. Complete stereospecific assignments and simplified spin systems enabled the determination of 15 (3)J coupling constants between H4' and H5'/H5", and the unambiguous assignment of 135 NOESY cross peaks originating from H4'/H5'/H5" resonances.


Cell-mediated immunity in rats bearing allogeneic skin in the anterior chamber of the eye. I. Response to mitogens.
Early studies have indicated that presentation of donor antigen via the anterior chamber (AC) of the eye diminished the host's ability to react immunologically in vivo. In the present study this reduced immunological activity has been studied in vitro. Compared to spleen cells from control rats, the spleen cells from Lewis rats bearing Brown Norway skin implants in the AC had a mild but consistently reduced in vitro blastogenic response to phytohemagglutinin 10-35 days postimplantation. Either a normal or slightly greater than normal response occurred thereafter. The implant-induced suppression of the mitogenic stimulation was evident only in splenocytes; lymph nodes and thymic lymphocytes from AC-implanted rats responded similarly to controls. The suppressed mitogenic reactivity appears to be specific for the T-cell population since the stimulation in the presence of lipopolysaccharide was no different from that in controls. Furthermore, the reduced activity was greatly enhanced in the T-cell-enriched population. These results suggest that allogeneic skin placed in the AC of the eye depresses the immune activity of the host's splenocytes which may contribute to the privileged nature of the anterior chamber.


Establishment of a knowledge base for identification of residual solvents in pharmaceuticals.
A knowledge base for identification of residual solvents in pharmaceuticals has been established using gas chromatograph-mass spectrometry (GC-MS) and gas chromatograph-Fourier transform infrared spectrometry (GC-FTIR). Sixty solvents were studied according to the guideline for residual solvents regulated by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The standard mass spectra library, the limit of detection (LOD) mass spectra library, the standard vapor-phase infrared spectra library, and the limit of detection (LOD) vapor-phase infrared spectra library were established and constituted the knowledge base. Using the knowledge base, the problem of qualitation, which was the difficulty of determining residual solvents, can be resolved.


A software system to record and analyze digitized cell images.
This paper describes basic software for digitization and processing of microscopic cell images used at the Department of Clinical Cytology at Uppsala University Hospital. A family of programs running on a PDP-8 minicomputer which is connected to a Leitz Orthoplan microscope with two image scanners, one diode-array scanner and a moving-stage photometer, is used for data collection. The digitized image data is converted by converted by conversion program to IBM compatible format. The data structures for image processing and statistical evaluation on the IBM system are also described. Finally, some experiences from the use of the software in cytology automation are discussed.


[Chemical Constituents of Alkaloids from the Bark of Sophora japonica].
To study the chemical constituents in the bark of Sophora japonica. The chemical constituents were separated and purified by silica gel,Sephadex LH-20 column chromatography,and HPLC. Their structures were identified by various spectroscopic analyses. Eleven compounds were obtained from the bark of Sophora japonica. Their structures were identified as( +)-oxymatrine( 1),isosophoridine( 2),lupanine( 3),( +)-matrine( 4),( +)-sophoramine( 5),(-)-14β-hydroxymatrine( 6),(-)-7,11-dehydromatrine( 7),alopecurin A( 8),( +)-sophoranol( 9),α-isolupanine( 10) and( +)-allomatrine( 11). Compounds 2,3,5 and 7 ~ 11 are isolated from this plant for the first time.


Are bone turnover markers associated with volumetric bone density, size, and strength in older men and women? The AGES-Reykjavik study.
Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). A total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.


[Current treatment of superficial mycosis.].
We revised the most important antifungal drugs used in cutaneous mycosis. We emphasize in pharmacokinetics, drug adverse reactions and its management in the different types of pathology.


Role of connexin-based gap junction channels in testis.
Spermatogenesis is a highly controlled process that allows proliferation and differentiation of male germ cells. This is under classical endocrine and paracrine controls. There is also evidence that gap junctions between Leydig cells, between Sertoli cells and between Sertoli and germ cells participate in the local regulation of spermatogenesis. Recent studies reveal that connexin 43 (Cx43), the predominant gap junction protein in the testis, is essential for the initiation and maintenance of spermatogenesis. In this review, we focus on the identification, distribution and control of connexins in the mammalian testis. The implication of connexin-based gap junctions in testicular physiology and in pathological disorders of spermatogenesis (spermatogenic arrest and testis cancer) is also discussed.


Energy constrains to increasing complexity in the biosphere.
Thirty years ago, the systems ecologist Howard T. Odum introduced the concept of transformity, which is a thermodynamic measure of quality within the trial and error evolutionary dynamics of ecosystems, namely an indicator of rank in the hierarchical system structure of the biosphere. Based on a global database of individual processes and whole economies, this paper extends, refines, and updates Odum's idea, demonstrating the strength of the postulated relation. In particular, an inverse linear logarithmic relationship is shown to hold between resource quantity (exergy) and quality (emergy), which is the result of an overall energetic efficiency characteristic of energy transformation processes of the biosphere. This relation extends from natural renewable energy sources to human information (including global internet data flows) and know-how embedded in national economies, thus identifying a consistent theory of hierarchical organization of the biosphere grounded in energetics and ultimately setting constraints to illusions of unlimited growth.


Invariant natural killer T cells trigger adaptive lymphocytes to churn up bile.
How innate immune response causes autoimmunity has remained an enigma. In this issue of Cell Host & Microbe, Mattner et al. demonstrate that invariant natural killer T cells activated by the mucosal commensal Novosphingobium aromaticivorans precipitate chronic T cell-mediated autoimmunity against small bile ducts that mirrors human primary biliary cirrhosis. These findings provide a mechanistic understanding of the role of innate immunity toward a microbe in the development of autoimmunity.


Association between apathy/depression and executive function in patients with Alzheimer's disease.
Apathy and depression may be strongly associated with executive dysfunction in Alzheimer's disease (AD). The Frontal Assessment Battery (FAB) is an instrument for assessing executive function. The dual task paradigm is also useful for assessing divided attention. However, the association between apathy/depression and these tasks is unclear. Both the FAB and the dual task were used to evaluate AD patients. A two-way analysis of variance was then conducted between the FAB and dual task results and the absence versus the presence of depression or the absence versus the presence of apathy. Of 88 patients with AD, 26 had both apathy and depression, 26 had depression only, 18 had apathy only, and 18 had neither. Total FAB scores and dual task scores differed significantly between the AD patients with depression and those without depression; the scores were also different between those with apathy and those without apathy. Also, a significant interaction between depression and apathy was noted for the total FAB and dual task scores. The deficits in the total FAB and dual task scores were larger in AD patients with both apathy and depression compared with patients with either apathy or depression alone. AD patients with both symptoms may have greater deficits in frontal lobe function relative to AD patients with either apathy or depression alone.


[Morphological evaluation of the viability of silicon-lavsan tracheal prostheses].
Time course of the healing process in the tracheal wall during silicon-lavsan tracheal grafting was investigated in experiments on 108 dogs with a new model of tracheal prosthesis. The formation of granulation tissue was noted as a result of postoperative inflammatory reaction in the prosthetic area. The tracheal epithelial layer adjacent to the anastomoses was hypertrophic and acquired the features of squamous epithelium. Later, after the implantation the prosthesis was surrounded by a thick fibrous capsula. In anastomoses, at tracheal tissue--implant border there was a poorly expressed inflammatory reaction, which had a local character and was compatible with 3 and more years of life in most experimental animals.


Quantitative analysis of traction in the glenohumeral joint. In vivo radiographic measurements.
To analyse change in distance between the humeral head and the glenoid fossa during traction in the maximally loose-packed position (MLPP) and the maximally closed-packed position (MCPP) under standardized conditions. Six healthy subjects (three male and three female) with a mean age of 40.5 years, volunteered to participate in this study. Subjects were placed with the right shoulder in a modified shoulder brace (Otto Bock Armabduktions-Orthese in Modular Bauweise in 45 degrees abduction in the plane of the scapula with neutral rotation (MLPP). A standard anterior-posterior radiograph of the glenohumeral joint was made. A 14 kg traction force was applied for 40s, and a second radiograph was made. The same procedure was repeated with the shoulder placed in the MCPP, which was 90 degrees abduction and 90 degrees external rotation. A radiologist, blinded for the variable traction or no traction, performed all radiographic measurements. Measurements were made on the same radiographs on two separate occasions (O1 and O2) with a 2-month interval. No significant differences were found in mean distance between the humeral head and the glenoid fossa during traction in the MLPP compared to traction in the MCPP (O1: P=1.00) and (O2: P=0.63). Application of a 14 kg force does not result in a significant increase of distance between the humeral head and the glenoid fossa. No significant difference was found between the change in distance of the humeral head and the glenoid fossa after traction in the MLPP compared to traction in the MCPP.


Prosthetic replacement of the aorta is a risk factor for aortic root aneurysm development.
Noncompliant prostheses are used in aortic replacement. We hypothesized that this leads to increased distension and wall stress in the aortic root because of the loss of ventriculo arterial coupling. Pressure relations in the aortic root caused by changes of aortic elasticity simulating prosthetic aortic replacement were tested in a computer model. We then developed an in vitro model using porcine aortas and performed in vivo validation. Findings in vitro and in vivo confirmed the predicted changes of the computer model. Pressure amplitude increased significantly by 17% after prosthetic replacement (p < 0.01). Pressure-time differential (Dp/dt) and dicrotic notch pressure amplitude both increased significantly. Echocardiography demonstrated systolic aortic root distension with percentage area change increasing in vitro from 28.2%+/-9.7% to 35.9%+/-10% (p < 0.05) and in vivo from 13.3%+/-3.1% to 24.3%+/-3.1% (p < 0.0001). Aortic root wall stress increased markedly. Replacement of the aorta with vascular prostheses causes important negative alterations of hemodynamics and increases in wall stress.


Systematic review and meta-analysis of the risk factors for sudden sensorineural hearing loss in adults.
To review the medical literature evidence of potential risk factors for sudden sensorineural hearing loss (SSNHL) in the adult general population. Systematic review of prospective and retrospective studies; meta-analysis of case-controlled studies. Three researchers independently reviewed MEDLINE (January 1, 1950-November 30, 2010), Embase (January 1, 1980-November 30, 2010), and Evidence-Based Medicine Reviews databases in addition to conducting a manual reference search. Randomized controlled trials, prospective cohort studies, consecutive/nonconsecutive case series, and retrospective reviews in which a clear definition of SSNHL was stated were included in the study. Researchers individually extracted data regarding patient information and the presumed risk factors. Discrepancies were resolved by mutual consensus. Twenty-two articles met the inclusion criteria. Cardiovascular risk factors (smoking, increased alcohol consumption) appeared to be associated with a higher risk of developing SSNHL. A low level of serum folate may also be implicated as a risk factor. Factor V Leiden and MTHFR gene polymorphisms were found to occur more frequently in patients with SSNHL in several studies, suggesting these inherited prothrombophilic mutations could be independent risk factors of SSNHL. Acquired and inherited cardiovascular risk factors appeared to be associated with an increased risk of developing SSNHL.


Evaluation of the Therapeutic Effect of Quadrivalent Human Papillomavirus (HPV) Vaccination on Cervical Intraepithelial Neoplasia Lesions.
Cervical cancer is the most common health problem among global young women. Cervical intraepithelial neoplasia (CIN) is a pre-invasive stage of cervical cancer, the major cause of which is human papillomavirus (HPV), and vaccination has a promising effect on reducing the progression of CIN lesions. The current study was a retrospective case control investigation in two centers, Shiraz and Sari Universities of Medical Sciences from 2018 to 2020 to evaluate the effect of quadrivalent HPV vaccination on CIN lesions (I, II, and III). Eligible patients diagnosed with CIN were selected and divided into two groups: one group received HPV vaccine and the control group did not. The patients were followed up after 12 and 24 months. The information about tests (e.g., Pap smear, colposcopy, and pathology biopsy) and history of vaccination was recorded and statistically analyzed. 150 patients were classified into the control group (without HPV vaccination) and the other 150 patients were in the Gardasil group (with HPV vaccination). The patients' mean age was 32 years old. Two groups were not significantly different according to age and CIN grades. Between two groups in 1 and 2 years' follow-up examinations, the high-grade lesions in both Pap smear and pathology were significantly diminished in patients in the HPV vaccinated group in comparison with the control group with p-values 0.001 and 0.004 in 1 year follow-up respectively and 0.00 after 2 years follow-up. HPV vaccination can prevent the progression of CIN lesions in 2-year follow-up examination.


Naloxone antagonizes striatally-induced suppression of globus pallidus unit activity.
This study was designed to examine the ability of naloxone to antagonize the inhibition of neurons in the globus pallidus produced by electrical stimulation of the caudate nucleus. In rats anesthetized with chloral hydrate, bipolar stimulating electrodes were placed in the head of the caudate and seven-barrel micropipettes were utilized for recording extracellular activity of globus pallidus cells as well as for microiontophoretic application of experimental drugs. In most globus pallidus cells which were inhibited by caudate stimulation, application of naloxone (at currents which antagonized morphine-elicited depression) attenuated the caudate-induced effect. Naloxone did not antagonize depression of globus pallidus neurons induced by gamma-aminobutyrate. The results indicate that caudate stimulation causes the release of endogenous enkephalins which act to suppress neuronal activity in the globus pallidus. Thus, this study supports biochemical and histochemical studies which provide evidence for an enkephalinergic component in the striatopallidal projection.


Exploration of anti-insect potential of trypsin inhibitor purified from seeds of Sapindus mukorossi against Bactrocera cucurbitae.
Peptidase inhibitors (PIs) are defense proteins of plants which are active against gut peptidases of different insects. Sapindus mukorossi was identified as a source of bioactive PIs which could confer resistance against Bactrocera cucurbitae, a most devastating pest of several economically important crops. In the present study, a trypsin inhibitor was purified from mature dry seeds of S. mukorossi and characterized for its biochemical properties as well as its potential for bio control of B. cucurbitae. The purified fractions from RP- HPLC through SDS-PAGE gave an apparent molecular weight of ~29 kDa. S. mukorossi trypsin inhibitor (SMTI) was found to be a non-competitive inhibitor which was active over a broad range of temperature (10-100 °C) and pH (6-11). SMTI when incorporated in artificial diet inhibited the growth and development of B. cucurbitae larvae. Gene expression analysis of trypsin and chymotrypsin genes via qRT-PCR indicated that their mRNA expression was down-regulated while that of other genes namely, Catalase, Elastase, Superoxide Dismutase, Glutathione -S-transferase and Alkaline Phosphatase was up regulated. SMTI also showed deleterious effects against different bacterial strains. The results of this study indicated that S. mukorossi trypsin inhibitor has potential to be used as a bio control agent that can reduce the harm caused by melon fruit fly and other devastating pests.


Metabolic evaluation of patients with urinary system stone disease: a research of pediatric and adult patients.
To determine the metabolic risk factors in children and adults with urinary system stone disease. Between September 2008 and February 2011, 257 patients who underwent 24-h urine analysis because of urinary system stone disease were included in the present study. Group I and II include only adult patients. The first-time stone formers were named as Group I (n = 106), and recurrent stone formers were named as Group II (n = 107). Group III was occurred by pediatric patients (n = 44). Control group includes 105 people was called as Group IV. This group was divided into two subgroups. Group IVa includes 70 adult people, and Group IVb includes 35 children. The metabolic evaluation results of patients and control groups were compared. Hypercalciuria (35.8, 44.9, and 47.7 % for Group I, II, and III, respectively) and hypocitraturia (42.5, 40.2, and 50 % for Group I, II, and III, respectively) were most common risk factors for stone formation. However, unlike the literature, we have seen that hypomagnesiuria is also an important risk factor in adults and children. Hypomagnesiuria was defined at 36.4 % in Group I, 29 % in Group II, and 56.8 % in Group III (p < 0.05 for each group). These three parameters were significantly different between patient and control groups. Hypomagnesiuria, hypocitraturia, and hypercalciuria are the most important risk factors for stone formation in adults and pediatric patients.


Negative pressure wound therapy.
Negative pressure wound therapy has become an increasingly important part of wound management. Over the last decade, numerous uses for this method of wound management have been reported, ranging from acute and chronic wounds, to closure of open sternal and abdominal wounds, to assistance with skin grafts. The biophysics behind the success of this treatment largely have focused on increased wound blood flow, increased granulation tissue formation, decreased bacterial counts, and stimulation of wound healing pathways through shear stress mechanisms. The overall success of negative pressure wound therapy has led to a multitude of clinical applications, which are discussed in this article.


Experience with first trimester prenatal diagnosis of Menkes disease.
We have performed 28 first trimester diagnoses for Menkes disease in 27 high risk pregnancies by direct copper measurement on chorionic villi (c.v.) Two male fetuses were found to be affected because of significantly increased copper content. In one male fetus a slightly increased copper content was observed indicating an exogenous copper contamination of the sample. This view was supported by normal results observed after abortion. Three out of 15 diagnostic c.v. samples with a female karyotype showed increased copper levels. In two of these cases, part of the copper content might have been released from the cannulae used for these particular biopsies. Histochemical visualization of copper accumulation in fixed chorionic villi of two affected fetuses and one female fetus was observed. [64Cu]-uptake studies have been performed on 11 diagnostic and 10 control c.v. samples. As the control samples in some cases were found to incorporate more [64Cu] than the corresponding diagnostic sample, this method cannot at present be used for diagnosis. Compiled results on newborn females gave evidence that two carriers expressed the paternal X-chromosome, and two carriers expressed the maternal X-chromosome in in chorionic villi.


Prescribing efficiently in nursing homes.
Giving medications in nursing homes is time consuming and expensive. The orders for medications in a community nursing home were examined to determine if nursing time could be saved by consolidating the administration of medications. Nineteen percent of the medication administration visits could be eliminated by this method according to the independent judgments of two physicians. This could save up to $19,000 in nursing time per year, and the time could be redirected to other nursing activities that could improve the quality of care in nursing homes.


Impact of reference panel composition on scores of script concordance test assessing basic nephrology knowledge in undergraduate medical education.
In the assessment of basic medical knowledge, the composition of the reference panel between specialists and primary care (PC) physicians is a contentious issue. We assessed the effect of panel composition on the scores of undergraduate medical students in a script concordance test (SCT). The scale of an SCT on basic nephrology knowledge was set by a panel of nephrologists or a mixed panel of nephrologists and PC physicians. The results of the SCTs were compared with ANOVA for repeated measurements. Concordance was assessed with Bland and Altman plots. Forty-five students completed the SCT. Their scores differed according to panel composition: 65.6 ± 9.73/100 points for nephrologists, and 70.27 ± 8.82 for the mixed panel, p < 0.001. Concordance between the scores was low with a bias of -4.27 ± 2.19 and a 95% limit of agreement of -8.96 to -0.38. Panel composition led to a change in the ranking of 71% of students (mean 3.6 ± 2.6 places). The composition of the reference panel, either specialist or mixed, for SCT assessment of basic knowledge has an impact on test results and student rankings.[Box: see text].


Reduction in emergency department visits for children's asthma, ear infections, and respiratory infections after the introduction of state smoke-free legislation.
Despite the benefits of smoke-free legislation on adult health, little is known about its impact on children's health. We examined the effects of tobacco control policies on the rate of emergency department (ED) visits for childhood asthma (N=128,807), ear infections (N=288,697), and respiratory infections (N=410,686) using outpatient ED visit data in Massachusetts (2001-2010), New Hampshire (2001-2009), and Vermont (2002-2010). We used negative binomial regression models to analyze the effect of state and local smoke-free legislation on ED visits for each health condition, controlling for cigarette taxes and health care reform legislation. We found no changes in the overall rate of ED visits for asthma, ear infections, and upper respiratory infections after the implementation of state or local smoke-free legislation or cigarette tax increases. However, an interaction with children's age revealed that among 10-17-year-olds state smoke-free legislation was associated with a 12% reduction in ED visits for asthma (adjusted incidence rate ratios (aIRR) 0.88; 95% CI 0.83, 0.95), an 8% reduction for ear infections (0.92; 0.88, 0.97), and a 9% reduction for upper respiratory infections (0.91; 0.87, 0.95). We found an overall 8% reduction in ED visits for lower respiratory infections after the implementation of state smoke-free legislation (0.92; 0.87, 0.96). The implementation of health care reform in Massachusetts was also associated with a 6-9% reduction in all children's ED visits for ear and upper respiratory infections. Our results suggest that state smoke-free legislation and health care reform may be effective interventions to improve children's health by reducing ED visits for asthma, ear infections, and respiratory infections.


Recurrent abdominal pain in children and the endogenous opiates: a brief hypothesis.
The aetiology of recurrent abdominal pain in children (RAP) remains unclear. Some features of this syndrome suggest that an opiate-like mechanism may be involved. The evidence for this is reviewed, and it is hypothesised that RAP may result from a differential gastrointestinal response to stress mediated by the endogenous opiate system.


Benefit-risk assessment of Covid-19 vaccine, MRNA (MRNA-1273) for males age 18-64 years.
Since the authorization of the Moderna mRNA COVID-19 vaccine, real-world evidence has indicated its effectiveness in preventing COVID-19 cases. However, increased cases of mRNA vaccine-associated myocarditis/pericarditis have been reported, predominantly in young adults and adolescents. The Food and Drug Administration conducted a benefit-risk assessment to inform the review of the Biologics License Application for use of the Moderna vaccine among individuals ages 18 and older. We modeled the benefit-risk per million individuals who receive two complete doses of the vaccine. Benefit endpoints were vaccine-preventable COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, and deaths. The risk endpoints were vaccine-related myocarditis/pericarditis cases, hospitalizations, ICU admissions, and deaths. The analysis was conducted on the age-stratified male population due to data signals and previous work showing males to be the main risk group. We constructed six scenarios to evaluate the impact of uncertainty associated with pandemic dynamics, vaccine effectiveness (VE) against novel variants, and rates of vaccine-associated myocarditis/pericarditis cases on the model results. For our most likely scenario, we assumed the US COVID-19 incidence was for the week of December 25, 2021, with a VE of 30% against cases and 72% against hospitalization with the Omicron-dominant strain. Our source for estimating vaccine-attributable myocarditis/pericarditis rates was FDA's CBER Biologics Effectiveness and Safety (BEST) System databases. Overall, our results supported the conclusion that the benefits of the vaccine outweigh its risks. Remarkably, we predicted vaccinating one million 18-25 year-old males would prevent 82,484 cases, 4,766 hospitalizations, 1,144 ICU admissions, and 51 deaths due to COVID-19, comparing to 128 vaccine-attributable myocarditis/pericarditis cases, 110 hospitalizations, zero ICU admissions, and zero deaths. Uncertainties in the pandemic trajectory, effectiveness of vaccine against novel variants, and vaccine-attributable myocarditis/pericarditis rate are important limitations of our analysis. Also, the model does not evaluate potential long-term adverse effects due to either COVID-19 or vaccine-attributable myocarditis/pericarditis.


Cardiometabolic profile of 15057 elderly Spanish workers: association of sociodemographic variables and tobacco consumption.
Aging of the world population is one of the most significant demographic changes of our time. Populations older than 60 years are heterogeneous, and age is an independent cardiovascular risk factor aggravated by frailty, obesity, and diabetes, and influenced by several factors, including sex and socioeconomic status. The objective of this study was to calculate cardiovascular risk in workers of both sexes over 60 years of age and to assess whether there are difference s by sex, social class, smoking, and type of job. A cross-sectional study was carried out in 15,057 elderly Spanish workers from different autonomous communities in Spain and with different labor occupations. Anthropometric, sociodemographic, clinical, and laboratory values were determined. People were classified according to age from 60 to 64 years inclusive and from 65 to 69 years, smokers and non-smokers, and both blue-collar and white-collar workers. Subsequently, a multivariate analysis was carried out. Men, blue-collar workers, smokers, and aging were factors that influenced cardiovascular risk: with an OR of 3.27 (95% CI: 2.64-4.05) in people 65 years of age or older versus the younger group, and an OR of 3.15 (95% CI: 2.69-3.69) in smokers versus non-smokers. A stronger independent association was found between smoking, age, and cardiovascular risk. The risk of developing non-alcoholic fatty liver and liver fibrosis was much higher in men than in women, with an OR of 4.06 (95% CI: 3.66-4.50) for the former and an OR of 2.10 (95% CI: 1.95-2.26) for the BARD index. The highest risk groups were observed in male subjects with a history of smoking and blue-collar workers and, as such, should be considered for cardiovascular risk screening programs.


Interpolation and the detection of fine structure in stereoscopic matching.
Under some conditions, the perceived depth of a stereogram made of regularly-spaced points depends on the disparity of the edges of the stereogram rather than on discrete stereo matching of the points themselves. These depth percepts are seen only if the viewing time is brief, less than 2-3 sec, and the spacing between the points is small, less than 5-7 min of arc. In this paper, we examine the hypothesis that depth interpolation reflects a failure of the stereo matching apparatus to resolve the fine structure of the stereogram. We show that fine structure can be resolved during brief presentations (160 msec). It seems likely that interpolation represents an intermediate stage in the stereo matching process.


Rapid transformation of Chlamydomonas reinhardtii without cell-wall removal.
Chlamydomonas reinhardtii is widely used to study many biological processes including biofuel production. Here, we present a rapid transformation technique for cell-walled Chlamydomonas strains without cell-wall removal using a square electric pulses-generating electroporator. This method could be applied to transformation of other industrially useful algae by optimizing the electric conditions.


Comparative bioavailability of single-dose methylphenidate from a multilayer-release bead formulation and an osmotic system: a two-way crossover study in healthy young adults.
This study was conducted to compare plasma levels of methylphenidate over time with single doses of a multilayer-release (MLR) bead formulation and an osmotic, controlled-release oral delivery system (OROS) of methylphenidate in young adults. This was a randomized, 2-way crossover study in which healthy, nonsmoking young adults (age 18-25 years) were randomized to receive methylphenidate MLR 20 mg QD or OROS methylphenidate 18 mg QD, with a 7-day washout between treatments. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 16, and 24 hours after dosing. Analysis of plasma samples was conducted by high-performance liquid chromatography with tandem mass-spectrometry detection. Adverse events were monitored by spontaneous reports, laboratory and biochemistry tests, urinalysis, and physical examinations conducted at screening and at the end of the study. Of the 24 subjects originally enrolled, 3 discontinued for personal reasons after the first phase and were not included in the pharmacokinetic analysis. The per-protocol population (11 females, 10 males) had a mean (SD) age of 22 (2) years (range, 19-25 years) and a mean body mass index of 23.6 (3.0) kg/m(2) (range, 19.0-28.5 kg/m(2)). The relative AUC0t and Cmax ratios for the MLR methylphenidate formulation compared with the OROS methylphenidate formulation were 110.88% and 121.84%, respectively. When OROS methylphendate values were dose normalized to 20 mg, the relative AUC0-t and Cmax ratios were 100.72% and 111.82%. The mean Tmax for the 2 formulations was 3.71 (2.03) and 4.96 (2.56) hours. Values were significantly higher with the MLR methylphenidate formulation compared with the OROS methylphenidate formulation for AUC(0-4) (P < 0.001), AUC(0-8) (P < 0.001), AUC(0-12) (P < 0.001), and AUC(4-12) (P = 0.037); the AUC(8-12) was not significantly different between the 2 formulations. Values were significantly higher for the MLR methylphenidate formulation relative to the OROS methylphenidate formulation for C(max0-4) (P < 0.001) and C(max4-12) (P = 0.002). Thirty-seven adverse events occurred in 11 and 10 subjects during receipt of MLR and OROS methylphenidate, respectively. The most commonly reported adverse events in the intent-to-treat population were catheter-site pain, reported by 8 of 24 subjects (33.3%), and headache, reported by 5 of 24 subjects (20.8%). In these healthy young subjects, MLR methylphenidate was associated with a concentration-time profile that resulted in a higher proportion of the administered methylphenidate dose being delivered in the first 4 hours after dosing compared with OROS methylphenidate while maintaining comparable levels of drug in the latter portion of the dosing interval. This led to maintenance of higher mean levels of methylphenidate throughout the day compared with the closest marketed dose of OROS methylphenidate. The 2 formulations are marketed in dissimilar strengths; however, after correction for administered dose, they yielded similar AUC values.


Insights into the behavioral difference of water in the presence of GM1.
Studies on the structure and dynamics of interfacial water, emphasizing on the properties of water near the surface of biomolecules, are well reported, but there is a lack of evidence on the behavior of water near a comparatively rough surface containing molecules with a bulky head group like GM1. In this report we comparatively analyze the structure and dynamics of water as a function of distance from the lipid head group in GM1 containing lipid bilayers, with the lipid bilayers where GM1 is not present. This approach effectively demonstrates the behavioral difference and hence delayed convergence from bound water to bulk water in the presence of GM1 compared to a relatively smooth surface.


Synthesis and characterization of nano crystallite carboxamide-based iron(III) complexes: SOD mimetic activity, antibacterial and anticancer activity and molecular docking study.
Three carboxamide-based ligands and their iron(III) complexes were prepared and structurally characterized. Analytical, thermal and mass spectra measurements showed a 1:1 stoichiometric (M:L) of the synthesized iron(III) complexes. The distorted octahedral geometry of the present iron(III) complexes was assigned based on the results of spectroscopy and magnetometry. Processing of X-ray diffraction data for powder samples by the software Expo 2014 confirmed the octahedral geometry of the three iron(III) complexes. Electrochemical properties of the present iron(III) complexes were studied by cyclic voltammetric measurements. The present iron(III) complexes exhibit SOD like activity with IC50 values of 16.45, 15.24 and 9.70 μM. The drive forces (-λ or ΔG°) controlling these biocatalytic reactions were determined and correlated with catalytic activity. The proposed catalytic mechanistic implications for the conversion of O2•- to H2O2 and H2O were discussed. The antimicrobial activity has been studied in vitro against G(+) and G(-) pathogenic bacteria. The in vitro anticancer activity of the carboxamide-based ligands and their iron(III) complexes against human Hepatocellular carcinoma (HepG-2) cell lines was examined. The obtained results demonstrated the potent anticancer activity of iron(III) complexes with increased safety on normal cells compared to cisplatin. Molecular docking calculations confirmed the experimental findings of the antibacterial and anticancer activities of both free ligands and their iron(III) chelates.Communicated by Ramaswamy H. Sarma.


Effects of fish oil capsules in two dosages on blood pressure, platelet functions, haemorheological and clinical chemistry parameters in apparently healthy subjects.
The effects of a fish oil concentrate with an omega-3 fatty acid content of 42% was determined in two dosages in a double-blind, placebo-controlled study with a parallel group comparison over a period of 5 weeks with 30 healthy subjects. The daily intake chosen was four and eight capsules corresponding to 1.26 or 2.52 g omega-3 fatty acids. Plasma viscosity, erythrocyte rigidity and systolic blood pressure were significantly decreased (p less than 0.01) after a 5-week administration of 2.52 g omega-3 fatty acid daily. The reduction in vitamin E concentration was significant (p less than 0.01) only in the low-dose fish oil group. Lipids and lipoproteins remained unchanged throughout this experiment.


Catalytic hydrodechlorination of trichloroethylene in a novel NaOH/2-propanol/methanol/water system on ceria-supported Pd and Rh catalysts.
The catalytic hydrodechlorination (HDC) of high concentrations of trichloroethylene (TCE) (4.9 mol%, 11.6 vol%) was studied over 1%Pd, 1%Rh and 0.5%Pd-0.5%Rh catalysts supported on CeO2 under conditions of room temperature and pressure. For this, a one-phase system of NaOH/2-propanol/methanol/water was designed with molar percentages of 13.2/17.5/36.9/27.6, respectively. In this system, the alcohols delivered the hydrogen required for the reaction through in-situ dehydrogenation reactions. PdRh/CeO2 was the most active catalyst for the degradation of TCE among the evaluated materials, degrading 85% of the trichloroethylene, with alcohol dehydrogenation rates of 89% for 2-propanol and 83% for methanol after 1 h of reaction. Fresh and used catalysts were characterized by Transmission Electron Microscopy (TEM), X-ray Photoelectron Spectroscopy (XPS), and Thermogravimetric analysis (TGA). These results showed important differences of the active phase in each catalyst sample. Rh/CeO2 had particle sizes smaller than 1 nm and the active metal was partially oxidized (Rh(0)/Rh(+δ) ratio of 0.43). This configuration showed to be suitable for alcohols dehydrogenation. On the contrary, Pd/CeO2 showed a Pd completed oxidized and with a mean particle size of 1.7 nm, which seemed to be unfavorable for both, alcohols dehydrogenation and TCE HDC. On PdRh/CeO2, active metals presented a mean particle size of 2.7 nm and more reduced metallic species, with ratios of Rh(0)/Rh(+δ) = 0.67 and Pd(0)/Pd(+δ) = 0.28, which showed to be suitable features for the TCE HDC. On the other hand, TGA results suggested some deposition of NaCl residues over the catalyst surfaces. Thus, the new reaction system using PdRh/CeO2 allowed for the degradation of high concentrations of the chlorinated compound by using in situ hydrogen liquid donors in a reaction at room temperature and pressure.


Genetic profiling for diffuse type and genomically stable subtypes in gastric cancer.
Gastric cancer is one of the most common and clinically important diseases worldwide. The traditional Laeuren classification divides gastric cancer into two histopathological subtypes: diffuse and intestinal. Recent cancer genomics research has led to the development of a new classification based on molecular characteristics. The newly defined genomically stable (GS) subtype shares many cases with the histopathologically diffuse type. In this study, we performed genetic profiling of recurrently and significantly mutated genes in diffuse type and GS subtype tumors. We observed significantly different genetic characteristics, although the two subtypes overlapped in many cases. In addition, based on the profiles of the significantly mutated genes, we identified molecular functions and mutational signatures characteristic of each subtype. These results will advance the clinical application of the diffuse type and GS subtype gastric cancer in precision medicine for treating gastric cancer.


Evaluation of radiographic abnormalities of the hand in patients with the Mayer-Rokitansky-Küster-Hauser syndrome.
Radiographs of the hand in a group of 40 patients with the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome were studied. Most of the patients had the following abnormalities: brachymesophalangy of digits 2-5 (22/39 patients), small distal phalanx of digit 1 (22/39 patients), long proximal phalanx of digits 3-4 (19/39 patients), and long metacarpals of digits 1-4 (20/39 patients). In addition, three patients had distinct radial dysplasia and abnormalities of the carpals.


Effect of smoking on serum levels of HDL apoproteins.
Quantitative determination of HDL apoproteins in serum from 97 healthy men showed a significantly lower apoA-I and apoA-II level in smokers than in non-smokers. Also a significant, negative correlation was found between the apoA-I or apoA-II levels, and the number of cigarettes smoked per day.


Screening for impaired renal function in outpatients before iodinated contrast injection: Comparing the Choyke questionnaire with a rapid point-of-care-test.
To determine the usefulness of the Choyke questionnaire with a creatinine point-of-care test (POCT) to detect impaired renal function amongst outpatients receiving intravenous iodinated contrast in a tertiary centre. Between July and December 2012, 1361 outpatients had their serum creatinine determined by POCT and answered the Chokye questionnaire just before their examination. Four hundred and eighty (35.2%) patients had at least one 'Yes' response. Forty-four patients (3.2%) had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and 14 patients (1.0%) have eGFR <45 mL/min/1.73 m(2). Sensitivity, specificity, positive predictive value and negative predictive value of the Choyke criteria in detecting patients with eGFR <60 mL/min/1.73 m(2) are respectively: 65.9%, 65.8%, 6.0% and 98.3% and to detect eGFR <45 mL/min/1.73 m(2): 92.9%, 65.3%, 2.7% and 99.9%. Only 'Yes' responses to 'Have you ever been told you have renal problems?' and 'Do you have diabetes mellitus?' were statistically significant in predicting eGFR <45 mL/min/1.73 m(2), with odds ratio 98.7 and 4.4 respectively. The Choyke questionnaire has excellent sensitivity and moderate-to-good specificity in detecting patients with <45 mL/min/1.73 m(2), below this level it has been shown that risk of contrast induced nephropathy increases significantly, making it an effective screening tool. Also the use of POCT can potentially reduce waiting time.


[Mechanism of stimulation of duodenal contractions by the greater splanchnic nerve].
The mechanism of duodenal motor activity stimulation has been studied in dogs during irritation of the chest area of the greater splanchnic nerve. It has been established that a stimulating effect of the splanchnic nerve was not removed either by bilateral vagotomy or by separate and combined injections of bretylium tosylate and benzohexamethonium, but was removed by the blockade of M-serotoninergic receptors of the autonomic ganglia with atropine or by the blockade of D-serotoninergic receptors of the smooth muscles with promethazine hydrochloride. The data obtained demonstrate the presence of noncholinergic and nonadrenergic fibers in the chest area of the greater splanchnic nerve, having a potent stimulating effect on duodenal contractions. According to our functional and biochemical tests, they are mediated by serotonin.


Fluorination of triptolide and its analogues and their cytotoxicity.
The reaction of triptolide and its analogues with a fluorinating agent, that is, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) or (diethylamino)sulfur trifluoride (DAST), was studied. One of the fluorinated products, 14beta-dehydroxy-14beta-fluoro triptolide, was found to be more cytotoxic than the parent natural triptolide.


Inhibition of recombinant dipeptidyl peptidase III by synthetic hemorphin-like peptides.
In order to find the most effective antagonist for dipeptidyl peptidase III degrading enkephalin, we synthesized hemorphin-like pentapeptides with aliphatic or aromatic amino acids at the N-termini, such as VVYPW, LVYPW, IVYPW, YVYPW, FVYPW and WVYPW. Among those pentapeptides, IVYPW and WVYPW showed the strongest inhibitory activity toward rDPP III. The K(i) values of IVYPW and WVYPW were 0.100+/-0.011 and 0.126+/-0.015 microM (mean+/-S.E.), respectively. The order of K(i) values was Ile> or =Trp>Phe> or =Tyr>Leu>Ala>Val>Ser>Gly. rDPP III activity is inhibited in a non-competitive manner by these peptides. The peptide VYPW did not inhibit rDPP III activity, but the sequence is essential for the expression of inhibitory activity.


Preliminary results of cataract extraction with implantation of a single-piece AcrySof intraocular lens.
To evaluate the intraoperative and postoperative performance of the single-piece AcrySof SA30AL intraocular lens (IOL) in a series of patients after cataract surgery and IOL implantation. Department of Ophthalmology and Neurosurgery, University of Siena, Siena, Italy. In this prospective study, 20 patients who had phacoemulsification and implantation of a single-piece AcrySof SA30AL lens from March to April 2000 were evaluated. Assessed were control of IOL folding, ease of IOL implantation, IOL centration, intraoperative and postoperative complications, visual acuity, and anterior (ACO) and posterior (PCO) capsule opacification. In all cases, the IOL was easily folded, inserted, and unfolded. It remained well centered in the capsular bag, and there were no intraoperative or postoperative complications. The best corrected visual acuity after surgery was 20/40 or better in all patients. No eye developed ACO or phimosis. One eye had a well-demarcated, oval area of lens epithelial cell proliferation on the posterior capsule that did not impair visual acuity. Initial results indicate that the single-piece AcrySof SA30AL IOL has good biocompatibility, haptic flexibility and resistance, and stability in the capsular bag. The incidence of PCO in 1 eye could have been the result of several factors and requires further evaluation. An area of future study is the wide haptic of the lens, which may create a path for cells to proliferate as they travel from the equatorial capsule.


Lanthanum ions assisted non-enzymatic ratiometric fluorescence probe for monitoring fenthion residues in agro-product samples.
In this work, a La3+ assisted glutathione-capped gold nanoclusters and carbon dots (GSH-Au NCs/CDs) nanoplatform for sensitive detection of fenthion (FEN) is fabricated. The fluorescence response of GSH-Au NCs significantly increases due to aggregation-induced emission enhancement (AIEE) effect induced by La3+, which is further enhanced with adding FEN due to the coordination between La3+ and FEN. Taking the fluorescence intensity of CDs as the signal background, the ratiometric fluorescence of GSH-Au NCs and CDs has a good linear relationship with the FEN concentration from 0.01 to 1.10 μg mL-1, and detecting FEN exhibits a good sensitivity at a low detection limit of 6.74 ng g-1. The La3+ assisted GSH-Au NCs/CDs nanoplatform demonstrates desirable selectivity and applicability for monitoring trace level of FEN in fruit and vegetable samples. The non-enzymatic strategy by taking advantage of successive AIEE of GSH-Au NCs has a great potential for facile screening organophosphate pesticides in agro-products.


Susceptibility to caspofungin and fluconazole and Als1/Als3 gene expression in biofilm and dispersal cells of Candida albicans.
The biofilm of Candida albicans has been implicated as a source of bloodstream infections. Dispersal cells, as the final biofilm stage, are responsible for its spread. The aim of this study was to compare the susceptibility of biofilm and dispersal cells vs. planktonic cells (overnight liquid culture) of C. albicans to caspofungin (CAS) and fluconazole (FLU) when the drugs were added: i) at the beginning of the experiment; ii) after 1.5 h (adherence stage); iii) after 24 h (early mature biofilm). The findings were evaluated after 48 h (mature biofilm) using the XTT reduction assay. Later administration of the drug increased biofilm sessile minimal inhibitory concentration (SMIC(80)) of both FLU and CAS from 1 μg mL(-1) to over 64 μg mL(-1) and from 0.125 μg mL(-1) to over 16 μg mL(-1), respectively. Susceptibility of dispersal cells also decreased with time of administration. We also determined the expression of the Als1 and Als3 genes in 48-h sessile biofilm and dispersal cells of C. albicans SC5314 and compared it to planktonic cells. The expression was normalised to the standard Act1 gene in every condition tested. Quantitative real-time PCR revealed a strong up-regulation of the Als1 gene in the dispersal cells but not in biofilm and high expression of the Als3 gene in both biofilm and dispersal cells. High expression of both Als1 and Als3 genes supports the hypothesis that dispersal cells pose a high-risk of infection.


Click-evoked otoacoustic emissions in a child with unilateral deafness.
In a 6-year-old boy with idiopathic unilateral deafness, click-evoked otoacoustic emissions were recorded in both ears with similar amplitudes and time courses. Following stimulation of the deaf ear, no component of auditory-evoked brainstem potentials was recorded. No space-occupying lesion was observed with high-resolution CT. At retest 1 year later these results were unchanged. In the deaf ear electrostimulation of the cochlear nerve was performed using an ear canal electrode. At a stimulus current of 20 microA the body consistently reported hearing sensation. Click-evoked otoacoustic emission indicated good outer hair cell function. Hearing sensation at low stimulus intensities with electrostimulation indicated fairly good functions of the cochlear nerve. Considering also the results of imaging and auditory-evoked potentials, findings suggested that the deafness was due to an inner hair cell disorder.


Genetic diversity in the non-structural gene of parvovirus B19 detected by single-stranded conformational polymorphism assay (SSCP) and partial nucleotide sequencing.
A homologous region in the parvovirus B19 non-structural gene (B19 nt 1399-1682) was examined in 50 samples from patients with a wide variety of B19-related disease from various countries by PCR amplification, single-stranded conformational polymorphism (SSCP) assay and nucleotide sequencing. Five SSCP types were confirmed by nucleotide sequence analysis. Of a total of 6 mutations, all were silent. Types 3 and 4 accounted for 92% of strains. There was no correlation between genome type and either clinical illness or patient age. However, there was a correlation between SSCP type and country of origin. Type 3 strains predominated in Japan (18/26) and the UK (6/8), whereas type 4 predominated in the USA (9/12). Notably, type 3 strains also predominated among females (14/18), whereas there were approximately equal numbers of strain types 3 (7/17) and 4 (8/17) among males; an observation which remains unexplained. Within the Japanese group, although type 3 strains predominated overall, strains isolated from 1981 to 1987 consisted of types 1 (2/15), 2 (1/15), 3 (8/15), and 4 (4/15), whereas strains isolated from 1990 to 1994 consisted almost entirely of type 3 (10/11).


Growth, survival, and metabolic activities of probiotic Lactobacillus spp. in fermented coffee brews supplemented with glucose and inactivated yeast derivatives.
Amidst rising interest in non-dairy probiotic foods, and growing global coffee consumption patterns, it would be opportune to ferment coffee brews with probiotics, yet it remains unexplored. In this study, we aimed to develop a fermented coffee beverage rich in live probiotics, by supplementing nutrient-deficient coffee brews with glucose and inactivated yeast derivatives. This was followed by fermentation with single probiotic bacteria cultures (Lactobacillus rhamnosus GG, L. paracasei Lpc-37, L. plantarum 299v, and L. acidophilus NCFM), and subsequent storage at 4 and 25 °C. We demonstrated that nutrient supplementation was essential in supporting probiotic growth and survival in coffee brews, as viabilities above 7 Log CFU/mL could not be sustained longer than 2 weeks in non-supplemented coffees. In contrast, viabilities above 7 Log CFU/mL were maintained for 10 weeks by L. rhamnosus GG and L. paracasei Lpc-37 in supplemented coffees stored under refrigeration. Probiotic metabolic activities led to consumption of glucose, glutamic acid, and alanine, with simultaneous formation of lactic acid, 3-methylbutanoic acid, and diacetyl. Nevertheless, endogenous coffee volatiles, bioactive components, and antioxidant capacities were retained. Overall, we illustrate the potential functionalities of probiotic fermented coffee brews, arising from high probiotic live counts and retention of major coffee bioactive components.


Functional imaging of mitochondria in genetically confirmed retinal dystrophies using flavoprotein fluorescence.
Whether by indirect oxidative stress or direct genetic defect, various genetic retinal dystrophies involve mitochondrial stress. Mitochondrial flavoprotein fluorescence (FPF), reported as either average signal intensity or variability (heterogeneity), may serve as a direct, quantifiable marker of oxidative stress. This observational study enrolled patients with genetically confirmed retinal dystrophies between January and December 2021. Patients with concomitant maculopathy and ocular hypertension were excluded. Patients were FPF imaged with OcuMet Beacon® third generation device during routine outpatient visit. The final analysis cohort included 242 images from 157 patients. Mean FPF intensity was significantly increased between age matched controls and patients with confirmed rod-cone dystrophy, Stargardt disease, Bardet-Biedl syndrome (BBS), and Mitochondrial ATP synthase mutation (P ≤ 0.007). Mean FPF heterogeneity was significantly increased between age matched controls and patients with confirmed rod-cone dystrophy, Stargardt disease, and BBS (P ≤ 0.011). FPF lesions were noted to correlate with Fundus Autofluorescence (FAF) lesions in diseases examined. FPF intensity and heterogeneity significantly increased in patients with retinal dystrophies. The correlation of FPF lesions with FAF lesions implies FPF may be a clinically useful biomarker in patients with IRDs.