Ventromedial hypothalamic knife-cut lesions in rats resistant to dietary obesity.
The effects of ventromedial hypothalamic (VMH) knife-cut lesions on food intake and body weight of S 5B/Pl rats, which are normally resistant to obesity when eating a high-fat diet, were examined in two experiments. In the first experiment body weight increased only slightly after VMH knife-cut lesions when animals were fed pelleted laboratory chow or a 10% corn oil diet. When eating the 30% corn oil diet, however, body weight increased in the VMH knife-cut rats. In the second experiment VMH knife-cut lesions produced a small weight gain in rats fed the 10% fat diet; this manipulation also increased food intake and disrupted the normal diurnal feeding pattern. Changes in the weight of the liver, interscapular brown adipose tissue, and white adipose tissue paralleled the changes in body weight. Plasma insulin increased in the rats eating the 30% corn oil diet ad libitum but not in the VMH-lesioned animals pair fed to the sham-operated rats. Incorporation of 3H from 3H2O into lipid was significantly increased in white fat of animals with VMH knife cuts. Similar results were obtained from incubation of adipose tissue in vitro with insulin and radioactively labeled glucose. These studies show that hypothalamic knife-cut lesions can remove the resistance of the S 5B/Pl rats to obesity when they are fed a high-fat diet.


[Expression of CD31, CD34 and CD105 in squamous cell carcinoma of tongue and their relationships with lymph node metastasis].
To research the expression of CD31, CD34 and CD105 in squamous cell carcinoma of tongue (TSCC) and discuss their relationships with lymph node metastasis. All the specimens' segments were stained by immunohistochemical method SP, and then the tumor's microvessel density (MVD) marked by CD31, CD34 and CD105 were counted by the Weidner's method. The expression of CD31, CD34 and CD105 in the tumor's tissue was much higher than that in the normal tissue (P<0.01). There was no obvious difference between the MVD values marked by CD31 and CD34 (P>0.05), but they were obviously different from which marked by CD105 (P<0.01). The MVD values between the male and female patients had no statistical difference (P>0.05). The MVD values marked by CD31 and CD34 had no statistical difference in different pathological grades and clinical stages (P>0.05), but there was statistical difference in different pathological grades and clinical stages marked by CD105 (P<0.05). Although the MVD value of the cases with lymph node metastasis was different from that without metastasis marked by CD31 and CD34 (P<0.05), there was much higher difference between the cases with lymph node metastasis and those without metastasis marked by CD105 (P<0.01). CD105 is a more satisfying vascular endothelial marker than others. It can predict the metastasis possibility of the TSCC patients, thus it may be particularly important in the development of TSCC.


A Novel Data-Driven Fault Detection Method Based on Stable Kernel Representation for Dynamic Systems.
With the steady improvement of advanced manufacturing processes and big data technologies, modern industrial systems have become large-scale. To enhance the sensitivity of fault detection (FD) and overcome the drawbacks of the centralized FD framework in dynamic systems, a new data-driven FD method based on Hellinger distance and subspace techniques is proposed for dynamic systems. Specifically, the proposed approach uses only system input/output data collected via sensor networks, and the distributed residual signals can be generated directly through the stable kernel representation of the process. Based on this, each sensor node can obtain the identical residual signal and test statistic through the average consensus algorithms. In addition, this paper integrates the Hellinger distance into the residual signal analysis for improving the FD performance. Finally, the effectiveness and accuracy of the proposed method have been verified in a real multiphase flow facility.


Mixed-methods approach to develop an agreed concept on patient relevance: study protocol for the 'PRO patients study'.
With respect to patient-centred care and shared decision-making, measuring care effects based on outcomes relevant to patients is becoming increasingly important. Recently, a scoping review of the international literature revealed a wide range of supposedly patient-relevant outcomes and found that there is neither a sound definition of patient relevance nor a consistent set of outcomes relevant to patients. To close this gap, this study aims to develop an agreed concept on patient relevance including a set of outcomes relevant to patients irrespective of diseases, which grades outcomes according to their importance. This prospective mixed-methods study will integrate the perspectives of patients across diseases, healthcare professionals and researchers. The consensus process will consist of four phases. Based on the results of the recent scoping review, a patient survey will be conducted first, followed by a multiprofessional group discussion. Finally, a two-round online Delphi approach based on data from the previous phases will be applied to agree on a concept. Ethics approval for the study was granted on 26 August 2020 by the Ethics Commission of Witten/Herdecke University (reference number: 156/2020). In the long run, the implementation of an agreed concept on patient relevance will help improve the comparability of study results regarding the patient benefit and thereby strengthen the role of patients in the decision-making process. Also, the experiences regarding grading outcomes according to importance will help to develop a method on how to individualise clinical trial outcomes according to each patient's individual specifics and priorities in order to more adequately represent the patient perspective in clinical research. Core Outcome Measures in Effectiveness Trials Initiative (registration number: 1685).


Rapid clearance of erythrodermic psoriasis with apremilast.
Apremilast is a new immunomodulatory drug, a small molecule inhibitor of PDE4, which down-regulates the expression of multiple pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin 17, interleukin 23. We describe a case of a 54-year-old man with erythroderma in the course of psoriasis (PASI=49), with contraindications to other psoriasis therapies, in whom total clearance of skin lesions was achieved by day 20 after therapy with apremilast at a dose of 30 mg bid (ΔPASI = 100). The patient had a history of prior use of cyclosporine, methotrexate and adalimumab. His comorbidities included obesity, fatty liver and hypercholesterolemia. In this case of erythroderma in the course of psoriasis apremilast led to total clearance of all cutaneous lesions.


[Acute encephalitis with refractory partial status epilepticus treated with early immunotherapies including plasma exchange: a case report].
We describe a patient of acute encephalitis with refractory partial status epilepticus who was successfully treated with early immunotherapy. A 35-year-old male presented with generalized seizures a week after febrile upper respiratory illness. He developed refractory multifocal and generalized seizures despite multiple antiepileptic drug therapies, thereby requiring intubation on the 8(th) day after admission. No significant improvement was observed after steroid pulse and intravenous immunoglobulin (IVIG) therapies. On the 18(th) day, he received plasma exchange (PE) therapy in combination with intravenous thiamylal and lidocaine to achieve burst-suppression coma. This multidisciplinary treatment led to remission of refractory status epilepticus and subsequent withdrawal from general anesthesia. Although anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid were negative, other neural surface antibodies may responsible for the development of status epilepticus in this case. Clinical features in this case, including previous good health, an antecedent febrile illness, and prolonged treatment-resistant status epilepticus, were similar to those of the acute phase of new-onset refractory status epilepticus (NORSE) syndrome. Consecutive use of glucocorticoids, IVIG, and PE in the early phase was speculated to ameliorate seizures by suppressing abnormal activation of humoral immunity. This indicates that early aggressive immunotherapy may prevent complications resulting from immune-mediated treatment-resistant status epilepticus.


Exacerbation rates in Japanese patients with obstructive lung disease: A subanalysis of the prospective, observational NOVELTY study.
Although clinical trials including asthma and COPD patients have revealed much about exacerbation frequencies, most studies are limited in that they recruited patients only with a clear diagnosis of one disease or the other, based on conventional diagnostic criteria, which may exclude many real-world patients with mixed symptoms. NOVELTY is a global prospective observational study of patients with asthma and/or COPD from real-world practice. In this subanalysis, we compared patient characteristics of obstructive pulmonary diseases between the Japanese population (n = 820) and the overall population excluding Japanese patients (n = 10,406). The Japanese population had fewer exacerbations than the overall population across most of the physician-assessed disease severities and all diagnoses. The difference in exacerbation frequencies was more prominent in patients with COPD and asthma + COPD. The Japanese population was older, had higher former smoking rates, lower BMI, fewer respiratory symptoms, and better health-related quality of life compared with the overall population across all diagnoses. We clarified differences in patient characteristics among patients with asthma and/or COPD in Japan compared with non-Japanese patients. Importantly, we found that Japanese patients with asthma and/or COPD had significantly fewer exacerbations compared with patients overall. The results from our study may contribute to the development of precision medicine and guidelines specific to Japan.


Distinguishing idiopathic Parkinson's disease from other parkinsonian syndromes by breath test.
Diagnosis of different parkinsonian syndromes is linked with high misdiagnosis rates and various confounding factors. This is particularly problematic in its early stages. With this in mind, the current pilot study aimed to distinguish between Idiopathic Parkinson's Disease (iPD), other Parkinsonian syndromes (non-iPD) and healthy subjects, by a breath test that analyzes the exhaled volatile organic compounds using a highly sensitive nanoarray. Breath samples of 44 iPD, 16 non-iPD patients and 37 healthy controls were collected. The samples were passed over a nanoarray and the resulting electrical signals were analyzed with discriminant factor analysis as well as by a K-fold cross-validation method, to test the accuracy of the model. Comparison of non-iPD with iPD states yielded 88% sensitivity, 88% accuracy, and 88% Receiver Operating Characteristic area under the curve in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and accuracy and 92% negative predictive value. Comparison between atypical parkinsonism states and healthy subjects scored 94% sensitivity and 85% accuracy in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and 78% accuracy. The obtained results were not affected by l-Dopa or MAO-B inhibitor treatment. Exhaled breath analysis with nanoarray is a promising approach for a non-invasive, inexpensive, and portable technique for differentiation between different Parkinsonian states. A larger cohort is required in order to establish the clinical usefulness of the method.


Two-year, prospective, multicenter study of the use of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in the clinical setting in France.
To evaluate patterns of use and long-term efficacy and safety of dexamethasone intravitreal implant (DEX implant) in the treatment of macular edema secondary to branch or central retinal vein occlusion (BRVO, CRVO) in French clinical practice. A 24-month, prospective, multicenter, longitudinal, observational study (LOUVRE) conducted at 48 randomly selected sites in metropolitan France enrolled consecutive adult patients with macular edema following retinal vein occlusion (RVO) who were treated with DEX implant at baseline. Re-treatment with DEX implant and use of other RVO treatments was at the physician's discretion. The primary endpoint was the change in best-corrected visual acuity (BCVA) from baseline to month 6. Secondary endpoints included change in BCVA, intraocular pressure (IOP), adverse events, and RVO treatments administered through month 24. The analysis population of 375 patients (53.9 % BRVO, 46.1 % CRVO) received a mean of 2.6 DEX implant injections over 2 years; mean time between injections was 6.6 months. Mean (SD) change in BCVA from baseline was 5.1 (19.0) letters at month 6 (p < 0.001) and 4.6 (22.3) letters at month 24 (p < 0.001). During the study, 208 patients (55.5 %) received treatment other than DEX implant for RVO, usually laser or ranibizumab therapy, with first use of other therapy occurring at a mean of 8.7 months. Mean change from baseline BCVA at month 6 was 5.5 letters (p < 0.001, N = 254) in patients who had received only DEX implant and 4.2 letters (p = 0.006, N = 121) in patients who had received additional other RVO treatment during the first 6 months. At month 24, mean change from baseline BCVA was +20.7 letters in patients treated with a single DEX implant only (p < 0.001), +4.9 letters in patients treated with ≥2 DEX implants only (p = 0.029), and +2.3 letters in patients treated with DEX implant and other RVO treatment (p = 0.143). The most common adverse events (incidence) were cataract progression (39.7 %) and increased IOP (34.4 %). No glaucoma incisional surgeries were required. Efficacy and safety of DEX implant in the treatment of RVO-associated macular edema were demonstrated in the French clinical setting. Patients who switched from DEX implant to other RVO treatments did not have improved outcomes. The study is registered at ClinicalTrials.gov with the identifier NCT01618266.


Electrospray formation of gelled nano-aluminum microspheres with superior reactivity.
Nanometallic fuels with high combustion enthalpy, such as aluminum, have been proposed as a potential fuel replacement for conventional metallic fuel to improve propellant performance in a variety of propulsive systems. Nevertheless, nanometallic fuels suffer from the processing challenges in polymer formulations such as increased viscosity and large agglomeration, which hinder their implementation. In this letter, we employ electrospray as a means to create a gel within a droplet, via a rapid, solvent evaporation-induced aggregation of aluminum nanoparticles, containing a small mass fraction of an energetic binder. The gelled aluminum microspheres were characterized and tested for their burning behavior by rapid wire heating ignition experiments. The gelled aluminum microspheres show enhanced combustion behavior compared to nanoaluminum, which possibly benefits from the nitrocellulose coating and the gelled microstructure, and is far superior to the corresponding dense micrometer-sized aluminum.


Computational systems biology analysis of biomarkers in lung cancer; unravelling genomic regions which frequently encode biomarkers, enriched pathways, and new candidates.
Exponentially growing scientific knowledge in scientific publications has resulted in the emergence of a new interdisciplinary science of literature mining. In text mining, the machine reads the published literature and transfers the discovered knowledge to mathematical-like formulas. In an integrative approach in this study, we used text mining in combination with network discovery, pathway analysis, and enrichment analysis of genomic regions for better understanding of biomarkers in lung cancer. Particular attention was paid to non-coding biomarkers. In total, 60 MicroRNA biomarkers were reported for lung cancer, including some prognostic biomarkers. MIR21, MIR155, MALAT1, and MIR31 were the top non-coding RNA biomarkers of lung cancer. Text mining identified 447 proteins which have been studied as biomarkers in lung cancer. EGFR (receptor), TP53 (transcription factor), KRAS, CDKN2A, ENO2, KRT19, RASSF1, GRP (ligand), SHOX2 (transcription factor), and ERBB2 (receptor) were the most studied proteins. Within small molecules, thymosin-a1, oestrogen, and 8-OHdG have received more attention. We found some chromosomal bands, such as 7q32.2, 18q12.1, 6p12, 11p15.5, and 3p21.3 that are highly involved in deriving lung cancer biomarkers.


Radiation-induced arteritis: thickened wall with prominent enhancement on cranial MR images report of five cases and comparison with 18 cases of Moyamoya disease.
To evaluate magnetic resonance (MR) imaging findings of radiation-induced cranial arteritis regarding arterial wall thickening and degree of enhancement, as well as to compare the findings with those of idiopathic moyamoya disease. We reviewed cerebral MR images in five patients with radiation-induced large cerebral arteritis. All patients had undergone irradiation 2-25 years prior to this study. Conventional nonenhanced MR, MR angiographic, and contrast material-enhanced MR images were evaluated. Special attention was paid to wall enhancement of the affected arteries (distal internal carotid artery). Wall enhancement was staged in three levels by two neuroradiologists. We also reviewed MR images in 18 patients with primary moyamoya disease for comparison and analyzed them statistically (Fisher exact test). Wall thickening and prominent ring enhancement of the wall of the affected large cerebral arteries were observed in all (five of five) patients with radiation-induced arteritis. In contrast, wall thickening and prominent ring enhancement of the wall of the occluded arteries either were not seen (13 of 18 patients) or were faint (five of 18 patients) in patients with moyamoya disease. Contrast enhancement of the arterial walls in patients with radiation-induced arteritis was significantly more prominent than in patients with moyamoya disease (P =.003). MR images of wall thickening and prominent ring enhancement of the wall of affected large cerebral arteries may be a diagnostic clue in differentiating radiation-induced arteritis from moyamoya disease.


Long-Term maintenance of anomia treatment effects in primary progressive aphasia.
This study examined the maintenance of anomia treatment effects in primary progressive aphasia (PPA). Following baseline testing, a phonological treatment and an orthographic treatment were administered over the course of six months. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (Prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (Remediation items). Naming accuracy was measured at baseline, and it was measured at 1 month, 8 months, and 15 months post-treatment. The change in naming accuracy from baseline to each post-treatment evaluation was calculated within each treatment condition, and within a matched untrained condition. The change in naming accuracy was then compared between the three conditions. The results of these analyses indicate that phonological and orthographic treatments are both effective in the Prophylaxis and Remediation of anomia in all three variants of PPA. For Prophylaxis items, some of the effects of each treatment can persist for as long as 15 months post-treatment. These long-term treatment effects were more robust in the orthographic treatment condition and for participants with the semantic variant of PPA.


Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF.
Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all patients with heart failure with reduced ejection fraction (HFrEF). However, MRAs are still largely underused in routine clinical practice. This study aims to describe the determinants and pattern of use of MRAs in HFrEF. BIOSTAT-CHF is a European multicentre, prospective study which enrolled patients suboptimally treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and/or beta-blockers, with the aim of optimizing guideline-based use of these agents. From the original 2516 subjects, this retrospective post hoc analysis included the 1325 patients with an indication for MRA therapy (i.e. left ventricular ejection fraction ≤35%, estimated glomerular filtration rate ≥30 mL/min/1.73 m2 , K+ ≤5.0 mmol/L). The mean age was 66.1 ± 12.2 years. At baseline an MRA was prescribed to 741 (56%) patients. Patients who were prescribed MRAs at baseline were younger, more often male, had higher body mass index, lower sodium, higher proportion of hypertension history and ACEi/ARB prescription (all P < 0.05). Of the 1049 patients who completed the baseline plus the 9 month visit, 585 (56%) had an MRA prescribed at baseline and 662 (63%) had an MRA prescribed at 9 months. Among the 585 patients with MRA at baseline, 91 (16%) had discontinued therapy and among the 461 (44%) patients without MRA at baseline 168 (36%) had initiated therapy subsequently. MRA discontinuation was more likely in subjects with higher left ventricular ejection fraction and NYHA class III/IV (P < 0.05 for both). MRA prescription both at baseline and 9 months was not associated with the outcome of death or heart failure hospitalization (adjusted hazard ratio 1.02, 95% confidence interval 0.66-1.58; P = 0.93). In this prospective observational study across Europe, MRAs were largely under-prescribed and frequently discontinued. Owing to these dynamic changes, outcome inferences are inconclusive.


Diffusive and subdiffusive axial transport of granular material in rotating mixers.
The segregation of granular mixtures in rotating cylinders into axial bands is not well understood so far. Abnormal diffusion of the grains has been proposed to play an important role in that process. We measure axial diffusion in binary mixtures, completely embedded in water, by means of nuclear magnetic imaging (magnetic resonance imaging). It is found that the small size particles in a radially segregated structure undergo normal (Fickian) axial diffusion, whereas an initial pulse of the large species shows subdiffusive behavior. An interpretation within a model for the particle dynamics is given. The diffusion of small particles occurs in the axial kernel, whereas particles of the large species migrate on the free surface of the granular bed.


[The role of cord blood stem cell transplantation in children; a retrospective analysis of 39 cases in a single institute].
We report the results of 39 children who underwent cord blood stem cell transplantation (CBSCT) at our institute during the period from February 1996 to July 2005. The patients consisted of 9 with non-malignant disease, 26 with malignant disease and 4 with Epstein-Barr virus (EBV) associated disease. The median age of the patients was 4 years and 8 months (range, 6 months to 16 years 2 months). The median infused cell dose was 4.9 (range, 1.7-11.4) x 10(7)/kg. Thirty-four transplants were from HLA-mismatched donors, and 33 patients underwent a tacrolimus-containing regimen for GVHD prophylaxis. As for CBSCT as the first transplant, 3 out of 4 children with non-malignant disease achieved engraftment after CBSCT with the use of a reduced-intensity conditioning regimen. For acute leukemia, 3 patients out of 5 in their first remission and 2 out of 9 in advanced stage at CBSCT continue in remission at the time of writing. Fourteen patients received CBSCT as a second or a third transplant. None of 4 patients who underwent CBSCT as rescue therapy after rejection/graft failure achieved engraftment. It should be emphasized that EBV-associated disease seems to be a suitable disease for CBSCT, because all of the 4 patients who underwent CBSCT are still in CR.


Dysregulated Krüppel-like factor 4 and vitamin D receptor signaling contribute to progression of hepatocellular carcinoma.
Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effects in hepatocellular carcinogenesis. We investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling. We performed microarray analysis of hepatocellular carcinoma (HCC) tissues. We used molecular biology analyses and animal models to evaluate activation and function of KLF4-vitamin D receptor (VDR) pathway. Expression of KLF4 protein was decreased or lost in primary HCC samples, in particular, lymph node metastases, compared with normal liver tissues. Loss of KLF4 from primary tumors was significantly associated with reduced survival time and was identified as a prognostic marker. Most human HCC cell lines had losses or substantial decreases in levels of KLF4. Exogenous expression of KLF4 in HCC cells upregulated expression of mesenchymal-epithelial transition (MET) and inhibited their migration, invasion, and proliferation in vitro. When these cells were injected into mice, tumors grew more slowly and metastasis was inhibited, compared with HCC cells that did not express KLF4. VDR is a direct transcriptional target of KLF4; we identified 2 sites in the VDR promoter that bound specifically to KLF4. Increased expression of VDR sensitized tumor cells to the inhibitory effects of vitamin D. KLF4 binds to the promoter of VDR to regulate its expression; levels of KLF4 are reduced and levels of VDR are increased in HCC cell lines and primary tumor samples. Expression of KLF4 in HCC cells sensitizes them to the anti-proliferative effects of VD3. This pathway might be manipulated to prevent or treat liver cancer.


Stimulation of exocytotic degranulation by microinjection of the ras oncogene protein into rat mast cells.
To investigate the possible role of ras proteins in the secretory process, we have microinjected the proto oncogenic and oncogenic forms of the human H-ras protein into rat peritoneal mast cells. Mast cells are secretory cells which, upon appropriate stimulus, liberate histamine and other mediators of the acute inflammatory reaction by exocytotic degranulation. We report here that microinjection of the ras oncogene protein into mast cells induces exocytotic degranulation. In contrast, microinjection of similar amounts of the proto-oncogenic protein has little apparent effect on mast cells. Degranulation induced by injection of the ras oncogene protein occurs in the absence of an external stimulus and requires the presence of external calcium. The ultrastructural features of exocytotic degranulation in mast cells injected with the ras oncogene protein are similar to those seen when mast cells are activated by soluble ligands. Our results suggest that ras proteins may be involved, possibly as regulatory elements, in cellular functions that control exocytosis.


Signal transduction by reactive oxygen species.
Although historically viewed as purely harmful, recent evidence suggests that reactive oxygen species (ROS) function as important physiological regulators of intracellular signaling pathways. The specific effects of ROS are modulated in large part through the covalent modification of specific cysteine residues found within redox-sensitive target proteins. Oxidation of these specific and reactive cysteine residues in turn can lead to the reversible modification of enzymatic activity. Emerging evidence suggests that ROS regulate diverse physiological parameters ranging from the response to growth factor stimulation to the generation of the inflammatory response, and that dysregulated ROS signaling may contribute to a host of human diseases.


Gastric outlet obstruction caused by heterotopic pancreas: A case report and a quick review.
A 46-year-old Chinese woman presented with nausea, recurrent vomiting, and abdominal pain. Gastroduodenal endoscopic examination revealed an oval-shaped submucosal tumor at the prepyloric area on the posterior wall of the stomach. A degenerated gastrointestinal stromal tumor was suspected. Distal gastrectomy was performed and a histological diagnosis of heterotopic pancreas (HPs) was confirmed. The patient had an uneventful postoperative course and was discharged 7 d after operation. The patient remains healthy and symptom-free in the follow-up of 6 mo. This is a report of a case of gastric outlet obstruction resulting from pancreatic heterotopia in the gastric antrum in an adult woman.


Sensitivity of clinical assessments of sagittal head posture.
Historically, clinicians visually evaluate posture using anatomical landmarks. Advances in technology made digital photographs now feasible to use in clinical practice. Photogrammetry may increase the reliability of the assessment of postural changes. However, differences between visually estimated and photogrammetric recorded changes in posture need to be tested. The objective of this study was to evaluate the sensitivity of visual assessments of changes in head posture in the sagittal plane in relation to photogrammetric recorded data. The head posture of 29 female subjects in a sagittal plane was assessed visually and photogrammetrically. The visual assessment of head posture was conducted using a postural grid with a plumb for checking the alignment. The patients were classified as having forward head posture (FHP), slight FHP or no FHP. Photogrammetry of head posture was performed using the Alcimage software (Alcimar B. Soares, Uberlândia, MG, Brasil). Three reference points were used to measure the head posture angle: mentus, external auditory meatus and manubrium. The visually classified groups were compared in relation to the photogrammetric angles using one-way ANOVA. A significant difference was found between the FHP and no FHP groups (P = 0.001), and between the FHP and slight FHP groups (P = 0.002). However, no significant difference was found between the slight FHP and no FHP groups. Visual assessments of sagittal head posture were sensitive to detect differences between no FHP and FHP groups, but were not sensitive to detect differences between no FHP and slight FHP groups. Head posture photogrammetry is recommended to quantitatively detect less evident differences in head posture.


Arthroscopic treatment for osteochondral defects of the talus. Results at follow-up at 2 to 11 years.
We reviewed 38 patients who had been treated for an osteochondral defect of the talus by arthroscopic curettage and drilling. The indication for surgical treatment was persistent symptoms after conservative treatment for at least six months. A total of 22 patients had received primary surgical treatment (primary group) and 16 had had failed previous surgery (revision group). The mean follow-up was 4.8 years (2 to 11). Good or excellent results, as assessed by the Ogilvie-Harris score, were found in 86% in the primary group and in 75% in the revision group. Two further procedures were required, one in each group. Radiological degenerative changes were seen in one ankle in the revision group after ten years. Arthroscopic curettage and drilling are recommended for both primary and revision treatment of an osteochondral defect of the talus.


Oxaliplatin immune-mediated thrombocytopenia: Is there a role for premedication or desensitization?
Oxaliplatin is a common chemotherapy agent that is used in the treatment of multiple solid malignancies. Immune-mediated thrombocytopenia is a rare and potentially life-threatening adverse effect of oxaliplatin that is characterized by severe thrombocytopenia, which may be accompanied by overt bleeding. This adverse effect is probably mediated via anti-platelet antibodies that become reactive in the presence of oxaliplatin. Due to its rarity and severity, information is scarce regarding the effect of desensitization or attempts at rechallenge after prolonged withdrawal of oxaliplatin. This short report describes 3 cases of oxaliplatin immune-mediated thrombocytopenia, including a case occurring under desensitization protocol and a case of recurrence after a prolo nged withdrawal. All 3 patients are female, have prolonged exposures to oxaliplatin and were all treated for metastatic colorectal cancer. Physicians should be aware of oxaliplatin immune-mediated thrombocytopenia as symptoms may appear rapidly. Oxaliplatin should be permanently discontinued for patients experiencing this adverse effect, as recurrence is highly likely even in the setting of desensitization.


Noninvasive pressure support ventilation: physiological and clinical results in patients with COPD and acute respiratory failure.
Noninvasive ventilation may bring considerable benefits in the treatment of acute respiratory failure, especially in patients with chronic obstructive pulmonary disease. Reduction in the need for endotracheal intubation has been well-documented. In selected groups a reduction in morbidity, mortality, and length of hospital stay have been demonstrated. The efficacy of the technique is very dependent on the skill and motivation of the team.


The acute calcific prevertebral tendinitis: report of two cases.
Acute calcific prevertebral tendinitis, which is also known as retropharyngeal calcific tendinitis and longus colli tendinitis, is an under-recognized cause of acute cervical pain produced by an inflammation of the longus colli muscle. The typical characteristics of this entity are calcifications at the superior insertion of the longus colli tendons at the C1-C2 level and fluid collection in the retropharyngeal space. The differential diagnosis includes a retropharyngeal abscess, infectious spondylitis or traumatic injury. Knowledge of the clinical and imaging findings can prevent a misdiagnosis and inappropriate attempts at surgical drainage.


A search for a defect of proximal transport in denervated kidneys of conscious dogs.
The influence of renal nerves on proximal Na+ reabsorption was studied in clearance experiments with unilaterally renal-denervated conscious dogs prepared by surgical bladder division. Two types of experiments were made : A. maximal water diuresis, and B. Total blockade of distal NaCl reabsorption with ethacrynic acid and chlorothiazide. In maximal water diuresis CH2O + CNa was used as a measure of fluid delivery to the distal nephron. At similar GFR on both sides, the proximal reabsorption estimated as GFR--(CH2O + CNa) was 38.4 +/- 5.6 ml/min for the intact and 35.9 +/- 4.2 ml/min for the denervated kidney (n = 6, difference NS). After distal tubular blockade, proximal Na+ reabsorption calculated as filtered load minus urinary excretion was 3.84 +/- 0.43 mmol/min for the intact and 3.91 +/- 0.36 mmol/min for the denervated kidney (n = 6, difference NS). The fractional reabsorption of NA+ was 64.9 +/- 1.0% for the intact and 66.9 +/- 1.1% for the denervated kidney (difference NS). In contrast to data from renal denervation studies with anaesthetized animals, the present experiments did not show any difference in proximal reabsorption between the innervated- and denervated kidney. We conclude that in absence of anaesthesia renal efferent nerves have no major effect on NaCl transport in dog proximal tubule.


Life satisfaction, health-related quality of life and physical activity after treatment for valvular aortic stenosis.
To investigate health-related quality of life and life satisfaction in children and adolescents treated for isolated congenital valvular aortic stenosis compared to healthy peers. Our second aim was to investigate the relationship between objectively measured physical activity, health-related quality of life and life satisfaction in the same group. Forty-eight patients, 8-18 years of age, were recruited, as well as 43 healthy peers matched for age, gender and residential area. Health-related quality of life was assessed by the KIDSCREEN-52 self-report and parent proxy report, and life satisfaction was evaluated with the Satisfaction With Life Scale. Physical activity was measured with an accelerometer for 7 days. Sports participation was self-reported. No differences in the health-related quality of life domains were found between patients and controls in the self-reports. In the proxy reports, parents of the adolescents rated their child's autonomy lower than did the parents of the healthy controls. A negative relationship was found between moderate to vigorous physical activity, sports participation, life satisfaction and the psychological well-being domain in adolescent patients. In children there was a positive relationship between moderate physical activity and the physical and psychological well-being domains. Overall, children and adolescents treated for valvular aortic stenosis reported similar life satisfaction and health-related quality of life as their healthy peers. The negative relationships between intense physical activity and sports participation with health-related quality of life and life satisfaction in adolescent patients might be explained by both physical and psychological factors in these teenagers with complex, lifelong heart disease.


[Supravoltage irradiation as a cause of maxillary fibrosarcoma].
Therapeutic doses of supravoltage radiation are not commonly thought to be carcinogenic and post-irradiation fibrosarcoma of the head and neck regions is rare. We present a 43-year-old man with post-irradiation fibrosarcoma of the maxilla, who had had supravoltage radiation 12 years before for nasopharyngeal carcinoma.


Separation of Mycobacterium lepraemurium from the subcutaneous tissues of the rat.
In an effort to obtain cell suspensions free from blood cells which interfere in spectrophotometric studies, a method was devised by which relatively large quantities of whole cell suspensions of M. lepraemurium are obtained for experimental purposes. We have routinely employed this procedure which is quite reliable, technically simple, moderate in equipment requirements, and in a matter of five minutes it can be ascertained whether or not the preparations are free from contaminants which render the purified bacillary suspensions unsuitable for studies involving spectrophotometric technics. However, in this procedure, certain points are essential in order to obtain large quantities of purified bacillary suspensions. It is important to homogenize the lepromata for only a few seconds at brief intervals. Excessive homogenization may cause considerable damage to the bacilli and it may be difficult to separate the bacilli from the host tissues. It is also important to use transparent bottles and tubes during centrifugation as the material can be seen and thus each fraction can be separated easily. Very few bacilli are lost in the discarded material and we have repeatedly obtained 2.5 to 3 gm wet weight of M. lepraemurium from one leproma weighing 25 gm to 30 gm.


Prediction of human pharmacokinetics--improving microsome-based predictions of hepatic metabolic clearance.
Physiologically based methods generally perform poorly in predicting in-vivo hepatic CL (CL(H)) from intrinsic clearance (CL(int)) in microsomes in-vitro and unbound fraction in blood (f(u,bl)). Various strategies to improve the predictability have been developed, and inclusion of an empirical scaling factor (SF) seems to give the best results. This investigation was undertaken to evaluate this methodology and to find ways to improve it further. The work was based on a diverse data set taken from Ito and Houston (2005). Another objective was to evaluate whether rationalization of CL(H) predictions can be made by replacing blood/plasma-concentration ratio (C(bl)/C(pl)) measurements with SFs. There were apparently no or weak correlations between prediction errors and lipophilicity, permeability (compounds with low permeability missing in the data set) and main metabolizing CYP450s. The use of CL(int) class (high/low) and drug class (acid/base/neutral) SFs (the CD-SF method) gives improved and reasonable predictions: 1.3-fold median error (an accurate prediction has a 1-fold error), 76% within 2-fold-error, and a median absolute rank ordering error of 2 for CL(H) (n = 29). This approach is better than the method with a single SF. Mean (P < 0.05) and median errors, fraction within certain error ranges, higher percentage with most accurate predictions, and ranking were all better, and 76% of predictions were more accurate with this new method. Results are particularly good for bases, which generally have higher CL(H) and the potential to be incorrectly selected/rejected as candidate drugs. Reasonable predictions of f(u,bl) can be made from plasma f(u) (f(u,pl)) and empirical blood cell binding SFs (B-SFs; 1 for low f(u,pl) acids; 0.62 for other substances). Mean and median f(u,bl) prediction errors are negligible. The use of the CD-SF method with predicted f(u,bl) (the BCD-SF method) also gives improved and reasonable results (1.4-fold median error; 66% within 2-fold-error; median absolute rank ordering error = 1). This new empirical approach seems sufficiently good for use during the early screening; it gives reasonable estimates of CL(H) and good ranking, which allows replacement of C(bl)/C(pl) measurements by a simple equation.


Clinical trials and the response rate illusion.
Clinical trial outcome data can be presented and analyzed as mean change scores or as response rates. These two methods of presenting the data can lead to divergent conclusions. This article explores the reasons for the apparently divergent outcomes produced by these methods and considers their implications for the analysis and reportage of clinical trial data. It is shown that relatively small differences in improvement scores can produce relatively large differences in expected response rates. This is because differences in response rates do not indicate differences in the number of people who have improved; they indicate differences in the number of people whose degree of improvement has pushed them over a specified criterion. Therefore, patients classified as non-responders may have shown substantial and clinically significant improvement, and these are the patients who are most likely to become responders when given medication. Response rates based on continuous data do not add information, and they can create an illusion of clinical effectiveness.


The Spectrum of Pediatric Orbital BB Gun Injuries: A Case Series.
Three cases of pediatric BB orbital injury are reported demonstrating varying outcomes. Pediatric orbital BB injuries have a wide spectrum of clinical outcomes depending on the ocular structures involved. Improved safety education of patients and parents is necessary to reduce the burden of these vision-threatening injuries.


Treating vascular lesions.
The treatment of acquired vascular lesions is one of the most commonly requested and performed cutaneous laser procedures. Furthermore, every year, 40,000 children are born in the United States each with congenital vascular lesions and malformations. Laser treatment of vascular lesion is based on the principle of selective photothermolysis, conceived in the 1980s. A variety of different lasers and light sources have since been used in the treatment of vascular lesions: lasers with wavelengths between green and yellow, near infrared lasers, and broadband light sources. Despite limitations, this remains the treatment of choice today. This publication addresses acquired and congenital vascular lesions as different entities and proposes a separation of vascular lesions into those that can easily be treated from those where clearance is difficult. Different treatment modalities and the various endpoints of individual vascular lesions will be discussed.


Fecal microbiota changes associated with dehorning and castration stress primarily affects light-weight dairy calves.
Gastrointestinal tract (GIT) microbiota and stress can impact animal health. Studies have shown that perturbations in the GIT microbiota can influence host health and productivity by affecting physiological homeostasis, metabolism, hematopoiesis and inflammation. The present study aimed to evaluate possible effects of dehorning and castration stress on the GIT microbiota of dairy calves. Dehorning and castration are routinely performed on over 90% of dairy farms, and analgesics like flunixin meglumine (FLU) are given at the time of these procedures to reduce pain. We analyzed fecal microbiota of 24 weaned male dairy calves at two different stages in their life (at 10 weeks for dehorning and 36 weeks age for castration) to determine any GIT microbiota changes due to these stressful procedures and the FLU treatment. Dehorning was performed using an electrocautery dehorner applied to the horn for 10 seconds, and surgical castration was used as the castration method. Our analysis showed that the Shannon diversity index was significantly higher in animals that were not dehorned compared to dehorned animals. Castration stress also resulted in a significant decrease in Shannon diversity index, which was more pronounced in lower weight calves. Body weight and stress had significant effects on the taxonomic profiles of the GIT microbiota. There was a significant difference in the GIT bacterial community structure between heavy- and light-weight calves at Day 3 after castration but not at Day 0 (prior to castration). Our results indicate that dehorning and castration stress reduced microbial diversity of the GIT microbiota, but only in light-weight calves. This work is important for elucidating biological effects of stress on dairy calves and identifying potential modulation points in the microbiota of these food-producing animals to improve animal health and production.


[Bone marrow transplantation for a patient with ALL from her 75-year-old mother using cryopreserved bone marrow cells].
We report a 42-year-old woman with acute lymphoblastic leukemia who received allogeneic bone marrow transplantation (BMT) in the first remission from her 75-year-old, HLA-identical, MLC-non-reactive mother. Considering the difficulty to obtain a sufficient number of bone marrow cells from such an old donor, we harvested the cells (2.31 x 10(8)/kg) on day -37 and cryopreserved them until use. BMT was performed on June 3rd, 1993 after conditioning regimen with total body irradiation, high-dose AraC and cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxisis was attempted by cyclosporin A and short-term methtrexate. Her hematopoietic recovery was favorable with no signs and symptoms of GVHD as far as day 218.


Development of an in vitro 3D tumor model to study therapeutic efficiency of an anticancer drug.
The importance and advantages of three-dimensional (3D) cell cultures have been well-recognized. Tumor cells cultured in a 3D culture system as multicellular tumor spheroids (MTS) can bridge the gap between in vitro and in vivo anticancer drug evaluations. An in vitro 3D tumor model capable of providing close predictions of in vivo drug efficacy will enhance our understanding, design, and development of better drug delivery systems. Here, we developed an in vitro 3D tumor model by adapting the hydrogel template strategy to culture uniformly sized spheroids in a hydrogel scaffold containing microwells. The in vitro 3D tumor model was to closely simulate an in vivo solid tumor and its microenvironment for evaluation of anticancer drug delivery systems. MTS cultured in the hydrogel scaffold are used to examine the effect of culture conditions on the drug responses. Free MTS released from the scaffold are transferred to a microfluidic channel to simulate a dynamic in vivo microenvironment. The in vitro 3D tumor model that mimics biologically relevant parameters of in vivo microenvironments such as cell-cell and cell-ECM interactions, and a dynamic environment would be a valuable device to examine efficiency of anticancer drug and targeting specificity. These models have potential to provide in vivo correlated information to improve and optimize drug delivery systems for an effective chemotherapy.


[Sequence variation and protein structure of pipo gene in Potato virus Y].
The objectives of this study were to understand the sequence variation and the putative protein structure of pipo gene in the Potato virus Y (PVY) collected from Solanum tuberosum. The pipo gene in PVY was cloned using a pair of degenerate primers designed from its conserved region and its sequences were used to re-construct phylogenetic tree in Potyvirus genera by a Bayesian inference method. An expected fragment of 235 bp was amplified in all 20 samples by RT-PCR and the pipo genes in the 20 samples assayed shared more than 92% nucleotide sequence similarity with the published sequences of PVY strains. Among the 20 pipo gene sequences, 13 polymorphic sites were detected, including 4 parsimony informative sites and 9 singleton variable sites. These results indicate that PVY pipo gene is highly conserved but some sequence variations exist. Further analyses suggest that the pipo gene encodes a hydrophilic protein without signal peptide and transmembrane region. The protein has theoretical isoelectric points (pI) ranging from 11.26 to 11.62 and contains three highly conserved regions, especially between aa 10 and 59. The protein is likely located in the mitochondria and has a-helix secondary structure. Bayesian inference of phylogenetic trees reveals that PVY isolates are clustered in the same branch with high posterior probability, while Sunflower chlorotic mottle virus (SoCMoV) and Pepper severe mosaic virus (PepSMV) are closely related, consisting with the classification of Potyvirus genera using other approaches. Our analyses suggest that the pipo gene can be a new marker for phylogenetic analysis of the genera. The results reported in this paper provide useful insights in the genetic variation and the evolution of PVY and can stimulate further research on structure and function of the PIPO protein.


Sexual dimorphism in dentition mineralization.
This study determined for 121 boys and 111 girls of the serial experimental group of the Burlington Growth Centre the age, time interval and age sequence of 14 stages of mineralization of all tooth types. The two sexes differed significantly in the age at which the stages of tooth mineralization appeared, and in the length of the interstage intervals. In the canines, there was maximum sex difference in mineralization, which was almost 20 per cent and resulted from a delay in the boys. Changes in sequence of mineralization were due to delay rather than to acceleration. Sex differences in tooth mineralization manifested themselves before puberty, and mineralization was not accelerated at puberty. In contrast, post-pubertal mineralization of third molars appeared to be accelerated in both sexes and occurred earlier in the boys.


Primitive nervous systems: electrical activity in the nerve cords of the parasitic flatworm, Gyrocotyle fimbriata.
A large compound potential (LCP) could be evoked in the longitudinal nerve cords of Gyrocotyle fimbriata. This potential was graded and showed decremental conduction. Decrement was more pronounced in the posterior direction and was exponential with distance, dropping to 50% of its initial value in less than 5 mm. Conduction velocities in the anterior to posterior direction were greater than the reverse direction (means = 37.3 cm sec-1 vs. means = 30.3 cm sec-1). Single suprathreshold stimuli evoked long-lasting trains of spikes. Frequency of spiking varied linearly with stimulus intensity and averaged 0.7 spikes per volt stimulus. Mechanical stimulation of the acetabulum produced a short-lasting (10 sec) facilitatory effect to the second of a pair of electrical stimuli, whereas mechanical stimulation of the holdfast resulted in facilitation lasting several minutes.


Prevalence and Predictors of Intimate Partner Violence in a Military Urogynecology Clinic.
Intimate partner violence (IPV) is common, with prevalence in women of 15 to 71% over the lifespan, 4 to 54% currently. Violence is associated with poor health, and may be more common in military populations. A history of abuse is also common in patients with pain, urinary/bowel symptoms, and dyspareunia. Our purpose was to determine the prevalence and predictors of abuse in a military urogynecology clinic. Patients presenting to a military urogynecology clinic were screened for IPV with the 4-item Hurt-Insult-Threaten-Scream (HITS) screen. Patients' abuse history, reason for visit, and risk factors for IPV were assessed. χ2 and Fisher's exact tests were used for categorical variables. Out of 142 surveys, only 4 (2.8%) indicated a positive HITS screen (score of 10 or greater on a scale of 4-20), and 39 (27.5%) responded positively to at least one item. These individuals were significantly more likely to have a history of physical abuse or abuse in their families, with at least one positive response in 45.4% of patients with a history of family abuse compared to 20.8% of patients without this history (p = 0.007). The lifetime prevalence of physical abuse by an intimate partner was reported by 10 women (7%). A total of 29 women (20%) reported a history of forced sex and 33 (23%) reported a history of abuse in their family. Participants with a family history of abuse were more likely to have a positive HITS score, relative risk (RR) 2.19 (95% confidence interval [CI] 1.29-3.71), p = 0.004, as were those with history of physical abuse RR 2.44 (95% CI 1.35-4.39), p = 0.003 and a history of forced sexual contact, RR 1.73 (95% CI 1.00-3.00), p = 0.049. Race, education, marital status, and employment showed no association with a positive HITS response. The self-reported rate of IPV in a sample of women presenting to a urogynecology clinic in a military setting was 2.8%, below the rate reported in the civilian literature of 4 to 54%. We found that lifetime prevalence of IPV (7%) was also lower than the civilian rate of 15 to 71%. Routine screening for IPV is recommended by the American College of Obstetricians and Gynecologists, U.S. Preventative Services Task Force, and the Joint Commission. Even though IPV rates in the military are below civilian rates, IPV affects 3 to 7% of our population and remains a significant and preventable problem affecting women. IPV in military urogynecology patients was lower than the civilian setting; however, women with a history of abuse may be at increased risk of experiencing current IPV, and continued screening is important.


[Is patient education using audiovisual methods helpful?].
In a prospective randomized study we compared the effectiveness of preparatory information with and without a video film show about a planned heart catheterization. 65 patients were included, 5 were later excluded for medical reasons. One group (n = 34) received preparatory disclosure from a standard pamphlet and a personal interview; the other group additionally watched a 14 min video (n = 26). Only the latter group had a significant reduction of anxiety scores. Patients said they received better information from the film than from the pamphlet. Duration of the personal interview did not differ. Viewing the video may improve patient compliance.


Irisin and myostatin responses to acute high-intensity interval exercise in humans.
Background The purpose of this study was to investigate irisin and myostatin responses to acute high-intensity interval exercise. Materials and methods Ten male professional kick-boxers aged between 18 and 24 years and 10 sedentary males with similar age and body weight participated in the present study. Participants performed 4 × 30-s Wingate test separated with 4 min of rest. Blood samples were taken immediately before and after exercise, and 3 and 6 h of recovery. Results and conclusion At rest, irisin levels were higher in the kick-boxers (p < 0.05). Immediately after the exercise, irisin levels were decreased in both groups (p < 0.05). A trend toward a return to baseline appeared after 3 h of recovery in the kick-boxers (p < 0.05). At rest, myostatin concentrations were not different between the groups (p > 0.05). Immediately after the exercise, myostatin levels were increased in both groups (p < 0.05). A trend toward a return to baseline appeared after 3 h of recovery in the kick-boxers (p < 0.05). Acute high-intensity interval exercise decreased irisin levels and increased myostatin levels.


Context for layering women's nutrition interventions on a large scale poverty alleviation program: Evidence from three eastern Indian states.
Over 70 million women of reproductive age are undernourished in India. Most poverty alleviation programs have not been systematically evaluated to assess impact on women's empowerment and nutrition outcomes. National Rural Livelihoods Mission's poverty alleviation and livelihoods generation initiative is an opportune platform to layer women's nutrition interventions being tapped by project Swabhimaan in three eastern Indian states-Bihar, Chhattisgarh and Odisha. A cross-sectional baseline survey covering 8755 mothers of children under-two years of age, one of the three primary target groups of program are presented. Standardized questionnaire was administered and anthropometric measurements were undertaken from October 2016 to January 2017. 21 indicators on women's empowerment, Body Mass Index and Mid-upper Arm Circumference for nutrition status, food insecurity indicators as per the Food Insecurity Experience Scale and selected indicators for assessing women's access to basic health services were included. National Rural Livelihoods Mission operates in contexts with stark social and gender inequalities. Self-help group members exhibited better control on financial resources and participation in community activities than non-members. Using Body Mass Index, at least 45% mothers were undernourished irrespective of their enrolment in self-help groups. Higher proportion of self-help group members (77%-87%) belonged to food insecure households than non-members (66%-83%). Proportion of mothers reporting receipt of various components of antenatal care service package varied from over 90% for tetanus toxoid vaccination to less than 10% for height measurement. Current use of family planning methods was excruciatingly low (8.2%-32.4%) in all states but positively skewed towards self-help group members. Participation in monthly fixed day health camps was a concern in Bihar. Layering women's nutrition interventions as stipulated under Swabhimaan may yield better results for women's empowerment and nutrition status under National Rural Livelihoods Mission. While this opportunity exists in all three states, Bihar with a higher proportion of matured self-help groups offers more readiness for Swabhimaan implementation.


Generation of the "perfect" optical vortex using a liquid-crystal spatial light modulator.
We introduce the concept of the perfect optical vortex whose dark hollow radius does not depend on the topological charge. It is shown analytically and experimentally that such a vortex can be approximately generated in the Fourier transforming optical system with a computer-controlled liquid-crystal spatial light modulator.


Litter size reduction accentuates maternal care and alters behavioral and physiological phenotypes in rat adult offspring.
Maternal behavior has a substantial impact on the behavioral, endocrine, and neural development of the pups. This study investigated the effect of altering the neonatal nutritional environment by modifying the litter size on maternal care and anxiety- and fear-like behaviors in rats during adulthood. On postnatal day (PND) 2, litters were adjusted to a small litter (SL) size of three pups per dam or normal litter (NL) size of 12 pups per dam. Maternal behaviors were scored daily during lactation (PND2-21). The weight gain, food intake, adiposity, and biochemical landmarks of offspring rats were evaluated. On PND60, performances in the open field, elevated plus-maze (EPM), and fear conditioning test were measured. The reduction of the litter size enhanced maternal care in lactating rats, increasing the arched-back posture and licking pups. SL offspring exhibited accelerated weight gain, hyperphagia, increased visceral fat mass, dyslipidemia, and hyperleptinemia in adulthood. The SL offspring of both sexes showed an increase in the anti-thigmotactic effect in the open field, an intact anxious-phenotype in the EPM, and a decrease in the time spent freezing during the fear-conditioning test, compared to NL. The neonatal environment as determined by litter size plays a crucial role in programming the adult metabolic phenotype as well as behavioral responses to stressful stimuli, with an impact on anxiety-like and fear behaviors. These behavioral changes in offspring may be, at least in part, a result of increased maternal care.


Astragalus improve aging bone marrow mesenchymal stem cells (BMSCs) vitality and osteogenesis through VD-FGF23-Klotho axis.
To clarify the regulation of astragalus on the aging BMSCs model and the effect of astragalus on Vitamin D (VD)-FGF23-Klotho axis. siRNA was used to interfere the expression of VDR gene in aging BMSCs. Serum containing astragalus in different concentrations was added to the cultured cells. The expression of osteocalcin and alkaline phosphatase were detected by alizarin red staining and ELISA. Cell vitality was detected by flow cytometry, CCK-8 test, and β-galactosidase staining. The expression of FGF23, Klotho, CYP27B1, and CYP24A1 was detected by qRT-PCR and western blot. The results showed that after reducing VDR gene expression, the aging BMSCs model showed decreased activity and osteogenic ability, increased expression of FGF23, Klotho and CYP24A1, and decreased expression of CYP27B1. After adding serum-containing astragalus, the activity of cells and the osteogenic ability was increased; the expression levels of FGF23, Klotho and CYP24A1 were decreased, the expression levels of CYP27B1 were increased, and the trend was more obvious with the increase of astragalus concentration. This study confirmed that astragalus could inhibit the aging of BMSCs and improve the osteogenesis ability by regulating the VD-FGF23-Klotho pathway. This study provided a certain research basis for the therapeutic of traditional Chinese medicine (TCM) on primary osteoporosis.


Developmental output failure: a study of low productivity in school-aged children.
Children with low academic productivity in late elementary and junior high school present a vexing problem to parents and schools. A subgroup of these youngsters may have underlying subtle handicaps that result in reduced productivity and chronic underachievement. Such children may be clinically characterized as exhibiting "developmental output failure." Using parent and teacher questionnaires, educational achievement tests, and pediatric neurodevelopmental assessments, a group of 26 children was selected according to predetermined criteria from among the clinic population seen in The School Function Program at The Children's Hospital Medical Center. Common findings among the group included problems with expressive language, fine motor tasks, finger agnosia, attention, and retrieval memory. It is suggested that clinicians be aware of the possibility that a child in this age group with low academic work output may have underlying developmental dysfunctions, whose manifestations may not have been evident earlier in life.


A direct PCA-based approach for real-time description of physiological organ deformations.
Dynamic magnetic resonance (MR)-imaging can provide functional and positional information in real-time, which can be conveniently used online to control a cancer therapy, e.g., using high intensity focused ultrasound or radio therapy. However, a precise real-time correction for motion is fundamental in abdominal organs to ensure an optimal treatment dose associated with a limited toxicity in nearby organs at risk. This paper proposes a real-time direct principal component analysis (PCA)-based technique which offers a robust approach for motion estimation of abdominal organs and allows correcting motion related artifacts. The PCA was used to detect spatio-temporal coherences of the periodic organ motion in a learning step. During the interventional procedure, physiological contributions were characterized quantitatively using a small set of parameters. A coarse-to-fine resolution scheme is proposed to improve the stability of the algorithm and afford a predictable constant latency of 80 ms. The technique was evaluated on 12 free-breathing volunteers and provided an improved real-time description of motion related to both breathing and cardiac cycles. A reduced learning step of 10 s was sufficient without any need for patient-specific control parameters, rendering the method suitable for clinical use.


Statin use and mortality in COVID-19 patients: Updated systematic review and meta-analysis.
Statin therapy is administered to patients with high cardiovascular risk. These patients are also at risk for severe course of coronavirus disease 2019 (COVID-19). Statins exhibit not only cardioprotective but also immunomodulatory and anti-inflammatory effects. This study performed a systematic review of published evidence regarding statin treatment and COVID-19 related mortality. A systematic PubMed/Embase search was performed from February 10, 2020 until March 05, 2021 for studies in COVID-19 patients that reported adjusted hazard or odds ratio for death in statin users versus non-users. 22 studies fulfilled the inclusion criteria and were included in the systematic review. Meta-analysis of 10 studies (n = 41,807, weighted age 56 ± 8 years, men 51%, hypertension 34%, diabetes 21%, statin users 14%) that reported adjusted hazard ratios for mortality in statin users versus non-users showed pooled estimate at 0.65 (95% confidence intervals [CI] 0.53, 0.81). Meta-analysis of 6 studies that reported continuation of statin therapy during hospitalization (58-100% of patients) revealed a pooled hazard ratio of 0.54 (95% CI 0.47, 0.62). Meta-analysis of 12 studies (n = 72,881, weighted age 65 ± 2 years, men 54%, hypertension 66%, diabetes 43%, statin users 30%) that reported adjusted odds ratios for mortality showed pooled estimate at 0.65 (95% CI 0.55, 0.78). Multivariable meta-regression analysis did not reveal any significant association of hazard or odds ratios with anthropometric characteristics or comorbidities. This meta-analysis of retrospective observational studies showed that statin therapy was associated with an about 35% decrease in the adjusted risk of mortality in hospitalized COVID-19 patients.


Trisomy of the short stature homeobox-containing gene (SHOX), resulting from a duplication-deletion of the X chromosome.
The Turner syndrome (TS) is a complex disorder associated with almost invariant short stature and gonadal dysgenesis, as well as a variety of other major organ malformations. Recently, a homeobox-containing gene entitled short-stature homeobox-containing gene (SHOX), was isolated from a minimal short stature gene interval from the pseudoautosomal region of Xp (and Yp). Together with the demonstrable escape of SHOX from X-inactivation, this suggested SHOX to be a strong candidate gene for the short stature component of TS, and as SHOX haploinsufficiency appears to be the molecular basis of a mesomelic short statured skeletal dysplasia (Leri-Weill syndrome), this suggested that SHOX protein expression levels may confer a dosage effect on human stature. However, in this communication we report a normal statured female with gonadal dysgenesis, due to the inheritance of a recombinant duplication-deletion X-chromosome. The karyotype of the proband was 46,X,rec(X)dup(Xp)inv(X)(p11.22q21.2)mat and fluorescent in situ hybridization of her metaphases with a SHOX cosmid confirmed the proband to be trisomic for SHOX. This communication suggests the relationship between levels of SHOX expression and human stature to be more complex than envisaged previously. The presence of normal stature in our patient rather than tall stature is likely to represent the natural variation seen in patients with transcription factor disorders.


Intrinsic sites of transcription termination and pausing in the c-myc gene.
We have studied transcription elongation and termination in the human c-myc gene. Transcription of c-myc gene sequences with purified mammalian RNA polymerase II revealed several sites of transcription termination and pausing in the vicinity of the exon 1-intron 1 junction. This region previously has been shown to block transcription elongation in vivo by nuclear run-on analysis (D. Bentley and M. Groudine, Nature [London] 321:702-706, 1986). These sites were recognized by purified RNA polymerase II, and we therefore designated them intrinsic sites of termination and pausing. Two of these sites cause termination of RNA polymerase III transcription as well. RNA polymerase II terminated transcription in a cluster of seven consecutive T residues in the nontranscribed strand and paused during transcription at three additional sites in this region. The intrinsic sites of transcription termination and pausing described here correspond closely to the 3' ends of transcripts synthesized in Xenopus oocytes injected with plasmids containing the c-myc termination region (D. Bentley and M. Groudine, Cell 53:245-256, 1988). This correspondence suggests that the intrinsic recognition of these termination and pause sites by purified RNA polymerase II may play a role in the transcription elongation block observed in vivo.


[Adjuvant radiotherapy of the neck lymph modes in patients after partial laryngectomies].
Adjuvant radiotherapy after partial laryngectomy is still controversial mainly due to high level morbidities which may occur in the irradiated larynx. The aim of this study was to evaluate the results (locoregional control) and toxicities (acute and late) of combined treatment. Between 1996 and 2001 the group of 14 patients (12 men, 2 women), aged less than 60 years, Karnofsky scale > 70, were investigated retrospectively. The following surgical procedures were carried out: cricohyoidopexy (CHP) and cricohyoidoepiglottopexy (CHEP) in 9 out of 14 patients, horizontal laryngectomy in 1 patient, fronto-lateral laryngectomy in 4 patients. In all cases diagnosis of squamous cell carcinoma was confirmed. According to pathological classification the stage of disease in the neck was as follows: N1 = 8 patients and N2 = 6 patients. Indications for adjuvant radiotherapy were a high risk of microscopic spread of disease and expectation of regular follow-up problems in treated patients. The main rule of radiotherapy technique was avoiding the irradiation of the preserved larynx. All patients were irradiated postoperatively in conventional way to the elective dose of 50 Gy to the neck with additional dose of 16 Gy to the area of high risk of local recurrence. During follow-up no patients had locoregional failure. The toxicities (early and late) concerned the skin and mucosa of pharynx. These toxicities, evaluated according to the RTOG scale, in all cases were less than III grade. We conclude that combination of partial laryngectomy and postoperative radiotherapy with protection of the larynx during irradiation in the group of patients with high risk of regional recurrence plays an important role in decrease of treatment failures and permits preservation of laryngeal function without any significant side effects. Therefore the described method is an effective treatment for selected patients with the carcinoma of the larynx.


Repositioning Chromones for Early Anti-inflammatory Treatment of COVID-19.
The COVID-19 pandemic is posing an unprecedented sanitary threat. In the absence of specific vaccines and anti-SARS-CoV-2 drugs, medicines that may assist in tackling the emergency and limiting the high number of fatalities are urgently needed. The repositioning of available drugs to treat COVID-19 is the only and rapid option in the face of the lack of direct antiviral agents and vaccines available. In this light it is important to focus on available drugs, which, based on their pharmacodynamics, could plausibly attenuate viral growth as well as COVID-19's worst complications. This is the case of chloroquine and tocilizumab which seem to limit virus replication and the severity of interstitial pneumonia, respectively. However, these treatments, particularly those aimed at containing inflammation, are still reserved for the most severe cases. This commentary elaborates on the pharmacological rationale of repositioning the mast cell stabilizer chromones as an adjunctive treatment for SARS-CoV-2 infection, and proposes their practical clinical testing as an early, safe, and cost-effective anti-inflammatory intervention in COVID-19 to limit the eventual secondary progression toward life-threatening respiratory complications.


Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes.
Multipotent mesenchymal stem cells (MSCs) are promising candidates for regenerative cell-based therapy. The mechanisms underlying MSC differentiation and other functions relevant to therapeutic avenues remain however a matter of debate. Recent reports imply a critical role for intercellular contacts in MSC differentiation. We studied MSC differentiation to vascular smooth muscle cells (VSMCs) in a coculture model using human primary MSCs and VSMCs. We observed that under these conditions, MSCs did not undergo the expected differentiation process. Instead, they revealed an increased proliferation rate. The upregulated MSC proliferation was initiated by direct contacts of MSCs with VSMCs; indirect coculture of both cell types in transwells was ineffective. Intercellular contacts affected cell growth in a unidirectional fashion, since VSMC proliferation was not changed. We observed formation of so-called tunneling nanotubes (TNTs) between MSCs and VSMCs that revealed an intercellular exchange of a fluorescent cell tracker dye. Disruption of TNTs using cytochalasin D or latrunculin B abolished increased proliferation of MSCs initiated by contacts with VSMCs. Using specific fluorescent markers, we identified exchange of mitochondria via TNTs. By generation of VSMCs with mitochondrial dysfunction, we show that mitochondrial transfer from VSMCs to MSCs was required to regulate MSC proliferation in coculture. Our data suggest that MSC interaction with other cell types does not necessarily result in the differentiation process, but rather may initiate a proliferative response. They further point to complex machinery of intercellular communications at the place of vascular injury and to an unrecognized role of mitochondria in these processes.


Molecular Tracking and Remote Sensing to Evaluate New Chemical Treatments Against the Maize Late Wilt Disease Causal Agent, Magnaporthiopsis maydis.
Late wilt is a destructive disease of corn: outbreaks occur at the advanced growth stage and lead to severe dehydration of susceptible hybrids. The disease's causal agent is the fungus Magnaporthiopsis maydis, whose spread relies on infested soils, seeds, and several alternative hosts. The current study aimed at advancing our understanding of the nature of this plant disease and revealing new ways to monitor and control it. Two field experiments were conducted in a heavily infested area in northern Israel seeded with highly sensitive corn hybrid. The first experiment aimed at inspecting the Azoxystrobin (AS) fungicide applied by spraying during and after the land tillage. Unexpectedly, the disease symptoms in this field were minor and yields were high. Nevertheless, up to 100% presence of the pathogen within the plant's tissues was measured using the quantitative real-time PCR method. The highest AS concentration tested was the most effective treatment, and resulted in a 6% increase in cob yield and a 4% increase in A-class yield. In the second experiment conducted in the following summer of the same year in a nearby field, the disease outbreak was dramatically higher, with about 350 times higher levels of the pathogen DNA in the untreated plots' plants. In this field, fungicide mixtures were applied using a dripline assigned for two coupling rows. The most successful treatment was AS and the Difenoconazole mixture, in which the number of infected plants decreased by 79%, and a 116% increase in crop yield was observed, along with a 41% increase in crop quality. Evaluation of the effectiveness of the treatments on the plants' health using a remote, thermal infra-red sensitive camera supported the results and proved to be an essential research tool.


Qubit Condensation for Assessing Efficacy of Molecular Simulation on Quantum Computers.
Quantum computers may demonstrate significant advantages over classical devices, as they are able to exploit a purely quantum-mechanical phenomenon known as entanglement in which a single quantum state simultaneously populates two-or-more classical configurations. However, due to environmental noise and device errors, elaborate quantum entanglement can be difficult to prepare on modern quantum computers. In this paper, we introduce a metric based on the condensation of qubits to assess the ability of a quantum device to simulate many-electron systems. Qubit condensation occurs when the qubits on a quantum computer condense into a single, highly correlated particle-hole state. While conventional metrics like gate errors and quantum volume do not directly target entanglement, the qubit-condensation metric measures the quantum computer's ability to generate an entangled state that achieves nonclassical long-range order across the device. To demonstrate, we prepare qubit condensations on various quantum devices and probe the degree to which qubit condensation is realized via postmeasurement analysis. We show that the predicted ranking of the quantum devices is consistent with the errors obtained from molecular simulations of H2 using a contracted quantum eigensolver.


Different phenotypes in human prostate cancer: alpha6 or alpha3 integrin in cell-extracellular adhesion sites.
The distribution of alpha6/alpha3 integrin in adhesion complexes at the basal membrane in human normal and cancer prostate glands was analyzed in 135 biopsies from 61 patients. The levels of the polarized alpha6/alpha3 integrin expression at the basal membrane of prostate tumor glands were determined by quantitative immunohistochemistry. The alpha6/alpha3 integrin expression was compared with Gleason sum score, pathological stage, and preoperative serum prostate-specific antigen (PSA). The associations were assessed by statistical methods. Eighty percent of the tumors expressed the alpha6 or alpha3 integrin and 20% was integrin-negative. Gleason sum score, but not serum PSA, was associated with the integrin expression. Low Gleason sum score correlated with increased integrin expression, high Gleason sum score with low and negative integrin expression. Three prostate tumor phenotypes were distinguished based on differential integrin expression. Type I coexpressed both alpha6 and alpha3 subunits, type II exclusively expressed alpha6 integrin, and type III expressed alpha3 integrin only. Fifteen cases were further examined for the codistribution of vinculin, paxillin, and CD 151 on frozen serial sections using confocal laser scanning microscopy. The alpha6/alpha3 integrins, CD151, paxillin, and vinculin were present within normal glands. In prostate carcinoma, alpha6 integrin was colocalized with CD 151, but not with vinculin or paxillin. In tumor phenotype I, the alpha6 subunit did not colocalize with the alpha subunit indicating the existence of two different adhesion complexes. Human prostate tumors display on their cell surface the alpha6beta1 and/or alpha3beta1 integrins. Three tumor phenotypes associated with two different adhesion complexes were identified, suggesting a reorganization of cell adhesion structures in prostate cancer.


Nutritional status and patterns of anemia in sudanese adult patients with active pulmonary tuberculosis: A cross-sectional study.
Malnutrition increases the risk of developing tuberculosis (TB) and causes reactivation of latent pulmonary TB. On the other hand, TB is a recognized cause of malnutrition. Evaluation of the nutritional status and anemia of tuberculous patients with active disease is an important step toward TB management. The objectives of the study were to determine the nutritional status and patterns of anemia in adult patients with active pulmonary TB. A. cross-sectional hospital-based study was performed on newly diagnosed patients with sputum-positive pulmonary TB. The nutritional status, total percentage of body fat (BF%), anemia, and general health of each patient were assessed with measurements of the body mass index (BMI), skin fold thickness, complete blood counts, and biochemical tests. Patients' ages ranged from 16- to 74-year old, with the majority between 20- and 40-year old. Male: female ratio was 2:1. The majority of males and females (91.2% and 84.5%, respectively) had low BF%. Underweight (BMI < 18.5) was 62%, whereas overweight (BMI ≥25.0) was 4%. BMI showed a significant decline with chronicity of the illness (P < 0.001). Eighty participants showed anemia, 90% microcytic hypochromic, and 10% normocytic normochromic. Serum albumin was low in 21%, with no relation to renal disease and insignificant association with proteinuria. Patients with active pulmonary TB are likely to have microcytic hypochromic anemia, low BF%, and low BMI, especially with a long duration of the disease.


Vascular endothelial growth factor suppresses dendritic cells function of human prostate cancer.
Prostate cancer (PCa) patients often have dendritic cell (DC) function defects, but the mechanism is not clear. The aim of this study was to detect the effect of vascular endothelial growth factor (VEGF) in mature DCs. In this study, we chose 30 PCa patients, 10 prostatic intraepithelial neoplasia (PIN) patients and 30 benign prostatic hyperplasia (BPH) patients, and compared the composition of peripheral blood T cells, the composition and function of local dendritic cells in prostate tissue, and the density of local VEGF. The results showed that the numbers of total DCs, mature and functional DCs, and CD4+ T cells were inhibited in PCa, and the inhibitory effect was enhanced with increased malignancy. In addition, the infiltration density of VEGF-positive cells was increased in PCa, and this increase was associated with an increased malignant degree of PCa. The inhibition of tumor immunity in patients with PCa is achieved by inhibiting the function of dendritic cells. VEGF plays an important role in the inhibition of the maturation and function of dendritic cells, and this inhibition is gradually increased with an increasing malignant degree of PCa.


[Adverse events of ABL tyrosine kinase inhibitors in chronic myeloid leukemia therapy].
Fatal events during treatment with ABL tyrosine kinase inhibitors (ABL TKIs) have been reported, and there have been concerns of high mortality rate in patients with chronic myeloid leukemia receiving ABL TKIs. The predictive factors of patients treated with ABL TKIs who are at risk of potentially fatal toxicities remain unknown. Although this scenario appears discouraging, the risk of severe toxicity might be predicted by investigating the effect of genetic variation on the disposition of ABL TKIs. Global genomic surveys should be conducted to identify factors contributing to an increased risk of toxicity using multivariable analyses with particular reference to ABL TKIs pharmacokinetics and baseline clinical characteristics.


Structure of the Y. pseudotuberculosis adhesin InvasinE.
Enteropathogenic Yersinia expresses several invasins that are fundamental virulence factors required for adherence and colonization of tissues in the host. Within the invasin-family of Yersinia adhesins, to date only Invasin has been extensively studied at both structural and functional levels. In this work, we structurally characterize the recently identified inverse autotransporter InvasinE from Yersinia pseudotuberculosis (formerly InvasinD from Yersinia pseudotuberculosis strain IP31758) that belongs to the invasin-family of proteins. The sequence of the C-terminal adhesion domain of InvasinE differs significantly from that of other members of the Yersinia invasin-family and its detailed cellular and molecular function remains elusive. In this work, we present the 1.7 Å crystal structure of the adhesion domain of InvasinE along with two Immunoglobulin-like domains. The structure reveals a rod shaped architecture, confirmed by small angle X-ray scattering in solution. The adhesion domain exhibits strong structural similarities to the C-type lectin-like domain of Yersinia pseudotuberculosis Invasin and enteropathogenic/enterohemorrhagic E. coli Intimin. However, despite the overall structural similarity, the C-type lectin-like domain in InvasinE lacks motifs required for Ca2+ /carbohydrate binding as well as sequence or structural features critical for Tir binding in Intimin and β1 -integrin binding in Invasin, suggesting that InvasinE targets a distinct, yet unidentified molecule on the host-cell surface. Although the biological role and target molecule of InvasinE remain to be elucidated, our structural data provide novel insights into the architecture of invasin-family proteins and a platform for further studies towards unraveling the function of InvasinE in the context of infection and host colonization.


Long-term follow-up of lichen planus.
Several large series of patients with lichen planus were reported some 30 years ago but no recent large surveys have been published. In this study, detailed enquiry was made into the natural history of the disease in 214 patients followed up 8 to 12 years after presentation to the Dermatology Department. The key findings from this study showed that the mean age of onset of lichen planus in males was significantly lower than in females (40.3 years in males compared with 46.4 years in females, p less than 0.05). The main eruption of lichen planus cleared within one year in 68% of the patients but we found a higher recurrence rate than in previous series at 49%. Many patients suffered from persistent brown staining many years after the rash had cleared.


Cigarette sales to African-American and white minors in low-income areas of Baltimore.
This study documented illegal sales of cigarettes to minors in low-income African-American and White urban areas in East Baltimore. Six youths, aged 14 through 16 years, were sent to a random sample of 83 corner stores to attempt to purchase cigarettes. The youths provided the investigators with data on merchant, store, and purchase characteristics. The youths successfully purchased cigarettes in 85.5% of the stores; 58% of the stores displayed five or more cigarette advertisements outside their premises. Cigarette sales to minors and associated advertising remain prevalent in this urban community.


Occurrence of iron deficiency in growing cattle.
Occurrence of iron (Fe) deficiency anaemia was investigated in 33 farms in 443 veal calves (group VC; 83% males and 17% females) fed whole, defatted or butter milk or milk powder without or with supplements and in 72 age- and weight-matched bull calves (group BC) fed roughage, concentrates with mineral and vitamin supplements. In group VC plasma Fe concentration was much more frequently decreased and total iron binding capacity was much more frequently increased than in group BC. In group VC haemoglobin concentration (Hb), packed cell volume (PCV) and red blood cell number (RBC) in 18, 23 and 3%, respectively, of calves were below--2SD of the mean of reference values (Hb: 105 +/- 14 g/l, PCV: 0.28 +/- 0.04 l/l, RBC: 8.2 +/- 1.0 T/l [means +/- 2 SD]), shown in another study to remain stable throughout the growth period when veal calves were fed 52 mg Fe/kg milk replacer. In contrast, in calves of group RC only 3% of Hb values, 3% of PCV and 1% of RBC were below reference values. Fe deficiency anaemia is therefore a rather frequent problem in veal calves, but not in young bulls, fed roughage, concentrates and mineral/vitamin supplements.


Ca(2+) channels and transmitter release at the active zone.
Ca(2+)-dependent transmitter release is the most important signaling mechanism for fast information transfer between neurons. Transmitter release takes places at highly specialized active zones with sub-micrometer dimension, which contain the molecular machinery for vesicle docking and -fusion, as well as a high density of voltage-gated Ca(2+) channels. In the absence of direct evidence for the ultrastructural localization of Ca(2+) channels at CNS synapses, important insights into Ca(2+) channel-vesicle coupling has come from functional experiments relating presynaptic Ca(2+) current and transmitter release, at large and accessible synapses like the calyx of Held. First, high slope values in log-log plots of transmitter release versus presynaptic Ca(2+) current indicate that multiple Ca(2+) channels are involved in release control of a single vesicle. Second, release kinetics in response to step-like depolarizations revealed fast- and slowly releasable sub-pools of vesicles, FRP and SRP, which, according to the "positional" model, are distinguished by a differential proximity to Ca(2+) channels. Considering recent evidence for a rapid conversion of SRP- to FRP vesicles, however, we highlight that multivesicular release events and clearance of vesicle membrane from the active zone must be taken into account when interpreting kinetic release data. We conclude that the careful kinetic analysis of transmitter release at presynaptically accessible and molecularly targeted synapses has the potential to yield important insights into the molecular physiology of transmitter release.


In situ based surface-enhanced Raman spectroscopy (SERS) for the fast and reproducible identification of PHB producers in cyanobacterial cultures.
The production of polyhydroxybutyrate (PHB) by autotrophic fermentation of cyanobacteria has received increasing interest in the light of carbon emission reducing process strategies. Biotechnological approaches are in development to optimize the yield of PHB, including adapted cultivation media, characterized by a limitation of key nutrients: cyanobacteria accumulate PHB as energy storage molecules under limited growth conditions. Since there is an increasing demand for fast, simple and reliable analytics, we report the establishment of surface enhanced Raman spectroscopy (SERS) as a suitable monitoring tool for up scaled PHB production processes. Both, pure Ag-colloids mixed with bacterial culture, and in situ prepared colloids (Ag-Synechocystis), generated on the cell surface directly, were successfully applied and evaluated for this purpose. SERS measurements with in situ prepared Ag-colloids improved the reproducibility of Raman signals from 54.8% to 93.9%. The measurement time could be reduced significantly, completing our secondary goal. The quality of classically and in situ prepared Ag-colloids was monitored by zeta potential measurements and scanning electron microscopy (SEM) respectively. For data interpretation and statistical model-building an in house written code in the open source software RStudio was implemented. It was applied for the differentiation of PHB producers at the cellular level, revealing heterogeneities within sample groups regarding the PHB amount accumulated. The results obtained using the statistical model were validated as well and were complementary to the reference HPLC analysis. Therefore, a fast and reliable identification in situ SERS tool for the selection of the most promising cyanobacterial PHB production was established.


Associations between Alzheimer's disease and blood homocysteine, vitamin B12, and folate: a case-control study.
There is a growing focus on nutritional therapy for Alzheimer's disease (AD), and controversy exists regarding the association between AD and homocysteine (Hcy), vitamin B12, and folate levels. The present study evaluated the association between AD and the combined levels of Hcy, vitamin B12, and folate. This case-control study consisted of 115 patients with AD and 115 matched controls. Serum folate and vitamin B12 were measured using an automated immunoassay analyzer. Plasma Hcy was measured using high-performance liquid chromatography. The association between AD and Hcy, vitamin B12, and folate was analyzed using binary logistic regression, adjusted for age and sex. With the combination of normal blood Hcy, vitamin B12, and folate levels as the reference category, low vitamin B12 in subjects with normal Hcy and folate was associated with AD (adjusted odds ratio [OR], 4.6; 95% confidence interval [CI]: 1.6-13.2). The combination of low vitamin B12 and folate in subjects with normal Hcy was associated with AD (adjusted OR, 4.3; 95% CI: 1.3-14.6). The combination of high Hcy and low folate levels in patients with normal vitamin B12 was associated with AD (adjusted OR, 17.0; 95% CI: 5.4- 53.4). The combination of high Hcy, low vitamin B12, and any folate level was associated with AD (adjusted OR, 30.5; 95% CI: 9.7-95.9). Vitamin B12 was directly associated with AD. The combination of high Hcy, low vitamin B12, and any folate level represented the poorest association with AD.


YAP suppresses human T-cell leukemia virus type 1 transcription.
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 encodes Tax protein that activates transcription from viral long terminal repeats (LTR). Multiple cofactors are involved in the regulation of HTLV-1 transcription via association with Tax. Yes-associated protein (YAP), which is the key effector of Hippo pathway, is elevated and activated in ATL cells. In this study, we reported that YAP protein suppressed Tax activation of HTLV-1 5' LTR but not 3' LTR. The activation of the 5' LTR by Tax was potentiated when YAP was depleted. Moreover, overexpression of YAP repressed HTLV-1 plus-strand viral gene expression and virion production, whereas compromising YAP by RNA inference augmented the expression of HTLV-1 protein. As mechanisms of YAP-mediated viral transcription inhibition, we found that YAP interacted with Tax, and prevented the association between Tax and p300. It finally led to the inhibition of recruitment of Tax to the Tax-responsive element in the 5' LTR of HTLV-1. Taken together, our results demonstrate the negative regulatory function of YAP in Tax activation of HTLV-1 transcription. It may achieve sufficient transcriptional repression to maintain persistent infection and long-term latency of HTLV-1 in the host cells.


Clearance in small ciliated airways in allergic asthmatics after bronchial allergen provocation.
Asthma tends to affect mucociliary clearance, as assessed from measurements in large airways. However, there is no knowledge about clearance in the smallest airways of the tracheobronchial region in acute exacerbation of asthma. The aim of the study was to investigate clearance from the bronchiolar region in patients with allergic asthma in a situation resembling a mild acute exacerbation of the disease. We also aimed to compare clearance data with corresponding data found for healthy subjects and asthmatics on therapy. Tracheobronchial clearance was studied twice in 9 patients with mild asthma of the allergic type after inhalation of 6 microm (aerodynamic diameter) monodisperse Teflon particles labelled with 111In. At one exposure, inhalation was performed 4 h after bronchial provocation with an allergen the patients were allergic to. The second exposure was a control measurement. The particles were inhaled at an extremely slow flow, 0.05 liter/s, which gives deposition mainly in the small ciliated airways (bronchioles). Lung retention was measured at 0, 24, 48 and 72 h. All patients demonstrated an early asthmatic reaction of varying degree after bronchial provocation. There was significant clearance of radioaerosol in each 24-hour period for both exposures, with the possible exception of the period between 24 and 48 h for the provocation exposure, with similar fractions of retained particles at all points of time. The retained fractions were significantly larger compared to a group of healthy subjects and asthmatics on regular treatment with anti-inflammatory drugs. Our results indicate that in allergic asthmatics a bronchial allergen provocation with an early asthmatic reaction does not significantly influence overall clearance from the bronchiolar region. However, in the present group of patients, retention in small ciliated airways was significantly higher compared to healthy subjects and asthmatics on regular treatment.


Oxygen uptake measurements during competitive marathon running.
Oxygen uptakes and running speeds of two marathon runners as well as average slopes of the running terrain were measured approximately every 3 miles of a competitive marathon. The runners had energy expenditures requiring from 68 to 100% of their Vo2 max, confirming previous estimates. As the race progressed, both runners exhibited decreases in V92 while running at similar rates and slopes. At 23.4 miles, one runner was found to be utilizing 4.54 l/min, a value equivalent to his Vo2 max.


Analysis of Heterogeneous Gelation Dynamics and Their Application to Blood Coagulation.
We present a scaling model based on a moving boundary picture to describe heterogeneous gelation dynamics. The dynamics of gelation induced by different gelation mechanisms is expressed by the scaled equation for the time taken for development of the gel layer with a few kinetic coefficients characterizing the system. The physical meaning obtained by the analysis for a simple boundary condition from the standpoint of the phase transition shows that the time development of the gelation layer depends on whether the dynamics of the order parameter expressing the gelation of the polymer solution is fast or slow compared with the diffusion of the gelators in the heterogeneous gelation. The analytical method is used to understand the coagulation of blood from various animals. An experiment using systems with plasma coagulation occurring at interfaces with calcium chloride solution and with packed erythrocytes is performed to provide the data for model fitting and it is clarified that a few key kinetic coefficients in plasma coagulation can be estimated from the analysis of gelation dynamics.