Hepatitis B virus mutation pattern rtA181S+T184I+M204I may contribute to multidrug resistance in clinical practice: Analysis of a large cohort of Chinese patients.
The study aimed to characterize the prevalence and virological features of the rtA181S + T184I + M204I mutant in a large cohort of patients with chronic HBV infection. In total, 22,009 nucleoside/nucleotide analog-treated patients who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2016 were enrolled. Serum samples were collected for HBV reverse-transcriptase gene sequencing. Phenotypic analysis of the viral replication capacity and drug susceptibility was performed. The rtA181S mutation was detected in 0.82% (180/22,009) of samples. rtA181S-positive patients had significantly higher lamivudine (LAM), adefovir (ADV), and entecavir (ETV) exposure than rtA181S-negative patients. Of 180 rtA181S-positive patients, 42 had no coexistent resistance mutations, 34 had coexisting LAM-resistance mutation (LAMr), 17 had coexisting ADV-resistance mutation (ADVr), and 86 had coexisting ETV-resistance mutation (ETVr), and one had ADVr + ETVr. rtA181S + T184I + M204I occurred in 79.1% (68/86) of patients with rtA181S + ETVr and 37.8% (68/180) of all rtA181S-positive patients. Longitudinal analysis of the clinical course of resistant mutant evolution for four representative cases showed that rtA181S + T184I + M204I developed in all patients who had received LAM/telbivudine ± ADV and was receiving ETV or ADV + ETV. Compared with wild-type, the rtA181S + T184I + M204I mutant had 53.7% lower replication capacity and >1000-, 3.9-, and 383.3-fold greater LAM, ADV, and ETV resistance, respectively, but remained sensitive to tenofovir. Artificial elimination of rtA181S from the rtA181S + T184I + M204I mutant restored viral susceptibility to ADV but decreased viral replication capacity. Our study presented the first evidence that HBV rtA181S + T184I + M204I mutation had features of multidrug-resistance that contributed to resistance to both nucleoside and nucleotide analogs.


Response of the anaerobe Desulfovibrio vulgaris Hildenborough to oxidative conditions: proteome and transcript analysis.
The method of two-dimensional protein gel electrophoresis was used to evaluate the changes at the proteins level following oxygen exposure of the anaerobic sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough. Fifty-seven proteins showed significant differential expression. The cellular concentration of 35 proteins decreased while that of nineteen increased as a specific consequence of oxidative conditions. The proteins that were less abundant belonged to various functional categories such as nucleic acid and protein biosynthesis, detoxification mechanisms, or cell division. Interestingly, quantitative real-time PCR revealed that the genes encoding detoxification enzymes (rubrerythrins, superoxide reductase) are down regulated. The loss of viability of D. vulgaris Hildenborough under these oxidative conditions (Fournier et al., J. Biol. Chem. 279 (2004) 1785) can be directly related to the decrease in the cellular concentrations of these proteins, thereby specifying the toxicity of oxygen for the cells. Among the proteins that were more abundant under oxygen exposure, several thiol-specific peroxidases (thiol-peroxidase, BCP-like protein, and putative glutaredoxin) were identified. Using RT-PCR, the up-regulation of the genes encoding the thiol-peroxidase and the BCP was demonstrated. That is the first time that these proteins have been shown to be involved in the defense of D. vulgaris toward an oxidative stress. Several hypothetical proteins were also shown to be differentially expressed. A function in the defense mechanism against an oxidative stress is proposed for these uncharacterized proteins.


Comparison of Direct Counts and Conductometric Measurements on a Hematology Analyzer Abacus Junior 5 Vet Myelokaryocyte Content in the Red Bone Marrow of Mice.
We studied the possibility of conductometric measurement of myelokaryocyte content in the red bone marrow of mice using a hematological Abacus Junior 5 Vet analyzer (Diatron). Statistical, correlation, and regression analyses were performed to assess of the results of myelokaryocyte counting in the suspensions of mouse red bone marrow by a direct method in cytometers and by using Abacus Junior 5 Vet analyzer. It was shown that in both intact mice and animals with modelled red bone marrow hypoplasia, irrespectively of the state of hematopoiesis in representative samples, conductometric measurements of myelokaryocyte content on the Abacus analyzer with high confidence reproduced direct counting results (in different tests p=0.64-0.82, p=0.83-0.98). This indicates that myelokaryocyte counting on the Abacus Junior 5 Vet analyzer can be an acceptable alternative to counting chamber measurements in mouse samplings. However, the variability of single measurements with the Abacus Junior 5 Vet in red bone marrow suspensions is high (5%) and this has to be considered in small samples.


First report of glucose-6-phosphate dehydrogenase (G6PD) variants (Mahidol and Acores) from malaria-endemic regions of northeast India and their functional evaluations in-silico.
G6PD deficiency results from numerous mutations in the G6PD gene and can cause alterations in enzyme function up to varying degrees. P. vivax malaria infections require G6PD deficiency screening because of the potential risk of haemolysis by the gametocytocidal drug (primaquine) during the radical treatment. The present study investigated the incidence of G6PD deficiency from northeast India and further, molecular characterization was performed. During 2014-16, a total of 1,015 patients from four north-eastern states of India (Tripura, Mizoram, Meghalaya & Arunachal Pradesh), were screened for G6PD deficiency, using Beutler's fluorescence spot test (FST) and confirmed with SPAN G6PD kit. The deficient individuals (55/1015, 5.4%) were further characterized by PCR-RFLP and DNA sequencing except one case of lost to follow up. As observed by FST, the frequency of G6PD deficient males (42/538, 7.8%) were found to be higher than females (13/477, 2.73%), (p < 0.0001). Two non-synonymous mutations; G6PD-D (Mahidol)487A (48/54, 88.9%; 36 hemizygous males, 8 homozygous and 4 heterozygous females) and G6PD-D (Acores)595T (2/54, 3.7%) were identified. Remaining (4/54, 7.4%) individuals could not be characterized. Molecular modeling and dynamic simulations were performed for the G6PD wild-type (G6PD-WT) enzyme and its variants. The in-silico results demonstrated alterations in the secondary structures & crucial loss of ligand-protein interactions, which might result in reduced enzyme function, leading to enzyme deficiency. To the best of our knowledge, this is the first report to document G6PD-Mahidol and G6PD-Acores variants from malaria-endemic regions of northeast India, and provided molecular insights on the varied genetic makeup of the studied population.


A possible complementary role of actin microfilaments and microtubules in triacylglycerol secretion by isolated rat hepatocytes.
Incubation of isolated rat hepatocytes with phalloidin, cytochalasins (which, respectively, stabilize and destabilize actin microfilaments), or colchicine (which inhibits polymerization of microtubules), resulted in a dose-dependent inhibition of triacylglycerol secretion (an index of very low density lipoprotein secretion). Upon removal of drugs from incubation media, the inhibitory effect of cytochalasin D on triacylglycerol secretion was reversible, while such was not the case of phalloidin. When used at maximal concentrations, the combined presence of phalloidin + colchicine or cytochalasin D + colchicine had additive inhibitory effects upon hepatic triacylglycerol secretion, which was virtually blocked; this was not the case for phalloidin + cytochalasin D. These experiments support the concept that microfilaments and microtubules may have complementary functions for the hepatic secretion of very low density lipoproteins.


Current use of oral contraceptives and the risk of first-ever ischemic stroke: A meta-analysis of observational studies.
To evaluate the risk of first-ever ischemic stroke associated with current use of oral contraceptive pills (OCPs), and to describe how the risk was influenced by estrogen dose, progestin type, and study characteristics. We obtained relevant articles published between 1970 and March 2014 by conducting a search of Pubmed, Embase and the Cochrane Library. Two investigators independently identified eligible studies based on selection criteria in a two-step method. The quality of studies was assessed with the Newcastle-Ottawa scale. Pooled odds ratios were calculated with a random-effects meta-analysis model. A total of 18 independent studies (3 cohort studies and 15 case-control studies) were identified. The overall summary odds ratio for first-ever ischemic stroke risk associated with current OCP use compared with noncurrent OCP use was 2.47 [95% confidence interval (CI), 2.04-2.99]. The risk of ischemic stroke among current OCP users decreased significantly with decreasing estrogen dose: OCPs of ≥50μg ethinyl estradiol (EE), 30-40 ug EE, 20 ug EE and progestin only pills implied odds ratios of 3.28 (95%CI, 2.49-4.32), 1.75 (95%CI, 1.61-1.89), 1.56 (95%CI, 1.36-1.79), and 0.99 (95%CI, 0.71-1.37), respectively. All four generations of progestin were associated with an elevated risk of ischemic stroke, and the risk of ischemic stroke among users of the fourth-generation progestins seemed to be slightly lower than those of other generations of progestins. Data from observational studies suggest that current use of modern OCPs is associated with an increased risk of first-ever ischemic stroke. OCPs containing lower estrogen doses incline to contribute to a smaller elevated risk of ischemic stroke.


Primary therapy and survival among patients with nodular lymphocyte-predominant Hodgkin lymphoma: a population-based analysis in the Netherlands, 1993-2016.
In this nationwide, population-based study, we assessed trends in primary treatment and survival among 687 patients with nodular lymphocyte-predominant Hodgkin lymphoma (75% males; median age, 40 years; and 74% stage-I/II disease) diagnosed in the Netherlands between 1993-2016. There were no noteworthy changes in the application of primary therapy over time among adult patients across the different disease stages and age groups. Survival among various subgroups of adult patients was largely comparable to the expected survival of the general population. A particularly encouraging finding was that young adult patients experienced virtually no excess mortality, as compared to the general population.


Interactions of diuretics with the renal kallikrein-kinin and prostaglandin systems.
The renal kallikrein-kinin system may participate in the diuretic, natriuretic and antihypertensive effect of diuretics. This possibility was investigated by studying the influence of hydrochlorothiazide on blood pressure and urinary kallikrein excretion in patients with essential hypertension. Furthermore, the effect of kallikrein-blockade and prostaglandin-synthesis inhibition on the acute furosemide-induced changes of diuresis, natriuresis, GFR and renal plasma flow were studied in normotensive subjects. Thiazide treatment normalized the reduced kallikrein excretion of the hypertensive patients. The fall in mean arterial blood pressure was significantly correlated with the increase in urinary kallikrein excretion. In the normotensive subjects aprotinin-induced kallikrein inhibition failed to alter the acute response to furosemide, whereas indomethacin attenuated the diuretic and natriuretic effect of furosemide. The combination of indomethacin and aprotinin had a greater suppressive effect on plasma renin activity than indomethacin alone, suggesting a participation of kallikrein in renin release. An increase in the activity of the renal kallikrein-kinin system may contribute to the long-term antihypertensive effect of thiazide diuretics but it does not seem to be involved in the acute renal responses to furosemide.


Multiple myeloma hinders erythropoiesis and causes anaemia owing to high levels of CCL3 in the bone marrow microenvironment.
Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.


Glycolytic enzyme expression in human granulosa cells.
To examine the differences in specific protein expression between mural and cumulus granulosa cells following 24-hour in vitro culture. Laboratory study. University Hospital. Human granulosa cells were collected at the time of egg collection during assisted reproduction. Cumulus cells associated with the oocyte were separated from mural cells from the periphery of the follicle before in vitro culture for 24 hours. Cells were then lysed and subjected to two-dimensional gel electrophoresis. Given that cumulus (cGC) and mural granulosa cells (mGC) differentiate from a single layer, it is likely that phenotypic differences between them may reflect specific molecular processes and structural adaptations. Computer-assisted analysis using dedicated software enabled the presence, absence, or relative volume of each individual protein spot to be estimated. Differentially expressed spots were identified using tandem mass spectrometry. The mean number of separate protein spots detected in mGC gels was 1,105 +/- 146, and in cGC it was 887 +/- 236, although there was no statistically significant difference between the two. Five enzymes of the glycolytic pathway were never expressed in cGC after 24 hours in vitro; these were triose-phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase 1, and two isoforms of alpha enolase. These are the first data collected in humans consistent with a recent demonstration that isolated murine cGC cultured in vitro exhibit decreased expression of mRNA encoding glycolytic enzymes, and support the suggestion that some factor or factors secreted by the oocyte may be responsible for the maintenance of glycolysis in the adjacent cGC.


Effect of excess iodine supplement on serum total proteins, electrophoretic patterns and body weight of Fayoumi chickens.
Total proteins and their major fractions were determined in the serum of 135 males and females of Fayoumi chickens, 65 were used as controls and 70 were treated with excess iodine in the form of KI. Serum proteins increased significantly with the increase in age till the 90th day in normals, then decreased gradually. Excess iodine supplement decreased body weight, serum total proteins, alpha2- and beta-globulins in most of males, while in females the decrease was pronounced till the 90 days old. Albumin increased in females than in males in normals, while in the treated groups it decreased in all females and in some of males. A/G ratio decreased with maturation in normals, but in the treated groups it increased in males and decreased in most of females than those of controls.


Histopathological tumour viability after neoadjuvant chemotherapy influences survival in resected pancreatic cancer: analysis of early outcome data.
Neoadjuvant therapy is increasingly recognized as an effective strategy prior to pancreatoduodenectomy. We investigate the role of neoadjuvant chemotherapy (NAC) followed by surgery and the predictive role of viable residual tumour cells histopathologically on outcomes. The study population comprised of 195 consecutive patients with pancreatic adenocarcinoma who were treated with either NAC or a surgery-first (SF) strategy. Histopathological viable tumour cells were examined in the NAC patients and clinicopathological factors were correlated with overall survival. Forty-two patients (22%) were treated with NAC and 153 patients (78%) underwent SF. NAC was associated with higher estimated blood loss during surgery (928 mL versus 615 mL; P = 0.004), fewer (<15) excised lymph nodes (37% versus 17%; P = 0.015) and lower rates of lymphovascular invasion (65% versus 45%; P = 0.044) when compared with SF. Two-year survival of patients undergoing NAC was 63% and 51% in patients undergoing SF (P = 0.048). The 2-year survival of patients who had >65% residual tumour cells was 45% and 90% in patients who had <65% residual tumour cells (P = 0.022). Favourable responders (<65% viable tumour cells) were observed to have shorter operation time (<420 min) (55% versus 13%; P = 0.038), trend towards negative lymph node status (38% versus 10%; P = 0.067) and greater lymph node harvest in node positive patients (≥4 positive lymph nodes) (77% versus 37%; P = 0.045). The improved survival of patients undergoing NAC indicates effective management of micrometastatic disease and is an effective option requiring further investigation. Histopathological viable tumour cells after NAC was a surrogate marker for survival.


Cortical network properties revealed by SSVEP in anesthetized rats.
Steady state visual evoked potentials (SSVEP) are assumed to be regulated by multiple brain areas, yet the underlying mechanisms are not well understood. In this study, we utilized multi-channel intracranial recordings together with network analysis to investigate the underlying relationships between SSVEP and brain networks in anesthetized rat. We examined the relationship between SSVEP amplitude and the network topological properties for different stimulation frequencies, the synergetic dynamic changes of the amplitude and topological properties in each rat, the network properties of the control state, and the individual difference of SSVEP network attributes existing among rats. All these aspects consistently indicate that SSVEP response is closely correlated with network properties, the reorganization of the background network plays a crucial role in SSVEP production, and the background network may provide a physiological marker for evaluating the potential of SSVEP generation.


A modified method of curve analysis in foot volumetry and its reference values.
Foot volumetry was introduced by Norgren & Thulesius in 1973 as a non-invasive method of functional evaluation of venous insufficiency. In the following paper we suggest a slightly different method of curve analysis, thus showing the possibility of reducing the methodological error by 30-40%. Based on healthy men and women between 15 and 75 years, new reference values are presented.


Presenilin-1 deficiency impairs glutamate-evoked intracellular calcium responses in neurons.
Presenilin 1 (PS1) plays a critical role in cleaving amyloid precursor protein (APP) to produce amyloid-beta (Abeta), the primary proteinaceous component of the senile plaques associated with Alzheimer's disease. In addition to mediating the cleavage of APP and a number of other proteins, a growing body of evidence suggests that PS1 also regulates intracellular endoplasmic reticulum calcium levels. Such findings suggest that PS1 activity may modulate neuronal excitability, as well. To address this issue we examined cytosolic intracellular calcium responses in PS1-deficient neurons stimulated by the excitatory amino acid neurotransmitter, glutamate. We found that glutamate-induced intracellular calcium levels were markedly reduced in neurons lacking PS1 (-/-) compared with heterozygous (+/-) and wild-type (+/+) neurons. To prove that PS1 was sufficient to mediate normal glutamate-induced calcium responses, we used a Semliki-forest virus (SFV) vector to express wild-type PS1 in PS1 knock-out neurons. We found that heterologous PS1 expression restored glutamate-evoked calcium responses in PS1-deficient neurons to levels matching non-infected wild-type cells. PS1-deficient neurons infected with SFV directing expression of beta-galactosidase failed to rescue the wild-type phenotype. These results support the idea that normal PS1 activity regulates neuronal responses to neurotransmitter stimulation.


Psychiatric symptoms in alcohol dependence: diagnostic and treatment implications.
Fifty consecutive alcohol dependent inpatient admissions are reported on. They were found to have grief, agoraphobic, paranoid and depressive symptoms secondary to the withdrawal state. These symptoms remitted with detoxification. Absence of anxiety signalled other disorders. Longituding observations aided diagnostic assessment and patient management. The history of the course of symptoms aids diagnoses when obtainable, but detoxification remains essential to discriminate primary from symptomatic or secondary psychiatric symptoms in the alcohol dependent person. Transient psychiatric symptoms may merely be less common forms of withdrawal symptoms and must not be confused with syndromes which attract ongoing drug treatment. This is a highly undesirable situation for those who are at risk of psychotropic drug abuse and overdose behaviour.


Comparison of volunteers' experience of using, and accuracy of reading, different types of home pregnancy test formats.
Women suspecting pregnancy need an accurate result when they conduct a home pregnancy test. A variety of tests are available from simple professional style strips to midstream tests with a digitally displayed result. However, it is not known whether all these formats can be used and read correctly by untrained women. The aim of this study is to evaluate usability and reading accuracy of home pregnancy test formats. Female volunteers, 18 - 45 years (Manchester, UK) completed questionnaires on their home-use experience of six pregnancy tests (strip, cassette, midstream visual and digital formats). These volunteers then evaluated device results using hCG-urine standards at a study centre, thereafter completing a questionnaire and ranking evaluation. Data were available from 111 volunteers. Women preferred midstream test formats; > 70% scored branded midstream digital and easy-use visual tests as 1or 2 (7-point Likert score), compared with ∼ 30% for store-brand and branded midstream visual tests, and < 10% for cassette or strip tests. Many cassette tests (23%) failed to provide a result (4, ≤ 2% for strips, midstream, respectively). Volunteers disagreed with study co-ordinator reading of test results in 30 and 40% of cases for the cassette and strip test results, respectively, compared with < 3% when using midstream digital or easy-use visual tests. Volunteers preferred the branded midstream digital, followed by branded midstream easy-use and visual tests. In this study, the branded midstream digital test was superior to other tests evaluated and fulfilled the criteria of being an easy-to-use and interpret test; strip and cassette tests showed poor performance in women's hands.


Quantitative two-dimensional NMR study of dermenkephalin, a highly potent and selective delta-opioid peptide.
Dermenkephalin, H-Tyr-(D)Met-Phe-His-Leu-Met-Asp-NH2, a highly potent and selective delta-opioid peptide isolated from frog skin, was studied in DMSO-d6 solution by two-dimensional nmr spectroscopy, including the determination of NH temperature coefficients, the evaluation of 3J coupling constants from phase-sensitive correlated spectroscopy (COSY) and the volumes of nuclear Overhauser effect (NOE) correlations. The two-dimensional NOE spectroscopy (NOESY) spectrum of dermenkephalin revealed sequential, medium-, and long-range effects. To put this information on a quantitative basis, special attention was devoted to J cross-peak suppression, quantification of the NOE volumes and analysis of the overlaps, normalization of the NOEs against diagonal peaks and H beta beta' geminal interactions. Although most of the dihedral angles deduced from the 3JN alpha coupling constants together with several Ni alpha i and alpha iNi+1 NOEs pointed to a partially extended peptide backbone, several NiNi+1 NOEs and beta iNi+1 interactions argued in favor of a folded structure. Moreover, several long-range correlations of strong intensities were found that supported a close spatial proximity between the side chains of D-Met2 and Met6, Tyr1 and His4, Tyr1 and Asp7, and His4 and the C-terminal amide group. In Phe, the g- rotamer in the side chain is deduced from the 3J alpha beta coupling constants and alpha beta and N beta NOE correlations. Whereas the amide proton dependency was not indicative of stable hydrogen bonds, the nonuniform values of the temperature coefficient may reflect an equilibrium mixture of folded and extended conformers. The overall data should provide realistic starting models for energy minimization and modelization studies.


Melatonin reduces phosphine-induced lipid and DNA oxidation in vitro and in vivo in rat brain.
Phosphine (PH(3)), a widely used pesticide, was found in our recent study to induce oxidative damage in the brain, liver and lung of rats. We also observed that melatonin significantly blocked this action. The present study focused on brain and the magnitude and mechanism of protection of PH(3)-induced oxidative damage by melatonin in vitro and in vivo. PH(3) in whole brain homogenate (3 mg protein/mL Tris-HCl pH 7.4 buffer) induced increasing lipid peroxidation [as malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] dependent on concentration (0.25-2 mM) and time (30-150 min), reaching a maximum level of 2.9-fold at 90 min after PH(3) at 1 mM. Elevation of MDA + 4-HDA levels by PH(3) at 1 mM was also observed in homogenates of cerebral cortex, cerebellum, hippocampus and hypothalamus examined individually. Melatonin at 0.1-2 mM progressively inhibited PH(3)-induced lipid peroxidation in brain and regions thereof. Additionally, PH(3) induced brain DNA oxidation in vitro and in vivo determined as 8-hydroxyguanosine (8-OH-dG). Melatonin at 1 mM significantly suppressed PH(3)-induced brain DNA oxidation in vitro. PH(3) at 4 mg/kg i.p. significantly elevated 8-OH-dG in frontal cortex and melatonin prevented it. PH(3) in vivo marginally lowered brain glutathione peroxidase activity and melatonin restored it completely. In contrast, PH(3) and melatonin both stimulated superoxide dismutase production. Brain glutathione (GSH) levels in PH(3)-treated rats were significantly reduced at 30 min and recovered gradually. It is concluded that melatonin, probably because of its free radical scavenging ability, confers marked protection against PH(3)-induced oxidative toxicity in brain.


Clear-cell meningioma of the cauda equina.
Meningiomas are rare tumours in children and lumbar lesions are exceptional. We report a clear-cell meningioma (CCM) of the cauda equina in a 10-year-old girl. The tumour was diagnosed by MRI, showing an enhancing intradural mass extending from L1 to L4. Pathology and immunohistochemical study demonstrated a CCM. The patient had a recurrence 6 months after the operation requiring further surgery. CCM are rare lesions, characterised by abundant cytoplasmic glycogen particles. Complete surgical removal is necessary because, despite their benign histological appearance, CCM are potentially aggressive and may recur, spread locally and even metastasize.


[Renal manifestations in vasculitides of small and medium-sized vessels].
Small-vessel vasculitides, in particular, are frequently manifested in the kidneys. A distinction is made between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and immune complex vasculitides. Even within the AAVs there are differences with respect to renal involvement, which manifest as necrotizing glomerulonephritis (GN) but renal involvement is much rarer in eosinophilic granulomatosis with polyangiitis than in microscopic polyangiitis and granulomatosis with polyangiitis. Disease progression, organ manifestation and prognosis vary according to the ANCA status. In immune complex vasculitides (cryoglobulinemic vasculitis, IgA vasculitis, hypocomplementemic urticarial vasculitis and antiglomerular basement membrane, GBM, disease), endothelial-adjacent activation of neutrophilic granulocytes leads to local vessel wall damage with subsequent ischemic tissue damage, similar to AAV. The sparse evidence of immune complexes is different in pauci-immune AAV. Polyarteritis nodosa is a disease with variable clinical presentations with necrotizing vasculitis of small and medium-sized arteries. Intrarenal aneurysms and hemorrhages but not GN lead to renal damage. Diagnostically, the detection of specific autoantibodies (e.g. anti-GBM), cryoglobulins or increased complement turnover can be decisive. Renal biopsy with qualified immunohistopathology is particularly important in cases of initial manifestation and unclear constellation of findings. The treatment of renal vasculitis is adapted to the severity, stage of disease, extrarenal organ manifestation and pathogenesis. It ranges from glucocorticoid monotherapy to moderate immunosuppression, up to targeted biologic therapy, chemotherapy and plasmapheresis.


[Factors influencing the referral of nursing home patients to the hospital].
Hospitalisation may cause negative effects on elderly patients. Therefore, it is important that referral and admission of older nursing home patients is well-considered. The aim of this study is to investigate the factors that affect the decision making process. Questionnaire survey among elderly care physicians and physicians following the elderly care physician training program. Of the 1,540 surveys, 200 were returned (response rate of 13%). Over 60% of the respondents had referred a nursing home patient to the hospital in the previous month. A stay at a geriatric rehabilitation ward, suspicion of a fracture, a good quality of life, a patient's or family's wish for referral, no treatment restrictions, and follow-up appointments in the hospital were factors which made referral to the hospital more likely according to the respondents. Medical specialist consultation and the in hospital presence of a physician specialised in geriatric care were considered to be important. Referral was less likely if a patient was diagnosed with dementia, had a low quality of life or had treatment restrictions. Both patient-related and non-patient-related factors influence hospital referral of nursing home patients. Further research is needed to determine whether these different factors contribute to the different outcomes of a hospital admission, to facilitate proper decision-making for elderly care physicians.


Incidence of pacing-induced cardiomyopathy in pacemaker-dependent patients is lower with leadless pacemakers compared to transvenous pacemakers.
Frequent right AQ4ventricular pacing (≥40%) with a transvenous pacemaker (TVP) is associated with the risk of pacing-induced cardiomyopathy (PICM). Leadless pacemakers (LPs) have distinct physical and mechanical differences from TVP. The risk of PICM with LP is not known. To identify incidence, predictors, and long-term outcomes of PICM in LP and TVP patients. The study comprised all pacemaker-dependent patients with LP or TVP who had left ventricular ejection fraction (LVEF) of ≥50 from 2014 to 2019. The incidence of PICM (≥10% LVEF drop) was assessed with an echocardiogram. Predictors for PICM were identified using multivariate analysis. Long-term outcomes after cardiac resynchronization (CRT) were assessed in both groups. A total of 131 patients with TVP and 67 with LP comprised the study. All patients in the TVP group and the majority in the LP group underwent atrioventricular node ablation. The mean follow-up duration in TVP and LP groups was 592 ± 549 and 817 ± 600 days, respectively. A total of 18 (13.7%) patients in TVP and 2 (3%) in LP developed PICM after a median duration of 254 (interquartile range: 470) days. The incidence of PICM was significantly higher with TVP compared with LP (p = .02). TVP as pacing modality was a positive (odds ratio [OR]: 1.07) while age was negative (OR: 0.94) predictor for PICM on multivariable analysis. Both patients in LP and all except two in the TVP group responded to CRT. Incidence of PICM is significantly lower with LP compared with TVP in pacemaker-dependent patients. Age and TVP as pacing modality were predictors for PICM.


Effect of thyroid replacement therapy on the stature of Colombian children with minimal thyroid dysfunction.
The effect of thyroid replacement therapy (TRT) was evaluated in 372 children with minimal thyroid dysfunction (MTD; augmented TSH response to TRH, deficient iodine consumption, goiter, short stature and retarded bone age), by comparison of pre- with post-observation height in periods of 6 months with and without TRT alternated. A significant (P < 0.05) height recovery was observed when children received TRT; however, during the period without TRT they showed a negative height recovery. Additionally, we followed 51 children with MTD who were observed from Tanner I until final height. The group with L-thyroxine (n = 43) during all follow-up (97 months) showed an important recovery in height (SDS-H = 1.67 +/- 0.93 vs. 1.08 +/- 0.74) which when compared with the untreated group (n = 8; 114 months; SDS-H = -1.50 +/- 0.83 vs. -1.93 +/- 0.33) was significant (P < 0.001).


A novel defined pyroptosis-related gene signature predicts prognosis and correlates with the tumour immune microenvironment in lung adenocarcinoma.
Lung adenocarcinoma (LUAD) is one of the most common causes of cancer-related death. The role of pyroptosis in LUAD remains unclear. Our study aimed to identify a prognostic signature of pyroptosis-related genes (PRGs) and explore the connection of PRGs with the tumour microenvironment in LUAD. Gene expression and clinical information were obtained from The Cancer Genome Atlas database. Consensus clustering was applied to classify LUAD patients. The least absolute shrinkage and selection operator Cox and multivariate Cox regression models were used to generate a PRG-related prognostic signature. The correlations between PRGs and tumour-infiltrating immune cells or the tumour mutational burden were analysed by Spearman's correlation analysis. In this study, 44 PRGs significantly differed in expression between LUAD and normal tissues. Based on these genes, patients were clustered into three clusters with significantly different distributions of tumour-infiltrating immune cells and immune checkpoint regulators. A total of four PRGs (NLRP1, HMGB1, CYCS, and BAK1) were used to construct a prognostic model. Significant correlations were observed between these prognostic PRGs and immune cell infiltration or the tumour mutational burden. Predictive nomogram results showed that BAK1 could be an independent prognostic biomarker in LUAD. Additionally, the expression level of BAK1 was validated in two independent Gene Expression Omnibus cohorts. Our identified prognostic PRG signature may provide insight for future studies targeting pyroptosis and the tumour microenvironment in LUAD. Future studies are needed to verify our current findings.


Ileal duplication cyst: the importance of sodium pertechnetate Tc 99m scanning.
Duplications of the alimentary tract may cause extensive bleeding when ectopic gastric mucosa is present. A successful diagnosis can be made preoperatively with the use of conventional barium studies as well as sodium pertechnetate Tc 99m scans.


Shaping science policy in Europe.
The Lisbon Strategy was adopted by the Heads of State and Government of the European Union (EU) in 2000. By moving science into a central position for the development of a European knowledge-based economy and society, its adoption at political level seems to have been a powerful catalyst for the increased involvement of scientists in science policy in the EU. Recognising the need for scientists to act collectively in order to contribute to shape the future of science policy in Europe, a pioneering group of European science organisations leaders and representatives, as well as other scientists, initiated a European, interdisciplinary, inclusive movement leading to the creation of the European Research Council (ERC) to support basic research of the highest quality. Having scientists' campaign for the funding of bottom-up research by the EU Framework Programmes exclusively on scientific grounds, and for an ERC, was a unique event in the recent history of European science policy. For the first time, the scientific community acted collectively and across disciplinary or national boundaries as a political actor for the sake of a better science policy for Europe. As is often the case when first-hand experience is gained through the creation of a new organization, novel forms of collaboration arise. The European biomedical community has recently proposed the creation of a strategic action plan for health research (the European Council of Health Research; EuCHR), provisionally translated at present into a Scientific Panel for Health (SPH) research in Horizon 2020, the EU's research-funding programme for the period 2014-2020. The creation of such Scientific Panel should be viewed as an important contribution by the biomedical community as a major political agreement has been reached on the need for a comprehensive and long-term scientific strategy to accelerate research and facilitate innovation at EU level. It is our belief that describing and analyzing the process leading to the creation of the ERC and SPH (2002-2014) should be widely shared with the research community in general, as this may contribute to the understanding of the evolving relations between scientists and science-policy making.


Creatine kinase role in anaphase chromosome movement.
Creatine kinase catalyses the conversion of ADP and phosphoryl creatine into ATP and creatine. In skeletal muscle a non-mitochondrial isoenzyme of creatine kinase has a major role in regulating the energy supply for muscle contraction by maintaining the ATP pools at relatively constant levels. Recently, this enzyme has been localized by immunofluorescence techniques on intermediate filaments and stress fibres in interphase cells and in mitotic spindles of dividing tissue culture cell lines, including the PtK1 cell line, and has been found to co-purify with spindles isolated from dividing sea urchin eggs and with muscle cell nuclei. Here I have used permeabilized PtK1 cells to investigate the possibility that creatine kinase may be involved in regulation of spindle energy metabolism by lysing cells in medium containing phosphoryl creatine. I find that spindle elongation will continue in these conditions, provided ADP is also present in the lysis medium. This finding is consistent with my previous demonstration that spindle elongation is the ATP-requiring step during anaphase and is a direct demonstration that creatine kinase may have a role in mitosis analogous to that observed during skeletal muscle contraction.


Integrative analysis of postharvest chilling injury in cherry tomato fruit reveals contrapuntal spatio-temporal responses to ripening and cold stress.
Postharvest chilling injury (PCI) reduces fruit quality and shelf-life in tomato (Solanum lycopersicum L.). PCI has been traditionally studied in the pericarp, however its development is likely heterogeneous in different fruit tissues. To gain insight into PCI's spatio-temporal development, we used postharvest biomarkers e.g. respiration and ethylene rates, ion leakage etc., to confirm the occurrence of PCI, and compared these data with molecular (gene expression), biophysical (MRI data) and biochemical parameters (Malondialdehyde (MDA) and starch content) from the pericarp or columella. Tissues were stored at control (12.5 °C) or PCI-inducing temperatures (2.5 or 5 °C) followed by rewarming at 20 °C. MRI and ion leakage revealed that cold irreversibly impairs ripening-associated membrane liquefaction; MRI also showed that the internal and external fruit tissues responded differently to cold. MDA and especially starch contents, were affected by chilling in a tissue-specific manner. The expression of the six genes studied: ACO1 and ACS2 (ripening), CBF1 (cold response), DHN, AOX1a and LoxB (stress-related) showed non-overlapping temporal and spatially-specific responses. Overall, the data highlighted the interconnectedness of fruit cold response and ripening, and showed how cold stress reconfigures the latter. They further underscored that multidimensional spatial and temporal biological studies are needed to develop effective solutions to PCI.


Quantum annealing in a kinetically constrained system.
Classical and quantum annealing is discussed in the case of a generalized kinetically constrained model, where the relaxation dynamics of a system with trivial ground state is retarded by the appearance of energy barriers in the relaxation path, following a local kinetic rule. Effectiveness of thermal and quantum fluctuations in overcoming these kinetic barriers to reach the ground state are studied. It has been shown that for certain barrier characteristics, quantum annealing might by far surpass its thermal counter part in reaching the ground state faster.


Moxifloxacin induced encephalopathy in disseminated tuberculosis: A case report.
Moxifloxacin is a third-generation fluoroquinolone antibiotic with broad spectrum activity and also used as component of anti-tubercular therapy (ATT). Though frequently prescribed, moxifloxacin induced encephalopathy is uncommonly seen. Here we describe a forty four year old male, with features of disseminated tuberculosis (TB) and suspected case of multi-drug resistance (MDR), who developed acute encephalopathy. Extensive laboratory investigations, neuroimaging of brain, cerebrospinal fluid analysis was unremarkable. On stopping moxifloxacin, which was being administerd as part of ATT for MDR TB, encephalopathy resolved completely, thereby proving it to be a case of moxifloxacin induced encephalopathy. To conclude, by presenting this case, we wish to raise awareness about moxifloxacin induced encephalopathy among healthcare providers.


Primary healthcare needs and barriers to care among Calgary's homeless populations.
Despite Canada's universal healthcare system, significant barriers impede individuals experiencing homelessness from accessing health services. Furthermore, there is a paucity in the qualitative literature describing how Canadians experiencing homelessness access health care services. Our objective was to qualitatively explore perceived healthcare needs and barriers among individuals experiencing homelessness in one large Canadian city - Calgary, Alberta. We conducted a qualitative descriptive study that included open-ended interviews and focus groups with a variety of stakeholders who are involved in healthcare among Calgary's homeless populations. These included individuals experiencing homelessness (n = 11) as well as employees from several healthcare service providers for those experiencing homelessness (n = 11). Transcripts from these interviews were thematically analyzed by two analysts. Stakeholder interviews yielded several pervasive themes surrounding the health care needs of the homeless and barriers to accessing care. Some of the primary health care needs which were identified included mental health, addictions, and allied health as well as care that addresses the social determinants of health. Notably, it was difficult for many stakeholders to pinpoint specific health care priorities, as they identified that the health care needs among Calgary's homeless populations are diverse and complex, often even describing the needs as overwhelming. Types of barriers to primary care that were identified by stakeholders included: emotional, educational, geographical, financial and structural barriers, as well as discrimination. Our findings highlight the diverse primary health care needs of Calgary's homeless populations. Despite the fact that Canada has a universal publicly funded health care system, individuals experiencing homelessness face significant barriers in accessing primary care.


Ocular injuries from fireworks: the 11-year experience of a US level I trauma center.
PurposeCharacterize ocular trauma and visual outcomes from firework injuries at a level I trauma center.MethodsRetrospective review of all firework injuries at Harborview Medical Center between 2003 and 2013.ResultsThree hundred and twenty-seven patients sustained firework injuries, of which 100 (31%) sustained ocular injuries. The average age of all patients who sustained fireworks injuries was 24.2 years, 89% were male and 54% of injuries occurred within 48 h of 4 July. Ocular injuries were most commonly caused by mortars (24%) and rockets (22%). Rockets were associated with four times the frequency of ocular injuries as compared with non-ocular injuries (P<0.001). Spectators were more likely to sustain ocular injuries than non-ocular injuries (P=0.001). The most common injuries sustained were corneal abrasions (67%), hyphemas (42%), eyelid injuries (39%), and ruptured globes (17%). Twenty-eight percent of patients with ocular injuries required surgical intervention. Ruptured globes occurred in 17% of patients, with the majority being complex corneoscleral lacerations. Fifty-eight percent of patients who sustained ruptured globes were left with no light perception in the affected eye. Average follow-up was 188 days. Average visual acuity significantly improved from logMAR 1.8±1.6 at presentation to logMAR 1.3±1.8 at last follow-up.ConclusionsFirework-related ocular trauma frequently results in vision-threatening pathology. Prompt referral to and treatment by ophthalmologists is critical. This study documents the dangers inherent in the personal use of fireworks and provides data that may help guide public policy to decrease the frequency of these devastating injuries.


Processed N-termini of mature proteins in higher eukaryotes and their major contribution to dynamic proteomics.
N-terminal-ubiquitinylation (NTU) is a newly discovered protein degradation pathway initiated by ubiquitin-tagging of the N-terminal alpha-amino group. We have used data from recent genomic studies, especially those on humans, to up-date and re-interpret biochemical data to identify the sequence features associated with NTU. We compared a mini-proteome for which experimental protein sequence is available with large-scale genomic data. We conclude that N-alpha-acetylation involves less than 30%, and not the widely assumed 90%, of the proteins encoded by any higher eukaryote genome, greatly increasing thereby the number of possible targets for NTU-mediated degradation. Next, straightforward rules linking the first N-terminal residues of any nascent polypeptides to the nature of their processed N-termini are established and dedicated prediction tool is made available at . We provide strong arguments indicating that the nature of the processed N-terminus is a major determinant factor of the half-life of the protein. We finally reveal that one third of the nuclear-encoded proteins starting with an unprocessed and unblocked methionine are at least one order of magnitude less stable than is average in higher eukaryotes. This appears to be the first common feature of proteins undergoing N-terminal ubiquitinylation. Hence, a pool of about 3000 proteins in each proteome could be unstable per se and tagged for rapid degradation via NTU.


Genetic characterization and phylogeny of a hantavirus from Western Mexico.
Hantaviruses can cause two serious illnesses when transmitted from their rodent reservoirs to humans; hantavirus pulmonary syndrome (HPS) in the New World and hemorrhagic fever with renal syndrome in the Old World. Cases of HPS were first recognized in the Americas in small, focal outbreaks in rural populations in the Southwestern USA in 1993. Since that time, outbreaks as well as sporadic cases of HPS have been recognized throughout the Americas. Remarkably, HPS cases have not been reported in Mexico. Mexico is one of the most biodiverse regions in the world and this is reflected in the species diversity of the peromyscine, sigmodontine and oryzomyine rodents; all potential hosts of hantaviruses. Hence, we collected and surveyed several rodent species in Western Mexico and identified three previously unrecognized rodents with antibodies to hantaviral antigens: Oryzomys couesi, Sigmodon mascotensis and Baiomys musculus. The S and M segments cloned from O. couesi and S. mascotensis, referred to herein as Playa de Oro (ORO) virus, showed strongest similarity to Bayou and Catacamas viruses with 92/93% and 92/92% similarity based on S/M amino acid sequences, respectively. This and phylogenetic analysis of the M and S segments suggests that ORO virus is a unique genotype within Hantavirus.


Substrate specificity of the human lymphokine leucocyte migration-inhibitory factor (LIF): radioenzymic assay and inhibition by cGMP.
The human lymphokine, leucocyte migration-inhibitory factor (LIF), appears to be a serine esterase and protease by virtue of its susceptibility to the irreversible enzyme inhibitor, phenylmethylsulfonyl fluoride (PMSF), and by the ability of arginine esters and amides to protect LIF against PMSF-induced inactivation. In this paper, three methods are described by which putative substrates for LIF may be investigated. Thus, molecules satisfying the substrate specificities of this lymphokine should (1) protect LIF against inactivation by PMSF, (2) reduce LIF activity in vitro on polymorphonuclear leucocytes, and (3) reduce the esterolytic activity of purified LIF-rich supernatants. The first two reactions were tested by means of the leucocyte migration agarose technique; the third reaction was tested by a sensitive enzyme assay using tritiated tosyl arginine methyl ester as substrate. Guanosine 3',5'-cyclic monophosphoric acid, which is capable of protecting LIF against PMSF-induced inhibition, also inhibited the esterolytic activity of the purified LIF preparation. Four synthetic oligopeptide substrates for trypsin, thombin and plasmin were investigated. Only one, the thrombin- and trypsin-specific benzoyl-phenylalanyl-valyl-agarine-p-nitroanilide, possessed high affinity for the LIF molecule and may therefore prove to be a potent substrate for this lymphokine.


Photoradiation therapy of bladder tumors.
Photoradiation therapy, in which hematoporphyrin derivative is activated by an argon-dye laser, was performed on 46 superficial bladder tumors in 9 patients. A fluorospectrophotometric study of biopsies from these tumors and normal mucosa revealed preferential hematoporphyrin derivative localization in malignant tissues. The tumor response was confirmed ultrasonographically in 36 stages Ta to Tl tumors. Treatment with 100 to 250 J./cm.2 obtained complete remission in 5 of 6 patients with tumors 1 cm. in size or less. For those with tumors up to 2 cm. in size the light intensity should be 300 mw./cm.2 for 5 to 10 minutes or more and the accumulated energy intensity of light dose should be 100 J./cm.2 or more. No patient with tumors more than 2 cm. in size had a complete remission.


No deterioration in insulin sensitivity, but impairment of both pancreatic beta-cell function and glucose sensitivity, in Japanese women with former gestational diabetes mellitus.
To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non-obese women with a history of GDM and eight non-obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18+/-0.34 vs 2.26+/-0.29 x 10(-2) min(-1), p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56% of that observed in control subjects (1250+/-87.4 vs 2223+/-304.3 pmol l(-1) min, p < 0.01). Our results indicate that in former GDM patients, who are japanese and non-obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved.


AIDS knowledge and attitudes in a Turkish population: an epidemiological study.
The aim of this study was to investigate and present some pertinent comments concerning Acquired Immunodeficiency Syndrome (AIDS) knowledge, attitudes and misconceptions among the general population in a city of west Turkey. This study was deemed important and relevant due to the increasing importance of AIDS in Turkey and the other countries. Using a multistage area sampling method, a random sample of individuals aged 11-83 years, living in 65 different quarters in the city of Eskisehir, Turkey during September, October and November 2004 were interviewed. In all, 1048 respondents completed the survey. In most items, respondents displayed a fairly good to excellent degree of knowledge about HIV/AIDS. Individuals with higher degrees of education indicated more correct responses in all items relating to knowledge of HIV/AIDS. In general, the respondents' attitudes towards AIDS and people with AIDS were found to be tolerant and positive, with one answer choice showing that the majority of the respondents agreed with the statement that those with HIV/AIDS must be supported, treated and helped (90.7%). Moreover, the proportions of the respondents' misconceptions were found to be significantly low for all the items. However, nearly one fourth of the respondents agreed with the misconceptions 'AIDS is a punishment by God' and 'One is not infected with HIV/AIDS if engaged in sport and well nourished'. In general HIV/AIDS related knowledge was high and people showed positive attitudes. However, people continue to hold misconceptions about AIDS and these need to be addressed by health education programs targeting those at higher risk.


Hippocampal LASP1 ameliorates chronic stress-mediated behavioral responses in a mouse model of unpredictable chronic mild stress.
Substantial evidence has revealed that abnormalities in synaptic plasticity play important roles during the process of depression. LASP1 (LIM and SH3 domain protein 1), a member of actin-binding proteins, has been shown to be associated with the regulation of synaptic plasticity. However, the role of LASP1 in the regulation of mood is still unclear. Here, using an unpredictable chronic mild stress (UCMS) paradigm, we found that the mRNA and protein levels of LASP1 were decreased in the hippocampus of stressed mice and that UCMS-induced down-regulation of LASP1 was abolished by chronic administration of fluoxetine. Adenosine-associated virus-mediated hippocampal LASP1 overexpression alleviated the UCMS-induced behavioral results of forced swimming test and sucrose preference test in stressed mice. It also restored the dendritic spine density, elevated the levels of AKT (a serine/threonine protein kinase), phosphorylated-AKT, insulin-like growth factor 2, and postsynaptic density protein 95. These findings suggest that LASP1 alleviates UCMS-provoked behavioral defects, which may be mediated by an enhanced dendritic spine density and more activated AKT-dependent LASP1 signaling, pointing to the antidepressant role of LASP1.


The effects of 1-methyl-1-nitrosourea on the survival pattern of cycling and noncycling HeLa cells.
The biological behavior of HeLa cells exposed to 1-methyl-1-nitrosourea was examined by determining the survival fraction in asynchronous and synchronous cultures. Asynchronous cell population exposed to 1-methyl-1-nitrosourea for 1 h exhibited a shoulder type survival curve, indicating that damage must be accumulated before the lethal effect occurs. A fraction of 25% of cells survives the concentration of 100 micrograms/ml. The duration of treatment with the drug did not have a significant effect on the cell survival. The experiments with synchronized cells showed that MNU exhibits the killing in all phases of the cell age, but the most sensitive are these in S phase. However, they are still six times more resistant at the same concentration than the culture in plateau phase. At the concentration of 100 micrograms/ml nondividing plateau cells are about 35 times more sensitive than exponentially growing cells. We can conclude that MNU acts as the most acting killing agents on the cells which are in nondividing plateau phase.


Influence of light on ochratoxin biosynthesis by Penicillium.
Light has a profound influence on ochratoxin biosynthesis by Penicillia. When incubated under constant daylight of a certain intensity, ochratoxin A biosynthesis is decreased by about 20-30% compared to incubation under constant darkness. Under day/night oscillation, the ochratoxin A polyketide synthase gene, a key gene of the ochratoxin A biosynthesis pathway, is rhythmically expressed, and moreover, the amount of ochratoxin also oscillates between the amounts produced either during constant darkness or during constant light. This indicates a partial degradation of ochratoxin A (20-30%) under light conditions until a certain lower limit is reached. This behavior is dependent on the light intensity. At 1,600 Lux, only weak effects could be observed; however, at 2,800 Lux, the effects became significant. After growth under constant light conditions, Penicillium produced ochratoxin B at amounts which are 5 times higher than after growth in constant dark or in alternating light/dark conditions. Growth experiments in the dark on medium with increasing amounts of ochratoxin A revealed that externally applied ochratoxin is moderately toxic. However, if the same growth experiments are carried out under light conditions, the growth inhibiting activity of ochratoxin A is greatly increased, indicating that light amplifies the toxic activity of ochratoxin. Because of the oscillation of the concentration of ochratoxin A during night and day incubation, Penicillium seems to have developed an adaptive mechanism to reduce the amount of ochratoxin A during daylight below a toxic level.


Dicarbofunctionalization of unactivated alkenes via organo-photoredox catalysis in water: access to cyanoalkylated fused quinazolinones.
A visible light-induced C-C bond cleavage/addition/cyclization cascade of oxime esters and unactivated alkenes has been developed using water as the solvent. This green protocol offers an easy access to medicinally valuable cyanoalkylated quinazolinones. Mild reaction conditions, functional group tolerance and late-stage functionalization of complex molecules are the important features of this transformation.


Fluorescein-tear breakup time as an assessment of efficacy of tear replacement therapy in dry eye patients: a systematic review and meta-analysis.
To review outcomes of studies where fluorescein-tear breakup time (fTBUT) measurements had been made before and after treatment with artificial tears. Peer-reviewed articles were identified that reported average values for fTBUT before and after approximately 1 month of treatment of dry eye with aqueous-based artificial tears. 48 data sets were used for calculating the net (percentage) change in fTBUT, with 21 including information of variability (as reported SD of average value) of the fTBUT data suitable for a meta-analysis. Prior to treatment, average fTBUT values ranged from 0.9 s to 11.8 s (group mean 4.7 +/- 1.7 s, n = 48 data sets). After treatment, these values ranged from 2.2 to 10.7 s (group mean 6.1 +/- 2.3 s; P<.001), with net increase for the treatment effect being 1.4 +/- 1.2 s (range - 1.4 to + 4.5 s). Similar changes were reported regardless of the type of product type. The meta-analysis confirmed a net effect at 1.3 s, with the magnitude of the variability (as a weighted SE) having a similar overall value of 1.1 s. Following use of 'artificial tears' by dry eye patients, a small but predictable increase in tear film stability has generally been reported, the net magnitude of which is close to a 33% improvement.


Experimental research on the therapeutic effect of MMR vaccine to juvenile-onset recurrent respiratory papillomatosis.
To evaluate the efficacy of MMR vaccine in the treatment of juvenile-onset recurrent respiratory papillomatosis as adjuvant therapy by experimental research. Thirty-one children with RRP were enrolled and assigned randomly to intervention group or control group. Fifteen subjects in intervention group were treated with local application MMR vaccine on the lesion after surgery; sixteen subjects in the control group were treated with surgical excision alone. The quantity of virus of positive specimens was measured by fluorescence quantitative polymerase chain reaction. After treatment with MMR vaccine, viral load of intervention group was (9.56 ± 11.03) × 108 copies/ml, that of control group was (22.01 ± 17.78) × 108 copies/ml, and there was significant difference between the two groups (P = 0.040). Local application MMR vaccine as adjuvant therapy can reduce HPV viral load significantly. It is suggested that the MMR vaccine may inhibit replication of HPV DNA, but the curative effect needs further confirmation.


Regulation of the biosynthetic pathway of aromatic amino acids in Nocardia mediterranei.
The regulation of enzymes in the biosynthetic pathway of aromatic amino acids in Norcardia mediterranei was studied. Anthranilate synthase was sensitive to feedback inhibition by very low concentrations of LTrp, and kinetic analysis showed that LTrp was competitive with respect to chorismate; the five enzymes in LTrp biosynthesis pathway, anthranilate synthase (AS), anthranilate-phosphoribosylpyrophosphate phosphoribosyltransferase (PRT), N-5'-phosphoribosylanthranilate isomerase (PRAI), indole-3-glycerol phosphate synthetase (InGPS) and tryptophan synthase (TS), were all repressed by LTrp; LTyr and LPhe inhibited chorismate mutase. Prephenate dehydratase activity was greatly inhibited by LPhe and activated by LTyr, nearly 60% of its activity was inhibited by 5 microM of LPhe, and 20 microM of LTyr increased the activity approx. 3-fold. In addition, the effects of LPhe and LTyr on prephenate dehydratase were highly specific. The regulatory circuit of the biosynthetic pathway of aromatic amino acids in N. mediterranei is presented.


Infection Risk of Lumbar Epidural Injection in the Operating Theatre Prior to Lumbar Fusion Surgery.
To determine the association between preoperative lumbar epidural injections (LEIs) in the operating theater (OR) and the occurrence of surgical site infection (SSI) after posterior lumbar instrumented fusion surgery. This study was performed from January 2015 to September 2019. We enrolled 2312 patients who underwent lumbar surgery without LEIs (control group) and 469 patients who underwent lumbar surgery after LEIs in the OR. We further separated the patients by the time interval between the LEIs and surgery: 1) for the 0-1 M group, lumbar surgery was performed within 1 month after the LEIs, and 2) for the >1 M group, it was performed more than 1 month after the LEIs. The postoperative infection rate in the 0-1 M group was considerably higher than that in the control group (p = 0.0101). We further subdivided the 0-1 M and >1 M groups into four subgroups: a) the 0-1 MNS group included patients in the 0-1 M group who did not receive steroids; b) the 0-1 MS group who received steroids; c) the >1 MNS group included patients in the >1 M group who did not receive steroids; d) the >1 MS group who received steroids. The postoperative infection rate in the 0-1 MS subgroup was considerably higher than that in the control group (p = 0.0018). However, the infection rate was lower in the >1 MS subgroup (p = 0.1650). There were no statistically significant differences in the postoperative infection rate between the control group and the two non-steroid groups (0-1 MNS group, p = 0.4961; 1 MNS group, p = 0.7381). The administration of LEIs without steroids in the OR before lumbar instrumented fusion does not significantly increase patients' risk of postoperative infection. We recommend avoiding steroid injections administered within 1 month before lumbar instrumented fusion.


Plasma proteomic signature of decline in gait speed and grip strength.
The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 × 10-15 ), pleiotrophin (1.23 × 10-9 ), and TIMP-1 (5.97 × 10-8 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10-7 ), CDON (2.38 × 10-7 ), and SMOC1 (7.47 × 10-7 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline.


Analysis of the influencing factors of atmospheric particulate matter accumulation on coniferous species: measurement methods, pollution level, and leaf traits.
Urban trees, especially their leaves, have the potential to capture atmospheric particulate matter (PM) and improve air quality. However, the amount of PM deposited on leaf surfaces detected by different methods varies greatly, and quantitative understanding of the relationship between PM retention capacity and various microstructures of leaf surfaces is still limited. In this study, three measurement methods, including the leaf washing (LW) method, aerosol regeneration (AR) method, and scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM-EDX) method, were used to determine the PM retention capacity of leaf surfaces of three coniferous species. Additionally, we analyzed the leaf traits and elemental composition of PM on leaves collected from different sites. The results showed that Pinus tabulaeformis and Abies holophylla were more efficient species in capturing PM than Juniperus chinensis, but different measurement methods could affect the detected results of PM accumulation on leaf surfaces. The concentrations of trace elements accumulated on leaf surfaces differed considerably between different sites. The greatest accumulation of elements that occurred on the leaf surface was at the Shenfu Highway site exposed to high PM pollution levels and the smallest accumulation at the Dongling park site. The stomatal density and contact angle were highly correlated with the PM retention capacity of leaf surfaces of the tested species (Pearson coefficient: r = 0.87, p < 0.01 and r = - 0.70, p < 0.05), while the roughness and groove width were not significantly correlated (Pearson coefficient: r = 0.16 and r = - 0.03). This study suggests that a methodological standardization for measuring PM is urgently required and this could contribute to selecting greening tree species with high air purification capacity.


Crossing the blood-brain barrier: a potential application of myristoylated polyarginine for in vivo neuroimaging.
As basic neurological research continues to reveal novel targets for therapy, the need to deliver therapeutic agents across the blood-brain barrier (BBB) becomes increasingly important. If developed, delivery modules would bring targeting molecules across the BBB to their respective active sites. In addition, it would be highly advantageous if the bioavailability of these delivered agents could be monitored over time using non-invasive imaging techniques. Here, we describe a versatile delivery module based on a myristoylated polyarginine backbone, which crosses the BBB. Incorporation of the fatty acid group was achieved using a Schotten-Bauman reaction with quantitative yield, and the peptide was further synthesized by conventional solid phase peptide synthesis (SPPS). We report for the first time the in vivo distribution of the delivery module over time into mouse brain using near-infrared (NIR) fluorescence imaging. The fluorescent cargo was detected in vivo from 24-48 h post IV injection and was further characterized in perfused brains. Immunohistochemical staining of excised brain showed that the delivery module primarily accumulated in neurons with occasional localization in astrocytes and endothelial cells. We conclude that this approach can be used for the delivery of imaging probes and potentially targeted therapeutics across the BBB.


Enhancement of tanshinone production in Salvia miltiorrhiza hairy root culture by Ag+ elicitation and nutrient feeding.
Ag (+) was employed as an abiotic elicitor to stimulate the secondary metabolite production in hairy root culture of Salvia miltiorrhiza, a valuable herbal plant. The addition of Ag (2)S (2)O (3) at 15 - 40 microM to the culture between 12 and 22 days post inoculation resulted in more than 2-fold increase in the yields of the three diterpenoid tanshinones, tanshinone I, tanshinone IIA and cryptotanshinone. This stimulating effect was dependent on the Ag (+) dose, the day of Ag (+) addition to the culture and the tanshinone species, while the total yield of the three tanshinones (TT) was mainly dependent on the Ag (+) dose, with the highest being attained at 30 microM. The Ag (+) treatment also caused a dose-dependent inhibition of hairy root growth. Sucrose feeding or medium renewal before the addition of Ag (+) to the culture effectively prevented the growth inhibition, and significantly increased the biomass concentration and volumetric tanshinone yield. With combined medium renewal and Ag (+) treatment, in particular, the TT yield was increased 6.6-fold relative to that of the control (55.7 mg/L versus 7.3 mg/L). The elicitor function of Ag (+) in the hairy root culture was validated by its ability to induce the characteristic elicitor responses of plants, the increase in cross-cell membrane ion fluxes and the production of reactive oxygen species.


The influence of dexamethasone on serum thyrotrophin and thyrotrophin synthesis in the rat.
Glucocorticoid hormones suppress circulating concentrations of thyrotrophin (TSH), but their effect on synthesis of TSH in the pituitary gland is unclear. We have examined the influence of the glucocorticoid dexamethasone on serum TSH, pituitary TSH content and TSH beta- and alpha-subunit mRNA concentrations in pituitary cytoplasm in both the euthyroid and hypothyroid rat, and following triiodothyronine (T3) treatment in the hypothyroid rat. The rise in serum TSH in hypothyroidism was attenuated in animals treated with dexamethasone; in addition the suppression of serum TSH 6 h after T3 administration to hypothyroid rats was enhanced by dexamethasone. In contrast to the changes in serum TSH, pituitary TSH content was unaffected by dexamethasone. Furthermore dexamethasone had no significant effect on changes in pituitary cytoplasmic TSH beta- and alpha-subunit mRNA levels with thyroid status. These findings demonstrate that dexamethasone exerts differential effects on serum TSH levels and TSH biosynthesis which contrast with those of thyroid hormones.


Paroxysmal Nocturnal Haemoglobinuria in the Differential Diagnosis of Unresponsive Iron Deficiency Anemia: A Case Report.
A 16-year-old male patient who was on oral iron treatment for iron deficiency anemia for the last one year was seen at the Haematology clinic with complaints of weakness, pallor, and jaundice. A complete blood count revealed Hb of 4.2 mmol/L, Hct of 0.14, and MCV of 76 fl. A blood smear showed 50% neutrophils, 40% lymphocytes, and 10% monocytes with anisocytosis, poikilocytosis, polichromasia in erythrocytes and normoblasts. Reticulocyte count was under 1%. There was a slight erythroid hyperplasia in the bone marrow aspiration. Biochemical examinations showed total bilirubin of 3.9 mg/dL, indirect bilirubin of 3.4 mg/dL, and lactate dehydrogenase (LDH) of 6085 U/L (220-450). In re-evaluating the history of the patient, he was seen to be complaining of dark discoloration of morning urine. Perl's reaction was found to be positive for hemosiderin in the urine sediment. Because Ham's test was positive, the levels of CD55, 58, and 59 proteins on erythrocyte membranes were found to be lower. The patient was started 32 mg of methylprednisolone and his anaemia was improved by the 14th day of treatment. When evaluating iron deficiency anemia resistant to iron supplementation, PNH should be kept in mind.


Pathological complete response to neoadjuvant chemoimmunotherapy correlates with peripheral blood immune cell subsets and metastatic status of mediastinal lymph nodes (N2 lymph nodes) in non-small cell lung cancer.
Neoadjuvant chemo-immunotherapy has got clinical benefits in parts of resectable non-small cell lung cancer (NSCLC) patients. The factors affecting the pathological response of NSCLC remain controversial. A retrospective study of 59 patients with resectable stage IIA-IIIB NSCLC who were treated with neoadjuvant chemo-immunotherapy was performed. The clinical characteristics were analyzed in the pathological complete response (pCR) group and the non-pCR group. The immune cell subsets in peripheral blood were detected by flow cytometry. By analyzing the correlation between pathological response and clinical characteristics, we found that patients with N2 metastases were less effective in neoadjuvant chemo-immunotherapy (P = 0.001). Programmed death-ligand 1 (PD-L1) expression and treatment cycle were not related to pathological response (P > 0.05). Lower levels of total T cells, Th cells, and higher levels of NK cells in baseline were associated with pCR (P < 0.05). And during neoadjuvant chemo-immunotherapy, total T cells and activated T cells were significantly increased in patients with pCR (P < 0.05). The peripheral blood immune cell subsets and lymph node status were closely related to pathological response in patients with neoadjuvant chemo-immunotherapy. No significant correlation was found between pathologic response and PD-L1 expression.


A case of aortic bicuspid valve with thrombus formation without severe stenosis and calcification.
We encountered a patient with a history of juvenile cerebral infarction with an unknown cause in whom a mass adhering to the aortic valve (AV) surface was observed on echocardiography performed upon the development of heart failure. Mild AV stenosis (AS) with moderate regurgitation was noted, and valve repair was applied. It was found during surgery that the AV was a bicuspid valve (BAV) without calcification, and the mass was an organized thrombus. Thrombus formation on the AV with severe AS in BAV has been reported, but the organic lesion in the AV was mild in this patient.


Frequency changes with time in vivo of radiation-induced chromosomal aberrations in skin fibroblasts.
5 Syrian hamster litter mates were each irradiated with X-rays on one flank to 300 rad. Skin biopsies were taken from both the irradiated and unirradiated (control) flanks of each animal at one day and at about 6 months after irradiation. The cells cultured from these biopsies were used to determine the frequencies of chromosomal aberrations. During the 6-month period there were significant reductions in the frequencies of both reciprocal translocations and terminal deletions. Translocations involving the short arm of the Y-chromosome, however, showed a significant increase during this period. It is possible that while the latter phenomenon was due to cell selection in vivo the general fall off in translocations and deletions was the result of a long term in vivo repair mechanism or perhaps the results of certain aberrations proving to be lethal with prolonged expression times.


Hb Jeddah [alpha68(E17)Asn-->His (alpha1)]: a newly recognized alpha chain variant, seen in combination with Hb S [beta6(A3)Glu-->Val], and found in three separate families of middle eastern origin.
We report a previously unrecognized alpha chain variant identified in three families from Saudi Arabia, Yemen and Abu Dhabi. The index patient presented for hemoglobinopathy screening and was identified to have both this novel alpha chain variant and Hb S [beta6(A3)Glu-->Val, GAG(-->)GTG]. Hb Jeddah results from a point mutation (AAC(-->)CAC) at codon 68 in exon 2 of the alpha1 gene. There were no apparent hematological abnormalities or clinical symptoms in the three individuals identified as heterozygotes for Hb Jeddah, as well as the index case with both Hb S and Hb Jeddah. As we have found this variant in three separate families, the incidence may be greater than currently recognized.


Full-scale computation for all the thermoelectric property parameters of half-Heusler compounds.
The thermoelectric performance of materials relies substantially on the band structures that determine the electronic and phononic transports, while the transport behaviors compete and counter-act for the power factor PF and figure-of-merit ZT. These issues make a full-scale computation of the whole set of thermoelectric parameters particularly attractive, while a calculation scheme of the electronic and phononic contributions to thermal conductivity remains yet challenging. In this work, we present a full-scale computation scheme based on the first-principles calculations by choosing a set of doped half-Heusler compounds as examples for illustration. The electronic structure is computed using the WIEN2k code and the carrier relaxation times for electrons and holes are calculated using the Bardeen and Shockley's deformation potential (DP) theory. The finite-temperature electronic transport is evaluated within the framework of Boltzmann transport theory. In sequence, the density functional perturbation combined with the quasi-harmonic approximation and the Klemens' equation is implemented for calculating the lattice thermal conductivity of carrier-doped thermoelectric materials such as Ti-doped NbFeSb compounds without losing a generality. The calculated results show good agreement with experimental data. The present methodology represents an effective and powerful approach to calculate the whole set of thermoelectric properties for thermoelectric materials.


Human health risks of Hg, As, Mn, and Cr through consumption of fish, Ticto barb (Puntius ticto) from a tropical river, Bangladesh.
Metals tend to accumulate in higher organisms, e.g., fish and human through biomagnification effects in food chain. So, their presence in any component of the environment has become a global ecosystem and health concern. Here, we measured four health concerned metals like As, Cr, Mn, and Hg via inductively coupled plasma-mass spectrometry (ICP-MS) and analyzed applying some chemometrics for the assessment of human health risk through consumption of Puntius ticto, a very commonly consumed small fish in Bangladesh. The average concentration (wet weight) of metals was in the following descending order: Hg (0.006 mg/kg) > Cr (0.004 mg/kg) > Mn (0.003 mg/kg) > As (0.002 mg/kg). Hg level exceeded the provisional tolerable weekly intake (PTWI), and all other metals were within the permissible limit. The estimated daily intake (EDI) index of heavy metals showed that all the concentration levels were under the recommended daily intake (RDA) except Hg. Increased level of Hg is of particular concern to human health due to its biomagnification nature and can cause several neurological and physiological disorders including kidney failure. The total target hazard quotients (TTHQs) and carcinogenic risk (CR) matrices revealed that the intakes of Hg and As through fish consumption were higher than the recommended values, indicating consumers' remain non-carcinogenic and carcinogenic (THQ > 1; CR > 10-5) health risks for lifetime consumption. Multivariate analyses (cluster and principal component) explained the sources of heavy metals in the study area originating from both anthropogenic and geological origin.


His bundle recordings in double tachycardias not due to digitalis intoxication.
Electrophysiological studies were performed in a patient with chronic chagasic cardiomyopathy, recurrent sustained ventricular tachycardia, and a history (without electrocardiographic documentation) of paroxysmal atrial flutter. Ventriculoauricular conduction occurred during short bursts of ventricular pacing. Moreover, the retrograde P of ectopic ventricular beats which appeared after pacing was stopped precipitated an atrial tachyarrhythmia with an irregular atrial rate. In addition, burst ventricular pacing, performed while this atrial tachyarrhythmia was present, initiated and subsequently terminated a ventricular tachycardia with similar characteristics to the one occurring spontaneously. The double (atrial and ventricular) tachycardias described in this communication were different from those previously reported in that the arrhythmias were not due to digitalis toxicity, but resulted from the modality of ventricular stimulation performed in a patient who had the specific type of cardiomyopathy seen in the chronic stage of Chagas' disease.


Association between the T6459C point mutation of the mitochondrial MT-CO1 gene and susceptibility to sepsis among Chinese Han people.
To search for an association between sepsis and mitochondrial genetic basis, we began our study. In this study, a proband harbouring mitochondrial T6459C mutation with sepsis and his Chinese Han pedigree including 7 members of 3 generations were enrolled. General information, blood parameters and mitochondrial full sequence scanning of all members were performed, and cellular functions, including cellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), degrees of cell apoptosis and adenosine triphosphate (ATP) concentrations, were measured in members with and without the T6459C mutation. Through mitochondrial full sequence scanning and analysis of all members we found, the maternal members (I-1, II-1, II-2 and II-4) in this Chinese Han pedigree all had the mitochondrial T6459C mutation and were used as the mutation group. The non-maternal members (II-3, III-1 and III-2) did not have this mutation and were used as the non-mutation group. The differences in all indicators, including the blood routine, blood biochemistry and coagulation function tests, between members in these two groups were not significant. Under the non-stimulation condition, the mutation group had higher ROS levels (4210.42 ± 1043.35 vs 3387.78 ± 489.66, P = .028) and apoptosis ratios (P = .004) and lower ATP concentrations (P = .049) and MMP levels (P = .047) than the non-mutation group. After 6 hours of simulated LPS stimulation, the mutation group had significantly increased ROS levels (5759.25 ± 2297.90 vs 3862.00 ± 1519.77, P = .045) compared with the non-mutation group, whereas the mutation group continued to demonstrate higher ROS levels (P = .045) and apoptosis ratios (P = .003) and lower MMP levels (P = .005) and ATP concentrations (P = .010). We speculated that the mtDNA T6459C mutation might be the basis for the genetic susceptibility to sepsis.


Spiral microchannel with rectangular and trapezoidal cross-sections for size based particle separation.
The paper reports a new method for three-dimensional observation of the location of focused particle streams along both the depth and width of the channel cross-section in spiral inertial microfluidic systems. The results confirm that particles are focused near the top and bottom walls of the microchannel cross-section, revealing clear insights on the focusing and separation mechanism. Based on this detailed understanding of the force balance, we introduce a novel spiral microchannel with a trapezoidal cross-section that generates stronger Dean vortices at the outer half of the channel. Experiments show that particles focusing in such device are sensitive to particle size and flow rate, and exhibits a sharp transition from the inner half to the outer half equilibrium positions at a size-dependent critical flow rate. As particle equilibration positions are well segregated based on different focusing mechanisms, a higher separation resolution is achieved over conventional spiral microchannels with rectangular cross-section.


Parametric study of lotus-type pore shape in solid subject to Henry's laws at interfaces.
Mechanisms of the length and maximum radius of lotus-type or single pores in ice or nonmetals satisfied by Henry's law at gas-liquid interfaces dissolved by a gas during unidirectional solidification are rigorously investigated and supported by a Table from algebraic predictions involving different dimensionless working parameters. Lotus-type porous materials characterized by directional properties have been often used as functional materials in food, biomedical, and micro- and nano-technologies. Following previous work taking into account solute amount and transport within the pore, and concentration boundary layers on the advancing solid-liquid interface and bubble cap, and the Young-Laplace equation and Henry's law at liquid-gas interfaces, the algebraic study further provides a Table for a quantitative and extensive understanding of different mechanisms of length and maximum radius. Dimensionless parameters include solute transport parameters of Henry's law constant, mass transfer coefficient, partition coefficient, solute gas amount in imposed ambient, and solute transport parameter, and fluid and thermal parameters of solidification rate, imposed gas pressure, hydrostatic pressure, and geometrical parameter of inter-pore spacing. The controlling of the shapes of lotus-type pores is achieved by a good comparison between predicted maximum diameter and inter-pore spacing during freezing of water dissolved by oxygen gas.


[Multifocal cancer of the breast. Considerations on the mammographic diagnosis].
A review is carried out of a series of mammographic investigations in 687 tumours observed at the Pascale Institute, Naples, between 1972 and 1977. Mammography shows in a high percentage of cases a multifocality of the disease which was unsuspected. This allows a better evaluation of the stage of the tumour and a correct therapeutic programme.


Step-by-step decision-making process in third party assisted reproduction: a qualitative study.
This study explores the experience of decision-making about the third party assisted reproduction in Iranian infertile patients using a qualitative approach. Data were collected in 2017-2019 through in-depth interviews of 20 infertile participants (3 couples and 14 individuals) who became pregnant or had children through third-party reproduction and 12 specialists. The interviews were transcribed verbatim, the data were managed using the MAXQDA 10 and analysed using a conventional content analysis approach. The main category that emerged was 'step-by-step process of adjustment to third party assisted reproduction'. From this, five sub-categories were extracted: (i) 'parental preference for biological children over non-biological children'; (ii) 'parental preference for non-biological children over childlessness threats'; (iii) 'strong preference for having partial genetic link with children'; (iv) 'flexibility in removing or overcoming barriers to third party reproduction'; and (v) 'parental preference for adopted children over childlessness'. The findings in the present study suggest the importance of lineage and biological relatedness in Iranian culture. Patients adjusted to non-biological parenting as a treatment option only if they have to. Using a step-by-step decision-making process helped participants make more thoughtful decisions by organising relevant information and defining alternatives. The results of the present study can help healthcare providers with counselling regarding parenting with or without genetic ties.


An outbreak of subacute fasciolosis in Soay sheep: ultrasonographic biochemical and histological studies.
A naturally occurring outbreak of subacute fasciolosis in a group of 17 seven-month-old Soay ram lambs was studied following the sudden death of two sheep. In addition to standard biochemical investigations, ultrasound examination of the liver and cranial abdominal cavity was undertaken. There was a significant positive linear correlation between liver weight and ultrasonographic determination of liver size (R=0.72, P<0.05). Ultrasonographic examination of the liver revealed multiple hyperechoic dots in the parenchyma giving a granular appearance to the hepatic texture in three sheep corresponding to the most advanced histopathological changes as determined by the size of the abscesses and their relatively mature fibrous capsules, and areas of hepatic necrosis. No distension of the bile duct system was noted nor was the gall bladder imaged. While serum concentrations of albumin, globulin and certain liver enzymes assisted in the diagnosis of subacute fasciolosis in sheep, only glutamate dehydrogenase, and gammaglutamyl transferase remained elevated four weeks after triclabendazole treatment.


Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer.
Although the conservation management of breast cancer has become a routine method of treatment in most centers, there is still considerable controversy surrounding the ultimate minimum treatment required for node-negative breast cancer to achieve adequate local control. Our purpose was to assess the value of breast irradiation in reducing breast relapse following conservation surgery for node-negative breast cancer. We attempted to define low-risk groups of women for breast and distant site relapse (i.e., recurrence outside the breast) who might be spared breast irradiation or adjuvant systemic therapy. Eight hundred thirty-seven patients were randomly assigned to receive radiation therapy or no radiation therapy following lumpectomy and axillary dissection for node-negative breast cancer. Breast irradiation reduced relapse in the breast from 25.7% in the controls to 5.5% in the irradiated patients. There was no difference in survival between the two groups (median follow-up, 43 months). A low-risk group (less than 5% chance of relapse in the breast without irradiation) could not be defined. Tumor size (greater than 2 cm), age (less than 40 years), and poor nuclear grade were important predictors for breast relapse. Age (less than 50 years) and poor nuclear grade were important predictors for mortality. The presence of ductal carcinoma in situ did not predict breast relapse. Breast irradiation significantly reduces breast relapse, but it does not influence survival. Important predictors of breast relapse are age, tumor size, and nuclear grade, but not the presence of ductal carcinoma in situ. Age and, in particular, nuclear grade predict survival. Further follow-up may define an acceptable low-risk group for breast relapse. Until then, we recommend that all patients receive breast irradiation. Systemic adjuvant therapy should be considered for patients with poor nuclear grade tumors.


ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics.
Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60kD to 80kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics.


Dysregulated cytokine profile associated with biochemical premature ovarian insufficiency.
Premature ovarian insufficiency (POI) imposes great challenge on female reproduction. Whether immune disturbance in ovarian environment was implicated in POI remains unclear. We aimed to characterize the cytokine profile in follicular fluid (FF) and paired serum in patients with biochemical POI (bPOI). Multiplex immunoassay containing 45 cytokines was performed for individual FF and paired serum samples from 35 bPOI patients and 37 matched controls. Cytokine profiles were compared between the two groups and cytokines correlated to ovarian reserve, and the rates of day-3 good-quality embryos were further analyzed. In FF, significantly elevated level of chemokines MIP-1α (P = .043), CXCL8 (P = .024), IP-10 (P = .041), and eotaxin-1 (P = .015) as well as growth factors VEGF-D (P = .047), BDNF (P = .043), LIF (P = .002), and bFGF (P = .046) was found in bPOI patients compared to controls. Yet RANTES manifested an opposite trend with reduced levels among bPOI patients (P = .006). All these chemokines and growth factors in FF were significantly correlated with ovarian reserve (P < .05). In paired serum, cytokine signature was not likely accordant with that in FF between two groups, except for increased IP-10 (P = .032) in bPOI patients and its significant correlation to FSH and AFC (P < .05). Among all differentially expressed cytokines, RANTES in FF was correlated with the rate of day-3 good-quality embryos (P = .035). Altered cytokine profile characterized by increased chemokines and growth factors was associated with early stage of POI, which may fuel the progression of the disease or even play a crucial role in the development of ovarian insufficiency.


Metformin protects human lens epithelial cells from high glucose-induced senescence and autophagy inhibition by upregulating SIRT1.
The aim of this study is to explore whether metformin (MET) protects the human lens epithelial cells (HLECs) from high glucose-induced senescence and to identify the underlying mechanisms. A cellular senescence model was established by treating HLE-B3 cells with D-glucose and then intervened with MET. Concentrations of high glucose (HG) and MET were detected using CCK-8 and western blot. qRT-PCR, western blot, and senescence-associated β-galactosidase (SA-β-gal) were performed to verify the protective effect of MET on senescent HLE-B3 cells. Additionally, western blot and qRT-PCR were conducted to detect the effects of MET on autophagy-related markers p62 and LC3, as well as SIRT1. In vitro, we observed apparent senescence in human lens epithelial cells (HLECs) under high glucose conditions. This was characterized by increased senescence-associated genes p21 and p53. However, the addition of MET significantly reduced the occurrence of HLECs senescence. We also observed that high glucose inhibited both autophagy and SIRT1, which could be restored by MET. Moreover, we verified that the anti-senescence effect of MET was mediated by SIRT1 using SIRT1 activators and inhibitors. We have demonstrated that autophagy and SIRT1 activity are inhibited in HLE-B3 cells using the HG induced senescence model. Furthermore, our results showed that MET can delay senescence by activating SIRT1 and autophagy. These findings suggest that MET may be a promising candidate for alleviating cataract development and provide a direction for further investigation into the underlying molecular mechanisms.


Animal navigation: the longitude problem.
Determining longitude is incredibly difficult--for humans. Are animals fooling us into thinking that they have bicoordinate maps? New experiments show that at least some creatures effortlessly solve the seemingly insoluble problem of longitude.